Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)

Abstract

Background

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it difficult to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015.

Objectives

To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD.

Search methods

We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate.

Selection criteria

We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non‐serious, general behaviour, and quality of life.

Data collection and analysis

Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel‐group trials and first‐period data from cross‐over trials formed the basis of our primary analyses. We undertook separate analyses using end‐of‐last period data from cross‐over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach.

Main results

We included 212 trials (16,302 participants randomised); 55 parallel‐group trials (8104 participants randomised), and 156 cross‐over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross‐over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male‐female ratio was 3:1. Most trials were carried out in high‐income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants.

Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias.

Primary outcomes: methylphenidate versus placebo or no intervention may improve teacher‐rated ADHD symptoms (standardised mean difference (SMD) −0.74, 95% confidence interval (CI) −0.88 to −0.61; I² = 38%; 21 trials; 1728 participants; very low‐certainty evidence). This corresponds to a mean difference (MD) of −10.58 (95% CI −12.58 to −8.72) on the ADHD Rating Scale (ADHD‐RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD‐RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low‐certainty evidence). The TSA‐adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68).

Secondary outcomes: methylphenidate may cause more adverse events considered non‐serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low‐certainty evidence). The TSA‐adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher‐rated general behaviour versus placebo (SMD −0.62, 95% CI −0.91 to −0.33; I² = 68%; 7 trials 792 participants; very low‐certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI −0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low‐certainty evidence).

Authors' conclusions

The majority of our conclusions from the 2015 version of this review still apply. Our updated meta‐analyses suggest that methylphenidate versus placebo or no‐intervention may improve teacher‐rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non‐serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear.

Due to the frequency of non‐serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials.

Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.

Plain language summary

Is methylphenidate an effective treatment for children and adolescents with attention deficit hyperactivity disorder (ADHD) and does it cause unwanted effects?

Key messages

‐ Methylphenidate might reduce hyperactivity and impulsivity and might help children to concentrate. Methylphenidate might also help to improve general behaviour, but does not seem to affect quality of life.

‐ Methylphenidate does not seem to increase the risk of serious (life‐threatening) unwanted effects when used for periods of up to six months. However, it is associated with an increased risk of non‐serious unwanted effects like sleeping problems and decreased appetite.

‐ Future studies should focus more on reporting unwanted effects and should take place over longer periods of time.

What is attention deficit hyperactivity disorder (ADHD)?

ADHD is one of the most commonly diagnosed and treated childhood psychiatric disorders. Children with ADHD find it hard to concentrate. They are often hyperactive (fidgety, unable to sit still for long periods) and impulsive (doing things without stopping to think). ADHD can make it difficult for children to do well at school, because they find it hard to follow instructions and to concentrate. Their behavioural problems can interfere with their ability to get on well with family and friends, and they often get into more trouble than other children.

How is ADHD treated?

Methylphenidate (for example, Ritalin) is the medication most often prescribed to children and adolescents with ADHD. Methylphenidate is a stimulant that helps to increase activity in parts of the brain, such as those involved with concentration. Methylphenidate can be taken as a tablet or given as a skin patch. It can be formulated to have an immediate effect, or be delivered slowly, over a period of hours. Methylphenidate may cause unwanted effects, such as headaches, stomachaches and problems sleeping. It sometimes causes serious unwanted effects like heart problems, hallucinations, or facial 'tics' (twitches).

What did we want to find out?

We wanted to find out if methylphenidate improves children's ADHD symptoms (attention, hyperactivity) based mainly on teachers' ratings using various scales, and whether it causes serious unwanted effects, like death, hospitalisation, or disability. We were also interested in less serious unwanted effects like sleep problems and loss of appetite, and its effects on children's general behaviour and quality of life.

What did we do?

We searched for studies that investigated the use of methylphenidate in children and adolescents with ADHD. Participants in the studies had to be aged 18 years or younger and have a diagnosis of ADHD. They could have other disorders or illnesses and be taking other medication or undergoing behavioural treatments. They had to have a normal IQ (intelligence quotient). Studies could compare methylphenidate with placebo (something designed to look and taste the same as methylphenidate but with no active ingredient) or no treatment. Participants had to be randomly chosen to receive methylphenidate or not. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 212 studies with 16,302 children or adolescents with ADHD. Most of the trials compared methylphenidate with placebo. Most studies were small with around 70 children, with an average age of 10 years (ages ranged from 3 to 18 years). Most studies were short, lasting an average of around a month; the shortest study lasted just one day and the longest 425 days. Most studies were in the USA.

Based on teachers' ratings, compared with placebo or no treatment, methylphenidate:

‐ may improve ADHD symptoms (21 studies, 1728 children)

‐ may make no difference to serious unwanted effects (26 studies, 3673 participants)

‐ may cause more non‐serious unwanted effects (35 studies, 5342 participants)

‐ may improve general behaviour (7 trials 792 participants)

‐ may not affect quality of life (4 trials, 608 participants)

Limitations of the evidence

Our confidence in the results of the review is limited for several reasons. It was often possible for people in the studies to know which treatment the children were taking, which could influence the results. The reporting of the results was not complete in many studies and for some outcomes the results varied across studies. Studies were small and they used different scales for measuring symptoms. And most of the studies only lasted for a short period of time, making it impossible to assess the long‐term effects of methylphenidate. Around 41% of studies were funded or partly funded by the pharmaceutical industry.

How up to date is this evidence?

This is an update of a review conducted in 2015. The evidence is current to March 2022.

Summary of findings

Summary of findings 1. Methylphenidate compared with placebo or no intervention for children and adolescents with ADHD.

Methylphenidate compared with placebo or no intervention for ADHD
Patient or population: children and adolescents (up to and including 18 years of age) with ADHD Settings: outpatient clinic, inpatient hospital ward and summer school Intervention: methylphenidate Comparison: placebo or no intervention
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo or no intervention	Methylphenidate
ADHD symptoms: all parallel‐group trials and first‐period cross‐over trials ADHD Rating Scale (teacher‐rated) Average trial duration: 68.7 days		Mean ADHD symptom score in the intervention groups corresponds to a mean difference of −10.58 (95% CI −12.58 to −8.72) on ADHD Rating Scale	SMD −0.74 (−0.88 to −0.61)	1728 (21 trials)	⊕⊝⊝⊝ Very lowa,b	The analysis was conducted on a standardised scale with data from studies that used different teacher‐rated scales of symptoms (Conners' Teacher Rating Scale (CTRS), Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) Scale, The Swanson, Nolan and Pelham (SNAP) Scale ‐ Teacher, Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB‐HKS)). We translated the effect size on to the ADHD Rating Scale from the SMD.
Proportion of participants with one or more serious adverse events	Trial population		RR 0.80 (0.39 to 1.67)	3673 (26 trials)	⊕⊝⊝⊝ Verylowa,c	TSA RIS = 9349 TSA showed a RR of 0.91 (TSA‐adjusted Cl 0.31 to 2.68)
	8 per 1000	6 per 1000 (5 less to 5 more)
Proportion of participants with one or more adverse events considered non‐serious	Trial population		RR 1.23 (1.11 to 1.37)	5342 (35 trials)	⊕⊝⊝⊝ Verylowa,b	TSA RIS = 9139 TSA showed a RR of 1.22 (TSA‐adjusted Cl 1.08 to 1.43)
	437 per 1000	538 per 1000 (348 less to 162 more)
General behaviour: all parallel‐group trials and first‐period cross‐over trials General behaviour rating scales (teacher‐rated)		Mean general behaviour score in the intervention groups was 0.62 standard mean deviations lower (95% CI 0.91 lower to 0.33 lower)	SMD −0.62 (−0.91 to −0.33)	792 (7 trials)	⊕⊝⊝⊝ Very lowa,b,d
Quality of life (parent‐rated)		Mean quality‐of‐life score in the intervention groups corresponds to a mean difference of 4.94 (95% CI −0.37 to 10.25) on the Child Health Questionnaire	SMD 0.40 (−0.03 to 0.83)	608 (4 trials)	⊕⊝⊝⊝ Verylowa,b,c,e
*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ADHD: attention deficit hyperactivity disorder; CI: confidence interval; RIS: required information size; RR: risk ratio; SMD: standardised mean difference; TSA: Trial Sequential Analysis
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^aDowngraded two levels due to high risk of bias (systematic errors causing overestimation of benefits and underestimation of harms) in several risk of bias domains, including lack of sufficient blinding and selective outcome reporting (many of the included trials did not report on this outcome).
^bDowngraded one level due to inconsistency: moderate statistical heterogeneity.
^cDowngraded two levels due to imprecision: wide confidence intervals and/or the accrued number of participants was below 50% of the diversity‐adjusted required information size (DARIS) in Trial Sequential Analysis.
^dDowngraded one level due to indirectness: children's general behaviour was assessed by different types of rating scales with different focus on behaviour.
^e Downgraded one level due to indirectness: children's quality of life was assessed by their parents.

Background

Description of the condition

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated developmental psychiatric disorders (Scahill 2000). It is acknowledged to be a complex heterogenous neurodevelopmental condition with no known cure (Buitelaar 2022). Many clinicians and academics see pharmacological treatments as being effective and safe but there is “considerable individual variability” of treatment response, dose needed, and tolerability (Buitelaar 2022).

The prevalence of ADHD in children and adolescents is estimated to be 3% to 5% (Polanczyk 2007), depending on the classification system used, with boys two to four times more likely to be diagnosed than girls (Schmidt 2009). Individuals with ADHD exhibit difficulties with attentional and cognitive functions including problem‐solving, planning, maintaining flexibility and orientation, sustaining attention, inhibiting responses, and sustaining working memory (Pasini 2007; Sergeant 2003). They also experience difficulties in managing affects, for example, motivational delay and mood dysregulation (Castellanos 2006; Nigg 2005; Schmidt 2009). The diagnosis of ADHD has become more aligned between the American Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5; APA 2013), and the World Health Organization’s (WHO) International Classification of Diseases (ICD), 11th Edition (ICD‐11; WHO 2019). The ICD‐11 was adopted in 2019, and came into effect in January 2022.

Both the DSM‐5 and the ICD‐11 base diagnoses on several inattentive and hyperactive‐impulsive symptoms being present before the age of 12 years, and causing impairment of functioning in several settings. There are also 'predominantly inattentive', 'predominantly hyperactive/impulsive' and 'combined' presentations in both systems (APA 2013; WHO 2019).

ADHD is increasingly recognised as a psychiatric disorder that extends into adulthood and occurs with high heterogeneity and comorbidity with other psychiatric disorders (Schmidt 2009). The Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) trial identified one or more co‐occurring conditions in almost 40% of participants (MTA 1999a). These included oppositional defiant disorder, conduct disorder, depression, anxiety, tics, learning difficulties and cognitive deficits (Jensen 2001; Kadesjö 2001). Some argue that ADHD should be “considered not only a neurodevelopmental disorder, but also a persistent and complex condition, with detrimental consequences for quality of life in adulthood” (Di Lorenzo 2021, p. 283).

Rising rates of ADHD diagnoses, possible harm to children resulting from drug treatment (Zito 2000), and variation in prevalence estimates are matters of increasing concern (Moffit 2007; Polanczyk 2014). The need for a validated diagnostic test to confirm the clinical diagnosis of ADHD has given rise to a debate about its validity as a diagnosis (Timimi 2004). Professional and national bodies have developed guidelines on assessment, diagnosis and treatment of ADHD in an attempt to ensure that high standards are maintained in diagnostic and therapeutic practice (American Academy of Pediatrics 2011; CADDRA 2011; NICE 2018; Pliszka 2007a; SIGN 2009). Psychosocial interventions, such as parent management training, are recommended in the first instance for younger children and for those with mild to moderate symptoms (American Academy of Pediatrics 2011; NICE 2018; Pliszka 2007a), whereas stimulants (given alone or in combination with psychosocial interventions) are recommended for children with more severe ADHD (American Academy of Pediatrics 2011; CADDRA 2011; NICE 2018).

Description of the intervention

Methylphenidate, lisdexamphetamine/dexamphetamine, atomoxetine (a non‐stimulant selective noradrenaline reuptake inhibitor) and guanfacine (an alpha‐2 agonist) are recommended medical treatments for children, aged five years and above, and adolescents with ADHD, when psychoeducation and environmental modification have been implemented and reviewed, according to the NICE guidelines 2018 (NICE 2018). Furthermore, research suggests that the combination of behaviour therapy (e.g. behavioural parent training, school consultation, direct contingency management) and pharmacotherapy might benefit children with ADHD (Gilmore 2001; MTA 1999a).

Globally, methylphenidate has been used for longer than 50 years for the treatment of children with ADHD (Kadesjö 2002; NICE 2018). It has been part of driving innovation in controlled‐release technologies and new formulations. However, it has also contributed to concerns of pharmaceutical cognitive enhancement as well as created debate on pharmaceutical sales techniques in medicine, driven by high and possibly still increasing prescription rates (Wenthur 2016). In Europe, around 3% to 5% of children and adolescents have a prescription for methylphenidate (Bachmann 2017; Hodgkins 2013; Schubert 2010; Trecenõ 2012; Zoëga 2011) and in the USA approximately 8% of children and adolescents under 15 years of age have a prescription of methylphenidate (Akinbami 2011). However, USA statistics reported a trend of reduction in 2019 (Drug Usage Statistics 2013‐2019).

Pharmacological treatment with methylphenidate of children and adolescents with ADHD is reported to have a beneficial effect of reducing the major symptoms of hyperactivity, impulsivity, and inattention. It is licensed for the treatment of children aged six years and older with ADHD (Kanjwal 2012), but is recommended by the NICE guideline as off‐label use from the age of five years (NICE 2018). Before starting medication for ADHD, a baseline assessment is necessary; the ADHD criteria must be reviewed, mental health and social circumstances considered and a review of physical health including a cardiovascular assessment with cardiological history, heart rate, and blood pressure should be conducted. If positive cardiovascular history or a co‐existing condition is being treated with a medicine that may pose an increased cardiac risk, electrocardiogram (ECG) is recommended (NICE 2018). Individual parent‐training programmes for parents and carers of children and young people with ADHD and symptoms of oppositional defiant disorder or conduct disorder must likewise be considered (NICE 2018).

Different releases (immediate, sustained, or extended‐release) and formulations (oral or transdermal) of methylphenidate are available and it is important to individualise the treatment to optimise effect and minimise adverse events (Childress 2019). Response of treatment is individual and intervention dose can vary significantly between children with some responding to relatively low dosages while others require larger doses to achieve the same effect (Stevenson 1989). Therefore, it is important that the dose of methylphenidate is titrated to an optimal level that maximises therapeutic benefits while producing minimal adverse events. Immediate‐release formulations of methylphenidate are usually initiated at 5 mg once or twice daily then titrated weekly by 5 mg to 10 mg daily, divided into two or three doses until effects are noted and adverse effects are tolerable. The dose can range from 5 mg to 60 mg methylphenidate, 1.4 mg/kg daily administered in two to three doses (BNF 2020; Pliszka 2007a). Under specialist supervision, the dose may be increased to 2.1 mg/kg daily in two to three doses (maximum 90 mg daily). Modified‐release formulations are initiated with 18 mg once daily and increased up to a maximum of 54 mg.

Immediate‐release methylphenidate has a bioavailability of 11% to 53% and an approximate duration of two to four hours with a peak blood concentration after two hours and a half‐life of two hours. Sustained‐release and extended‐release formulations of methylphenidate have a duration of action of three to eight hours and eight to 12 hours, respectively (Kimko 1999; NICE 2018).

Studies have indicated impairments in children's height and weight during treatment with methylphenidate (Schachar 1997a; Swanson 2004b; Swanson 2009). McCarthy and colleagues' study using the ‘German Health Interview and Examination Survey for Children and Adolescents’ (KiGGS) database found that methylphenidate use in boys with ADHD was associated with low body mass index (BMI) but were “unable to confirm that methylphenidate use is also associated with low height (≤3rd percentile) and changes in blood pressure” (McCarthy 2018).

Monitoring of height, weight, heart rate, blood pressure, and adverse events, as well as encouraging adherence for effective treatment, are suggested. Medication‐free periods are recommended to reassess the treatment efficacy on ADHD symptoms (Kidd 2000; NICE 2018). Adverse effects of methylphenidate are common and dose‐dependent (Rossi 2010; Storebø 2018b). In a large Cochrane Review of observational studies, more than half (51.3%) of participants being treated with methylphenidate experienced one or more adverse events considered non‐serious such as headache, sleep difficulties, abdominal pain, decreased appetite, anxiety, and sadness (Storebø 2018b). Furthermore, 16% discontinued methylphenidate due to ‘unknown’ reasons and another 6% due to adverse events considered non‐serious (Storebø 2018b).

Serious adverse events such as psychosis, mood disorders (Block 1998; Cherland 1999; MTA 1999a), serious cardiovascular events, and sudden unexplained death have also been reported (Cooper 2011; Habel 2011), but methylphenidate does not seem to increase serious adverse events in randomised clinical trials (Storebø 2015a). It must however be taken into consideration that this meta‐analysis was considerably underpowered and not able to draw firm conclusions (Storebø 2015a).

As a stimulant, methylphenidate carries the risk of addiction, and the nonmedical use has been reported to vary from 5% to 35% (Clemow 2014), with a peak risk at ages estimated to be between 16 and 19 years, and a new user rate of 0.7% to 0.8% per year (Austic 2015). Conversely, methylphenidate has been correlated with the reduction of harmful outcomes such as reducing emergency department visits (Dalsgaard 2015), reducing criminality (Lichtenstein 2012), reducing transport accidents (Chang 2017), and having a protective effect on abuse of other substances (Chang 2014).

How the intervention might work

The pharmacodynamics of methylphenidate have been extensively investigated in animal and human studies with brain imaging and chemistry studies, yet they remain uncertain. It is presumed that the effects of methylphenidate on ADHD symptoms are related to its effects on dopaminergic and noradrenergic neurotransmissions within the central nervous system (Engert 2008). Methylphenidate is assumed to act by inhibiting catecholamine reuptake, primarily as a dopamine‐norepinephrine re‐uptake inhibitor, modulating levels of dopamine and, to a lesser extent, levels of norepinephrine (Heal 2006; Iversen 2006).

Methylphenidate binds to and blocks dopamine and norepinephrine transporters (Heal 2006; Iversen 2006), and increased concentrations of dopamine and norepinephrine in the synaptic cleft lead to escalated neurotransmission. On average, methylphenidate elicits a 3 to 4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex (Hodgkins 2013), which is responsible for executive functions and produces effects such as increased alertness, reduced fatigue, and improved attention.

Methylphenidate is thought to activate self‐regulated control processes to ameliorate what are believed to be the core neurofunctional problems of ADHD (Barkley 1977a; Schulz 2012; Solanto 1998). Evidence suggests that symptom control is strongly related to functional improvement (Biederman 2003a; Cox 2004a; Swanson 2004a).

Studies indicate that methylphenidate is effective for treating both the core symptoms of ADHD (inattention, hyperactivity, and impulsivity) and aggression (Connor 2002), since children can manage their impulsivity better (Barkley 1981; Barkley 1989a; Shaw 2012). Barkley noted differences in response to methylphenidate between ADHD inattentive and combined subtypes: children with the inattentive subtype were judged to have a less favourable response to methylphenidate than those diagnosed with the combined presentation (Barkley 1991b). Some children and adolescents may become less responsive to methylphenidate treatment over time (Molina 2009). However, magnetic resonance imaging studies suggest that long‐term treatment with ADHD stimulants may decrease abnormalities in the brain structure and function found in patients with ADHD (Frodl 2012; Spencer 2013).

Why it is important to do this review

During the past 20 years, several systematic reviews and narrative reviews have investigated the efficacy of methylphenidate for ADHD (with or without meta‐analysis). Fifteen reviews have pooled results on methylphenidate treatment for children and adolescents with ADHD (Bloch 2009; Charach 2011; Charach 2013; Faraone 2002; Faraone 2006; Faraone 2009; Faraone 2010; Hanwella 2011; Kambeitz 2014; King 2006; Maia 2014; Punja 2013; Reichow 2013; Schachter 2001; Van der Oord 2008). However, none of these were conducted as Cochrane systematic reviews. Most of them did not adhere to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022a), nor the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) guidelines (Liberati 2009; Moher 2015). None of these reviews had a peer‐reviewed protocol published before the analyses were conducted. Thirteen did not undertake subgroup analyses examining the effects of comorbidity on treatment effects (Bloch 2009; Charach 2011; Charach 2013; Faraone 2002; Faraone 2006; Faraone 2009; Faraone 2010; Hanwella 2011; Kambeitz 2014; Maia 2014; Punja 2013; Schachter 2001; Van der Oord 2008). Some did not control for treatment effects by ADHD subtype (Bloch 2009; Charach 2013; Faraone 2002; Hanwella 2011; Kambeitz 2014; King 2006; Maia 2014; Punja 2013; Schachter 2001; Van der Oord 2008). Others did not consider effects according to the dose of methylphenidate (Charach 2011; Charach 2013; Faraone 2006; Faraone 2009; Hanwella 2011; Kambeitz 2014; Maia 2014; Punja 2013; Reichow 2013; Van der Oord 2008). As for the outcomes, most meta‐analyses pooled data from parents, teachers and independent assessors (Bloch 2009; Charach 2011; Charach 2013; Hanwella 2011; Kambeitz 2014; King 2006; Reichow 2013), and did not separate outcome measures for inattention and hyperactivity/impulsivity (Bloch 2009; Charach 2013; Faraone 2002; Faraone 2006; Faraone 2009; Hanwella 2011; Kambeitz 2014; Van der Oord 2008). Moreover, most previous reviews only investigated the effects of methylphenidate on symptoms of ADHD; review authors did not present data on spontaneous adverse events (Charach 2013; Faraone 2002; Faraone 2006; Faraone 2009; Faraone 2010; Hanwella 2011; Kambeitz 2014; Maia 2014; Van der Oord 2008), nor on adverse events, as measured by rating scales (Bloch 2009; Charach 2013; Faraone 2002; Faraone 2006; Faraone 2009; Faraone 2010; Hanwella 2011; Kambeitz 2014; King 2006; Maia 2014; Punja 2013; Reichow 2013; Schachter 2001; Van der Oord 2008), and they did not try to explain why such information was not provided. Finally, these reviews did not systematically assess the risk of random errors, risk of bias, or trial quality (Bloch 2009; Charach 2011; Charach 2013; Faraone 2002; Faraone 2006; Faraone 2009; Faraone 2010; Hanwella 2011; Kambeitz 2014; King 2006; Van der Oord 2008). These shortcomings plus other methodological limitations including potential bias in excluding non‐English language publications (Charach 2013; Faraone 2010; Punja 2013; Van der Oord 2008), and not searching the principal major international databases nor reporting search terms clearly (Bloch 2009; Faraone 2002; Kambeitz 2014; Reichow 2013), may have compromised data collection, consequently calling the results of these previous meta‐analyses into question.

The first version of this systematic review was published in 2015 (Storebø 2015a). In this version, we reported that methylphenidate may improve teacher‐reported ADHD symptoms, teacher‐reported general behaviour, and parent‐reported quality of life among children and adolescents diagnosed with ADHD. We also underlined that the low quality of the evidence meant that we could not be certain of the magnitude of the effects. There was evidence that methylphenidate is associated with an increased risk of adverse events considered non‐serious, such as sleep problems and decreased appetite. We did not have evidence that methylphenidate increased the risk of serious adverse events, but this was unclear due to underreporting of serious adverse events (Storebø 2015a). We received many critical responses which were published as articles and letters to editors as well as blog comments. Six comments were received on the BMJ version of this review (Storebø 2015b). An editorial by Mina Fazel commenting on the article in the BMJ was also published alongside the review article (Fazel 2015). Mina Fazel recognised that our review was a comprehensive and rigorous Cochrane systematic review and meta‐analysis of the use of methylphenidate in young people with ADHD. She underlined the need for more research as she concluded: "The slow progress of ADHD research and limited evidence base for treatments are in stark contrast with the hallmarks of the disorder itself, with its high prevalence and broad symptomology" (Fazel 2015). A short version of the review was also published in JAMA in 2016 (Storebø 2016b), followed by a commenting editorial by Philip Shaw who concluded: "Sometimes in medicine, the best available data are imperfect. Such imperfections do not render the data unusable; rather, the limitations can be weighed by physicians and other health care professionals, and by families as they decide how best to help a child struggling with ADHD. Psychostimulants improve ADHD symptoms and quality of life. This meta‐analysis highlights the complexities in quantifying this benefit." (Shaw 2016 p. 1954). Philip Shaw wrote that in a meta‐analysis of methylphenidate for adults with ADHD (Epstein 2014), the trial biases were similar to those in our review and that the bias assessment seemed to be very subjective (Shaw 2016). The review by Epstein and colleagues (Epstein 2016), was withdrawn from the Cochrane Library on 26 May 2016 due to several methodological problems including erroneous risk of bias assessment (Boesen 2017; Storebø 2015b [pers comm]).

Several critical comments on our 2015 review from different authors were published in blog posts, articles and letters to editors (Hollis 2016; Banaschewski 2016a; Banaschewski 2016b; Hoekstra 2016; Romanos 2016). All these comments and our responses are listed with references in the 2015 published version of this review (Storebø 2015a). The critical points raised focused on our certainty assessment, including our use of the vested interest risk of bias domain, concerns that blinding may be affected by easily recognisable adverse events, concerns that we erroneously included too many non‐eligible trials (such as cross‐over trials and trials with add‐on treatment to methylphenidate), and that we had errors in the data extracted. We showed in several response articles and letters to editors that our trial selection was not flawed and that our data collection and interpretation of data in most aspects was systematic and sound (Storebø 2016a; Storebø 2016c; Storebø 2016d; Storebø 2016e; Storebø 2016f; Storebø 2018a). We answered all criticism, but in one case our response to a critical editorial (Gerlach 2017), in the Journal ADHD Attention Deficit and Hyperactivity Disorders was declined by the editor. In addition, we have argued that our assessment of quality and our conclusion were not misleading (Storebø 2016c; Storebø 2016d; Storebø 2016e; Storebø 2016f; Storebø 2018a). We agreed that minor errors were present in the review, yet we were still able to show that the effects were negligible and that these minor errors did not affect our conclusions (Storebø 2016c; Storebø 2016d; Storebø 2016e; Storebø 2016f; Storebø 2018a). We stated that the evidence for the use of methylphenidate in children and adolescents with ADHD was flawed (Storebø 2016c; Storebø 2016d; Storebø 2016e; Storebø 2016f; Storebø 2018a).

In 2018 an application for including methylphenidate on the 21st update of the WHO's List of Essential Medicines was rejected due to concerns regarding the quality of the evidence for benefits and harms (Storebø 2021). An extended research team made a comparable application in 2020 for the 22nd update of the list. The decision of the committee was — for the second time — not to include methylphenidate on the WHO Model List of Essential Medicines due to low quality of evidence, lack of data after 12 weeks, and adverse effects of concern (Pereira Ribeiro 2022). The committee also stressed that "evidence of the effectiveness and safety of methylphenidate in the treatment of ADHD of at least 52 weeks duration, outcomes of the revision of the of the Mental Health Gap Action Programme (mhGAP) Guideline for Mental, Neurological and Substance use Disorders, and evaluation of health system capacity to provide appropriate diagnostic, non‐pharmacological and pharmacological treatment and monitoring in low‐resource settings would be informative for any future consideration for inclusion of methylphenidate on the Model Lists" (WHO 2021 p. 538).

We have published an overview article where we found 24 eligible systematic reviews and meta‐analyses published after the 2015 version of the current review (Ribeiro 2021). The results showed that the evidence was uncertain due to the low quality of evidence. There was also an underreporting of adverse events in randomised clinical trials. We concluded that there is uncertain evidence to support that methylphenidate is beneficial in treating children and adolescents with ADHD. (Ribeiro 2021).

In October 2021 the European ADHD Guidelines Group (EAGG) published an overview article summarising the current evidence and identified methodological issues and gaps in the current evidence (Coghill 2021). The authors of this article were mostly the same authors that had published the many critical comments to our 2015 version of this review. They wrote in this article: "We have summarized the current evidence and identified several methodological issues and gaps in the current evidence that we believe are important for clinicians to consider when evaluating the evidence and making treatment decisions. These include understanding potential impact of bias such as inadequate blinding and selection bias on study outcomes; the relative lack of high‐quality data comparing different treatments and assessing long‐term effectiveness, adverse effects and safety for both pharmacological and non‐pharmacological treatments; and the problems associated with observational studies, including those based on large national registries and comparing treatments with each other" (Coghill 2021).

Combined, this indicates a need to update this systematic review on the benefits and harms of methylphenidate for children and adolescents with ADHD and that this should continue to be done until more solid evidence for the recommendation about the use of methylphenidate for children and adolescents with ADHD can be established. Given the mounting concerns regarding the increasing use of methylphenidate in children younger than six years, it is vital that researchers explore the risks versus benefits of treatment in this younger population (US FDA 2011). Although stimulant medications may have a favourable risk‐benefit profile, they might carry potential risks of both serious and non‐serious adverse events.

To expand our understanding of adverse events, particularly where these are rare or take time to become apparent, we felt it necessary to bolster the limited data from randomised clinical trials (RCTs) by including data from non‐randomised studies (Storebø 2015a). Our Cochrane systematic review from 2018 focused on the harms of methylphenidate treatment in children and adolescents with ADHD (Storebø 2018b). This review included 260 non‐randomised studies: four patient‐controlled studies, seven comparative cohort studies, 177 cohort studies, two cross‐sectional studies, and 70 patient reports, including over 2.2 million participants. In contrast to our 2015 review based on RCTs (Storebø 2015a), methylphenidate compared to no intervention significantly increased the risk of serious adverse events in comparative studies (risk ratio (RR) 1.36, 95% confidence interval (CI), 1.17 to 1.58; 2 trials; 72,005 participants). Serious adverse events included psychotic disorders, arrhythmia, seizures, and hypertension. Approximately half (51.2%) of participants experienced one or more non‐serious adverse event (95% CI 41.2 to 61.1%; 49 trials; 13,978 participants). These were sleep difficulties (17.9%), decreased appetite (31.1%), and abdominal pain (10.7%). Furthermore, 16.2% (95% CI 13.0 to 19.9%; 57 trials, 8340 participants) discontinued methylphenidate because of 'unknown' reasons and 6.20% (95% CI 4.90 to 8.00%; 37 trials; 7142 participants) because of non‐serious adverse events. We assessed most included studies as having critical risk of bias. The GRADE quality rating of the certainty of evidence was very low. Some studies indicated that methylphenidate can decrease children's normal growth rate (Schachar 1997b; Swanson 2004a; Swanson 2009). Given the unclear evidence in this field and the need for better data, we, therefore, conducted the present update of this systematic review of the benefits and harms of methylphenidate for children and adolescents with ADHD in RCTs while adhering to the Cochrane guidance (Higgins 2022a), and to the PRISMA guidelines (Liberati 2009; Moher 2015).

Objectives

To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD.

Methods

Criteria for considering studies for this review

Types of studies

RCTs of methylphenidate for the treatment of children and adolescents with ADHD. We included trials irrespective of language, publication year, publication type or publication status.

Types of participants

Children and adolescents aged 18 years and younger with a diagnosis of ADHD, according to the DSM‐III (APA 1980), DSM‐III‐R (APA 1987), DSM‐IV (APA 1994), and DSM‐5 (APA 2013), or with a diagnosis of hyperkinetic disorders according to the ICD‐9, ICD‐10 (WHO 1992), and ICD‐11 (WHO 2019) . We included participants with ADHD with or without comorbid conditions such as conduct or oppositional disorders, tics, depression, attachment disorders or anxiety disorders. Trials eligible for inclusion were those in which at least 75% of participants were aged 18 years or younger, and the mean age of the trial population was 18 years or younger. We also required that at least 75% of participants had a normal intellectual quotient (IQ > 70).

Types of interventions

Methylphenidate, administered at any dosage or in any formulation, versus placebo or no intervention.

We permitted co‐interventions if the experimental and control intervention groups received the co‐interventions similarly. In some trials that included co‐interventions in both groups, such as a behavioral intervention combined with methylphenidate versus a behavioral intervention, we considered these as methylphenidate versus no intervention. We did not permit polypharmacy as a co‐intervention in only one of the intervention groups.

Types of outcome measures

Primary outcomes

• ADHD symptoms (attention, hyperactivity and impulsivity), measured over the short term (within six months) and over the long term (longer than six months) by psychometric instruments or by observations of behaviour, using, for example, Conners' Teacher Rating Scales (Conners 1998a; Conners 2008). Raters could be teachers, independent assessors, or parents. We chose to report the results of teacher‐rated outcomes as the primary outcome (see Results).

• Number of serious adverse events. We defined a serious adverse event as any event that led to death, was life‐threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability, or as any important medical event that may have jeopardised the patient's life or that required intervention for prevention. We considered all other adverse events to be considered non‐serious (ICH 1996).

Secondary outcomes

• Non‐serious adverse events. We assessed all adverse events, including, for example, growth retardation and cardiological, neurological and gastrointestinal events, as described in ICH (International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use) Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R1) (ICH 1996).

• General behaviour in school and at home, as rated by psychometric instruments such as the Child Behaviour Checklist (CBCL; Achenbach 1991), measured over the short term (within six months) and over the long term (longer than six months). Raters could be teachers, independent assessors, or parents. We chose to report the results of teacher‐rated outcomes as primary outcomes (see Results).

• Quality of life, as measured by psychometric instruments such as the Child Health Questionnaire (CHQ; Landgraf 1998). Raters could be teachers, the children, independent assessors, or parents.

Search methods for identification of studies

Electronic searches

We ran the first literature searches in October 2011 and updated them in November 2012, March 2014, between 26 February and 10 March 2015 and most recently 11 January 2021 and 25 March 2022. We searched the following sources.

• Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 1; part of the Cochrane Library, which includes the Specialised Register of the Cochrane Developmental, Psychosocial and Learning Problems Group), searched 25 March 2022

• MEDLINE Ovid (1946 to current), searched 25 March 2022

• Embase Ovid (1980 to current), searched 25 March 2022

• CINAHL EBSCOhost (Cumulative Index to Nursing and Allied Health Literature; 1980 to current), searched 25 March 2022

• PsycINFO Ovid (1806 to current), searched 25 March 2022

• Epistemonikos (www.epistemonikos.org/) searched 25 March 2022

• Conference Proceedings Citation Index ‐ Science (CPCI‐S) and Conference Proceedings Citation Index ‐ Social Science & Humanities (CPCI‐SS&H) (Web of Science; 1990 to 25 March 2022)

• ClinicalTrials.gov (ClinicalTrials.gov ), searched 25 March 2022

• World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; who.int/ictrp/en), searched 25 March 2022

• Networked Digital Library of Theses and Dissertations (NDLTD; ndltd.org), searched 29 November 2022)

• DART Europe E‐Theses Portal (www.dart-europe.eu/basic-search.php), searched 28 November 2022)

• Theses Canada (library-archives.canada.ca/eng/services/services-libraries/theses/Pages/theses-canada.aspx), searched 29 November 2022

• Worldcat (worldcat.org), searched 28 November 2022

The search strategy for each database is shown in Appendix 1. We used a broad strategy to capture trials on efficacy and trials on adverse events. To overcome poor indexing and abstracting, we listed individual brand names within the search strategies. We did not limit searches by language, year of publication or type or status of the publication. We sought translation of relevant sections of non‐English language articles.

Searching other resources

To find additional relevant trials not identified by electronic searches, we checked the bibliographic references of identified review articles, meta‐analyses and a selection of included trials. Furthermore, we requested published and unpublished data from pharmaceutical companies manufacturing methylphenidate, including Takeda Pharmaceuticals, Medice (represented in Denmark by HB Pharma), Janssen‐Cilag, Novartis, Rhodes Pharmaceuticals, Ironshore Pharmaceuticals and Pfiizer (Appendix 2). We also requested data from unpublished trials from experts in the field.

Data collection and analysis

We conducted this review according to the recommendations provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022a), and performed analyses using Review Manager 5 (RevMan 5; Review Manager 2020).

Selection of studies

In this update of the Storebø 2015a review, seven review authors (OJS, HEC, JPS, JPR, MROS, PDR, CMLH) worked together in groups of two and independently screened titles and abstracts of all publications obtained from the literature searches. We obtained full‐text papers for any abstract/title that might match our inclusion criteria and assessed them against our listed inclusion criteria. We discussed disagreements, and if we were unable to reach agreement or consensus, we consulted a third review author (OJS).

Data extraction and management

In this update of the Storebø 2015a review, working together in groups of two, six review authors extracted data (MROS, CMLH, JPR, JPS, MS, OJS). We resolved disagreements by discussion and we used an arbiter if required. When data were incomplete, or when data provided in published trial reports were unclear, we contacted trial authors to ask for clarification of missing information. We contacted the authors of all cross‐over trials to obtain first‐period data on ADHD symptoms.

We developed data extraction forms a priori. After performing data extraction pilots, we updated these forms to accommodate the extraction of more detailed data and to facilitate standardised approaches to data extraction among review authors. All data extractors used these extraction forms (see Appendix 3; Appendix 4).

Six review authors (MS, HEC, JPR, JPS, MROS and OJS) entered data into RevMan 5 (Review Manager 2020).

Assessment of risk of bias in included studies

For each included trial, data extractors (MROS, CMLH, JPR, JPS, MS, OJS) independently evaluated risk of bias domains (listed below), resolving disagreements by discussion. For each domain, we assigned each trial to one of the following three categories: low risk of bias, unclear (uncertain) risk of bias or high risk of bias, according to guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Given the risk of overestimation of beneficial intervention effects and underestimation of harmful intervention effects in RCTs with unclear or inadequate methodological quality (Kjaergard 2001; Lundh 2012; Lundh 2018; Moher 1998; Savović 2012a; Savović 2012b; Savovic 2018; Schulz 1995; Wood 2008), we assessed the influence of risk of bias on our results (see Subgroup analysis and investigation of heterogeneity). Risk of bias components were as follows: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other potential sources of bias. We defined low risk of bias trials as trials that had low risk of bias in all domains. We considered trials with one or more unclear or high risk of bias domains as trials with high risk of bias.

Measures of treatment effect

We defined the treatment effect as an improvement in ADHD symptoms, general behaviour and quality of life.

Dichotomous data

We summarised dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs). We calculated the risk difference (RD).

Continuous data

If all trials used the same measure of a given continuous outcome in a meta‐analysis, we calculated mean differences (MDs) with 95% CIs. If trials used different measures, we calculated standardised mean differences (SMDs) with 95% CIs. If trials did not report means and standard deviations but did report other values (e.g. t‐tests, P values), we transformed these into standard deviations.

For primary analyses of teacher‐rated ADHD symptoms, teacher‐rated general behaviour and quality of life, we transformed SMDs into MDs on the following scales to assess whether results exceeded the minimal clinically relevant difference: ADHD Rating Scale (ADHD‐RS; DuPaul 1991a), Conners' Global Index (CGI; Conners 1998a), and Child Health Questionnaire (CHQ; Landgraf 1998). We transformed SMDs into MDs on the ADHD‐RS by using the SD 14.3 from Riggs 2011, on the CGI by using the SD 5.79 from Greenhill 2002, and on the CHQ by using the SD 12.35 from Newcorn 2008. We identified a minimal clinically relevant difference (MIREDIF) of 6.6 points on the ADHD‐RS, ranging from 0 to 72 points, based on a trial by Zhang 2005, and a MIREDIF of 7.0 points on the CHQ, ranging from 0 to 100 points, based on a trial by Rentz 2005. We could find no references describing a MIREDIF on the CGI (range 0 to 30 points).

Unit of analysis issues

Many ADHD trials use cross‐over methods. We aimed to obtain data from the first period of these trials and to pool these data with data from parallel‐group trials, as they are similar (Curtin 2002). We requested these data from trial authors if they were not available in the published report. When we were not able to obtain first‐period data from cross‐over trials, we established another group comprising only end‐of‐last‐period data. Our original intention was to adjust for the effect of the unit of analysis error in cross‐over trials by conducting a covariate analysis, but data were insufficient for this. As cross‐over trials are more prone to bias from carry‐over effects, period effects and unit of analysis errors (Curtin 2002), we conducted a subgroup analysis to compare these two groups. We tested for the possibility of a carry‐over effect and a period effect (Subgroup analysis and investigation of heterogeneity). We found similar treatment effects in the two groups and no significant subgroup differences. However, we noted considerable heterogeneity, and so we presented the results of the analyses separately (Effects of interventions). In a methods article, we investigated the risk of carry‐over effect and unit of analysis error due to period effects comparing parallel‐group trials, the first period of cross‐over trials and the end of the last period of cross‐over trials and found no signs of period effects or carry‐over effects in cross‐over trials assessing methylphenidate for children and adolescents with ADHD (Krogh 2019).

For dichotomous outcomes in cross‐over trials, we were unable to adjust the variance to account for the correlation coefficient as advised by Elbourne 2002 due to insufficient information or to estimate the RR using the marginal probabilities as recommended by Becker 1993. Consequently, we used end‐of‐last‐period data for estimating RRs. As these effect estimates are prone to potential bias, we performed a sensitivity analysis by removing these trials to assess the robustness of the pooled results.

We used endpoint data when these were reported or could be obtained from trial authors. However, when RCTs reported only 'change scores', we pooled these with scores from the end of intervention (da Costa 2013). We used only endpoint standard deviations in the trials with 'change scores'. We explored whether inclusion of change data affected the outcomes by performing a sensitivity analysis (see Sensitivity analysis).

Dealing with missing data

We obtained missing data by contacting trial authors. When we were not able to obtain missing data, we conducted analyses using available (incomplete) data. Although some trials reported that they used intention‐to‐treat (ITT) analyses, data were missing for many primary outcomes (Hollis 1999). We could not use 'best‐case scenario' and 'worst‐case scenario' analyses on our assessment of benefit as there were no dichotomous outcomes. Also, we decided not to use 'best‐case scenario' and 'worst‐case scenario' analyses in our assessment of adverse events because we evaluated these analyses to be imprecise due to the high number of trials not reporting adverse events, and due to the high number of dropouts in the trials reporting adverse events.

Assessment of heterogeneity

We identified three types of heterogeneity: clinical, methodological and statistical. Clinical heterogeneity reflects variability among participants, interventions and outcomes of trials; methodological heterogeneity reflects variability in the trial designs; and statistical heterogeneity reflects differences in effect estimates between trials. We assessed clinical heterogeneity by comparing differences in trial populations, interventions and outcomes, and we evaluated methodological heterogeneity by comparing the trial designs. We identified potential reasons for clinical and methodological heterogeneity by examining individual trial characteristics and subgroups. Furthermore, we observed statistical heterogeneity in trials both by visual inspection of a forest plot and by use of a standard Chi² test value with a significance level of α (alpha) = 0.1. We examined the I² statistic (Higgins 2003). We judged values between 0% and 40% to indicate little heterogeneity, between 30% and 60% to indicate moderate heterogeneity, between 50% and 90% to indicate substantial heterogeneity, and between 75% and 100% to indicate considerable heterogeneity (Deeks 2022).

Assessment of reporting biases

We followed the recommendations for reporting bias, including publication bias and outcome reporting bias, provided in the Cochrane Handbook for Systematic Reviews of Interventions (Page 2022). We drew funnel plots (estimated differences in treatment effects against their standard error) and performed Egger's statistical test for small‐study effects; asymmetry could be due to publication bias or could indicate genuine heterogeneity between small and large trials (Page 2022). We did not visually inspect the funnel plot if fewer than 10 trials were included in the meta‐analysis, in accordance with the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Page 2022). We compared results extracted from published journal reports to results obtained from other sources (including correspondence) as a direct test for publication bias.

Data synthesis

We performed statistical analyses as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2022). We synthesised data statistically when clinical heterogeneity was not excessive (e.g. variability in participant characteristics was minimal). Furthermore, we included and analysed trials undertaken in any configuration or setting (e.g. in groups, at home, or at a centre).

We used the inverse variance method, which gives greater weight to larger trials, to generate more precise estimates. For some adverse events we combined dichotomous and continuous data using the generic inverse variance method. We synthesised data using change‐from‐baseline scores or endpoint data. If data were available for several intervals, we used the longest period assessed. We used the fixed‐effect and random‐effects models in all meta‐analyses, however, we reported the results of the random‐effects model when we included more than one trial in the meta‐analysis. This approach gives greater weight to smaller trials. Statistical significance did not change when we applied a fixed‐effect model (Jakobsen 2014). We performed separate meta‐analyses for three types of raters (teachers, independent assessors, and parents) for data from parallel‐group trials combined with data from the first period of cross‐over trials and data from the end of the last period from cross‐over trials.

ADHD symptom scales describe the severity of inattention, hyperactivity and impulsivity at home and at school; high scores indicate severe ADHD. We judged that, in spite of the diversity of psychometric instruments, they could be used for our outcomes, and we integrated different types of scales into the analyses. We used MDs if all trials used the same measure and SMDs when different trials used different outcome measures for the same construct.

When separate measures of hyperactivity, impulsivity and inattention were available, we used combined scores. When symptoms were measured and reported at different time points during the day (after ingestion of medication or placebo), we used the time point closest to noon.

Three types of raters, teachers, independent assessors and parents measured two outcomes — ADHD symptoms and general behaviour. We considered these data as showing different outcomes. We presented the results of teacher‐rated measures as the primary outcome because symptoms of ADHD are more readily detectable in the school setting (Hartman 2007).

For children weighing 25 kg or less, the maximum recommended dose of methylphenidate is 30 mg/day compared to 60 mg/day for children weighing more than 25 kg. After careful consideration, we renamed the high‐dose group as 'moderate/high' dose because doses are not always 'high' in heavier children. When trials reported data for different doses, we used data for the dose that we defined as moderate/high (> 20 mg/day) in our primary analyses.

We summarised adverse event data as RRs with 95% CIs for dichotomous outcomes. For the purposes of this review, we used only dichotomous outcomes that reflected the number of participants affected by the event per the total number of participants.

Diversity‐adjusted required information size and Trial Sequential Analysis

Trial Sequential Analysis is a method that combines the required information size (RIS) for a meta‐analysis with the threshold for statistical significance to quantify the statistical reliability of data in a cumulative meta‐analysis, with P value thresholds controlled for sparse data and repetitive testing of accumulating data (Brok 2008; Brok 2009; Thorlund 2009; Wetterslev 2008; Wetterslev 2017).

Comparable to the a priori sample size estimation provided in a single RCT, a meta‐analysis should include a RIS at least as large as the sample size of an adequately powered single trial to reduce the risk of random error. A Trial Sequential Analysis calculates the RIS in a meta‐analysis and provides trial sequential monitoring boundaries with an adjusted P value.

When new trials emerge, multiple analyses of accumulating data lead to repeated significance testing and hence introduce multiplicity. Use of conventional P values exacerbates the risk of random error (Berkey 1996; Lau 1995; Wetterslev 2017). Meta‐analyses not reaching the RIS are analysed with trial sequential monitoring boundaries analogous to interim monitoring boundaries in a single trial (Wetterslev 2008; Wetterslev 2017).

If a Trial Sequential Analysis does not result in significant findings (no Z‐curve crossing the trial sequential monitoring boundaries) before the RIS has been reached, the conclusion should be that more trials are needed to reject or accept an intervention effect that was used to calculate the required sample size, or when the cumulated Z‐curve enters the futility area, the anticipated intervention effect should be rejected.

For calculations with the Trial Sequential Analysis programme, we included trials with zero events by substituting 0.25 for zero (CTU 2022; Thorlund 2011).

For the outcomes 'total serious adverse events' and 'total non‐serious adverse events', we calculated the a priori diversity‐adjusted required information size (DARIS; i.e. number of participants in the meta‐analysis required to detect or reject a specific intervention effect) and performed a Trial Sequential Analysis for these outcomes based on the following assumptions (Brok 2008; Brok 2009; Thorlund 2009; Wetterslev 2008; Wetterslev 2009).

• Proportion of participants in the control group with adverse events

• Relative risk reduction of 20% (25% on 'total serious adverse events')

• Type I error of 5%

• Type II error of 20%

• Observed diversity of the meta‐analysis

Subgroup analysis and investigation of heterogeneity

We performed the following subgroup analyses of teacher‐rated ADHD symptoms (primary outcome) to test the robustness of this estimate.

• Age of participants (trials with participants aged 2 to 6 years compared to trials with participants aged 7 to 11 years compared to trials with participants aged 12 to 18 years)

• Sex (boys compared to girls)

• Comorbidity (children with comorbid disorders compared to children without comorbid disorders)

• Type of ADHD (participants with predominantly inattentive subtype compared to participants with predominantly combined subtype)

After learning about other factors that may affect the effects of methylphenidate, we performed the following additional post hoc subgroup analyses on teacher‐rated ADHD symptoms to test the robustness of the estimate.

• Types of scales (e.g. Conners' Teacher Rating Scale (CTRS; Conners 1998a), compared to Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN) Scale (Swanson 2006)

• Dose of methylphenidate (low dose (≤ 20 mg/day or ≤ 0.6 mg/kg/day) compared to moderate or high dose (> 20 mg/day or > 0.6 mg/kg/day)).

• Duration of treatment (short‐term trials (≤ 6 months) compared to long‐term trials (> 6 months))

• Trial design (parallel‐group trials compared to cross‐over trials (first‐period data and end‐of‐last‐period data))

• Medication status before randomisation (medication naive (> 80% of included participants were medication naive) compared to not medication naive (< 20% of included participants were medication naive))

• Risk of bias (trials at low risk of bias compared to trials at high risk of bias)

• Enrichment trials. Enrichment trials (trials that excluded methylphenidate non‐responders, placebo responders, and/or participants who had adverse events due to the medication before randomisation) compared to trials without enrichment

• Vested interest ((conflict of interest regarding funding) trials at either high or unclear risk of vested interest compared to trials at low risk of vested interest). Our assessment of vested interest for the individual studies can be seen in Table 2.

