Effect of amphetamines on blood pressure

Abstract

Background

Daily ingestion of amphetamines is common, as they are widely prescribed for attention‐deficit hyperactivity disorder (ADHD) and other diagnoses. People also use amphetamines recreationally or in an attempt to boost cognitive or athletic performance. Amphetamines have the potential to increase blood pressure, and we do not know if the long‐term benefits of daily amphetamine use outweigh the potential harms.

Objectives

Primary: to quantify the changes in systolic and diastolic blood pressure in children and adults taking amphetamines, compared to placebo.

Secondary: to quantify the changes in heart rate in children and adults taking amphetamines, compared to placebo; to quantify the number of withdrawals due to adverse effects of amphetamine, compared to placebo.

Search methods

We used the Cochrane Hypertension Specialized Register, CENTRAL, MEDLINE, Embase and two clinical trial registers, together with reference checking and contact with study authors to identify the studies included in the review. We imposed no restrictions on language, publication year or publication status. The latest search date was March 2023.

Selection criteria

Randomized controlled trials (RCTs) that compared the effects of daily oral amphetamines versus placebo on blood pressure. There were no restrictions on participants' age or gender.

Data collection and analysis

We used standard methods expected by Cochrane. Primary outcomes were change in systolic and diastolic blood pressure (measured in millimeters of mercury (mmHg) above atmospheric pressure; continuous outcomes). Secondary outcomes were heart rate (measured as beats per minute; continuous outcome) and withdrawals due to adverse effects (dichotomous outcome). We calculated continuous outcomes as mean differences (MD) with 95% confidence intervals (CI). We expressed withdrawals due to adverse effects as a risk ratio with 95% CI. We used a fixed‐effect model to pool effect sizes from all studies.

Main results

We included 56 RCTs with a total of 10,583 participants, both adults and children. Most studies were conducted in North America (mainly the USA), followed by Europe. A few studies took place in Asia (Japan) and Australia. The studies tested racemic amphetamine, dextroamphetamine, mixed amphetamine salts, lisdexamfetamine dimesylate, methyl​enedioxy​methamphetamine (MDMA) and methylphenidate. The amphetamines were prescribed for ADHD, weight loss and other indications. In 48 RCTs, blood pressure was measured within 24 hours of the last dose.

Based on data from all included studies, amphetamines increased systolic blood pressure (SBP) by 1.93 mmHg (95% CI 1.54 to 2.31) and diastolic blood pressure (DBP) by 1.84 mmHg (95% CI 1.51 to 2.16) (56 studies, 10,583 participants; high‐certainty evidence for both). Amphetamines increased heart rate by 3.71 beats per minute (95% CI 3.27 to 4.14; 47 studies, 10,075 participants; high‐certainty evidence). In a subgroup analysis limited to studies that gave participants amphetamines for at least eight weeks, the effects were similar, suggesting that these are sustained effects. These findings suggest that people taking daily oral amphetamines are at increased risk of adverse cardiovascular events. Participants in the amphetamine group were also more likely to withdraw from the study due to adverse effects compared to those given placebo (risk ratio 2.69, 95% CI 2.13 to 3.40; absolute risk increase of 4.3% over an average duration of 1 month; 42 studies, 8952 participants; high‐certainty evidence).

In general, the studies were well‐executed, and the methodology was sound. We judged most studies to have a low risk of bias across most domains. Selection bias (random sequence generation and allocation concealment) was the domain most often rated as at unclear risk of bias, because the methods used were not reported. We judged 13 studies (23%) to have a high risk of bias in at least one of the seven domains, primarily due to high dropout rates, leading to a high risk of attrition bias.

Authors' conclusions

Daily oral amphetamines increase blood pressure, heart rate, and withdrawals due to adverse effects, with these effects observed across all time points, including shorter (≤ four weeks) and longer durations (> four weeks to < eight weeks; ≥ eight weeks) of use. Future trials should measure blood pressure using 24‐hour ambulatory monitoring and assess the effect of long‐term use.

Plain language summary

Do amphetamines increase blood pressure?

Key messages

• Amphetamines are substances that increase activity in the brain and central nervous system. Taking them every day by mouth for at least 8 weeks increases blood pressure and heart rate.
• In studies that gave participants amphetamines or placebo medicine (an inactive substance), more people given amphetamines quit the studies due to unwanted or harmful effects than people given placebo.

What are amphetamines, and what are they prescribed for?

Amphetamines are medicines that have a stimulant effect on the brain. They can make you more alert, improve concentration, and increase your energy levels. Doctors prescribe amphetamines for children, adolescents and adults with attention‐deficit hyperactivity disorder (ADHD) and other conditions.

What are some possible harms of amphetamines?

Like all medicines, amphetamines can cause adverse effects – that is, unwanted or harmful effects. Two possible adverse effects are an increase in blood pressure and heart rate. Long‐term elevated blood pressure and heart rate increase the risk of stroke, heart attack, heart failure and kidney failure.

What did we want to find out?

We aimed to find out whether people taking amphetamines by mouth daily experienced an increase in blood pressure, heart rate or adverse effects causing them to stop treatment.

What did we do?

We searched for studies that compared amphetamines with a placebo and measured participants' blood pressure. Our primary focus was on the blood pressure results. Additionally, if the studies measured heart rate and the number of participants who withdrew from the study due to adverse effects, we also included those findings in our analysis. We combined the results of these studies (blood pressure, heart rate, withdrawals) and evaluated our confidence in the evidence based on the study design and methods.

What did we find?

We found 56 studies that involved a total of 10,583 people. Almost two‐thirds (64%) of the participants were given a type of amphetamine, while the rest were given a placebo. One‐third (33%) of the participants were children, and two‐thirds (67%) were adults. Participants took amphetamines for varying lengths of time, but the average duration was one month.

What are the main results?

We found that, compared to the placebo group, people given amphetamines had higher blood pressure and heart rate (4 beats per minute higher). Amphetamines also led to more people withdrawing from the studies due to adverse effects: for every 1000 people given placebo, 25 people withdrew, whereas for every 1000 people given amphetamines, 68 people withdrew (54 to 85 people).

What are the main limitations of the evidence?

We are confident that amphetamines increase blood pressure, heart rate and the number of withdrawals due to adverse effects. In general, the studies were well‐executed, and we did not have concerns about the methods they used that would have lowered our confidence in the evidence.

How current is the evidence?

The evidence is current to March 2023.

Summary of findings

Summary of findings 1. Effect of amphetamines compared to placebo on blood pressure.

Effect of amphetamines compared to placebo on all outcomes in all participants
Patient or population: individuals of all ages, genders and with comorbid conditions, including hypertension Setting: outpatient Intervention: amphetamines Comparison: placebo
Outcomes (Average duration of follow‐up: 1 month)	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Effect with placebo (95% CI)	Effect with amphetamine (95% CI)
Systolic blood pressure (mmHg)	‐2.50 (‐3.40 to ‐1.62)a	MD 1.93 higher (1.54 higher to 2.31 higher)	‐	10,583 (56)	⊕⊕⊕⊕ Highb	I2 = 62%. Not downgraded for inconsistency because high variability is expected.
Diastolic blood pressure (mmHg)	‐1.45 (‐2.19 to ‐0.72)a	MD 1.84 higher (1.51 higher to 2.16 higher)	‐	10,583 (56)	⊕⊕⊕⊕ Highb	I2 = 58%. Not downgraded for inconsistency because high variability is expected.
Heart rate (beats/minute)	+1.75 (0.88 to 2.69)a	MD 3.71 higher (3.27 higher to 4.14 higher)	‐	10,075 (47)	⊕⊕⊕⊕ Highb	I2 = 64%. Not downgraded for inconsistency because high variability is expected.
Withdrawals due to adverse effects	25 withdrawals per 1000 participants	66 withdrawals per 1000 participants (54 to 86 withdrawals)	Risk ratio 2.69 (2.13 to 3.40)	8952 (42)	⊕⊕⊕⊕ Highb	I2 = 0% Absolute risk increase = 4.3%
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the placebo group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference
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.

^aPlacebo values from Kornstein 2019, the study with the greatest weight in the meta‐analysis.
^bSensitivity analyses showed that downgrading for risk of bias or study sponsorship was unnecessary. See Discussion.

Background

Many people take daily medications on a long‐term basis. For many of those drugs, it is not known whether the long‐term benefits outweigh the harms. One possible long‐term adverse effect associated with daily medication is an increase in blood pressure. Two drug classes have the potential to cause an increase in blood pressure: oral decongestants and amphetamines. In this review, we are studying amphetamines. Oral decongestants are studied in a companion review using a similar methodology (Chan 2021).

Description of the condition

Blood pressure is the force that arterial blood exerts on the arterial wall. Blood pressure is measured in millimeters of mercury (mmHg) above atmospheric pressure, commonly represented in a fraction form: systolic (the maximum pressure) / diastolic (the minimum pressure) in a single cardiac cycle. The average resting blood pressure reading is around 120/80 mmHg. A person is considered to have elevated blood pressure (hypertension) if their resting blood pressure is consistently above 140/90 mmHg. However, it is important to know that that number is purely an accepted convention and varies between guidelines. Low resting blood pressure (hypotension) is conventionally defined as a consistent resting blood pressure of less than 90/60 mmHg.

Blood pressure is important because it is the most important modifiable risk factor for cardiovascular disease. Usual blood pressure is a graded risk factor for stroke and ischemic heart disease over the range of blood pressures above 115/75 mmHg in adults (Lewington 2002). Thus, any intervention that changes blood pressure by even a small amount at a population level could have important consequences (He 2013).

High blood pressure is estimated to cause 7 million deaths globally per year (Perkovic 2007). The Global Burden of Disease studies quantify the disease burden of hypertensive diseases. In each updated study report, hypertension is consistently listed as one of the top causes, if not the leading cause, of disability and death worldwide (Bromfield 2013). For example, in 2010, elevated blood pressure was estimated to be responsible for 7% of disability and 17.8% of premature deaths worldwide (Campbell 2015). This statistic makes sense when considering how hypertension is a significant risk factor for many diseases with a varying degree of severity.

Description of the intervention

Amphetamines are a group of central nervous system (CNS) stimulants that were first synthesized in the 1890s but were not used clinically until the early 1930s (MacKenzie 1997). At present, amphetamines are primarily being used in four clinical settings. The first and most well‐known is to treat attention‐deficit hyperactivity disorder (ADHD) in children, adolescents and adults (Heal 2013). A second medical use is the treatment of narcolepsy. A third use is to enhance athletic performance or boost cognitive performance in healthy individuals (Cooter 1980). Fourth, amphetamines are also widely used recreationally. For this review, we are primarily interested in settings where an individual would be taking daily amphetamines in the long term. This would be most relevant to the first two clinical settings. This review explores whether daily amphetamine intake increases blood pressure.

The amphetamines we examine in this review include racemic amphetamine, dextroamphetamine, mixed amphetamine salts (d‐amphetamine and l‐amphetamine) and methyl​enedioxy​methamphetamine (MDMA). Methylphenidate is not considered an amphetamine but has similar indications and effects (Mayorga 2000), so we have included it for the purposes of this review.

Amphetamines are administered orally, and the dosages depend on the age of the patient. The peak plasma level time for amphetamine depends on the formulation used: the immediate‐release (IR) version reaches its peak plasma concentration in about three hours, while the extended‐release (XR) version peaks around seven hours after administration (Weisler 2005). The elimination half‐life for amphetamine is nine to 11 hours in children and three to four hours longer in adults (Weisler 2005). The elimination half‐life of methylphenidate is around three hours.

How the intervention might work

Amphetamines may exert their effects on blood pressure by activating the alpha‐adrenoreceptors in blood vessels, thereby causing vasoconstriction (Sheng 2018). Moreover, amphetamines can activate beta‐adrenoreceptors in the heart, increasing heart rate and contractility (Backer 2017). This combination of increased peripheral resistance from vasoconstriction and enhanced cardiac output could lead to an increase in systemic blood pressure (Mayet 2003). Besides effects on systemic blood pressure, amphetamine use is associated with pulmonary arterial hypertension, with features such as higher right atrial pressure, lower cardiac output and lower right ventricular stroke volume compared to idiopathic pulmonary arterial hypertension (Kolaitis 2021). Amphetamines could also affect blood pressure through an effect on the brain.

Why it is important to do this review

To date, there are few systematic reviews evaluating the effects of amphetamine on blood pressure. One review reported that people taking amphetamines after a stroke had increased blood pressure (Martinsson 2007). Another review concluded that blood pressure was elevated in children with ADHD taking amphetamines (Hennissen 2017). However, the results from these two reviews cannot be extended to the general population because they were conducted on specific populations. Identifying the effects of amphetamines on individuals with normal, elevated or hypertensive blood pressure is crucial, given the broad use of this drug class among the public. This is the first systematic review using Cochrane methodology that analyzes and summarizes the effects of amphetamine on blood pressure in the general population.

Objectives

Primary: to quantify the changes in systolic and diastolic blood pressure in children and adults taking amphetamines, compared to placebo.

Secondary:

• to quantify the changes in heart rate in children and adults taking amphetamines, compared to placebo;

• to quantify the number of withdrawals due to adverse effects of amphetamine, compared to placebo.

Methods

Criteria for considering studies for this review

Types of studies

Included study designs were randomized placebo‐controlled clinical trials (RCTs) with random allocation to the experimental amphetamine or a parallel placebo group. Cross‐over trials were not included in order to prevent any carry‐over effects.

Types of participants

We excluded studies involving pregnant participants because blood pressure is often altered during pregnancy (Grindheim 2012). There were no other restrictions on participants' age, sex, blood pressure status (e.g. hyper/hypotensive) or other comorbid conditions.

Types of interventions

The review included studies that gave participants racemic amphetamine, dextroamphetamine, mixed amphetamine salts (d‐amphetamine and l‐amphetamine), methylphenidate and methyl​enedioxy​methamphetamine (MDMA). Methylphenidate is not chemically an amphetamine but has similar indications and effects (Mayorga 2000), so we included it for the purposes of this review. Included studies needed to have a placebo control. Participants in both the experimental arm and the control arm could have received standard medical therapy for existing comorbid conditions, as long as these medications did not change over the course of the study.

Types of outcome measures

Primary outcomes

• Change in systolic and diastolic blood pressure (mmHg)

Secondary outcomes

• Change in heart rate (beats per minute)

• Withdrawals due to adverse effects

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist searched the following databases without language, publication year or publication status restrictions:

• Cochrane Hypertension Specialized Register via the Cochrane Register of Studies (CRS‐Web) (to 20 March 2023);

• Cochrane Central Register of Controlled Trials (CENTRAL; 2023, Issue 3) via the Cochrane Register of Studies (CRS‐Web) (searched 20 March 2023);

• MEDLINE ALL (R) Ovid (1946 to 20 March 2023);

• Embase Ovid (1974 to 20 March 2023);

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (to 20 March 2023).

The World Health Organization International Clinical Trials Registry Platform was searched via CRS‐Web (searched 20 March 2023)

The Information Specialist modeled subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying RCTs, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). We present search strategies for major databases in Appendix 1.

Searching other resources

• The Cochrane Hypertension Information Specialist searched the Hypertension Specialized Register segment (which includes searches of MEDLINE and Embase for systematic reviews) to retrieve existing reviews relevant to this systematic review, so that we could scan their reference lists for additional trials.

• We searched Epistemonikos for related systematic reviews.

• We checked the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.

• Where necessary, we contacted authors of key papers and abstracts to request additional information about their trials.

• We searched clinical study reports for additional information about relevant trials.

Data collection and analysis

The selection of studies, data extraction and management, and assessment of risk bias in included studies were all conducted using Covidence systematic review software (Covidence 2019).

Selection of studies

Working independently, two review authors (MC and JJC) screened the identified title and abstract records retrieved from the electronic search databases. Using Covidence software, we coded the title and abstract records as “yes”, “no” or “maybe”. We discussed any disagreements about the appropriate coding until we reached consensus.

After the initial selection of RCTs, two review authors (MC and JJC) independently analyzed the full texts of studies that were coded as “yes” or “maybe”. This analysis was done in duplicate to determine which studies met the aforementioned inclusion criteria and should therefore be included in the review. We treated any studies with multiple full‐text papers as a single study. For any full‐text papers that reported on multiple eligible studies, we disaggregated the results in order to treat each study as a unique, primary study. We resolved any disagreements at this stage through discussion. We consulted a third review author (JMW) to resolve any disagreements. We documented records excluded at the full‐text screening stage in the Characteristics of excluded studies, with a reason for exclusion. We adopted the PRISMA study flow diagram template to capture the record screening and study flow process (Moher 2009).