• Type of control group (trials with placebo control group compared to trials with no‐intervention control group)

1. Vested interest of included studies.

Study	Vested interest	Support for judgement
Abikoff 2009	High	Funding: investigator‐initiated trial funded by a grant from Ortho‐McNeil Janssen Scientific Affairs to Dr Abikoffx Conflicts of interest: Drs Abikoff and Gallagher have a contract with Multi‐Health Systems to further develop the Children’s Organizational Skills Scale (COSS) used in this trial. Dr Abikoff has served on the ADHD Advisory Board of Shire Pharmaceuticals and of Novartis Pharmaceuticals. Dr Boorady has served on the ADHD Advisory Board and Speakers’ Bureau of Shire Pharmaceuticals. Other trial authors report no conflicts of interest
Ahmann 1993	Low	Funding: trial was funded by Marshfield Clinic grants Conflict of interest: not declared
Arnold 2004	High	Funding: trial was supported by the Celgene Corporation Conflicts of interest: Drs Arnold, Wigal and Bohan received research Funding from Celgene for the trial reported. Dr Wigal and Dr West are on the Advisory Panel and Speakers' Bureau for Novartis. Dr Arnold and Dr Bohan are on the Speakers' Bureau for Novartis. Dr Zeldis is Chief Medical Officer and Vice President of Medical Affairs at the Celgene Corporation.
Barkley 1989b	Low	Funding: trial was internally funded by the medical school Conflict of interest: not declared
Barkley 1991	Low	Funding: research was supported by the National Institute of Mental Health (NIMH) Conflicts of interest: not declared
Barkley 2000	Low	Funding: University of Massachusetts Medical School Conflict of interest: not declared
Barragán 2017	High	Funding: trial was funded by Vifor Pharma Conflict of interest: trial authors affiliated with the medical industry
Bedard 2008	Low	Funding: funding and operating grant from the Canadian Institute of Health Research and Funding from the Canada Research Chairs Programme Conflicts of interest: none
Bhat 2020	High	Funding: this work was supported in part by a grant from the Fond de Recherche du Québec and the Canadian Institutes of Health Research. Weam Fageera is a recipient of a PhD scholarship from the Ministry of Education of Saudi Arabia. Conflicts of interest: authors affiliated with medical industry
Biederman 2003b	High	Funding: received from Novartis Conflict of interest: not declared
Bliznakova 2007	Unclear	Funding: not declared Conflict of interest: not declared
Blum 2011	High	Funding: trial was supported by an investigator‐initiated grant from Ortho McNeil Janssen Scientific Affairs, the manufacturer of OROS methylphenidate (Concerta) Conflict of interest: not declared
Borcherding 1990	Unclear	Funding: not declared Conflicts of interest: not declared
Brams 2008	High	Funding: sponsored by Novartis Pharmaceuticals Corporation Conflicts of interest: first trial author has been a speaker, consultant and advisory board member for Novartis and Shire
Brams 2012	High	Funding: Novartis Pharmaceuticals Corporation, with the following involvement reported: design and conduct of the trial; collection, management, analysis and interpretation of data; and preparation, review and approval of the manuscript. All trial authors are employees or consultants or have received research grants from pharmaceutical companies. Conflicts of interest: all trial authors are employees or consultants or have received research grants from pharmaceutical companies.
Brown 1984a	Unclear	Funding: funded by National institute of Mental Health and National institutes of Health. Placebo and methylphenidate were supplied by CIBA‐GEIGY Corporation, Summit, New Jersey Conflicts of interest: not declared
Brown 1985	Unclear	Funding: research supported by US Public Health Services Grant from the National Institute of Mental Health (NIMH), and by the Biomedical Research Award from the National Institutes of Health (NIH). Methylphenidate provided by CIBA‐GEIGY Corporation, Summit, New Jersey Conflicts of interest: not declared
Brown 1988	Low	Funding: Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health and Emory University Research Conflicts of interest: not declared
Brown 1991	Unclear	Funding: Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health, and by the Emory University Research Fund Conflicts of interest: not declared
Buitelaar 1995	Unclear	Funding: not declared Conflicts of interest: no affiliations with pharmaceutical companies were declared
Bukstein 1998	Unclear	Funding: no Funding declared Conflicts of interest: not declared
Butter 1983	Low	Funding: the Scientific Development Group, Organon International BV, Oss, the Netherlands Conflicts of interest: none
Carlson 1995	Unclear	Funding: not declared Conflict of interest: not declared
Carlson 2007	High	Funding: research was funded by Eli Lilly and Company, Indianapolis, Indiana Conflicts of interest: Dr Carlson has received research support or has consulted with the following companies: Abbott Laboratories, Cephalon, Eli Lilly and Company, Janssen, McNeil, Otsuka and Shire Pharmaceuticals. Dr Dunn has received research support or has served on Speakers' Bureaus of the following companies: AstraZeneca, Eli Lilly and Company, National Institues of Health, Otsuka and Pfizer Pharmaceuticals. Drs Kelsey, Ruff, Ball and Allen and Ms Ahrbecker are employees and/or shareholders of Eli Lilly and Company.
Castellanos 1997	Unclear	Funding: unclear Conflicts of interest: not declared
Chacko 2005	High	Funding: during the conduct of this research, Dr Pelham was supported by grants from the National Institute of Mental Health (NIMH) (MH48157, MH47390, MH45576, MH50467, MH53554, MH62946), NIAAA (AA06267, AA11873), National Institute on Drug Abuse (NIDA) (DA05605, DA12414), National Institute of Neurological Disorders and Stroke (NINDS) (NS39087), National Institute for Environmental Studies (NIES) (ES05015) and National Institute of Child Health and Human Development (NICHHD) (HD42080) Conflicts of interest: several trial authors have affiliations with medical companies
Childress 2009	High	Funding: Novartis Pharmaceuticals Corporation. Novartis Pharma has been helping with development of the manuscript. Conflicts of interest: several trial authors have received research support from, are speakers for, are consultants of, are on the Advisory Board, have served on the Speakers' Bureaus of or are employees of several pharmaceutical companies
Childress 2017	High	Funding: this trial was supported by funds from Neos Therapeutics, Inc, PI. Conflicts of interest: Carolyn R Sikes is affiliated with Neos Therapeutics, Inc.
Childress 2020a	High	Funding: trial was funded by Purdue Pharma Conflict of interest: trial authors affiliated with medical industry
Childress 2020b	High	Funding: trial funded by Ironshore Pharmaceuticals Conflict of interest: trial authors affiliated with the medical industry
Childress 2020c	High	Funding: trial funded by Rhodes Pharmaceuticals LP. Conflict of interest: authors affiliated with medical industry
Chronis 2003	High	Funding: supported by a grant from Shire‐Richwood Pharmaceuticals, Incorporated ‐ manufacturer of Adderall ‐ and from the National Institute of Mental Health (NIMH) Conflict of interest: not declared
Coghill 2007	High	Funding: this work was supported by a local trust through a Tenovus Scotland initiative. Conflicts of interest: some trial authors have affiliations with different pharmaceutical companies
Coghill 2013	High	Funding: Shire Development LLC Conflicts of interest: C Anderson, R Civil, N Higgins, A Lyne and L Squires are employees of Shire and own stock/stock options. Some trial authors have received compensation for serving as consultants or speakers, or they or the institutions they work for have received research support or royalties from different companies or organisations.
Connor 2000	Low	Funding: supported by a UMMS (University of Massachusetts Medical School) Small Grants Project Award Conflicts of interest: not declared
Cook 1993	Low	Funding: supported by the Medical Center Rehabilitation Hospital Foundation and the School of Medicine, University North Dakota; the Veterans Hospital; the Dakota Clinic; and The Neuropsychiatric Institute, Fargo, North Dakota Conflicts of interest: not declared
Corkum 2008	Low	Funding: research was supported by a grant from the Izaak Walton Killam IWK Health Centre in Halifax, Nova Scotia Conflicts of interest: "none declared"
Corkum 2020	Low	Funding: the Canadian Institutes of Health Research Conflicts of interest: there were no conflicts of interest of any trial investigator with the pharmaceutical or equipment manufacturers.
Cox 2006	High	Funding: trial was supported by Funding from McNeil Pediatrics, a division of McNeil‐PPC Incorporated Conflicts of interest: none declared
CRIT124US02	High	Funding: trial by Novartis Conflicts of interest: no information on investigators
Döpfner 2004	High	Funding: trial was conducted and sponsored by MEDICE Arzneimittel Pütter GmbH & Co. KG as part of the drug approval process for Medikinet‐Retard Conflicts of interest: some trial authors have affiliations with medical companies
Douglas 1986	Low	Funding: research was supported by Grant Number MA 6913, from the Medical Research Council of Canada Conflicts of interest: not declared
Douglas 1995	Low	Funding: grants from the Medical Research Council of Canada and by William T Grant Foundation Faculty Scholar Program Conflicts of interest: none
DuPaul 1996	Unclear	Funding: unclear Conflict of interest: no conflicts of interest declared
Duric 2012	Low	Funding: the Child and Adolescent Psychiatry Department of Helse Fonna Hospital Haugesund, Helse Fonna Trust Haugesund, Norway Conflicts of interest: trial authors declare no potential conflicts of interests with regard to authorship or publication of this article.
Epstein 2011	Low	Funding: National Institutes of Health (NIH) and National Institute of Mental Health (NIMH) Conflicts of interest: no evidence of conflicts of interest
Fabiano 2007	Low	Funding: National Institute of Mental Health (NIMH) grant MH62946 Conflicts of interest: supported only by National Institutes
Findling 2006	High	Funding: provided by Celltech Americas Incorporated, currently part of UCB (Union Chimique Belge) Conflicts of interest: Drs Hatch and DeCory and Miss Cameron were employees of Celltech at the time of this trial. Dr Findling received research support, acted as a consultant and/or served on a Speakers' Bureau for Abbott, AstraZeneca, Bristol‐Myers Squibb, Celltech‐Medeva, Forest, GlaxoSmithKline, Johnson & Johnson, Lilly, New River, Novartis, Otsuka, Pfizer, Sanofi‐Synthelabo, Shire, Solvay and Wyeth. Dr Quinn claims no competitive interests. Dr McDowell has consulted for Janssen‐Cilag and Lilly.
Findling 2007	High	Funding: the Stanley Medical Research Institute Conflicts of interest: some trial authors have affiliations with pharmaceutical companies
Findling 2008	High	Funding: Shire Development Incorporated, Wayne, Pennsylvania Conflicts of interest: some trial authors received research support, acted as consultants and/or served on a Speakers' Bureau for several pharmaceutical companies.
Findling 2010	High	Funding: Shire Development Incorporated, which was involved in trial design, conduct and data analysis. The open‐label trial was industry‐sponsored. Conflicts of interest: Dr Findling has acted as consultant to, has served on Speakers' Bureaus of and/or has received research support from Abbott, Addrenex, AstraZeneca, Biovail, Bristol‐Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, KemPharm, Johnson & Johnson, Lundbeck, Neuropharm, Novartis, Noven, Organon, Otsuka, Pfizer, Sanofi‐Aventis, Sepracor, Shire, Solvay, Supernus, Validus and Wyeth. Dr. Turnbow receives or has received research support, acted as a consultant and/or served on Speakers' Bureaus for Eli Lilly, Novartis US, Sanofi‐Aventis, Shire and UCB (Union Chimique Belge). Dr Burnside has acted as consultant to, has served on Speakers’ Bureaus of and/or has received research support from Eli Lilly, Johnson & Johnson, Shire and Wyeth. Dr Melmed has acted as consultant to, has served on Speakers' Bureaus of and/or has received research support from Bristol‐Myers, Eli Lilly, McNeil, Novartis and Shire. Drs Civil and Li are full‐time employees of Shire Development Incorporated.
Fine 1993	High	Funding: CIBA‐GEIGY Canada Conflicts of interest: not declared
Firestone 1981	Low	Funding: Ministry of Health Conflicts of interest: not stated
Fitzpatrick 1992a	Low	Funding: National Institute of Mental Health (NIMH) grant MH38118 Conflicts of interest: not declared
Flapper 2008	Low	Funding: none (no funding was available). This double‐blind placebo‐controlled (DBPC) trial of methylphenidate was performed as a clinical treatment program as best clinical practice to determine the effects of methylphenidate and optimal dose compared with placebo. Conflicts of interest: no affiliations with pharmaceutical companies or similar declared.
NCT02039908	Low	Funding: Florida International University Conflicts of interest: nothing declared for trial investigators
Forness 1992	Low	Funding: National Institute of Mental Health (NIMH) grant MH38686 Conflicts of interest: no affiliations described
Froehlich 2011	High	Funding: National Institute of Mental Health (NIMH) and Cincinnati Children’s Hospital Center for Education and Research Therapeutics Award Conflicts of interest: Dr Epstein receives Funding from Eli Lilly and Co. Dr Stein has received research support from Eli Lilly and Co., McNeil Pharmaceuticals, Novartis and Shire. He has served on a Speakers' Bureau for Novartis and has served as consultant to Novartis, Shire and Shinogi Pharmaceuticals.
Froehlich 2018	High	Funding: data collection for the project was supported by the National Institute of Mental Health (Bethesda, MD) by R01MH074770 [Epstein] and K23MH083881 [Froehlich], while investigators’ time on the project was funded by National Institute of Mental Health K24MH064478 [Epstein], K23MH083027 [Brinkman], and R01MH070564 [Stein]). Conflicts of interest: trial authors are affiliated with the medical industry
Gadow 1990	Unclear	Funding: Ciba Pharmaceutical Company supplied methylphenidate placebo Conflicts of interest: not declared
Gadow 1995	Low	Funding: research grants from the Tourette Syndrome Association and the National Institute of Mental Health (NIMH) Conflicts of interest: not declared
Gadow 2007	Low	Funding: this trial was supported in part by a research grant from the Tourette Syndrome Association Incorporated, and by Public Health Service (PHS) grant number MH45358 from the National Institute of Mental Health (NIMH). Conflicts of interest: trial authors have no financial relationships to disclose.
Gadow 2011	Unclear	Funding: National Institute of Mental Health (NIMH) and the Tourette Syndrome Association Incorporated. CIBA Pharmaceutical Company supplied methylphenidate placebos. Novartis supplied immediate‐release methylphenidate. Conflicts of interest: "Kenneth D. Gadow is a shareholder in Checkmate Plus, publisher of the Child Symptom Inventory‐4"
Garfinkel 1983	Low	Funding: Ontario Mental Health Foundation Conflicts of interest: none
Gonzalez‐Heydrich 2010	High	Funding: supported by National Institute of Mental Health (NIMH) Grant, Number K23 MH066835 Conflicts of interest: 4 trial authors are involved in the pharmaceutical sector.
Gorman 2006	Low	Funding: National Institute of Mental Health (NIMH) Conflicts of interest: trial authors have no financial relationships to declare
Green 2011	Low	Funding: the Basil O’Connor Starter Scholar Research Award of the March of Dimes, NARSAD (National Alliance for Research in Schizophrenia and Affective Disorders) Young Investigator Award, the Marguerite Stolz Award from the Sackler Faculty of Medicine and the National Institute on Drug Abuse (NIDA) Conflicts of interest: trial authors have had no institutional or corporate/commercial relationships for the past 36 months that might pose a conflict of interest.
Greenhill 2002	High	Funding: Celltech Pharmaceuticals Incorporated Conflicts of interest: Dr Greenhill is a consultant for Celltech‐Medeva and a member of its medical advisory board. Drs Findling and Swanson are consultants for Celltech‐Medeva.
Greenhill 2006	High	Funding: Novartis Conflicts of interest: 2 trial authors are employed by Novartis. Only Roberta R Ball has no conflicts of interest.
Gruber 2007	Low	Funding: this was not an industry‐supported trial. Conflicts of interest: trial authors have indicated no financial conflicts of interest.
Hale 2011	Low	Funding: research part funded by the Neuropsychiatric Research Institute, Fargo, North Dakota, USA Conflicts of interest: trial authors disclose no conflicts of interest
Hawk 2018	Low	Funding: supported by grants from the National Institute of Mental Health (NIMH) and from the National Institute on Drug Abuse (NIDA) Conflicts of interest: no conflicts declared
Heriot 2008	Low	Funding: no funding to conduct the trial was received from any party. Conflicts of interest: none of the trial authors are affiliated with pharmaceutical companies.
Hicks 1985	Low	Funding: National Institutes of Health (NIH) Conflicts of interest: not declared
Hoeppner 1997	Unclear	Funding: not declared Conflicts of interest: not declared
Horn 1991	Unclear	Funding: not declared Conflicts of interest: not declared
Huang 2021	High	Funding: this work is supported by Orient Pharma Co, Ltd. Conflicts of interest: authors affiliated with medical industry
Ialongo 1994	Unclear	Funding: not declared Conflicts of interest: not declared
Jacobi‐Polishook 2009	Unclear	Funding: not declared Conflicts of interest: not declared
Jensen 1999 (MTA)	High	Funding: this trial was supported by several grants from the National Institute of Mental Health, Bethesda, Maryland. Conflicts of interest: several trial authors have affiliations with medical companies.
Johnston 1988	Unclear	Funding: not declared. During the writing of this report, C Johnston was supported by a Doctoral Fellowship from the Social Sciences and Humanities Research Council of Canada. Conflicts of interest: not declared
Kaplan 1990	Unclear	Funding: not declared Conflicts of interest: not declared
Kelly 1989	Unclear	Funding: CIBA Geigy Pharmaceuticals provided placebos Conflicts of interest: not declared
Kent 1995	Low	Funding: this work was supported by the John and Maxine Bendheim Fellowship and by the Leon Lowenstein Foundation. Conflicts of interest: not declared
Kent 1999	High	Funding: Ms Kent was a summer medical student supported in part by the IWK Grace Research Foundation, Halifax, NovaScotia, and by the Pharmaceutical Manufacturers Association of Canada Studentship, Ottawa, Ontario Conflicts of interest: trial authors sponsored by Pharmaceutical Manufacturers’ Association of Canada Studentship
Klorman 1990	Low	Funding: National Institute of Mental Health (NIMH) grant MH38118 Conflicts of interest: no corporate affiliations declared
Kolko 1999	Unclear	Funding: not declared Conflicts of interest: not declared
Kollins 2006 (PATS)	High	Funding: Phase 5 (cross‐over): sponsored by the National Institute of Mental Health, Columbia/New York State Psychiatric Institute, Johns Hopkins University, Columbia University, University of California Irvine, Duke University Medical Center, New York University Child Study Center and University of California Los Angeles, Arizona Institute of Mental Health Research to JKG. Generic methylphenidate was purchased by grant funds. Phase 6 (parallel‐group): sponsored by the National Institute of Mental Health, Columbia/New York State Psychiatric Institute, Johns Hopkins University, Columbia University, University of California Irvine, Duke University Medical Center, New York University Child Study Center and University of California Los Angeles, Arizona Institute of Mental Health Research to JKG. Generic methylphenidate was purchased by grant funds. Phase 8 (discontinuation): sponsored by the National Institute of Mental Health, Columbia/New York State Psychiatric Institute, Johns Hopkins University, Columbia University, University of California Irvine, Duke University Medical Center, New York University Child Study Center and University of California Los Angeles, Arizona Institute of Mental Health Research to JKG. Generic methylphenidate was purchased by grant funds. Conflicts of interest: Phase 5 (cross‐over): multiple trial authors had relationships with several pharmaceutical companies for the period 2000‐2007. Phase 6 (parallel‐group): multiple trial authors had relationships with several pharmaceutical companies for the period 2000‐2007. Placebo responders in phase 5 were excluded from phase 6. Participants with no clinical benefit any week were excluded from phase 6 (methylphenidate non‐responders). Phase 8 (discontinuation): multiple trial authors had relationships with several pharmaceutical companies for the period 2000‐2007.
Kollins 2021	High	Funding: clinical research was funded by KemPharm, Inc. Funding for editorial and writing assistance in the form of proofreading, copyediting, and fact‐checking was provided by Corium, Inc. Conflicts of interest: authors affiliated with medical industry
Konrad 2004	Low	Funding: the German Society for the Advancement of Scientific Research (DFG grant KFO112) Conflicts of interest: none declared
Konrad 2005	Low	Funding: provided through a grant from the German Research Foundation (DFG grant: KFO112–TP5) Conflicts of interest: none declared
Kortekaas‐Rijlaarsdam 2017	High	Funding: unclear, but Shire was a collaborator Conflicts of interest: the second trial author has some affiliation to the medical industry.
Kritchman 2019	Low	Funding: Shalvata Mental Health Center Conflicts of interest: “The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.”
Leddy 2009	High	Funding: not declared Conflicts of interest: Dr Waxmonsky has served on the Speakers' Board for Novartis, received an honorarium from Shire and received research support from Shire and Eli Lilly. Dr Erbe has received educational and research support from Genzyme Corporation. Dr Pelham was paid an honorarium by Shire Pharmaceuticals.
Lehmkuhl 2002	High	Funding: Medice Arzneimittel Pütter GmbH & Co. KG, Kuhloweg 37, D‐58638 Iserlohn Conflicts of interest: Dr Doepfner is a consultant for Lilly, Medice, Novartis and Union Chimique Belge; serves on the Advisory Boards of Lilly, Medice, Shire, Novartis and Union Chimique Belge; participates as a member of the Speakers' Bureaus of Lilly, Medice, Janssen‐Cilag and Union Chimique Belge; and has research contracts with Lilly, Medice, Novartis, Union Chimique Belge, the German Research Foundation and the Federal Ministry of Health. Dr Lehmkuhl is on the Advisory Boards of Lilly and Medice. Dr Sinzig has no financial relationships to disclose.
Lijffijt 2006	Unclear	Funding: not declared Conflicts of interest: none declared
Lin 2014	High	Funding: Ely Lilly Conflicts of interest: 5 authors work for Lilly.
Lopez 2003	High	Funding: Novartis Conflicts of interest: Dr Silva is a consultant and a member of the Speakers' Bureau for Novartis. Dr Lopez is a consultant for Eli Lilly, Novartis and Shire. He is also a member of the Speakers' Bureaus for Novartis and Shire.
Lufi 1997	Unclear	Funding: not declared Conflits of interest: not declared
Lufi 2007	Unclear	Funding: not declared Conflicts of interest: not declared
Manos 1999	High	Funding: in part by from Shire Pharmaceutical Development Incorporated to Dr Faraone Conflicts of interest: trial authors acknowledge partial support to the second author from the National Institute on Drug Abuse (NIDA) (grants R01‐DA07957 and MCJ‐390592) and from the Maternal and Child Health Program, Health Resources and Service Administration, Department of Health and Human Services (grant 390715), and to the third author from the Stanley Foundation.
Martins 2004	Unclear	Funding: methylphenidate and placebo pills were supplied by Novartis Pharmaceuticals (São Paulo, Brazil) at no cost and without restrictions. No additional funding was requested or received from Novartis or any other commercial entity. Conflicts of interest: trial authors have reported no conflicts of interest
Matthijssen 2019	Low	Funding: The Netherlands Organization for Health Research and development (ZonMw, grant 836011014) Conflicts of interest: not declared
McBride 1988a	Unclear	Funding: not declared Conflicts of interest: not declared
McCracken 2016	High	Funding: National Institute of Mental Health (NIMH) Research Center grant P50MH077248, “Translational Research to Enhance Cognitive Control” Conflicts of interest: trial authors affiliated with the medical industry
McGough 2006	High	Funding: Shire US Inc Conflicts of interest: 2 medical writers acknowledged (Amy M Horton & Michelle Roberts) but were unclear about where they came from or what their role was in the publication.
McInnes 2007	High	Funding: the Psychiatric Endowment Fund Conflicts of interest: trial authors had received Funding from Eli Lilly, Shire Pharmaceuticals, Janssen‐Ortho and McNeil Pharmaceuticals
Merrill 2021	Unclear	Funding: not stated Conflicts of interest: trial authors declare that they have no conflict of interest
Moshe 2012	Low	Funding: none Conflicts of interest: none declared
Muniz 2008	High	Funding: "This study was funded by Novartis Pharmaceuticals Corporation and reports the following involvement: design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, and approval of the manuscript" Conflicts of interest: Dr Muniz is an employee of Novartis Pharmaceuticals Corporation. He has no other relationships to disclose. Dr Brams reports the following relationships: serves as speaker, consultant and Advisory Board member for Novartis and Shire; receives grant research support from Novartis, Shire and Eli Lilly. Dr Mao reports the following relationships: speaker for Novartis, Eli Lilly, Bristol‐Myers Squibb, AstraZeneca and Shire; consultant for Eli Lilly, Novartis and Shire; receives grant research support from Novartis. Mr McCague is an employee of Novartis Pharmaceuticals Corporation. He has no other relationships to disclose. Ms Pestreich is an employee of Novartis Pharmaceuticals Corporation. She has no other relationships to disclose. Dr Silva reports the following relationships: none since 15 December 2006; before that, she was a speaker for Novartis, AstraZeneca and Janssen; received grant/research support from Novartis and Celgene.
Murray 2011	High	Funding: Ortho‐McNeil Janssen Scientific Affairs, LLC Conflicts of interest: several trial authors had affiliations with pharmaceutical companies producing methylphenidate
Musten 1997	Low	Funding: Health Canada grant Conflicts of interest: none declared
NCT00409708	High	Funding: Novartis Conflicts of interest: no information on investigators
NCT02293655	Unclear	Funding: Children's Hospital Medical Center, Cincinnati Conflicts of interest: not stated
NCT02536105	High	Funding: Massachusetts General Hospital Conflicts of interest: trial investigators affiliated with the medical industry
Newcorn 2008	High	Funding: Eli Lilly and Company Conflicts of interest: Dr Newcorn receives grant support from Eli Lilly and McNeil; is a consultant and/or advisor for Eli Lilly, McNeil, Shire, Novartis and Sanofi‐Aventis; and is a member of Speakers' Bureaus for Eli Lilly and Novartis. Dr Kratochvil receives grant support from Abbott, Cephalon, Eli Lilly, McNeil, Pfizer, Shire and Somerset; receives from Eli Lilly trial medication for an NIMH (National Institute of Mental Health)‐funded trial; is a consultant for Abbott, AstraZeneca, Eli Lilly and Pfizer; and is a member of the Eli Lilly Speakers' Bureau. Dr Casat receives research Funding from Eli Lilly, Novartis and Abbott, and serves on an advisory board for Eli Lilly. Dr Allen and Dr Ruff are employees and shareholders of Eli Lilly. Dr Michelson and Dr Moore are former employees of Eli Lilly.
Newcorn 2017a (flexible dose)	High	Funding: Shire Conflicts of interest: trial authors affiliated with pharmaceutical companies
Newcorn 2017b (forced dose)	High	Funding: Shire Conflicts of interest: trial authors heavily affiliated with pharmaceutical companies
Nikles 2006	Low	Funding: the General Practice Evaluation Program, the Department of Health and Aged Care, Queensland Medical Laboratory, and the Royal Australian College of General Practitioners Conflicts of interest: trial authors have indicated that they have no financial relationships relevant to this article to disclose
Oesterheld 1998	Low	Funding: University of South Dakota/USF‐Mini Grant Conflicts of interest: none declared
Overtoom 2003	Low	Funding: Netherlands Organisation for Scientific Research (NWO) Grant 575‐63‐082 Conflicts of interest: not declared
Palumbo 2008	High	Funding: NIH (National Institutes of Health) and NINDS (National Institute of Neurological Disorders and Stroke) Conflicts of interest: some trial authors are on the ADHD Advisory Board and the Speakers' Bureau of; are scientific consultants or principal or site investigators for; and/or have received educational or funding support from several pharmaceutical companies.
Pearson 2013	Low	Funding: grant number MH072263 from National Institute of Mental Health (NIMH) Conflicts of interest: none declared
Pelham 1989	Unclear	Funding: not declared Conflicts of interest: not declared
Pelham 1990a	Unclear	Funding: not declared Conflicts of interest: not declared
Pelham 1993a	Unclear	Funding: not declared Conflicts of interest: not declared
Pelham 1999	High	Funding: grants from the Shire Richwood Pharmaceutical Company and National Institute of Mental Health (Grants MH53554, MH45576 and MH50467) Conflicts of interest: not declared
Pelham 2001a	High	Funding: ALZA Corporation, the manufacturers of Concerta Conflicts of interest: Dr Pelham is a member of the ALZA advisory committee on Concerta and its development. Drs Hoffman and Lock are members of the ALZA paediatric advisory board.
Pelham 2002	High	Funding: NIMH (Grant MH48157) Conflicts of interest: Pelham served as an advisor for ALZA Corporation (see Pelham 2001a)
Pelham 2005	High	Funding: Noven Pharmaceuticals. Furthermore, Dr Pelham was supported by grants from NIAAA, NIDA, NIMH and NINDS. Conflicts of interest: several trial authors have received consulting fees and research funding and have been consultants and/or served on the Speakers' Bureaus of several pharmaceutical companies in the past year.
Pelham 2011	High	Funding: grant from Noven Pharmaceuticals Conflicts of interest: Dr Pelham has served as a consultant for Shire, McNeil, Noven, Celltech/Medeva, Novartis and Abbott Laboratories; has received honoraria from Shire and Janssen and research support from Shire, Alza, Eli Lilly, Noven and Cephalon; and holds common stock in Abbott Laboratories. Dr Waxmonsky has served on the Speakers' Bureau for Novartis and has received research support from Eli Lilly and Shire Incorporated. Dr Hoffman has served on the advisory board and Speakers’ Bureau for Shire Pharmaceuticals and on the Speakers' Bureau for McNeil. Dr Ballow has received research support from GlaxoSmithKline, Panacos, Boehringer Ingelheim, Pharmasset, Jacobus and Pharmena. Dr Schentag has served as a consultant for or received support from Noven, Wyeth, Daiichi, Targanta Therapeutics and Astellas. Dr Gonzalez is a full‐time employee of P’Kinetics International Incorporated. No other conflicts of interest are known.
Pelham 2014	Low	Funding: grant from the National Institute of Mental Health (MH62946). Dr Pelham was funded by grants from the National Institutes of Health (MH62946, MH69614, MH53554, MH69434, MH65899, MH78051, MH062946, NS39087, AA11873, DA12414, HD42080) and the Institute of Education Sciences (L03000665A). Dr Fabiano was supported in part by a Ruth S Kirschstein National Research Service Award Predoctoral Fellowship (1F31MH064243‐01A1) and by the Department of Education, Institute of Education Sciences (R324J06024, R324B06045). Conflicts of interest: not declared
Perez‐Alvarez 2009	Low	Funding: none. Research was part of the work day, participants were voluntary and no funding was needed to implement the trial Conflicts of interest: none. Investigators are staff members at institutions (affiliations) reported in the paper.
Pliszka 1990	Low	Funding: National Institute of Mental Health (NIMH) Conflicts of interest: not declared
Pliszka 2000	High	Funding: Shire Richwood Incorporated Conflicts of interest: Dr Browne is currently with Watson Pharmaceuticals, Corona, California
Pliszka 2007	High	Funding: National Institute of Mental Health Grant R01 MH63986 Conflicts of interest: Pliszka received honoraria and research support from Shire and MacNeil and research support from Ely Lilly and Cephalon
Pliszka 2017	High	Funding: Ironshore Pharmaceuticals Conflicts of interest: trial authors affiliated with the medical industry
Quinn 2004	High	Funding: Celgene Conflicts of interest: all trial authors disclosed that they have past and present affiliations with the pharmaceutical industry.
Ramtvedt 2013	High	Funding: the first phase was conducted as part of ordinary clinical practice at Neuropsychiatric Unit, Østfold Hospital Trust. The second and third phases, data analysis and preparation of manuscript were sponsored by South‐Eastern Norway Regional Health Authority, and also by Østfold Hospital Trust and National Resource Centre for ADHD, both under the umbrella of South‐Eastern Norway Regional Health Authority. Conflicts of interest: Henning Aabech is a member of the Strattera Advisory Board, Eli Lilly, Norway.
Rapport 1985	Unclear	Funding: not declared Conflicts of interest: not declared
Rapport 1987	Low	Funding: none, neither external nor internal. This project was supported in part by a Biomedical Research Support Grant (no. S07 RR05712), which was awarded to the first trial author by the Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health. Conflicts of interest: not declared
Rapport 2008	Low	Funding: none Conflicts of interest: no financial, corporate or commercial relationships to disclose
Reitman 2001	Unclear	Funding: not declared Conflict of interest: none
Riggs 2011	High	Funding: OROS methylphenidate and matching placebo were supplied to the Clinical Trials Network contract pharmacy (EMINENT Services Corporation) by McNeil Consumer and Specialty Pharmaceuticals (distributor for Concerta), at no cost. Principal investigators are not employed by the organisation sponsoring the trial. No agreement between principal investigators and trial sponsor (or its agents) restricts the principal investigator's rights to discuss or publish trial results after the trial is complete Conflicts of interest: some trial authors have received research support from, served on Speakers' Bureaus of or acted as consultants for pharmaceutical companies.
Rubinsten 2008	Low	Funding: the research was completed while Dr Rubinsten was a post‐doctoral fellow at the Hospital for Sick Children (HSC), in Toronto, Canada, and was supported by the Rothschild Fellowship from Israel. It was undertaken, in part, through funding received from the Canadian Institutes of Health (CIHR: grant #MOP 64312), a CIHR post‐doctoral fellowship, and the Canada Research Chairs Program (RT). Conflicts of interest: not declared
Samuels 2006	Unclear	Funding: not declared Conflicts of interest: not declared
Schachar 1997a	High	Funding: Medical Research Council of Canada, National Health Research Development Program of Canada and the Department of Psychiatry, The Hospital for Sick Children, Toronto. Placebo pills were provided by Ciba Geigy, Canada, Ltd Conflicts of interest: 2 trial authors have reported working as consultants for pharmaceutical companies, and 1 has furthermore received industry‐sponsored research grants.
Schachar 2008	High	Funding: Purdue Pharma (Canada) Conflicts of interest: some trial authors are working for Purdue Pharma
Schrantee 2016	Low	Funding: this trial was funded by faculty resources of the Academic Medical Center, University of Amsterdam, and by grant 11.32050.26 from the European Research Area Network Priority Medicines for Children (Sixth Framework Programme). Dr Rombouts was supported by Vici (Netherlands Organisation for Scientific Research), and Dr Andersen was supported by grant DA‐015403 from the National Institute on Drug Abuse Conflicts of interest: Dr Niessen reported being cofounder, shareholder, and part‐time scientific officer of Quantib BV. No other disclosures were reported. Through personal correspondence it was clarified that Dr Niessen did not facilitate any part of the trial, but was involved in the data‐analysis of MRI imaging sequence technique used (arterial spin labelling).
Schulz 2010	High	Funding: Novartis Pharma GmbH, Germany. Trial aimed at showing efficacy of Ritalin LA with purpose of obtaining marketing authorisation Conflicts of interest: almost all trial authors have received grants, research support or other kinds of financial support from the medical industry.
Schwartz 2004	High	Funding: grants from Le Fonds de la Recherche en Santé du Québec and the Canadian Institutes of Health Research Conflicts of interest: yes. Dr Joober is a principal investigator on a clinical trial not related to this trial that is sponsored by AstraZeneca Canada Incorporated, and receives no direct compensation for this trial. Dr Boivin has the following industry financial ties: The Litebook Company Ltd., Medicine Hat, Alberta, Canada; and Pulsar Informatics Inc., Vancouver, British Columbia, Canada.
Sharp 1999	Unclear	Funding: not declared Conflicts of interest: not declared
Shiels 2009	High	Funding: National Institute of Mental Health Conflicts of interest: "In the past 3 years, James G. Waxmonsky has served on the Speakers Bureau for Novartis, received honoraria from Scepter, and received research support from Eli Lilly"
Silva 2005a	High	Funding: Novartis Pharmaceuticals Corporation Conflicts of interest: all trial authors have been consultants, have received honoraria or have worked for Novartis.
Silva 2006	High	Funding: Novartis Conflicts of interest: some trial authors have affiliations with medical companies
Silva 2008	High	Funding: Novartis Conflicts of interest: some trial authors have affiliations with medical companies
Smith 1998	Low	Funding: grants from the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Child Health and Human Development Conflicts of interest: not declared
Smith 2004	Unclear	Funding: not declared Conflicts of interest: not declared
Smithee 1998	Low	Funding: National Institute of Mental Health (NIMH) Grant MH 38228; Rafael Klorman Conflicts of interest: not declared
Solanto 2009	High	Funding: the National Institute of Mental Health Conflicts of interest: 3 trial authors have served or received grants from pharmaceutical companies in the past.
Soleimani 2017	Low	Funding: Guilan University of Medical Sciences Conflicts of interest: none declared
Stein 1996	Low	Funding: the work was supported by the Smart Family Foundation. Conflicts of interest: no affiliations with pharmaceutical companies stated
Stein 2003	High	Funding: the National Institute of Mental Health, the General Clinical Research Center Program of the National Center for Research Resources and the National Institutes of Health, Department of Health and Human Services Conflicts of interest: Drs Stein, Robb, Conlon and Newcorn participate in the Speakers' Bureau for McNeil Consumer and Specialty Pharmaceuticals, and Drs Stein and Newcorn are members of the Concerta National Advisory Committee.
Stein 2011	High	Funding: investigator‐initiated trial sponsored by Novartis Pharmaceuticals, with additional support provided by the University of Illinois at Chicago (UIC) Center for Clinical and Translational Science (CCTS) Conflicts of interest: some trial authors are affiliated with pharmaceutical companies
Stoner 1994	Low	Funding: National Association of School Psychologists Conflicts of interest: not declared
Sumner 2010	Unclear	Funding: it was not clear who sponsored the trial, but someone did (see authors' affiliations). Conflicts of interest: Calvin R Sumner is an employee of and an equity holder for the trial sponsor. Virginia S Haynes, PhD, is an employee of 3i Global (Basking Ridge, NJ) and a paid consultant for the trial sponsor. Martin H Teicher, MD, PhD, served as paid consultant and clinical investigator for the sponsor. Jeffrey H Newcorn, MD, serves as advisor and consultant for Lilly, Ortho‐McNeil Janssen, Schering‐Plough and Shire. He receives research support from Lilly, Ortho‐McNeil Janssen and Shire.
Sunohara 1999	High	Funding: RESTRACOM graduate studentship for The Hospital for Sick Children Research Institute and Novartis Pharmaceuticals Conflicts of interest: not declared
Swanson 1998	High	Funding: grant from Richwood Pharmaceutical Company Conflicts of interest: not declared
Swanson 1999	High	Funding: ALZA Corporation, Palo Alto, California Conflicts of interest: not declared
Swanson 2002a	High	Funding: ALZA Corporation Conflicts of interest: not declared
Swanson 2002b	High	Funding: ALZA Corporation Conflicts of interest: not declared
Swanson 2004b	High	Funding: Celltech Pharmaceuticals Incorporated Conflicts of interest: some trial authors are consultants for pharmaceutical companies
Symons 2007	Unclear	Funding: A McKnight Land‐Grant Professorship to the first author Conflicts of interest: this work was supported, in part, by a McKnight Land‐Grant Professorship to Frank Symons.
Szobot 2004	High	Funding: research funds from Hospital de Clínicas de Porto Alegre, FAPERGS and NOVARTIS Conflicts of interest: not declared
Szobot 2008	High	Funding: "The ADHD outpatient program receives research support from Bristol‐Myers Squibb, Eli‐Lilly, Janssen‐Cilag and Novartis" Conflicts of interest: trial authors are consultants and speakers for various companies
Tannock 1989	Low	Funding: jointly funded by Ontario Mental Health Foundation (Grant No. 963‐86/88) and Health and Welfare Canada (Grant No. 6606‐3166‐42) Conflict of interest: not declared
Tannock 1992	Low	Funding: grant from the Canadian Psychiatric Research Foundation and a post‐doctoral fellowship by the Ontario Mental Health Foundation Conflicts of interest: not declared
Tannock 1993	Low	Funding: the Canadian Psychiatric Research Foundation and the Medical Research Council of Canada Conflicts of interest: not declared
Tannock 1995a	Low	Funding: Medical Research Council of Canada and Health and Welfare Canada Conflicts of interest: nothing to declare
Tannock 1995b	Low	Funding: in part, by the Ontario Mental Health Foundation and the National Health Research and Development Program, Health Canada Conflicts of interest: not declared
Tannock 2018	Unclear	Funding: an operating grant from the Canadian Institutes of Health Research (Grant # MT 13366), and by the donation of placebo medication from Novartis Pharmaceuticals Conflict of interest: none declared
Taylor 1987	High	Funding: partially funded by grant from CIBA Ltd., which provided medicine and placebo Conflicts of interest: Dr Schachar was supported during this period by a fellowship from the Medical Research Council of Canada.
Taylor 1993	Unclear	Funding: not declared Conflicts of interest: not declared
Tervo 2002	Unclear	Funding: not declared Conflicts of interest: no conflicts of interest have been disclosed
Tirosh 1993a	Unclear	Funding: none Conflicts of interest: not declared
Tirosh 1993b	Unclear	Funding: not declared Conflicts of interest: not declared
Tourette's Syndrome Study Group 2002	Unclear	Funding: National Institute of Neurological Disorders and Stroke, the General Clinical Research Center, the National Center for Research Resources, the Tourette Syndrome Association Boeringer Ingelheim Inc. (particularly Dr Virgil Dias), for supplying clonidine and matching placebo; Bausch and Lomb, Inc., for supplying small gifts for our trial participants Conflicts of interest: none declared
Tucker 2009	High	Funding: Novartis Pharmaceuticals Corporation Conflicts of interest: some trial authors were employed by Novartis (5 of 8 had a Novartis email address)
Ullmann 1985	Unclear	Funding: National Institutes of Mental Health (NIMH). Ciba‐Geigy provided medication and placebo Conflicts of interest: not declared
Ullmann 1986	Unclear	Funding: in part by a National Institute of Mental Health (NIMH) grant. Ciba‐Geigy provided medication and placebo Conflicts of interest: not declared
Urman 1995	Low	Funding: in part by funds from the Medical Research Council of Canada and the Research Institute of the Hospital for Sick Children Conflicts of interest: not declared
Van der Meere 1999a	High	Funding: grants from the Sophia Foundation for Medical Research and Boehringer Ingelheim BV, the Netherlands Conflicts of interest: not declared
Wallace 1994	Low	Funding: The Veterans Administration Medical Center, Vermont Conflicts of interest: not declared
Wallander 1987	Low	Funding: in part by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grants and the University of Southern California Faculty Research and Innovation Fund Conflicts of interest: not declared
Waxmonsky 2008	High	Funding: National Institute of Mental Health (NIMH) Grant MH62946 and a Klingenstein Third Generation Foundation Fellowship in Child and Adolescent Depression Research Conflicts of interest: several authors have affiliations with pharmaceutical companies
Weiss 2021	High	Funding: Rhodes Pharmaceuticals, LP Conflict of interest: the trial authors are affiliated with the medical industry.
Whalen 1990	Unclear	Funding: not declared Conflicts of interest: not declared
Wigal 2003	High	Funding: Celltech Americas Incorporated Conflicts of interest: some trial authors are working for Celltech Americas Incorporated
Wigal 2004	High	Funding: Celgene Corporation Conflicts of interest: Dr Wigal reports extensive disclosure.
Wigal 2011	High	Funding: Ortho‐McNeil‐Janssen Scientific Affairs, LLC. Phase IV trial Conflicts of interest: several trial authors had affiliations with pharmaceutical companies producing methylphenidate
Wigal 2013	High	Funding: trial received funds from NextWave Pharmaceutics (Belden and Berry are with NextWave) Conflicts of interest: all trial authors are affiliated with NextWave Pharmaceuticals.
Wigal 2014	High	Funding: Rhodes Pharmaceuticals LP Conflicts of interest: several trial authors work for, or have received grant and research support or both from pharmaceutical companies
Wigal 2015	High	Funding: Rhodes Pharmaceuticals […]. Medical writing assistance was provided by Linda Wagner, PharmD, from Excel Scientific Solutions and funded by Rhodes Pharmaceuticals LP Conflicts of interest: not declared
Wigal 2017	High	Funding: the research was sponsored by NextWave Pharmaceuticals, a wholly owned subsidiary of Pfizer, Inc. Conflicts of interest: trial authors are affiliated with the medical industry
Wilens 2006b	High	Funding: McNeil Consumer and Specialty Pharmaceuticals Conflicts of interest: several trial authors have had commitments (e.g. speakers, consultants, advisors) with various pharmaceutical companies
Wilens 2008	High	Funding: Shire Development Incorporated Conflicts of interest: several trial authors have affiliations with medical companies
Wilens 2010	High	Funding: trial and medication/placebo were funded by a grant through Shire Pharmaceuticals. Shire had no role in design, collection, analysis, interpretation, writing or decision to submit Conflicts of interest: some trial authors have received research support from medical companies
Wilkison 1995	Low	Funding: a University of Utah Biomedical Sciences research grant and a grant from the University Research Committee Conflicts of interest: no corporate affiliations described
Wodrich 1998	Unclear	Funding: not declared Conflicts of interest: not declared
Wolraich 2001	High	Funding: ALZA Corporation Conflicts of interest: trial authors are part of the Concerta Study Group
Zeiner 1999	Low	Funding: the Norwegian Medical Research Council, the Norwegian Public Health Association and the Legacy of Haldis and Josef Andresen Conflicts of interest: not declared
Zeni 2009	High	Funding: research grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil) (Grant 471761=03‐6) and Hospital de Clinicas de Porto Alegre (GPPG 03‐325). Aripiprazole was provided by Bristol‐Myers Squibb without restriction. Conflicts of interest: stated, "this is an independent investigator trial"; however some study authors have affiliations with medical companies.

ADHD: Attention deficit hyperactivity disorder; BV: besloten vennootschap (corresponding to a private limited liability company (LLC) in the USA); DFG: Deutsche Forschungsgemeinschaft; NIH: National Institutes of Health; Inc.: Incorporated; IWK: Izaak Walton Killam; LA: Long acting; Ldt.: Limited liability; LLC: Limited liability company; LP: Limited partnership; MRI: Magnetic resonance imaging; NIAAA: National Institute on Alcohol Abuse and Alcoholism; NIDA: National Institute on Drug Abuse; NIMH: National Institute of Mental Health; NINDS: National institute of Neurological Disorders and Stroke; OROS: osmotic‐release oral system; PI: Primary Investigator; ZonMw: Organisation for Health Research and Development in the Netherlands

Sensitivity analysis

We conducted sensitivity analyses to determine whether findings were sensitive to the following.

• Decisions made during the review process, such as our assessment of clinical heterogeneity (listed below)

• Combined 'change scores' and 'endpoint data' in the meta‐analyses

• Random‐effects and fixed‐effect model meta‐an lyses

No sufficiently well‐designed method has been used to combine the results of trials at high risk of bias and trials at low risk of bias (Higgins 2022a). We performed sensitivity analyses by grouping together trials with similar classifications of bias, as described above, and investigated the impact on intervention effects.

We excluded the following trials from the sensitivity analyses.

• IQ under 70 (Oesterheld 1998; Pearson 2013; Smith 1998; Taylor 1987)

• Change scores (Carlson 2007; Findling 2008; Kollins 2021; McCracken 2016; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Tucker 2009)

• Older than 18 years of age (Green 2011; Szobot 2008)

Summary of findings and assessment of the certainty of the evidence

We constructed a summary of findings table in which to document all review outcomes. Two review authors (HEC and OJS) assessed the evidence using the GRADE approach. The GRADE approach appraises the certainty of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. Considerations are due to within‐trial risk of bias; directness of the evidence; heterogeneity of the data; precision of effect estimates; and risk of publication bias (Guyatt 2011; Schünemann 2022). When possible, that is, when the MD or the RR was available, we used the results from the Trial Sequential Analysis as the rating for imprecision (Jakobsen 2014). We downgraded imprecision in GRADE by two levels if the accrued number of participants was below 50% of the DARIS, and one level if between 50% and 100% of the DARIS (Korang 2020). We did not downgrade for imprecision if the cumulative Z‐curve crossed the monitoring boundaries for benefit, harm, futility, or the DARIS (Korang 2020). We reported two primary outcomes (teacher‐rated ADHD symptoms and serious adverse events) and three secondary outcomes (non‐serious adverse events, teacher‐rated general behaviour, and quality of life) at end of treatment in Table 1.

Results

Description of studies

For more information, please see Characteristics of included studies, Characteristics of excluded studies, Characteristics of studies awaiting classification and Characteristics of ongoing studies, as well as Table 3 for an overview of study characteristics and Table 4 for an overview of key inclusion and exclusion criteria.

2. Key demographics of included studies.

Key demographics	Number of trials	Cross‐over trials	Parallel trials
Sample size
Sample size above 100 participants	49	17 trials: Ahmann 1993; Bedard 2008; Bhat 2020; Brams 2012; CRIT124US02; Froehlich 2011; Froehlich 2018; Huang 2021; Kollins 2006 (PATS); Manos 1999; NCT02039908; Pelham 2002; Schulz 2010; Swanson 2004b; Ullmann 1986; Waxmonsky 2008; Wilens 2008	33 trials: Biederman 2003b; Childress 2009; Childress 2020a; Childress 2020b; Coghill 2013; Findling 2006; Findling 2008; Findling 2010; Greenhill 2002; Greenhill 2006; Horn 1991; Jensen 1999 (MTA); Kollins 2006 (PATS); Kollins 2021; Lin 2014; Matthijssen 2019; McCracken 2016; NCT00409708; NCT02293655; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Perez‐Alvarez 2009; Pliszka 2017; Riggs 2011; Tourette's Syndrome Study Group 2002; Tucker 2009; Weiss 2021; Wigal 2004; Wigal 2015; Wilens 2006b; Wolraich 2001
Risk of bias
Trials with low risk of bias	21	13 trials: Cook 1993; DuPaul 1996; Flapper 2008; Kollins 2006 (PATS); McGough 2006; Moshe 2012; Rapport 2008; Soleimani 2017; Stein 1996; Stein 2011; Waxmonsky 2008; Wilkison 1995; Zeni 2009	9 trials: Childress 2020a; Jacobi‐Polishook 2009; Kollins 2006 (PATS); Lehmkuhl 2002; Pliszka 2017; Riggs 2011; Schrantee 2016; Tourette's Syndrome Study Group 2002; Weiss 2021
Setting
Outpatient	186	134 trials: Abikoff 2009; Ahmann 1993; Barkley 1989b; Barkley 1991; Barkley 2000; Bedard 2008; Bhat 2020; Blum 2011; Borcherding 1990; Brams 2008; Brams 2012; Brown 1984a; Brown 1988; Buitelaar 1995; Bukstein 1998; Castellanos 1997; Chacko 2005; Chronis 2003; Coghill 2007; Cook 1993; Corkum 2008; Corkum 2020; Cox 2006; Döpfner 2004; Douglas 1986; Douglas 1995; DuPaul 1996; Epstein 2011; Fabiano 2007; Findling 2007; Fine 1993; Fitzpatrick 1992a; Flapper 2008; Forness 1992; Froehlich 2011; Froehlich 2018; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Gorman 2006; Gruber 2007; Hale 2011; Hawk 2018; Hoeppner 1997; Huang 2021; Johnston 1988; Kelly 1989; Kent 1999; Klorman 1990; Kollins 2006 (PATS); Kortekaas‐Rijlaarsdam 2017; Kritchman 2019; Leddy 2009; Lijffijt 2006; Lopez 2003; Lufi 1997; Lufi 2007; Manos 1999; McBride 1988a; McGough 2006; McInnes 2007; Merrill 2021; Moshe 2012; Muniz 2008; Murray 2011; Musten 1997; NCT02039908; NCT02536105; Nikles 2006; Oesterheld 1998; Overtoom 2003; Pearson 2013; Pelham 1989; Pelham 1990a; Pelham 1999; Pelham 2001a; Pelham 2005; Pelham 2011; Pelham 2014; Pliszka 1990; Quinn 2004; Ramtvedt 2013; Rapport 1985; Rapport 1987; Rapport 2008; Reitman 2001; Rubinsten 2008; Samuels 2006; Schachar 2008; Schulz 2010; Schwartz 2004; Sharp 1999; Shiels 2009; Silva 2006; Silva 2008; Smith 1998; Smith 2004; Smithee 1998; Soleimani 2017; Stein 1996; Stein 2003; Stein 2011; Sumner 2010; Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Symons 2007; Szobot 2008; Tannock 1989; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1987; Taylor 1993; Tervo 2002; Tirosh 1993a; Tirosh 1993b; Ullmann 1986; Waxmonsky 2008; Whalen 1990; Wigal 2003; Wigal 2011; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 2010; Wilkison 1995; Wodrich 1998; Zeiner 1999; Zeni 2009	52 trials: Arnold 2004; Barragán 2017; Biederman 2003b; Butter 1983; Carlson 2007; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Connor 2000; Duric 2012; Findling 2006; Findling 2008; Findling 2010; Firestone 1981; Greenhill 2002; Greenhill 2006; Heriot 2008; Horn 1991; Ialongo 1994; Jacobi‐Polishook 2009; Jensen 1999 (MTA); Kollins 2006 (PATS); Kollins 2021; Lehmkuhl 2002; Lin 2014; Martins 2004; Matthijssen 2019; NCT00409708; NCT02293655; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Perez‐Alvarez 2009; Pliszka 2000; Pliszka 2017; Riggs 2011; Schrantee 2016; Szobot 2004; Tannock 2018; Tourette's Syndrome Study Group 2002; Tucker 2009; Van der Meere 1999a; Weiss 2021; Wigal 2004; Wigal 2015; Wigal 2017; Wilens 2006b; Wolraich 2001
Inpatient	9	9 trials: Brown 1991; Carlson 1995; Gonzalez‐Heydrich 2010; Kent 1995; Konrad 2005; Pelham 1993a; Pelham 2002; Solanto 2009; Wallace 1994	0 trials
Both outpatient and inpatient	8	7 trials: Garfinkel 1983; Hicks 1985; Kaplan 1990; Kolko 1999; Konrad 2004; Tannock 1992; Wallander 1987	1 trial: Green 2011
Laboratory classroom	21	17 trials: Brams 2008; Brams 2012; Lopez 2003; Murray 2011; Oesterheld 1998; Schachar 2008; Sharp 1999; Silva 2005a; Silva 2006; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Wigal 2003; Wigal 2011; Wigal 2014; Wilens 2008	4 trials: Childress 2017; Childress 2020a; Childress 2020b; Kollins 2021
Naturalistic school setting	3	1 trial: Ullmann 1986	2 trials: Biederman 2003b; Greenhill 2006
Summer school/summer treatment camp/summer treatment programme/summer research programme	21	21 trials: Bukstein 1998; Chacko 2005; Chronis 2003; Fabiano 2007; Johnston 1988; Kolko 1999; Leddy 2009; Merrill 2021; NCT02039908; Pelham 1989; Pelham 1990a; Pelham 1993a; Pelham 2001a; Pelham 2002; Pelham 2005; Pelham 2014; Reitman 2001; Shiels 2009; Smith 1998; Waxmonsky 2008; Whalen 1990	0 trials
Not stated	8	6 trials: Bliznakova 2007; CRIT124US02; Pliszka 2007; Stoner 1994; Ullmann 1985; Urman 1995	2 trials: Brown 1985; McCracken 2016
Research unit at hospital	0	0 trials	1 trial: Schachar 1997a
Psychiatric comorbidities (if specific data on participant comorbidities were available, we used this information for the table. If not, but some psychiatric comorbidities were part of the inclusion/exclusion criteria, we used them for the table). Learning disorders are not included in this table.
Only ODD and/or CD and/or ODD and/or socially aggressive and/or disturbance in social behavior	52	39 trials: Brown 1988; Brown 1991; Bukstein 1998; Chacko 2005; Chronis 2003; Corkum 2008; Corkum 2020; Döpfner 2004; Douglas 1995; DuPaul 1996; Findling 2007b; Forness 1992; Hawk 2018; Johnston 1988; Kelly 1989; Kent 1995; Leddy 2009; McGough 2006; Merrill 2021; Musten 1997; Pelham 1989; Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Pelham 2002; Pelham 2011; Pliszka 2007; Schulz 2010; Shiels 2009; Smith 1998; Solanto 2009; Stein 1996; Sunohara 1999; Tannock 1989; Tannock 1995a; Taylor 1987; Waxmonsky 2008; Zeiner 1999	13 trials: Carlson 2007; Findling 2008; Heriot 2008; Horn 1991; Ialongo 1994; Lin 2014; Martins 2004; McCracken 2016; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Tannock 2018
Only ODD and/or CD and/or OCD and/or anxiety disorder and/or specific developmental disorders and/or mood disorders and/or adjustment disorder and/or depression/dysthymia and/or sleep disorders and/or communication disorders and/or Asperger syndrome and/or trichotillomania and/or tic disorder	57	46 trials: Abikoff 2009; Bedard 2008; Bhat 2020; Blum 2011 Buitelaar 1995; Carlson 1995; Castellanos 1997; Coghill 2007; Epstein 2011; Fitzpatrick 1992a; NCT02039908; Froehlich 2011; Froehlich 2018; Gadow 1995; Gadow 2007; Gorman 2006; Gruber 2007; Gadow 2011; Hale 2011; Klorman 1990c; Kolko 1999; Konrad 2004; Kortekaas‐Rijlaarsdam 2017; Lijffijt 2006; McInnes 2007; Murray 2011; NCT02536105; Overtoom 2003; Pearson 2013; Pliszka 1990; Ramtvedt 2013; Schwartz 2004; Sharp 1999; Smithee 1998; Stein 2003; Stein 2011; Swanson 2004b; Szobot 2008; Tannock 1992; Tannock 1993; Tannock 1995b; Urman 1995d; Wigal 2013; Wigal 2014; Wilens 2010; Zeni 2009e	11 trials: Duric 2012; Green 2011; Jensen 1999 (MTA); Lehmkuhl 2002; Pliszka 2000; Riggs 2011; Schachar 1997a; Szobot 2004; Tourette's Syndrome Study Group 2002; Van der Meere 1999a; Wolraich 2001
All had ODD and/or CD/and or disruptive behavior disorder	4	3 trials: Carlson 1995; Gadow 1990; Kaplan 1990f	1 trial: Connor 2000
All had Tourette's syndrome or chronic motor tics	5	4 trials: Castellanos 1997; Gadow 1995; Gadow 2007; Gadow 2011	1 trial: Tourette's Syndrome Study Group 2002
All had bipolar disorder or borderline personality	2	2 trials: Findling 2007; Zeni 2009	0 trials
All had a non‐nicotine substance use disorder	2	1 trial: Szobot 2008	1 trial: Riggs 2011
Some psychiatric comorbidities excluded	20	11 trials: Barkley 1989b; Barkley 1991; Cook 1993; Douglas 1986; Gadow 1990; Gonzalez‐Heydrich 2010; Konrad 2005; Oesterheld 1998; Silva 2006; Silva 2008; Wodrich 1998	9 trials: Barragán 2017; Brown 1985; Childress 2020c; Firestone 1981;Jacobi‐Polishook 2009; Matthijssen 2019; NCT02293655; Wigal 2015; Wilens 2006b
Some psychiatric comorbidities and substance use excluded	23	11 trials: Borcherding 1990; Brams 2008; Brams 2012; Kaplan 1990; Kritchman 2019; Lopez 2003; Murray 2011; Silva 2005a; Sumner 2010; Wigal 2003; Wigal 2011	12 trials: Arnold 2004; Biederman 2003b; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Findling 2006; Kollins 2021; Pliszka 2017; Schrantee 2016; Weiss 2021; Wigal 2004
Substance use excluded	2	0 trials	2 trials: Coghill 2013; Findling 2010
Psychiatric comorbidities allowed	6	5 trials: Cox 2006; Gadow 2011; Kent 1999; Kollins 2006 (PATS); Symons 2007	2 trials: Coghill 2013; Kollins 2006 (PATS)
No psychiatric comorbidities	21	15 trials: Flapper 2008; Garfinkel 1983; Huang 2021; Lufi 1997; Moshe 2012; Muniz 2008; Quinn 2004; Schachar 2008; Soleimani 2017; Swanson 1998; Swanson 2002a; Tirosh 1993a; Tirosh 1993b; Wilens 2008; Wilkison 1995	6 trials: Findling 2010; Greenhill 2002; Greenhill 2006; Perez‐Alvarez 2009; Tucker 2009; Wigal 2017
Not stated or unclear	35	33 trials: Ahmann 1993; Barkley 2000; Bliznakova 2007; Brown 1984a; CRIT124US02; Fabiano 2007; Fine 1993; Hicks 1985; Hoeppner 1997; Lufi 2007; Manos 1999; McBride 1988a; Merrill 2021; Nikles 2006; Pelham 2005; Pelham 2014; Rapport 1985; Rapport 1987; Rapport 2008; Reitman 2001; Rubinsten 2008; Samuels 2006; Smith 2004; Stoner 1994; Swanson 1999; Swanson 2002b; Taylor 1993; Tervo 2002; Ullmann 1985; Ullmann 1986; Wallace 1994; Wallander 1987; Whalen 1990	2 trials: Butter 1983; NCT00409708
Comedication (sometrialsin more than one category)
None allowed	35	27 trials: Brown 1988; Bukstein 1998; Gadow 1995; Garfinkel 1983; Gorman 2006; Gruber 2007; Klorman 1990; Kollins 2006 (PATS); Konrad 2004; Konrad 2005; Leddy 2009; Lufi 1997; Lufi 2007; Moshe 2012; Muniz 2008; NCT02536105; Pliszka 1990; Ramtvedt 2013; Rubinsten 2008; Schulz 2010; Schwartz 2004; Solanto 2009; Swanson 1998; Tirosh 1993a; Tirosh 1993b; Wigal 2003; Wilkison 1995	9 trials: Carlson 2007; Childress 2017; Heriot 2008; Ialongo 1994; Jacobi‐Polishook 2009; Kollins 2006 (PATS); Perez‐Alvarez 2009; Tucker 2009; Wigal 2017
No medication for chronic conditions or no long‐term use of any medicine	2	1 trial: Pliszka 2007	1 trial: Barragán 2017
Allergy medication allowed	2	1 trial: Brown 1991	1 trial: Childress 2009
Non‐sedating antihistamines; acetaminophen (paracetamol); ibuprofen; antibiotics for treatment of a minor illness; and vitamins allowed	1	0 trials	1 trial: Childress 2020c
Haloperidol allowed	1	1 trial: Castellanos 1997	0 trials
Comedication allowed with few or no exceptions	3	2 trials: McBride 1988a; Pelham 1989	1 trial: Matthijssen 2019
CNS medications excluded	9	6 trials: Abikoff 2009; Barkley 1991; Corkum 2008; McGough 2006; Pelham 2001a; Stein 2011	3 trials: Arnold 2004; Findling 2008; McCracken 2016
CNS medications excluded except for bronchodilators	3	1 trial: Wigal 2011	2 trials: Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose)
No concurrent treatment with other psychoactive drugs; or currently receiving psychotropic medication; or no other psychotropic medication during the trial/psychotropic medication had to be discontinued for > 6/3 weeks prior to screening; or no psychiatric medication for the past 6 months; or no prior psychotropic medication use; or no use of other medication for ADHD; or no current medication; or no current or previous use of medication that influences the dopamine system	43	26 trials: Blum 2011; Brams 2008; Brams 2012; Corkum 2008; DuPaul 1996; NCT02039908; Forness 1992; Froehlich 2018; Hawk 2018; Huang 2021; Oesterheld 1998; Pelham 2001a; Pelham 2011; Quinn 2004; Rapport 1985; Rapport 1987; Schachar 2008; Shiels 2009; Silva 2006; Smithee 1998; Stein 2003; Stein 2011; Taylor 1987; Waxmonsky 2008; Wigal 2013; Zeiner 1999	17 trials: Arnold 2004; Biederman 2003b; Brown 1985; Findling 2008; Green 2011; Greenhill 2006; Lehmkuhl 2002; Martins 2004; Newcorn 2008; Palumbo 2008; Riggs 2011; Schrantee 2016; Szobot 2004; Tourette's Syndrome Study Group 2002; Van der Meere 1999a; Wigal 2015; Wolraich 2001
Exclusion of some specified medications including some psychostimulants and or other medication	15	7 trials: Findling 2007; McGough 2006; Pearson 2013; Silva 2006; Silva 2008; Sumner 2010; Wigal 2014	8 trials: Findling 2010; Greenhill 2002; NCT02293655; Pliszka 2017; Weiss 2021; Wigal 2004; Wigal 2015; Wilens 2006b
Washout for some psychotropic medications specified	1	1 trial: Gadow 2007	0 trials
Comedication for comorbidities allowed	2	1 trial: Buitelaar 1995	1 trial: Van der Meere 1999a
Stable psychotropic medication was continued throughout the trial	1	1 trial: Gonzalez‐Heydrich 2010	0 trials
Comedication as part of the trial design	10	6 trials: Carlson 1995; Findling 2007; Gonzalez‐Heydrich 2010; Kaplan 1990; Szobot 2008g; Zeni 2009	4 trials: Carlson 2007; Connor 2000; McCracken 2016; Riggs 2011g
Not stated	98	82 trials: Ahmann 1993; Barkley 1989b; Barkley 2000; Bhat 2020; Bliznakova 2007; Borcherding 1990; Brown 1984a; Chacko 2005; Chronis 2003; Coghill 2007; Cook 1993; Corkum 2020; Cox 2006; CRIT124US02; Döpfner 2004; Douglas 1986; Douglas 1995; Epstein 2011; Fabiano 2007; Fine 1993; Fitzpatrick 1992a; Flapper 2008; Froehlich 2011; Gadow 1990; Gadow 2011; Hale 2011; Hicks 1985; Hoeppner 1997; Johnston 1988; Kelly 1989; Kent 1995; Kent 1999; Kolko 1999; Kortekaas‐Rijlaarsdam 2017; Kritchman 2019; Lijffijt 2006; Lopez 2003; Manos 1999; McInnes 2007; Merrill 2021; Murray 2011; Musten 1997; Nikles 2006; Overtoom 2003; Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2002; Pelham 2005; Pelham 2014; Rapport 2008; Reitman 2001; Samuels 2006; Sharp 1999; Silva 2005a; Smith 1998; Smith 2004; Soleimani 2017; Stein 1996; Stoner 1994; Sunohara 1999; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Symons 2007; Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1993; Tervo 2002; Ullmann 1985; Ullmann 1986; Urman 1995; Wallace 1994; Wallander 1987; Whalen 1990; Wilens 2008; Wilens 2010; Wodrich 1998	16 trials: Butter 1983; Childress 2020a; Childress 2020b; Coghill 2013; Connor 2000; Duric 2012h; Findling 2006; Firestone 1981; Horn 1991; Jensen 1999 (MTA); Kollins 2021; Lin 2014; NCT00409708; Pliszka 2000; Schachar 1997a; Tannock 2018
Cotherapy
Cognitive training/behavioral therapy/parent training as part of the intervention	15	5 trials: Döpfner 2004; Fabiano 2007; Kolko 1999; Pelham 2014; Waxmonsky 2008	10 trials: Brown 1985; Firestone 1981; Heriot 2008; Horn 1991i; Jensen 1999 (MTA); NCT00409708; Palumbo 2008; Perez‐Alvarez 2009; Riggs 2011; Tucker 2009
Ongoing behavioral therapy permitted; but new therapy was not allowed to be initiated	1	0 trials	1 trial: Biederman 2003b
Only psychotherapy initiated > 3 months before screening allowed	3	1 trial: Brams 2012	2 trials: Childress 2009; Greenhill 2006
Not allowed to start psychosocial therapy	1	0 trials	1 trial: Matthijssen 2019
No psychotherapy initiated within 3 months before screening	3	3 trials: Muniz 2008; Silva 2006; Silva 2008	0 trials
Behaviour management treatment/uncontrolled parent training prior to medication phase as part of the trial design	2	1 trial: Kollins 2006 (PATS)	2 trials: Childress 2020c; Kollins 2006 (PATS)
No current behavioral intervention allowed	3	2 trials: Froehlich 2018; Lufi 1997	1 trial: NCT02293655;
Not stated	184	145 trials: Abikoff 2009; Ahmann 1993; Barkley 1989b; Barkley 1991; Barkley 2000; Bedard 2008; Bhat 2020; Bliznakova 2007; Blum 2011; Borcherding 1990; Brams 2008; Brown 1984a; Brown 1988; Brown 1991; Buitelaar 1995; Bukstein 1998; Carlson 1995; Castellanos 1997; Chacko 2005; Chronis 2003; Coghill 2007; Cook 1993; Corkum 2008; Corkum 2020; Cox 2006; CRIT124US02; Douglas 1986; Douglas 1995; DuPaul 1996; Epstein 2011; Findling 2007; Fine 1993; Fitzpatrick 1992a; Flapper 2008; Forness 1992; Froehlich 2011; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Garfinkel 1983; Gonzalez‐Heydrich 2010; Gorman 2006; Gruber 2007; Hale 2011; Hawk 2018; Hicks 1985; Hoeppner 1997; Huang 2021; Johnston 1988; Kaplan 1990; Kelly 1989; Kent 1995; Kent 1999; Klorman 1990; Konrad 2004; Konrad 2005; Kortekaas‐Rijlaarsdam 2017; Kritchman 2019; Leddy 2009; Lijffijt 2006; Lopez 2003; Lufi 2007; Manos 1999; McBride 1988a; McGough 2006; McInnes 2007; Merrill 2021; Moshe 2012; Murray 2011; Musten 1997; NCT02039908; NCT02536105; Nikles 2006; Oesterheld 1998; Overtoom 2003; Pearson 2013; Pelham 1989; Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Pelham 2002; Pelham 2005; Pelham 2011; Pliszka 1990; Pliszka 2007; Quinn 2004; Ramtvedt 2013; Rapport 1985; Rapport 1987; Rapport 2008; Reitman 2001; Rubinsten 2008; Samuels 2006; Schachar 2008; Schulz 2010; Schwartz 2004; Sharp 1999; Shiels 2009; Silva 2005a; Smith 1998; Smith 2004; Smithee 1998; Solanto 2009; Soleimani 2017; Stein 1996; Stein 2003; Stein 2011; Stoner 1994; Sumner 2010; Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Symons 2007; Szobot 2008; Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1987; Taylor 1993; Tervo 2002; Tirosh 1993a; Tirosh 1993b; Ullmann 1985; Ullmann 1986; Urman 1995; Wallace 1994; Wallander 1987; Whalen 1990; Wigal 2003; Wigal 2011; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 2010; Wilkison 1995; Wodrich 1998; Zeiner 1999; Zeni 2009	39 trials: Arnold 2004; Barragán 2017; Butter 1983; Carlson 2007; Childress 2017; Childress 2020a; Childress 2020b; Coghill 2013; Connor 2000; Duric 2012h; Findling 2006; Findling 2008; Findling 2010; Green 2011; Greenhill 2002; Ialongo 1994; Jacobi‐Polishook 2009; Kollins 2021; Lehmkuhl 2002; Lin 2014; Martins 2004; McCracken 2016; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Pliszka 2000; Pliszka 2017; Schachar 1997a; Schrantee 2016; Szobot 2004; Tannock 2018; Tourette's Syndrome Study Group 2002; Van der Meere 1999a; Weiss 2021; Wigal 2004; Wigal 2015; Wigal 2017; Wilens 2006b; Wolraich 2001
Participant mean age
2‐6 years	6	4 trials: Chacko 2005; Kollins 2006 (PATS); Musten 1997; Reitman 2001	3 trials: Childress 2020c; Heriot 2008; Kollins 2006 (PATS)
7‐11 years	172	128 trials: Abikoff 2009; Barkley 1989b; Barkley 1991; Bedard 2008; Bhat 2020; Blum 2011; Borcherding 1990; Brams 2008; Brams 2012; Brown 1984a; Buitelaar 1995; Bukstein 1998; Castellanos 1997; Chronis 2003; Cook 1993; Corkum 2020; Döpfner 2004; Douglas 1986; Douglas 1995; DuPaul 1996; Epstein 2011; Fabiano 2007; Findling 2007; Fine 1993; Fitzpatrick 1992a; Flapper 2008; Forness 1992; Froehlich 2011; Froehlich 2018; Gadow 1995; Gadow 2007; Gadow 2011; Garfinkel 1983; Gonzalez‐Heydrich 2010; Gorman 2006; Gruber 2007; Hale 2011; Hawk 2018; Hicks 1985; Hoeppner 1997; Huang 2021; Johnston 1988; Kelly 1989; Kent 1995; Kolko 1999; Konrad 2004; Konrad 2005; Kortekaas‐Rijlaarsdam 2017; Kritchman 2019; Lijffijt 2006; Lopez 2003; Lufi 1997; Lufi 2007; Manos 1999; McBride 1988a; McGough 2006; McInnes 2007; Merrill 2021; Moshe 2012; Muniz 2008; Murray 2011; NCT02536105; Nikles 2006; Oesterheld 1998; Overtoom 2003; Pearson 2013; Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Pelham 2002; Pelham 2005; Pelham 2011; Pelham 2014; Pliszka 1990; Ramtvedt 2013; Rapport 1985; Rapport 2008; Rubinsten 2008; Schachar 2008; Schulz 2010; Schwartz 2004; Sharp 1999; Shiels 2009; Silva 2005a; Silva 2006; Silva 2008; Smith 2004; Smithee 1998; Soleimani 2017; Stein 1996; Stein 2003; Stein 2011; Stoner 1994; Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Symons 2007; Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1987; Taylor 1993; Tervo 2002; Tirosh 1993a; Tirosh 1993b; Ullmann 1985; Ullmann 1986; Urman 1995; Wallace 1994; Wallander 1987; Waxmonsky 2008; Whalen 1990; Wigal 2003; Wigal 2011; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 2010; Wilkison 1995; Wodrich 1998; Zeiner 1999; Zeni 2009	44 trials: Barragán 2017; Biederman 2003b; Brown 1985; Carlson 2007; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Coghill 2013; Connor 2000; Duric 2012; Findling 2006; Findling 2008; Firestone 1981; Green 2011; Greenhill 2002; Greenhill 2006; Horn 1991; Ialongo 1994; Jacobi‐Polishook 2009; Jensen 1999 (MTA); Kollins 2021; Lehmkuhl 2002; Lin 2014; Martins 2004; McCracken 2016; NCT00409708; NCT02293655; Newcorn 2008; Palumbo 2008; Perez‐Alvarez 2009; Pliszka 2000; Pliszka 2017; Schachar 1997a; Schrantee 2016; Szobot 2004; Tannock 2018; Tourette's Syndrome Study Group 2002; Tucker 2009; Van der Meere 1999a; Wigal 2004; Wigal 2015; Wigal 2017; Wolraich 2001
12‐18 years	17	10 trials: Barkley 2000; Bliznakova 2007; Brown 1988; Brown 1991; Cox 2006; CRIT124US02; Kaplan 1990; Pliszka 2007; Smith 1998; Szobot 2008	7 trials: Findling 2010; Matthijssen 2019; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Riggs 2011; Weiss 2021; Wilens 2006b
Not stated	17	15 trials: Ahmann 1993; Carlson 1995; Coghill 2007; Corkum 2008; Gadow 1990; Kent 1999; Klorman 1990; Leddy 2009; NCT02039908; Pelham 1989; Quinn 2004; Rapport 1987; Samuels 2006; Solanto 2009; Sumner 2010	2 trials: Arnold 2004; Butter 1983
Sex
Only male participants	35	30 trials: Bliznakova 2007; Borcherding 1990; Brown 1984a; Brown 1988; Brown 1991; Carlson 1995; Castellanos 1997; Coghill 2007; Cook 1993; Forness 1992; Gadow 1990; Garfinkel 1983; Johnston 1988; Kaplan 1990; Kolko 1999; Merrill 2021; Moshe 2012; Overtoom 2003; Pelham 1990a; Pelham 1993a; Pelham 2002; Pelham 2011; Quinn 2004; Smith 2004; Stein 1996; Stoner 1994; Szobot 2008; Taylor 1987; Wilkison 1995; Zeiner 1999	5 trials: Butter 1983; Connor 2000; Martins 2004; Schrantee 2016; Szobot 2004
Only female participants	2	2 trials: CRIT124US02; Sharp 1999	0 trials
Both male and female participants	167	119 trials: Abikoff 2009; Ahmann 1993; Barkley 1989b; Barkley 1991; Barkley 2000; Bedard 2008; Bhat 2020; Blum 2011; Brams 2008; Brams 2012; Buitelaar 1995; Bukstein 1998; Chacko 2005; Chronis 2003; Corkum 2008; Corkum 2020; Cox 2006; Döpfner 2004; Douglas 1986; Douglas 1995; DuPaul 1996; Fabiano 2007; Findling 2007; Fitzpatrick 1992a; Flapper 2008; Froehlich 2011; Froehlich 2018; Gadow 1995; Gadow 2007; Gadow 2011; Gonzalez‐Heydrich 2010; Gorman 2006; Gruber 2007; Hale 2011; Hawk 2018; Hicks 1985; Hoeppner 1997; Huang 2021; Kelly 1989; Kent 1995; Kent 1999; Klorman 1990; Kollins 2006 (PATS); Konrad 2004; Konrad 2005; Kortekaas‐Rijlaarsdam 2017; Kritchman 2019; Leddy 2009; Lijffijt 2006; Lopez 2003; Lufi 1997; Lufi 2007; Manos 1999; McBride 1988a; McGough 2006; McInnes 2007; Muniz 2008; Murray 2011; Musten 1997; NCT02039908; NCT02536105; Nikles 2006; Oesterheld 1998; Pearson 2013; Pelham 1989; Pelham 1999; Pelham 2001a; Pelham 2005; Pelham 2014; Pliszka 1990; Pliszka 2007; Ramtvedt 2013; Rapport 1985; Rapport 1987; Rapport 2008; Reitman 2001; Rubinsten 2008; Schachar 2008; Schulz 2010; Schwartz 2004; Shiels 2009; Silva 2005a; Silva 2006; Silva 2008; Smith 1998; Smithee 1998; Soleimani 2017; Stein 2003; Stein 2011; Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Symons 2007; Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1993; Tervo 2002; Tirosh 1993a; Tirosh 1993b; Ullmann 1985; Ullmann 1986; Urman 1995; Wallander 1987; Waxmonsky 2008; Whalen 1990; Wigal 2003; Wigal 2011; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 2010; Wodrich 1998; Zeni 2009	49 trial: Arnold 2004; Barragán 2017; Biederman 2003b; Carlson 2007; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Duric 2012; Findling 2006; Findling 2008; Findling 2010; Firestone 1981; Green 2011; Greenhill 2002; Greenhill 2006; Heriot 2008; Horn 1991; Ialongo 1994; Jacobi‐Polishook 2009; Jensen 1999 (MTA); Kollins 2006 (PATS); Kollins 2021; Lehmkuhl 2002; Lin 2014; Matthijssen 2019; McCracken 2016; NCT00409708; NCT02293655; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Perez‐Alvarez 2009; Pliszka 2017; Riggs 2011; Schachar 1997a; Tannock 2018; Tourette's Syndrome Study Group 2002; Tucker 2009; Van der Meere 1999a; Weiss 2021; Wigal 2004; Wigal 2015; Wigal 2017; Wilens 2006b; Wolraich 2001
Not stated	8	6 trials: Epstein 2011; Fine 1993; Samuels 2006; Solanto 2009; Sumner 2010; Wallace 1994	2 trials: Brown 1985; Pliszka 2000
Diagnostic classification
DSM‐III	30	27 trials: Borcherding 1990; Brown 1984a; Brown 1988; Cook 1993; Douglas 1986; Douglas 1995; Fitzpatrick 1992a; Gadow 1990; Garfinkel 1983; Hicks 1985; Kaplan 1990; Kelly 1989; Klorman 1990; McBride 1988a; Pelham 1989; Pliszka 1990; Rapport 1985; Rapport 1987; Tannock 1989; Tannock 1992; Tannock 1993; Taylor 1987; Tirosh 1993a; Tirosh 1993b; Ullmann 1985; Ullmann 1986; Wallander 1987	3 trials: Brown 1985; Butter 1983; Firestone 1981
DSM‐III‐R	42	37 trials: Ahmann 1993; Barkley 1989b; Barkley 1991; Brown 1991; Buitelaar 1995; Bukstein 1998; Castellanos 1997; Chacko 2005; Douglas 1995; DuPaul 1996; Fine 1993; Forness 1992; Gadow 1995; Gadow 2007; Gadow 2011; Hoeppner 1997; Johnston 1988; Kent 1995; Kolko 1999; Musten 1997; Overtoom 2003; Pelham 1990a; Pelham 1993a; Pelham 2002; Smith 1998; Stein 1996; Stoner 1994; Sunohara 1999; Tannock 1995a; Tannock 1995b; Taylor 1993; Urman 1995; Wallace 1994; Whalen 1990; Wilkison 1995; Wodrich 1998; Zeiner 1999	5 trials: Connor 2000; Horn 1991; Ialongo 1994; Schachar 1997a; Van der Meere 1999a
DSM‐IV	105	77 trials: Abikoff 2009; Barkley 2000; Bedard 2008; Bhat 2020; Brams 2008; Brams 2012; Carlson 1995; Chronis 2003; Coghill 2007; Corkum 2008; Cox 2006; Döpfner 2004; Epstein 2011; Fabiano 2007; Findling 2007; Flapper 2008; Froehlich 2011; Froehlich 2018; Gadow 2011; Gorman 2006; Gruber 2007; Hawk 2018; Kent 1999; Kollins 2006 (PATS); Konrad 2004; Konrad 2005; Kortekaas‐Rijlaarsdam 2017; Leddy 2009; Lijffijt 2006; Lopez 2003; Lufi 1997; Lufi 2007; Manos 1999; Moshe 2012; Muniz 2008; Nikles 2006; Oesterheld 1998; Pearson 2013; Pelham 1999; Pelham 2001a; Pelham 2005; Pelham 2011; Pelham 2014; Pliszka 2007; Quinn 2004; Rapport 2008; Rubinsten 2008; Samuels 2006; Schachar 2008; Schulz 2010; Schwartz 2004; Sharp 1999; Shiels 2009; Silva 2005a; Silva 2006; Silva 2008; Smith 2004; Smithee 1998; Solanto 2009; Stein 2003; Stein 2011; Sumner 2010; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Symons 2007; Szobot 2008; Tervo 2002; Waxmonsky 2008; Wigal 2003; Wigal 2013; Wilens 2008; Wilens 2010; Zeiner 1999; Zeni 2009	29 trials: Arnold 2004; Biederman 2003b; Carlson 2007; Childress 2009; Childress 2017; Findling 2006; Findling 2010; Greenhill 2002; Greenhill 2006; Heriot 2008; Jacobi‐Polishook 2009; Jensen 1999 (MTA); Kollins 2006 (PATS); Lehmkuhl 2002; Martins 2004; McCracken 2016; NCT00409708; Newcorn 2008; Palumbo 2008; Pliszka 2000; Riggs 2011; Schrantee 2016; Szobot 2004; Tannock 2018; Tourette's Syndrome Study Group 2002; Tucker 2009; Wigal 2004; Wilens 2006b; Wolraich 2001
DSM‐IV‐TR	21	12 trials: Blum 2011; Corkum 2020; NCT02039908; Gonzalez‐Heydrich 2010; Hale 2011; McGough 2006; McInnes 2007; Murray 2011; Ramtvedt 2013; Soleimani 2017; Wigal 2011; Wigal 2014	9 trials: Barragán 2017; Coghill 2013; Findling 2008; Green 2011; Lin 2014; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Perez‐Alvarez 2009; Wigal 2015
DSM‐5	10	3 trials: Gadow 2007; Huang 2021; NCT02536105	7 trials: Childress 2020a; Childress 2020b; Childress 2020c; Kollins 2021; NCT02293655; Pliszka 2017; Weiss 2021
ICD‐10	3	2 trials: Bliznakova 2007; Döpfner 2004	1 trial: Duric 2012
Not stated	6	4 trials: CRIT124US02; Kritchman 2019; Merrill 2021; Reitman 2001	2 trials: Matthijssen 2019; Wigal 2017
Attention deficit hyperactivity disorder subtype
Combined type only	14	12 trials: Blum 2011; Coghill 2007; Cook 1993; Douglas 1995; Konrad 2005; Overtoom 2003; Pliszka 2007; Rapport 2008; Schachar 2008; Soleimani 2017; Symons 2007; Tannock 1989	2 trials: Connor 2000; Jensen 1999 (MTA)
Hyperactive type only	2	2 trials: Bliznakova 2007; Forness 1992	0 trials
Multiple subtypes	101	64 trials: Abikoff 2009; Barkley 1991; Bedard 2008; Bhat 2020; Brams 2008; Brams 2012; Corkum 2008; Corkum 2020; Cox 2006; CRIT124US02; Döpfner 2004; Epstein 2011; Findling 2007; Fitzpatrick 1992a; Flapper 2008; Froehlich 2011; Froehlich 2018; Gonzalez‐Heydrich 2010; Gorman 2006; Gruber 2007; Hale 2011; Huang 2021; Kollins 2006 (PATS); Konrad 2004; Leddy 2009; Lijffijt 2006; Manos 1999; McBride 1988a; McGough 2006; McInnes 2007; Moshe 2012; Muniz 2008; Murray 2011; Oesterheld 1998; Pearson 2013; Pelham 1989; Pelham 2011; Quinn 2004; Ramtvedt 2013; Rubinsten 2008; Schulz 2010; Shiels 2009; Silva 2005a; Silva 2006; Silva 2008; Smithee 1998; Solanto 2009; Stein 1996; Stein 2003; Stein 2011; Swanson 2002a; Swanson 2002b; Swanson 2004b; Szobot 2008; Tervo 2002; Tirosh 1993a; Ullmann 1985; Waxmonsky 2008; Wigal 2011; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 2010; Zeni 2009	38 trials: Arnold 2004; Barragán 2017; Biederman 2003b; Carlson 2007; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Findling 2006; Findling 2008; Green 2011; Greenhill 2002; Greenhill 2006; Heriot 2008; Kollins 2006 (PATS); Kollins 2021; Lehmkuhl 2002; Lin 2014; Martins 2004; McCracken 2016; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Perez‐Alvarez 2009; Pliszka 2017; Riggs 2011; Schrantee 2016; Szobot 2004; Tourette's Syndrome Study Group 2002; Weiss 2021; Wigal 2004; Wigal 2015; Wigal 2017; Wolraich 2001
Not stated	95	79 trials: Ahmann 1993; Barkley 1989b; Barkley 2000; Borcherding 1990; Brown 1984a; Brown 1988; Brown 1991; Buitelaar 1995; Bukstein 1998; Carlson 1995; Castellanos 1997; Chacko 2005; Chronis 2003; Douglas 1986; DuPaul 1996; Fabiano 2007; Fine 1993; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Garfinkel 1983; Hawk 2018; Hicks 1985; Hoeppner 1997; Johnston 1988; Kaplan 1990; Kelly 1989; Kent 1995; Kent 1999; Klorman 1990; Kolko 1999; Kortekaas‐Rijlaarsdam 2017; Kritchman 2019; Lopez 2003; Lufi 1997; Lufi 2007; Merrill 2021; Musten 1997; NCT02039908; NCT02536105; Nikles 2006; Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Pelham 2002; Pelham 2005; Pelham 2014; Pliszka 1990; Rapport 1985; Rapport 1987; Reitman 2001; Samuels 2006; Schwartz 2004; Sharp 1999; Smith 1998; Smith 2004; Stoner 1994; Sumner 2010; Sunohara 1999; Swanson 1998; Swanson 1999; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1987; Taylor 1993; Tirosh 1993b; Ullmann 1986; Urman 1995; Wallace 1994; Wallander 1987; Whalen 1990; Wigal 2003; Wilkison 1995; Wodrich 1998; Zeiner 1999	16 trials: Brown 1985; Butter 1983; Duric 2012; Findling 2010; Firestone 1981; Horn 1991; Ialongo 1994; Jacobi‐Polishook 2009; Matthijssen 2019; NCT00409708; NCT02293655; Pliszka 2000; Tannock 2018; Schachar 1997a;Tucker 2009; Van der Meere 1999a; Wilens 2006b
Methylphenidate‐naive
100%	35	29 trials: Abikoff 2009; Buitelaar 1995; Coghill 2007; Cook 1993; Corkum 2008; Corkum 2020; Epstein 2011; Fine 1993; Flapper 2008; Forness 1992; Froehlich 2011; Froehlich 2018; Kelly 1989; Kollins 2006 (PATS); Konrad 2004; Lufi 1997; Moshe 2012; Oesterheld 1998; Ramtvedt 2013; Rapport 1987; Stoner 1994; Sunohara 1999; Szobot 2008; Taylor 1987; Tirosh 1993a; Tirosh 1993b; Urman 1995; Wallander 1987; Zeiner 1999	8 trials: Barragán 2017; Heriot 2008; Kollins 2006 (PATS); Perez‐Alvarez 2009; Schachar 1997a; Schrantee 2016; Tucker 2009; Van der Meere 1999a
50%‐99%	38	23 trials: Barkley 1989b; Bedard 2008; Douglas 1986; Douglas 1995; Fitzpatrick 1992a; Gadow 1990; Gadow 1995; Gadow 2011; Garfinkel 1983; Gorman 2006; Kaplan 1990; Kent 1995; Klorman 1990; McBride 1988a; McInnes 2007; Murray 2011; Musten 1997; Pearson 2013; Pliszka 2007; Smithee 1998; Stein 2003; Tannock 1992; Tannock 1995a	15 trials: Arnold 2004; Biederman 2003b; Childress 2009; Coghill 2013; Connor 2000; Findling 2008; Findling 2010; Green 2011; Ialongo 1994; Jensen 1999 (MTA); Kollins 2021; Lin 2014; Weiss 2021; Wigal 2004; Wigal 2015
1%‐49%	27	17 trials: Borcherding 1990; Carlson 1995; Chronis 2003; Hawk 2018; Leddy 2009; McGough 2006; Nikles 2006; Pelham 2005; Schachar 2008; Schwartz 2004; Smith 1998; Solanto 2009; Stein 1996; Stein 2011; Tannock 1989; Taylor 1993; Wilens 2010	10 trials: Carlson 2007; Greenhill 2002; Greenhill 2006; Lehmkuhl 2002; Newcorn 2008; Palumbo 2008; Pliszka 2000; Tourette's Syndrome Study Group 2002; Wilens 2006b; Wolraich 2001
0%	35	29 trials: Bliznakova 2007; Brams 2008; Brams 2012; Döpfner 2004; Kortekaas‐Rijlaarsdam 2017; Lijffijt 2006; Lopez 2003; Lufi 2007; Muniz 2008; Overtoom 2003; Pelham 2001a; Pelham 2011; Quinn 2004; Reitman 2001; Rubinsten 2008; Schulz 2010; Silva 2005a; Silva 2006; Silva 2008; Smith 2004; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Whalen 1990; Wigal 2013; Wigal 2014; Wilkison 1995	6 trials: Childress 2017; Childress 2020b; Findling 2006; Jacobi‐Polishook 2009; Matthijssen 2019; Pliszka 2017
Not stated or unclear	76	59 trials: Ahmann 1993; Barkley 1991; Barkley 2000; Bhat 2020j; Blum 2011; Brown 1984a; Brown 1988; Brown 1991; Bukstein 1998; Castellanos 1997; Chacko 2005; Cox 2006; CRIT124US02; DuPaul 1996; Fabiano 2007; Findling 2007; Gadow 2007; Gonzalez‐Heydrich 2010; Gruber 2007; Hale 2011; Hicks 1985; Hoeppner 1997; Huang 2021; Johnston 1988; Kent 1999; Kolko 1999; Konrad 2005; Kritchman 2019; Manos 1999; Merrill 2021; NCT02039908; NCT02536105; Pelham 1989; Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2002; Pelham 2014; Pliszka 1990; Rapport 1985; Rapport 2008; Samuels 2006; Sharp 1999; Shiels 2009; Soleimani 2017; Sumner 2010; Symons 2007; Tannock 1993; Tannock 1995b; Tervo 2002; Ullmann 1985; Ullmann 1986; Wallace 1994; Waxmonsky 2008; Wigal 2003; Wigal 2011; Wilens 2008; Wodrich 1998; Zeni 2009	17 trials: Brown 1985; Butter 1983; Childress 2020a; Childress 2020c; Duric 2012; Firestone 1981; Horn 1991; Martins 2004; McCracken 2016; NCT00409708; NCT02293655; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Riggs 2011; Szobot 2004; Tannock 2018; Wigal 2017
Methylphenidate release
Extended‐release and/or  modified‐release	61	32 trials: Abikoff 2009; Blum 2011; Brams 2008; Brams 2012; Corkum 2020; Cox 2006; CRIT124US02; Epstein 2011; Froehlich 2011; Froehlich 2018; Gonzalez‐Heydrich 2010; Hawk 2018; Huang 2021; Kortekaas‐Rijlaarsdam 2017; Lopez 2003; Muniz 2008; Murray 2011; NCT02039908; NCT02536105; Schulz 2010; Shiels 2009; Silva 2005a; Silva 2006; Silva 2008; Stein 2003; Stein 2011; Sumner 2010; Swanson 2004b; Szobot 2008; Wigal 2011; Wigal 2013; Wigal 2014	29 trials: Barragán 2017; Biederman 2003b; Carlson 2007; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Greenhill 2002; Greenhill 2006; Kollins 2021; Lehmkuhl 2002; Lin 2014; Matthijssen 2019; McCracken 2016; NCT00409708; NCT02293655; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Perez‐Alvarez 2009; Pliszka 2017k; Riggs 2011; Tucker 2009; Weiss 2021; Wigal 2015; Wigal 2017; Wilens 2006b
Immediate‐release	101	83 trials: Ahmann 1993; Barkley 1989b; Barkley 1991; Barkley 2000; Bhat 2020; Borcherding 1990; Brown 1984a; Brown 1988; Brown 1991; Buitelaar 1995; Bukstein 1998; Carlson 1995; Castellanos 1997; Chacko 2005; Chronis 2003; Coghill 2007; Corkum 2008; Douglas 1986; DuPaul 1996; Fabiano 2007; Findling 2007; Forness 1992; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Garfinkel 1983; Gorman 2006; Gruber 2007; Hale 2011; Hicks 1985; Hoeppner 1997; Kaplan 1990; Kelly 1989; Kent 1995; Kent 1999; Klorman 1990; Kolko 1999; Kollins 2006 (PATS); Konrad 2004; Konrad 2005; Kritchman 2019; Leddy 2009; Manos 1999; McBride 1988a; Merrill 2021; Moshe 2012; Musten 1997; Nikles 2006; Oesterheld 1998; Pelham 1989; Pelham 1993a; Pelham 1999; Pelham 2002; Pelham 2014; Pliszka 1990; Pliszka 2007; Ramtvedt 2013; Rapport 2008; Schwartz 2004; Sharp 1999; Smith 1998; Smith 2004; Smithee 1998; Solanto 2009; Soleimani 2017; Stein 1996; Sunohara 1999; Swanson 1999; Swanson 2002al; Tannock 1989; Tannock 1993; Tannock 1995a; Taylor 1993; Tervo 2002; Tirosh 1993a; Tirosh 1993b; Wallander 1987; Waxmonsky 2008; Whalen 1990; Wodrich 1998; Zeiner 1999; Zeni 2009	19 trials: Arnold 2004; Brown 1985; Connor 2000; Duric 2012; Firestone 1981; Green 2011; Heriot 2008; Jacobi‐Polishook 2009; Jensen 1999 (MTA); Kollins 2006 (PATS); Martins 2004; Palumbo 2008; Pliszka 2000; Schachar 1997a; Szobot 2004; Tannock 2018; Tourette's Syndrome Study Group 2002; Van der Meere 1999a; Wigal 2004
Transdermal patch	5	4 trials: McGough 2006; Pelham 2005; Wilens 2008; Wilens 2010	1 trial: Findling 2010
Both immediate‐release and transdermal patch administered during the trial	1	1 trial: Pelham 2011	0 trials
Both Immediate‐release and extended‐release and/or  modified‐release administered during the trial	11	9 trials: Döpfner 2004; Fitzpatrick 1992a; Johnston 1988; Pearson 2013; Pelham 1990a; Pelham 2001a; Schachar 2008; Swanson 2002b; Wigal 2003	2 trials: Findling 2006; Wolraich 2001
Both transdermal patch and extended‐release administered during the trial	1	0 trials	1 trial: Findling 2008
Not stated or unclear	32	28 trials: Bedard 2008; Bliznakova 2007; Cook 1993; Douglas 1995; Fine 1993; Flapper 2008; Lijffijt 2006; Lufi 1997; Lufi 2007; McInnes 2007; Overtoom 2003; Quinn 2004; Rapport 1985; Rapport 1987; Reitman 2001; Rubinsten 2008; Samuels 2006; Stoner 1994; Swanson 1998; Symons 2007; Tannock 1992; Tannock 1995b; Taylor 1987; Ullmann 1985; Ullmann 1986; Urman 1995; Wallace 1994; Wilkison 1995	4 trials: Butter 1983; Horn 1991; Ialongo 1994; Schrantee 2016
Dosage
Low dose (≤ 20 mg/d or ≤ 0.6 mg/kg/d)	51	43 trials: Barkley 2000; Bhat 2020; Brams 2008; Brown 1984a; Brown 1991; Buitelaar 1995; Cook 1993; Douglas 1986; Garfinkel 1983; Gruber 2007; Hale 2011; Kaplan 1990; Kelly 1989; Kent 1995; Konrad 2004; Kritchman 2019; Lufi 1997; Lufi 2007; McGough 2006; McInnes 2007; Moshe 2012; Oesterheld 1998; Overtoom 2003; Pelham 1989; Pelham 1990a; Pelham 2002; Quinn 2004; Rapport 1985; Rapport 1987; Rapport 2008; Reitman 2001; Rubinsten 2008; Schulz 2010; Silva 2006; Silva 2008; Smith 2004; Stoner 1994; Symons 2007; Tervo 2002; Whalen 1990; Wilens 2010; Wilkison 1995; Zeiner 1999	8 trials: Brown 1985; Butter 1983; Green 2011; Heriot 2008; Jacobi‐Polishook 2009; Kollins 2006 (PATS)m; McCracken 2016; Van der Meere 1999a
Moderate/high dose (> 20 mg/day or > 0.6 mg/kg/d)	57	29 trials: Abikoff 2009; Ahmann 1993; Barkley 1989b; Blum 2011; Borcherding 1990; Bukstein 1998; Castellanos 1997; Corkum 2020; Cox 2006; Döpfner 2004; Epstein 2011; Forness 1992; Gonzalez‐Heydrich 2010; Gorman 2006; Hawk 2018; Huang 2021; Klorman 1990; McBride 1988a; Murray 2011; Pelham 2011; Ramtvedt 2013; Schachar 2008; Schwartz 2004; Sharp 1999; Shiels 2009; Smithee 1998; Wigal 2011; Wigal 2013; Wigal 2014	28 trials: Barragán 2017; Carlson 2007; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Connor 2000; Firestone 1981; Greenhill 2002; Greenhill 2006; Jensen 1999 (MTA); Matthijssen 2019; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Pliszka 2000; Pliszka 2017; Riggs 2011; Schachar 1997a; Schrantee 2016; Szobot 2004; Tourette's Syndrome Study Group 2002; Weiss 2021; Wigal 2017; Wilens 2006b; Wolraich 2001
Both low and moderate/high dose were given in a cross‐over design or in different arms in a parallel trial	75	68 trials: Barkley 1991; Bedard 2008; Brams 2012; Brown 1988; Carlson 1995; Chacko 2005; Chronis 2003; Coghill 2007; Corkum 2008; Douglas 1995; DuPaul 1996; Fabiano 2007; Findling 2007; Fine 1993; Fitzpatrick 1992a; Flapper 2008; Froehlich 2011; Froehlich 2018; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Hicks 1985; Hoeppner 1997; Johnston 1988; Kent 1999; Kolko 1999; Kollins 2006 (PATS)n; Konrad 2005; Leddy 2009; Lijffijt 2006; Lopez 2003; Manos 1999; Merrill 2021; Muniz 2008; Musten 1997; Pearson 2013; Pelham 1993a; Pelham 1999; Pelham 2005; Pliszka 1990; Pliszka 2007; Silva 2005a; Smith 1998; Solanto 2009; Soleimani 2017; Stein 1996; Stein 2003; Stein 2011; Sumner 2010; Sunohara 1999; Swanson 2004b; Szobot 2008; Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1993; Tirosh 1993a; Ullmann 1985; Ullmann 1986; Urman 1995; Wallander 1987; Waxmonsky 2008; Wigal 2003; Wodrich 1998; Zeni 2009	7 trials: Childress 2009; Horn 1991; Ialongo 1994; Lin 2014; Martins 2004; Wigal 2004; Wigal 2015
Not stated or unclear	30	17 trials: Bliznakova 2007; CRIT124US02; Kortekaas‐Rijlaarsdam 2017; NCT02039908; NCT02536105; Nikles 2006; Pelham 2001a; Pelham 2014; Samuels 2006; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Taylor 1987; Tirosh 1993b; Wallace 1994; Wilens 2008	13 trials: Arnold 2004; Biederman 2003b; Duric 2012; Findling 2006; Findling 2008; Findling 2010; Kollins 2021; Lehmkuhl 2002; NCT00409708; NCT02293655; Perez‐Alvarez 2009; Tannock 2018; Tucker 2009
Duration of intervention
Single day/single dosage	9	7 trials: Kritchman 2019; Lopez 2003; Murray 2011; Overtoom 2003; Samuels 2006; Wigal 2011; Wilkison 1995	2 trials: Green 2011; Jacobi‐Polishook 2009
2‐14 days	104	92 trials: Ahmann 1993; Barkley 1989bo; Barkley 2000; Bedard 2008; Bhat 2020; Bliznakova 2007; Blum 2011; Brams 2008; Brams 2012; Brown 1984a; Brown 1991; Bukstein 1998; Chacko 2005; Chronis 2003; Corkum 2008; Corkum 2020; Döpfner 2004; Douglas 1986; Douglas 1995; Epstein 2011; Fine 1993; Gonzalez‐Heydrich 2010p; Gruber 2007; Hawk 2018; Hoeppner 1997; Huang 2021; Johnston 1988; Kent 1995; Kent 1999; Klorman 1990; Kolko 1999; Konrad 2004; Konrad 2005; Kortekaas‐Rijlaarsdam 2017; Lijffijt 2006; McBride 1988a; McGough 2006; McInnes 2007; Moshe 2012; NCT02039908; Nikles 2006; Oesterheld 1998; Pelham 1989; Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Pelham 2002; Pelham 2005; Pelham 2011; Pelham 2014; Pliszka 1990; Quinn 2004; Ramtvedt 2013; Reitman 2001; Rubinsten 2008; Schachar 2008; Schulz 2010; Schwartz 2004; Shiels 2009; Silva 2005a; Silva 2006; Silva 2008; Smith 2004; Smithee 1998; Stoner 1994; Sumner 2010; Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Symons 2007; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1993; Tervo 2002; Tirosh 1993a; Tirosh 1993b; Urman 1995; Wallace 1994; Whalen 1990; Wigal 2003; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 2010; Wodrich 1998; Zeni 2009	12 trials: Arnold 2004; Biederman 2003b; Butter 1983; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Kollins 2021; Szobot 2004; Wigal 2015; Wigal 2017; Wilens 2006b
15 days‐6 months	93	56 trials: Abikoff 2009; Barkley 1991; Borcherding 1990; Brown 1988; Buitelaar 1995; Carlson 1995; Castellanos 1997; Coghill 2007; Cook 1993; Cox 2006; CRIT124US02; DuPaul 1996; Fabiano 2007; Findling 2007; Fitzpatrick 1992a; Flapper 2008; Forness 1992; Froehlich 2011; Froehlich 2018; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Garfinkel 1983; Gorman 2006; Hale 2011; Hicks 1985q; Kaplan 1990; Kollins 2006 (PATS); Leddy 2009; Lufi 1997; Lufi 2007; Manos 1999; Merrill 2021; Muniz 2008; Musten 1997; NCT02536105; Pearson 2013; Pliszka 2007; Rapport 1985; Rapport 1987; Rapport 2008; Sharp 1999; Smith 1998; Solanto 2009; Soleimani 2017; Stein 1996; Stein 2003; Stein 2011; Szobot 2008; Taylor 1987; Ullmann 1985; Ullmann 1986; Wallander 1987; Waxmonsky 2008; Zeiner 1999	38 trials: Brown 1985; Carlson 2007; Childress 2009; Coghill 2013; Connor 2000; Duric 2012; Findling 2006; Findling 2008; Findling 2010; Firestone 1981; Greenhill 2002; Greenhill 2006; Heriot 2008; Horn 1991; Ialongo 1994; Kollins 2006 (PATS); Lehmkuhl 2002; Lin 2014; Martins 2004; Matthijssen 2019; McCracken 2016; NCT00409708; NCT02293655; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Pliszka 2000; Pliszka 2017; Riggs 2011; Schrantee 2016; Tourette's Syndrome Study Group 2002; Tannock 2018; Tucker 2009; Van der Meere 1999a; Weiss 2021; Wigal 2004; Wolraich 2001
More than 6 months	4	0 trials	4 trials: Barragán 2017; Jensen 1999 (MTA); Perez‐Alvarez 2009; Schachar 1997a
Not stated or unclear	2	2 trials: Kelly 1989; Tannock 1989	0 trials
Titration period
After randomisation	36	13 trials: Abikoff 2009; Borcherding 1990; Castellanos 1997; Cook 1993; Cox 2006; Gadow 1990; Gorman 2006; Ramtvedt 2013; Sharp 1999; Stein 1996; Taylor 1987; Ullmann 1985; Wilens 2010	23 trials: Barragán 2017; Carlson 2007; Childress 2009; Coghill 2013; Connor 2000; Findling 2008; Findling 2010; Firestone 1981; Greenhill 2006; Jensen 1999 (MTA); Lehmkuhl 2002; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Pliszka 2017; Schachar 1997a; Schrantee 2016; Szobot 2004; Tannock 2018; Tourette's Syndrome Study Group 2002; Weiss 2021; Tucker 2009; Wigal 2004
Before randomisation	32	20 trials: Blum 2011; Brown 1991; Döpfner 2004; Epstein 2011; Huang 2021; Kent 1995; Kollins 2006 (PATS); Konrad 2004; Konrad 2005; Lopez 2003; McGough 2006; Murray 2011; NCT02039908; NCT02536105; Pearson 2013; Wallace 1994; Wigal 2011; Wigal 2013; Wigal 2014; Wilens 2008	13 trials: Arnold 2004; Biederman 2003b; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Kollins 2006 (PATS); Kollins 2021; NCT02293655; Riggs 2011; Wigal 2017; Wilens 2006b; Wolraich 2001
None	139	120 trials: Ahmann 1993; Barkley 1989b; Barkley 1991; Barkley 2000; Bedard 2008; Bhat 2020; Bliznakova 2007; Brams 2008; Brams 2012; Brown 1984a; Brown 1988; Buitelaar 1995; Bukstein 1998; Carlson 1995; Castellanos 1997; Chronis 2003; Coghill 2007; Corkum 2008; Corkum 2020; Douglas 1986; Douglas 1995; DuPaul 1996; Fabiano 2007; Findling 2007; Fine 1993; Fitzpatrick 1992a; Flapper 2008; Forness 1992; Froehlich 2011; Froehlich 2018; Gadow 1995; Gadow 2007; Gadow 2011; Garfinkel 1983; Gonzalez‐Heydrich 2010; Gruber 2007; Hale 2011; Hawk 2018; Hicks 1985; Hoeppner 1997; Johnston 1988; Kaplan 1990; Kelly 1989; Kent 1999; Klorman 1990; Kolko 1999; Kortekaas‐Rijlaarsdam 2017; Kritchman 2019; Leddy 2009; Lijffijt 2006; Lufi 1997; Lufi 2007; Manos 1999; McBride 1988a; McInnes 2007; Merrill 2021; Moshe 2012; Muniz 2008; Musten 1997; Nikles 2006; Oesterheld 1998; Overtoom 2003; Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2001a; Pelham 2002; Pelham 2005; Pelham 2011; Pelham 2014; Pliszka 1990; Pliszka 2007; Quinn 2004; Rapport 1985; Rapport 1987; Rapport 2008; Reitman 2001; Rubinsten 2008; Samuels 2006; Schachar 2008; Schulz 2010; Schwartz 2004; Shiels 2009; Silva 2005a; Silva 2006; Silva 2008; Smith 1998; Smith 2004; Smithee 1998; Soleimani 2017; Stein 2003; Stein 2011; Stoner 1994; Sumner 2010; Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Symons 2007; Szobot 2008; Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1993; Tervo 2002; Tirosh 1993a; Ullmann 1986; Urman 1995; Wallander 1987; Waxmonsky 2008; Whalen 1990; Wigal 2003; Wilkison 1995; Wodrich 1998; Zeiner 1999; Zeni 2009	19 trials: Brown 1985; Butter 1983; Findling 2006; Green 2011; Greenhill 2002; Heriot 2008; Horn 1991; Ialongo 1994; Jacobi‐Polishook 2009; Lin 2014; Martins 2004; Matthijssen 2019; McCracken 2016; NCT00409708; Newcorn 2008; Perez‐Alvarez 2009; Pliszka 2000; Van der Meere 1999a; Wigal 2015
Unclear	5	4 trials: Chacko 2005; CRIT124US02; Pelham 1989; Solanto 2009	1 trial: Duric 2012
Funding
Funded by grants from universities; authorities or research foundations	82	70 trials: Ahmann 1993; Barkley 1991; Barkley 2000; Bedard 2008; Bhat 2020; Brown 1988; Brown 1991; Chacko 2005; Coghill 2007; Cook 1993; Corkum 2008; Corkum 2020; Cox 2006; Douglas 1986; Douglas 1995; Epstein 2011; Fabiano 2007; Findling 2007; Fitzpatrick 1992a; Forness 1992; Froehlich 2011; Froehlich 2018; Gadow 1995; Gadow 2007; Garfinkel 1983; Gonzalez‐Heydrich 2010; Gorman 2006; Hale 2011; Hawk 2018; Hicks 1985; Kent 1995; Klorman 1990; Kollins 2006 (PATS); Konrad 2004; Konrad 2005; Kritchman 2019; McInnes 2007; Musten 1997; NCT02039908; NCT02536105; Nikles 2006; Oesterheld 1998; Overtoom 2003; Pearson 2013; Pelham 2002; Pelham 2014; Pliszka 1990; Pliszka 2007; Ramtvedt 2013; Rubinsten 2008; Schwartz 2004; Shiels 2009; Smith 1998; Smithee 1998; Soleimani 2017; Stein 1996; Stein 2003; Stoner 1994; Symons 2007; Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Urman 1995; Wallace 1994; Wallander 1987; Waxmonsky 2008; Wilkison 1995; Zeiner 1999	12 trials: Butter 1983; Connor 2000; Duric 2012; Firestone 1981; Green 2011; Jensen 1999 (MTA); Kollins 2006 (PATS); Matthijssen 2019; McCracken 2016; NCT02293655; Palumbo 2008; Schrantee 2016
Funded or partially funded by pharmaceutical industry	87	48 trials: Abikoff 2009; Blum 2011; Brams 2008; Brams 2012; Brown 1984a; Chronis 2003; CRIT124US02; Döpfner 2004; Fine 1993; Gadow 1990; Gadow 2011; Huang 2021; Kelly 1989; Kent 1999; Kortekaas‐Rijlaarsdam 2017; Lopez 2003; Manos 1999; McGough 2006; Muniz 2008; Murray 2011; Pelham 1999; Pelham 2001a; Pelham 2005; Pelham 2011; Quinn 2004; Schachar 2008; Schulz 2010; Silva 2005a; Silva 2006; Silva 2008; Stein 2011; Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Szobot 2008; Taylor 1987; Ullmann 1985; Ullmann 1986; Wigal 2003; Wigal 2011; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 2010; Zeni 2009	39 trials: Arnold 2004; Barragán 2017; Biederman 2003b; Brown 1985; Carlson 2007; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Findling 2006; Findling 2008; Findling 2010; Greenhill 2002; Greenhill 2006; Kollins 2021; Lehmkuhl 2002; Lin 2014; Martins 2004; NCT00409708; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Pliszka 2000; Pliszka 2017; Riggs 2011; Schachar 1997a; Szobot 2004; Tannock 2018; Tourette's Syndrome Study Group 2002; Tucker 2009; Van der Meere 1999a; Weiss 2021; Wigal 2004; Wigal 2015; Wigal 2017; Wilens 2006b; Wolraich 2001
No funding received	8	6 trials: Barkley 1989b; Flapper 2008; Moshe 2012; Rapport 1987; Rapport 2008; Tirosh 1993a	2 trials: Heriot 2008; Perez‐Alvarez 2009
Unclear funding	36	33 trials: Bliznakova 2007; Borcherding 1990; Buitelaar 1995; Bukstein 1998; Carlson 1995; Castellanos 1997; DuPaul 1996; Gruber 2007r; Hoeppner 1997; Johnston 1988; Kaplan 1990; Kolko 1999; Leddy 2009; Lijffijt 2006; Lufi 1997; Lufi 2007; McBride 1988a; Merrill 2021; Pelham 1989; Pelham 1990a; Pelham 1993a; Rapport 1985; Reitman 2001; Samuels 2006; Sharp 1999; Smith 2004; Solanto 2009; Sumner 2010; Taylor 1993; Tervo 2002; Tirosh 1993b; Whalen 1990; Wodrich 1998	3 trials: Horn 1991; Ialongo 1994; Jacobi‐Polishook 2009
Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events while taking methylphenidate before randomisation
Yes	88	60 trials: Barkley 1991; Barkley 2000; Blum 2011; Brams 2008; Brams 2012; Brown 1991; Cox 2006; Döpfner 2004; Fabiano 2007; Gonzalez‐Heydrich 2010; Gruber 2007; Huang 2021; Kent 1995; Klorman 1990; Kollins 2006 (PATS); Konrad 2004; Konrad 2005; Kortekaas‐Rijlaarsdam 2017; Lijffijt 2006; Lopez 2003; Manos 1999; McGough 2006; Muniz 2008; Murray 2011; NCT02039908; NCT02536105; Nikles 2006; Overtoom 2003; Pearson 2013; Pelham 2001a; Pelham 2011; Pelham 2014; Quinn 2004; Reitman 2001; Samuels 2006; Schachar 2008; Schulz 2010; Schwartz 2004; Silva 2005a; Silva 2006; Silva 2008; Stein 2011; Sumner 2010; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Tannock 1992; Tannock 1995a; Tannock 1995b; Wallace 1994; Waxmonsky 2008; Whalen 1990; Wigal 2003; Wigal 2011; Wigal 2013; Wigal 2014; Wilens 2008; Wilens 2010	29 trials: Arnold 2004; Biederman 2003b; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Findling 2006; Findling 2008; Findling 2010; Greenhill 2002; Greenhill 2006; Jacobi‐Polishook 2009; Jensen 1999 (MTA); Kollins 2006 (PATS); Kollins 2021; Matthijssen 2019; NCT02293655; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Pliszka 2017; Tannock 2018; Weiss 2021; Wigal 2004; Wigal 2015; Wigal 2017; Wilens 2006b; Wolraich 2001
No	112	86 trials: Abikoff 2009; Ahmann 1993; Barkley 1989b; Bedard 2008; Bhat 2020; Bliznakova 2007; Borcherding 1990; Brown 1984a; Brown 1988; Buitelaar 1995; Bukstein 1998; Carlson 1995; Castellanos 1997; Chronis 2003; Coghill 2007; Cook 1993; Corkum 2008; Corkum 2020; CRIT124US02; Douglas 1986; Douglas 1995; DuPaul 1996; Epstein 2011; Findling 2007; Fine 1993; Flapper 2008; Forness 1992; Froehlich 2011; Froehlich 2018; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Garfinkel 1983; Gorman 2006; Hale 2011; Hawk 2018; Hicks 1985; Hoeppner 1997; Kaplan 1990; Kelly 1989; Kent 1999; Kolko 1999; Kritchman 2019; Lufi 1997; McBride 1988a; McInnes 2007; Moshe 2012; Musten 1997; Oesterheld 1998; Pelham 1990a; Pelham 1993a; Pelham 1999; Pelham 2002; Pelham 2005; Pliszka 1990; Pliszka 2007; Ramtvedt 2013; Rapport 1985; Rapport 1987; Rapport 2008; Rubinsten 2008; Sharp 1999; Shiels 2009; Smith 1998; Smith 2004; Smithee 1998; Soleimani 2017; Stein 1996; Stein 2003; Stoner 1994; Szobot 2008; Tannock 1989; Taylor 1987; Taylor 1993; Tervo 2002; Tirosh 1993a; Tirosh 1993b; Ullmann 1985; Ullmann 1986; Urman 1995; Wallander 1987; Wilkison 1995; Wodrich 1998; Zeiner 1999; Zeni 2009	26 trials: Barragán 2017; Brown 1985; Butter 1983; Carlson 2007; Childress 2009; Connor 2000; Duric 2012; Firestone 1981; Green 2011; Heriot 2008; Horn 1991; Ialongo 1994; Lehmkuhl 2002; Lin 2014; Martins 2004; McCracken 2016; NCT00409708; Palumbo 2008; Perez‐Alvarez 2009; Pliszka 2000; Schachar 1997a; Schrantee 2016; Szobot 2004; Tourette's Syndrome Study Group 2002; Tucker 2009; Van der Meere 1999a
Not stated or unclear	12	11 trials: Chacko 2005; Fitzpatrick 1992a; Johnston 1988; Leddy 2009; Lufi 2007; Merrill 2021; Pelham 1989; Solanto 2009; Sunohara 1999; Symons 2007; Tannock 1993	1 trial: Riggs 2011
Withdrawals due to adverse events
Yes	68	36 trials: Ahmann 1993; Barkley 1989b; Bhat 2020; Castellanos 1997; Fabiano 2007; Findling 2007; Hawk 2018; Huang 2021; Kolko 1999; Kollins 2006 (PATS); Kortekaas‐Rijlaarsdam 2017; Lijffijt 2006; Manos 1999; Murray 2011; Nikles 2006; Pelham 1999; Pelham 2011; Pelham 2014; Silva 2006; Silva 2008; Solanto 2009; Stein 1996; Stein 2003; Stein 2011; Swanson 2004b; Szobot 2008; Tannock 1992; Taylor 1987; Tervo 2002; Tirosh 1993b; Waxmonsky 2008; Wigal 2014; Wilens 2008; Wilens 2010; Wodrich 1998; Zeni 2009	33 trials: Barragán 2017; Biederman 2003b; Carlson 2007; Childress 2009; Childress 2020c; Coghill 2013; Findling 2006; Findling 2008; Findling 2010; Firestone 1981; Greenhill 2002; Greenhill 2006; Horn 1991; Ialongo 1994; Jensen 1999 (MTA); Kollins 2006 (PATS); Lehmkuhl 2002; Lin 2014; Matthijssen 2019; McCracken 2016; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Pliszka 2000; Pliszka 2017; Schachar 1997a; Schrantee 2016; Weiss 2021; Wigal 2004; Wigal 2015; Wilens 2006b; Wolraich 2001
No	116	101 trials: Abikoff 2009; Barkley 1991; Barkley 2000; Bedard 2008; Bliznakova 2007; Blum 2011; Borcherding 1990; Brams 2008; Brams 2012; Brown 1984a; Brown 1988; Brown 1991; Buitelaar 1995; Bukstein 1998; Carlson 1995; Chacko 2005; Chronis 2003; Coghill 2007; Cook 1993; Corkum 2008; Corkum 2020; Cox 2006; CRIT124US02; Döpfner 2004; Douglas 1995; DuPaul 1996; Fine 1993; Flapper 2008; Froehlich 2011; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Garfinkel 1983; Gonzalez‐Heydrich 2010; Gruber 2007; Hicks 1985; Hoeppner 1997; Johnston 1988; Kaplan 1990; Kelly 1989; Kent 1995; Kent 1999; Konrad 2004; Kritchman 2019; Lopez 2003; Lufi 1997; Lufi 2007; McBride 1988a; McGough 2006; McInnes 2007; Merrill 2021; Moshe 2012; Muniz 2008; NCT02536105; Oesterheld 1998; Overtoom 2003; Pearson 2013; Pelham 1990a; Pelham 1993a; Pelham 2001a; Pelham 2002; Pelham 2005; Pliszka 2007; Quinn 2004; Ramtvedt 2013; Rapport 1985; Rapport 2008; Reitman 2001; Rubinsten 2008; Schachar 2008; Schulz 2010; Schwartz 2004; Sharp 1999; Shiels 2009; Silva 2005a; Smith 1998; Smith 2004; Soleimani 2017; Stoner 1994; Sunohara 1999; Swanson 1998; Swanson 2002a; Swanson 2002b; Symons 2007; Tannock 1989; Tannock 1993; Tannock 1995a; Tannock 1995b; Taylor 1993; Tirosh 1993a; Ullmann 1985; Ullmann 1986; Urman 1995; Wallace 1994; Wallander 1987; Whalen 1990; Wigal 2003; Wigal 2011; Wigal 2013; Zeiner 1999	15 trials: Arnold 2004; Brown 1985; Butter 1983; Childress 2017; Childress 2020a; Childress 2020b; Connor 2000; Green 2011; Jacobi‐Polishook 2009; Kollins 2021; Martins 2004; Perez‐Alvarez 2009; Szobot 2004; Tucker 2009; Van der Meere 1999a
Not stated or unclear	28	20 trials: Douglas 1986; Epstein 2011; Fitzpatrick 1992a; NCT02039908; Forness 1992; Froehlich 2018; Gorman 2006; Hale 2011; Klorman 1990; Konrad 2005; Leddy 2009; Musten 1997; Pelham 1989; Pliszka 1990; Rapport 1987; Samuels 2006; Smithee 1998; Sumner 2010; Swanson 1999; Wilkison 1995	8 trials: Duric 2012; Heriot 2008; NCT00409708; NCT02293655; Riggs 2011; Tannock 2018; Tourette's Syndrome Study Group 2002; Wigal 2017
Availability for quantitative analyses
No usable data	47	41 trials: Ahmann 1993; Bliznakova 2007; Douglas 1995; Forness 1992; Froehlich 2011; Gruber 2007; Hale 2011; Hicks 1985; Johnston 1988; Kelly 1989; Kent 1999; Leddy 2009; Lijffijt 2006; Lopez 2003; McInnes 2007; Nikles 2006; Oesterheld 1998; Pliszka 2007; Rubinsten 2008; Samuels 2006; Shiels 2009; Soleimani 2017; Stoner 1994; Sumner 2010; Sunohara 1999; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Symons 2007; Tannock 1992; Tannock 1995b; Taylor 1993; Tervo 2002; Ullmann 1985; Wallace 1994; Wallander 1987; Waxmonsky 2008; Wigal 2003; Wilkison 1995; Wodrich 1998	6 trials: Connor 2000; Heriot 2008; Horn 1991; Martins 2004; Perez‐Alvarez 2009; Szobot 2008
ADHD: attention deficit hyperactivity disorder; CD: conduct disorder; CNS: central nervous system; ODD: Oppositional defiant disorder;DSM:Diagnostic and Statistical Manual of Mental Disorders; DSM‐III:Diagnostic and Statistical Manual of Mental Disorders Third Edition; DSM‐III‐R:Diagnostic and Statistical Manual of Mental Disorders Third Edition Revised; DSM‐IV:Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; DSM‐IV‐TR:Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision; DSM‐5:Diagnostic and Statistical Manual of Mental Disorders Fifth Edition; ICD‐10:International Statistical Classification of Diseases and Related Health Problems 10th Revision;OCD: obsessive compulsive disorder; ODD: oppositional defiant disorder