Data extraction and management

We developed a data extraction form based on the Cochrane Public Health template, modified to best extract all relevant data for this review (Data Extraction and Assessment Template 2011). We piloted the form on three studies to ensure the appropriateness and accuracy of the extracted data. Any studies published in languages other than English were translated into English prior to data extraction. For studies with multiple publications, we extracted data from the publication containing the most complete data.

For each included study, we populated a 'Characteristics of included studies' table, including details of the PICO (population, intervention, comparison, outcome) characteristics, primary and secondary outcomes, study design details and results. Results included effect estimates, means, mean differences, confidence intervals and standard deviations.

Working independently, two review authors (MC and JJC) extracted data using our tailored data extraction form. We resolved any disagreements by double‐checking the data and discussing any discrepancies. If necessary, we consulted a third review author (JMW) to resolve discrepancies.

Assessment of risk of bias in included studies

Working independently, two review authors (MC and JC) assessed the included studies for risk of bias using the method described in the Cochrane Handbook (Higgins 2017). We involved a third author (JMW) to discuss and resolve any disagreements. In the case of missing data or unclear experimental methods, we attempted to contact study authors via email to retrieve missing information or seek clarification.

We assessed all RCTs using the Cochrane risk of bias 1 tool, which considers the following domains:

• random sequence generation (selection bias);

• allocation concealment (selection bias);

• blinding of participants and personnel (performance bias);

• blinding of outcome assessment (performance and detection bias);

• incomplete outcome data (attrition bias);

• selective outcome reporting (reporting bias);

• other potential sources of bias not covered by the other domains, such as the presence of a conflict of interest.

We used these results to produce a risk of bias table, as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). For each of the domains, we assessed the study as having a high, low or unclear risk of bias. We rated studies as having an overall low risk of bias if we assessed all domains as low risk. We rated studies as having an overall unclear risk of bias if we assessed one or more domains as having an unclear risk of bias. We rated studies as having an overall high risk of bias if we assessed one or more domains as high risk (Higgins 2017).

We included all studies that met the inclusion criteria in the meta‐analysis, irrespective of the assessed risk of bias. We used the risk of bias assessment to understand the certainty of the evidence, including by performing a sensitivity analysis excluding studies assessed as having an overall high risk of bias to evaluate their effect on the treatment effect estimate. The risk of bias assessment informed the GRADE assessment of the overall certainty of evidence.

Measures of treatment effect

The position of the body during a blood pressure measurement is a factor that affects blood pressure measurement readings (Netea 2003). However, placing a restriction on the measurement position is impractical as that could lead to a loss of valuable data. Therefore, we included all data derived from at least one blood pressure measurement in any position. We employed a preferential hierarchy if there was more than one position measurement available, with sitting as the most preferable position, followed by standing, with supine being the least favorable position.

In the case that there were multiple intervention arms in a study, we only extracted data from the relevant intervention arm and the comparison group if they met the inclusion criteria of this review. We ignored all other intervention arms.

For continuous outcomes such as blood pressure and heart rate, we calculated the mean difference (MD) for our summary statistic using mean values, standard deviation and sample size from studies (Higgins 2020). For outcome measurements, the change from baseline was our preferred data. We used the end‐of‐treatment value if change‐from‐baseline data were not available. We reported the dichotomous outcome of withdrawals due to adverse effects as a risk ratio (RR). We analyzed both continuous and dichotomous outcomes with a 95% confidence interval (CI).

Unit of analysis issues

We did not include cross‐over data from cross‐over trials so we did not anticipate any unit of analysis issues. In multi‐arm studies with multiple dosage arms, we combined the dosage groups to create a single pairwise comparison for continuous and dichotomous outcome data, as illustrated in Axon 2023.

Dealing with missing data

We sought to obtain data missing from the included studies by contacting the investigators of the studies. When needed, we imputed missing data for an intention‐to‐treat analysis and conducted a sensitivity analysis to evaluate how the results were altered by the imputed data (Higgins 2020). If the data for an intention‐to‐treat analysis were dichotomous, we assumed that missing participants experienced the event.

In the case of missing standard deviations of the change in blood pressure, we imputed the standard deviation based on other information in the same trial, if available (Higgins 2024). If imputation was not possible, we assumed an SD of 14 mmHg for systolic blood pressure and 9 mmHg for diastolic blood pressure, based on empirical evidence from Musini 2009. We used the following hierarchy, listed from high to low preference, to impute standard deviation values:

• standard deviation of change in blood pressure taken in a different position than that of the blood pressure data used;

• standard deviation of blood pressure at the end of treatment;

• standard deviation of blood pressure at the end of treatment measured in a different position than that of the blood pressure data used;

• standard deviation of blood pressure at baseline (except if this measure was used for entry criteria);

• mean standard deviation of change in blood pressure from other trials using the same drug;

• mean standard deviation of change in blood pressure from other trials using any amphetamine.

We specified all methods used to manage missing data.

Assessment of heterogeneity

We did not use the Chi² test to assess heterogeneity because the test has low power when meta‐analyses contain few studies, and therefore, it is poor at identifying true heterogeneity. In contrast, for analyses containing many large studies, the test may have excessive power, which also does not accurately describe the degree of heterogeneity.

Due to the issues with quantifying heterogeneity using the Chi² test, we employed the I² statistic to quantify the effect of heterogeneity. The I² quantity is the percentage of variation across studies that results from heterogeneity as opposed to chance. Therefore, I² values range from 0% to 100%, with 0% indicating no observed heterogeneity and subsequently increasing percentages indicating greater heterogeneity. I² values of 25%, 50% and 75% are considered to be low, moderate and high values of heterogeneity, respectively (Higgins 2003). We evaluated the factors leading to statistical heterogeneity if the I² statistic was 50% or higher, meaning there was moderate to high heterogeneity.

Assessment of reporting biases

We assessed for publication bias using funnel plots, where effect estimates are plotted against the standard error of the effect estimate, as described in Chapter 13 of the Cochrane Handbook (Page 2020). We used funnel plots only when there were at least 10 trials evaluating the same outcome in a meta‐analysis. We used funnel plots as visual aids to assess the presence of small study effects, often indicated by the plot's asymmetry. We used Egger's test to analyze the extent of asymmetry in the funnel plots (Egger 1997).

Data synthesis

We entered all the randomized placebo‐controlled trials into Review Manager software to perform data synthesis and meta‐analyses (RevMan 2025). One review author (MC) entered the data and another review author (JJC) double‐checked that the data were correct. We used the inverse‐variance method for continuous outcomes to calculate MDs with 95% CIs using a fixed‐effect model. We used the Mantel‐Haenszel method for dichotomous outcomes to calculate risk ratios with 95% CIs using a fixed‐effect model.

For any moderate to high heterogeneity, as indicated by an I² statistic of 50% or higher, we used a random‐effects model to evaluate whether the pooled effect was statistically significant. If so, we explored and attempted to explain the reasons underlying the heterogeneity.

Subgroup analysis and investigation of heterogeneity

When possible, we performed the following subgroup analyses:

• men versus women;

• hypertensive participants versus non‐hypertensive participants;

• high dosage versus low dosage;

• participants under the age of 18 versus participants 18 years of age and older;

• shorter duration (≤ four weeks) versus longer durations (> four weeks to < eight weeks; ≥ eight weeks).

We assessed heterogeneity within subgroups and evaluated whether any heterogeneous outcomes were truly different, using a Chi² statistical test for subgroup differences, with significance set at a P value of less than 0.05.

When there was an I² statistic of 50% or higher, we attempted to identify the studies that contributed to this moderate to high heterogeneity and explored potential reasons behind this heterogeneity.

Sensitivity analysis

We conducted the following prespecified sensitivity analyses to assess the robustness of the results from our primary meta‐analysis:

• an analysis excluding studies rated as overall high risk of bias;

• an analysis excluding any imputed data;

• a comparison between a fixed‐effect and random‐effects model (Chan 2020).

We also decided to conduct four further post hoc sensitivity analyses (see Differences between protocol and review), in which we excluded studies:

• funded by industry (i.e. pharmaceutical companies);

• that were shorter than seven days' duration;

• that measured blood pressure more than 24 hours after the final dose of amphetamines/placebo;

• that gave participants methylenedioxymethamphetamine (MDMA).

Summary of findings and assessment of the certainty of the evidence

We created a summary of findings table, using GRADEpro software (GRADEpro GDT), which presents anticipated absolute effects for continuous outcomes (systolic and diastolic blood pressure, heart rate), the relative effect for the dichotomous outcome (withdrawals due to adverse effects), all related statistics, the number of trials and participants, and the certainty of the evidence (GRADE).

We used the GRADE approach to assess the certainty of the evidence for the effect estimates, and assigned one of four levels of evidence certainty: high, moderate, low or very low. All results from randomized trials with no limitations are, by default, regarded as high certainty of evidence. We evaluated the evidence against five domains, as outlined in the GRADE Handbook: limitations in study design or execution (risk of bias), inconsistency of results, indirectness of evidence, imprecision and publication bias (Schünemann 2013). Each domain with an issue leads to a downgrade in the certainty of the evidence by one level, in an additive manner. If there were serious limitations in a single domain, the certainty of the evidence could be downgraded by two levels based on this single domain alone (Schünemann 2020).

Since determining the certainty of evidence is a subjective matter, we discussed any decision to downgrade the certainty of the evidence to reach a fair and accurate judgment.

Results

Description of studies

Results of the search

The electronic searches yielded 2314 records. At the title/abstract screening stage, we excluded two duplicate records and 2123 records as clearly irrelevant to the review. We retrieved the full texts of the remaining 189 records for detailed screening. We excluded 125 records with reasons (Excluded studies), identified nine ongoing studies, and included 56 studies (reported in 55 articles) in the review. Please refer to Figure 1 for a detailed flow diagram.

1.

PRISMA study flow diagram

Included studies

All 56 RCTs involving 10,583 participants used a parallel‐group design. The studies ranged in size: Kornstein 2019 was the largest, with 739 participants, and Dymowski 2016 the smallest, with 10 participants. The average number of participants per trial was 188. All included trials, except for Mathew 1989, clearly stated a double‐blind study design. We contacted the authors of the included studies, but we did not include any additional data beyond what was reported in the publications.

In the included studies, amphetamines were prescribed for attention‐deficit hyperactivity disorder (ADHD), weight loss and other indications. In 48 RCTs, blood pressure was measured within 24 hours of the last dose. The amphetamines studied included racemic amphetamine, dextroamphetamine, mixed amphetamine salts, lisdexamfetamine dimesylate (LDX), methyl​enedioxy​methamphetamine (MDMA) and methylphenidate. Almost two‐thirds (64%) of the participants were given a type of amphetamine, while the rest were given a placebo. Participants took amphetamines for varying lengths of time, with an average duration of one month. Children under 18 years of age made up 33% of participants, and adults made up 67%.

Most studies were conducted in North America, primarily in the USA, with some also conducted in Canada and Mexico. Europe was the next most common continent, with studies conducted in Germany, Sweden, Spain, Hungary, France, the UK, Italy, Belgium, Poland and the Netherlands. A few studies were conducted in Asia (Japan and Taiwan), Australia and South America (Argentina and Chile). Studies were primarily funded by pharmaceutical companies, with some also supported by government grants and independent sources.

For further details on each included study, please refer to Characteristics of included studies and Table 2.

1. Trial characteristics.

Trial ID	Amphetamine(s) used	Dose (mg)	Average participant age (years)	Study duration (weeks)
Adler 2008	Lisdexamfetamine	30–70	35	4
Adler 2009	OROS methylphenidate	36–108	39	7
Adler 2013	Lisdexamfetamine	30–70	34	10
Biederman 2006	OROS methylphenidate	36–80	35	6
Biederman 2007	OROS methylphenidate / IR methylphenidate	30–70	35	6
Biederman 2012	Lisdexamfetamine	30–70	22	6
Brams 2018	Mixed amphetamine salts	25	12	4
Casas 2013	OROS methylphenidate	54	35	13
Childress 2022	Lisdexamfetamine	5–30	61	6
Coghill 2013	Lisdexamfetamine /OROS methylphenidate	18–54	11	7
Daviss 2008	Methylphenidate	<60	10	16
Dymowski 2016	Methylphenidate	50	33	7
Ermer 2019	Lisdexamfetamine	70	38	2.5
Findling 2005	XR mixed amphetamine salts	10–30	9	6
Findling 2011	Lisdexamfetamine	30–70	15	4
Frick 2017	Mixed amphetamine salts	25–75	38	6
Gasior 2014	Lisdexamfetamine	25–70	28	24 hours
Ginsberg 2012	OROS methylphenidate	72	34	5
Green 2011	Methylphenidate	16	11	90 mins
Guerdjukova 2016	Lisdexamfetamine	20–70	38	12
Hegerl 2017	Methylphenidate	40	46	2.5 days
Kornstein 2019	Lisdexamfetamine dimesylate	50–70	38	13
Lasser 2010	Lisdexamfetamine	50–70	35	5
Lasser 2010a	Mixed amphetamine salts–XR	20–40	38	5
Lin 2014	OROS methylphenidate	36–54	10	8
Martinsson 2003	Dextroamphetamine	2.5–10	68	1
Matthew 1985	Dextroamphetamine sulfate	15	28	45 mins
Matthew 1989	Dextroamphetamine sulfate	15	31	1 day
Mattingly 2020	Mixed amphetamine salts	6.25	9	5
McElroy 2014	Lisdexamfetamine	20–70	43	8
McElroy 2015	Lisdexamfetamine dimesylate	30–70	39	8
McElroy 2016	Lisdexamfetamine	50–70	38	12
McElroy 2016a	Lisdexamfetamine	50–70	38	12
Medori 2008	Prolonged‐release methylphenidate	18–72	34	5
Mitchell 2021	Methyl​enedioxy​methamphetamine (MDMA)	80–180	41	14
Mooney 2015	Lisdexamfetamine	70	46	14
Newcorn 2008	Osmotic‐release methylphenidate	18–72	10	6
Newcorn 2017	Lisdexamfetamine/OROS methylphenidate	18–72	15	6
Newcorn 2017a	Lisdexamfetamine/OROS methylphenidate	18–72	15	8
Nordin 2013	Dextroamphetamine	20	25	10 hours
Paterson 1999	Dextroamphetamine	23	36	6
Patkar 2006	XR methylphenidate	18–54	49	4
Platz 2005	Dextroamphetamine	10	58	2 hours
Press 2021	Methylphenidate	10–30	76	3 days
Retz 2012	Methylphenidate–XR	66	37	8
Richards 2017	Lisdexamfetamine	10–70	41	15
Roache 2000	Methylphenidate	15–60	35	1
Rosler 2009	Methylphenidate–XR	41.2	34	24
Simonoff 2013	Dextroamphetamine	49.6	11	16
Spencer 2008	Mixed amphetamine salts	12.5–75	37	7
Sprigg 2007	Dextroamphetamine	10	71	5
Weisler 2017	Mixed amphetamine salts	12.5 or 37.5	32	4
Westover 2013	OROS methylphenidate	18–72	37	11
Whiting 2008	Dextroamphetamine	10	23	5 days
Wigal 2017	Extended–release methylphenidate	20–60	10	6
Winhusen 2010	OROS methylphenidate	72	38	11

IR: immediate release; OROS: osmotic release oral system; XR: extended release

Excluded studies

We excluded 125 records at the full‐text screening stage. The main reasons for exclusion included ineligible study design, ineligible outcomes (i.e. studies did not measure or report blood pressure) and being unable to obtain missing information despite attempts to contact authors (see Characteristics of excluded studies).

We identified nine trials as ongoing at the time of analysis (see Characteristics of ongoing studies).

Risk of bias in included studies

The risk of bias across included studies was generally low in most domains, with some concerns noted, primarily about selection bias due to unclear reporting of random sequence generation and allocation concealment methods. Specifically, 40 of 56 studies did not report allocation concealment, and 30 studies lacked details on their randomization method. Additionally, a minority of studies (23%) showed a high risk of bias in at least one domain, primarily for attrition bias due to high dropout rates. We rated the risks of performance and detection biases as mostly low across the studies due to double‐blind designs and blinding in outcome assessments, respectively. The risk of publication bias appears minimal, as indicated by symmetric funnel plots. The Characteristics of included studies table provides details about our risk of bias judgments for each study, and Figure 2 presents a summary of the risk of bias assessment.

2.

Review authors' judgements about each risk of bias item for each included randomised controlled trial.

Allocation

Regarding trial allocation methods, we assessed two categories of potential selection bias: random sequence generation and allocation concealment.

Random sequence generation

We assessed 31 trials as having an unclear risk of bias for random sequence generation. Although all trials included in this review randomized participants, we rated studies as having an unclear risk if they did not describe a specific randomization method. We classified 24 studies as having a low risk of bias because they described a specific randomization method. Lasser 2010b was the only study we judged as being at high risk of bias in this domain, as authors did not report the sequence generation process and randomization resulted in exceptionally uneven ratios, with almost 80% of participants randomized to the amphetamine arm.

Allocation concealment

We classified 40 trials as having an unclear risk of bias as they did not report their allocation concealment method, and the remaining 16 trials as low risk because they did report this information. Methods included (but were not limited to): prescribing both groups identical‐looking pills; appointing an external pharmacist to conduct the randomization and conceal the results to all parties within the study until the end of the trial; and appointing an external clinical supply group to conduct the randomization using a computer program and locking the results until the end of the study.

Blinding

We assessed all studies but one as having a low risk of performance bias, as all were double‐blind experiments. We rated Mathew 1989 as having an unclear risk in this domain as the authors did not specify the blinding procedures.

We classified 53 studies as having a low risk of detection bias, as individual(s) blinded to treatment assignment conducted the outcome assessments, including blood pressure measurement. We classified two trials as having an unclear risk of detection bias. In Mathew 1985, it was unclear who assessed the blood pressure measurements, so we cannot determine whether blood pressure outcomes were likely biased by knowledge of the treatment group. In Mathew 1989, the trial does not indicate whether it was an open‐label study or whether there was any blinding. We rated the remaining trial, Green 2011, as having a high risk of detection bias due to being an open‐label study.

Incomplete outcome data

We classified 13 trials as having a high risk of attrition bias, as they either had a high dropout rate or an unbalanced dropout rate between the control and intervention groups. We judged four trials to have an unclear risk of attrition bias as they did not report their attrition rates (Kornstein 2019; Lasser 2010a; Lasser 2010b; Mathew 1985). We assessed the remaining 39 trials as having a low risk of bias because the great majority of participants completed the trials, and attrition rates for both groups were low.

Selective reporting

We classified 48 trials as having a low risk of selective reporting bias as they fully reported blood pressure measurements. We judged six trials as having a high risk of selective reporting as they either did not report the blood pressure measurement in full, did not provide independent data for different dosages, or did not report the titrated dosages for participants. We assessed the two remaining trials as having an unclear risk of bias as they only published blood pressure readings for certain time points (McElroy 2016a; McElroy 2016b).

Other potential sources of bias

We used a funnel plot to assess symmetry and evaluate potential publication bias or small‐study effects. Funnel plots can be found in Figure 3, Figure 4, Figure 5, and Figure 6. Since the funnel plots appear symmetric, we do not suspect any publication bias.

3.

Funnel plot of studies for systolic blood pressure

4.

Funnel plot of studies for diastolic blood pressure

5.

Funnel plot of studies for heart rate

6.

Funnel plot of studies for withdrawals due to adverse effects

Effects of interventions

See: Table 1

See Table 1 for a summary of the pooled effect of amphetamines versus placebo on systolic and diastolic blood pressure, heart rate and withdrawals due to adverse effects. As noted in the Sensitivity analysis section, we performed sensitivity analyses (three prespecified and four post hoc analyses) to test the robustness of the results of the primary analysis with all studies pooled. We found that the effect estimates for all outcomes were robust to the substitution of a random‐effects model for the default fixed‐effect model we employed. We also found that the effect estimates for all outcomes were robust to the exclusion of studies:

• in which we imputed standard deviations;

• with an overall high risk of bias rating;

• funded by industry;

• that were shorter than seven days' duration;

• that measured blood pressure more than 24 hours after participants' final dose of amphetamines/placebo;

• that gave participants methylenedioxymethamphetamine (MDMA).

We present details of the sensitivity analysis for each outcome below, and discuss these results further in the Discussion.

Systolic blood pressure

Systolic blood pressure (SBP) was reported in all 56 trials. Compared to placebo, amphetamines increased systolic blood pressure by 1.93 mmHg (95% CI 1.54 to 2.31; P < 0.001, I² = 61%; 56 trials, 10,583 participants; high‐certainty evidence; Analysis 1.1).

1.1. Analysis.

Comparison 1: Amphetamines versus placebo: primary analysis, Outcome 1: Systolic blood pressure

Subgroup analysis

Many studies did not separate the data in a way that would enable us to perform a subgroup analysis. Of our five planned subgroup analyses (Subgroup analysis and investigation of heterogeneity), we were able to compare: (1) participants under 18 years versus participants aged 18 years and older; and (2) trials with a shorter duration (≤ four weeks) versus those with longer durations (> four weeks to < eight weeks; ≥ eight weeks).

In participants under age 18, amphetamines increased SBP by 1.09 mmHg compared to placebo (95% CI 0.37 to 1.81; 13 trials, 3255 participants). In participants aged 18 and over, amphetamines increased SBP by 2.26 mmHg compared to placebo (95% CI 1.81 to 2.72; 43 trials, 7328 participants). The effect of amphetamines on SBP was greater in adults than in children (Chi² = 7.26, degrees of freedom (df) = 1 [P = 0.007], I² = 86.2%). Detailed analysis in Analysis 2.1.

2.1. Analysis.

Comparison 2: Subgroup analysis by population age, Outcome 1: Systolic blood pressure

For trials shorter than or equal to four weeks in duration, amphetamines increased participants' SBP by 2.07 mmHg (95% CI 1.28 to 2.86; 17 trials, 1794 participants). For trials longer than four weeks but less than eight weeks, amphetamines increased participants' SBP by 1.24 mmHg (95% CI 0.62 to 1.86; 20 trials, 4356 participants). For trials equal to or longer than eight weeks in duration, amphetamines increased participants' SBP by 2.55 mmHg (95% CI 1.92 to 3.17; 19 trials, 4433 participants). Thus, amphetamines appeared to have a lesser effect on SBP in trials of four to eight weeks' duration (Chi² = 8.57, df = 2 [P = 0.01], I² = 76.7%). Detailed analysis in Analysis 3.1.

3.1. Analysis.

Comparison 3: Subgroup analysis by trial length, Outcome 1: Systolic blood pressure

The available data were insufficient to perform the other planned subgroup analyses.

Sensitivity analysis

Using a random‐effects model instead of a fixed‐effect model did not appreciably alter the estimate of the effect size on systolic blood pressure: 2.16 mmHg (95% CI 1.45 to 2.87) versus 1.93 mmHg (95% CI 1.54 to 2.31), respectively.

The primary summary effect estimate of increased systolic blood pressure for participants given amphetamines (1.94 mmHg) was robust to the exclusion of studies:

• for which we imputed standard deviations (SBP remained increased, at 1.95 mmHg, 95% CI 1.55 to 2.34; 51 trials, 9776 participants; Analysis 4.1);

• with an overall high risk of bias (SBP remained increased, at 2.20 mmHg, 95% CI 1.71 to 2.69; 37 trials, 6474 participants; Analysis 5.1);

• funded by the pharmaceutical industry (SBP remained increased, at 2.08 mmHg, 95% CI 1.25 to 2.92; 19 trials, 1676 participants; Analysis 6.1);

• shorter than seven days' duration (SBP remained increased, at 1.84 mmHg, 95% CI 1.43 to 2.24; 47 trials, 10,239 participants; Analysis 7.1);

• that measured blood pressure more than 24 hours after the final amphetamine/placebo dose (SBP remained increased, at 1.70 mmHg, 95% CI 1.25 to 2.15; 48 trials, 7513 participants; Analysis 8.1);

• that gave participants MDMA (SBP remained increased, at 1.90 mmHg, 95% CI 1.52 to 2.29; 55 trials, 10,504 participants; Analysis 9.1).

4.1. Analysis.

Comparison 4: Sensitivity analysis excluding studies with imputed standard deviations (SDs) in results, Outcome 1: Systolic blood pressure

5.1. Analysis.

Comparison 5: Sensitivity analysis excluding studies with high risk of bias, Outcome 1: Systolic blood pressure

6.1. Analysis.

Comparison 6: Sensitivity analysis excluding pharmaceutical industry‐sponsored studies, Outcome 1: Systolic blood pressure

7.1. Analysis.

Comparison 7: Sensitivity analysis excluding studies shorter than 7 days in duration, Outcome 1: Systolic blood pressure

8.1. Analysis.

Comparison 8: Sensitivity analysis excluding studies that measured blood pressure more than 24 hours after final dose, Outcome 1: Systolic blood pressure

9.1. Analysis.

Comparison 9: Sensitivity analysis excluding studies administering MDMA, Outcome 1: Systolic blood pressure

Diastolic blood pressure

Diastolic blood pressure (DBP) was reported in all 56 trials. Compared to placebo, amphetamines increased diastolic blood pressure by 1.84 mmHg (95% CI 1.51 to 2.16; P < 0.001, I² = 56%; 56 trials, 10,583 participants; high‐certainty evidence; Analysis 1.2).

1.2. Analysis.

Comparison 1: Amphetamines versus placebo: primary analysis, Outcome 2: Diastolic blood pressure

Subgroup analysis

In participants under age 18, amphetamines increased DBP by 2.16 mmHg (95% CI 1.53 to 2.78; 13 trials, 3255 participants). In participants aged 18 and over, amphetamines increased DBP by 1.72 mmHg (95% CI 1.34 to 2.10; 43 trials, 7328 participants). Thus, the effect on DBP was not different between children and adults (Chi² = 1.38, df = 1 [P = 0.24], I² = 27.3%). Detailed analysis in Analysis 2.2.

2.2. Analysis.

Comparison 2: Subgroup analysis by population age, Outcome 2: Diastolic blood pressure

In studies of four weeks' duration or less, amphetamines increased participants' DBP by 1.89 mmHg (95% CI 1.16 to 2.63; 17 trials, 1794 participants). In studies longer than four weeks but of less than eight weeks' duration, amphetamines increased participants' DBP by 1.75 mmHg (95% CI 1.24 to 2.27; 20 trials, 4356 participants). For studies of eight weeks' duration or longer, amphetamines increased participants' DBP by 1.89 mmHg (95% CI 1.39 to 2.38; 19 trials, 4433 participants). Thus, the duration of the trials did not appear to alter amphetamines' effect on DBP (Chi² = 0.16, df = 2 [P = 0.92], I² = 0%). Detailed analysis in Analysis 3.2.

3.2. Analysis.

Comparison 3: Subgroup analysis by trial length, Outcome 2: Diastolic blood pressure

The available data were insufficient to perform the other planned subgroup analyses.

Sensitivity analysis

Testing the effect of using the random‐effects model instead of the fixed‐effect model showed no difference in the estimate of the effect size (1.82 mmHg, 95% CI 1.27 to 2.36 versus 1.84 mmHg, 95% CI 1.51 to 2.16, respectively).

The primary summary effect estimate of increased diastolic blood pressure for participants given amphetamines (1.84 mmHg) was robust to the exclusion of studies:

• for which we imputed standard deviations (DBP remained increased at 1.81 mmHg, 95% CI 1.48 to 2.14; 51 trials, 9776 participants; Analysis 4.2);

• with a high risk of bias (DBP remained increased at 2.17 mmHg, 95% CI 1.76 to 2.59; 37 trials, 6474 participants; Analysis 5.2);

• funded by the pharmaceutical industry (DBP remained increased at 1.62 mmHg, 95% CI 0.90 to 2.34; 19 trials, 1676 participants; Analysis 6.2);

• shorter than seven days' duration (DBP remained increased at 1.83 mmHg, 95% CI 1.49 to 2.16; 47 trials, 10,239 participants; Analysis 7.2);

• that measured blood pressure more than 24 hours after final dose (DBP remained increased at 1.76 mmHg, 95% CI 1.38 to 2.13; 48 trials, 7513 participants; Analysis 8.2);

• that gave participants MDMA (DBP remained increased at 1.82 mmHg, 95% CI 1.49 to 2.14; 55 trials, 10,504 participants; Analysis 9.2).

4.2. Analysis.

Comparison 4: Sensitivity analysis excluding studies with imputed standard deviations (SDs) in results, Outcome 2: Diastolic blood pressure

5.2. Analysis.

Comparison 5: Sensitivity analysis excluding studies with high risk of bias, Outcome 2: Diastolic blood pressure

6.2. Analysis.

Comparison 6: Sensitivity analysis excluding pharmaceutical industry‐sponsored studies, Outcome 2: Diastolic blood pressure

7.2. Analysis.

Comparison 7: Sensitivity analysis excluding studies shorter than 7 days in duration, Outcome 2: Diastolic blood pressure

8.2. Analysis.

Comparison 8: Sensitivity analysis excluding studies that measured blood pressure more than 24 hours after final dose, Outcome 2: Diastolic blood pressure

9.2. Analysis.

Comparison 9: Sensitivity analysis excluding studies administering MDMA, Outcome 2: Diastolic blood pressure

Heart rate

Heart rate was reported in 47 studies. Compared to placebo, amphetamines increased heart rate by 3.71 beats/minute (95% CI 3.27 to 4.14; P < 0.001, I² = 63%; 47 trials, 10,075 participants; high‐certainty evidence; Analysis 1.3).

1.3. Analysis.

Comparison 1: Amphetamines versus placebo: primary analysis, Outcome 3: Heart rate (beats per minute)

Subgroup analyses

In participants under age 18, amphetamines increased heart rate by 2.67 beats/minute (95% CI 1.79 to 3.56; 11 trials, 3135 participants). In participants aged 18 and over, amphetamines increased heart rate by 4.04 beats/minute (95% CI 3.54 to 4.54; 36 trials, 6922 participants). The effect of amphetamines on heart rate was greater in adults than in children (Chi² = 6.95, df = 1 [P = 0.008], I² = 85.6%). Detailed analysis in Analysis 2.3.

2.3. Analysis.

Comparison 2: Subgroup analysis by population age, Outcome 3: Heart rate (beats per minute)

In studies of four weeks' duration or less, amphetamines increased participants' heart rate by 3.99 beats/minute (95% CI 3.00 to 4.99; 12 trials, 1637 participants). For studies longer than four weeks but of less than eight weeks' duration, amphetamines increased participants' heart rate by 3.79 beats/minute (95% CI 3.07 to 4.50; 18 trials, 4228 participants). For studies of eight weeks' duration or longer, amphetamines increased participants' heart rate by 3.50 beats/minute (95% CI 2.84 to 4.17; 17 trials, 4210 participants). Thus, trial duration did not have any effect on the heart rate increase caused by amphetamines (Chi² = 0.71, df = 2 [P = 0.70], I² = 0%). Detailed analysis in Analysis 3.3.

3.3. Analysis.

Comparison 3: Subgroup analysis by trial length, Outcome 3: Heart rate (beats per minute)

The available data were insufficient to perform the other planned subgroup analyses.

Sensitivity analysis

Testing the effect of using the random‐effects model instead of the fixed‐effect model showed no difference in the estimate of the effect size (3.90 beats/minute, 95% CI 3.11 to 4.70, versus 3.71 beats/minute, 95% CI 3.27 to 4.14, respectively).

The primary summary effect estimate of increased heart rate for participants given amphetamines (3.71 beats/minute) was robust to the exclusion of studies:

• for which we imputed standard deviations (heart rate remained increased at 3.71 beats/minute, 95% CI 3.27 to 4.14; 47 trials, 10,075 participants; Analysis 4.3);

• with a high risk of bias (heart rate remained increased at 3.62 beats/minute, 95% CI 3.06 to 4.18; 31 trials, 6051 participants; Analysis 5.3);

• funded by the pharmaceutical industry (heart rate remained increased at 2.03 beats/minute, 95% CI 0.91 to 3.14; 12 trials, 1218 participants; Analysis 6.3);

• shorter than seven days' duration (heart rate remained increased at 3.87 beats/minute, 95% CI 3.41 to 4.32; 42 trials, 9838 participants; Analysis 7.3);

• that measured blood pressure more than 24 hours after final dose (heart rate remained increased at 3.86 beats/minute, 95% CI 3.35 to 4.37; 39 trials, 6998 participants; Analysis 8.3);

• that gave participants MDMA (heart rate remained increased at 3.67 beats/minute, 95% CI 3.23 to 4.11; 46 trials, 9996 participants; Analysis 9.3).

4.3. Analysis.

Comparison 4: Sensitivity analysis excluding studies with imputed standard deviations (SDs) in results, Outcome 3: Heart rate (beats per minute)

5.3. Analysis.

Comparison 5: Sensitivity analysis excluding studies with high risk of bias, Outcome 3: Heart rate (beats per minute)

6.3. Analysis.

Comparison 6: Sensitivity analysis excluding pharmaceutical industry‐sponsored studies, Outcome 3: Heart rate (beats per minute)

7.3. Analysis.

Comparison 7: Sensitivity analysis excluding studies shorter than 7 days in duration, Outcome 3: Heart rate (beats per minute)

8.3. Analysis.

Comparison 8: Sensitivity analysis excluding studies that measured blood pressure more than 24 hours after final dose, Outcome 3: Heart rate (beats per minute)

9.3. Analysis.

Comparison 9: Sensitivity analysis excluding studies administering MDMA, Outcome 3: Heart rate (beats per minute)

Withdrawals due to adverse effects

This outcome was reported in 42 studies. Amphetamines increase withdrawals due to adverse effects (risk ratio 2.69, 95% CI 2.13 to 3.40; absolute risk increase [ARI] = 4.30%; P = 0.52, I² = 0%; 42 trials, 8952 participants; high‐certainty evidence; Analysis 1.4).