^aResearch unit at a hospital.
^bIn addition to bipolar disorder, which was an inclusion criterion for this trial.
^c2 participants also had drug or alcohol abuse.
^dParticipants were grouped to be with or without anxiety.
^e50% also suffered from psychosis. All participants had either bipolar disorder or borderline personality disorder.
^fAggressive conduct disorder.
^gDrug/alcohol use.
^hNeurofeedback was part of the intervention.
ⁱFor the review, we used data from arms with no behavioural intervention.
^jDifferent reporting across different articles, ranging between 39% and 63%.
^kDelayed‐release and extended‐release methylphenidate.
^lGiven 3 times a day as well as an experimental delivery, to evaluate the effect of applying an osmotically driven, continuous delivery system.
^mFor the parallel trial.
ⁿFor the cross‐over trial.
^oIn this cross‐over trial, children received methylphenidate twice for 7‐10 days, resulting in a full methylphenidate intervention period of 14‐20 days.
^pBetween 7‐21 days depending on group size. The mean intervention period considered 14 days for this review.
^qTwelve days for the 20 inpatients, 19 days for the 24 outpatients.
^rIt is only stated that this trial was not industry‐funded.

3. Key inclusion and exclusion criteria.

Criteria	Number of trials	Trials
Inclusion criteria of special interest
A diagnosis of ODD or CD or disruptive behavior disorder	4	Brown 1991; Bukstein 1998; Connor 2000; Gadow 1990
A diagnosis of bipolar disorder and treated with a stable dose of mood stabilisers or either bipolar disorder or borderline disorder	2	Findling 2007; Zeni 2009
A diagnosis of Tourette's syndrome or motor tic disorder	5	Castellanos 1997; Gadow 1995; Gadow 2007; Gadow 2011; Tourette's Syndrome Study Group 2002
A diagnosis of developmental co‐ordination disorder	2	Flapper 2008; Soleimani 2017
A diagnosis of epilepsy	1	Gonzalez‐Heydrich 2010
A diagnosis of velocardiofacial syndrome	1	Green 2011
A diagnosis of cerebral palsy	1	Symons 2007
Non‐nicotine substance use disorder	2	Riggs 2011; Szobot 2008
Positive response to methylphenidate prior to screening or being on a stable dose of methylphenidate before screening/entering trial or familiar with methylphenidate intake for at least 2 weeks‐2 years	27	Childress 2017; Childress 2020b; Cox 2006; Döpfner 2004; Findling 2006; Findling 2008; Kortekaas‐Rijlaarsdam 2017; Lijffijt 2006; Matthijssen 2019; Muniz 2008; Nikles 2006; Pelham 2001a; Pelham 2011; Pliszka 2017; Samuels 2006; Schulz 2010; Silva 2005a; Silva 2006; Silva 2008; Swanson 1998; Swanson 1999; Swanson 2002a; Swanson 2002b; Swanson 2004b; Tannock 2018; Wigal 2003; Wilkison 1995
Most common exclusion criteria and exclusion criteria of special interest
Intellectual disability, or estimated/measured IQ < 60‐85, or deemed by investigators to have below‐average cognitive capacity, or history of neurological impairment, or history of significant developmental delay, or to be home‐schooled, or intellectual disability	126	Ahmann 1993; Barkley 1989b; Barkley 1991; Barragán 2017; Bedard 2008; Bhat 2020; Blum 2011; Brams 2008; Brams 2012; Brown 1984a; Brown 1988; Brown 1991; Butter 1983; Carlson 1995; Carlson 2007; Castellanos 1997; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Coghill 2007; Coghill 2013; Cook 1993; Corkum 2008; Corkum 2020; Döpfner 2004; Douglas 1995; DuPaul 1996; Duric 2012; Epstein 2011; Findling 2006; Findling 2007; Findling 2008; Findling 2010; Fine 1993; Firestone 1981; Flapper 2008; Forness 1992; Froehlich 2011; Froehlich 2018; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Gonzalez‐Heydrich 2010; Gorman 2006; Greenhill 2002; Gruber 2007; Hale 2011; Heriot 2008; Horn 1991; Huang 2021; Ialongo 1994; Jensen 1999 (MTA); Kelly 1989; Klorman 1990; Kollins 2006 (PATS); Kollins 2021; Konrad 2004; Kortekaas‐Rijlaarsdam 2017; Leddy 2009; Lehmkuhl 2002; Lufi 1997; Martins 2004; Matthijssen 2019; McCracken 2016; McGough 2006; McInnes 2007; Murray 2011; NCT00409708; NCT02039908; NCT02293655; NCT02536105; Oesterheld 1998; Palumbo 2008; Pearson 2013; Pelham 1989; Pelham 2001a; Pelham 2011; Pelham 2014; Pliszka 2007; Pliszka 2017; Quinn 2004; Ramtvedt 2013; Reitman 2001; Rubinsten 2008; Schachar 2008; Schrantee 2016; Schwartz 2004; Sharp 1999; Shiels 2009; Silva 2005a; Silva 2008; Smith 1998; Smithee 1998; Solanto 2009; Soleimani 2017; Stein 1996; Stein 2003; Stein 2011; Sunohara 1999; Swanson 1998; Swanson 2004b; Szobot 2004; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Tannock 2018; Taylor 1987; Taylor 1993; Tourette's Syndrome Study Group 2002; Tucker 2009; Van der Meere 1999a; Waxmonsky 2008; Weiss 2021; Wigal 2004; Wigal 2011; Wigal 2013; Wigal 2014; Wigal 2015; Wilens 2008; Wilens 2010; Wolraich 2001; Zeiner 1999; Zeni 2009
Learning disability, or not having an age‐appropriate academic level, or at least an average learning score	17	Abikoff 2009; Biederman 2003b; Childress 2009; Coghill 2007; Cook 1993; CRIT124US02; Froehlich 2018; Greenhill 2006; Moshe 2012a; Muniz 2008; Murray 2011; NCT02293655; Pelham 2001a; Pliszka 2007; Rubinsten 2008; Wigal 2011; Wilkison 1995
Any psychiatric disorder that could contraindicate treatment or confound efficacy or safety assessments, or any psychiatric comorbidity, or any concurrent significant psychiatric illness, or any psychiatric disorder with few specified exceptions, or any comorbid axis I psychiatric disorder requiring treatment, or any psychiatric comorbidity requiring treatment	54	Biederman 2003b; Borcherding 1990; Brams 2008; Brams 2012; Carlson 2007; Castellanos 1997b; Childress 2020c; Corkum 2008; Corkum 2020; Duric 2012; Findling 2006; Findling 2008; Findling 2010; Flapper 2008; NCT02039908; Greenhill 2002; Greenhill 2006; Jacobi‐Polishook 2009; Kollins 2006 (PATS); Konrad 2004; Kortekaas‐Rijlaarsdam 2017; Lopez 2003; Lufi 1997; Matthijssen 2019; McGough 2006; Moshe 2012; Muniz 2008; Murray 2011; NCT02536105; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Pelham 2011; Perez‐Alvarez 2009; Pliszka 2017; Quinn 2004; Schachar 2008; Schrantee 2016; Schulz 2010; Silva 2005a; Silva 2006; Silva 2008; Soleimani 2017; Swanson 1998; Szobot 2008; Taylor 1987; Waxmonsky 2008; Weiss 2021; Wigal 2013; Wigal 2014; Wigal 2015; Wigal 2017; Wilens 2006b; Wilens 2010; Wilkison 1995
Psychiatric disorders that might be the primary cause of ADHD symptoms	2	Froehlich 2011; Wodrich 1998
Significant neurological history, or other significant CNS disorders, or gross sensory or motor deficits/impairment, or brain damage/traumatic brain injury, or head injury requiring hospitalisation, or major organic brain dysfunction, or history of electroencephalographic abnormalities	74	Ahmann 1993; Arnold 2004; Barkley 1989b; Barkley 2000; Barragán 2017; Bedard 2008; Blum 2011; Borcherding 1990; Brown 1984a; Brown 1985; Brown 1988; Brown 1991; Castellanos 1997; Childress 2020c; Coghill 2007; Cook 1993; Corkum 2008; Corkum 2020; Douglas 1986; DuPaul 1996; Duric 2012; Findling 2007; Firestone 1981; Froehlich 2011; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Gorman 2006; Hale 2011; Hawk 2018; Heriot 2008; Jacobi‐Polishook 2009; Jensen 1999 (MTA); Kelly 1989; Klorman 1990; Kortekaas‐Rijlaarsdam 2017; Leddy 2009; Lin 2014; Martins 2004; Moshe 2012; Murray 2011; Musten 1997; NCT02293655; Oesterheld 1998; Pearson 2013; Pelham 1989; Pliszka 2007; Quinn 2004; Ramtvedt 2013; Rapport 1985; Rapport 1987; Rapport 2008; Schachar 2008; Schrantee 2016; Sharp 1999; Shiels 2009; Smithee 1998; Solanto 2009; Soleimani 2017; Sumner 2010; Szobot 2004; Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Tannock 2018; Tirosh 1993a; Tirosh 1993b; Waxmonsky 2008; Weiss 2021; Wigal 2004; Zeiner 1999
History of epilepsy or seizures	60	Ahmann 1993; Barkley 1989b; Barragán 2017; Blum 2011; Brams 2008; Brams 2012; Carlson 2007; Childress 2009; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Cook 1993; Corkum 2008; Corkum 2020; DuPaul 1996; Findling 2008; Findling 2010; Firestone 1981; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Greenhill 2002; Greenhill 2006; Hale 2011; Hawk 2018; Huang 2021; Leddy 2009; Lehmkuhl 2002; Lin 2014; McGough 2006; Moshe 2012; Muniz 2008; NCT00409708; NCT02536105; NCT02293655; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Oesterheld 1998; Pliszka 2017; Ramtvedt 2013; Schrantee 2016; Sharp 1999; Shiels 2009; Soleimani 2017; Stein 2003; Swanson 2004b; Tannock 1989; Tucker 2009; Waxmonsky 2008; Weiss 2021; Wigal 2003; Wigal 2011; Wigal 2013; Wigal 2015; Wigal 2017; Wilens 2006b; Wilens 2010; Wolraich 2001
History or diagnosis of and/or family history of Tourette's syndrome or tic disorders	62	Ahmann 1993; Abikoff 2009; Barkley 1989b; Barkley 1991; Barkley 2000; Bhat 2020; Blum 2011; Borcherding 1990; Brams 2008; Brams 2012; Buitelaar 1995; Childress 2009; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; DuPaul 1996; Findling 2008; Fine 1993; Greenhill 2002; Gruber 2007; Heriot 2008; Huang 2021; Jensen 1999 (MTA); Kent 1995; Kollins 2006 (PATS); Kollins 2021; Lehmkuhl 2002; Lin 2014; McCracken 2016; McGough 2006; Moshe 2012; Muniz 2008; Murray 2011; NCT02536105; Newcorn 2008; Overtoom 2003; Palumbo 2008; Pearson 2013; Pliszka 2000; Pliszka 2017; Riggs 2011; Schachar 1997a; Schrantee 2016; Schwartz 2004; Silva 2005a; Silva 2006; Silva 2008; Solanto 2009; Stein 2003; Stein 2011; Sumner 2010; Swanson 2004b; Tannock 1989; Wigal 2003; Wigal 2004; Wigal 2011; Wigal 2013; Wigal 2017; Wilens 2006b; Wilens 2010; Wolraich 2001
History or diagnosis of autism or pervasive development disorder or Asperger's disorder	49	Abikoff 2009; Barkley 1989b; Barragán 2017; Bhat 2020; Blum 2011; Buitelaar 1995; Carlson 2007; Corkum 2008; Döpfner 2004; DuPaul 1996; Findling 2007; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Gorman 2006; Gruber 2007; Hawk 2018; Heriot 2008; Kent 1999; Klorman 1990; Kollins 2006 (PATS); Kollins 2021; Konrad 2005; Kritchman 2019; Leddy 2009; Lehmkuhl 2002; Lin 2014; McCracken 2016; Murray 2011; Musten 1997; NCT02039908; Newcorn 2008; Overtoom 2003; Palumbo 2008; Pearson 2013; Schachar 2008; Schwartz 2004; Shiels 2009; Stein 1996; Stein 2011; Taylor 1987; Tourette's Syndrome Study Group 2002; Van der Meere 1999a; Waxmonsky 2008; Wigal 2004; Wigal 2011; Zeiner 1999; Zeni 2009
History or diagnosis of and/or family history of: major depression or depressive disorder or bipolar disorder or affective disorder or mood disorder	45	Abikoff 2009; Barkley 1989b; Blum 2011; Carlson 1995c; Carlson 2007; Childress 2020b; Döpfner 2004; Findling 2007; Gonzalez‐Heydrich 2010; Gorman 2006; Horn 1991; Ialongo 1994; Kent 1995; Kollins 2006 (PATS); Kollins 2021; Kritchman 2019; Lehmkuhl 2002; Lin 2014; Martins 2004; McCracken 2016; Murray 2011; NCT02293655; Newcorn 2008; Oesterheld 1998; Palumbo 2008; Pearson 2013; Pliszka 1990; Pliszka 2000; Riggs 2011; Schachar 1997a; Solanto 2009; Stein 2003; Stein 2011; Sumner 2010; Swanson 2002a; Szobot 2004; Tourette's Syndrome Study Group 2002; Tucker 2009; Waxmonsky 2008; Wigal 2003; Wigal 2004; Wigal 2011; Wilens 2006b; Wilens 2010; Zeiner 1999
History or diagnosis of eating disorder	9	Childress 2020b; Kritchman 2019; Murray 2011; Palumbo 2008; Tourette's Syndrome Study Group 2002; Waxmonsky 2008; Wigal 2004; Wigal 2011; Wilens 2006b
Diagnosis of post‐traumatic stress disorder	1	Abikoff 2009
History or diagnosis of obsessive‐compulsive disorder	8	Abikoff 2009; Blum 2011; Childress 2009; Jensen 1999 (MTA); Kollins 2021; Murray 2011; Wigal 2004; Wigal 2011
Diagnosis of panic disorder, or severe anxiety disorder, or in the investigator's evaluation very anxious, tense or agitated, or separation anxiety disorder	23	Abikoff 2009; Barkley 1989b; Childress 2020b; Döpfner 2004; Horn 1991; Huang 2021; Ialongo 1994; Kent 1995; Kritchman 2019; Lehmkuhl 2002; Lin 2014; McCracken 2016; Murray 2011; Newcorn 2008; Schachar 1997a; Sumner 2010; Sunohara 1999; Swanson 2002a; Tannock 1995a; Tucker 2009; Wigal 2003; Wigal 2011; Wilens 2006b
History or diagnosis of CD/behaviour disorder	11	Childress 2020b; Coghill 2013; Kollins 2021; Murray 2011; Sunohara 1999; Swanson 2002a; Tannock 1989; Tannock 1992; Wigal 2003; Wigal 2011; Wilens 2008
History or diagnosis of ODD	2	Swanson 2002a; Wigal 2003
Lifetime history of psychosis or thought disturbance or thought disorder or schizoid, schizotypal or frank psychotic features	66	Abikoff 2009; Barkley 1989b; Bedard 2008; Bhat 2020; Blum 2011; Brown 1985; Brown 1991; Childress 2009; Childress 2020b; Cook 1993; Döpfner 2004; Douglas 1986; DuPaul 1996; Findling 2007; Firestone 1981; Froehlich 2018; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Gonzalez‐Heydrich 2010; Gorman 2006; Gruber 2007; Hawk 2018; Heriot 2008; Horn 1991; Huang 2021; Ialongo 1994; Kaplan 1990; Kelly 1989; Kent 1995; Klorman 1990; Kollins 2006 (PATS); Kollins 2021; Kritchman 2019; Leddy 2009; Lehmkuhl 2002; Lin 2014; McCracken 2016; Murray 2011; NCT02293655; Newcorn 2008; Palumbo 2008; Pliszka 1990; Pliszka 2000; Ramtvedt 2013; Riggs 2011; Schachar 2008; Schrantee 2016; Schwartz 2004; Shiels 2009; Smithee 1998; Solanto 2009; Stein 2011; Sumner 2010; Tannock 1993; Tourette's Syndrome Study Group 2002; Tucker 2009; Waxmonsky 2008; Wigal 2003; Wigal 2004; Wigal 2011; Wilens 2006b; Wolraich 2001; Zeiner 1999; Zeni 2009
Lifetime history or diagnosis of mania or hypomania	7	Abikoff 2009; Findling 2007; Froehlich 2011; Froehlich 2018; Gonzalez‐Heydrich 2010; NCT02293655; Pliszka 2000
History or diagnosis of sleep disorder	5	Corkum 2008; Corkum 2020; Murray 2011; Wigal 2004; Wigal 2011
Significant suicidality or dangerous to self or others	23	Abikoff 2009; Blum 2011; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Findling 2007; Findling 2010; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Jensen 1999 (MTA); Kollins 2006 (PATS); Kollins 2021; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Pliszka 2017; Riggs 2011; Schrantee 2016; Waxmonsky 2008; Weiss 2021; Zeni 2009
Has a known history of physical, sexual or emotional abuse in the last year, or history of child abuse	5	Childress 2020a; Childress 2020c; Heriot 2008; Jensen 1999 (MTA); Kollins 2006 (PATS)
History or diagnosis of substance abuse or positive drug screening test or suspected drug abuse	41	Abikoff 2009; Arnold 2004; Biederman 2003b; Brams 2008; Brams 2012; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Coghill 2007; Coghill 2013; Cox 2006; Findling 2006; Findling 2007; Findling 2010; Greenhill 2006; Huang 2021; Kollins 2021; Kritchman 2019; Lopez 2003; Martins 2004; Muniz 2008; Murray 2011; NCT02536105; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Pliszka 2007; Pliszka 2017; Schrantee 2016; Silva 2005a; Silva 2006; Silva 2008; Stein 2011; Sumner 2010; Swanson 2004b; Szobot 2004; Tucker 2009; Weiss 2021; Wigal 2004; Wigal 2011; Zeni 2009
Living with a person with a current or earlier substance abuse disorder or family history of drug abuse	12	Biederman 2003b; Childress 2009; Childress 2017; Childress 2020a; Childress 2020c; Findling 2006; Greenhill 2002; Huang 2021; Jensen 1999 (MTA); Kollins 2006 (PATS); Swanson 2004b; Wigal 2003
Inability to take/swallow or tolerate methylphenidate/ingredients in the medication or history of adverse reactions/adverse events	54	Arnold 2004; Barkley 1991; Barkley 2000; Biederman 2003b; Blum 2011; Brams 2008; Brams 2012; Carlson 2007; Childress 2017; Childress 2020b; Childress 2020c; Coghill 2013; Cox 2006; CRIT124US02; Fabiano 2007; Findling 2007; NCT02039908; Gonzalez‐Heydrich 2010; Greenhill 2002; Greenhill 2006; Gruber 2007; Huang 2021; Jensen 1999 (MTA); Kent 1995; Kollins 2006 (PATS); Kollins 2021; Murray 2011; NCT02536105; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Pearson 2013; Pelham 2005; Pelham 2014; Pliszka 2017; Quinn 2004; Schachar 2008; Schwartz 2004; Silva 2005a; Stein 2011; Sumner 2010; Swanson 2004b; Tannock 2018; Waxmonsky 2008; Weiss 2021; Wigal 2003; Wigal 2004; Wigal 2011; Wigal 2015; Wilens 2006b; Wilens 2010; Wolraich 2001; Zeni 2009
History of failed/poor response/being non‐responsive to methylphenidate (unless naive to stimulants), or past treatment failure on a methylphenidate trial	27	Brams 2012; Childress 2020b; Childress 2020c; Coghill 2013; Fabiano 2007; Findling 2006; Findling 2010; Greenhill 2006; Kollins 2021; McGough 2006; Murray 2011; NCT02039908; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Pearson 2013; Schachar 2008; Schulz 2010; Silva 2006; Silva 2008; Stein 2011; Tannock 2018; Wigal 2003; Wigal 2011; Wilens 2006b; Wilens 2008; Wilens 2010
Satisfied with current pharmacological treatment (if not stimulant‐naive) or having effective control of symptoms with acceptable tolerability on current ADHD medication	10	Childress 2020a; Coghill 2013; NCT02536105; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Nikles 2006; Weiss 2021; Wigal 2013; Wigal 2014; Wigal 2015
Had been receiving methylphenidate > 6 months, or daily dose was above dose specified in the research protocol	1	Musten 1997
Previous pharmacological treatment for ADHD	23	Barragán 2017; Buitelaar 1995; Coghill 2007; Cook 1993; Corkum 2008; Corkum 2020; Flapper 2008; Froehlich 2018; Kollins 2006 (PATS); Konrad 2004; Oesterheld 1998; Perez‐Alvarez 2009; Ramtvedt 2013; Schachar 1997a; Szobot 2008; Taylor 1987; Tirosh 1993a; Tirosh 1993b; Tucker 2009; Urman 1995; Van der Meere 1999a; Wallander 1987; Zeiner 1999
Any medical/physical disease	10	Castellanos 1997; Flapper 2008; Perez‐Alvarez 2009; Pliszka 1990; Pliszka 2000; Quinn 2004; Swanson 1998; Swanson 2002a; Wilkison 1995; Zeiner 1999
Any ongoing chronic condition, or poor physical health, or somatic disorder/medical condition that could contraindicate treatment or confound efficacy or safety, or physical disability, or their medical condition affecting cognitive or neuropsychological performance	92	Barragán 2017; Bedard 2008; Biederman 2003b; Borcherding 1990; Brams 2008; Brams 2012; Brown 1985; Carlson 2007; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Connor 2000; Cox 2006; CRIT124US02; Douglas 1995; Fabiano 2007; Findling 2006; Findling 2007; Findling 2008; Gadow 1990; Gadow 1995; Gadow 2007; Gadow 2011; Gonzalez‐Heydrich 2010; Gorman 2006; Greenhill 2002; Greenhill 2006; Hale 2011; Hawk 2018; Heriot 2008; Horn 1991; Huang 2021; Ialongo 1994; Jacobi‐Polishook 2009; Jensen 1999 (MTA); Kelly 1989; Kollins 2006 (PATS); Kollins 2021; Lin 2014; Lopez 2003; Lufi 1997; Martins 2004; Matthijssen 2019; McCracken 2016; Musten 1997; NCT00409708; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Oesterheld 1998; Pearson 2013; Pelham 2001a; Pelham 2011; Pelham 2014; Pliszka 2017; Riggs 2011; Schachar 1997a; Schachar 2008; Schulz 2010; Sharp 1999; Shiels 2009; Silva 2005a; Silva 2006; Silva 2008; Smithee 1998; Solanto 2009; Stein 2003; Stein 2011; Sumner 2010; Swanson 2004b; Tannock 1989; Tannock 1992; Tannock 1993; Tannock 1995a; Tannock 1995b; Tannock 2018; Tirosh 1993a; Tirosh 1993b; Tourette's Syndrome Study Group 2002; Van der Meere 1999a; Weiss 2021; Wigal 2003; Wigal 2013; Wigal 2014; Wigal 2015; Wigal 2017; Wilens 2008; Wilens 2010; Wolraich 2001; Zeni 2009
Cardiac abnormalities or cardiac surgery, or clinically significant abnormalities in ECG results, or family history of sudden death or long‐QT syndrome, or ventricular arrhythmia, or hypertension, or hypotension, or bradycardia, or syncope	50	Arnold 2004; Barkley 1989b; Barkley 1991; Barkley 2000; Blum 2011; Brams 2012; Buitelaar 1995; Carlson 1995; Childress 2009; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Coghill 2013; Döpfner 2004; DuPaul 1996; Duric 2012; Findling 2008; Findling 2010; Froehlich 2018; Lin 2014; McCracken 2016; NCT02293655; NCT02536105; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Overtoom 2003; Palumbo 2008; Pelham 2001a; Pelham 2011; Quinn 2004; Riggs 2011; Schrantee 2016; Stein 2011; Sumner 2010; Swanson 1998; Swanson 2002a; Swanson 2004b; Tannock 1989; Tourette's Syndrome Study Group 2002; Tucker 2009; Weiss 2021; Wigal 2003; Wigal 2004; Wigal 2011; Wigal 2013; Wigal 2014; Wigal 2015; Wilens 2006b; Wilens 2010
History or evidence of renal disease or impaired renal function	6	Arnold 2004; Childress 2020c; Palumbo 2008; Quinn 2004; Tourette's Syndrome Study Group 2002; Wigal 2004
History or evidence of hepatic disease	2	Childress 2020c; Döpfner 2004
History or evidence of respiratory (other than asthma/allergy) disease	5	Arnold 2004; Buitelaar 1995; Childress 2020c; Quinn 2004; Wigal 2004
History or evidence of endocrine disease (e.g. hyperthyroidism) or insulin dependent diabetes or any metabolic disease	16	Arnold 2004; Barkley 2000; Buitelaar 1995; Childress 2020a; Childress 2020c; Corkum 2008; Corkum 2020; Greenhill 2002; NCT00409708; NCT02536105; Schrantee 2016; Swanson 2004b; Weiss 2021; Wigal 2003; Wigal 2004; Wigal 2015
History or evidence of immune disease	3	Arnold 2004; Childress 2020c; Wigal 2004
Gastrointestinal narrowing, or significant gastrointestinal problems	7	Childress 2020c; Coghill 2013; Huang 2021; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Wigal 2011; Wilens 2006b
Glaucoma	19	Blum 2011; Childress 2020a; Childress 2020c; Coghill 2013; Greenhill 2002; Huang 2021; Kent 1995; NCT02536105; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Schrantee 2016; Swanson 2004b; Weiss 2021; Wigal 2003; Wigal 2011; Wigal 2013; Wigal 2015; Wilens 2006b; Wolraich 2001
Not within 30% of normal body weight, or outside 18/22‐59/75 kg at trial entry, or underweight or overweight or weighs less than 9 kg or 79.5 lb, or weight < 3rd percentile for age	16	Arnold 2004; Carlson 2007; Childress 2020a; Childress 2020b; Coghill 2013; Döpfner 2004; Findling 2008; Gonzalez‐Heydrich 2010; Lin 2014; Murray 2011; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Oesterheld 1998; Pearson 2013; Pliszka 2017; Wigal 2004
Pregnant or lactating or inadequate form of birth control or female who had undergone menarche	41	Barkley 2000; Biederman 2003b; Brams 2008; Brams 2012; Childress 2009; Childress 2020a; Childress 2020b; Coghill 2013; CRIT124US02; Findling 2006; Findling 2007; Findling 2008; Findling 2010; Gonzalez‐Heydrich 2010; Greenhill 2002; Greenhill 2006; McCracken 2016; Muniz 2008; NCT02293655; NCT02536105; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Oesterheld 1998; Palumbo 2008; Pelham 2001a; Pliszka 2017; Riggs 2011; Silva 2005a; Silva 2006; Silva 2008; Stein 2011; Sumner 2010; Swanson 2004b; Tourette's Syndrome Study Group 2002; Weiss 2021; Wigal 2003; Wigal 2004; Wigal 2015; Wilens 2010; Wolraich 2001; Zeni 2009
Abnormal laboratory parameters and/or vital signs and/or physical examination	15	Brams 2012; Findling 2008; Greenhill 2002; Greenhill 2006; McGough 2006; NCT02536105; Oesterheld 1998; Overtoom 2003; Pelham 2011; Pliszka 2017; Swanson 1998; Tucker 2009; Weiss 2021; Wigal 2015; Wigal 2017
ADHD: Attention deficit hyperactivity disorder; CD: conduct disorder; CNS: central nervous system; ECG: electrocardiogram; IQ: Intelligence quotient; ODD: oppositional defiant disorder

^aSevere learning disability (defined by special education enrolment).
^bExceptions: obsessive‐compulsive disorder, conduct or oppositional disorder, overanxious disorder and specific developmental disorders.
^cOnly bipolar disorder, not major depressive disorder.

Results of the search

An overview of the searches can be seen in Figure 1.

1.

We carried out electronic searches over six periods. The four searches that took place from October 2011 to February 2015 are described in detail in the previous version of this review (Storebø 2015a). All searches from the previous version of the review resulted in 183 included trials (from 433 reports), one study (from one report) awaiting classification, and five ongoing trials (from six reports).

Searches up to January 2021 produced an additional 2244 records after duplicates were removed (3132 initial records). Searches up to March 2022 produced an additional 285 records after duplicates were removed (401 initial records). Searches for dissertations up to December 2022 resulted in an additional 100 records after duplicates were removed (237 initial records). We identified an additional 347 records after duplicates were removed (409 initial records) by reading through the reference lists of other reviews on ADHD and stimulant therapy published since 2015, and by corresponding with study authors of included studies and with pharmaceutical companies. We also looked through all included studies from all searches to look for protocols or trial registrations that were not already included, which resulted in 35 of the 347 records. We rescreened studies awaiting classification and ongoing studies from the previous version of the review (eight reports).