1.4. Analysis.

Comparison 1: Amphetamines versus placebo: primary analysis, Outcome 4: Withdrawals due to adverse effects

Subgroup analyses

In participants under age 18, amphetamines increased withdrawals due to adverse effects by 2.68 times compared to placebo (95% CI 1.63 to 4.42; 11 trials, 2655). In participants aged 18 and over, amphetamines increased withdrawals due to adverse effects by 2.70 times compared to placebo (95% CI 2.07 to 3.51; 31 trials, 6297 participants). Thus, children and adults given amphetamines withdrew from the trials at roughly the same rate (Chi² = 0.00, df = 1 [P = 0.98], I² = 0%). Detailed analysis in Analysis 2.4.

2.4. Analysis.

Comparison 2: Subgroup analysis by population age, Outcome 4: Withdrawals due to adverse effects

In studies of four weeks' duration or less, amphetamines increased withdrawals due to adverse effects by 3.23 times compared to placebo (95% CI 1.59 to 6.57; 10 trials, 1552 participants). In studies longer than four weeks but of less than eight weeks' duration, amphetamines increased withdrawals due to adverse effects by 2.33 times compared to placebo (95% CI 1.64 to 3.32; 16 trials, 3351 participants). In studies of eight weeks' duration or longer, amphetamines increased withdrawals due to adverse effects by 2.93 times compared to placebo (95% CI 2.07 to 4.15; 16 trials, 4049 participants). Thus, people given amphetamines withdrew from the trials due to adverse effects at roughly the same rate, regardless of trial duration (Chi² = 1.13, df = 2 [P = 0.57], I² = 0%). Detailed analysis in Analysis 3.4.

3.4. Analysis.

Comparison 3: Subgroup analysis by trial length, Outcome 4: Withdrawals due to adverse effects

The available data were insufficient to perform the other planned subgroup analyses.

Sensitivity analysis

Testing the effect of using the random‐effects model instead of the fixed‐effect model showed no difference in the estimate of the effect size (2.32 times, 95% CI 1.83 to 2.95, versus 2.69 times, 95% CI 2.13 to 3.40, respectively).

The primary summary effect estimate of increased withdrawals due to adverse effects among participants given amphetamines (by 2.69 times) was robust to the exclusion of studies:

• for which we imputed standard deviations (withdrawals due to adverse effects remained increased: RR 2.69, 95% CI 2.13 to 3.40; 42 trials, 8952 participants; Analysis 4.4);

• with a high risk of bias (withdrawals remained increased: RR 2.72, 95% CI 1.88 to 3.94; 22 trials, 5172 participants; Analysis 5.4);

• funded by the pharmaceutical industry (withdrawals remained increased: RR 1.57, 95% CI 0.31 to 7.94; 8 trials, 450 participants; Analysis 6.4);

• shorter than seven days' duration (withdrawals remained increased: RR 2.72, 95% CI 2.15 to 3.44; 38 trials, 8761 participants; Analysis 7.4);

• that measured blood pressure more than 24 hours after final dose (withdrawals remained increased: RR 2.69, 95% CI 2.07 to 3.49; 35 trials, 6400 participants; Analysis 8.4);

• that gave participants MDMA (withdrawals remained increased: RR 2.69, 95% CI 2.13 to 3.40; 35 trials, 8952 participants; Analysis 9.4).

4.4. Analysis.

Comparison 4: Sensitivity analysis excluding studies with imputed standard deviations (SDs) in results, Outcome 4: Withdrawals due to adverse effects

5.4. Analysis.

Comparison 5: Sensitivity analysis excluding studies with high risk of bias, Outcome 4: Withdrawals due to adverse effects

6.4. Analysis.

Comparison 6: Sensitivity analysis excluding pharmaceutical industry‐sponsored studies, Outcome 4: Withdrawals due to adverse effects

7.4. Analysis.

Comparison 7: Sensitivity analysis excluding studies shorter than 7 days in duration, Outcome 4: Withdrawals due to adverse effects

8.4. Analysis.

Comparison 8: Sensitivity analysis excluding studies that measured blood pressure more than 24 hours after final dose, Outcome 4: Withdrawals due to adverse effects

9.4. Analysis.

Comparison 9: Sensitivity analysis excluding studies administering MDMA, Outcome 4: Withdrawals due to adverse effects

Discussion

Summary of main results

In this systematic review, we identified all randomized placebo‐controlled trials which compared an oral amphetamine with a placebo and measured participants' blood pressure. The pooled results are shown in Table 1.

We are confident that oral amphetamine use increases blood pressure. In our systematic review of 56 trials, with a median duration of one month, amphetamines were shown to increase systolic and diastolic blood pressure by approximately 2 mmHg and heart rate by approximately four beats per minute. Amphetamines also increased participant withdrawal due to adverse effects 2.7 times more than in the placebo group (4.3% absolute risk increase). Sensitivity analyses supported the robustness of these findings, showing little variation when different parameters, such as study risk of bias, sponsorship and short‐term trials, were taken into account.

The subgroup analyses that we were able to perform included comparing children (participants < 18 years old) with adults (≥ 18 years old). The effect of amphetamines on systolic blood pressure and heart rate was greater in adults than in children. However, the effect on systolic blood pressure and heart rate was still clinically significant in children. The effect on diastolic blood pressure was the same in the two age groups.

The second subgroup analysis we were able to perform explored the effect of amphetamines in three different duration subgroups: trials lasting four weeks or less, more than four weeks and up to eight weeks, and eight weeks or longer. The only significant difference discovered in this analysis was that the effect of amphetamines on systolic blood pressure appeared to be attenuated in trials lasting between four and eight weeks. This difference is hard to explain. The fact that the duration of trials made no difference to amphetamine's effects in increasing diastolic blood pressure and heart rate suggests that the systolic blood pressure difference was a chance finding. The major conclusion of the subgroup analyses is that the effect of amphetamines on systolic and diastolic blood pressure was 2.6 mmHg and 1.9 mmHg, respectively, in the trials lasting eight weeks or longer. This means that the effect is sustained and does not dissipate with duration of administration. Neither age nor duration of the trial had any effect on the increase in withdrawals due to adverse effects caused by amphetamines. No other subgroup analyses were possible due to lack of data.

We performed the following sensitivity analyses on each of the outcomes: the effect of using a random‐effects model instead of a fixed‐effect model, excluding studies with imputed standard deviations in results, excluding studies with a high risk of bias, excluding pharmaceutical industry‐sponsored studies, excluding studies shorter than seven days in duration, excluding studies that measured blood pressure more than 24 hours after final dose, and excluding studies that gave participants MDMA. All these analyses proved that the effect of amphetamines in increasing systolic and diastolic blood pressure, heart rate and withdrawals due to adverse effects was insensitive and not appreciably affected by any of these parameters (see Effects of interventions for details and Analysis 4.1; Analysis 4.2; Analysis 4.3; Analysis 4.4; Analysis 5.1; Analysis 5.2; Analysis 5.3; Analysis 5.4; Analysis 6.1; Analysis 6.2; Analysis 6.3; Analysis 6.4; Analysis 7.1; Analysis 7.2; Analysis 7.3; Analysis 7.4; Analysis 8.1; Analysis 8.2; Analysis 8.3; Analysis 8.4; Analysis 9.1; Analysis 9.2; Analysis 9.3; Analysis 9.4). These analyses attest to the robustness of the effects of amphetamines compared to placebo.

Possible mechanisms to explain the results

Most amphetamine effects stem from the increase in extracellular dopamine and norepinephrine neurotransmitters in the brain. Currently, there is good evidence that shows amphetamine exerts its effect through three major mechanisms (Heal 2013). First, amphetamine acts as a competitive substrate of monoamine reuptake transporters, thereby blocking the reuptake of monoamines and prolonging the synaptic concentration of monoamines. This blockage involves amphetamine acting as an intracellular receptor (TAAR1) agonist; the binding triggers a signaling cascade (Faraco 2013). Second, amphetamines weakly inhibit monoamine oxidase (MAO), an enzyme that normally degrades monoamines (Heal 2013). Third, amphetamine located in the presynaptic terminal displaces monoamines, causing the release of monoamines into the synaptic cleft (Heal 2013). These three mechanisms all serve to enhance the activity of monoamines, most notably, norepinephrine (noradrenaline).

Norepinephrine binds to the alpha‐adrenergic receptor (Overgaard 2008). When this receptor is stimulated in the peripheral circulation, the downstream regulatory G protein is activated (Overgaard 2008). The G protein then acts within the phospholipase C enzyme system and increases inositol 1,4,5‐triphosphate (IP3) concentration in the cell (Overgaard 2008). The increase in IP3 in the cell, in turn, increases cytosolic Ca2+ ions in the cell, which leads to constriction of the smooth muscle cells; in addition, Ca2+ can also act through calmodulin‐dependent protein kinases to increase vascular smooth muscle activity, which leads to vasoconstriction (Overgaard 2008). Constricted vessels lead to increased peripheral resistance and higher blood pressure. The effect of norepinephrine on the heart is to increase heart rate.

Overall completeness and applicability of evidence

This review screened all records retrieved from a comprehensive search using the search methodology described in Appendix 1. We are confident that all RCTs measuring blood pressure are included.

In these included studies, most participants took amphetamine for various study objectives other than the effect on blood pressure. These included investigating how learning abilities and weight‐loss schemes can be affected by the drug. There is the possibility that these other objectives could have a confounding effect on blood pressure. For example, it is known that weight loss can lower blood pressure. This could have confounded the blood pressure increase that we have demonstrated. However, the magnitude of weight loss was small, and we do not think it would be a significant confounding factor.

This systematic review included studies from North America, Europe and Asia. Studies from Asia formed only a small subgroup, and none of the studies that met the inclusion criteria were from Africa or South America. Previous research has shown that people from different ethnic groups can respond to drugs heterogeneously. Therefore, more comprehensive studies examining the effects of amphetamine on diverse populations would be valuable.

In this systematic review, we found that oral amphetamines increased systolic and diastolic blood pressure and heart rate. These findings are relevant to a wide spectrum of the population as the review had no restrictions on age or any comorbidities. The findings are important for patients and their caregivers, prescribing clinicians, policymakers and regulators. The magnitude of the effects – 2 mmHg for systolic and diastolic blood pressure and four beats per minute for heart rate – may seem small. However, even these small changes on a chronic daily basis can increase risk at a population level (Cook 1995; Federico 2023; Perret‐Guillaume 2009; Stamler 1991). Furthermore, blood pressure and heart rate are independent risk factors for adverse cardiovascular events (Perret‐Guillaume 2009).

The magnitude of the increase in blood pressure reported here is probably an underestimate of the true increase. There exists a risk of bias in this review against observing an increase in blood pressure because the drug companies who promote the drugs also funded and conducted most of the included trials. The possibility that our estimate is overly conservative is supported by the sensitivity test removing the 37 trials funded by the drug industry, in which the estimate of the effect on systolic blood pressure increased, from 1.94 mmHg to 2.15 mmHg (95% CI 1.32 to 2.98; 19 trials, 1704 participants). Even this estimate is imperfect, as we cannot be certain that the drug industry did not influence some of these 19 trials. Therefore, we are confident that the increase in blood pressure is at least 2 mmHg. Furthermore, it does not take into account the possibility of publication bias against an increase in blood pressure: that is, the likelihood that RCTs finding an increase in blood pressure remain unpublished or that trials we excluded for not reporting blood pressure data deliberately did not report it because it was elevated. However, when we examined the funnel plots, we could not demonstrate any evidence for publication bias (Figure 3; Figure 4; Figure 5).

Unfortunately, we were unable to complete a subgroup analysis comparing people with hypertension to those without hypertension due to a lack of studies. It is, however, likely that the blood pressure effect in people with hypertension would be similar or greater. This combination is likely to occur, given the prevalence of people taking amphetamines regularly and the large number of people living with hypertension in the general population.

All studies included were conducted over a relatively short period of time, with the longest study, Rosler 2009, being six months in duration. As discussed above, the subgroup analysis exploring trial duration as a potential effect modifier showed the effect to be similar between all trials and only those lasting eight weeks or longer. This is evidence that the effect persists. Furthermore, in a sensitivity test excluding studies shorter than seven days' duration (consistent with the methodology used in a similar review studying the effect of oral decongestants on blood pressure (Chan 2021)), systolic blood pressure remained increased at 1.84 mmHg (95% CI 1.43 to 2.24; 45 trials, 10,239 participants). This indicates that the effect of amphetamines on blood pressure is stable, meaning that no apparent tolerance occurs over weeks. Therefore, it is likely that the effect would be similar in people taking amphetamines daily for many months and years.

The 56 included studies examined a wide range of amphetamines, at a range of recommended doses, in participants ranging in age from six (Findling 2005; Mattingly 2020) to their early 80s (Press 2021), and over a wide range of durations (study characteristics summarized in Table 2). We are thus confident that the results are applicable to all the various clinical settings where amphetamines are prescribed.

Certainty of the evidence

We assessed the overall certainty of the evidence using the GRADE approach for the four outcomes of interest (systolic and diastolic blood pressure, heart rate and withdrawals due to adverse effects). We rated the certainty of the evidence for all outcomes as high, meaning we are confident that the effect estimates from this review reflect the true effects of amphetamines. We did not downgrade the blood pressure and heart rate outcomes for inconsistency. We expected a degree of inconsistency because of the inherently variable and fluctuating nature of these measures, which is expected due to physiological differences among participants and study conditions. Blood pressure and heart rate variability are widely recognized phenomena, particularly in terms of their variations over a 24‐hour period (Singh 2018; Stevens 2016). Thus, we are confident that amphetamines increase the three cardiovascular outcomes by at least the magnitude demonstrated. The withdrawals due to adverse effects data were not inconsistent. We explained above why we think that the true magnitude of the effect of amphetamines on blood pressure and heart rate could be greater than the effect measures.

Potential biases in the review process

To minimize the risk of selection bias, we utilized highly sensitive search strategies to identify studies eligible for inclusion in the review. When information was insufficient or missing, we contacted the authors of the included studies to try to retrieve relevant data.

Each data extraction step and risk of bias assessment was conducted independently by two review authors to minimize potential biases in the review process. However, there were several limitations in the data reported. First, there was the possibility of imprecision bias due to the imputation of missing standard deviations. We performed a sensitivity test that demonstrated that this was unlikely to be a problem (Musini 2009). Second, we combined the results across a wide range of participants with different indications, ages and clinical settings. We feel this approach was justified as we were interested in establishing the pharmacological effects of amphetamines on blood pressure and heart rate, and these effects occur regardless of the indication or clinical setting. Third, the timing of the blood pressure measurements varied widely across studies. For example, the time between drug treatment and blood pressure measurement ranged from 30 minutes to 48 hours. We know that amphetamine's peak plasma concentration is three hours post‐dose and the half‐life is nine to 12 hours (FDA 2007). Therefore, it is possible that some studies captured blood pressure readings before the drug took effect, while other studies recorded blood pressure readings after the drug had been eliminated from the body. In addition, amphetamines come in many formulations, including extended‐release formulations in which the drug is absorbed over an extended period of time. These variations in formulation could impact the peak plasma drug level. To fully comprehend the peak effect of amphetamine on blood pressure, recent studies have started using a 24‐hour ambulatory blood pressure monitoring system. This allows researchers to understand how drugs affect an individual's vital signs over time and capture the peak effect of the drug. However, since these data were not available, we have used the reported blood pressure and heart rate measures, most often taken at the end of the study.

Another potential limitation is the use of the number of randomized participants as the denominator for dichotomous outcomes without imputing missing data for participants lost to follow‐up. While this approach aligns with our intention‐to‐treat analysis as outlined in the protocol, it assumes that the outcomes of those lost to follow‐up are similar to those who completed the study, which may not always be the case. This assumption could introduce bias if the reasons for loss to follow‐up differed systematically between intervention and control groups.

Agreements and disagreements with other studies or reviews

Two previous reviews have investigated the effects of amphetamine on blood pressure. A Cochrane review by Martinsson and colleagues reported an increase in systolic blood pressure of 8.4 mmHg (95% CI 1.6 to 15.2; 2 trials, 73 participants) and diastolic blood pressure of 10.6 mmHg (95% CI 3.3 to 17.8; 2 trials, 73 participants) in people who had recently had a stroke and were taking amphetamines (Martinsson 2007). This reinforces our findings and the fact that the magnitude of elevation can be substantially higher in some settings. In a systematic review of 17 studies (4687 participants) in children with ADHD taking amphetamines, Hennissen and colleagues reported that systolic blood pressure was elevated by 0.18 standardized mean difference (SMD) (95% CI 0.1 to 0.27) and diastolic blood pressure by 0.18 SMD (95% CI 0.09 to 0.26) (Hennissen 2017). Using the average standard deviations of 14 mmHg for systolic and 8 mmHg for diastolic blood pressure (Musini 2009), we converted the SMD data to derive elevated blood pressure readings of 2.5 mmHg for systolic and 1.4 mmHg for diastolic blood pressure. Thus, this study in children is in agreement with our findings in all age groups. Our review includes a broad spectrum of people and clinical settings, and we conclude that oral amphetamines taken daily raise blood pressure.

To our knowledge, our review is the most comprehensive investigation of the effects of amphetamines on blood pressure to date. The agreement in results between our review and reviews with a narrower scope shows that blood pressure and heart rate increases from amphetamines are highly likely in most, if not all, clinical settings.

Authors' conclusions

Implications for practice.

This review incorporated trials with no exclusions for age, gender or health conditions and, therefore, is applicable to the general population. Amphetamines increase blood pressure, heart rate and adverse effects, leading to individuals stopping their medication. Subgroup analysis demonstrated that these effects were similar in trials exceeding eight weeks' duration compared to trials of any duration, meaning that they are likely sustained effects. It is important that individuals, caregivers, healthcare providers and policymakers are aware of the potential adverse effects of these commonly prescribed drugs. The average magnitude of the increases – 2 mmHg in blood pressure and four beats per minute in heart rate – may seem small, but at a population level, they are clinically significant even for children and adolescents (Zhang 2024). Furthermore, because we included trials in which the timing of blood pressure measurement was not reported or was not optimal (48 hours after the drug was ingested), we feel that the true magnitude of the effects of amphetamines on blood pressure and heart rate is likely larger than what is reported here.

Implications for research.

This review quantified the general effects of amphetamines on blood pressure, heart rate and withdrawals due to adverse effects. However, many questions remain unanswered, and more specific randomised controlled trials are needed to answer them. These questions include the dose‐dependent effect of amphetamines, the effect of various formulations, and how amphetamines may affect specific population subgroups, including those with pre‐existing conditions such as hypertension, and people from various ethnic backgrounds.

The studies included in this review assessed amphetamines for various indications unrelated to blood pressure. Future studies that focus solely on the effect of amphetamines on blood pressure would be valuable.

For future trials, we recommend using 24‐hour ambulatory blood pressure monitoring to measure the change in blood pressure over a full day. Looking specifically at time points proximal to amphetamine administration may allow an assessment of the peak effect on blood pressure and heart rate.

We also recommend that future studies be free from industry sponsorship and should clearly report the methods used to achieve randomization, allocation concealment and blinding.

History

Protocol first published: Issue 3, 2009

Date	Event	Description
1 December 2020	New citation required and major changes	New authors. Background, methods including search strategies updated.

Appendices

Appendix 1. Search strategies

Database: Ovid MEDLINE(R) ALL <1946 to March 17, 2023>
Search Date: 20 March 2023
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 exp amphetamines/ 
2 amphetamine/ 
3 (amphetamin* or amfetamine or amphamed or amphamine or amphezamin or centramina or centramine or chloroamphetamin* or desoxynorephedrin or fenamine or hydroxyamphetamin* or iofetamine or levamfetamine or levamphetamine or levedrine or levoamphetamine or mydrial or phenamin or phenamine or phenoprominum or phenopromin or thyramine).tw,kf. 
4 exp dextroamphetamine/ 
5 (dextroamphetamine or adderall or afatin or afettine or albemap or amfetasul or amfexa or amitrene or amphedrine or amphex or amsustain or ardex or attentin or betafedrina or betaphedrine or biphetamine or carboxyphen or curban or dadex or daprisal or dephadren or dexadrine or dexaline or dexalme or dexalone or dexamed or dexamfetamine or dexamfetaminesulfaat or dexampex or dexamphetamin? or dexamphoid or dexamyl or dexaspan or dexeamphetanine or dexedrine or dexoval or dextrostat or diocarb or diocurb or domafate or domefate or doxedrine or durophet or dynaphenyl or elvanse or evekeo or evrodex or ferndex or hetamine or lisdexamfetamine or methylphenethylamin? or obesedrin or obesonil oxydess or phetadex or simpamina or sympamin or tentin or vyvanse).tw,kf. 
6 methylphenidate/ 
7 (methylphenidate or adaphen or addwize or adhansia or aptensio or artige or attenta or centedrin or cognil or concerta or cotempla or daytrana or difumenil or equasym or focalin or inspiral or jornay or medanef or medicebran or medikinet or mefinad or metadate or methylfenidaat or methylfenidate or methylin or methyl phenidate or methylphenidylacetate or methylphenindate or methylphenydate or methypatch or penid or phenida or phenidyl hydrochloride or phenidylate or prohiper or quasym or quillichew or quillivant or ritalin or ritalin‐sr or ritalina or ritaline or ritaphen or rubifen or tradea or tranquilyn or tsentedrin).tw,kf. 
8 or/1‐7 
9 exp cardiovascular diseases/ 
10 cardiovasc*.hw,mp. 
11 exp hemodynamics/ 
12 (haemodynamic* or hemodynamic*).tw,kf. 
13 exp hypertension/ 
14 essential hypertension/ 
15 (hypertens* or hipertens*).tw,kf,ot. 
16 (prehypertens* or prehipertens*).tw,kf,ot. 
17 exp blood pressure/ 
18 (blood pressur* or bloodpressur*).mp. 
19 ((arterial adj2 pressur*) or (diastolic adj2 pressur*) or (systolic adj2 pressur*)).tw,kf. 
20 (bp or dbp or mbp or sbp).tw,kf. 
21 heart rate/ 
22 (heart rate? or pulse rate?).tw,kf. 
23 chronotrop*.tw,kf. 
24 or/9‐23 
25 randomized controlled trial.pt. 
26 controlled clinical trial.pt. 
27 randomi?ed.tw.
28 placebo.ab. 
29 dt.fs. 
30 randomly.ab. 
31 trial.ab.
32 groups.ab. 
33 or/25‐32 
34 animals/ not (humans/ and animals/) 
35 33 not 34 
36 8 and 24 and 35

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Cochrane Hypertension Specialised Register via Cochrane Register of Studies 
Search Date: 20 March 2023
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 MESH DESCRIPTOR Amphetamines EXPLODE ALL AND INREGISTER
#2 MESH DESCRIPTOR Amphetamine AND INREGISTER
#3 (amphetamin* OR amfetamine OR amphamed OR amphamine OR amphezamin OR centramina OR centramine OR chloroamphetamin* OR desoxynorephedrin OR fenamine OR hydroxyamphetamin* OR iofetamine OR levamfetamine OR levamphetamine OR levedrine OR levoamphetamine OR mydrial OR phenamin OR phenamine OR phenoprominum OR phenopromin OR thyramine) AND INREGISTER
#4 MESH DESCRIPTOR Dextroamphetamine EXPLODE ALL AND INREGISTER
#5 (dextroamphetamine OR adderall OR afatin OR afettine OR albemap OR amfetasul OR amfexa OR amitrene OR amphedrine OR amphex OR amsustain OR ardex OR attentin OR betafedrina OR betaphedrine OR biphetamine OR carboxyphen OR curban OR dadex OR daprisal OR dephadren OR dexadrine OR dexaline OR dexalme OR dexalone OR dexamed OR dexamfetamine OR dexamfetaminesulfaat OR dexampex OR dexamphetamin* OR dexamphoid OR dexamyl OR dexaspan OR dexeamphetanine OR dexedrine OR dexoval OR dextrostat OR diocarb OR diocurb OR domafate OR domefate OR doxedrine OR durophet OR dynaphenyl OR elvanse OR evekeo OR evrodex OR ferndex OR hetamine OR lisdexamfetamine OR methylphenethylamin* OR obesedrin OR obesonil oxydess OR phetadex OR simpamina OR sympamin OR tentin OR vyvanse) AND INREGISTER
#6 MESH DESCRIPTOR Methylphenidate AND INREGISTER
#7 (methylphenidate OR adaphen OR addwize OR adhansia OR aptensio OR artige OR attenta OR centedrin OR cognil OR concerta OR cotempla OR daytrana OR difumenil OR equasym OR focalin OR inspiral OR jornay OR medanef OR medicebran OR medikinet OR mefinad OR metadate OR methylfenidaat OR methylfenidate OR methylin OR methyl phenidate OR methylphenidylacetate OR methylphenindate OR methylphenydate OR methypatch OR penid OR phenida OR phenidyl hydrochlORide OR phenidylate OR prohiper OR quasym OR quillichew OR quillivant OR ritalin OR ritalin‐sr OR ritalina OR ritaline OR ritaphen OR rubifen OR tradea OR tranquilyn OR tsentedrin) AND INREGISTER
#8 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
#9 RCT:DE AND INREGISTER
#10 Review:ODE AND INREGISTER
#11 (#9 OR #10)
#12 #8 AND #11

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Cochrane Central Register of Controlled Trials (Issue 2, 2023) via Cochrane Register of Studies 
Search Date: 20 March 2023
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 MESH DESCRIPTOR Amphetamines EXPLODE ALL AND CENTRAL:TARGET
#2 MESH DESCRIPTOR Amphetamine AND CENTRAL:TARGET
#3 (amphetamin* OR amfetamine OR amphamed OR amphamine OR amphezamin OR centramina OR centramine OR chloroamphetamin* OR desoxynorephedrin OR fenamine OR hydroxyamphetamin* OR iofetamine OR levamfetamine OR levamphetamine OR levedrine OR levoamphetamine OR mydrial OR phenamin OR phenamine OR phenoprominum OR phenopromin OR thyramine) AND CENTRAL:TARGET
#4 MESH DESCRIPTOR Dextroamphetamine EXPLODE ALL AND CENTRAL:TARGET
#5 (dextroamphetamine OR adderall OR afatin OR afettine OR albemap OR amfetasul OR amfexa OR amitrene OR amphedrine OR amphex OR amsustain OR ardex OR attentin OR betafedrina OR betaphedrine OR biphetamine OR carboxyphen OR curban OR dadex OR daprisal OR dephadren OR dexadrine OR dexaline OR dexalme OR dexalone OR dexamed OR dexamfetamine OR dexamfetaminesulfaat OR dexampex OR dexamphetamin* OR dexamphoid OR dexamyl OR dexaspan OR dexeamphetanine OR dexedrine OR dexoval OR dextrostat OR diocarb OR diocurb OR domafate OR domefate OR doxedrine OR durophet OR dynaphenyl OR elvanse OR evekeo OR evrodex OR ferndex OR hetamine OR lisdexamfetamine OR methylphenethylamin* OR obesedrin OR obesonil oxydess OR phetadex OR simpamina OR sympamin OR tentin OR vyvanse) AND CENTRAL:TARGET
#6 MESH DESCRIPTOR Methylphenidate AND CENTRAL:TARGET
#7 (methylphenidate OR adaphen OR addwize OR adhansia OR aptensio OR artige OR attenta OR centedrin OR cognil OR concerta OR cotempla OR daytrana OR difumenil OR equasym OR focalin OR inspiral OR jornay OR medanef OR medicebran OR medikinet OR mefinad OR metadate OR methylfenidaat OR methylfenidate OR methylin OR methyl phenidate OR methylphenidylacetate OR methylphenindate OR methylphenydate OR methypatch OR penid OR phenida OR phenidyl hydrochlORide OR phenidylate OR prohiper OR quasym OR quillichew OR quillivant OR ritalin OR ritalin‐sr OR ritalina OR ritaline OR ritaphen OR rubifen OR tradea OR tranquilyn OR tsentedrin) AND CENTRAL:TARGET
#8 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
#9 MESH DESCRIPTOR Cardiovascular Diseases EXPLODE ALL AND CENTRAL:TARGET
#10 cardiovasc* AND CENTRAL:TARGET
#11 MESH DESCRIPTOR Hemodynamics EXPLODE ALL AND CENTRAL:TARGET
#12 (haemodynamic* OR hemodynamic*) AND CENTRAL:TARGET
#13 MESH DESCRIPTOR Hypertension EXPLODE ALL AND CENTRAL:TARGET
#14 MESH DESCRIPTOR Essential Hypertension AND CENTRAL:TARGET
#15 (hypertens* OR hipertens*) AND CENTRAL:TARGET
#16 (prehypertens* OR prehipertens*) AND CENTRAL:TARGET
#17 MESH DESCRIPTOR Blood Pressure EXPLODE ALL AND CENTRAL:TARGET
#18 (blood pressur* OR bloodpressur*) AND CENTRAL:TARGET
#19 ((arterial NEAR2 pressur*) OR (diastolic NEAR2 pressur*) OR (systolic NEAR2 pressur*)) AND CENTRAL:TARGET
#20 (bp OR dbp OR mbp OR sbp) AND CENTRAL:TARGET
#21 MESH DESCRIPTOR Heart Rate AND CENTRAL:TARGET
#22 (heart rate* OR pulse rate*) AND CENTRAL:TARGET
#23 chronotrop* AND CENTRAL:TARGET
#24 (#9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23)
#25 #8 AND #24

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Embase <1974 to 2023 March 17>
Search Date: 20 March 2023
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 exp amphetamine derivative/ 
2 (amphetamin* or amfetamine or amphamed or amphamine or amphezamin or centramina or centramine or chloroamphetamin* or desoxynorephedrin or fenamine or hydroxyamphetamin* or iofetamine or levamfetamine or levamphetamine or levedrine or levoamphetamine or mydrial or phenamin or phenamine or phenoprominum or phenopromin or thyramine).tw,kf. 
3 dexamphetamine/ 
4 (dextroamphetamine or adderall or afatin or afettine or albemap or amfetasul or amfexa or amitrene or amphedrine or amphex or amsustain or ardex or attentin or betafedrina or betaphedrine or biphetamine or carboxyphen or curban or dadex or daprisal or dephadren or dexadrine or dexaline or dexalme or dexalone or dexamed or dexamfetamine or dexamfetaminesulfaat or dexampex or dexamphetamin? or dexamphoid or dexamyl or dexaspan or dexeamphetanine or dexedrine or dexoval or dextrostat or diocarb or diocurb or domafate or domefate or doxedrine or durophet or dynaphenyl or elvanse or evekeo or evrodex or ferndex or hetamine or lisdexamfetamine or methylphenethylamin? or obesedrin or obesonil oxydess or phetadex or simpamina or sympamin or tentin or vyvanse).tw,kf. 
5 methylphenidate/ 
6 (methylphenidate or adaphen or addwize or adhansia or aptensio or artige or attenta or centedrin or cognil or concerta or cotempla or daytrana or difumenil or equasym or focalin or inspiral or jornay or medanef or medicebran or medikinet or mefinad or metadate or methylfenidaat or methylfenidate or methylin or methyl phenidate or methylphenidylacetate or methylphenindate or methylphenydate or methypatch or penid or phenida or phenidyl hydrochloride or phenidylate or prohiper or quasym or quillichew or quillivant or ritalin or ritalin‐sr or ritalina or ritaline or ritaphen or rubifen or tradea or tranquilyn or tsentedrin).tw,kf. 
7 or/1‐6 
8 exp cardiovascular disease/ 
9 cardiovasc*.mp. 
10 exp hemodynamics/ 
11 (haemodynamic* or hemodynamic*).tw,kf. 
12 exp hypertension/ 
13 (hypertens* or hipertens*).tw,kf,ot. 
14 (prehypertens* or prehipertens*).tw,kf,ot. 
15 exp blood pressure/ 
16 (blood pressur* or bloodpressur*).mp. 
17 ((arterial adj2 pressur*) or (diastolic adj2 pressur*) or (systolic adj2 pressur*)).tw,kf. 
18 (bp or dbp or mbp or sbp).tw,kf. 
19 heart rate/
20 (heart rate? or pulse rate?).tw,kf. 
21 chronotropism/
22 chronotrop*.tw,kf. 
23 or/8‐22 
24 randomized controlled trial/ 
25 crossover procedure/ 
26 double‐blind procedure/ 
27 (randomi?ed or randomly).tw,kf. 
28 (crossover* or cross‐over*).tw,kf. 
29 placebo.ab. 
30 (doubl* adj blind*).tw,kf. 
31 assign*.ab. 
32 allocat*.ab. 
33 or/24‐32 
34 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) 
35 33 not 34 
36 7 and 23 and 35

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: ClinicalTrials.gov
Search Date: 20 March 2023
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Other terms: randomized
Study type: Interventional Studies (Clinical Trials)
Intervention/treatment:(amphetamine OR amphetamines OR dexamphetamine OR dextroamphetamine OR methylphenidate)
Outcome measures: (blood pressure OR heart rate)