During 2021 we contacted authors of 24 of the new included trials twice for supplemental information and data; nine responded and we received data from seven trials. Additionally, we contacted two authors of studies included during the latest search in March 2022 only once but they did not respond in due time to be applied to this review.

For the searches in 2021 and 2022 we excluded non‐randomised studies during screening, focusing only on RCTs. From 3019 screened records we excluded 2574 clearly irrelevant reports on the basis of titles and abstract. We retrieved the full texts of the remaining 445 reports, which we assessed for eligibility. They were all accessible in English. We excluded 254 full‐text reports and identified two studies as awaiting classification (from 2 reports; see Characteristics of studies awaiting classification) and 16 trials as ongoing (from 17 reports; see Characteristics of ongoing studies). We included 172 reports of which 109 described 29 new RCTs, while 63 reports were added to the trials included in the previous version of the review. Additional information about all included trials can be found in the Characteristics of included studies tables.

Included studies

We included a total of 212 trials (from 607 reports) in this review (Figure 1). Of these, 55 are parallel‐group trials (from 222 reports) and 156 are cross‐over trials (from 359 reports). One study (24 reports) includes a parallel phase as well as a cross‐over phase, thus we used data from this study in the parallel trial analyses as well as the cross‐over trial analyses (Kollins 2006 (PATS)). A total of 165 trials (14,271 participants) provided usable data for the quantitative analyses. An overview of key demographics for all included trials can be seen in Table 3, and the distribution of key inclusion and exclusion criteria across the trials is available in Table 4 .

Included parallel‐group trials

Including Kollins 2006 (PATS), we included 56 parallel‐group trials described in 244 reports. Fifty trials (7895 participants) provided usable data for the quantitative analyses.

Duration

Most trials (n = 51) were short‐term (< 6 months in duration). Only four were long‐term trials (conducted for ≥ 6 months; Barragán 2017; Jensen 1999 (MTA); Perez‐Alvarez 2009; Schachar 1997a). The duration of one trial was unclear, but lasted somewhere between three to five months (Tannock 2018). The mean duration of the methylphenidate intervention across 56 trials was 67.1 days (range 1 to 425 days).

Location

Thirty‐five of the 56 trials (including Kollins 2006 (PATS)), were conducted in the USA. Three trials were conducted in the USA and Canada (Biederman 2003b; Jensen 1999 (MTA); Weiss 2021); one in the USA, Canada and Australia (Findling 2006); and one in the USA, Canada, Taiwan, Mexico and Puerto Rico (Lin 2014). Three trials each were conducted in Canada (Butter 1983; Schachar 1997a; Tannock 2018), and the Netherlands (Matthijssen 2019; Schrantee 2016; Van der Meere 1999a). Two trials each were conducted in Brazil (Martins 2004; Szobot 2004), Israel (Green 2011; Jacobi‐Polishook 2009). Single trials were conducted in Mexico (Barragán 2017), New Zealand (Heriot 2008), Germany (Lehmkuhl 2002), and Norway (Duric 2012). One trial was conducted in Germany, Sweden, Spain, Hungary, France, UK, Italy, Belgium, Poland, and the Netherlands (Coghill 2013).

The location of one trial was not clear (Firestone 1981).

Setting

All but the following 10 trials were conducted in outpatient clinics. One was carried out in an outpatient as well as inpatient setting (Green 2011), two were carried out in a naturalistic classroom setting (Biederman 2003b; Greenhill 2006), four in a laboratory classroom (Childress 2017; Childress 2020a; Childress 2020b; Kollins 2021), one in a research unit at a hospital (Schachar 1997a), and two provided no information on setting (Brown 1985; McCracken 2016).

Participants

The 56 trials included a total of 8218 participants with a boy‐to‐girl ratio of 3:1 (with the percentage of girls ranging from 0% to 41% (mean across studies 23.8%)). All participants were between 3 and 20 years of age (mean 9.9 years).

Thirty‐nine trials described the percentage of methylphenidate‐naive participants (range 0% to 100%; mean 51.6%).

Thirty‐seven trials described the proportion of participants with combined subtype ADHD (range 25% to 100%; mean 69.9%); 33 trials reported the proportion of participants with hyperactive subtype (range 0% to 56%; mean 4.5%) and 34 trials revealed the proportion with inattentive subtype (range 0% to 72.9%; mean 25.8%).

Six trials excluded children and adolescents with any psychiatric comorbidity (Findling 2010; Greenhill 2002; Greenhill 2006; Perez‐Alvarez 2009; Tucker 2009; Wigal 2017). Eleven trials clearly stated what comorbidities were or could be included, (Duric 2012; Green 2011; Jensen 1999 (MTA); Lehmkuhl 2002; Pliszka 2000; Riggs 2011; Schachar 1997a; Szobot 2004; Tourette's Syndrome Study Group 2002; Van der Meere 1999a; Wolraich 2001), and 21 trials excluded psychiatric comorbidities to some extent. Thirteen of the trials only allowed the psychiatric comorbidities oppositional defiant disorder, conduct disorder, socially aggressive, or disturbance in social behavior (Carlson 2007; Findling 2008; Heriot 2008; Horn 1991; Ialongo 1994; Lin 2014; Martins 2004; McCracken 2016; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose); Palumbo 2008; Tannock 2018). One only included participants with oppositional defiant disorder or conduct disorder but there was no information on the presence of other psychiatric comorbidities (Connor 2000). For two trials there was no limit to psychiatric comorbidities (Coghill 2013; Kollins 2006 (PATS)). Two trials stated nothing about the inclusion or exclusion of comorbidities or their prevalence among participants (Butter 1983; NCT00409708). Opositional defiant disorder was the most commonly reported comorbidity (prevalence clearly reported for 19 trials, range 8.2% to 53%; mean 35.1%), followed by conduct disorder (prevalence clearly reported for 11 trials, range 2% to 32.3%; mean 11.2%). Three trials reported oppositional defiant disorder and conduct disorder together (range 57.6% to 100%) (Connor 2000; Martins 2004; Szobot 2004), therefore we could not use them for the calculated mean.

Nine trials specifically excluded participants taking other medications (Carlson 2007; Childress 2017; Heriot 2008; Ialongo 1994; Jacobi‐Polishook 2009; Kollins 2006 (PATS); Perez‐Alvarez 2009; Tucker 2009; Wigal 2017), and 35 trials specified the exclusion or inclusion of some medications. Four trials had comedication as part of the intervention (Carlson 2007; Connor 2000; McCracken 2016; Riggs 2011). No information on comedication was available for 16 of the trials.

Some form of co‐therapy was part of the intervention in 10 of the trials (Brown 1985; Firestone 1981; Heriot 2008; Horn 1991; Jensen 1999 (MTA); NCT00409708; Palumbo 2008; Perez‐Alvarez 2009; Riggs 2011; Tucker 2009). Two trials had a therapy phase prior to medication (Childress 2020c; Kollins 2006 (PATS)), and five trials specified limitations to therapy during the study (Biederman 2003b; Childress 2009; Greenhill 2006; Matthijssen 2019; NCT02293655). Nothing was stated about co‐therapy for the remaining 39 trials.

Interventions

Twenty‐nine trials used extended‐ and modified‐release methylphenidate. Two trials used immediate‐ and extended‐release methylphenidate (Findling 2006; Wolraich 2001). One trial used transdermal methylphenidate patches (Findling 2010), and one trial used both transdermal patches and extended‐release methylphenidate (Findling 2008). The type used in four trials was unclear (Butter 1983; Horn 1991; Ialongo 1994; Schrantee 2016). The remaining 19 trials used immediate‐release methylphenidate.

The method of reporting the dosage of methylphenidate varied considerably between trials, but the overall daily dose ranged from 5 mg to 68 mg with a mean reported total daily dose of 34.4 mg/day or 0.78 mg/kg/day. The average dose of any type of modified‐ or extended‐release methylphenidate was 44.2 mg, and the average dose of immediate‐release methylphenidate was 23.0 mg.

Forty‐eight trials used placebo as control, and eight used no intervention as control (Barragán 2017; Brown 1985; Duric 2012; Heriot 2008; Jensen 1999 (MTA); NCT00409708; Perez‐Alvarez 2009; Tucker 2009).

Eight trials used clonidine (Connor 2000; Palumbo 2008; Tourette's Syndrome Study Group 2002), omega 3/6 (Barragán 2017), atomoxetine (Carlson 2007), guanfacine (McCracken 2016), or lisdexamphetamine (Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose)), as a co‐intervention in both the intervention and control groups. Three trials used parent training (Firestone 1981; Heriot 2008; Schachar 1997a), two used cognitive‐behavioural therapy (Brown 1985; Riggs 2011), and six used other behavioural therapies (Duric 2012; Horn 1991; Jensen 1999 (MTA); NCT00409708; Perez‐Alvarez 2009; Tucker 2009), as co‐interventions for the intervention and control groups. One trial used neurofeedback as co‐intervention in both the intervention and control group (Duric 2012).

Included cross‐over trials

We included 157 cross‐over trials (including Kollins 2006 (PATS)), described in 383 reports. Of these, 116 trials (6490 participants) provided usable data for the quantitative analyses

Seventy‐five trials were described in a single publication. Sixteen trials yielded five or more publications. One trial, that ran until 2020 is reported across the greatest number of publications per trial, with 27 publications all reporting preliminary data with a varying number of participants across reports (Bhat 2020).

Duration

Three cross‐over trials did not report duration (Kelly 1989; Sunohara 1999; Tannock 1993). The remaining 154 cross‐over trials had a duration of less than six months.

The duration of methylphenidate treatment, including all periods of methylphenidate at any dose for the individual participant, without counting the duration of the placebo intervention, ranged between 1 and 56 days with a mean of 15.2 days.

Location

A total of 109 trials were carried out in the USA; 21 in Canada; and one in both the USA and Canada (Quinn 2004). Six trials were conducted in Israel (Kritchman 2019; Lufi 1997; Lufi 2007; Moshe 2012; Tirosh 1993a; Tirosh 1993b); five in Germany (Bliznakova 2007; Döpfner 2004; Konrad 2004; Konrad 2005; Schulz 2010); five in the Netherlands (Buitelaar 1995; Flapper 2008; Kortekaas‐Rijlaarsdam 2017; Lijffijt 2006; Overtoom 2003); two each in the UK (Coghill 2007; Taylor 1987), Norway (Ramtvedt 2013; Zeiner 1999), and Brazil (Szobot 2008; Zeni 2009); and one each in Australia (Nikles 2006), Iran (Soleimani 2017), and Taiwan (Huang 2021). One trial did not specify the country of origin (Hicks 1985).

Setting

Twenty‐one trials were completed as a part of summer treatment programmes or summer schools. Nine trials were conducted in inpatient wards (Brown 1991; Carlson 1995; Gonzalez‐Heydrich 2010; Kent 1995; Konrad 2005; Pelham 1993a; Pelham 2002; Solanto 2009; Wallace 1994), and seven in both outpatient clinics and inpatient wards (Garfinkel 1983; Hicks 1985; Kaplan 1990; Kolko 1999; Konrad 2004; Tannock 1992; Wallander 1987). Sixteen trials were conducted in a laboratory classroom setting and one in a naturalistic school setting (Ullmann 1986). Six trials did not report the setting (Bliznakova 2007; CRIT124US02; Pliszka 2007; Stoner 1994; Ullmann 1985; Urman 1995). All remaining trials were conducted in outpatient clinics only.

Participants

The 157 cross‐over trials included a total of 8198 participants (range 1 to 430 per trial; mean 52.2). The percentage of girls ranged from 0% in 30 trials to 100% in one trial (CRIT124US02); (mean across the 149 studies that reported ratio; 18.7%, equivalent to a boy‐to‐girl ratio of 7:2). All participants were between 4 and 21 years of age (mean 9.7 years). Sixteen trials did not report average age; however, all of these trials reported age range (Ahmann 1993; Carlson 1995; Coghill 2007; Corkum 2008; Gadow 1990; Kent 1999; Klorman 1990; Leddy 2009; NCT02039908; Pelham 1989; Quinn 2004; Rapport 1987; Solanto 2009; Sumner 2010).

A total of 97 trials described the percentage of methylphenidate‐naive participants included (range 0% to 100%; mean 52.7%). In 29 trials, all participants were methylphenidate‐naive. Thirty trials only included participants previously treated with methylphenidate.

Eighty‐one trials described the proportion of participants with combined ADHD subtype (range 0% to 100%; mean 70.3%), 73 trials reported the proportion with hyperactive subtype (range 0% to 100%; mean 7.8%) and 74 trials reported the proportion with inattentive subtype (range 0% to 73.7%; mean 21.6%).

Fifteen trials excluded children with any psychiatric comorbdity (Flapper 2008; Garfinkel 1983; Huang 2021; Lufi 1997; Moshe 2012; Muniz 2008; Quinn 2004; Schachar 2008; Soleimani 2017; Swanson 1998; Swanson 2002a; Tirosh 1993a; Tirosh 1993b; Wilens 2008; Wilkison 1995). Forty‐six trials clearly stated what comorbidities were or could be included and 22 trials excluded psychiatric comorbidities to some extent. Thirty‐eight of the trials only allowed the psychiatric comorbidities oppositional defiant disorder, conduct disorder, socially aggressive or disturbance in social behaviour. For five trials there was no limit to psychiatric comorbidities (Cox 2006; Gadow 2011; Kent 1999; Kollins 2006 (PATS); Symons 2007). Thirty‐three stated nothing about the inclusion or exclusion of comorbidities or their prevalence among participants.

Opposotional defiant disorder was the most commonly reported comorbidity (prevalence clearly reported for 67 trials, range 1.36% to 100%; mean 43.2%), followed by conduct disorder (prevalence clearly reported for 56 trials, range 2.9% to 100%; mean 24%). Six trials reported oppositional defiant disorder and conduct disorder together (range 57.6 to 100%) therefore we could not use them for the calculated mean (Carlson 1995; Döpfner 2004; Gorman 2006; Hale 2011; Pelham 2011; Tannock 1995a). Six trials reported participants with Tourette's syndrome (range 2.7% to 100%; mean 67%; Castellanos 1997; Coghill 2007; Gadow 1995; Gadow 2007; Gadow 2011; Kent 1999). One trial only included participants with epilepsy (Gonzalez‐Heydrich 2010), one trial only included participants with cerebral palsy (Symons 2007), and two trials only included participants with bipolar disorder or borderline personality (Findling 2007; Zeni 2009). Twenty‐eight trials reported prevalence of participants with comorbid anxiety (range 2.7% 46% mean 20.8%).

Twenty‐seven trials specifically excluded participants taking other medications, and 48 trials specified the exclusion or inclusion of some medications. Six trials had comedication as part of the intervention (Carlson 1995; Findling 2007; Gonzalez‐Heydrich 2010; Kaplan 1990; Szobot 2008; Zeni 2009). No information on comedication was available for 82 of the trials.

Some form of co‐therapy was part of the intervention in five of the trials (Döpfner 2004; Fabiano 2007; Kolko 1999; Pelham 2014; Waxmonsky 2008). One trial had a therapy phase prior to medication (Kollins 2006 (PATS)), and six trials specified limitations to therapy during the study (Brams 2012; Froehlich 2018; Lufi 1997; Muniz 2008; Silva 2006; Silva 2008). The remaining 145 trials stated nothing about co‐therapy.

Interventions

Thirty‐two of the trials used extended‐ and modified‐release methylphenidate and 83 of the trials used immediate‐release methylphenidate. Nine trials used both immediate‐ and extended‐release methylphenidate (Döpfner 2004; Johnston 1988; Fitzpatrick 1992a; Pearson 2013; Pelham 1990a; Pelham 2001a; Schachar 2008; Swanson 2002b; Wigal 2003), four trials used two different types of extended‐release methylphenidate (Lopez 2003; Schulz 2010; Silva 2005a; Swanson 2004b), one trial used three different types of extended‐release methylphenidate (NCT02536105), and five trials used transdermal methylphenidate patches (McGough 2006; Pelham 2005; Pelham 2011; Wilens 2008; Wilens 2010). It was unclear what type of methylphenidate the remaining 28 trials used.

The method of reporting the dose of methylphenidate varied considerably between trials, and the dose administered to participants was unclear for 20 trials. Overall daily dose ranged from 4 mg to 72 mg, with a mean reported total daily dose of 24.6 mg or 0.77 mg/kg/day. Doses of immediate‐release methylphenidate ranged from 4 mg to 50 mg, with a mean reported total daily dose of 21.4 mg or 0.8 mg/kg. Doses of extended‐release methylphenidate ranged from 15 mg to 72 mg, with a mean reported total daily dose of 35.2 mg or 1.1 mg/kg. The duration of methylphenidate treatment ranged from 1 to 56 days, with an average duration of 15.2 days.

All trials used a placebo as a control.

In six trials, participants received some kind of comedication in both the intervention and control groups (antidepressant: Carlson 1995; divalproex sodium: Findling 2007; continuation of stable antiepileptic medication: Gonzalez‐Heydrich 2010; diphenhydramine 50 mg: Kaplan 1990; marijuana and/or cocaine: Szobot 2008; an antipsychotic: Zeni 2009).

In five trials some form of therapy was part of the intervention in both the intervention and control groups (Döpfner 2004; Fabiano 2007; Kolko 1999; Pelham 2014; Waxmonsky 2008).

Outcomes

Some psychometric ADHD instruments measured the total score for ADHD symptoms, whereas others assessed only specific symptom domains of ADHD (e.g. inattention, hyperactivity, impulsivity). We categorised all scales into five subgroups: ADHD symptoms; serious adverse events; non‐serious adverse events; general behaviour; and quality of life. Some psychometric instruments are abbreviated versions or revised versions, but all have been validated.

ADHD symptoms

Conners' questionnaires were the most frequently used measures of ADHD symptoms; more than 30 different versions measured core symptoms of ADHD (normative data are generally well intercorrelated in revised versions; Goyette 1978).

Table 5 presents the list of all measures that the included trials used to assess ADHD symptoms. This list primarily refers to original articles describing the psychometric properties of measurement scales, but in a few cases, we refer to trials describing the use of a specific measurement scale.

4. ADHD symptoms rating scales.

Name of scale	Abbreviation	Reference
Abbreviated Conners’ Rating Scales, Parent (ACPRS) and Teacher (ACTRS), including Abbreviated Parent Rating Scale (APRS) and Teacher Rating Scale, Hyperkinesis Index and ADHD and Emotional Lability subscales	ACRS	Conners 1997a
Abbreviated Symptom Questionnaire, including ASQ Teacher and ASQ Parent	ASQ	Conners 1995
Academic Performance Rating Scale	APRS	DuPaul 1991a
The ADD/H Comprehensive Teacher Rating Scale	ACTeRS	Ullmann 1984
ADHD/ODD Rating Scale, Parent‐ and Teacher‐Rated	ADHD‐RS	Barkley 1998
ADHD Rating Scale, including ADHD Rating Scale Parent and Teacher Ratings	ADHD‐RS	DuPaul 1991a
ADHD Rating Scale‐IV, including ADHD Rating Scale‐IV Parent and Teacher Versions	ADHD‐RS‐IV	DuPaul 1991a
Brief Psychiatric Rating Scale for Children	BPRS	Gale 1986
Child Attention Problems Rating Scale	CAP	Achenbach 1986
Child Attention Profile	CAP	Barkley 1988b
Child Behavior Rating Form	NCBHF	Aman 1996
Child Symptom Inventory	CSI	Gadow 1994
Children’s Psychiatric Rating Scale	CPRS	Pfefferbaum‐Levine 1983
Conners’ Abbreviated Hyperactivity Questionnaire	C‐HI	Conners 1997a
Conners’ Abbreviated Questionnaire	ASQ	Conners 1995
Conners’ Abbreviated Parent Teacher Questionnaire	APTQ	Rowe 1997
Conners’ Abbreviated Rating Scale	ABRS	Conners 1997a
Conners’ Abbreviated Symptom Questionnaire	ASQ	Conners 1995
Conners Abbreviated Symptom Questionnaire for Parents	ASQ‐Parent	Conners 1995
Conners’ Abbreviated Symptom Questionnaire for Teachers	ASQ‐Teacher	Conners 1997a
Conners’ Abbreviated Teacher Rating Scale	ABTRS	Conners 2001
Conners’ ADHD/DSM‐IV Scales Adolescent	CADS‐A	Conners 1997b
Conners’ ADHD/DSM‐IV Scales Parent	CADS–P, CADS‐P DSM‐IV	Conners 1997a
Conners’ ADHD/DSM‐IV Scale Teacher, including Inattentive and Hyperactive‐Impulsive subscales	CADS‐T, CADS‐T DSM‐IV	Conners 1997a
Conners’ Rating Scale ‐ Revised, Parent and Teacher: Hyperactivity and Conduct Factors score	CPRS‐R and CTRS‐R	Goyette 1978
Conners’ Hyperactivity Index, Parent and Teacher, including abbreviated versions	CPRS/CTRS‐Hyperactivity index	Conners 1997a
Conners’ Hyperkinesis Index	‐	Milich 1980
Conners, Loney and Milich Scale	CLAM	Milich 1980
Conners’ Parent and Teacher Rating Scale ‐ Revised, Short Form	CRS‐R:S	Conners 1997a
Conners’ Parent Rating Scale, including abbreviated versions	CPRS	Conners 1998b
Conners’ Parent Rating Scale ‐ Revised	CPRS‐R	Conners 1997a
Conners’ Parent Rating Scale ‐ Revised, Short Form	CPRS‐R:S	Conners 1997a
Conners’ Parent Rating Scale ‐ Revised, Long Version	CPRS‐R:L	Conners 1997a
Conners’ Rating Scale ‐ Revised	CRS‐R	Conners 1997a
Conners’ Short Form Rating Scale, Parent and Teacher	‐	Conners 1997a
Conners’ Teacher Rating Scale	CTRS	Conners 1998a
Conners’ Teacher Rating Scale ‐ Revised, Long Version	CTRS‐R:L	Conners 1998a
Diagnostic and Statistical Manual of Mental Disorders Total	DSM‐IV	APA 1994
Diagnostiksystem für Psychische Störungen im Kindes ‐ und Jugendalter nach ICD‐10 und DSM‐IV Parental Questionnaire of ADHD symptoms	DISYPS	Döpfner 2000
Fremdbeurteilungsbogen für Hyperkinetische Störungen	FBB‐HKS	Döpfner 2008
German Teacher’s report on ADHD symptoms	FBB‐HKS of the DISYPS	Döpfner 2000
Hyperactivity Index of the Revised Conners Parent and Teacher Rating Scales	‐	Goyette 1978
IOWA Conners Parent Rating Scale, including abbreviated versions	IOWA CPRS	Loney 1982
IOWA Conners Teacher Rating Scale, including abbreviated versions	IOWA CTRS	Loney 1982
IOWA Conners Teacher Rating Scale, Inattention/Overactivity (I/O) and Oppositional/Defiant (O/D) subscales	IOWA‐I/O and O/D subscales	Loney 1982
IOWA Inattention/Overactivity and Aggression/Noncompliance scales ‐ Parent and Teacher rating	IOWA	Loney 1982
Lehrer‐Fragenbogen von Steinhausen	LF	Steinhausen 1993
Loney’s Time on Task Scale, Hyperactivity, Attention and Aggression subscales	TOTS	Fitzpatrick 1992b
Modified Conner Scale Parent and Teacher	ACR	Conners 1997a
Mothers’ Objective Method for Subgrouping	MOMS	Loney 1984
Parent Symptom Checklist	PSC ADHD	Döpfner 2000
Parental Account of Children’s Symptoms	PACS	Chen 2006
Restricted Academic Situation Scale	RASS	Fischer 1998
Schedule for Affective Disorders and Schizophrenia	K‐SADS/ K‐SADS‐E for diagnosis	Chambers 1985
Swanson, Nolan, and Pelham ‐ IV SNAP‐ADHD Rating scale	SNAP‐ADHD	Swanson 1992
Swanson, Nolan, and Pelham ‐ IV SNAP‐IV (Brazilian Version)	SNAP‐IV	Clark 1993; Clark 1996
Swanson, Kotkin, Atkins, M‐Flynn, Pelham Scale (SKAMP combined, SKAMP attention, and SKAMP deportment)	SKAMP (SKAMP combined, SKAMP attention, and SKAMP deportment)	Wigal 1998; Murray 2009
Teacher Self‐control Rating Scale	SCRS	Kendall 1979
Turgay ‐ DSM‐IV Scale, Parent	T‐DSM‐IV Scale, Parent	Turgay 1994; Ercan 2001
Turgay ‐ DSM‐IV Scale, Teacher	T‐DSM‐IV Scale, Teacher	Turgay 1994; Ercan 2001
Teacher Hyperactivity Index	THI	Achenbach 1991b
Teacher Symptom Checklist	TSC	Döpfner 2000
Vanderbilt ADHD Rating Scale	VADP(T)RS	Wolraich 2003
Wender Utah Rating Scale	WURS	Ward 1993
Wide Range Achievement Test	WRAT‐4	Wilkinson 2006
Wide Range Achievement Test Revised	WRAT‐R	Woodcock 2001
ADD/H: Attention deficit disorder/with hyperactivity; ADHD: Attention deficit hyperactivity disorder; DSM‐IV:Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ICD‐10:International Classification of Diseases, Tenth Edition; ODD: ODD

Serious and non‐serious adverse events

Trials used rating scales or spontaneous reports to measure adverse events, or they were recorded by investigators at regular interviews or visits, or both. Some trials included physical examinations or paraclinical examinations, or both, such as blood testing, electrocardiogram, blood pressure reading, measurement of heart rate and assessment of weight and height. We recorded serious adverse events in accordance with the ICH classification (ICH 1996). However, when in doubt, we asked trial authors which classification or definition they had used in their trial.

Some trials combined all of the above modes of measurement; others used a single measure such as spontaneous reports or rating scales. Sixty‐eight trials employed rating scales; the Barkley Side Effect Rating Scale (SERS) was used most frequently (Barkley 1990).

Other scales used included the Significant Adverse Event Reviews Questionnaire (SAERS; Barkley 1990; Zeni 2009), the Pittsburgh Side Effect Rating Scale (PSERS; Pelham 1993b; Pelham 2005a) and Subject’s Treatment Emergent Symptom Scale (STESS; Guy 1976a).

For the purpose of measuring specific adverse events, some trials used rating scales such as Paediatric Sleep Questionnaire (PSQ; Chervin 2000), Sleep Disturbances Scale for Children (SDSC; Bruni 1996), Children’s Sleep Habits Questionnaire (CSHQ; Owens 2000), Childrens' Depression Rating Scale (CDRS‐R; Poznanski 1983), The Colombia Suicide Severity Rating Scale (C‐SSRS, Posner 2011), Young Mania Rating Scale (YMRS; Young 1978), Yale Global Tic Severity Scale (YGTSS; Leckman 1989), Tic Symptom Self Report Scale (TSSR; Leckman 1988), and the Massachusetts General Hospital (MGH) Abuse and Diversion Questionnaire (Wilens 2006a).

General behaviour

Trials used many different scales to assess general behaviour. These scales have different foci, such as aggression or oppositional behaviour, but all describe participants’ behaviour and the influence of methylphenidate. Higher scores on general behaviour symptom scales signify better outcomes.

Table 6 presents the list of all measures used to assess general behaviour. This list refers primarily to the original articles describing the psychometric properties of measurement scales used to measure general behaviour in the included trials. In a few cases, we refer to trials that describe the use of a specific measurement scale.

5. General behaviour rating scales.

Name of scale	Abbreviation	Reference
Achenbach Child Behaviour Checklist	CBCL	Achenbach 1991a
Achenbach’s Teacher Report	ATRF	Achenbach 1991b; Achenbach 2001
ADHD Rating Scale	ADHD‐RS	DuPaul 1991a
ADHD School Observation Code	ADHD‐SOC	Gadow 1996
Barkley Scales, Disruptive Behavior Disorders Rating Scale	‐	Barkley 1991a
Before School Functioning Questionnaire	BSFQ	Faraone 2018
Behavior Rating Inventory of Executive Function	BRIEF	Gioia 2000
Child Attention Problems Scale	CAP	Barkley 1991
Child Attention Profile	CAP	Barkley 1988b
Child Behavior Checklist	CBCL	Achenbach 1991a
Child Health Questionnaire	CHQ	Landgraf 1998
Child and Adolescent Psychiatric Assessment, selected items	CAPA	Angold 1995
Children’s Psychiatric Rating Scale	CPRS	Fish 1985
Classroom Observation Code (Abikoff Classroom Observational System)	COC	Abikoff 1980
Code for Observing Social Activity	COSA	Sprafkin 1986
Conners' Child Behavior Scale	UC‐CCBS	Ladd 1996
Conners Early Childhood Behavior—Parent Short Response scale	‐	Conners 2009
Conners' Global Index Scale	CGI‐S	Conners 1998a
Conners’ Global Index ‐ Parent	CGI‐P	Conners 1997a
Conners' Global Index ‐ Teacher	CGI‐T	Conners 1998a
Conners', Loney and Milich Scale	CLAM	Milich 1980
Conners’ Parent Questionnaire	CPQ	Conners 1995
Conners’ Parent Rating Scale	CPRS	Conners 1998b
Conners’ Teacher Rating Scale	CTRS	Conners 1998a
Conners’ Teacher Rating Conduct Problems	‐	Miller 1997
Disruptive Behavior Disorders Rating Scale, Parent‐ and Teacher‐Rated	DBS	Mendelsohn 1978
Disruptive Behavior Disorders Rating Scale	DBD	Silva 2005b
Groninger Behaviour Observation Scale	GOO and GBO	Van der Meere 1999b
Groninger Behaviour Checklists, Parent and Teacher Versions of the abbreviated Groninger	GGGS and GGBS	Van der Meere 1999b
Hillside Behavior Rating Scale	HBRS	Gittleman‐Klein 1976
Home Situations Questionnaire	HSQ	Barkley 1987
Home Situations Questionnaire ‐ Revised	HSQ‐R	DuPaul 1992
Humphrey’s Teacher Self‐Control Rating Scale	TSCRS	Humphrey 1982
Hyperactivity Index from the Conners Revised Teacher Rating Scale	CTRS‐R‐Hyperactivity Index	Goyette 1978
Impairment Rating Scale	IRS	Fabiano 2006
Inpatient Global Rating Scale, Revised	IGRS	Conners 1985
Inpatient Global Rating Scale, Somatic factor	IGRS‐S	Conners 1985
IOWA Conners' Rating Scale, Oppositional/Defiant (O/D) subscales	IOWA‐O/D subscales	Loney 1982
Nisonger Child Behavior Rating Form	NCBRF	Aman 1996
Paired Associates Learning	PAL	Wechsler 1945
Parent Global Assessment for Improvement	PGA	McGough 2006a
Parent Rating of Evening and Morning Behavior‐Revised, Morning	PREMP‐R AM	Sutton 2003
Parent Rating of Evening and Morning Behavior‐Revised, Evening	PREMP‐R PM	Sutton 2003
Peer Conflict Scale	PCS	Marsee 2007
Personality Inventory for Children	PIC	Lachar 1986
School Situations Questionnaire	SSQ	Barkley 1987
School Situations Questionnaire ‐ Revised	SSQ‐R	DuPaul 1992
Retrospective Modified Overt Aggression Scale	R‐MOAS	Bladder 2009
Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Scale, Parent and Teacher	SWAN	Swanson 2006; Polderman 2007
Subjective Treatment Emergent Symptom Scale	STESS‐R	Guy 1976
Swanson, Nolan and Pelham, Fourth Edition	SNAP‐IV	Bussing 2008
Teachers Report Form	TRF	Achenbach 1991b
Telephone Interview Probe (Parent and Teacher)	TIP	Corkum 2007
Vanderbilt ADHD rating scales: Vanderbilt ADHD Diagnostic Parent Rating Scale and Vanderbilt ADHD Diagnostic Teacher Rating Scale	VADPRS and VADTRS	Wolraich 2003
Wahler, House and Stambaugh’s Ecobehavioral Assessment System	ECO	Wahler 1976
The Weekly Parent Ratings of Evening and Morning Behaviour	WREMB‐R	Kelsey 2004
Werry‐Weiss‐Peters Activity Rating Scale	WWP	Routh 1978
Woodcock‐Johnson Achievement Battery	WJ‐III Ach	Woodcock 2001
ADHD: attention deficit hyperactivity disorder

Quality of life

Seven scales measured quality of life in relation to both ADHD and life in general. For all scales, higher values equated to better health. Only four could be used in meta‐analyses: Child Health Questionnaire (CHQ; Landgraf 1998); Children's Global Assessment Scale (CGAS; Shaffer 1983); Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP‐CE: PRF; Riley 2004); and The Parent‐ and Child‐rated Revised Questionnaire for Children and Adolescents to record health‐related quality of life (KINDL‐R; Ravens‐Sieberer 1998).

See Table 7 for additional information on the types of rating scales used to assess the quality of life in the included trials.

6. Quality of life ratings scales.

Name of scale	Abbreviation	Reference
ADHD Impact Module‐Child	AIM‐C	AIM‐C 2013
Child Impact Scale and Home Impact Scale	CIS/HIS	Landgraf 2002
Child Health and Illness Profile, Child Edition: Parent Report Form	CHIP‐CE:PRF	Riley 2004
Child Health Questionnaire	CHQ‐P	Landgraf 1998
Children's Global Assessment Scale	CGAS	Shaffer 1983
Comprehensive Psychopathological Rating Scale	CPRS	Aasberg 1978
Health Utilities Index ‐ 2	HUI‐2	Torrance 1982
The parent‐ and child‐rated Revised questionnaire for Children and adolescents to record health‐related quality of life	KINDL‐R	Ravens‐Sieberer 1998
ADHD: attention deficit hyperactivity disorder

Excluded studies

In the previous review we excluded 691 full‐text reports for reasons reported in Storebø 2015a [https://revman.cochrane.org/#/700705021509502610/dashboard/htmlCompare/current/4.36.11?version1WithProductionChanges=false&version2WithProductionChanges=false#REF‐Storeb_x00f8_‐2015a]. For this update, we excluded an additional 254 full‐text reports, which were ineligible for the following reasons: ineligible study design (94 reports), ineligible intervention (40 reports), ineligible comparator (31 reports), study not executed (8 reports), irrelevant supplement (11 reports), ineligible population (13 reports), other reasons (1 report).

The remaining 47 trials (from 56 reports) initially seemed to meet our eligibility criteria but on closer inspection did not, because they examined the impact of methylphenidate on very specific domains that were outside the focus of this review such as motor co‐ordination, reaction time, memory tasks, and reading skills. We added these to the Characteristics of excluded studies [https://revman.cochrane.org/#/700705021509502610/dashboard/htmlCompare/current/4.36.11?version1WithProductionChanges=false&version2WithProductionChanges=false#CHARACTERISTICS_OF_EXCLUDED_STUDIES], which now lists 125 trials. For more information on these trials, please see Characteristics of excluded studies.

Studies awaiting classification

Two trials (Drtílková 1997; Wang 2020), are currently awaiting classification for various reasons. Drtílková 1997 required translation from the Czech language into English, which we were unable to procure within the time frame of working with the update of this review. The other trial Wang 2020 was unavailable to us with all institutional library IDs in our possession. We contacted the trial authors in an attempt to retrieve their report or further information on outcome data but did not receive any reply. For further details on each trial see Studies awaiting classification.

Ongoing trials

We included 16 ongoing trials assessing methylphenidate for children and adolescents with ADHD but for which outcome data have not yet been made available. Ten trials have a parallel design (ChiCTR1800014945; EUCTR2007‐004664‐46‐NL; EUCTR2008‐001291‐71‐DE; IRCT138804132000N2; IRCT201701131556N94; IRCT20190317043079N; NCT00414921; NCT00485550; NCT02807870; Verlaet 2017), and six have a cross‐over design (EUCTR2008‐004425‐42‐NL; EUCTR2020‐003660‐11‐NL; Müller 2021; NCT00141050; NCT00254878; NCT00446537). See Ongoing studies for further information regarding each trial.

Risk of bias in included studies

We assessed the risk of bias of each included trial using the Cochrane risk of bias tool (RoB 1; Higgins 2011). A summary of our assessment is displayed in Figure 2 and Figure 3. One trial, Kollins 2006 (PATS), includes a parallel as well as a cross‐over phase and accounts for a low risk of bias trial among both parallel and cross‐over trials. As shown, we assessed 13 of the 157 cross‐over trials (8.3%) and nine of the 56 included parallel‐group trials (16.1%) at low risk of bias in all domains apart from blinding. However, even the 21 trials (here, counting Kollins 2006 (PATS) as a single trial) likely had breaks in their blinding due to prevalent adverse events due to methylphenidate (see below). We assessed the remaining 191 trials (90.1%) at high risk of bias. Accordingly, we judged all 212 trials to be trials at high risk of bias.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial

We assessed nine of the 56 included parallel trials at low risk of bias in all bias domains (Childress 2020a; Jacobi‐Polishook 2009; Kollins 2006 (PATS); Lehmkuhl 2002; Pliszka 2017; Riggs 2011; Schrantee 2016; Tourette's Syndrome Study Group 2002; Weiss 2021). However, we still considered these trials at risk of deblinding due to prevalent adverse events (see below).

Thirteen of the 157 included cross‐over trials were at low risk of bias in all bias domains (Cook 1993; DuPaul 1996; Flapper 2008; Kollins 2006 (PATS); McGough 2006; Moshe 2012; Rapport 2008; Soleimani 2017; Stein 1996; Stein 2011; Waxmonsky 2008; Wilkison 1995; Zeni 2009). However, even these were considered at risk of deblinding due to prevalent adverse events (see below).

Allocation

Parallel trials

Random sequence generation

We considered 34 trials to be at low risk of bias for random sequence generation, four trials to be at high risk of bias (Connor 2000; Green 2011; Heriot 2008; Tannock 2018), and 18 at unclear risk of bias.

Allocation concealment

We considered 26 trials to be at low risk of bias for allocation concealment (often because medications and packaging were identical in appearance for blinding purposes) and two trials to be at high risk of bias (Barragán 2017; Green 2011). Twenty‐eight trials did not report allocation concealment in sufficient detail to allow us to make a judgement, so were at unclear risk.

Cross‐over trials

Random sequence generation

We considered 64 trials to be at low risk for random sequence generation, nine trials at high risk of bias (Carlson 1995; Fitzpatrick 1992a; Kaplan 1990; Kelly 1989; Manos 1999; McBride 1988a; Szobot 2008; Tirosh 1993b; Wigal 2014), and 84 trials at unclear risk of bias.

Allocation concealment

We considered 57 trials to be at low risk of bias for allocation concealment (often because medications and packaging were identical in appearance for blinding purposes), five trials at high risk of bias (Carlson 1995; Fitzpatrick 1992a; Szobot 2008; Ullmann 1985; Wigal 2014), and 95 trials did not sufficiently report allocation concealment so we judged them at unclear risk of bias.

Blinding

Parallel trials

We considered that 40 trials adequately described their method of blinding of participants and personnel so we judged them to be at low risk of bias. Ten trials gave insufficient information about their methods so we judged them to be at unclear risk of bias (Biederman 2003b; Childress 2009; Childress 2017; Childress 2020b; Childress 2020c; Findling 2010; Greenhill 2006; Lin 2014; Tucker 2009; Wigal 2017). Six trials were not blinded (Barragán 2017; Brown 1985; Duric 2012; Jensen 1999 (MTA); NCT00409708; Perez‐Alvarez 2009), so we judged them to be at high risk of bias.

We considered that 34 trials adequately described their method of blinding of outcome assessment so we judged them to be at low risk of bias. Seventeen trials gave insufficient information about their methods and were considered to be at unclear risk of bias. Six trials did not include blinded outcome assessors (Barragán 2017; Brown 1985; Duric 2012; Jensen 1999 (MTA); NCT00409708; Perez‐Alvarez 2009), so we judged them to be at high risk of bias.

Cross‐over trials

We judged that 118 trials adequately described their method of blinding of participants and personnel so we therefore judged them at low risk of bias. Thirty‐one trials were considered at unclear risk of bias. Eight trials were not blinded (Lopez 2003; Manos 1999; Pearson 2013; Pelham 2014; Ramtvedt 2013; Stein 2003; Ullmann 1985; Wigal 2013), so we judged them to be at high risk of bias.

We judged that 86 trials adequately described their method of blinding of outcome assessment and were therefore considered at low risk of bias, and 66 trials were considered at unclear risk of bias. Five trials did not include blinded outcome assessors (Cox 2006; Douglas 1986; Manos 1999; Wigal 2013; Wodrich 1998), so we judged them to be at high risk of bias.

Incomplete outcome data

Parallel trials

Thirty trials adequately addressed incomplete data and were considered at low risk of bias. Twenty trials did not so we judged them to be at high risk of bias. Six trials gave insufficient information for us to assess whether the method they used to handle missing data was likely to bias the estimate of effect (Childress 2020b; Coghill 2013; Firestone 1981; NCT02293655; Palumbo 2008; Wigal 2004), and we therefore considered them at unclear risk of bias.

Cross‐over trials

Eighty‐five trials adequately addressed incomplete data so we judged them to be at low risk of bias. Forty‐eight trials gave insufficient information to assess whether the method they used to handle missing data was likely to bias the estimate of effect so we judged them to be at unclear risk of bias. Twenty‐four trials had incomplete outcome data and were therefore considered at high risk of bias.

Selective reporting

Parallel trials

Thirty‐four trials reported all pre‐defined or otherwise expected outcomes so we judged them at low risk of bias. Five trials did not (Childress 2020b; Greenhill 2006; Lin 2014; NCT02293655; Wigal 2015), and these were considered at high risk of bias. In 17 trials it was unclear whether trial authors reported all pre‐defined or otherwise expected outcomes (Arnold 2004; Barragán 2017; Biederman 2003b; Brown 1985; Butter 1983; Findling 2006; Firestone 1981; Greenhill 2002; Heriot 2008; Horn 1991; Ialongo 1994; Schachar 1997a; Szobot 2004; Tannock 2018; Tucker 2009; Wigal 2004; Wolraich 2001), so we judged them at unclear risk of bias.

Cross‐over trials

Forty‐seven trials reported all pre‐defined or otherwise expected outcomes so we judged them at to be at low risk of bias. Thirteen trials did not so these were considered at high risk of bias (Castellanos 1997; Chacko 2005; CRIT124US02; Froehlich 2018; Gonzalez‐Heydrich 2010; Gorman 2006; Hawk 2018; Huang 2021; McInnes 2007; NCT02536105; Stein 2003; Taylor 1993; Wallace 1994). In 97 trials it was unclear whether trial authors reported all pre‐defined or otherwise expected outcomes so we judged them at unclear risk of bias.

Other potential sources of bias

We identified no other potential sources of bias for either parallel or cross‐over trials.

Effects of interventions

See: Table 1

Below, we present the results of meta‐analyses performed for the comparison methylphenidate versus placebo or no intervention for two primary outcomes (ADHD symptoms and serious adverse events) and three secondary outcomes (non‐serious adverse events, general behaviour, and quality of life). Twenty‐nine parallel‐group trials (50%) and 60 cross‐over trials (38.2%) excluded methylphenidate non‐responders, placebo responders or patients with methylphenidate adverse events before randomisation. The subgroup analyses on enrichment designs compared to no enrichment designs are described in each outcome section below.
For a summary of key results, please see Table 1.

Primary outcomes

ADHD symptoms

We were able to combine data on ADHD symptoms from 47 parallel‐group trials and 82 cross‐over trials, of which five also provided first‐period data.

Teacher‐rated ADHD symptoms

Parallel‐group trials and cross‐over trials (end of first‐period data only)

A meta‐analysis showed a difference in effects between methylphenidate and placebo on teacher‐rated ADHD symptoms favouring methylphenidate (SMD −0.74, 95% CI −0.88 to −0.61; I² = 38%; 21 trials, 1728 participants; Analysis 1.1). The SMD of −0.74 for ADHD symptoms corresponds to a mean difference (MD) of −10.58 points (95% CI −12.58 to −8.72) on the ADHD Rating Scale (DuPaul 1991a). This is an effect above the minimal relevant difference (MIREDIF; Zhang 2005).

1.1. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 1: All parallel‐group trials and first‐period cross‐over trials

• Subgroup analyses

  • We found that types of scales used influenced the intervention effect of methylphenidate (test for subgroup differences: Chi² = 24.94, df = 10 (P = 0.005), I² = 59.9%; Analysis 1.2). The differences between the scale that influenced the effect most and least was more than SMD −0.5.

  • We found lower effect of methylphenidate in long‐term trials (SMD −0.47, 95% CI −0.72 to −0.22; 1 trial, 253 participants) compared to that of short‐term trials (SMD −0.77, 95% CI −0.91 to −0.64; I² = 30%; 20 trials, 1475 participants). Test for subgroup differences showed Chi² = 4.26, df = 1 (P = 0.04), I² = 76.5%; Analysis 1.3. The SMD effect of −0.47 for ADHD long‐term trials corresponds to an MD of −6.72 points (95% CI −10.3 to −3.15) on the ADHD‐RS (DuPaul 1991a). This is an effect just above the MIREDIF (Zhang 2005).

  • No evidence suggested that any of the following influenced the estimated intervention effect:

    • the risk of bias (test for subgroup differences: Chi² = 0.13, df = 1 (P = 0.71), I² = 0%; Analysis 1.1)

    • dose (test for subgroup differences: Chi² = 3.15, df = 2 (P = 0.21), I² = 36.5%; Analysis 1.4)

    • medication status before randomisation (test for subgroup differences: Chi² = 0.59, df = 1 (P = 0.44), I² = 0%; Analysis 1.5)

    • enrichment design (test for subgroup differences: Chi² = 0.07, df = 1 (P = 0.79), I² = 0%; Analysis 1.6)

    • trial design (parallel‐group trials compared to first‐period cross‐over trials, test for subgroup differences: Chi² = 0.71, df = 1 (P = 0.40), I² = 0%; Analysis 1.7)

    • vested interest (test for subgroup differences: Chi² = 2.64, df = 1 (P = 0.10), I² = 62.1%; Analysis 1.8) or

    • type of control group (test for subgroup differences: Chi² = 0.59, df = 1 (P = 0.44), I² = 0%; Analysis 1.9)

  • Inspection of the funnel plot in Figure 4 suggested potential bias (asymmetry), although we found no evidence of significant publication bias: Egger’s regression intercept (bias) was −0.2260 (two‐tailed, P = 0.81).

  • One of the trials in this meta‐analysis used change‐from‐baseline scores (Palumbo 2008), but removing this trial did not significantly change the estimate.

1.2. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 2: Subgroup analysis: types of scales

1.3. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 3: Subgroup analysis: duration of treatment

1.4. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 4: Subgroup analysis: dose

1.5. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 5: Subgroup analysis: medication status ‐ medication naive versus not medication naive

1.6. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 6: Subgroup analysis: trials with enrichment design compared with trials without enrichment design

1.7. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 7: Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials

1.8. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 8: Subgroup analysis: vested interest

1.9. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 9: Subgroup analysis: type of control group

4.

Funnel plot of comparison 1. Teacher‐rated ADHD symptoms, outcome: 1.8 All data at low and high risk of bias (parallel‐group and cross‐over trials)

We assessed the evidence to be of very low certainty (see GRADE assessment below). Therefore we are uncertain that the estimated effect accurately reflects the true effect, and the addition of more data could change the findings.

Cross‐over trials (end of last period)

Meta‐analysis suggested a difference in effect between methylphenidate and placebo on teacher‐rated ADHD symptoms favouring methylphenidate (SMD −0.88, 95% CI −1.01 to −0.75; I² = 82%; 64 trials, 6341 participants; Analysis 1.10).

1.10. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 10: Cross‐over trial (endpoint data)

• Subgroup analyses

  • The estimated intervention effect varied according to risk of bias (test for subgroup differences: Chi² = 4.76, df = 1 (P = 0.03), I² = 79.0%; Analysis 1.10), and dose of methylphenidate (test for subgroup differences: Chi² = 4.12, df = 1 (P = 0.04), I² = 75.7%; Analysis 1.11). Three of the trials included some participants with an IQ less than 70 (Pearson 2013; Smith 1998; Taylor 1987). Removing these trials from the analyses did not significantly change the results.

1.11. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 11: Subgroup analysis: cross‐over trials (endpoint data): dose

Parallel‐group trials and cross‐over trials (end of first period) and cross‐over trials (end of last period)

Meta‐analysis suggested a difference in effects between methylphenidate and placebo on reduced teacher‐rated ADHD symptoms favouring methylphenidate (SMD −0.82, 95% CI −0.87 to −0.77; I² = 78%; 81 trials, 7564 participants; Analysis 1.12).

1.12. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 12: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data)

• Subgroup analyses

  • No evidence suggested that the intervention effect varied according to trial design (parallel and first period cross‐over compared to cross‐over trials end of last period; test for subgroup differences: Chi² = 3.41, df = 1 (P = 0.06), I² = 70.6%; Analysis 1.12).

  • No evidence suggested that the intervention effect varied according to the risk of bias assessment in subgroups (low risk of bias compared to high risk of bias; test for subgroup differences: Chi² = 2.13, df = 1 (P = 0.14), I² = 53.0%; Analysis 1.13).

  • Nor did it vary according to high or low risk of vested interest (test for subgroup differences: Chi² = 0.02, df = 1 (P = 0.89), I² = 0%, Analysis 1.14).

1.13. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 13: All parallel‐group trials and cross‐over trials: risk of bias

1.14. Analysis.

Comparison 1: Teacher‐rated ADHD symptoms, Outcome 14: All parallel‐group trials and cross‐over trials: vested interest

Independent assessor‐rated ADHD symptoms

Most independent assessors were clinicians.

Parallel‐group trials and cross‐over trials (end first‐period data only)

A meta‐analysis suggested there was a difference in effect between methylphenidate and placebo on independent assessor‐rated ADHD symptoms favouring methylphenidate (SMD −1.10, 95% CI −1.44 to −0.77; I² = 95%; 22 trials, 3724 participants; Analysis 2.1). The SMD effect of −1.10 for ADHD symptoms corresponds to an MD of −15.7 points (95% CI −14.7 to −7.9) on the ADHD‐RS (DuPaul 1991a). This is a clinical effect above the MIREDIF (Zhang 2005). Five trials reported change from baseline scores (Findling 2008; McCracken 2016; Newcorn 2008; Newcorn 2017a (flexible dose); Newcorn 2017b (forced dose)), but removing these trials did not significantly change the estimate. Two trials were outliers as they reported unrealistically high effect sizes. These were: Kollins 2021 and Wigal 2017. Removing these trials showed a SMD effect of −0.62 (95% CI −0.79 to −0.46). The SMD effect of −0.62 for ADHD symptoms corresponds to an MD of −8.86 points (95% CI −11.3 to −6.6) on the ADHD‐RS (DuPaul 1991a), which is a clinical effect above the MIREDIF (Zhang 2005).

2.1. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 1: All parallel‐group trials and first‐period cross‐over trials

• Subgroup analyses

  • We found lower effect of methylphenidate in trials at low risk of bias (SMD −0.40, 95% CI −0.78 to −0.03; I² = 86%; 4 trials, 942 participants), compared to trials at high risk of bias (SMD −1.30, 95% CI −1.70 to −0.89; I² = 96%; 18 trials, 2782 participants; test for subgroup differences: Chi² = 9.97, df = 1 (P = 0.002), I² = 90.0%; Analysis 2.1). The SMD effect of −0.40 in trials at low risk of bias corresponds to a MD of only −5.7 points (95% CI −10.4 to −0.4) on the ADHD‐RS (DuPaul 1991a). This is an effect below the MIREDIF (Zhang 2005).

  • Types of scales used (test for subgroup differences: Chi² = 16.05, df = 3 (P = 0.001), I² = 81.3%; Analysis 2.2).The differences between the scales that influenced the effect most and least was more than SMD −2.0.

  • We found lower effect of methylphenidate in long‐term trials (SMD −0.35, 95% CI −0.61 to −0.08; 1 trial, 221 participants) compared to short‐term trials (SMD −1.15, 95% CI −1.50 to −0.80; I² = 95%; 21 trials, 3503 participants; test for subgroup differences: Chi² = 12.82, df = 1 (P = 0.0003), I² = 92.2%; Analysis 2.3). The SMD effect of −0.35 for ADHD long‐term trials corresponds to an MD of only −5 points (95% CI −8.7 to −1.1) on the ADHD‐RS (DuPaul 1991a), which is a clinical effect below the MIREDIF (Zhang 2005).

  • We found larger effect of methylphenidate at high doses (SMD −0.84, 95% CI −1.13 to −0.55; I² = 95%; 17 trials, 3005 participants) compared to lower doses (SMD −0.19, 95% CI −0.52 to 0.15; 1 trial, 138 participants; test for subgroup differences: Chi² = 12.95, df = 2 (P = 0.002), I² = 84.6%; Analysis 2.4. Four trials comprised a subgroup of unknown dose (Findling 2008; Findling 2010; Kollins 2021; Taylor 1987). Including this subgroup in the analysis did not significantly change the subgroup differences between doses.

  • We found larger effects of methylphenidate in trials with enrichment design (SMD −1.24, 95% CI −1.61 to −0.87; I² = 95%; 19 trials, 3245 participants) compared to trials without enrichment designs (SMD −0.22, 95% CI −0.62 to 0.17; I² = 70%; 3 trials, 479 participants; test for subgroup differences: Chi² = 13.65, df = 1 (P = 0.0002), I² = 92.7%; Analysis 2.5).

  • We found larger effects of methylphenidate in trials with placebo control group (SMD −1.22, 95% CI −1.58 to −0.85; I² = 95%; 20 trials, 3200 participants) compared to trials with no‐intervention control groups (SMD −0.14, 95% CI −0.52 to 0.23; I² = 79%; 2 trials, 524 participants; test for subgroup differences: Chi² = 16.00, df = 1 (P < 0.0001); I² = 93.8%; Analysis 2.6).

  • No evidence suggested that trial design (parallel‐group trials compared to first‐period cross‐over trials) influenced the estimated intervention effect (test for subgroup differences: Chi² = 3.38, df = 1 (P = 0.07), I² = 70.4%; Analysis 2.7). There were not enough data to conduct a test of vested interest.

2.2. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 2: Subgroup analysis: types of scales

2.3. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 3: Subgroup analysis: duration of treatment

2.4. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 4: Subgroup analysis: dose

2.5. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 5: Subgroup analysis: trials with enrichment design compared with trials without enrichment design

2.6. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 6: Subgroup analysis: type of control group

2.7. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 7: Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials

Cross‐over trials (end of last period)

A meta‐analysis suggested a difference in effect between methylphenidate and placebo on independent assessor‐rated ADHD symptoms favouring methylphenidate (SMD −0.97, 95% CI −1.11 to −0.83; I² = 71%; 22 trials, 3854 participants; Analysis 2.8).

2.8. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 8: Cross‐over trials (endpoint data)

• Subgroup analyses

  • We assessed all 22 trials to be at high risk of bias, therefore we could not conduct a subgroup analysis.

  • The estimated intervention effect varied according to dose of methylphenidate, with a seemingly increased effect of a high dose (SMD −1.07, 95% CI −1.27 to −0.86; 13 trials, 2051 participants; I² = 77%) compared to a low dose (SMD −0.72, 95% CI −0.86 to −0.58; I²= 61%; 17 trials, 3067 participants; test for subgroup differences: Chi² = 8.86, df = 2 (P = 0.01); I² = 77.4%; Analysis 2.9). One trial comprised a subgroup of unknown dose (NCT02536105). Including this subgroup in the analysis did not significantly change the subgroup differences between doses.

2.9. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 9: Subgroup analysis: cross‐over trials (endpoint data): dose

Parallel‐group trials and cross‐over trials (end of first period) and cross‐over trials (end of last period)

A meta‐analysis suggested there was a difference in effect between methylphenidate and placebo on independent assessor‐rated ADHD symptoms favouring methylphenidate (SMD −0.99, 95% CI −1.18 to −0.80; I² = 92%; 42 trials, 7277 participants; Analysis 2.10).

2.10. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 10: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data)

• Subgroup analyses

  • The risk of bias assessment influenced the estimated intervention effect when combining parallel and first‐period cross‐over data with end‐of‐last‐period cross‐over data, with a seemingly lower effect in the subgroup of trials assessed to be at low risk of bias (SMD −0.40, 95% CI −0.78 to −0.03; I² = 86%; 4 trials, 942 participants), compared to those assessed to be at high risk of bias (SMD −1.06, 95% CI −1.25 to −0.86; I² = 92%; 38 trials, 6335 participants; test for subgroup differences: Chi² = 9.02, df = 1 (P = 0.003), I² = 88.9%; Analysis 2.11).

  • We did not find any subgroup difference on intervention effect between trials at high or unclear risk of vested interest compared to trials at low risk of vested interest (test for subgroup differences: Chi² = 0.02, df = 1 (P = 0.89), I² = 0%; Analysis 2.12).

  • No evidence suggested that the intervention effect varied according to trial design (parallel and first‐period cross‐over compared to cross‐over trials end of last period; test for subgroup differences: Chi² = 1.42, df = 1 (P = 0.23), I² = 29.5%; Analysis 2.10).

2.11. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 11: All parallel‐group trials and cross‐over trials: risk of bias

2.12. Analysis.

Comparison 2: Independent assessor‐rated ADHD symptoms, Outcome 12: All parallel‐group trials and cross‐over trials: vested interest

Parent‐rated ADHD symptoms

Parallel‐group trials and cross‐over trials (end of first‐period data only)

A meta‐analysis suggested there is a difference in effects between methylphenidate and placebo in parent‐rated ADHD symptoms favouring methylphenidate (SMD −0.63, 95% CI −0.76 to −0.50; I² = 58%; 27 trials, 2927 participants; Analysis 3.1). The SMD effect of −0.63 for ADHD symptoms corresponds to an MD of −9.0 points (95% CI −10.9 to −7.0) on the ADHD‐RS (DuPaul 1991a). This is a clinical effect above the MIREDIF (Zhang 2005). Three trials in the meta‐analysis reported change from baseline scores (Carlson 2007; Newcorn 2008; Tucker 2009), but removing these trials did not significantly change the estimate.

3.1. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 1: All parallel‐group trials and first‐period cross‐over trials

• Subgroup analyses

  • Types of scales (test for subgroup differences: Chi² = 27.14, df = 11 (P = 0.004), I² = 59.5%; Analysis 3.2). The difference between the scales that influenced the effect most and least was more than SMD −0.5.

  • No evidence suggested that the following influenced the intervention effect:

    • risk of bias assessment (test for subgroup differences: Chi² = 1.56, df = 1 (P = 0.21), I² = 36.0%; Analysis 3.1)

    • duration of treatment (test for subgroup differences: Chi² = 0.27, df = 1 (P = 0.60), I² = 0%; Analysis 3.3)

    • dose of methylphenidate (test for subgroup differences: Chi² = 0.54, df = 2 (P = 0.76), I² = 0%, Analysis 3.4)

    • medication status before randomisation (test for subgroup differences: Chi² = 0.51, df = 1 (P = 0.48), I² = 0%; Analysis 3.5)

    • enrichment design (test for subgroup differences: Chi² = 0.02, df = 1 (P = 0.88), I² = 0%; Analysis 3.6)

    • trial design (parallel group trials compared to first period cross‐over trials) (test for subgroup differences: Chi² = 0.03, df = 1 (P = 0.86), I² = 0%; Analysis 3.7)

    • type of control group (test for subgroup differences: Chi² = 0.10, df = 1 (P = 0.75), I² = 0%; Analysis 3.8)

  • There were not enough data to test the influence of vested interest on the effect estimate.

3.2. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 2: Subgroup analysis: types of scales

3.3. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 3: Subgroup analysis: duration of treatment

3.4. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 4: Subgroup analysis: dose

3.5. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 5: Subgroup analysis: medication status ‐ medication naive versus not medication naive

3.6. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 6: Subgroup analysis: trials with enrichment design compared with trials without enrichment design

3.7. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 7: Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials

3.8. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 8: Subgroup analysis: type of control group

Cross‐over trials (end of last period data)

A meta‐analysis suggested a difference in effect between methylphenidate and placebo in parent‐rated ADHD symptoms favouring methylphenidate (SMD −0.70, 95% CI −0.86 to −0.55; I² = 84%; 45 trials, 4971 participants; Analysis 3.9).

3.9. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 9: Cross‐over trials (endpoint data)

• Subgroup analyses

  • This effect did not vary between:

    • assessed risk of bias ratings (test for subgroup differences: Chi² = 2.41, df = 1 (P = 0.12), I² = 58.5%; Analysis 3.9);

    • dose of methylphenidate (test for subgroup differences: Chi² = 3.81, df = 2 (P = 0.15), I² = 47.5%; Analysis 3.10); or

    • trial design (parallel and first‐period cross‐over compared to cross‐over trials, test for subgroup differences: Chi² = 0.58, df = 1 (P = 0.45), I² = 0%; Analysis 3.11).

  • Two trials included some participants with an IQ less than 70 (Pearson 2013; Taylor 1987), but removing these trials did not significantly change the estimate.

3.10. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 10: Subgroup analysis: cross‐over trials (endpoint data): dose

3.11. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 11: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data)

Parallel‐group trials and cross‐over trials (end of first period) and cross‐over trials (end last of last period)

When combining data from parallel‐group trials with endpoint data from cross‐over trials our meta‐analysis suggested a difference in effects between methylphenidate and placebo on reduced parent‐rated ADHD symptoms favouring methylphenidate (SMD −0.67, 95% CI −0.78 to −0.56; I² = 79%; 69 trials, 7838 participants; Analysis 3.11).

• Subgroup analyses

  • No evidence suggested that the intervention effect varied according to:

    • the risk of bias assessment (test for subgroup differences: Chi² = 3.24, df = 1 (P = 0.07), I² = 69.1%; Analysis 3.12);

    • high or unclear and low risk of vested interest (test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.95), I² = 0%; Analysis 3.13).

3.12. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 12: All parallel‐group trials and cross‐over trials: risk of bias

3.13. Analysis.

Comparison 3: Parent‐rated ADHD symptoms, Outcome 13: All parallel‐group trials and cross‐over trials: vested interest

Additional subgroup analyses

• We tested for differences between raters (teachers, independent assessors and parents) and found no significant differences (test for subgroup differences: Chi² = 2.73, df = 2 (P = 0.26), I² = 26.7%; Analysis 4.1).

• We found no evidence suggesting that age (test for subgroup differences: Chi² = 2.84, df = 2 (P = 0.24), I² = 29.6%; Analysis 4.2) or comorbidity influenced the intervention effect (test for subgroup differences: Chi² = 0.15, df = 1 (P = 0.70), I² = 0%; Analysis 4.3). However, the intervention effect was influenced by ADHD subtype, with a greater intervention effect noted for the inattentive subtype (SMD −1.31, 95% CI −1.61 to −1.01; 1 trial, 204 participants) compared to the combined subtype (SMD 0.65, 95% CI −1.30 to 2.60; I² = 99%; 2 trials, 559 participants; test for subgroup differences: Chi² = 3.79, df = 1 (P value = 0.05); I² = 73.6%; Analysis 4.4). This difference rested upon one single trial.

• We found no evidence of a 'carry‐over effect' in the cross‐over trials. We conducted a subgroup analysis to investigate the difference between first‐period data and endpoint data from four cross‐over trials (372 participants), and we found no subgroup differences (test for subgroup differences: Chi² = 1.91, df = 1 (P = 0.17), I² = 47.6%; Analysis 4.5).

4.1. Analysis.

Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 1: Parallel‐group trials and first‐period cross‐over trials: comparison of raters

4.2. Analysis.

Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 2: Parallel‐group trials and first‐period cross‐over trials: age

4.3. Analysis.

Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 3: Parallel‐group trials and first‐period cross‐over trials: comorbidity versus no comorbidity

4.4. Analysis.

Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 4: Parallel‐group trials and first‐period cross‐over trials: subtypes ADHD: ADHD Rating Scale (parent‐, teacher‐ or independent assessor‐rated)

4.5. Analysis.

Comparison 4: Additional subgroup analyses of ADHD symptoms, Outcome 5: Cross‐over trials: first‐period data versus endpoint data (parent‐, independent assessor‐ and teacher‐rated)

Serious adverse events

We were only able to combine data on serious adverse events from 26 parallel‐group trials and 17 cross‐over trials.

Parallel‐group trials and cross‐over trials (first‐period data only)

Overall serious adverse events

There was no clear evidence of a difference between participants in the methylphenidate group versus those in the control group with regards to the proportion of participants with serious adverse events (RR 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; Analysis 5.1).

5.1. Analysis.

Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 1: Proportions of participants with serious adverse events (SAE)

We assessed the evidence to be of very low certainty (see GRADE assessment below). Therefore we are uncertain that the estimated effect accurately reflects the true effect, and the addition of more data could change the findings.

• Trial Sequential Analysis

  • We conducted a Trial Sequential Analysis on the 'proportion of participants with serious adverse events’ outcome, involving 26 parallel‐group and first‐period cross‐over trials. We had planned to use a relative risk reduction of 20%, but the distance between the accrued information and the required information was too large, and the program failed to calculate and draw an interpretable figure. Therefore, we increased the relative risk reduction to 25%. We included trials with zero serious adverse events by substituting zero with a constant of 0.25 (Carlson 2007; Childress 2017; Childress 2020a; Childress 2020b; Childress 2020c; Green 2011; Huang 2021; Jacobi‐Polishook 2009; Kollins 2021; Matthijssen 2019; McCracken 2016; NCT00409708; Pliszka 2017; Schrantee 2016; Wigal 2017; Wolraich 2001). We calculated the DARIS on the basis of serious adverse events in the control group of 2%; a relative risk reduction or increase in the experimental group of 25%; type I error of 5%; type II error of 20% (80% power); and diversity (D²) of 0%. The DARIS was 9349 participants. The cumulative Z‐curve did not cross the conventional or trial sequential monitoring boundaries for benefit, harm, or futility (see Figure 5). As only less than 36% of the DARIS was accrued, risks of random type II error cannot be excluded. The Trial Sequential Analysis‐adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68).

  • Specific serious adverse events:

    • nervous system: aggression (RR 0.50, 95% CI 0.05 to 5.49; 1 trial, 303 participants; Analysis 5.2)

    • nervous system: concussion (RR 0.34, 95% CI 0.01 to 8.17; 1 trial, 303 participants; Analysis 5.2)

    • nervous system: loss of consciousness (RR 0.33, 95% CI 0.01 to 8.02; 1 trial, 221 participants; Analysis 5.2)

    • nervous system: psychosis (RR 0.81, 95% CI 0.13 to 5.12; I² = 0%; 4 trials, 919 participants; Analysis 5.2)

    • nervous system: syncope (RR 1.39, 95% CI 0.23 to 8.47; I²= 0%; 3 trials, 741 participants; Analysis 5.2)

    • nervous system: suicidal ideation (RR 1.63, 95% CI 0.07 to 38.55; 6 trials, 1032 participants; Analysis 5.2)

    • nervous system: suicidal behaviour: no events; 2 trials, 233 participants; Analysis 5.2)

    • nervous system: oppositional behaviour/negativism (RR 0.17, 95% CI 0.01 to 4.04, 1 trial, 217 participants; Analysis 5.2)

    • nervous system: adjustment disorder (RR 0.78, 95% CI 0.03 to 18.91; 1 trial, 230 participants; Analysis 5.2)

    • digestive system: appendicitis (RR 2.11, 95% CI 0.22 to 20.04; I² = 0%; 2 trials, 414 participants; Analysis 5.3)

    • cardiovascular systems: haematoma (RR 0.33, 95% CI 0.01 to 8.02; 1 trial, 221 participants; Analysis 5.4)

    • cardiovascular systems: tachycardia (RR 3.10, 95% CI 0.13 to 73.14; 1 trial, 59 participants; Analysis 5.4)

    • respiratory system: bronchitis (RR 0.34, 95% CI 0.01 to 8.17; 1 trial, 303 participants; Analysis 5.5)

    • respiratory system: asthma (RR 3.02, 95% CI 0.12 to 73.54; 1 trial, 303 participants; Analysis 5.5)

    • urinary system: renal cyst (RR 1.49, 95% CI 0.06 to 36.27; 1 trial, 275 participants; Analysis 5.6)

    • urinary system: kidney infection (RR 3.02, 95% CI 0.12 to 73.54; 1 trial, 303 participants; Analysis 5.6)

    • skeletal and muscular system: clavicle fracture (RR 0.33, 95% CI 0.01 to 8.02; 1 trial, 221 participants; Analysis 5.7)

    • immune system: cyst rupture (RR 3.02, 95% CI 0.12 to 73.54; 1 trial, 303 participants; Analysis 5.8)

    • other: drug toxicity (RR 0.34, 95% CI 0.01 to 8.17; 1 trial, 303 participants; Analysis 5.9

    • other: overdose (RR 2.97, 95% CI 0.12 to 72.20; 1 trial, 221 participants; Analysis 5.9

5.

Trial Sequential Analysis: proportion of participants with one or more serious adverse events

5.2. Analysis.

Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 2: Nervous system (including psychiatry)

5.3. Analysis.

Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 3: Digestive system

5.4. Analysis.

Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 4: Cardiovascular systems

5.5. Analysis.

Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 5: Respiratory systems

5.6. Analysis.

Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 6: Urinary system

5.7. Analysis.

Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 7: Skeletal and muscular system (including pain)

5.8. Analysis.

Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 8: Immune system (including infections)

5.9. Analysis.

Comparison 5: Serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 9: Other

Cross‐over trials (end of last period data)

There were no clear differences between participants in the methylphenidate group and individuals in the control group regarding the proportion of participants with serious adverse events (RR 2.46, 95% CI 0.50 to 12.03; I² = 0%; 16 trials, 3323 participants; Analysis 6.1).

6.1. Analysis.

Comparison 6: Serious adverse events: cross‐over trials (endpoint data), Outcome 1: Proportion of participants with serious adverse events (SAE)

• Specific serious adverse events:

  • nervous system: hallucinations (RR 1.33, 95% CI 0.06 to 30.42; 1 trial, 37 participants; Analysis 6.2)

  • nervous system: psychiatric disorders (RR 3.21, 95% CI 0.13 to 78.04; 1 trial, 267 participants; Analysis 6.2)

  • urinary system: proteinuria (RR 3.00, 95% CI 0.12 to 72.37; 1 trial, 136 participants; Analysis 6.3)

  • immune system: peritonsillar abscess (RR 2.93, 95% CI 0.12 to 71.32; 1 trial, 322 participants; Analysis 6.4)

  • immune system: oral bullae (RR 2.93, 95% CI 0.12 to 71.32; 1 trial, 322 participants; Analysis 6.4)

6.2. Analysis.

Comparison 6: Serious adverse events: cross‐over trials (endpoint data), Outcome 2: Nervous system (including psychiatry)

6.3. Analysis.

Comparison 6: Serious adverse events: cross‐over trials (endpoint data), Outcome 3: Urinary system

6.4. Analysis.

Comparison 6: Serious adverse events: cross‐over trials (endpoint data), Outcome 4: Immune system

Secondary outcomes

Adverse events considered non‐serious

We were able to combine data on non‐serious adverse events from 26 parallel‐group trials and 67 cross‐over trials in meta‐analyses. We assessed the evidence to be of very low certainty (see GRADE assessment below). Therefore we are uncertain that the estimated effect accurately reflects the true effect and the addition of more data could change the findings.

Parallel‐group trials and cross‐over trials (end of first‐period data only)

Overall adverse events considered non‐serious

Participants receiving methylphenidate were more likely to experience non‐serious adverse events overall (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials, 5342 participants; Analysis 7.1). We observed substantial heterogeneity between trials: Tau² = 0.05; Chi² = 118.99, df = 33, (P < 0.00001); I² = 72%. This heterogeneity could be related to dose, as we observed differences between low‐dose and high‐dose methylphenidate trials (test for subgroup differences: Chi² = 18.52, df = 2 (P < 0.0001), I² = 89.2%; Analysis 7.2). Eight trials did not specify the dose they used. Including these trials in the dose subgroup analysis did not significantly alter the subgroup difference between methylphenidate doses.

7.1. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 1: Proportion of participants with non‐serious adverse events

7.2. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 2: Subgroup analysis: proportion of participants with non‐serious adverse events according to dose

• Trial Sequential Analysis

  • We conducted a Trial Sequential Analysis on the 'proportion of participants with non‐serious adverse events’ outcome involving 35 parallel‐group and first‐period cross‐over trials. We included one trial with zero non‐serious adverse events by substituting zero with a constant of 0.25 (Jacobi‐Polishook 2009). We calculated the DARIS on the basis of adverse events in the control group of 44%; relative risk reduction in the intervention group of 20%; type I error of 5%; type II error of 20% (80% power); and diversity (D‐square) of 89.6%. The DARIS was 9139 participants. The cumulative Z‐curve (blue line) crossed the trial sequential monitoring boundaries for harm (red inward sloping line) after the 25th trial (Figure 6). Accordingly, risk of random error in the finding can be excluded according to the Lan‐DeMetz‐O’Brien‐Fleming monitoring boundary. The Trial Sequential Analysis‐adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43).

  • Non‐serious adverse events included those affecting the nervous system (Analysis 7.3), the digestive system (Analysis 7.4), the cardiovascular system (Analysis 7.5), respiratory system (Analysis 7.6), the urinary system (Analysis 7.7), the skeletal and muscular system (Analysis 7.8), the immune system (Analysis 7.9), and the integumentary system (Analysis 7.10). Other reported adverse events included sleep variability (Analysis 7.11; Analysis 7.12), vital signs (Analysis 7.13), physical parameters (Analysis 7.14) and others including drug toxicity (Analysis 7.15).

  • Compared with those in the control group, participants in the methylphenidate may be more likely to report the following:

    • nervous system: headache (RR 1.33, 95% CI 1.04 to 1.70; I² = 32%; 32 trials, 5041 participants; Analysis 7.3)

    • nervous system: tension (RR 23.00, 95% CI 1.42 to 373.44; 1 trial, 60 participants; Analysis 7.3)

    • digestive system: a decrease in appetite (RR 3.35, 95% CI 2.49 to 4.50; I² = 48%; 30 trials, 5127 participants; Analysis 7.4)

    • digestive system: a decrease in weight (RR 5.44, 95% CI 2.47 to 11.98; I² = 0%; 11 trials, 2001 participants; Analysis 7.4)

    • physical parameters: having a lower body mass index (BMI) (SMD −1.00, 95% CI −1.26 to −0.73; I² = 65%; 3 trials, 810 participants; Analysis 7.14)

    • digestive system: having dry mouth (RR 3.79, 95% CI 1.26 to 11.39; I² = 0%; 4 trials, 1057 participants; Analysis 7.4)

    • cardiovascular system: pallor (RR 23.00, 95% CI 1.42 to 373.44; 1 trial, 60 participants; Analysis 7.5)

    • sleep variability: trouble sleeping or sleep problems (RR 1.62, 95% CI 1.18 to 2.21; I² = 0%; 15 trials, 2620 participants; Analysis 7.11)

    • sleep variability: insomnia (RR 1.90, 95% CI 1.12 to 3.22; I² = 49%; 15 trials, 2315 participants; Analysis 7.11)

    • sleep variability: having a lower sleep efficiency percentage (time spent asleep while in bed) after treatment discontinuation (MD 5.42, 95% CI 0.21 to 10.63; 1 trial, 48 participants; Analysis 7.12)

    • vital signs: having a higher diastolic blood pressure (MD 1.90, 95% CI 0.68 to 3.11; I² = 54%; 13 trials, 2032 participants; Analysis 7.13

    • vital signs: having a higher pulse (MD 3.86, 95% CI 2.09 to 5.63; I² = 65%; 13 trials, 2205 participants; Analysis 7.13).

    • other: excoriation (chronic skin‐picking) (RR 3.22, 95% CI 1.20 to 8.64; I² = 0%; 2 trials, 389 participants; Analysis 7.15)

6.

Trial Sequential Analysis: proportion of participants with one or more non‐serious adverse events

7.3. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 3: Nervous system (including psychiatry)

7.4. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 4: Digestive system

7.5. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 5: Cardiovascular system

7.6. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 6: Respiratory system

7.7. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 7: Urinary system

7.8. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 8: Skeletal and muscular systems (including pain)

7.9. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 9: Immune system (including infections)

7.10. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 10: Integumentary system

7.11. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 11: Sleep variability

7.12. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 12: Sleep variability continuous outcomes

7.13. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 13: Vital signs

7.14. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 14: Physical parameters

7.15. Analysis.

Comparison 7: Non‐serious adverse events: parallel‐group trials and first‐period cross‐over trials, Outcome 15: Other (including drug toxicity)

Cross‐over trials (end‐of‐last‐period data)

Overall adverse events considered non‐serious

Participants receiving methylphenidate were significantly more likely to experience adverse events considered non‐serious compared with the control group (RR 1.39, 95% CI 1.13 to 1.70; I² = 60%; 24 trials, 2696 participants; Analysis 8.1). In addition, we noted differences in the numbers of events reported in trials of low doses of methylphenidate compared to trials of high doses of methylphenidate as there were more events in the high‐dose group (test for subgroup differences: Chi² = 5.72, df = 2 (P = 0.026, I² = 65.0%; Analysis 8.2). Five trials did not specify the dose they used. Including these in the dose subgroup analysis did not alter the subgroup difference between methylphenidate doses.

8.1. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 1: Proportion of participants with non‐serious events

8.2. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 2: Subgroup analysis: total number of non‐serious adverse events according to dose

Categories of non‐serious adverse events included those affecting the nervous system (Analysis 8.3; Analysis 8.4), the digestive system (Analysis 8.5), the cardiovascular system (Analysis 8.6), the respiratory system (Analysis 8.7), the urinary system (Analysis 8.8), the skeletal and muscular system (Analysis 8.9; Analysis 8.10), the immune system (Analysis 8.11), and the integumentary system (Analysis 8.12). Other reported adverse events included effects on sleep variability (Analysis 8.13; Analysis 8.14), vital signs (Analysis 8.15), physical parameters (Analysis 8.16), and others including drug toxicity (Analysis 8.17).

8.3. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 3: Nervous system (including psychiatry)

8.4. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 4: Nervous system (including psychiatry) continuous outcomes

8.5. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 5: Digestive system

8.6. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 6: Cardiovascular system

8.7. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 7: Respiratory system

8.8. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 8: Urinary system

8.9. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 9: Skeletal and muscular system

8.10. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 10: Skeletal and muscular system continuous outcomes

8.11. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 11: Immune system (including infections)

8.12. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 12: Integumentary system

8.13. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 13: Sleep variability continuous outcomes

8.14. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 14: Sleep variability

8.15. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 15: Vital signs

8.16. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 16: Physical parameters

8.17. Analysis.

Comparison 8: Non‐serious adverse events: cross‐over trials (endpoint data), Outcome 17: Other (including drug toxicity)

Compared with the control group, participants in the methylphenidate group were less likely to report experiencing the following:

• nervous system: anger (RR 0.45, 95% CI 0.26 to 0.77; I² = 0%; 3 trials, 264 participants; Analysis 8.3)

• nervous system: behavioural complaints (RR 0.55, 95% CI 0.35 to 0.86; 1 trial, 82 participants; Analysis 8.3)

• nervous system: daydreaming (RR 0.66, 95% CI 0.44 to 0.98; I² = 0%; 3 trials, 222 participants; Analysis 8.3)

• digestive system: an increase in appetite (RR 0.20, 95% CI 0.08 to 0.50; 1 trial, 136 participants; Analysis 8.5)

• sleep variability: a reduction in actigraphic sleep onset latency (time to transition from full wakefulness to sleep; MD 21.10, 95% CI 1.33 to 40.87; 1 trial, 52 participants; Analysis 8.13)

However, they were more likely to report the following:

• nervous system: compulsive acts (RR 2.57, 95% CI 1.45 to 4.56; 1 trial, 90 participants; Analysis 8.3)

• nervous system: headache (RR 1.25, 95% CI 1.06 to 1.48; I² = 0%; 43 trials, 5981 participants; Analysis 8.3)

• nervous system: being overly meticulous (RR 40.77, 95% CI 2.35 to 706.72; 1 trial, 96 participants; Analysis 8.3)

• nervous system: obsessive thinking (RR 2.35, 95% CI 1.53 to 3.62; 1 trial, 90 participants; Analysis 8.3)

• nervous system: tics or nervous movements ((RR 1.23, 95% CI 1.02 to 1.50; I² = 3%; 24 trials, 3429 participants; Analysis 8.3)

• nervous system: emotional lability (RR 9.25, 95% CI 2.24 to 38.22; 1 trial, 154 participants; Analysis 8.3)

• nervous system: being prone to crying (RR 1.72, 95% CI 1.04 to 2.86; 1 trial, 1052 participants; Analysis 8.3)

• digestive system: a decrease in appetite (RR 3.89, 95% CI 2.76 to 5.48; I² = 78%; 41 trials, 6091 participants; Analysis 8.5)

• digestive system: nausea (RR 1.67, 95% CI 1.13 to 2.46; I² = 0%; 11 trials, 1182 participants; Analysis 8.5)

• digestive system: stomach ache (RR 1.70, 95% CI 1.35 to 2.15; I² = 34%; 38 trials, 5803 participants; Analysis 8.5)

• sleep variability: insomnia or sleep problems (RR 1.88, 95% CI 1.39 to 2.56; I² = 69%; 37 trials, 5499 participants; Analysis 8.14)

• vital signs: increased pulse/heart rate (SMD 0.43, 95% CI 0.23 to 0.64; I² = 53%; 14 trials, 939 participants; Analysis 8.15).

• skeletal and muscular system: somatic complaints (MD 0.85, 95% CI 0.79 to 0.91; 1 trial, 82 participants; Analysis 8.10)

General behaviour

We were able to include in our analyses data on general behaviour from 13 parallel‐group trials and from 21 cross‐over trials.

Teacher‐rated general behaviour

Parallel‐group trials and cross‐over trials (end‐of‐first‐period data only)

A meta‐analysis suggested a difference in effect between methylphenidate and placebo in teacher‐rated general behaviour favouring methylphenidate (SMD −0.62, 95% CI −0.91 to −0.33; I² = 68%; 7 trials, 792 participants; Analysis 9.1). The SMD effect of −0.62 for general behaviour corresponds to an MD of −3.58 points (95% CI −5.26 to −1.91) on the CGI (Conners 1998a). Due to a lack of MIREDIF, we do not know whether this is a clinical relevant difference.

9.1. Analysis.

Comparison 9: Teacher‐rated general behaviour, Outcome 1: All parallel‐group trials and first‐period cross‐over trials

We assessed the evidence to be of very low certainty (see GRADE assessment below). Therefore we are uncertain that the estimated effect accurately reflects the true effect and the addition of more data could change the findings.

• Subgroup analyses

  • We were not able to test for subgroup differences based on the risk of bias as all seven trials were at high risk of bias (Analysis 9.1).

  • The intervention effect varied according to type of scale (test for subgroup differences: Chi² = 18.75, df = 5 (P = 0.002), I² = 73.3%; Analysis 9.2).

  • We found no evidence to suggest a difference in effects between doses (test for subgroup differences: Chi² = 0.29, df = 2 (P = 0.87), I² = 0%; Analysis 9.3).

  • We were not able to test for subgroup differences according to duration, as all trials were of short duration, that is, less than six months (Analysis 9.4), or according to trial design, as all trials in the analysis were parallel‐group trials (Analysis 9.5).

9.2. Analysis.

Comparison 9: Teacher‐rated general behaviour, Outcome 2: Subgroup analysis: types of scales

9.3. Analysis.

Comparison 9: Teacher‐rated general behaviour, Outcome 3: Subgroup analysis: dose

9.4. Analysis.

Comparison 9: Teacher‐rated general behaviour, Outcome 4: Subgroup analysis: duration of treatment

9.5. Analysis.

Comparison 9: Teacher‐rated general behaviour, Outcome 5: Subgroup analysis: parallel‐group trials versus first‐period cross‐over trials

Cross‐over trials (endpoint data)

Meta‐analysis suggested a difference in effects between methylphenidate and placebo in reduced teacher‐rated general behaviour favouring methylphenidate (SMD −0.75, 95% CI −0.87 to −0.63; I² = 5%; 16 trials, 1302 participants; Analysis 9.6).

9.6. Analysis.

Comparison 9: Teacher‐rated general behaviour, Outcome 6: Cross‐over trials (endpoint data)

• Subgroup analyses

  • The intervention effect varied according to dose of methylphenidate favouring the high‐dose group (test for subgroup differences: Chi² = 5.64, df = 1 (P = 0.02), I² = 82.3%; Analysis 9.7).

9.7. Analysis.

Comparison 9: Teacher‐rated general behaviour, Outcome 7: Subgroup analysis: cross‐over trials (endpoint data): dose

Parallel‐group trials and cross‐over trials (endpoint data)

When combining data from parallel‐group trials with endpoint data from cross‐over trials our meta‐analysis similarly suggested a difference in effects between methylphenidate and placebo in reduced teacher‐rated general behaviour favouring methylphenidate (SMD −0.72, 95% CI −0.84 to −0.60; I²= 37%; 23 trials, 2094 participants; Analysis 9.8). The intervention effect did not vary according to high or low risk of vested interest (Analysis 9.9)

9.8. Analysis.

Comparison 9: Teacher‐rated general behaviour, Outcome 8: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (teacher‐rated) versus cross‐over trials (endpoint data)

9.9. Analysis.

Comparison 9: Teacher‐rated general behaviour, Outcome 9: Subgroup analysis: all parallel‐group trials and cross‐over trials: vested interest

Independent assessor‐rated general behaviour

Parallel‐group trials and cross‐over trials (first‐period data only)

Meta‐analysis suggested a difference in effects between methylphenidate and placebo in reduced independent assessor‐rated general behaviour favouring methylphenidate (MD 1.10, 95% CI −1.01 to 3.21; 1 trial, 94 participants; Analysis 10.1).

10.1. Analysis.

Comparison 10: Independent assessor‐rated general behaviour, Outcome 1: All parallel‐group trials and first‐period cross‐over trials

• Subgroup analyses

  • We found only one parallel‐group trial that provided data on independent assessor‐rated general behaviour, so we were unable to perform any subgroup analyses.

Cross‐over trials (endpoint data)

Meta‐analysis suggested a difference in effects between methylphenidate and placebo in reduced independent assessor‐rated general behaviour favouring methylphenidate (SMD −0.98, 95% CI −1.39 to −0.57; I² = 87%; 9 trials, 987 participants; Analysis 10.2).

10.2. Analysis.

Comparison 10: Independent assessor‐rated general behaviour, Outcome 2: Cross‐over trials (endpoint data)

• Subgroup analyses

  • We were not able to test for subgroup differences based on the risk of bias as all trials were at high risk of bias.

  • The intervention effect did not vary according to dose of methylphenidate (test for subgroup differences: Chi² = 1.83, df = 1 (P = 0.18), I² = 45.3%; Analysis 10.3)

  • The intervention effect varied according to trial design (test for subgroup differences: Chi² = 16.36, df = 1 (P < 0.0001), I² = 93.9%; Analysis 10.4).

10.3. Analysis.

Comparison 10: Independent assessor‐rated general behaviour, Outcome 3: Subgroup analysis: general behaviour, cross‐over trials (endpoint data): dose

10.4. Analysis.

Comparison 10: Independent assessor‐rated general behaviour, Outcome 4: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (independent assessor‐rated) compared with cross‐over trials (endpoint data)

Parallel‐group trials and cross‐over trials (endpoint data)

When combining data from parallel‐group trials with endpoint data from cross‐over trials our meta‐analysis similarly suggested a difference in effects between methylphenidate and placebo in reduced independent assessor‐rated general behaviour favouring methylphenidate (SMD −0.86, 95% CI −1.27 to −0.46; I² = 89; 10 trials, 1081 participants; Analysis 10.4).

• Subgroup analyses

  • The intervention effect did not vary according to high or low risk of vested interest (test for subgroup differences: Chi² = 0.26, df = 1 (P = 0.61), I² = 0%; Analysis 10.5). One trial had unclear risk of vested interest (Merrill 2021) and including this trial in the subgroup analysis significantly changed the results (test for subgroup differences: Chi² = 51.05, df = 2 (P < 0.00001), I² = 96.1%; Analysis 10.5).

10.5. Analysis.

Comparison 10: Independent assessor‐rated general behaviour, Outcome 5: Subgroup analysis: all parallel‐group trials and cross‐over trials: vested interest

Parent‐rated general behaviour

Parallel‐group trials and cross‐over trials (first‐period data only)

Meta‐analysis suggested a difference in effects between methylphenidate and placebo in reduced parent‐rated general behaviour favouring methylphenidate (SMD −0.42, 95% CI −0.62 to −0.23; I² = 57%; 10 trials, 1376 participants; Analysis 11.1).

11.1. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 1: All parallel‐group trials and first‐period cross‐over trials

• Subgroup analyses

  • The intervention effect was significantly influenced by the type of scale (test for subgroup differences: Chi² = 15.13, df = 6 (P = 0.02), I² = 60.3%; Analysis 11.2).

  • We found no evidence to suggest that trial design influenced the intervention effect (test for subgroup differences: Chi² = 0.63, df = 1 (P = 0.43), I² = 0%; Analysis 11.3).

  • We found no evidence to suggest that risk of bias assessment influenced the intervention effect (test for subgroup differences: Chi² = 1.90, df = 1 (P = 0.17), I² = 47.5%; Analysis 10.1).

  • We were not able to test for subgroup differences according to duration, as all trials were of short duration, that is, less than six months (Analysis 11.4), or according to dose, as no trials reporting parent‐rated general behaviour used low‐dose methylphenidate (Analysis 11.5).

11.2. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 2: Subgroup analysis: types of scales

11.3. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 3: Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials

11.4. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 4: Subgroup analysis: duration of treatment

11.5. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 5: Subgroup analysis: dose

Cross‐over trials (endpoint data)

Meta‐analysis suggested a difference in effects between methylphenidate and placebo in reduced parent‐rated general behaviour favouring methylphenidate (SMD −0.84, 95% CI −1.05 to −0.63; I² = 0%; 6 trials, 384 participants; Analysis 11.6)

11.6. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 6: Cross‐over trials (endpoint data)

• Subgroup analyses

  • The intervention effect was not influenced by the dose of methylphenidate (test for subgroup differences: Chi² = 0.91, df = 1 (P = 0.34), I² = 0%; Analysis 11.7).

  • All trials were at high risk of bias therefore we could not conduct a subgroup analysis.

11.7. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 7: Subgroup analysis: cross‐over trials (endpoint data): dose

Parallel‐group trials and cross‐over trials (endpoint data)

When combining data from parallel‐group trials with endpoint data from cross‐over trials our meta‐analysis similarly suggested a difference in effects between methylphenidate and placebo in reduced parent‐rated general behaviour favouring methylphenidate (SMD −0.56, 95% CI −0.74 to −0.39; I² = 59%; 16 trials, 1760 participants; Analysis 11.8).

11.8. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 8: Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials (parent‐rated) compared with cross‐over trials (endpoint data)

• Subgroup analyses

  • The intervention effect varied according to trial design (test for subgroup differences: Chi² = 8.26, df = 1 (P = 0.004), I² = 87.9%; Analysis 11.8).

  • No evidence suggested a difference between subgroups of trials assessed with high, or low risk of bias (test for subgroup differences: Chi² = 3.33, df = 1 (P = 0.07), I² = 69.9%; Analysis 11.9).

  • No evidence suggested a difference between subgroups of trials with low and high risk of vested interest (test for subgroup differences: Chi² = 0.04, df = 1 (P = 0.83), I² = 0%; Analysis 11.10).

11.9. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 9: All parallel‐group trials and cross‐over trials: risk of bias

11.10. Analysis.

Comparison 11: Parent‐rated general behaviour, Outcome 10: Subgroup analysis: all parallel‐group trials and cross‐over trials: vested interest

Additional subgroup analyses

• Additional subgroup analysis suggested that the intervention effect varied according to raters (teacher, independent assessor and parents), with a higher intervention effect for teacher‐rated trials (SMD −0.62, 95% CI −0.91 to −0.33; I² = 68%; 7 trials, 792 participants) compared with parent‐rated trials (SMD −0.42, 95% CI −0.62 to −0.23; I² = 57%; 10 trials, 1376 participants), and independent assessor‐rated trials (SMD 0.21, 95% CI −0.20 to 0.61; 1 trial, 94 participants; test for subgroup differences: Chi² = 10.89, df = 2 (P = 0.004), I² = 81.6%; Analysis 12.1).

• We found no evidence that comorbidity influences the intervention effect (test for subgroup differences: Chi² = 0.13, df = 1 (P = 0.72), I² = 0%; Analysis 12.2)

• We found no evidence of a 'carry‐over effect' in the cross‐over trials (test for subgroup differences: Chi² = 2.14, df = 1 (P = 0.14), I² = 53.3%; Analysis 12.3).

• No data were available for subgroup analyses by age, sex or ADHD subtype.

12.1. Analysis.

Comparison 12: Additional subgroup analyses of general behaviour, Outcome 1: Parallel‐group trials and first‐period cross‐over trials: comparisons of raters

12.2. Analysis.

Comparison 12: Additional subgroup analyses of general behaviour, Outcome 2: Parallel‐group trials and first‐period cross‐over trials: comorbidity versus no comorbidity

12.3. Analysis.

Comparison 12: Additional subgroup analyses of general behaviour, Outcome 3: Cross‐over trials: first‐period data versus endpoint data in the same trials (teacher‐, parent‐, and independent assessor‐rated)

Quality of life

We could include data on quality of life from only four parallel‐group trials in our analyses. We assessed the evidence to be of very low certainty (see GRADE assessment below).

There was no difference in effects between methylphenidate versus placebo in quality of life at end of treatment (SMD 0.40, 95% CI −0.03 to 0.83; I²= 81%; 4 trials, 608 participants; Analysis 13.1). The SMD of 0.40 for quality of life corresponds to an MD of 4.94 (95% CI −0.37 to 10.25) on the Child Health Questionnaire (CHQ; Landgraf 1998), which ranges from 0 to 100 points. This is below the MIREDIF of 7.0 points on CHQ (Rentz 2005).

13.1. Analysis.

Comparison 13: Quality of life: parallel‐group trials and first‐period cross‐over trials, Outcome 1: Subgroup analysis: types of scales

• Subgroup analysis

  • All trials were at high risk of bias therefore we could not conduct a subgroup analysis.

  • It was not possible to investigate subgroup differences of vested interest bias as there were no trials reporting quality of life with low risk in all risk of bias domains.

  • There was no evidence indicating that the type of rating scale influenced the effect of the intervention (Analysis 13.1).

Additional sensitivity analysis

We tested whether a change from a random‐effects model meta‐analysis to a fixed‐effect model meta‐analysis changed our results. This was only the case in one analysis 'Socially withdrawn – decreased interaction with others (Analysis 8.3.20). The P value using a random‐effects model was P = 0.0002, which changed to P = 0.10 with a fixed‐effect model.

Discussion

Summary of main results

We included 55 parallel‐group trials and 156 cross‐over trials in this review and one trial with a parallel‐phase (114 participants randomised) and a cross‐over phase (165 participants randomised). Altogether, these trials randomised more than 16,000 participants and were reported in 614 publications. The majority compared methylphenidate with placebo in short‐term trials of less than six months' duration. The average trial duration in the 56 parallel trials was 67.1 days (range 1 to 425 days). Most were conducted in outpatient clinics in high‐income countries, particularly the USA. Participants' ages ranged from 3 to 18 years across most studies; in two studies ages ranged from 3 to 21 years (Green 2011; Szobot 2008). Both boys and girls were recruited, in a ratio of 3:1.

We considered 22 trials (9 parallel‐group trials and 13 cross‐over trials, including the two phases in Kollins 2006 (PATS)) to have an overall assessment at low risk of bias. We considered 191 trials to have an overall assessment at high risk of bias. We considered all trials to be of high risk of bias due to the risk of deblinding described elsewhere. This raises important concerns, which are discussed after a summary of the results.

Primary outcomes

ADHD symptoms

A meta‐analysis of data from parallel‐group trials combined with data from the first period of cross‐over trials suggests that methylphenidate may improve ADHD symptoms as reported by teachers. The SMD calculated modest improvement in ADHD symptoms on the ADHD‐RS scale (DuPaul 1991a), however, we judged the certainty of the evidence to be ‘very low’ (see Quality of the evidence).

We found that the types of scales used influenced the intervention effect of methylphenidate. The differences between scales ranged from 0.5 SMD to 2.0 SMD. We found lower effects of methylphenidate in long‐term trials compared to short‐term trials. There was no difference between the subgroups of trials using placebo compared to the trials using no intervention in the control group.

Serious adverse events

Methylphenidate does not appear to be associated with an increased occurrence of serious adverse events. However, data for this outcome were only available in 42 of the 212 included trials (20%) and we judged the certainty of the evidence to be ‘very low’ (see Quality of the evidence).

Secondary outcomes

Adverse events considered non‐serious

Amongst those in the methylphenidate‐exposed groups, 538 per 1000 experienced non‐serious adverse events, compared with 437 per 1000 in the control group. The most common non‐serious adverse events were sleep problems and decreased appetite.

We also judged the overall certainty of the evidence for this outcome to be ‘very low’, and as a result, we are uncertain of the magnitude of the harmful effects. Furthermore, for methodological reasons, we used only dichotomous outcomes reflecting the number of participants affected by the event per the total number of participants. As most participants reported more than one adverse event, the actual increase in risk of non‐serious adverse events may very well be higher than the 23% calculated.

General behaviour

Meta‐analyses of data from only seven parallel‐group trials indicated that methylphenidate was associated with an improvement in children’s general behaviour, as reported by teachers. We cannot state anything for sure about the clinical importance of this SMD value. Comparable findings emerged from meta‐analyses of cross‐over trials (endpoint data) as reported by teachers, and from meta‐analyses of nine cross‐over trials (endpoint data) as rated by independent assessors. We also judged this evidence to be of ‘very low’ certainty (see Quality of the evidence).

Quality of life

Meta‐analyses of data from only four parallel‐group trials indicated that methylphenidate was associated with no improvement in children’s quality of life as reported by parents and clinicians. We judged the certainty of the evidence to be ‘very low’ (see Quality of the evidence).

The very low certainty of the evidence, as assessed using the GRADE approach, undermines the confidence that can be placed in the magnitude of any effect. In particular, the prevalence of non‐serious adverse events raises questions about the effectiveness of blinding in these trials. If blinding was broken in just 20% or 30% of participants given methylphenidate, the resulting bias might well account for the small but statistically significant findings concerning the possible benefits of methylphenidate (Coghill 2021; Storebø 2015a).

Overall completeness and applicability of evidence

This review highlights two major issues concerning the overall completeness and applicability of the evidence of the benefits and harms of methylphenidate for children with ADHD: the dearth of trials conducted in children and adolescents in low‐ and middle‐income countries, and the lack of follow‐up beyond six months. Here, we focus on the impact on the applicability of findings of decisions taken as part of this review (choice of rater for assessing change in ADHD symptoms and quality of life, choice of dose and diagnosis), together with issues relating to rating scales, diagnostic criteria, choice of comparators and adverse events.

ADHD symptoms ‐ choice of teacher report

We chose to use teacher‐rated outcomes as the primary measure for both ADHD symptoms and general behaviour, although a number of trials used or relied on parent reports. Some researchers have argued that parent evaluations of ADHD symptoms may not be as reliable as those of other raters such as teachers of pre‐school children (Murray 2007), or college students (Lavigne 2012). For example, Caye 2017 suggests inconsistency in ratings between parents, and in the MTA trial (MTA 1999b), information provided by parents was not always thought to be strong (Efstratopoulou 2013). We tested the robustness of our decision by conducting subgroup analyses and found no significant differences between this score and those of other raters.

Importantly, we do not really know what a lower score on an ADHD symptom scale (like that reported in this review) means for a child’s quality of life and ability to live, learn and function with other people.

Short‐term versus long‐term effects

Based on a subgroup analysis comparing 20 short‐term trials of six months or less to a single long‐term trial of more than six months, we found that the treatment effect for teacher‐rated ADHD symptoms decreased over time (test for subgroup differences: P = 0.04). This was also the case for independent assessor ADHD symptoms (test for subgroup differences: P = 0.0003). However, this was not the case for parent‐rated ADHD symptoms, for which we found no significant differences between short‐term and long‐term duration (test for subgroup differences: P = 0.60). The power was limited in all three subgroup analyses.

We did not identify any trials that examined the effects of more extended exposure on children's general behaviour. Overall, evidence on the long‐term effects of methylphenidate for children and young people with ADHD is lacking, and it is possible that when used for longer periods, any beneficial effects may be diminished or offset by an increase in the risk of harm (Light 2015). Decisions to initiate and persist with treatment will need to weigh potential improvement in ADHD symptoms against adverse events, such as lack of sleep, since this may impact effects on quality of life and learning abilities. This review indicates that these important issues have not been studied sufficiently.

Quality of life

ADHD can exert a significant, negative impact on children’s quality of life, broadly defined. Yet only eight of the 212 included trials measured quality of life in relation both to ADHD and life in general, and it was only possible to synthesise data from four of these trials. In each case the assessments were made by parents, teachers or independent assessors, rather than by children themselves. These external assessors observed no beneficial effects of methylphenidate on quality of life. Children might well have had different views on their own quality of life, and the failure to include child‐reported ratings of quality of life is a significant limitation on the completeness of the evidence. Furthermore, observations of quality of life reported by parents, teachers and independent assessors may be subject to both systematic and random errors.