Data and analyses

Comparison 1. Amphetamines versus placebo: primary analysis.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Systolic blood pressure	56	10583	Mean Difference (IV, Fixed, 95% CI)	1.93 [1.54, 2.31]
1.2 Diastolic blood pressure	56	10583	Mean Difference (IV, Fixed, 95% CI)	1.84 [1.51, 2.16]
1.3 Heart rate (beats per minute)	47	10075	Mean Difference (IV, Fixed, 95% CI)	3.71 [3.27, 4.14]
1.4 Withdrawals due to adverse effects	42	8952	Risk Ratio (M‐H, Fixed, 95% CI)	2.69 [2.13, 3.40]

Comparison 2. Subgroup analysis by population age.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Systolic blood pressure	56	10583	Mean Difference (IV, Fixed, 95% CI)	1.93 [1.54, 2.31]
2.1.1 Age < 18 years	13	3255	Mean Difference (IV, Fixed, 95% CI)	1.09 [0.37, 1.81]
2.1.2 Age ≥ 18 years	43	7328	Mean Difference (IV, Fixed, 95% CI)	2.26 [1.81, 2.72]
2.2 Diastolic blood pressure	56	10583	Mean Difference (IV, Fixed, 95% CI)	1.84 [1.51, 2.16]
2.2.1 Age < 18 years	13	3255	Mean Difference (IV, Fixed, 95% CI)	2.16 [1.53, 2.78]
2.2.2 Age ≥ 18 years	43	7328	Mean Difference (IV, Fixed, 95% CI)	1.72 [1.34, 2.10]
2.3 Heart rate (beats per minute)	47	10075	Mean Difference (IV, Fixed, 95% CI)	3.71 [3.27, 4.14]
2.3.1 Age < 18 years	11	3135	Mean Difference (IV, Fixed, 95% CI)	2.67 [1.79, 3.56]
2.3.2 Age ≥ 18 years	36	6940	Mean Difference (IV, Fixed, 95% CI)	4.04 [3.54, 4.54]
2.4 Withdrawals due to adverse effects	42	8952	Risk Ratio (M‐H, Fixed, 95% CI)	2.69 [2.13, 3.40]
2.4.1 Age < 18 years	11	2655	Risk Ratio (M‐H, Fixed, 95% CI)	2.68 [1.63, 4.42]
2.4.2 Age ≥ 18 years	31	6297	Risk Ratio (M‐H, Fixed, 95% CI)	2.70 [2.07, 3.51]

Comparison 3. Subgroup analysis by trial length.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Systolic blood pressure	56	10583	Mean Difference (IV, Fixed, 95% CI)	1.93 [1.54, 2.31]
3.1.1 Trial duration ≤ 4 weeks	17	1794	Mean Difference (IV, Fixed, 95% CI)	2.07 [1.28, 2.86]
3.1.2 Trial duration > 4 weeks to < 8 weeks	20	4356	Mean Difference (IV, Fixed, 95% CI)	1.24 [0.62, 1.86]
3.1.3 Trial duration ≥ 8 weeks	19	4433	Mean Difference (IV, Fixed, 95% CI)	2.55 [1.92, 3.17]
3.2 Diastolic blood pressure	56	10583	Mean Difference (IV, Fixed, 95% CI)	1.84 [1.51, 2.16]
3.2.1 Trial duration ≤ 4 weeks	17	1794	Mean Difference (IV, Fixed, 95% CI)	1.89 [1.16, 2.63]
3.2.2 Trial duration > 4 weeks to < 8 weeks	20	4356	Mean Difference (IV, Fixed, 95% CI)	1.75 [1.24, 2.27]
3.2.3 Trial duration ≥ 8 weeks	19	4433	Mean Difference (IV, Fixed, 95% CI)	1.89 [1.39, 2.38]
3.3 Heart rate (beats per minute)	47	10075	Mean Difference (IV, Fixed, 95% CI)	3.71 [3.27, 4.14]
3.3.1 Trial duration ≤ 4 weeks	12	1637	Mean Difference (IV, Fixed, 95% CI)	3.99 [3.00, 4.99]
3.3.2 Trial duration > 4 weeks to < 8 weeks	18	4228	Mean Difference (IV, Fixed, 95% CI)	3.79 [3.07, 4.50]
3.3.3 Trial duration ≥ 8 weeks	17	4210	Mean Difference (IV, Fixed, 95% CI)	3.50 [2.84, 4.17]
3.4 Withdrawals due to adverse effects	42	8952	Risk Ratio (M‐H, Fixed, 95% CI)	2.69 [2.13, 3.40]
3.4.1 Trial duration ≤ 4 weeks	10	1552	Risk Ratio (M‐H, Fixed, 95% CI)	3.23 [1.59, 6.57]
3.4.2 Trial duration > 4 weeks to < 8 weeks	16	3351	Risk Ratio (M‐H, Fixed, 95% CI)	2.33 [1.64, 3.32]
3.4.3 Trial duration ≥ 8 weeks	16	4049	Risk Ratio (M‐H, Fixed, 95% CI)	2.93 [2.07, 4.15]

Comparison 4. Sensitivity analysis excluding studies with imputed standard deviations (SDs) in results.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Systolic blood pressure	51	9776	Mean Difference (IV, Fixed, 95% CI)	1.95 [1.55, 2.34]
4.2 Diastolic blood pressure	51	9776	Mean Difference (IV, Fixed, 95% CI)	1.81 [1.48, 2.14]
4.3 Heart rate (beats per minute)	47	10075	Mean Difference (IV, Fixed, 95% CI)	3.71 [3.27, 4.14]
4.4 Withdrawals due to adverse effects	42	8952	Risk Ratio (M‐H, Fixed, 95% CI)	2.69 [2.13, 3.40]

Comparison 5. Sensitivity analysis excluding studies with high risk of bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Systolic blood pressure	37	6474	Mean Difference (IV, Fixed, 95% CI)	2.20 [1.71, 2.69]
5.2 Diastolic blood pressure	37	6474	Mean Difference (IV, Fixed, 95% CI)	2.17 [1.76, 2.59]
5.3 Heart rate (beats per minute)	31	6051	Mean Difference (IV, Fixed, 95% CI)	3.62 [3.06, 4.18]
5.4 Withdrawals due to adverse effects	27	5172	Risk Ratio (M‐H, Fixed, 95% CI)	2.72 [1.88, 3.94]

Comparison 6. Sensitivity analysis excluding pharmaceutical industry‐sponsored studies.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Systolic blood pressure	19	1676	Mean Difference (IV, Fixed, 95% CI)	2.08 [1.25, 2.92]
6.2 Diastolic blood pressure	19	1676	Mean Difference (IV, Fixed, 95% CI)	1.62 [0.90, 2.34]
6.3 Heart rate (beats per minute)	12	1218	Mean Difference (IV, Fixed, 95% CI)	2.03 [0.91, 3.14]
6.4 Withdrawals due to adverse effects	8	450	Risk Ratio (M‐H, Fixed, 95% CI)	1.57 [0.31, 7.94]

Comparison 7. Sensitivity analysis excluding studies shorter than 7 days in duration.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Systolic blood pressure	47	10239	Mean Difference (IV, Fixed, 95% CI)	1.84 [1.43, 2.24]
7.2 Diastolic blood pressure	47	10239	Mean Difference (IV, Fixed, 95% CI)	1.83 [1.49, 2.16]
7.3 Heart rate (beats per minute)	42	9838	Mean Difference (IV, Fixed, 95% CI)	3.87 [3.41, 4.32]
7.4 Withdrawals due to adverse effects	38	8761	Risk Ratio (M‐H, Fixed, 95% CI)	2.72 [2.15, 3.44]

Comparison 8. Sensitivity analysis excluding studies that measured blood pressure more than 24 hours after final dose.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Systolic blood pressure	48	7513	Mean Difference (IV, Fixed, 95% CI)	1.70 [1.25, 2.15]
8.2 Diastolic blood pressure	48	7513	Mean Difference (IV, Fixed, 95% CI)	1.76 [1.38, 2.13]
8.3 Heart rate (beats per minute)	39	6998	Mean Difference (IV, Fixed, 95% CI)	3.86 [3.35, 4.37]
8.4 Withdrawals due to adverse effects	35	6400	Risk Ratio (M‐H, Fixed, 95% CI)	2.69 [2.07, 3.49]

Comparison 9. Sensitivity analysis excluding studies administering MDMA.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Systolic blood pressure	55	10504	Mean Difference (IV, Fixed, 95% CI)	1.90 [1.52, 2.29]
9.2 Diastolic blood pressure	55	10504	Mean Difference (IV, Fixed, 95% CI)	1.82 [1.49, 2.14]
9.3 Heart rate (beats per minute)	46	9996	Mean Difference (IV, Fixed, 95% CI)	3.67 [3.23, 4.11]
9.4 Withdrawals due to adverse effects	42	8952	Risk Ratio (M‐H, Fixed, 95% CI)	2.69 [2.13, 3.40]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Adler 2008.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 62 Mean Age (years): 35.2 Male (N): 32 Female (N): 30 Mean Weight (lb): 181.3 Mean Height (in): 67.9 30mg Lisdexamfetamine N: 119 Mean Age (years): 35.3 Male (N): 67 Female (N): 52 Mean Weight (lb): 178.1 Mean Height (in): 67.9 50mg Lisdexamfetamine N: 117 Mean Age (years): 34.2 Male (N): 66 Female (N): 51 Mean Weight (lb): 173.1 Mean Height (in): 67.6 70mg Lixdexamfetamine N: 122 Mean Age (years): 35.8 Male (N): 63 Female (N): 59 Mean Weight (lb): 174.3 Mean Height (in): 67.4 Inclusion criteria: "Adults 18 to 55 years; Primary diagnosis of ADHD by DSM‐IV‐TR; 12‐lead ECG with QT/QTc‐F interval <450 ms for men and <470 ms for women, resting heart rate 40 to 100 bmp, PR interval < 200 ms, and QRS interval < 110 ms." Exclusion criteria: "Comorbid psychiatric diagnosis with significant symptoms that might preclude treatment with lisdexamfetamine; History of seizures; Taking medications that affect the central nervous system or blood pressure (excluding current ADHD medications); Known cardiac structural abnormality or any other condition that might affect cardiac performance; Clinically significant ECG or laboratory abnormality at screening or baseline; History of hypertension or resting SBP > 139mmHg or DBP > 89 mmHg; Pregnancy or lactation; Positive urine drug results"
Interventions	Intervention Characteristics Placebo 30mg Lisdexamfetamine 50mg Lisdexamfetamine 70mg Lixdexamfetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: This study was funded by Shire Pharmaceuticals. Country: USA Setting: Participants recruited from clinics. Setting not specified. Authors' names: Lenard A Adler, David W Goodman, Scott H Kollins, Richard H Weisler, Suma Krishnan, Yuxin Zhang, Joseph Biederman Institution: New York University School of Medicine Email: lenard.adler@med.nyu.edu Address: 530 First Ave. #7D, New York, NY 10016, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: authors did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: authors did not describe the method used for concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Both the investigator and the patient were blinded to treatment". Comment: the capsules were identical in size, weight and shape. Blood pressure collection is unlikely to be biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 71/420 = 17% of randomized participants discontinued. Specifically, 21/358 = 6% of participants randomized to the amphetamine group withdrew due to adverse events, while 1/62 = 2% of participants randomized to the placebo group withdrew due to adverse events. Due to the overall high attrition rate, and the differences in attrition due to adverse events between treatment arms, we rated Adler 2008 as having a high risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure change is reported for all arms

Adler 2009.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 116 Mean Age (years): 38.2 BMI: 28.22 Male (N): 64 Female (N): 52 Daily Mean Dose 67.68mg of OROS Methylphenidate N: 110 Mean Age (years): 39.9 BMI: 28.81 Male (N): 63 Female (N): 47 Overall N: 226 Mean Age (years): 39.0 years BMI: 28.51 Male (N): 127 Female (N): 99 Inclusion criteria: "Adults between 18 to 65 years of age (inclusive) with ADHD and weighed a minimum of 100 lb (45.4 kg). Subject must have described a chronic course of ADHD symptoms from childhood to adulthood, have had an AISRS score of 24 or greater, and have had a global assessment of functioning score of between 41 and 60 (inclusive), indicating moderate or serious symptoms (according to DSM‐IV criteria). Previous formal diagnosis of and/or treatment of ADHD were not required. Diagnosis of ADHD was confirmed by using the Adult ADHD Clinical Diagnostic Scale version 1.228 at baseline." Exclusion criteria: "Patients who met the DSMIV criteria for depressive or anxiety disorders; Known nonresponders to methylphenidate; History of allergy to methylphenidate; Any coexisting medical condition or taking any medication that was likely to interfere with the safe administration of methylphenidate; Known or suspected structural cardiac abnormality as assessed by history, physical examination, or electrocardiogram (ECG); Diagnosis or family history of Tourette syndrome or motor or verbal tics; History of seizure disorder, uncontrolled hyperthyroidism, or hypothyroidism; Comorbid psychiatric diagnosis per DSM‐IV criteria of bipolar disorder, cyclothymic disorder, schizophrenia, pervasive developmental disorder, severe obsessive‐compulsive disorders, or any other diagnosis that in the judgment of the investigator could have deemed the subject to be inappropriate for the study; History of drug or alcohol abuse within the past 6 months or with suicidal ideation or behavior during the past year; Current or history of an eating disorder for the last 3 years; Taking antipsychotic medication, bupropion, modafinil, clonidine or other alpha‐2 adrenergic receptor agonists, tricyclic antidepressants, theophylline, coumarin anticoagulants, anticonvulsants, monoamine oxidase inhibitors, guanethidine, ora serotonin norepinephrine reuptake inhibitor (eg, venlafaxine and duloxetine) were excluded from the study; Patients taking a selective serotonin reuptake inhibitor (eg, fluoxetine, paroxetine, sertraline, citalopram, or escitalopram) who were not stable on their medication for at least 30 days before the screening visit were excluded"
Interventions	Intervention Characteristics Placebo Daily Mean Dose 67.68mg of OROS Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study and the production of the manuscript were funded by Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ. Country: USA Setting: 27 clinical research sites Authors' names: Lenard A Adler, Brenda Zimmerman, H Lynn Starr, Steve Silber, Joseph Palumbo, Camille Orman, Thomas Spencer Institution: NYU Email: lenard.adler@med.nyu.edu Address: NYU School of Medicine, New York VA Harbor Healthcare System, New York, NY 10016, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: participants randomized using a computer‐generated randomization schedule stratified by investigator site with a block size of 4. This sequence generation is sufficiently randomized.
Allocation concealment (selection bias)	Low risk	Quote: "The system identified the unique kit number of the dosing package that the study staff was to dispense to the subject. Each subject received overencapsulated tablets that appeared identical to the treatment of all other subjects at the beginning of the study."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study is double‐blind (blinding of participants and investigator), it is unlikely that blood pressure measurements were biased by knowledge of treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: in the OROS methylphenidate group, 37.2% (42/113) of the participants withdrew. In the placebo group, 22.4% (26/116) withdrew. The reasons for withdrawal were: adverse events (OROS methylphenidate, 16/42 participants; placebo, 6/26 participants), participants’ request (OROS methylphenidate, 8/42; placebo, 5/26), non‐adherence (OROS methylphenidate, 5/42; placebo, 5/26), and other reasons (OROS methylphenidate, 2/42; placebo, 6/26). In addition, 12 participants were lost to follow‐up (OROS methylphenidate, 8; placebo, 4).
Selective reporting (reporting bias)	High risk	Comment: SBP and DBP in the review are reported incompletely. Change in blood pressure is not specified for the different doses of methylphenidate. Study did not report how long it took for each participant to achieve their final dispensed dose.