Dose – choice of moderate or high dose

For children weighing 25 kg or less, the maximum recommended dose of methylphenidate is 30 mg/day compared to 60 mg/day for children weighing more than 25 kg. After careful consideration, we renamed the high‐dose group as 'moderate/high' dose because doses are not always 'high' in heavier children.

Guidelines from the National Institute for Health and Care Excellence (NICE) recommend that methylphenidate can be increased to 0.7 mg/kg per dose up to three times a day, or a total daily dose of 2.1 mg/kg/day (NICE 2018). European guidelines recommend that dosage should begin at a low level of 0.2 mg/kg per dose up to three times a day and should increase according to response, to a ceiling of 0.7 mg/kg per dose (up to three times a day), or a total daily dose of 60 mg/day. (Taylor 2004).

In the parallel‐group trials included in this review, the overall daily dose ranged from 5 mg to 68 mg with a mean reported total daily dose of 34.4 mg/day or 0.78 mg/kg/day. The average dose of any type of modified‐ or extended‐release methylphenidate was 44.2 mg, and the average dose of immediate‐release methylphenidate was 23.0 mg.

However, many of the included trials were short‐term trials, involving medication‐naive children who consequently received lower doses. Furthermore, many of the cross‐over trials used only morning and midday doses to achieve a cross‐over for trial purposes, with no afternoon dose given. However, extended‐release methylphenidate is designed to reduce symptoms in the late afternoon too, so the average expected daily dose would be higher.

We performed subgroup analyses to test differences in the estimate of effect based on differences in dosage. These analyses revealed no differences between low doses (≤ 20 mg/day) compared to moderate/high doses (> 20 mg/day) of methylphenidate. Given the many adverse events that can result when this medication is used, evidence suggests that higher doses may not be needed.

Rating scales

This review included trials from several countries conducted between 1981 and 2022. Pioneers in ADHD research conduct trials in different countries, and psychometric instruments change with trends over time; this is reflected in the variety of rating scales used by investigators in the included trials. Scales based on the diagnostic criteria of the DSM and the ICD measure slightly different constructs. We found significant differences between scales measuring ADHD symptoms, but not between scales measuring general behaviour; we found fewer differences when we performed sensitivity analyses where we pooled subgroups of scales measuring the same ADHD subtype (e.g. scales measuring the inattentive subtype). All trials using subjective rating scales as proxy measures of outcomes are affected by these problems.

Diagnostic criteria

The concept of ADHD has evolved over many years from Sir George Still’s “defect of moral control” in 1902, to Tredgold’s 1908 “ostencephalitic behaviour disorder”, and Kramer’s “hyperkinetic disease of infancy” in 1932 (Lange 2010). Bradley 1937 first reported the positive effects of dextroamphetamine on hyperactive children in 1937 and methylphenidate came onto the market in 1954 (Lange 2010). “Minimal Brain Damage” and “Minimal Brain Dysfunction” were terms used to describe suspected but unproved damage or dysfunction (Lange 2010).

In 1968 the DSM‐II included the term “Hyperkinetic Reaction of Childhood” (APA 1968). In this the DSM‐II referred to a condition “characterized by overactivity, restlessness, distractibility, and short attention span, especially in young children; the behaviour usually diminishes by adolescence” (APA 1968, p. 50).

In the 1970s the emphasis shifted to inattention in the DSM‐III, while the International Classification of Diseases (ICD‐9) continued to focus on hyperactivity (WHO 1988). The DSM‐III introduced the term “Attention Deficit Disorder: with and without hyperactivity (APA 1980).

The DSM‐III‐R then introduced the term “Attention deficit hyperactivity disorder”, removing the subtypes, and focused on a single list of symptoms of inattention, hyperactivity and impulsivity, with a single cut‐off score (Lange 2010).

The DSM‐IV reintroduced subtypes: a predominantly inattentive type and a predominantly hyperactive‐impulsive type, and they added a combined type, with both inattentive and hyperactive‐impulsive symptoms (APA 1994). The DSM‐IV‐TR modified some descriptive text.

In 2013 the DSM‐5 was introduced with several changes, including being placed in the neurodevelopmental section and taking a view across the lifespan (APA 2013). The same 18 symptoms were continued; nine inattentive and nine hyperactive‐impulsive symptoms. At least six symptoms of one domain were required for a diagnosis. Subtypes were replaced with presentation specifiers; “predominantly inattentive presentation”, “predominantly hyperactive‐impulsive presentation” and “combined presentation”. Several symptoms are required in each setting, the age of onset has been changed to require that several inattentive or hyperactive‐impulsive symptoms should have been present before the age of 12 and examples are provided to the criteria to facilitate diagnosis across the lifespan (APA 2013). Comorbid diagnosis with autism is now permitted as well.

The ICD‐11 (WHO 2019), has become more closely aligned with the DSM‐5 (APA 2013), with the diagnosis now being called Attention Deficit Hyperactivity Disorder, based on several inattentive and hyperactive‐impulsive symptoms being present before the age of 12 and causing impairment of functioning in several settings. There are also “predominantly inattentive”, “predominantly hyperactive/impulsive” and “combined” presentations (WHO 2019).

The criteria of both the ICD‐11 (WHO 2019), and the DSM‐5 (APA 2013), encompass a broader spectrum of children with ADHD compared to the earlier criteria for hyperkinetic disorder in the ICD‐10 (WHO 1992) and the DSM‐IV‐TR (APA 2000).

Comparators

The majority of trials in this review compared methylphenidate with placebo, and we previously highlighted the problems surrounding blinding in these trials, due to the prevalence of non‐serious adverse events caused by methylphenidate. Trials that assess methylphenidate using an ‘active placebo’ (or 'nocebo tablets' ‐ tablets with a placebo‐like substance that causes similar adverse events as in the experimental drug arm), can strengthen double‐blinding and are thus recommended (Jakobsen 2013; Jakobsen 2014; Moncrieff 2004). We identified no such trials, and so far, no substance has yet been identified that has the necessary properties to act as a nocebo in trials of stimulants. The use of nocebo tablets for all conditions is ethically uncertain, and any decision to conduct nocebo tablet‐controlled trials in children would normally be deferred by the Food and Drug Administration (FDA) in the USA or the European Medicines Agency (EMA) regulators, until trials have been done safely in adults. If these show methylphenidate to be superior compared with nocebo in treating ADHD symptoms, a rationale would exist for conducting such trials in children. Laursen and colleagues have conducted a systematic review with the aim of investigating the difference between an active versus a standard placebo when these are compared with an experimental (drug) intervention (Laursen 2022). This difference in effects of the pharmaceutical intervention can be estimated by directly comparing the effect difference between the active and standard placebo intervention. Laursen 2022 included 21 trials with both an active placebo and a standard placebo control arm. The primary analysis showed no difference on patient‐reported outcomes between standard and active placebo in preclinical and clinical trials. However, an analysis including only trials at low risk of bias showed a difference of SMD −0.24 (95% CI −0.34 to −0.13). This means that a drug intervention compared with an active placebo (nocebo) control group will show a SMD between −0.34 to −0.13 lower effect than when the drug is compared with standard placebo (Laursen 2020; Laursen 2022).

Adverse events

Twenty‐four parallel‐group trials and 61 cross‐over trials excluded methylphenidate non‐responders, placebo responders or participants with methylphenidate adverse events before randomisation. Such designs are often named enrichment designs (Burnett 2021). We compared the intervention effect of methylphenidate in these trials with that in the remaining trials in subgroup analyses (Analysis 1.6; Analysis 2.5; Analysis 3.6), which found no differences in terms of the intervention effect of methylphenidate in teacher‐rated and parent‐rated ADHD symptoms. However, there were differences in the intervention effects of methylphenidate when we compared the independent‐rated ‘enrichment trials’ with the remaining trials.

Some of our included trials involved participants who were not medication‐naive before randomisation, which may have exaggerated the benefits of methylphenidate. They might have detected the physiological effects (for example, improved concentration or adverse events such as appetite suppression) through prior exposure to the effects of methylphenidate. To investigate this, we performed post hoc subgroup analyses and found that effects of methylphenidate were not different in trials involving medication‐naive participants (> 80% of included participants were medication‐naive) than in trials involving participants already familiar with methylphenidate before randomisation (< 20% of included participants were medication‐naive) for teacher‐rated ADHD symptoms (P = 0.44), and parent‐rated ADHD symptoms (P = 0.48). One might expect the issue of prior exposure to be of greatest concern in cross‐over trials. However, we found no differences between parallel‐group trials and cross‐over trials in teacher‐rated, independent‐rated or parent‐rated ADHD outcomes. Consequently, we believe that prior exposure is not a major concern when the effects of methylphenidate are assessed.

Our Cochrane systematic review from 2018, which focused on the harms from methylphenidate for children and adolescents with ADHD included 260 non‐randomised studies, with around 2.2 million participants (Storebø 2018b). We found that methylphenidate compared to no intervention significantly increased the risk of serious adverse events in comparative studies (RR 1.36, 95% CI, 1.17 to 1.58; 2 trials, 72,005 participants). Serious adverse events included psychotic disorders, arrhythmia, seizures, and hypertension. More than half of participants (51.2%) experienced one or more non‐serious adverse event (95% CI 41.2% to 61.1%; 49 trials, 13,978 participants). These included sleep difficulties (17.9%), decreased appetite (31.1%), and abdominal pain (10.7%). Furthermore, 16.2% (95% CI 13.0 to 19.9%; 57 trials, 8340 participants) discontinued methylphenidate because of “unknown” reasons and 6.20% (95% CI 4.90 to 8.00%; 37 trials, 7142 participants) because of non‐serious adverse events (Storebø 2018b).

Many claims have been made about significant increases in global rates of methylphenidate prescribing; this drug is usually prescribed for long‐term use and seldom with medication‐free periods. However, a recent paper reports that many children in primary care in the UK do not continue methylphenidate treatment for longer than six months (Raman 2015). Furthermore, the prevalence of ADHD diagnoses in the UK has decreased between 1998 and 2010 (Holden 2013). In the USA, however, almost 70% of children with ADHD, estimated at 6.4 million children, take medication (Visser 2014). This might mean that clinicians in the UK are more cautious about prescribing methylphenidate, while clinicians in the USA assume that evidence for the safe use of methylphenidate is sound.

Our assessment of the evidence does not deny that some patients may benefit from methylphenidate. However, despite more than 70 years of research in this field, we do not yet know how to identify those in whom the benefits outweigh the harms. Further research, possibly through individual patient data meta‐analyses or other new methodologies, is needed to identify such patient characteristics. This personalised medicine approach can be used for discovering predictors and moderators for treatment response (Buitelaar 2022).

Quality of the evidence

We assessed the certainty of the evidence that contributed to all outcomes using the GRADE approach. We downgraded all primary and secondary outcomes by two levels due to the high risk of bias. This was due to risk of bias in several domains, including loss of blinding (explained below) and selective outcome reporting. We rated the risk of outcome reporting bias for adverse events to be high, as we only managed to obtain data on the proportion of participants with total serious adverse events from 43 of the 212 included trials, and on proportions of participants with total non‐serious adverse events from 60 of the 212 included trials.

Except for results on serious adverse events, we additionally downgraded all other primary outcomes by one level due to inconsistency as a result of moderate statistical heterogeneity. We additionally downgraded the results on serious adverse events by two levels due to imprecision as a result of wide confidence intervals and because the acquired number of participants was below 50% of the DARIS in Trial Sequential Analysis. Finally, we additionally downgraded general behaviour and quality of life by one level each due to indirectness, considering the discrepancy in the use of rating scales and because the assessment was performed by the parents, respectively. As a result, we assessed the certainty of the evidence for each outcome to be very low, thus reflecting the uncertainty in the robustness of our estimates.

We initially rated 22 of the included trials at low risk of bias, but it is likely that these trials may, in fact, be trials at high risk of bias. This is because methylphenidate gives rise to common, easily recognisable adverse events. This can lead to loss of blinding and overestimation of benefits whilst underestimating the harms (Kjaergard 2001; Savović 2012b; Storebø 2015a; Wood 2008).

To ensure adequate blinding, it is therefore important for researchers to try to reduce the bias that may arise from this. This could include using separate assessors to measure adverse effects and efficacy, which could help maintain blinding of those assessing efficacy whilst allowing both adverse effects and efficacy to be measured. As we found no trials in which separate assessors evaluated adverse effects and efficacy and no trials that used active placebos, we cannot assess the extent of this bias. There is also increasing interest in finding a safe active placebo (a nocebo) that could mimic the adverse effects in the control group without acting as a stimulant. This too could improve blinding significantly. But the practicalities of identifying such a substance, testing the safety, and obtaining regulatory approval for its use, are likely to take many years to achieve. There are researchers working on this already, and increasing interest to find solutions to the important area of protecting blinding. The fact that the intervention effect of methylphenidate on ADHD symptoms did not differ significantly between trials at low risk of bias compared to trials at high risk of bias may be taken as an indication that deblinding has occurred among former trials. Also, the average duration of treatment was no longer than about two months. Therefore, we can conclude little about the benefits and harms of methylphenidate used for longer than six months. (Coghill 2021; Laursen 2020; Laursen 2022).

Potential biases in the review process

The present systematic review has many strengths. We developed a protocol for this review according to instructions provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022a), and this protocol was published before we embarked on the review itself. We conducted extensive searches of relevant databases, and we requested published and unpublished data from pharmaceutical companies manufacturing methylphenidate, including Takeda Pharmaceuticals, Medice (represented in Denmark by HB Pharma), Janssen‐Cilag, Novartis, Rhodes Pharmaceuticals, Ironshore Pharmaceuticals and Pfiizer. Two review authors, working independently, selected trials for inclusion and extracted data. We resolved disagreements by discussion with team members. We assessed risk of bias in all trials according to the recommendations provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We conducted Trial Sequential Analyses to control the risk of type I errors and type II errors and to estimate how far we were from obtaining the DARIS to detect or reject a certain plausible intervention effect (CTU 2022). In the meta‐analyses on non‐serious adverse events, the Trial Sequential Analysis showed that observed intervention effects were not likely to be due to type I error and confirmed that sufficient data had been obtained.

Although we added new search terms to the strategy, we limited the search to the period since the previous search (2015 onwards), so it is possible that we did not capture pre‐2015 records containing the new search terms. However, we believe that we are unlikely to have missed any important trials because of our supplementary searches, which included identifying studies through reference checks of relevant reviews, and contacting pharmaceutical companies.

We excluded 126 trials described in 144 reports, which assessed the effects of methylphenidate on specialised outcomes (e.g. experimental, neurocognitive or functional outcomes) in children or adolescents with ADHD (see Characteristics of excluded studies). This raises the issue of bias in our review process as we did not write to these authors asking whether they collected data on other outcomes. This potential bias, however, is not likely to change our conclusions.

Agreements and disagreements with other studies or reviews

Over the past 20 years, several published systematic reviews and narrative reviews have examined the efficacy of methylphenidate for ADHD (with or without meta‐analysis). All of them described methylphenidate as being very helpful to children and adolescents with ADHD. However, they each had methodological shortcomings.

The 2015 version of this review contradicted earlier published reviews as we reported that methylphenidate may improve teacher‐reported ADHD symptoms, teacher‐reported general behaviour, and parent‐reported quality of life among children and adolescents diagnosed with ADHD, but the low quality of the evidence meant that we could not be certain of the true magnitude of these effects (Storebø 2015a). The 2015 version of this review provoked many critical responses, published in articles, letters to editors and blogs. We responded to all of the comments; for more details please see the section “Why it is important to do this review". An overview article found 24 eligible systematic reviews and meta‐analyses published after our 2015 review (Ribeiro 2021). The results from the overview also showed that the evidence was uncertain due to its low quality. Additionally, this overview highlighted the underreporting of adverse events in RCTs, and concluded that evidence supporting methylphenidate being beneficial in the treatment of children and adolescents with ADHD remains uncertain (Ribeiro 2021).

Our current updated review confirms our 2015 findings with 29 additional RCTs included (Storebø 2015a). These results differ from the large network meta‐analysis by Cortese and colleagues (Cortese 2018), in which the use of methylphenidate in children and adolescents was strongly supported by the evidence where they compared the efficacy and tolerability of methylphenidate for ADHD to placebo alongside other medications (Cortese 2018). We published a letter to the editor of the Lancet in which we highlighted several problems with their review, namely, the exclusion of many relevant trials in order to fulfil statistical and methodological assumptions that they made. While the pooled comparison for clinician‐rated effects of methylphenidate versus placebo for children was rated as "moderate quality of evidence", they also assessed all of the indirect comparisons as being of “low to very low quality of evidence”. Indirect evidence differentiates network meta‐analyses from conventional meta‐analyses. Given the decreased interpretability of the indirect comparisons, there are no novel findings in this network meta‐analysis (Faltinsen 2018a; Storebø 2018a). In sum, the part of the network meta‐analysis that is different from our review published in 2015 (Storebø 2015a), consists of evidence of low to very low certainty.

In a response to our letter, the authors confirmed that they had excluded 65% of the trials that we had included in our 2015 review. They excluded 51 trials that had under seven days of treatment, 38 cross‐over trials without pre‐crossover data or a washout, 18 trials with responders to previous treatment, and 14 trials where treatment was not monotherapy (Cipriani 2018). They did this because including these trials would have been a clear violation of their published protocol and would have compromised the transitivity of the network meta‐analyses (Cipriani 2018).

Catalá‐López and colleagues published a large systematic review with network meta‐analyses in 2017 (Catala‐Lopez 2017). They included 190 RCTs with a total of 26,114 children and adolescents with ADHD, and found that stimulant monotherapy was significantly more efficacious than placebo; however, all analyses were assessed in GRADE at “low or very low certainty”. The authors of the review concluded that stimulants may improve the symptoms of ADHD, but the strength of the underlying evidence remains uncertain (Catala‐Lopez 2017).

Padilha and colleagues published a network meta‐analysis investigating the benefits and harms of different types of ADHD medication (including methylphenidate) for children and adolescents with ADHD, including 48 trials with 4169 participants (Padilha 2018). The review found that there were beneficial effects of methylphenidate on the Clinical Global Impressions Improvement scale (CGI‐I) and that methylphenidate was more effective than the non‐stimulants atomoxetine and guanfacine (Padilha 2018). There are several methodological problems with this review which we commented on in a letter to the editor (Faltinsen 2019). The issues we raised were focused on selection bias (as the authors had excluded placebo‐controlled trials), the fact that authors judged the methodological quality of the included trials to be good, asserting that they were well designed, reported, and conducted, even when this clearly was not the case and that they did not include an overall assessment of certainty such as the GRADE system. They also included cross‐over trials without reporting the method as to how they pooled this data with that from parallel‐group trials and they failed to discuss other possible issues, such as carry‐over and period effects (Faltinsen 2019). Furthermore, they did not assess the transitivity assumption in their network meta‐analyses (Faltinsen 2018b; Faltinsen 2019).

A review by Cerrillo‐Urbina and colleagues investigating the benefits and harms of stimulants and non‐stimulants included 15 RCTs, with 4648 children or adolescents, or both, from 6 to 17 years of age diagnosed with ADHD (Cerrillo‐Urbina 2018). Only four trials assessed methylphenidate, all of which were conducted before 2013. The GRADE assessment of the evidence concerning the total score of ADHD symptoms was assessed to be “moderately high quality of evidence” for both stimulant and non‐stimulant medications. They downgraded the quality of evidence by one level due to a high degree of heterogeneity in the pooled results (I² > 75%) but did not downgrade it further for risk of bias or publication bias, even though they found that there was significant publication bias for all outcomes. It is striking that this review only included four trials on methylphenidate, whereas we found 184 trials in our 2015 review covering the same period (Storebø 2015a).

A network meta‐analysis by Li and colleagues found that methylphenidate was beneficial in the treatment of ADHD in children and adolescents (Li 2017). Methylphenidate was considered the second safest treatment compared to the other ADHD medications. The review included 62 trials in a meta‐analysis, which included 12,930 participants. They did not make any attempt to evaluate the risk of bias or the certainty of evidence, which significantly lowers the robustness and validity of this review.

The NICE guideline recommends methylphenidate as the first‐line pharmacological treatment for children over five and adolescents, "1.7.7: Offer methylphenidate (either short or long acting) as the first‐line pharmacological treatment for children aged 5 years and over and young people with ADHD" (NICE 2018). The NICE guideline committee concluded that methylphenidate and lisdexamphetamine provide clinically important benefits to patients with ADHD as compared to placebo and other drugs (NICE 2018). We found several methodological problems in the NICE ADHD guidelines as we believe they conducted an erroneous assessment of the certainty of the included studies. They assessed the quality of meta‐analysis to be “ high quality”, when it could be strongly argued that it was, in fact, “low quality”. In their assessment of the effect of methylphenidate, they included only 16 trials that focused solely on immediate and osmotic‐release methylphenidate in children and adolescents. We included 185 trials (175 of which were placebo‐controlled) in our 2015 review (Storebø 2015a). NICE did not adjust for multiple comparisons and did not discuss the concern that all the data arose from short‐term follow‐up (NICE 2018).

The American Academy of Pediatrics guideline was updated in 2019 based on patients’ age (Wolraich 2019). With regard to preschool children, the guideline recommends evidence‐based behavioural interventions (behavioural parent training or behavioural classroom interventions, or both) as the first‐choice treatment. Methylphenidate may be considered when a child has moderate to severe problems with functioning and if the behavioural treatment does not provide the necessary improvements. With regard to school children, the guideline strongly recommends pharmaceutical treatments (FDA‐approved medications for ADHD) together with behavioural interventions. Regarding adolescents, the guideline strongly recommends pharmaceutical treatment and if possible, evidence‐based behavioural interventions. The guideline states that there is a strong effect observed in the trials investigating the effects of stimulant medications (Wolraich 2019). For the comparison of pharmacological treatments versus placebo or usual care, the review only identified eight articles representing seven studies. The review concluded that there was limited additional evidence concerning FDA‐approved ADHD medications compared with placebo or usual care across all outcomes in this updated systematic evidence review. The conclusions regarding methylphenidate, therefore, seem overly positive. The risk of harm is considered as low and the benefits, in general, are described as outweighing the risks.

Our current updated review is in line with two recent Cochrane systematic reviews of methylphenidate in adults. These two reviews found low‐ or very low‐certainty evidence that methylphenidate, compared with placebo, improved ADHD symptoms (Boesen 2022; Candido 2021).

Authors' conclusions

Implications for practice.

Methylphenidate may improve attention deficit hyperactivity disorder (ADHD) symptoms and general behaviour in children and adolescents with ADHD aged 18 years and younger. We rated the evidence to be of very low certainty and, as a result, we cannot be certain about the magnitude of the effects from the meta‐analyses. The evidence is limited by the serious risk of bias in the included trials, underreporting of relevant outcome data, and a high level of statistical variation between the results of the trials. There is also very low‐certainty evidence that methylphenidate causes numerous adverse events. The risk of serious adverse events seems low, but data were only available from 43 of the 212 included trials. It is also problematic that only 93 of the 212 included trials reported on specific and overall non‐serious adverse events. Accordingly, we cannot rule out the possibility that non‐serious harms are more prevalent than reported in our review.

If methylphenidate treatment is considered, clinicians might need to use it for short periods, with careful monitoring of both benefits and harms, and cease its use if no evidence of clear improvement of symptoms is noted, or if harmful effects appear. A problem is that clinicians very often rely on their assessment of methylphenidate in their clinical evaluation. Arguments like "I know that this medication helps" can be problematic when they are based on anecdotal evidence and case reports. A new review found that clinicians had difficulties in assessing benefits or harms following treatment, with inaccuracies in both directions (Hoffmann 2017). Clinicians mostly underestimated instead of overestimated harms and overestimated rather than underestimated benefits. Inaccurate perceptions of the benefits and harms of treatments are likely to result in uncertain clinical management choices (Hoffmann 2017).

Implications for research.

This review highlights the urgent need for long‐term, high‐quality, and large randomised clinical trials (RCTs), at low risk of bias, to investigate the benefits and harms of methylphenidate treatment versus placebo in children and adolescents with ADHD. Such trials ought to be designed according to the SPIRIT (Standard Protocol Items: Recommendations for Intervention Trials) guidelines (Chan 2013), and reported in keeping with the CONSORT (Consolidated Standards of Reporting Trials) standards Moher 2010). Pre‐published protocols could help reduce the inconsistent measurement of benefits and harms caused by the use of many different rating scales and by lack of assessment of adverse events.

The important issue of protecting blinding of these trials needs to be addressed urgently. Immediate measures could be implemented to improve blinding. Having independent, blinded assessors monitor adverse effects, whilst separate, independent blinded assessors measure efficacy, is likely to reduce the risk of unblinding due to adverse effects. Active placebos need to be sought and are likely to be important in the future, but their development is still at the very early stages. Research in this field should be strongly supported, but it is likely to take many years before such substances can be used safely and ethically in research with children and adolescents. The prevalent use of cross‐over trials needs to be reconsidered as they usually only provide short‐term interventions, which can limit the assessment of benefits and harms. However, we were not able to identify major differences when comparing parallel‐group trials with cross‐over trials.

Future trials ought to publish depersonalised individual participant data and should report all outcomes, including adverse events, to ensure that future systematic reviews and meta‐analyses can access and use individual participant data. Only through meta‐analyses will we be able to assess differences between intervention effects according to age, sex, comorbidity, ADHD subtype, and dose. Reviews show that many different rating scales are used for children with ADHD. Consistent use of well‐validated scales is needed, as is a country‐wide adverse events reporting system, such as the Food and Drug Administration, to increase awareness of adverse events. In addition, the findings in this review clearly show the urgent need for large RCTs to investigate the efficacy of non‐pharmacological treatments. As with RCTs, systematic reviews of such trials assess average effects in groups of individuals. Such average effects may comprise strong benefits for a single participant or a few participants and no effect or negative effects for others. Despite more than 50 years of research in this field, we have no knowledge on how to identify patients who may obtain more benefits than harms. Individual patient data meta‐analyses are needed to identify such patient characteristics. Therefore, it would be extremely helpful for review authors to gain full access to anonymised individual participant data for inclusion in meta‐analyses examining these data (Gluud 2015). Patient subgroups may benefit from intervention if those with reduced rates of adverse events can be identified. This personalised medicine approach can be used for discovering predictors and moderators for treatment response. The use of biomarkers for both more precise diagnoses and for more precise assessment of treatment response is necessary in future RCTs. The use of enrichment designs will improve statistical power for biomarker analyses (Buitelaar 2022).

Feedback

Comments on the BMJ version of this review, 29 November 2016

Summary

Fazel M. Methylphenidate for ADHD. BMJ 2015;351:h5875. [DOI: 10.1136/bmj.h5875]. Available from bmj.com/content/351/bmj.h5875.long

Grant E. Re: Methylphenidate for attention‐deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials [personal communication]. Response to: OJ Storebø, HB Krogh, E Ramstad, CR Moreira‐Maia, M Holmskov, M Skoog, et al. 27 November 2015. Available from bmj.com/content/351/bmj.h5203/rr

Kremer HJ. Re: Methylphenidate for attention‐deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials [personal communication]. Response to: OJ Storebø, HB Krogh, E Ramstad, CR Moreira‐Maia, M Holmskov, M Skoog, et al. 27 November 2015. Available from bmj.com/content/351/bmj.h5203/rr-0

Chandrasekaran V, Mahadevan S. Re: Methylphenidate for attention‐deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials [personal communication]. Response to: OJ Storebø, HB Krogh, E Ramstad, CR Moreira‐Maia, M Holmskov, M Skoog, et al. 29 November 2015. Available from bmj.com/content/351/bmj.h5203/rr-1

Büchter RB, Thomas S. Re: Methylphenidate for attention‐deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials [personal communication]. Response to: OJ Storebø, HB Krogh, E Ramstad, CR Moreira‐Maia, M Holmskov, M Skoog, et al. 10 December 2015. Available from bmj.com/content/351/bmj.h5203/rr-3

Saripanidis S. Management and treatment of hyperactivity and ADHD, without methylphenidate [personal communication]. Response to: OJ Storebø, HB Krogh, E Ramstad, CR Moreira‐Maia, M Holmskov, M Skoog, et al. 27 December 2015. Available from bmj.com/content/351/bmj.h5203/rr-5

Banaschewski T, Buitelaar J, Chui CSL, Coghill D, Cortese S, Simonoff E, et al, on behalf of the European ADHD Guidelines Group. Are Methylphenidate Effects in Children with ADHD Really Uncertain? [personal communication]. Response to Storebø OJ, Krogh HB, Ramstad E, Moreira‐Maia CR, Holmskov M, Skoog M, et al. 27 July 2016. Available from bmj.com/content/351/bmj.h5203/rr-6

Reply

Storebø OJ, Gluud C. Re: Methylphenidate for attention‐deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials [personal communication]. Response to: E Grant, HJ Kremer, V Chandrasekaran, S Mahadevan. 30 November 2015. Available from bmj.com/content/351/bmj.h5203/rr-2

Storebø OJ, Gluud C. Re: Methylphenidate for attention‐deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials [personal communication]. Response to: RB Büchter, S Thomas. 22 December 2015. Available from bmj.com/content/351/bmj.h5203/rr-4

Storebø OJ, Zwi M, Gluud C. Re: Methylphenidate for attention‐deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials [personal communication]. Response to: T Banaschewski, J Buitelaar, CSL Chui, D Coghill, S Cortese, E Simonoff, et al. 29 July 2016. Available from bmj.com/content/351/bmj.h5203/rr-9

Storebø OJ, Zwi M, Gluud C. Re: Methylphenidate for attention‐deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials [personal communication]. Response to: T Banaschewski, J Buitelaar, CSL Chui, D Coghill, S Cortese, E Simonoff. 29 July 2016. Available from bmj.com/content/351/bmj.h5203/rr-10

Storebø OJ, Zwi M, Gluud C. Re: Methylphenidate for attention‐deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials [personal communication]. Response to: T Banaschewski, J Buitelaar, CSL Chui, D Coghill, S Cortese, E Simonoff. 29 July 2016. Available from bmj.com/content/351/bmj.h5203/rr-11

Contributors

Contributor 1: Mina Fazel, National Institute for Health Research (NIHR) Postdoctoral Research Fellow, Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Consultant in Child and Adolescent Psychiatry, Department of Children’s Psychological Medicine, The Children’s Hospital, Oxford University Hospitals Foundation Trust, Oxford, UK.
Contributor 2: Ellen Grant, Physician and Medical Gynaecologist, Retired, Kingston‐upon‐Thames, UK.
Contributor 3: Hans‐Joachim Kremer, Medical Writer, Medical Writing Service, Alemannenstraße 101, 79117 Freiburg, Germany.Contributor 4: Venkatesh Chandrasekaran Assistant Professor of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Dhanvantri Nagar,Puducherry‐605006, India.Contributor 5: Subramanian Mahadevan, Senior Professor and Head of the Department, Department of Pediatrics, JIPMER, Dhanvantri Nagar,Puducherry‐605006, India.Contributor 6: Roland Brian Büchter Medical Writer, Institute for Quality and Efficiency in Health Care (IQWiG), Im Mediapark 8, 50670 Cologne, Germany.Contributor 7: Stefanie Thomas, Head of Quality Assurance Unit, IQWiG, Im Mediapark 8, 50670 Cologne, Germany. Contributor 8: Stavros Saripanidis, Consultant in Obstetrics and Gynaecology, Thessaloniki, Greece.
Contributor 9: Tobias Banaschewski, Department of Child Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany.
Contributor 10: Jan Buitelaar, Department of Cognitive Neuroscience, Donders Institute of Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands.
Contributor 11: Celine SL Chui, Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China.
Contributor 12: David Coghill, Departments of Paediatrics and Psychiatry, University of Melbourne, Victoria, Australia.
Contributor 13: Samuele Cortese, Department of Psychology, University of Southampton, Southampton, UK; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton.
Contributor 14: Emily Simonoff, Department of Child & Adolescent Psychiatry, Institute of Psychiatry Psychology & Neuroscience, King’s College London, London, UK.
Contributor 15: Ian C. K. Wong, UCL School of Pharmacy, Faculty of Life Sciences, UCL, London, UK; Institute of Child Health, London, UK.

Author 1: Ole Jakob Storebø, Senior Researcher, Psychiatric Research Unit, Psychiatric Department, Region Zealand, Slagelse, Denmark; Department of Psychology, Faculty of Health Science, University of Southern Denmark.
Author 2: Christian Gluud, Head of department, The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen, Denmark.
Author 3: Morris Zwi, Consultant Child & Adolescent Psychiatrist and Clinical Lead, Islington CAMHS, Whittington Health, London, UK.

Mental Elf Blog, 29 November 2016

Summary

Hollis C. Methylphenidate for ADHD: have Cochrane got it wrong this time? [personal communication]. Response to: Storebø OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, et al. 10 March 2016. Available from nationalelfservice.net/mental-health/adhd/methylphenidate-for-adhd-have-cochrane-got-it-wrong-this-time

Reply

Storebø OJ, Gluud C. Re: Methylphenidate for ADHD: have Cochrane got it wrong this time? [personal communication]. Response to: Chris Hollis. March 2016. Available from nationalelfservice.net/mental-health/adhd/methylphenidate-for-adhd-have-cochrane-got-it-wrong-this-time/#comment-1002564

Hollis C. Re: Methylphenidate for ADHD: have Cochrane got it wrong this time? [personal communication]. Response to: OJ Storebø, C Gluud. April 2016. Availabe from nationalelfservice.net/mental-health/adhd/methylphenidate-for-adhd-have-cochrane-got-it-wrong-this-time/#comment-1007912

Storebø OJ, Gluud C. Re: Methylphenidate for ADHD: have Cochrane got it wrong this time? [personal communication]. Response to: C Hollis. April 2016. Available from nationalelfservice.net/mental-health/adhd/methylphenidate-for-adhd-have-cochrane-got-it-wrong-this-time/#comment-1008187

Hollis C. Re: Methylphenidate for ADHD: have Cochrane got it wrong this time? [personal communication]. Response to: OJ Storebø, C Gluud. April 2016. Available from nationalelfservice.net/mental-health/adhd/methylphenidate-for-adhd-have-cochrane-got-it-wrong-this-time/#comment-1010366

Storebø OJ, Gluud C. Re: Methylphenidate for ADHD: have Cochrane got it wrong this time? [personal communication]. Response to: C Hollis. April 2016. Available from nationalelfservice.net/mental-health/adhd/methylphenidate-for-adhd-have-cochrane-got-it-wrong-this-time/#comment-1011280

Storebø OJ, Gluud C. Methylphenidate for ADHD: have Chris Hollis also got it wrong this time? [personal communication]. Response to: C Hollis. June 2016. Available from nationalelfservice.net/mental-health/adhd/methylphenidate-for-adhd-have-cochrane-got-it-wrong-this-time/#comment-1018081

Contributors

Contributor 1: Chris Hollis, Professor Child & Adolescent Psychiatry, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK.

Author 1: Ole Jakob Storebø, Senior Researcher, Psychiatric Research Unit, Psychiatric Department, Region Zealand, Slagelse, Denmark; Department of Psychology, Faculty of Health Science, University of Southern Denmark.
Author 2: Christian Gluud, Head of department, The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen, Denmark.

Comments on the JAMA version of this review, 29 November 2016

Summary

Shaw P. Quantifying the benefits and risks of Methylphenidate as treatment for childhood attention‐deficit/hyperactivity disorder. JAMA. 2016;315(18):1953‐5. [DOI:10.1001/jama.2016.3427]. Available from jamanetwork.com/journals/jama/article-abstract/2520612

Romanos M, Reif A, Banaschewski T. Methylphenidate for attention‐deficit/hyperactivity disorder. JAMA. 2016;316(9):994‐5. [DOI:10.1001/jama.2016.10279]. Available from jamanetwork.com/journals/jama/article-abstract/2547744

Reply

Storebø OJ, Simonsen E, Gluud C. Methylphenidate for attention‐deficit/hyperactivity disorder — Reply. JAMA. 2016;316(9):995. [DOI:10.1001/jama.2016.10300]. Available from jamanetwork.com/journals/jama/article-abstract/2547750

Contributors

Contributor 1: Philip Shaw, Section on Neurobehavioral Clinical Research, Social and Behavioral Research Behavioral Research Branch, National Human Genome Research Institute, Bethesda, Maryland; National Institute of Mental Health, Bethesda, Maryland.
Contributor 2: Marcel Romanos, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.
Contributor 3: Andreas Reif, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
Contributor 4: Tobias Banaschewski, Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Mannheim, Germany.

Author 1: Ole Jakob Storebø, Psychiatric Research Unit, Region Zealand, Denmark.
Author 2: Erik Simonsen, Psychiatric Research Unit, Region Zealand, Denmark.
Author 3: Christian Gluud, Copenhagen Trial Unit, Copenhagen, Denmark.

Other comments on this review published elsewhere, 29 November 2016

Summary

Mulder R, Hazell P, Rucklidge JJ, Malhi GS. Methylphenidate for attention‐deficit/hyperactivity disorder: too much of a good thing? Australian & New Zealand Journal of Psychiatry 2016;50(2):113–4. [DOI: 10.1177/0004867415626823] Available from anp.sagepub.com/search/results?fulltext=storebo&x=0&y=0&submit=yes&journal_set=spanp&src=selected&andorexactfulltext=and

Levy F. Methylphenidate for attention‐deficit/ hyperactivity disorder: the longest debate. Australian & New Zealand Journal of Psychiatry 2016;50(7):616–7. [DOI: 10.1177/0004867416643390] Available from anp.sagepub.com/content/50/7/616.full.pdf

Hoekstra PJ, Buitelaar JK. Is the evidence base of methylphenidate for children and adolescents with attention‐deficit/hyperactivity disorder flawed? European Child & Adolescent Psychiatry 2016;25(4):339–40. [DOI: 10.1007/s00787‐016‐0845‐2] Available from link.springer.com/article/10.1007/s00787-016-0845-2

Banaschewski T, Gerlach M, Becker K, Holtmann M, Döpfner M, Romanos M. The errors and misinterpretations in the Cochrane analysis by O. J. Storebo and colleagues on the efficacy and safety of methylphenidate for the treatment of children and adolescents with ADHD. Trust, but verify. Zeitschrift für Kinder‐ und Jugendpsychiatrie und Psychotherapie 2016;44:307‐14. [DOI: 10.1024/1422‐4917/a000433] Available from econtent.hogrefe.com/doi/abs/10.1024/1422-4917/a000433

Banaschewski T, Buitelaar J, Chui CSL, Coghill D, Cortese S, Simonoff E, et al. Methylphenidate for ADHD in children and adolescents: throwing the baby out with the bathwater. Evidence‐Based Mental Health 2016;19(4):97‐9. [DOI: 10.1136/eb‐2016‐102461 ] Available from ebmh.bmj.com/content/19/4/97.full

Reply

Storebø OJ, Simonsen E, Gluud C. The evidence base of methylphenidate for children and adolescents with attention‐deficit hyperactivity disorder is in fact flawed. European Child & Adolescent Psychiatry 2016;25(9):1037–8. [DOI:10.1007/s00787‐016‐0855‐0]. Available from link.springer.com/article/10.1007/s00787-016-0855-0

Storebø OJ, Zwi M, Moreira‐Maia CR, Skoog M, Camilla G*, Gillies D, et al. Response to “Trust, but verify” by Banaschewski et al. Zeitschrift für Kinder‐ und Jugendpsychiatrie und Psychotherapie 2016;44:334‐5. [DOI: 10.1024/1422‐4917/a000472]. Available from econtent.hogrefe.com/doi/abs/10.1024/1422-4917/a000472

Storebø OJ, Gluud C. Re: Trust, but verify. The errors and misinterpretations in the Cochrane analysis by O. J. Storebo and colleagues on the efficacy and safety of methylphenidate for the treatment of children and adolescents with ADHD [personal communication]. Response to: T BanaschewskI, M Gerlach, K Becker, M Holtmann, M Döpfner, M Romanos. 24 June 2016. Available from ncbi.nlm.nih.gov/pubmed/27270192#cm27270192_16360

Storebø OJ, Zwi M, Krogh HB, Moreira‐Maia CR, Holmskov M, Gillies D, et al. Evidence on methylphenidate in children and adolescents with ADHD is in fact of ‘very low quality'. Evidence‐Based Mental Health 2016;19(4):100‐2. Available from ebmh.bmj.com/content/19/4/100.full

Contributors

Contributor 1: Roger Mulder, Department of Psychological Medicine, University of Otago — Christchurch, Christchurch, New Zealand.
Contributor 2: Philip Hazell, Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.Contributor 3: Julia J Rucklidge, University of Canterbury, Christchurch, New Zealand.Contributor 4: Gin S Malhi, Discipline of Psychiatry, Kolling Institute, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; CADE Clinic, Department of Psychiatry, Royal North Shore Hospital, St Leonards, NSW, Australia.Contributor 5: Florence Levy, Child and Family East, Prince of Wales Hospital and School of Psychiatry, University of New South Wales, Sydney, NSW, Australia. Contributor 6: Pieter J Hoekstra, Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.Contributor 7: Jan K Buitelaar, Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands.
Contributor 8: Tobias Banaschewski, Zentralinstitut für Seelische Gesundheit Mannheim, Klinik für Psychiatrie und Psychotherapie des Kindes‐ und Jugendalters (KJP) / Department of Child & Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany. Contributor 9: Manfred Gerlach, Zentrum für Psychische Gesundheit, Klinik für Kinder‐ und Jugendpsychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg / Centre for Mental Health, Department of Child & Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.Contributor 10: Katja Becker, Klinik für Kinder‐ und Jugendpsychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Gießen und Marburg / Department of Child & Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Giessen and Marburg, Marburg, Germany.Contributor 11: Martin Holtmann, Klinik für Kinder‐ und Jugendpsychiatrie, Psychotherapie und Psychosomatik, LWL‐Universitätsklinik Hamm der Ruhr‐Universität Bochum / Department of Child & Adolescent Psychiatry, Psychotherapy and Psychosomatics, LWL University Hospital of Hamm of Ruhr University Bochum, Bochum, Germany.Contributor 12: Manfred Döpfner, Ausbildungsinstitut für Kinder‐ und Jugendlichenpsychotherapie (AKiP) am Klinikum der Universität zu Köln; Medizinische Fakultät, Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes‐ und Jugendalters, Universität zu Köln / Institute of Child and Adolescent Psychiatry (AKiP), University Hospital of Cologne, Cologne, Germany; Medical School, Department of Child & Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Cologne, Cologne, Germany. Contributor 13: Marcel Romanos, Zentrum für Psychische Gesundheit, Klinik für Kinder‐ und Jugendpsychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg / Centre for Mental Health, Department of Child & Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
Contributor 14: Celine SL Chui, Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China.Contributor 15: David Coghill, Department of Paediatrics and Psychiatry Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia.Contributor 16: Samuele Cortese, Department of Psychology, University of Southampton, Southampton, UK; Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, UK.Contributor 17: Emily Simonoff, Department of Psychology, University of Southampton, Southampton, UK; Department of Child & Adolescent Psychiatry, Institute of Psychiatry Psychology & Neuroscience,King's College London, London, UK.Contributor 18: Ian CK Wong, Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China; Research Department of Practice and Policy, UCL School of Pharmacy, London, UK.

Author 1: Ole Jakob Storebø, Psychiatric Research Unit, Region Zealand Psychiatry, Region Zealand, Denmark; Child and Adolescent Psychiatric Department, Region Zealand, Denmark; Department of Psychology, Faculty of Health Science, University of Southern Denmark, Odense, Denmark.
Author 2: Erika Simonsen, Psychiatric Research Unit, Region Zealand Psychiatry, Region Zealand, Denmark; Institute of Clinical Medicine and Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
Author 3: Christian Gluud, The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; The Cochrane Hepato‐Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Author 4: Morris Zwi, Islington CAMHS, Whittington Health, London, UK.
Author 5: Carlos R Moreira‐Maia, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Author 6: Maria Skoog, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Author 7: Camilla Groth, Pediatric Department, Herlev University Hospital, Herlev, Denmark.
Author 8: Donna Gillies, Western Sydney Local Health District, Mental Health, Parramatta, Australia.
Author 9: Helle B Krogh, Psychiatric Research Unit, Region Zealand Psychiatry, Slagelse, Denmark; Child and Adolescent Psychiatric Department, Region Zealand, Roskilde, Denmark.
Author 10: Mathilde Holmskov, Psychiatric Research Unit, Region Zealand Psychiatry, Slagelse, Denmark; Child and Adolescent Psychiatric Department, Region Zealand, Roskilde, Denmark.

*Typo in article. Author's name should be reported as Groth C.

What's new

Date	Event	Description
27 March 2023	New citation required but conclusions have not changed	Twenty‐nine new studies included in the review
27 March 2023	New search has been performed	Updated following a new search in January 2021 and a top‐up search in March 2022

History

Protocol first published: Issue 5, 2012
Review first published: Issue 12, 2015

Date	Event	Description
29 November 2016	Feedback has been incorporated	This review was published in the Cochrane Library on 25 November 2015, with abridged versions appearing in the BMJ on 26 November 2015 and JAMA on 10 May 2016. These abridged reviews have received many comments in editorials, 'letters to the editor', articles, rapid responses, and blogs. Interestingly, however, no comment has been directed to the full review in the Cochrane Library. In order to inform readers of the Cochrane Library, we have provided the links to these comments, as well as review authors' responses, in the Feedback section below.

Appendices

Appendix 1. Search strategies

Database	Search strategy
Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane Library)	#1 MeSH descriptor: [Methylphenidate] explode all trees #2 (methylphenidate):ti,ab,kw #3 adaphen or adhansia or addwize or aptensio or artige or attenta or biphentin or calocain or centredrin or concerta or cotempla #4 daytrana or dexmethylphenidat* or difumenil or elmifiten or equasym or focalin or foquest or inspiral or jornay or matoride or medikid or medikinet* #5 meridil or metadate or methyl phenidat* or methyl phenidylacetat* or methylfenid* or methylin or methylofenidan or methylphenid* or methyl phenid* #6 methyl phenidyl acetat* or methypatch or metidate or metilfenidat* or motiron* or MPH or omzin or penid* or phenid* or phenidyl hydrochlorid* or phenidylat* or plimasin #7 PMS‐methylphenid* or prohiper or quasym* or quilli* or relexxii or Richter Works or riphenidat* or ritalin* or rubifen or stimdat* or tifinidat or tradea or tranquilyn or tsentedrin #8 #1 or #2 or #3 or #4 or #5 or #6 or #7 #9 MeSH descriptor: [Child] explode all trees #10 MeSH descriptor: [Adolescent] explode all trees #11 MeSH descriptor: [Infant] explode all trees #12 (child* OR boy* OR girl* OR adolescen* OR teen* OR preschool OR pre school OR infant* OR baby OR babies OR toddler* OR school child* or youth*) #13 #9 or #10 or #11 #12 #14 #8 and #13 #15 MeSH descriptor: [Attention Deficit and Disruptive Behavior Disorders] explode all trees #16 adhd or addh or adhs or add #17 (((attention* or behav*) near/3 (defic* or dysfunc* or disorder*))):ti,ab,kw (Word variations have been searched) #18 ((impulsiv* or inattentiv* or inattention*)):ti,ab,kw (Word variations have been searched) #19 MeSH descriptor: [Hyperkinesis] explode all trees #20 (hyperkine*):ti,ab,kw (Word variations have been searched) #21 ((minimal near/3 brain near/3 (disorder* or dysfunct* or damage*))):ti,ab,kw (Word variations have been searched) #22 ((disrupt* near/3 disorder*) or (disrupt* near/3 behav*) or (defian* near/3 disorder*) or (defian* near/3 behav*)):ti,ab,kw (Word variations have been searched) #23 (hyperactiv*):ti,ab,kw #24 #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 #25 #14 and #24 #26 MeSH descriptor: [] explode all trees and with qualifier(s): [adverse effects ‐ AE, drug effects ‐ DE, chemically induced ‐ CI] #27 ((safe or safety or adverse or tolerability or toxicity or toxic or adrs or adr or tolerance or tolerate or harm or harms or harmful or complication* or risk or risks)):ti,ab,kw (Word variations have been searched) #28 (side next effect*):ti,ab,kw #29 (undesirable next effect*):ti,ab,kw (Word variations have been searched) #30 (treatment next emergent):ti,ab,kw (Word variations have been searched) #31 (unintended next event):ti,ab,kw (Word variations have been searched) #32 (unintended next effect):ti,ab,kw (Word variations have been searched) #33 #26 or #27 or #28 or #29 or #30 or #31 or #32 827410 #34 MeSH descriptor: [Mood Disorders] explode all trees #35 (depression or depressive):ti,ab,kw (Word variations have been searched) #36 MeSH descriptor: [Psychotic Disorders] explode all trees #37 (psychosis or (psychotic near/4 symptom*)):ti,ab,kw (Word variations have been searched) #38 MeSH descriptor: [Body Weight] explode all trees #39 MeSH descriptor: [Anorexia] explode all trees #40 ((loss or lose or losing or decreas* or reduc*) near/3 (weight or appetite)):ti,ab,kw (Word variations have been searched) #41 ((reduc* or retard* or inhibit* or deficit*) near/4 growth):ti,ab,kw (Word variations have been searched) 5140 #42 MeSH descriptor: [Hypertension] explode all trees #43 MeSH descriptor: [Heart Rate] explode all trees #44 MeSH descriptor: [Tachycardia] explode all trees #45 MeSH descriptor: [Death] explode all trees #46 (death):ti,ab,kw (Word variations have been searched) #47 MeSH descriptor: [Infertility] explode all trees #48 MeSH descriptor: [Carcinogens] explode all trees #49 ((increas* near/4 (heart rate or pulse or blood pressure))):ti,ab,kw (Word variations have been searched) #50 ((((loss or reduc*) near/4 fertility) or infertility)):ti,ab,kw (Word variations have been searched) #51 MeSH descriptor: [Neoplasms] explode all trees #52 (((risk near/2 cancer) or (cytogenetic near/2 effect*))):ti,ab,kw (Word variations have been searched) #53 #33 or #34 or #35 or #36 or #37 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 #54 #8 and #13 and #24 #55 #8 and #13 and #53 #56 #54 or #55 with Publication Year from 2015 to 2021, in Trials
Ovid MEDLINE	1 exp "Attention Deficit and Disruptive Behavior Disorders"/ 2 adhd.mp. 3 addh.mp. 4 adhs.mp. 5 "add".mp. 6 (ad adj hd).mp. ( 7 ((attention* or behav*) adj3 (defic* or dysfunc* or disorder*)).mp. 8 ((disrupt* adj3 disorder*) or (disrupt* adj3 behav*) or (defian* adj3 disorder*) or (defian* adj3 behav*)).mp. 9 (impulsiv* or inattentiv* or inattention*).mp. 10 hyperactiv*.mp. 11 hyperkinesis*.mp. 12 exp Hyperkinesis/ 13 (minimal adj brain adj3 disorder*).mp. 14 (minimal adj brain adj3 dysfunction*).mp. 15 (minimal adj brain adj3 damage*).mp. 16 or/1‐15 17 randomized controlled trial.pt. 18 controlled clinical trial.pt. 19 randomized controlled trials.mp. 20 exp Randomized Controlled Trial/ 21 random allocation.mp. or Random Allocation/ 22 double blind method.mp. 23 single blind method.mp. 24 clinical trial.pt. 25 (clin* adj25 trial*).ab,ti. 26 ((singl* or doubl* or tripl* or trebl*) adj25 (blind* or mask* or dumm*)).mp. 27 exp Clinical Trial/ 28 placebos.mp. 29 "placebo*".ab,ti. 30 "random*".ab,ti. 31 comparative study.mp. 32 comparative trial.mp. 33 Evaluation Studies as Topic/ 34 exp Clinical Trials as Topic/ 35 follow up studies.mp. 36 prospective studies.mp. 37 (control* or prospectiv* or volunteer*).ab,ti. 38 or/17‐37 39 methylphenidate.mp. or exp Methylphenidate/ 40 adaphen.mp. 41 adhansia.mp. 42 addwize.mp. 43 aptensio.mp. 44 artige.mp. 45 attenta.mp. 46 biphentin.mp. 47 calocain.mp. 48 centedrin*.mp. 49 concerta*.mp. 50 cotempla.mp. 51 daytrana.mp. 52 dexmethylphenidat*.mp. 53 difumenil.mp. 54 elmifiten.mp. 55 equasym*.mp. 56 elmifiten*.mp. 57 focalin.mp. 58 focalin*.mp. 59 foquest.mp. 60 inspiral.mp. 61 jornay.mp. 62 matoride.mp. 63 medikid.mp. 64 medikinet*.mp. 65 meridil.mp. 66 metadate*.mp. 67 methyl phenidat*.mp. 68 methyl phenid*.mp. 69 methyl phenidylacetat*.mp. 70 methylfenid*.mp. 71 methylin*.mp. 72 methylofenid*.mp. 73 methylphenid*.mp. 74 methyl phenid*.mp. 75 methypatch.mp. 76 metidate.mp. 77 metilfenidat*.mp. 78 motiron*.mp. 79 MPH.mp. 80 omozin*.mp. 81 penid*.mp. 82 phenida.mp. 83 phenidyl hydrochlorid*.mp. 84 phenidylat*.mp. 85 phenidyl*.mp. 86 plimasin*.mp. 87 PMS‐methylphenid*.mp. 88 prohiper.mp. 89 quazym*.mp. 90 quilli*.mp. 91 relexxii.mp. 92 Richter Works.mp. 93 riphenidat*.mp. 94 ritalin*.mp. 95 rubifen*.mp. 96 stimdat*.mp. 97 tifinidat*.mp. 98 tradea.mp. 99 tranquilyn.mp. 100 tsentedrin*.mp. 101 or/39‐100 102 exp Child/ 103 exp Adolescent/ 104 exp Infant/ 105 (child* or boy* or girl* or adolescen* or teen* or preschool* or pre school or infant* or baby or babies or toddler* or school child* or youth* or young).mp. 106 or/102‐105 107 16 and 38 and 101 and 106 108 (ae or co or de).fs. 109 (((safe or safety or (side adj1 effect*) or undesirable) adj1 effect*) or (treatment adj1 emergent) or tolerability or tolerance or tolerate or toxicity or toxic or adrs or adr or harm or harms or harmful or complication* or risk or risks or (unintended adj1 event*)).mp. or (un‐intendend adj1 effect*).ab,ti. 110 (adverse adj2 (effect or effects or reaction or reactions or event or events or outcome or outcomes)).ab,ti. 111 Methylphenidate/ae, po, to 112 exp Mood Disorders/ 113 (depression or depressive).ab,ti. 114 exp Psychotic Disorders/ 115 (psychosis or (psychotic adj4 symptom*)).ab,ti. 116 exp body weight/ or anorexia/ 117 ((loss or lose or losing or reduc*) adj3 (weight or appetite)).ab,ti. 118 ((reduc* or retard* or inhibit* or deficit*) adj4 growth).ab,ti. 119 exp Hypertension/ 120 Heart Rate/ 121 Tachycardia/ 122 (increas* adj4 (heart rate or pulse or blood pressure)).ab,ti. 123 exp Death, Sudden/ 124 death.ab,ti. 125 exp Infertility/ 126 (((loss or reduc*) adj4 fertility) or infertility).ab,ti. 127 exp Carcinogens/ 128 exp Neoplasms/ 129 ((risk adj2 cancer) or (cytogenic adj2 effect*)).ab,ti. 130 or/108‐129 131 38 and 101 and 106 and 130 132 107 or 131 133 101 and 106 and 130 134 16 and 101 and 106 and 38 135 131 or 134 136 limit 135 to yr="2015 ‐Current"
Embase (Ovid)	1 exp attention deficit disorder/ 2 adhd.ti,ab. 3 addh.ti,ab. 4 ADHS.ti,ab. 5 (ad adj HD).ti,ab. 6 "(ADD)".mp. 7 ((disrupt* adj3 disorder*) or (disrupt* adj3 behav*) or (defian* adj3 disorder*) or (defian* adj3 behav*)).ti,ab. 8 ((attention* or behav*) adj3 (defic* or dysfunc* or disorder*)).ti,ab. 9 (impulsiv* or inattentiv* or inattention*).ti,ab. 10 exp hyperactivity/ 11 hyperkinesia/ 12 "hyperactiv*".ti,ab. 13 "hyperkinesis*".ti,ab. 14 (minimal adj brain adj3 disorder*).ti,ab. 15 (minimal adj brain adj3 dysfunction*).ti,ab. 16 (minimal adj brain adj3 damage*).ti,ab. 17 or/1‐16 18 exp methylphenidate/ or methylphenidate.mp. 19 adaphen.mp. 20 adhansia.mp. 21 addwize.mp. 22 aptensio.mp. 23 artige.mp. 24 attenta.mp. 25 biphentin*.mp. 26 calocain.mp. 27 centedrin*.mp. 28 concerta*.mp. 29 cotempla.mp. 30 daytrana.mp. 31 dexmethylphenidat*.mp. 32 difumenil*.mp. 33 elmifiten*.mp. 34 equasym.mp. 35 focalin*.mp. 36 foquest.mp. 37 inspiral.mp. 38 jornay.mp. 39 matoride.mp. 40 medikid.mp. 41 medikinet*.mp. 42 meridil.mp. 43 metadate.mp. 44 methyl phenidat*.mp. 45 methyl phenidylacetat*.mp. 46 methylfenid*.mp. 47 methylin*.mp. 48 methylofenid*.mp. 49 methylphenid*.mp. 50 methyl phenidyl acetat*.mp. 51 methypatch.mp. 52 metidate.mp. 53 metilfenidat*.mp. 54 motiron.mp. 55 MPH.mp. 56 omozin*.mp. 57 penid*.mp. 58 phenidyl hydrochlorid.mp. 59 phenidyl hydrochlorid*.mp. 60 phenidyl*.mp. 61 plimasin*.mp. 62 PMS‐methylphenid*.mp. 63 quasym.mp. 64 quilli*.mp. 65 relexxii.mp. 66 Richter Works.mp. 67 riphenidat*.mp. 68 ritalin*.mp. 69 rubifen*.mp. 70 stimdat*.mp. 71 tifinidat*.mp. 72 tradea.mp. 73 tranquilyn.mp. 74 tsentedrin*.mp. 75 or/18‐62 76 exp child/ 77 exp adolescent/ 78 exp juvenile/ 79 exp infant/ 80 (child* or boy* or girl* or adolescen* or teen* or preschool or pre school or infant* or baby or babies or toddler* or school child* or young or youth*).mp. 81 76 or 77 or 78 or 79 or 80 82 clinical trial/ 83 randomized controlled trial/ 84 randomization/ 85 single blind procedure/ 86 double blind procedure/ 87 crossover procedure/ 88 placebo/ 89 prospective study/ 90 (randomi?ed controlled adj1 trial*).ti,tw. 91 rct.ti,tw. 92 randomly allocated.ti,tw. 93 allocated randomly.ti,tw. 94 random allocation.ti,tw. 95 (allocated adj2 random).ti,tw. 96 (single adj1 blind*).ti,tw. 97 (double adj1 blind*).ti,tw. 98 ((treble or triple) adj1 blind*).ti,tw. 99 "placebo*".ti,tw. 100 or/82‐99 101 17 and 75 and 81 and 100 102 (safe or safety or (side adj1 effect*) or (undesirable adj1 effect*) or (treatment adj1 emergent) or tolerability or tolerance or tolerate or toxicity or toxic or adrs or adr or harm or harms or harmful or complication* or risk or risks or (unintended adj1 event*) or (un‐intended adj1 effect*)).ab,ti. 103 (adverse adj2 (effect or effects or reaction or reactions or event or events or outcome or outcomes)).ab,ti. 104 exp adverse drug reaction/ 105 exp side effect/ 106 methylphenidate/ae, to [Adverse Drug Reaction, Drug Toxicity] 107 exp mood disorder/si [Side Effect] 108 (depression or depressive).ab,ti. 109 exp psychosis/si [Side Effect] 110 (psychosis or (psychotic adj4 symptom*)).ab,ti. 111 growth retardation/ 112 growth inhibition/ 113 ((loss or lose or losing or reduc*) adj3 (weight or appetite)).ab,ti. 114 ((reduc* or retard* or inhibit* or deficit*) adj4 growth).ab,ti. 115 hypertension/si [Side Effect] 116 heart rate/ 117 cardiovascular effect/ 118 tachycardia/si [Side Effect] 119 (increas* adj4 (heart rate or pulse or blood pressure)).ab,ti. (68994) 120 sudden death/ 121 death.ab,ti. 122 infertility/si [Side Effect] 123 (((loss or reduc*) adj4 fertility) or infertility).ab,ti. 124 cancer risk/ 125 drug carcinogenicity/ or carcinogenicity/ 126 chromosome aberration/si [Side Effect] 127 childhood cancer/si [Side Effect] 128 ((risk adj2 cancer) or (cytogenic adj2 effect*)).ab,ti. 129 or/102‐128 130 75 and 81 and 100 and 129 131 101 or 130 132 limit 131 to yr="2015 ‐Current"
CINAHL (Cumulative Index to Nursing and Allied Health Literature; EBSCOhost)	S1 (MH "Methylphenidate") S2 AB methylphenidate S3 TI methylphenidate S4 S2 OR S3 S5 TI ( adaphen or adhansia or addwize or aptensio or artige or attenta or biphentin ) OR AB ( adaphen or adhansia or addwize or aptensio or artige or attenta or biphentin ) S6 TI ( calocain or centedrin or concerta or cotempla or daytrana or dexmethylphenidat* or difumenil or elmifiten or equasym or focalin or foquest or inspiral or jornay or motoride ord medikid or medikinet* ) OR AB ( calocain or centedrin or concerta or cotempla or daytrana or dexmethylphenidat* or difumenil or elmifiten or equasym or focalin or foquest or inspiral or jornay or motoride ord medikid or medikinet* ) S7 TI ( meridil or metadate or methyl phenidat or methyl phenidylacetat* or methylphenid* or methylfenid* or methylin or methylofenidan or methylphenid* or methyl phenid* ) OR AB ( meridil or metadate or methyl phenidat or methyl phenidylacetat* or methylphenid* or methylfenid* or methylin or methylofenidan or methylphenid* or methyl phenid* ) S8 TI ( methylphenidyl acetat* or methypatch or metidate or metilfenidat* or motiron* or MPH or omzin* or penid* or phenid* or phenidyl hydrochlorid* or phenidylat* or plimasin* ) OR AB ( methylphenidyl acetat* or methypatch or metidate or metilfenidat* or motiron* or MPH or omzin* or penid* or phenid* or phenidyl hydrochlorid* or phenidylat* or plimasin* ) S9 TI ( PMS‐methylphenid* or prohiper or quasym* or quilli* or relexxii or Richter Works or riphenidat* or ritalin* or rubifen or stimdat* or tifinidat or tradea or tranquilyn or tsentedrin ) OR AB ( PMS‐methylphenid* or prohiper or quasym* or quilli* or relexxii or Richter Works or riphenidat* or ritalin* or rubifen or stimdat* or tifinidat or tradea or tranquilyn or tsentedrin ) S10 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 S11 (MH "Child+") OR (MH "Infant+") OR (MH "Adolescence+") S12 TI ( (child* OR boy* OR girl* OR adolescen* OR teen* OR preschool OR pre school OR infant* OR baby OR babies OR toddler* OR school child* or youth*) ) OR AB ( (child* OR boy* OR girl* OR adolescen* OR teen* OR preschool OR pre school OR infant* OR baby OR babies OR toddler* OR school child* or youth*) ) S13 S11 OR S12 S14 S10 AND S13 S15 (MH "Randomized Controlled Trials+") OR (MH "Double‐Blind Studies") OR (MH "Single‐Blind Studies") OR (MH "Random Assignment") OR (MH "Pretest‐Posttest Design+") OR (MH "Cluster Sample+") S16 TI randomised or randomized S17 AB random* S18 TI trial S19 (MH "Sample Size") AND AB ( assigned or allocated or control ) S20 (MH "Placebos") S21 PT Randomized Controlled Trials S22 PT randomized controlled trial S23 AB control W5 group S24 (MH "Crossover Design") OR (MH "Comparative Studies+") S25 AB cluster W3 RCT S26 (MH "Animals+") S27 (MH "Animal Studies") S28 TI animal model* S29 S26 OR S27 OR S28 S30 (MH "Human") S31 S29 NOT S30 S32 S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 S33 S32 NOT S31 S34 S14 AND S33 S35 S14 AND S33
PsycINFO (Ovid)	1 exp Attention Deficit Disorder/ 2 adhd.ab,ti. 3 addh.ab,ti. 4 ADHS.ab,ti. 5 (AD adj HD).ab,ti. 6 "ADD".ab,ti. 7 ((attention* or behav*) adj3 (defic* or dysfunc* or disorder*)).ab,ti. 8 ((disrupt* adj3 disorder*) or (disrupt* adj3 behav*) or (defian* adj3 disorder*) or (defian* adj3 behav*)).ab,ti. 9 (impulsiv* or inattentiv* or inattention*).ab,ti. 10 "hyperactiv*".ab,ti. 11 hyperkinesis.ab,ti. 12 exp HYPERKINESIS/ 13 (minimal adj brain adj3 disorder*).ab,ti. 14 (minimal adj brain adj3 dysfunction*).ab,ti. 15 (minimal adj brain adj3 damage*).ab,ti. 16 or/1‐15 17 exp Treatment Effectiveness Evaluation/ 18 exp "Treatment outcomes"/ 19 Placebo/ 20 Followup Studies/ 21 placebo*.ab,ti. 22 random*.ab,ti. 23 comparative stud*.ab,ti. 24 (clinical adj3 trial*).ab,ti. 25 (research adj3 design).ab,ti. 26 (evaluat* adj3 stud*).ab,ti. 27 (prospectiv* adj3 stud*).ab,ti. 28 ((singl* or doubl* or trebl* or tripl*) adj3 (blind* or mask*)).ab,ti. 29 or/17‐28 30 methylphenidate.mp. or exp METHYLPHENIDATE/ 31 adaphen.mp. 32 adhansia.mp. 33 addwize.mp. 34 aptensio.mp. 35 artige.mp. 36 attenta.mp. 37 biphentin.mp. 38 calocain.mp. 39 centedrin.mp. 40 concerta.mp. 41 cotempla.mp. 42 daytrana.mp. 43 dexmethylphenidat*.mp. 44 difumenil.mp. 45 elmifiten.mp. 46 equasym*.mp. 47 focalin*.mp. 48 foquest.mp. 49 inspiral.mp. 50 jornay.mp. 51 matoride.mp. 52 medikid.mp. 53 medikinet*.mp. 54 meridil.mp. 55 metadate*.mp. 56 methyl phenidat*.mp. 57 methyl phenidylacetat*.mp. 58 methylfenid*.mp. 59 methylin.mp. 60 methylofenidan.mp. 61 methylphenid*.mp. 62 methyl phenid*.mp. 63 methyl phenidyl acetat*.mp. 64 methypatch.mp. 65 metidate.mp. 66 metilfenidat*.mp. 67 motiron*.mp. 68 MPH.mp. 69 omozin.mp. 70 penid*.mp. 71 phenid*.mp. 72 phenidyl hydrochlorid*.mp. 73 phenidylat*.mp. 74 plimasin*.mp. 75 PMS‐methylphenid*.mp. 76 prohiper.mp. 77 quasym*.mp. 78 quilli*.mp. 79 relexxii.mp. 80 Richter works.mp. 81 riphenidat*.mp. 82 ritalin*.mp. 83 rubifen.mp. 84 stimdat*.mp. 85 tifinidat.mp. 86 tradea.mp. 87 tranquilyn.mp. 88 tsentedrin*.mp. 89 or/30‐88 90 (child* or boy* or girl* or adolescen* or teen* or preschool or pre school or infant* or baby or babies or toddler* or school child* or young or youth*).ab,ti. 91 16 and 29 and 89 and 90 92 exp "Side Effects (Drug)"/ 93 (safe or safety or (side adj1 effect*) or (undesirable adj1 effect*) or (treatment adj1 emergent) or tolerability or tolerance or tolerate or toxicity or toxic or adrs or adr or harm or harms or harmful or complication* or risk or risks or (unintended adj1 event*) or (un‐intended adj1 effect*)).ab,ti. 94 (adverse adj2 (effect or effects or reaction or reactions or event or events or outcome or outcomes)).ab,ti. 95 92 or 93 or 94 96 exp Major Depression/ 97 exp Affective Disorders/ 98 (depression or depressive).ab,ti. 99 exp Psychosis/ 100 (psychosis or (psychotic adj4 symptom*)).ab,ti. 101 exp Body Weight/ 102 exp Appetite Depressing Drugs/ 103 exp Appetite/ 104 ((loss or lose or losing or reduc*) adj3 (weight or appetite)).mp. [mp=title, abstract, heading word, table of contents, key concepts, original title, tests & measures, mesh] 105 ((reduc* or retard* or inhibit* or deficit*) adj4 growth).ab,ti. 106 exp Cardiovascular Disorders/ 107 exp Heart Rate/ 108 exp Heart Rate Affecting Drugs/ 109 (increas* adj4 (heart rate or pulse or blood pressure)).ab,ti. 110 exp "Death and Dying"/ 111 death.ab,ti. 112 exp Infertility/ 113 exp Fertility/ 114 (((loss or reduc*) adj4 fertility) or infertility).ab,ti. 115 exp Neoplasms/ 116 exp Carcinogens/ 117 ((risk adj2 cancer) or (cytogenic adj2 effect*)).ab,ti. 118 or/96‐117 119 29 and 89 and 90 and 118 120 91 or 119 121 limit 120 to yr="2015 ‐Current"
Epistemonikos	searched with a simple search: (title:((title:(attention deficit OR adhd OR hyperactivity OR hypekinetic) OR abstract:(attention deficit OR adhd OR hyperactivity OR hypekinetic)) AND (title:(methylphenidate OR ritalin OR MPH) OR abstract:(methylphenidate OR ritalin OR MPH)) AND ((title:children OR child OR young OR youth OR adolescent) OR abstract:(children OR child OR young OR youth OR adolescent))) 2015‐2021 Combined with search for ten published reviews where all included studies for each review where downloaded if possible. 1. Catala‐Lopez F, Hutton B, Nunez‐Beltran A, et al. The pharmacological and non‐pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta‐analyses of randomised trials. PLOS ONE 2017;12:e0180355. doi: 10.1371/journal.pone.0180355 2. Cerrillo‐Urbina AJ, Garcia‐Hermoso A, Pardo‐Guijarro MJ, et al. The effects of long‐acting stimulant and nonstimulant medications in children and adolescents with attention‐deficit/hyperactivity disorder: A meta‐analysis of randomized controlled trials. J Child Adolesc Psychopharmacol 2018;28:494‐507. doi: 10.1089/cap.2017.0151 3. Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention‐deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta‐analysis. Lancet Psychiatry 2018;5:727‐38. doi: 10.1016/s2215‐0366(18)30269‐4 4. Holmskov M, Storebø OJ, Moreira‐Maia CR, et al. Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder: A systematic review with meta‐analysis and Trial Sequential Analysis of randomised clinical trials. PLOS ONE 2017;12:e0178187. doi: 10.1371/journal.pone.0178187 5. Kemper AR, Maslow GR, Hill S, et al. AHRQ Comparative Effectiveness Reviews Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 [Available from: Available from: https://www.ncbi.nlm.nih.gov/books/NBK487761/. 6. Liu H, Feng W, Zhang D. Association of ADHD medications with the risk of cardiovascular diseases: a meta‐analysis. Eur Child Adolesc Psychiatry 2019;28:1283‐93. doi: 10.1007/s00787‐018‐1217‐x 7. Osland ST, Steeves TD, Pringsheim T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev 2018;6:Cd007990. doi: 10.1002/14651858.CD007990.pub3 8. Punja S, Xu D, Schmid CH, et al. N‐of‐1 trials can be aggregated to generate group mean treatment effects: a systematic review and meta‐analysis. J Clin Epidemiol 2016;76:65‐75. doi: 10.1016/j.jclinepi.2016.03.026 9. Ramstad E, Storebø OJ, Gerner T, et al. Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention‐deficit/hyperactivity disorder: a Cochrane systematic review with meta‐analysis and trial sequential analysis. Scandinavian Journal of Child and Adolescent Psychiatry and Psychology 2018;6(1):52‐71. doi: https://doi.org/10.21307/sjcapp‐2018‐003 10. Solmi M, Fornaro M, Ostinelli EG, et al. Safety of 80 antidepressants, antipsychotics, anti‐attention‐deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta‐review of 78 adverse effects. World Psychiatry 2020;19(2):214‐32. doi: https://doi.org/10.1002/wps.20765
CPCI‐S (Conference Proceedings Citation Index ‐ Science); CPCI‐SSH (Conference Proceedings Citation Index ‐ Social Science & Humanities) (Web of Science)	#2 AND #1 #2 TS=(child* or boy* or girl* or adolescen* or teen* or preschool* or "pre school*" or infant* or baby or babies or toddler* or "school child*" or schoolchild* or youth*) #1 TS=(Methylphenidate or Attenta or Biphentin or Calocain or Centedrin* or Concerta or Daytrana or Dexmethylphenidat* or Elmifiten or Equasym or Focalin or Medikid or Medikinet or Meridil or Metadate or "Methyl phenidat*" or "Methyl phenidylacetat" or Methylfenid or Methylin or Methylofenidan or Methylphenid* or "Methyl phenidyl acetat*" or Methypatch or Metilfenidato or Motiron or MPH or Penid or Omozin or Quazym or "Phenidyl hydrochlorid*" or Phenidylat* or Plimasin* or "PMS‐Methylphenid* " or "Richter Works" or Riphenidat* or Ritalin* or Rubifen or Stimdat* or Tifinidat or Tranquilyn or Tsentedrin*)
ClinicalTrials.gov	Advanced search: Methylphenidate OR concerta OR daytrana OR dexmethylphenidate OR equasym OR focalin OR medikinet OR MPH OR Ritalin Studies with results Age group: Child Studies With Results | Methylphenidate OR concerta OR daytrana OR dexmethylphenidate OR equasym OR focalin OR medikinet OR MPH OR Ritalin | Child Applied Filters: With Results Child (birth–17)
WHO ICTRP (World Health Organisation International Clinical Trials Registry Platform; who.int/ictrp/en)	Methylphenidate OR concerta OR daytrana OR dexmethylphenidate OR equasym OR focalin OR medikinet OR MPH OR Ritalin Children
NDLTD (Networked Digital Library of Theses and Dissertations; ndltd.org/)	methylphenidate AND child* AND (attention deficit or hyperactiv*)
DART‐Europe E‐theses Portal (https://www.dart-europe.org/basic-search.php)	methylphenidate AND child*
Thesis Canada (https://library-archives.canada.ca/eng/services/services-libraries/theses/Pages/theses-canada.aspx)	methylphenidate
Worldcat (https://www.worldcat.org/search?q=methylphenidate)	methylphenidate

Appendix 2. Letter to pharmaceutical companies

Date: September 2021

The Cochrane Methylphenidate Group

Psychiatric Research Unit

Fælledvej 6

4200 Slagelse, Denmark

Ole Jakob Storebø

Email: ojst@regionsjaelland.dk

Phone: +45 24965917

To whom it might concern,

Regarding: Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – a Cochrane systematic review.

On behalf of the Cochrane Methylphenidate Group we address you in order to request your assistance. We are presently updating our systematic review on the effects of methylphenidate for children and adolescents with ADHD, first version published in 2015 [1, 2]. We are entrusted the elaboration of this review by the Cochrane Developmental, Psychosocial and Learning Problems Group, and it has become relevant to update the review with new randomized clinical trials and data.

The Cochrane systematic review intends to include all relevant literature empirically describing both the positive and negative effects of the treatment. We believe the elaboration of this review is in common interest of patients, physicians and manufacturers of methylphenidate. The results from the first version of the review has been cited 202 times (Cochrane version), 129 (BMJ version), and applied into 7 guidelines. By updating the review, it will continue to be applicable to guide authorities, clinicians and researchers when it comes to considering the use of methylphenidate in the treatment for children and adolescents with ADHD.

For the original version of the review, we contacted authors of significant publications, experts in the field and pharmaceutical companies, asking for information on possible relevant clinical trials. We did this because the published literature only provides us with limited and possibly selective knowledge, as it is unlikely that all studies and data are available through these databases. In 2015 we received many additional possible relevant studies for screening. We are now using the same approach for the update of the Cochrane review and are hoping that you will be as forthcoming in assisting us in our work to include published as well as unpublished studies.

We hope you will assist us with providing data that are relevant for our review. As previously noted, we are interested in data regarding both positive and negative effects of methylphenidate from randomized clinical trials, regardless of the year the data was recorded or published.

It is important for us to point out that we are not investigating specific methylphenidate preparations but simply the effect of the active substance, methylphenidate. Thus, we will not refer to or recommend any specific methylphenidate preparation or drug company. However, as we did in 2015 we will state which companies we had been in contact with, and which of these who have assisted us with data.

If possible, we would be very pleased to meet a representative from your company.

Enclosed to this letter are a list of the currently included studies in our review.

We are hoping to hear from you. If you have any questions, please contact us.

With best wishes

On behalf of the study authors

Ole Jakob Storebø, Project coordinator, Ph.D, Research Manager at Center for Evidence Based Psychiatry, Psychiatric Research Unit and senior researcher at Department of Child and Adolescent Psychiatry, Region Zealand. Professor at Department of Psychology, University of Southern Denmark, Odense, Denmark.
Phone: +45 24965917 E‐mail: ojst@regionsjaelland.dk

Erik Simonsen, Medical Director, PhD, Dr.h.c. Psychiatric Research Unit, Region Zealand. Professor at Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Christian Gluud, MD, Dr, Med, Sci, Head of Department, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital − Rigshospitalet, Denmark. Professor at Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

1. Storebø, O.J.; Ramstad, E.; Krogh, H.B.; Nilausen, T.D.; Skoog, M.; Holmskov, M.; Rosendal, S.; Groth, C.; Magnusson, F.L.; Moreira‐Maia, C.R.; Gilles, D. et al. Methylphenidate for children and adolescents with attention deficit hyperac‐tivity disorder (ADHD). Cochrane Database Syst. Rev. 2015, CD009885, doi:10.1002/14651858.cd009885.pub2.

2. Cochrane Central Register of Controlled Trials (CENTRAL) part of the Cochrane Library, MEDLINE, PsycINFO, EMBASE, CINAHL, ISI Conference Proceedings Citation Index (Science, and Social Science and Humanities), Clinical Trials.gov, and International Clinical Trials Registry Platform (ICTRP)

Appendix 3. Data extraction sheet RCTs: parallel‐group trials

Version 09.04.2014

Source

Trial ID (e.g. Plizska 2000)

Trial registry with ID Searchclinicaltrials.gov(from 2008 ‐) andwho.int/ictrp/en(from 2004 ‐)

Full citation

Form filled by

Author contact information

Other publications on same trial

^{ID: identifier.}

Eligibility

Confirm eligibility

Yes No Awaiting assessment

Correspondence

Correspondence required

Method

Cluster‐randomised	Yes/no Intervention (n (number)) =, control (n) =
Location (e.g. hospital, out‐clinic)	‐
Summary (method)	Parallel trial with 2 arms: Methylphenidate Control

Participants

Summary (participants)

Number of participants screened Number of participants included Number of participants randomly assigned to methylphenidate and control Number of participants followed up in each arm: methylphenidate and control Number of withdrawals in each arm: Methylphenidate and control Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM‐III) diagnosis of attention deficit hyperactivity disorder (ADHD) (combined (%), hyperactive‐impulsive (%), inattentive (%)) Age (years) (mean, range) IQ (mean, range) Sex (male, female) Methylphenidate naive (%/number) Ethnicity (white (%), African American (%), Asian (%), Hispanic (%), other (%)) Country Comorbidity (type %) Comedication (no/yes) Sociodemographics (e.g. double or single parent family, low, middle or upper class) Inclusion criteria Exclusion criteria

Interventions

Participants were randomly assigned to type of (e.g. immediate‐release (IR), extended‐release (ER)) (dex‐) methylphenidate or control
Methylphenidate dosage: Mean (standard deviation (SD))
Administration schedule: time points
Duration of intervention
Titration period: none/duration initiated before/after randomisation
Treatment compliance

Outcome listing

(Our outcomes according to our protocol: short, general description) ADHD symptoms Measure instrument (e.g. ADHD Rating Scale (ADHD‐RS); Swanson, Kotkin, Atkins, M‐Flynn and Pelham (SKAMP) Scale), parent‐/teacher‐/independent assessor‐rated, time point General behaviour Measure instrument (e.g. Child Behavior Checklist (CBCL)), parent‐/teacher‐/independent assessor‐rated, time point Quality of life Measure instrument, parent‐/teacher‐/independent assessor‐rated, time point Serious adverse events Type of outcome/adverse event, measure method/instrument, parent‐/teacher‐/independent assessor‐rated, time point Non‐serious adverse events Type of outcome/adverse event, measure method/instrument, parent‐/teacher‐/independent assessor‐rated, time point

Outcomes (positive effects)

*e.g. copy of table from article*

Outcomes (adverse events)

*e.g. copy of table from article*

Outcomes specified	Type of adverse events/responses	Total numbers	Mean	SD	Time point
Serious adverse events (temporal association, but not necessarily causal relationship)
Serious adverse reaction (response to the drug)
Non‐serious adverse events (temporal association)

Risk of bias

Item	Quote	Risk of bias (high, unclear, low)
Random sequence generation/generation of allocation sequence (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (intention‐to‐treat (ITT), imputation method) (attrition bias)
Selective outcome reporting (according to protocol?)
Vested interest
Other sources of bias	Authors’ affiliations (e.g. Novartis) Selection bias (e.g. titration after randomisation → exclusion of methylphenidate non‐responders or placebo responders)

Notes

Sample calculation Ethics approval Inclusion of methylphenidate responders only/exclusion of methylphenidate non‐responders/children who have previously experienced adverse events while taking methylphenidate Any withdrawals due to adverse events Comments from trial authors Key conclusions of trial authors Comments from review authors Supplemental information/data received through personal email correspondence with trial authors in *month* 2014

Appendix 4. Data extraction sheet RCTs: cross‐over trials

Version 09.04.2014

Source

Trial ID (e.g. Plizska 2000)
Trial registry with ID Searchclinicaltrials.gov(from 2008 ‐) andwho.int/ictrp/en(from 2004 ‐)
Full citation
Form filled by	Date and name
Author contact information
Other publications on same trial

^{ID: identifier}

Eligibility

Confirm eligibility

Yes No Awaiting assessment

Correspondence

Correspondence required

Data for each intervention period

Method

Cluster‐randomised	Yes/No Intervention (number (n)) =, control (n) =
Location (e.g. hospital, out‐clinic)
Ethics approval	Yes/No/No information
Summary (method)	Cross‐over trial with 2 interventions: Methylphenidate Control Phases

Participants

Summary (participants)

Number of participants screened Number of participants included Participants were randomly assigned to 1 of X possible drug condition orders Number of participants followed up Number of withdrawals Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) diagnosis of attention deficit hyperactivity disorder (ADHD) (combined (%), hyperactive‐impulsive (%), inattentive (%)) Age (years) (mean, range) IQ (mean, range) Sex (male, female) Methylphenidate naive (%/number) Ethnicity (white (%), African‐american (%), Asian (%), Hispanic (%), other (%)) Country Comorbidity (type %) Comedication (no/yes) Sociodemographics (e.g. double‐ or single‐parent family, low, middle or upper class) Inclusion criteria Exclusion criteria

Interventions

Participants were randomly assigned to 1 of X possible drug condition orders of methylphenidate and control
Methylphenidate dosage: mean (standard deviation (SD))
Administration schedule: time points
Duration of each medication condition
Washout before trial initiation
Medication‐free period between interventions
Titration period: none/duration initiated before/after randomisation
Treatment compliance

Outcome listing

(Our outcomes according to our protocol: short, general description) ADHD symptoms Measure instrument (e.g. ADHD Rating Scale (ADHD‐RS), Swanson, Kotkin, Atkins, M‐Flynn and Pelham (SKAMP) scale), parent‐/teacher‐/independent assessor‐rated, time point General behaviour Measure instrument (e.g. Child Behavior Checklist (CBCL)), parent‐/teacher‐/independent assessor‐rated, time point Quality of life Measure instrument, parent‐/teacher‐/independent assessor‐rated, time point Serious adverse events Type of outcome/adverse event, measure method/instrument, parent‐ /teacher‐/independent assessor‐rated, time point Non‐serious adverse events Type of outcome/adverse event, measure method/instrument, parent‐ /teacher‐/independent assessor‐rated, time point

Outcomes (positive effects)

*e.g. copy of table from article*

Outcomes (adverse events)

*e.g. copy of table from article*

Outcomes specified	Types of adverse events/responses	Total numbers	Mean	SD	Time point
Serious adverse events (temporal association, but not necessarily causal relationship)
Serious adverse reaction (response to the drug)
Non‐serious adverse events (temporal association)

Risk of bias

Item	Quote	Risk of bias (high, unclear, low)
Random sequence generation/generation of allocation sequence (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (intention‐to‐treat (ITT), imputation method) (attrition bias) Exclusion of placebo responders etc.: methylphenidate non‐responders (after randomisation)
Selective outcome reporting (according to protocol?)
Vested interest
Other sources of bias	Authors’ affiliations (e.g. Novartis) Selection bias (e.g. titration after randomisation → exclusion of methylphenidate non‐responders or placebo responders)

Notes

Sample calculation Ethics approval Comments from trial authors Key conclusions of trial authors Comments from review authors Inclusion of methylphenidate responders only/exclusion of methylphenidate non‐responders/children who have previously experienced adverse events while taking methylphenidate Any withdrawals due to adverse events Supplemental information/data received through personal email correspondence with trial authors in *month* 2014

Data and analyses

Comparison 1. Teacher‐rated ADHD symptoms.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All parallel‐group trials and first‐period cross‐over trials	21	1728	Std. Mean Difference (IV, Random, 95% CI)	‐0.74 [‐0.88, ‐0.61]
1.1.1 Low risk of bias	3	206	Std. Mean Difference (IV, Random, 95% CI)	‐0.67 [‐1.11, ‐0.22]
1.1.2 High risk of bias	18	1522	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐0.90, ‐0.61]
1.2 Subgroup analysis: types of scales	20		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
1.2.1 Conners' Teacher Rating Scale (CTRS)	9	470	Std. Mean Difference (IV, Random, 95% CI)	‐0.63 [‐0.82, ‐0.45]
1.2.2 Abbreviated Conners' Rating Scale (ACRS) ‐ Teacher	2	105	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐1.79, 0.29]
1.2.3 Conners' Abbreviated Symptom Questionnaire for Teachers (ASQ‐Teacher)	1	59	Std. Mean Difference (IV, Random, 95% CI)	‐0.28 [‐0.79, 0.23]
1.2.4 IOWA Conners' Teacher Rating Scale (IOWA CTRS) ‐ hyperactivity	2	193	Std. Mean Difference (IV, Random, 95% CI)	‐1.08 [‐1.39, ‐0.77]
1.2.5 The Swanson, Nolan, and Pelham (SNAP) Scale ‐ Teacher	2	328	Std. Mean Difference (IV, Random, 95% CI)	‐0.61 [‐0.96, ‐0.25]
1.2.6 Teacher ratings of attention	1	20	Std. Mean Difference (IV, Random, 95% CI)	‐0.55 [‐1.45, 0.35]
1.2.7 Teacher ratings of impulsivity	1	20	Std. Mean Difference (IV, Random, 95% CI)	0.04 [‐0.83, 0.92]
1.2.8 IOWA Conners' Teacher Rating Scale ‐ Inattention/Overactivity (IOWA‐I/O)	2	197	Std. Mean Difference (IV, Random, 95% CI)	‐1.03 [‐1.36, ‐0.69]
1.2.9 Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB‐HKS)	1	85	Std. Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.52, ‐0.61]
1.2.10 Conners’ ADHD/DSM‐IV Scales ‐ Teacher (CADS‐T)	2	254	Std. Mean Difference (IV, Random, 95% CI)	‐1.05 [‐1.31, ‐0.78]
1.2.11 Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) Scale	1	64	Std. Mean Difference (IV, Random, 95% CI)	‐0.33 [‐0.82, 0.17]
1.3 Subgroup analysis: duration of treatment	21	1728	Std. Mean Difference (IV, Random, 95% CI)	‐0.74 [‐0.88, ‐0.61]
1.3.1 Short term (up to 6 months)	20	1475	Std. Mean Difference (IV, Random, 95% CI)	‐0.77 [‐0.91, ‐0.64]
1.3.2 Long term (over 6 months)	1	253	Std. Mean Difference (IV, Random, 95% CI)	‐0.47 [‐0.72, ‐0.22]
1.4 Subgroup analysis: dose	21		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
1.4.1 Low dose	7	361	Std. Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.82, ‐0.39]
1.4.2 High dose	8	766	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐1.00, ‐0.50]
1.4.3 Unknown dose	8	753	Std. Mean Difference (IV, Random, 95% CI)	‐0.85 [‐1.02, ‐0.68]
1.5 Subgroup analysis: medication status ‐ medication naive versus not medication naive	11	882	Std. Mean Difference (IV, Random, 95% CI)	‐0.76 [‐0.94, ‐0.59]
1.5.1 Medication naive	7	480	Std. Mean Difference (IV, Random, 95% CI)	‐0.70 [‐0.88, ‐0.51]
1.5.2 Not medication naive	4	402	Std. Mean Difference (IV, Random, 95% CI)	‐0.85 [‐1.20, ‐0.50]
1.6 Subgroup analysis: trials with enrichment design compared with trials without enrichment design	20	1679	Std. Mean Difference (IV, Random, 95% CI)	‐0.75 [‐0.89, ‐0.62]
1.6.1 Trials with enrichment design of all participants	8	1072	Std. Mean Difference (IV, Random, 95% CI)	‐0.74 [‐0.96, ‐0.53]
1.6.2 Trials without enrichment design of all participants	12	607	Std. Mean Difference (IV, Random, 95% CI)	‐0.78 [‐0.96, ‐0.60]
1.7 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials	21	1728	Std. Mean Difference (IV, Random, 95% CI)	‐0.74 [‐0.88, ‐0.61]
1.7.1 Parallel‐group trials	19	1633	Std. Mean Difference (IV, Random, 95% CI)	‐0.76 [‐0.90, ‐0.61]
1.7.2 First‐period cross‐over trials	2	95	Std. Mean Difference (IV, Random, 95% CI)	‐0.57 [‐0.98, ‐0.15]
1.8 Subgroup analysis: vested interest	18	1460	Std. Mean Difference (IV, Random, 95% CI)	‐0.74 [‐0.90, ‐0.58]
1.8.1 Low risk of vested interest	4	186	Std. Mean Difference (IV, Random, 95% CI)	‐0.49 [‐0.79, ‐0.20]
1.8.2 High risk of vested interest	14	1274	Std. Mean Difference (IV, Random, 95% CI)	‐0.78 [‐0.96, ‐0.60]
1.9 Subgroup analysis: type of control group	21	1728	Std. Mean Difference (IV, Random, 95% CI)	‐0.74 [‐0.88, ‐0.61]
1.9.1 Placebo control group	17	1358	Std. Mean Difference (IV, Random, 95% CI)	‐0.77 [‐0.92, ‐0.63]
1.9.2 No‐intervention control group	4	370	Std. Mean Difference (IV, Random, 95% CI)	‐0.62 [‐0.99, ‐0.24]
1.10 Cross‐over trial (endpoint data)	64	6341	Std. Mean Difference (IV, Random, 95% CI)	‐0.88 [‐1.01, ‐0.75]
1.10.1 Low risk of bias	7	733	Std. Mean Difference (IV, Random, 95% CI)	‐0.62 [‐0.84, ‐0.40]
1.10.2 High risk of bias	57	5608	Std. Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.06, ‐0.77]
1.11 Subgroup analysis: cross‐over trials (endpoint data): dose	58	7403	Std. Mean Difference (IV, Random, 95% CI)	‐0.82 [‐0.93, ‐0.71]
1.11.1 Low dose	43	4530	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐0.86, ‐0.59]
1.11.2 High dose	31	2873	Std. Mean Difference (IV, Random, 95% CI)	‐0.96 [‐1.15, ‐0.77]
1.12 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data)	81	7564	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.82 [‐0.87, ‐0.77]
1.12.1 All parallel‐group trials and first‐period cross‐over trials	21	1728	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.74 [‐0.84, ‐0.64]
1.12.2 Cross‐over trials (endpoint data)	60	5836	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.85 [‐0.90, ‐0.79]
1.13 All parallel‐group trials and cross‐over trials: risk of bias	81	7564	Std. Mean Difference (IV, Random, 95% CI)	‐0.85 [‐0.96, ‐0.74]
1.13.1 Low risk of bias	8	518	Std. Mean Difference (IV, Random, 95% CI)	‐0.68 [‐0.91, ‐0.45]
1.13.2 High risk of bias	73	7046	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐0.99, ‐0.75]
1.14 All parallel‐group trials and cross‐over trials: vested interest	77	7212	Std. Mean Difference (IV, Random, 95% CI)	‐0.85 [‐0.96, ‐0.73]
1.14.1 Low risk of vested interest	23	1446	Std. Mean Difference (IV, Random, 95% CI)	‐0.83 [‐1.08, ‐0.58]
1.14.2 High risk of vested interest	54	5766	Std. Mean Difference (IV, Random, 95% CI)	‐0.85 [‐0.98, ‐0.72]

Comparison 2. Independent assessor‐rated ADHD symptoms.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All parallel‐group trials and first‐period cross‐over trials	22	3724	Std. Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.44, ‐0.77]
2.1.1 Low risk of bias	4	942	Std. Mean Difference (IV, Random, 95% CI)	‐0.40 [‐0.78, ‐0.03]
2.1.2 High risk of bias	18	2782	Std. Mean Difference (IV, Random, 95% CI)	‐1.30 [‐1.70, ‐0.89]
2.2 Subgroup analysis: types of scales	22		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
2.2.1 Swanson, Kotkin, Agler, M‐Glynn and Pelham (SKAMP) Scale	6	778	Std. Mean Difference (IV, Random, 95% CI)	‐2.79 [‐4.10, ‐1.47]
2.2.2 ADHD Rating Scale (ADHD‐RS )	14	2802	Std. Mean Difference (IV, Random, 95% CI)	‐0.60 [‐0.81, ‐0.38]
2.2.3 Swanson, Nolan and Pelham (SNAP) Scale	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.61, ‐0.08]
2.2.4 Unknown	1	78	Std. Mean Difference (IV, Random, 95% CI)	‐0.94 [‐1.41, ‐0.47]
2.3 Subgroup analysis: duration of treatment	22	3724	Std. Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.44, ‐0.77]
2.3.1 Short term (up to 6 months)	21	3503	Std. Mean Difference (IV, Random, 95% CI)	‐1.15 [‐1.50, ‐0.80]
2.3.2 Long term (over 6 months)	1	221	Std. Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.61, ‐0.08]
2.4 Subgroup analysis: dose	22	3724	Std. Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.44, ‐0.77]
2.4.1 Low dose	1	138	Std. Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.52, 0.15]
2.4.2 High dose	17	3005	Std. Mean Difference (IV, Random, 95% CI)	‐0.84 [‐1.13, ‐0.55]
2.4.3 Unknown dose	4	581	Std. Mean Difference (IV, Random, 95% CI)	‐2.57 [‐4.40, ‐0.74]
2.5 Subgroup analysis: trials with enrichment design compared with trials without enrichment design	22	3724	Std. Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.44, ‐0.77]
2.5.1 Trials with enrichment design of all participants	19	3245	Std. Mean Difference (IV, Random, 95% CI)	‐1.24 [‐1.61, ‐0.87]
2.5.2 Trials without enrichment design of all participants	3	479	Std. Mean Difference (IV, Random, 95% CI)	‐0.22 [‐0.62, 0.17]
2.6 Subgroup analysis: type of control group	22	3724	Std. Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.44, ‐0.77]
2.6.1 Placebo control group	20	3200	Std. Mean Difference (IV, Random, 95% CI)	‐1.22 [‐1.58, ‐0.85]
2.6.2 No‐intervention control group	2	524	Std. Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.52, 0.23]
2.7 Subgroup analysis: parallel‐group trials compared with first‐period cross‐over trials	22	3724	Std. Mean Difference (IV, Random, 95% CI)	‐1.10 [‐1.44, ‐0.77]
2.7.1 Parallel‐group trials	19	3550	Std. Mean Difference (IV, Random, 95% CI)	‐1.17 [‐1.54, ‐0.80]
2.7.2 First‐period cross‐over trials	3	174	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐1.03, ‐0.41]
2.8 Cross‐over trials (endpoint data)	22	3854	Std. Mean Difference (IV, Random, 95% CI)	‐0.97 [‐1.11, ‐0.83]
2.8.1 High risk of bias	22	3854	Std. Mean Difference (IV, Random, 95% CI)	‐0.97 [‐1.11, ‐0.83]
2.9 Subgroup analysis: cross‐over trials (endpoint data): dose	22	5257	Std. Mean Difference (IV, Random, 95% CI)	‐0.88 [‐1.00, ‐0.76]
2.9.1 Low dose	17	3067	Std. Mean Difference (IV, Random, 95% CI)	‐0.72 [‐0.86, ‐0.58]
2.9.2 High dose	13	2051	Std. Mean Difference (IV, Random, 95% CI)	‐1.07 [‐1.27, ‐0.86]
2.9.3 Unknown dose	1	139	Std. Mean Difference (IV, Random, 95% CI)	‐1.03 [‐1.39, ‐0.68]
2.10 Subgroup analysis: all parallel‐group trials and first‐period cross‐over trials compared with cross‐over trials (endpoint data)	42	7277	Std. Mean Difference (IV, Random, 95% CI)	‐0.99 [‐1.18, ‐0.80]
2.10.1 All parallel‐group trials and first‐period cross‐over trials	21	3586	Std. Mean Difference (IV, Random, 95% CI)	‐1.15 [‐1.50, ‐0.81]
2.10.2 Cross‐over trials (endpoint data)	21	3691	Std. Mean Difference (IV, Random, 95% CI)	‐0.93 [‐1.07, ‐0.78]
2.11 All parallel‐group trials and cross‐over trials: risk of bias	42	7277	Std. Mean Difference (IV, Random, 95% CI)	‐0.99 [‐1.18, ‐0.80]
2.11.1 Low risk of bias	4	942	Std. Mean Difference (IV, Random, 95% CI)	‐0.40 [‐0.78, ‐0.03]
2.11.2 High risk of bias	38	6335	Std. Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.25, ‐0.86]
2.12 All parallel‐group trials and cross‐over trials: vested interest	43	7414	Std. Mean Difference (IV, Random, 95% CI)	‐0.98 [‐1.17, ‐0.80]
2.12.1 Low risk of vested interest	6	600	Std. Mean Difference (IV, Random, 95% CI)	‐0.96 [‐1.43, ‐0.48]
2.12.2 High risk or unclear risk of vested interest	37	6814	Std. Mean Difference (IV, Random, 95% CI)	‐0.99 [‐1.19, ‐0.79]

Comparison 3. Parent‐rated ADHD symptoms.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 All parallel‐group trials and first‐period cross‐over trials	27	2927	Std. Mean Difference (IV, Random, 95% CI)	‐0.63 [‐0.76, ‐0.50]
3.1.1 Low risk of bias	6	702	Std. Mean Difference (IV, Random, 95% CI)	‐0.49 [‐0.71, ‐0.26]
3.1.2 High risk of bias	21	2225	Std. Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.81, ‐0.51]
3.2 Subgroup analysis: types of scales	27		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only
3.2.1 Conners' Parent Rating Scale (CPRS)	8	800	Std. Mean Difference (IV, Random, 95% CI)	‐0.53 [‐0.80, ‐0.26]
3.2.2 ADHD Rating Scale ‐ Fourth Edition (ADHD‐RS‐IV)	5	753	Std. Mean Difference (IV, Random, 95% CI)	‐0.37 [‐0.53, ‐0.21]
3.2.3 Fremdbeurteilungsbogen für Hyperkinetische Störungen (FBB‐HKS)	1	85	Std. Mean Difference (IV, Random, 95% CI)	‐0.91 [‐1.36, ‐0.46]
3.2.4 Conners’ ADHD/DSM‐IV Scales ‐ Parent (CADS‐P)	2	195	Std. Mean Difference (IV, Random, 95% CI)	‐1.12 [‐1.44, ‐0.81]
3.2.5 CADS‐P Inattentive subscale	1	109	Std. Mean Difference (IV, Random, 95% CI)	‐0.78 [‐1.17, ‐0.39]
3.2.6 CADS‐P Hyperactivity subscale	1	109	Std. Mean Difference (IV, Random, 95% CI)	‐0.93 [‐1.32, ‐0.53]
3.2.7 Clinican's Manual for the Assesment of Disruptive Behavior Disorders Rating Scale for Parents (Barkley)	1	41	Std. Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.82, 0.41]