Adler 2013.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 80 Mean Age (years): 34.9 Male (N): 43 Female (N): 37 Mean Weight (kg): 80 Mean Daily Dose 56.9mg Lisdexamfetamine N: 79 Mean Age (years): 34.2 Male (N): 40 Female (N): 39 Mean Weight (kg): 81.8 Overall N: 159 Mean Age (years): 34.6 Male (N): 83 Female (N): 76 Mean Weight (kg): 80.9 Inclusion criteria: Participants were required to be in a close domicile relationship (e.g. spouse or significant other) for ≥ 6 months prior to screening to ensure the availability of an informant who was willing to report on the participant's behavior and symptoms. Additional inclusion criteria included a baseline BRIEF‐A Global Executive Composite (GEC) T‐score ≥ 65, indicating clinically significant executive function impairment at baseline, and a baseline total score ≥ 28 on the ADHD‐RS‐IV with adult prompts. Exclusion criteria: Adults with comorbid psychiatric conditions that were controlled with a prohibited medication or were uncontrolled and associated with significant symptoms, including severe Axis I or II disorders, were excluded from the study. Other key exclusion criteria included cardiovascular disease, which may increase vulnerability to the sympathomimetic effects of a psychostimulant; a history of moderate to severe hypertension; ADHD that was well‐controlled on current ADHD therapy; and a history of failure to respond to an adequate course of amphetamine therapy.
Interventions	Intervention Characteristics Placebo Mean Daily Dose 56.9mg Lisdexamfetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The clinical research was funded by Shire Pharmaceuticals. Country: USA Setting: 33 clinical research sites Authors' names: Lenard A Adler, Bryan Dirks, Patrick F Deas, Aparna Raychaudhuri, Matthew R Dauphin, Robert A Lasser, Richard H Weisler Institution: New York University Email: Lenard.Adler@nyumc.org Address: Department of Psychiatry, New York University School of Medicine, and Psychiatry Service, New York Veterans Affairs Harbor Healthcare System, New York, New York 10016, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: the study sufficiently described the process of random sequence generation. Participants were randomized via interactive voice/web response system.
Allocation concealment (selection bias)	Unclear risk	Comment: the study did not describe the method of concealment used.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: only 78.5% of participants randomized to lisdexamfetamine dimesylate and 66.3% of those randomized to placebo completed the study. The high dropout rate and the uneven completion rate between the two treatment groups (~12%) give this study a high risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: change in blood pressure was reported

Biederman 2006.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 74 Mean Age (years): 37.6 Male (N): 35 Female (N): 39 Mean Daily dose 80.9mg OROS methylphenidate (MPH) N: 67 Mean Age (years): 32.7 Male (N): 38 Female (N): 29 Overall N: 141 Mean Age (years): 35.3 Male (N): 73 Female (N): 68 Inclusion criteria: "Outpatient adults with ADHD aged 19 – 60 years; Satisfy full diagnostic criteria for DSM‐IV ADHD on the basis of clinical assessment and confirmation by structured diagnostic interview" Exclusion criteria: "Clinically significant chronic medical conditions; Abnormal baseline laboratory values; Intelligence quotient less than 80; Delirium, dementia, or amnesic disorders; Other clinically unstable psychiatric conditions (i.e., bipolar disorder, psychosis, suicidality); Drug or alcohol abuse or dependence within the 6 months preceding the study, or a previous adequate trial of MPH; Pregnant or nursing women"
Interventions	Intervention Characteristics Placebo Mean Daily dose 80.9mg OROS MPH
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: Research was supported by McNeil Consumer and Specialty Pharmaceuticals. Lead author receives research support from numerous pharmaceutical companies, including Shire. Country: USA Setting: Clinical outpatient setting Authors' names: Joseph Biederman, Eric Mick, Craig Surman, Robert Doyle, Paul Hammerness, Theresa Harpold, Stephanie Dunkel, Meghan Dougherty, Megan Aleardi, Thomas Spencer Institution: Massachusetts General Hospital Email: jbiederman@partners.org Address: Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Boston, MA 02114‐3139, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe how the random sequence generation was completed.
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind (wherein “raters and subjects were blind to treatment assignment”), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 131 out of 149 randomized participants were analyzed
Selective reporting (reporting bias)	Low risk	Comment: changes in blood pressure are reported

Biederman 2007.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 116 Mean Age (years): 38.5 Male (N): 58 Female (N): 58 Mean Weight (kg): 82.9 Mean Daily Dose 80.9mg OROS methylphenidate (MPH) N: 67 Mean Age (years): 32.7 Male (N): 38 Female (N): 29 Mean Weight (kg): 84.1 Mean Daily Dose 74.8mg Immediate release (IR) MPH (MPH) N: 102 Mean Age (years): 35.7 Male (N): 60 Female (N): 62 Mean Weight (kg): 79.9 Overall N: 285 Mean Age (years): 36.1 Male (N): 156 Female (N): 149 Mean Weight (kg): 82.1 Inclusion criteria: "Satisfy full diagnostic criteria for DSM‐IV ADHD based on clinical assessment and confirmed by structured diagnostic interview" Exclusion criteria: "Clinically significant chronic medical conditions, abnormal baseline laboratory values, I.Q. <80, delirium, dementia, or amnestic disorders, other clinically unstable psychiatric conditions (i.e., bipolar disorder, psychosis, suicidality), drug or alcohol abuse ordependence within the six months preceding the study, or previous adequate trial of methylphenidate; Pregnant or nursing females"
Interventions	Intervention Characteristics Placebo Mean Daily Dose 80.9mg OROS‐MPH Mean Daily Dose 74.8mg IR‐MPH
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: "Shire Development LLC provided funding to SCI for support in writing and editing this manuscript. The sponsor was involved in the design, collection, analysis, interpretation, and fact‐checking of information." Country: USA Setting: Clinical and academic outpatient setting Authors' names: Joseph Biederman, Eric O Mick, Craig Surman, Robert Doyle, Paul Hammerness, Evan Michel, Jessica Martin, Thomas J Spencer Institution: Massachusetts General Hospital Email: Clinical and Research Program in Pediatric Psychopharmacology and Adult ADHD at the Massachusetts General Hospital, Boston, MA 02114, USA Address: jbiederman@partners.org
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the random sequence generation process.
Allocation concealment (selection bias)	Unclear risk	Comment: study did not describe the method of concealment used.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind (wherein “raters and subjects were blind to treatment assignment”), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 85% of placebo‐treated participants, 75% of the IR‐MPH‐treated participants, and 81% (N = 54) of the OROS‐MPH‐treated participants completed the 6‐week trial.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

Biederman 2012.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 30 Lisdexamfetamine (LDX) 30‐70 mg daily N: 31 Overall N: 61 Mean Age (years): 21.6 Male (N): 38 Female (N): 23 Inclusion criteria: "Male or female 18‐26 years of age; Fully meet DSM‐IV criteria for ADHD based on a clinical evaluation supplemented by structured diagnostic interview; Subjects had an onset of symptoms in childhood, a persistence of impairing symptoms into adulthood, and did not have pharmacological treatment for ADHD in the past month" Exclusion criteria: "Other clinically significant psychiatric or medical conditions, including clinically significant laboratory or ECG values, hypertension, pre‐existing structural cardiac abnormalities, or a known hypersensitivity to LDX or any amphetamine compounds; Individuals who used psychotropics or any medication in the past month with clinically significant central nervous system effects; IQ < 80; History of substance dependence or abuse within six months preceding the study; Pregnant or nursing females; Individuals who had never held a valid driver’s license"
Interventions	Intervention Characteristics Placebo LDX 30‐70 mg daily
Outcomes	Systolic Blood Pressure (6 weeks) Outcome type: Continuous Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure (6 weeks) Outcome type: Continuous Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Heart rate (6 weeks) Withdrawals due to adverse effects (6 weeks)
Identification	Sponsorship source: Research was supported by McNeil Consumer and Specialty Pharmaceuticals. Lead author receives research support from numerous pharmaceutical companies, including Shire. Country: USA Setting: Massachusetts General Hospital and Massachusetts Institute of Technology Authors' names: Joseph Biederman, Ronna Fried, Paul Hammerness, Craig Surman, Bruce Mehler, Carter R Petty, Stephen V Faraone, Carolyn Miller, Michelle Bourgeois, Benjamin Meller, Kathryn M Godfrey, Bryan Reimer Institution: Massachusetts General Hospital Email: jbiederman@partners.org Address: Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Boston, MA 02114‐3139, USA
Notes	The medication dose was started at 30 mg and titrated by physicians to 50 mg at week 2 and 70 mg at week 3 based on response or adverse effects. Final doses not reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process used
Allocation concealment (selection bias)	Unclear risk	Comment: study did not describe the method of concealment used
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study is double‐blind (wherein “physician raters and subjects were blind to treatment assignment”), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 62/69 randomized participants included in final analysis
Selective reporting (reporting bias)	Low risk	Comment: baseline and endpoint blood pressure provided. Baseline characteristics not provided

Brams 2018.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 131 Mean Age (years): 12.5 Male (N): 77 Female (N): 54 Mean Weight (kg): 51.92 Max 25mg SPH465 mixed amphetamine salts (MAS) N: 132 Mean Age (years): 12.4 Male (N): 86 Female (N): 46 Mean Weight (kg): 51.3 Overall N: 263 Mean Age (years): 12.5 Male (N): 163 Female (N): 100 Mean Weight (kgs): 51.61 Inclusion criteria: "Males or nonpregnant nonlactating females (aged 6–17 years at the time of consent) with a primary ADHD diagnosis based on DSM‐IV‐TR criteria and baseline ADHDRS‐IV total scores ≥ 28; Have a satisfactory medical assessment with no clinically significant or relevant abnormalities and to be functioning at an age‐appropriate intellectual level; Untreated or not completely satisfied with their current ADHD medication" Exclusion criteria: "Comorbid psychiatric diagnosis with significant symptoms/symptomatic manifestations that could contraindicate treatment or confound efficacy or safety assessments or a concurrent condition that could confound safety assessments or increase participant risk; History of a chronic tic disorder, a current tic disorder, a history of tics that were judged by the investigator to be exclusionary, or a diagnosis of Tourette’s syndrome; Considered a suicide risk, or having had a previous suicide attempt, or demonstrating active suicidal ideation; Underweight (BMI <3rd percentile) or overweight (BMI >97th percentile) at screening based on the Centers for Disease Control and Prevention’s age‐ and sex‐specific values; Blood pressure exceeding the 90th percentile for age, sex, and height at screening and baseline; Hypertension; Symptomatic cardiovascular disease, cardiac issues, a clinically significant ECG, or a family historyof sudden cardiac death or ventricular arrhythmia; Having a documented allergy, hypersensitivity, or intolerance to amphetamine orexcipients in SHP465 MAS; Having failed to respond to a previous course of amphetamine therapy; Having a history of suspected substance abuse or dependence (excluding nicotine) based on DSM‐IV‐TR criteria; Taking a prohibited medication that was excluded or had not been appropriately washed out."
Interventions	Intervention Characteristics Placebo Max 25mg SPH465 MAS
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: This study was funded by Shire Pharmaceuticals Country: USA Setting: 36 clinical sites in the USA Authors' names: Matthew Brams, Ann C Childress, Michael Greenbaum, Ming Yu, Brian Yan, Margo Jaffee, Brigitte Robertson Institution: Baylor College of Medicine Email: drmattbrams@aol.com Address: Baylor College of Medicine, Houston, Texas
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 116 of 264 randomized participants completed the study, which is less than a 44% completion rate. Therefore, the study has a high risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: all prespecified outcomes, including measurements for systolic and diastolic blood pressure, were fully reported, supporting a low risk of selective reporting bias.

Casas 2013.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 97 Mean Age (years): 35.5 Male (N): 52 Female (N): 45 Mean Weight (kg): 76.5 Mean Height (cm): 174 54mg OROS MPH N: 90 Mean Age (years): 35.8 Male (N): 44 Female (N): 46 Mean Weight (kg): 77.1 Mean Height (cm): 173.1 72mg OROS MPH N: 92 Mean Age (years): 35.8 Male (N): 50 Female (N): 42 Mean Weight (kg): 78 Mean Height (cm): 173 Overall N: 279 Mean Age (years): 35.7 Male (N): 146 Female (N): 133 Mean Weight (kg): 77.2 Mean Height (cm): 173.4 Inclusion criteria: "Adults (18–65 years) with ADHD according to the criteria described in the Diagnostic and Statistical Manual for Mental Disorders 4th Edition Text Revision (DSM‐IV‐TR), confirmed using Conners' Adult ADHD Diagnostic Interview Part II for DSM ‐ IV (Conners et al. 1999)" Exclusion criteria: "Known nonresponse to MPH; Any clinically unstable psychiatric condition; Family history of schizophrenia or affective psychosis; Autism; Asperger’s syndrome; Eating disorder; Motor tics or history (including family history) of Tourette’s syndrome; Substance use disorder (not including caffeine or nicotine dependence); Hyperthyroidism; Myocardial infarction or stroke 6 months before screening; History of seizures, glaucoma or uncontrolled hypertension; Angina pectoris or cardiac arrhythmias; Women who were pregnant or breastfeeding."
Interventions	Intervention Characteristics Placebo 54mg OROS MPH 72mg OROS MPH
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by Janssen‐Cilag EMEA, a pharmaceutical company. Country: Spain Setting: 42 European sites (specific locations not specified) Authors' names: Miguel Casas, Michael Rösler, JJ Sandra Kooij, Ylva Ginsberg, Josep Antoni Ramos‐Quiroga, Steffen Heger, Joris Berwaerts, Joachim Dejonckheere, Erik van der Vorst, Barbara Schäuble Institution: Universitat Autònoma de Barcelona Email: mcasasb@gmail.com Address: Department of Psychiatry, Hospital Universitari Vall d'Hebron and Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: randomization was based on a computer‐generated scheme prepared by the sponsor, balanced by using permuted blocks of treatments and stratified by study centre
Allocation concealment (selection bias)	Low risk	Comment: medication kit numbers were pre‐printed on drug labels and assigned as participants were randomly assigned to treatment. Treatment codes obtained from central interactive voice response system giving medication kit number for drug to which participant had been assigned.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 178/279 completed the study, meaning less than 64% completion rate. The study therefore has a high risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure at baseline and change in blood pressure were both reported

Childress 2022.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 45 Mean Age (months): 61.9 Male (N): 29 Female (N): 16 Mean Weight (kg): 20.6 5mg Lisdexamfetamine N: 39 Mean Age (months): 60.7 Male (N): 27 Female (N): 12 Mean Weight (kg): 21.0 10mg Lisdexamfetamine N: 35 Mean Age (months): 60.9 Male (N): 22 Female (N): 13 Mean Weight (kg): 21.6 20mg Lixdexamfetamine N: 34 Mean Age (months): 61.1 Male (N): 24 Female (N): 10 Mean Weight (kg): 22.4 30mg Lixdexamfetamine N: 38 Mean Age (months): 61.2 Male (N): 27 Female (N): 11 Mean Weight (kg): 21.2 Inclusion criteria: "The study enrolled boys and girls (aged 4‐5 years [inclusive] at time of consent) meeting DSM‐IV‐TR criteria for a primary ADHD diagnosis. Participants were required to have baseline scores ≥28 (boys) or ≥24 (girls) on the parent‐reported ADHD‐RS‐IV‐PS‐TS and ≥4 on the Clinical Global Impression–Severity (CGI‐S) scale. Participants were required to have undergone an adequate course of nonpharmacologic treatment or to have had symptoms severe enough to warrant enrollment without prior nonpharmacologic treatment and to be engaged in structured group activities that allowed for assessment of ADHD symptoms and impairment outside of the home. Participants were required to have a screening Peabody Picture Vocabulary Test standard score ≥70 and to have lived with the same parent/LAR for ≥6 months." Exclusion criteria: "Participants were excluded if they required or anticipated the need for medications with central nervous system effects or with effects that could influence performance or if their ADHD symptoms were well controlled with acceptable tolerability on their current ADHD medication. Participants were also excluded if they had a concurrent illness, condition (except enuresis), or disability that could confound safety assessments or increase participant risk, or if they had a current, controlled or uncontrolled, comorbid Axis I or Axis II psychiatric disorder (including but not limited to posttraumatic stress disorder, bipolar disorder, pervasive development disorder, obsessive‐compulsive disorder, oppositional defiant disorder, conduct disorder, anxiety disorders, and psychosis/schizophrenia)."
Interventions	Intervention Characteristics Placebo 5mg Lisdexamfetamine 10mg Lisdexamfetamine 20mg Lisdexamfetamine 30mg Lisdexamfetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: "This clinical research was funded by Shire Development, LLC, a member of the Takeda group of companies, Lexington, MA, USA." Shire is a pharmaceutical firm that produces amphetamine‐based ADHD drugs. Country: USA Setting: 44 US sites (specific locations not specified) Authors' names: Ann C. Childress, Eric Lloyd, Leslie Jacobsen, Lhanoo Gunawardhana, Steven A. Johnson, Jr., Robert L. Findling Institution: Center for Psychiatry and Behavioral Medicine, Las Vegas, Nevada; Takeda Development Center Americas, Inc., Lexington, Massachusetts; Virginia Commonwealth University, Richmond Email: drann87@aol.com Address: Center for Psychiatry and Behavioral Medicine, 7351 Prairie Falcon Road, Suite 160, Las Vegas, NV 89128
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Treatment assignments were determined using a randomization schedule, with each treatment assigned by an interactive Web‐response system (IWRS)
Allocation concealment (selection bias)	Low risk	The treatment assignment was broken only in an emergency situation requiring identification of the investigational product to continue further treatment. If the treatment assignment was broken, the date, the signature of the person who broke the code, and the reason for breaking the code were recorded in the IWRS and the source documents.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind study. Quote: "To protect study blinding, LDX [lisdexamfetamine] and PBO [placebo] capsules appeared identical… If the blinding was broken, the participant was withdrawn from the study but was followed up for safety analyses"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Given that this study was double‐blind (wherein LDX and placebo capsules appeared identical) and “if the blinding was broken, the participant was withdrawn from the study”, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	191 randomized participants completed the safety analysis set. Among these, 37 of 45 participants (82%) in the placebo arm and 113 of 146 participants (77%) in the amphetamine arm completed the study. Among those who withdrew, 4% (2 of 45) of withdrawals in the placebo arm and 5% (8 of 146) in the amphetamine arm were due to adverse events. Given the comparable overall attrition rates and similar attrition due to adverse events between the treatment arms, we assessed Childress 2022 as having a low risk of attrition bias.
Selective reporting (reporting bias)	Low risk	SBP and DBP data provided.

Coghill 2013.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 110 Mean Age (years): 11 Male (N): 91 Female (N): 19 53.8mg per day LDX N: 111 Mean Age (years): 10.9 Male (N): 87 Female (N): 24 45.4mg per day OROS‐MPH N: 111 Mean Age (years): 10.9 Male (N): 90 Female (N): 21 Overall N: 332 Mean Age (years): 10.95 Male (N): 178 Female (N): 43 Inclusion criteria: "Male and female children (6–12 years old) and adolescents (13–17 years old) who satisfied the DSM‐IV‐TR) criteria for a primary diagnosis of ADHD; Patients had ADHD of at least moderate severity, as defined by a baseline ADHD Rating Scale version IV total score of 28 or higher; Age‐appropriate intellectual functioning; Blood pressure measurements within the 95th percentile for age, sex, and height; Ability to swallow a capsule; Girls of childbearing potential had to have a negative urine pregnancy test at baseline and to comply with any contraceptive requirements of the protocol." Exclusion criteria: "Failure to respond to previous OROS‐MPH therapy; Presence of a comorbid psychiatric diagnosis with significant symptoms; Conduct disorder (excluding oppositional defiant disorder); Pregnancy or lactation; Weight below 22.7 kg; BMI greater than the 97th percentile for age and sex; Positive urine drug test (with the exception of the patient’s current ADHD therapy); Clinically significant electrocardiogram or laboratory abnormalities; Suspected substance abuse or dependence disorder (excluding nicotine) within the previous 6 months; History of seizures; Tics or Tourette’s disorder; Known structural cardiac abnormality or any other condition that might increase vulnerability to the sympathomimetic effects of a stimulant drug. Patients whose current ADHD medication provided effective control of symptoms with acceptable tolerability."
Interventions	Intervention Characteristics Placebo 53.8mg per day LDX OR 45.4mg per day OROS‐MPH
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was supported by funding from Shire Development LLC. Country: The study was conducted across 10 European countries (Germany, Sweden, Spain, Hungary, France, UK, Italy, Belgium, Poland, and the Netherlands). Setting: 48 centers across 10 European countries Authors' names: David Coghill, Tobias Banaschewski, Michel Lecendreux, Cesar Soutullo, Mats Johnson, Alessandro Zuddas, Colleen Anderson, Richard Civil, Nicholas Higgins, Andrew Lyne, Liza Squires Institution: University of Dundee, University of Heidelberg, CHU Robert Debré, University Clinic of Navarra, Queen Silvia Children's Hospital, University of Cagliari, Shire Development LLC, Shire Pharmaceutical Development Ltd. Email: d.r.coghill@dundee.ac.uk Address: Division of Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 196 of 336 randomized participants completed the study, which is a 58% completion rate. Studies with low completion rate have a high risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: baseline and endpoint measures for blood pressure were provided

Daviss 2008.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 30 30.2mg MPH N: 29 Overall N: 59 Inclusion criteria: 7 to 12 years of age, with a confirmed DSM‐IV diagnosis of ADHD. Exclusion criteria: "tic disorder, major depression, pervasive developmental disorder, autism, psychosis, mental retardation, anorexia nervosa, bulimia, a serious cardiovascular (e.g., significant hypotension, congenital heart disease) or other medical disorder that would preclude the safe use of methylphenidate or clonidine; impaired renal function; pregnancy; prolonged QTc interval (9440 milliseconds), high‐grade ventricular ectopy, atrioventricular block beyond first degree, bundle‐branch block, intraventricular conduction block (9100 milliseconds), pacemaker rhythm or HR <60 bpm on the ECG, significant hypotension, cardiomyopathy, congenital heart disease, aortic or pulmonary stenosis, history of syncope, blood pressure at least 2 SDs above or below the age‐ and 2 sex‐adjusted mean, and family history of cardiovascular problems (e.g., long QT syndrome, cardiomyopathy, premature death at younger than 45 years of age)."
Interventions	Intervention Characteristics Placebo 30.2mg MPH
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and additional support from the National Institutes of Health (NIH). Country: USA Setting: The study was conducted at 27 investigative sites in the United States. Comments: Numerous authors in this study held positions (e.g. consultant, on the speakers' bureau) at Shire Pharmaceuticals, a pharmaceutical company that manufactures amphetamines. Authors' names: W. Burleson Daviss, Nick C. Patel, Adelaide S. Robb, Michael P. McDermott, Oscar G. Bukstein, William E. Pelham, Jr., Donna Palumbo, Peter Harris, Floyd R. Sallee Institution: University of Texas Health Science Center at San Antonio, University of Cincinnati, University of Rochester, George Washington University School of Medicine, and Children’s National Medical Center. Email: floyd.sallee@uc.edu Address: Department of Psychiatry, University of Cincinnati School of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: completion rates differed between the placebo and intervention groups: 30% (9 of 30) in the placebo group and 59% (17 of 29) in the methylphenidate group. Additionally, none of the withdrawals in the placebo group were due to adverse events, while 21% (6 of 29) of participants in the amphetamine group withdrew due to adverse events. Given these high and uneven completion rates across groups, we assessed this study as having a high risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: changes in SBP and DBP were reported for both the placebo and methylphenidate arms

Dymowski 2016.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 4 Mean Age (years): 32.5 Male (N): 2 Female (N): 2 50mg Methylphenidate N: 6 Mean Age (years): 35 Male (N): 4 Female (N): 2 Overall N: 10 Mean Age (years): 34 Male (N): 6 Female (N): 4 Inclusion criteria: diagnosis of complicated mild to severe traumatic brain injury, age between 16 and 65 years, sufficient English language, cognitive and physical abilities to complete tasks (as advised by their neuropsychologist), and attentional and/or processing speed deficits on neuropsychological assessment. Exclusion criteria: significant history of neurological or psychiatric disorder, substance abuse, epilepsy, previous treatment with methylphenidate for attentional disturbance, or current treatment with medication or presence of a medical condition for which methylphenidate is contraindicated.
Interventions	Intervention Characteristics Placebo 50mg Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The study was supported by the Epworth Research Institute [grant number 80940]. Country: Australia Setting: The study was conducted at inpatient and outpatient units of the Acquired Brain Injury Rehabilitation Program, Epworth Rehabilitation, Richmond and Camberwell. Authors' names: Alicia R. Dymowski, Jennie L. Ponsford, Jacqueline A. Owens, John H. Olver, Michael Ponsford, Catherine Willmott Institution: Monash University, Monash‐Epworth Rehabilitation Research Centre, Epworth HealthCare Email: Alicia.Dymowski@monash.edu Address: Monash‐Epworth Rehabilitation Research Centre, 185‐187 Hoddle Street, Richmond, Victoria 3121, Australia
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: randomization schedule was created using a random number generator with blocks of 4 and 6 with manual correction for 1:1 ratio within each block
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: participants, families, doctors, therapists and researchers were blinded to treatment group
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind (wherein “participants, families, doctors, therapists and researchers were blinded to treatment group”), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 9 of 11 randomized participants completed the trial and analysis
Selective reporting (reporting bias)	Low risk	Comment: blood pressure change scores were calculated from baseline to on‐drug and baseline to week 8 (off‐drug)

Ermer 2019.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 28 Mean Age (years): 37.7 Male (N): 4 Female (N): 2 Mean Weight (kg): 71.6 70mg Lisdexamfetamine N: 6 Mean Age (years): 38.2 Male (N): 20 Female (N): 8 Mean Weight (kg): 68.75 Overall N: 34 Mean Age (years): 38 Male (N): 24 Female (N): 10 Mean Weight (kg): 69.3 Inclusion criteria: aged 18–55 years with a BMI of 18.0 to 30.0 kg/m2 inclusive and body weight of 50 kg or more. Exclusion criteria: suicide risk; history of hypertension; history of seizure (other than infantile febrile seizures); any tic disorder or current diagnosis and/or family history of Tourette's syndrome; history of cardiovascular diseases; glaucoma; pregnancy.
Interventions	Intervention Characteristics Placebo 70mg Lisdexamfetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by Shire Development LLC. "An employee of Caudex, Oxford, UK, provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing and fact‐checking the manuscript, and coordination and collation of comments were also provided by Caudex. Shire reviewed and edited the manuscript. Shire International GmbH provided funding to Caudex, Oxford, UK, for support in writing and editing this manuscript. Employees of Shire and Shionogi & Co., Ltd. were involved in the design, collection, analysis, interpretation, and fact‐checking information." Country: USA Setting: A single site in the USA (type of site not specified) Authors' names: James Ermer, Patrick Martin, Mary Corcoran, Yumiko Matsuo Institution: Shire, Wayne, PA, USA; Shire, Lexington, MA, USA; Shionogi & Co., Ltd., Osaka, Japan Email: pmartin@shire.com Address: Shire, 300 Shire Way, Lexington, MA 02421, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: randomized through the use of a four‐digit randomization number allocated prior to dosing
Allocation concealment (selection bias)	Low risk	Comment: treatment assignments giving details of individual participant treatment were provided in code‐break envelopes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 27 of the 34 randomized participants finished the multiple‐dose trial. 27/34 = 79% completion rate
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

Findling 2005.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 209 10mg Mixed Amphetamine Salts Extended‐release formulation N: 129 20mg Mixed Amphetamine Salts Extended‐release formulation N: 119 30mg Mixed Amphetamine Salts Extended‐release formulation N: 123 Overall N: 568 Mean Age (years): 8.7 Male (N): 442 Female (N): 126 Mean Weight (kg): 33.5 Mean Height (cm): 134.4 Inclusion criteria: Children aged 6 to 12 years with attention‐deficit/hyperactivity disorder Exclusion criteria: Hypertension or any other cardiovascular disorder
Interventions	Intervention Characteristics Placebo 10mg Mixed Amphetamine Salts Extended‐release formulation 20mg Mixed Amphetamine Salts Extended‐release formulation 30mg Mixed Amphetamine Salts Extended‐release formulation
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: Drs. Findling, Biederman, Wilens, Spencer, McGough, and Lopez are consultants to Shire Pharmaceutical Development, Inc. Dr. Tulloch is an employee of Shire Pharmaceutical Development, Inc. However, the source of funding is not reported. Country: USA Setting: The study was conducted at 27 investigative sites across the United States. Authors' names: Robert L. Findling, Joseph Biederman, Timothy E. Wilens, Thomas J. Spencer, James J. McGough, Frank A. Lopez, Simon J. Tulloch Institution: University Hospitals of Cleveland, Massachusetts General Hospital, UCLA Neuropsychiatric Institute, Children's Developmental Center, Shire Pharmaceutical Development Inc. Email: Robert.Findling@uhhs.com Address: Department of Psychiatry, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: blood pressure was taken for 580/584 participants
Selective reporting (reporting bias)	Low risk	Comment: all blood pressure measurements are reported

Findling 2011.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 77 30mg Lisdexamfetamine N: 78 50mg Lisdexamfetamine N: 77 70mg Lisdexamfetamine N: 78 Overall N: 310 Mean Age (years): 14.6 Male (N): 218 Female (N): 92 Inclusion criteria: "Adolescent participants (13 through 17 years at the time of consent and baseline) who met DSM‐IV‐TR diagnostic criteria for ADHD. ADHD diagnosis and confirmed using the Kiddie‐SADS—Present and Lifetime Diagnostic Interview (K‐SADSPL); Moderate to severe ADHD symptoms at baseline (score of ≥ 28 on ADHDRS‐IV assessment); Age‐appropriate intellectual function and blood pressure (BP) measurements ≤ 95th percentile for age, gender, and height." Exclusion criteria: "Conduct disorder or a comorbid psychiatric diagnosis (oppositional defiant disorder was not exclusionary) requiring medication were excluded; Concurrent chronic/acute medical condition that might confound efficacy/safety assessments or pose a safety risk, a history of seizures, tic disorder or family history of Tourette disorder, family history of sudden cardiac death or arrhythmia, abnormal thyroid function (a stable dose of thyroid medication for at least 3 months was permitted), glaucoma, or those considered a suicide risk were excluded. Body mass index could not be 5th or 97th percentile for age and gender; Positive on urine drug screen (except current stimulant therapy), or had a recent history of suspected substance abuse (excluding nicotine); Pregnant/lactating females; Clinically ECG findings, who required medications with central nervous system effects, with failure to respond to and/or intolerance of amphetamine therapy, and/or who were well controlled on current ADHD medication with acceptable safety and efficacy were disqualified; Anyone who previously participated in an LDX trial could not participate"
Interventions	Intervention Characteristics Placebo 30mg Lisdexamfetamine 50mg Lisdexamfetamine 70mg Lisdexamfetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: "The study was funded by Shire Development Inc. Shire Development Inc. provided funding to Ogilvy CommonHealth Scientific Communications (OCHSC) for support in writing and editing this manuscript. Michael McKay, M.B.A., from Shire Development Inc. coordinated the management of the study." Country: USA Setting: The study was conducted at 45 US sites. Authors' names: Robert L. Findling, Ann C. Childress, Andrew J. Cutler, Maria Gasior, Mohamed Hamdani, M. Celeste Ferreira‐Cornwell, Liza Squires Institution: University Hospitals Case Medical Center, Center for Psychiatry and Behavioral Medicine Inc., Florida Clinical Research Center, Shire Development Inc. Email: Robert.Findling@UHhospitals.org Address: University Hospitals Case Medical Center, Case Western Reserve University, Department of Psychiatry, 10524 Euclid Avenue, Suite 1155A, Cleveland, OH 44106, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: Interactive Voice Response System/Interactive Web Response System Screening used for randomization/treatment assignments, dispensing, and managing study medication (i.e. numbering treatment bottles for each participant in the appropriate treatment arm)
Allocation concealment (selection bias)	Low risk	Comment: Interactive Voice Response System/Interactive Web Response System Screening used for dispensing and managing study medication (i.e. numbering treatment bottles for each participant in the appropriate treatment arm)
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: low attrition rate
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

Frick 2017.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 104 Mean Age (years): 35.6 Male (N): 58 Female (N): 46 Mean Weight (lb): 181.8 Mean BMI: 27.6 25mg SHP465 MAS N: 104 Mean Age (years): 38 Male (N): 54 Female (N): 50 Mean Weight (lb): 186.6 Mean BMI: 28.6 50mg SHP465 MAS N: 101 Mean Age (years): 37.2 Male (N): 66 Female (N): 35 Mean Weight (lb): 181.3 Mean BMI: 27.3 75mg SHP465 MAS N: 102 Mean Age (years): 37.9 Male (N): 55 Female (N): 47 Mean Weight (lb): 184.4 Mean BMI: 28.4 Overall N: 411 Mean Age (years): 37.7 Male (N): 175 Female (N): 132 Mean Weight (lb): 184.1 Mean BMI: 28.1 Inclusion criteria: "Adults (men or nonpregnant, nonlactating women aged 18‐55 years) meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM‐IV‐TR; American Psychiatric Association, 2000) criteria for a primary ADHD diagnosis established using the Adult ADHD Clinical Diagnostic Scale Version 1.2 and having baseline ADHDRS‐IV (Adler, Spencer, et al., 2009) total scores ≥32 were eligible. All eligible participants had satisfactory medical assessments, with no clinically significant or relevant abnormalities." Exclusion criteria: "Key exclusion criteria included current comorbid psychiatric disorders (defined by the Structured Clinical Interview for the DSM‐IV‐TR [SCID] Axis I Disorders and controlled with prohibited medications or uncontrolled and associated with significant symptoms); any conditions/ symptoms that could confound clinical assessments at screening; chronic or acute illnesses or unstable medical conditions that could confound safety assessments, lead to increased risk, or make it difficult to comply with the protocol; a history of seizures (excluding infantile febrile seizures), any tic disorder, or a current diagnosis and/or family history of Tourette disorder; known cardiac abnormalities or conditions affecting cardiac performance, a history of hypertension, or sitting SBP >139 mmHg or DBP >89 mmHg; a clinically significant electrocardiogram (ECG) or laboratory abnormality at baseline or screening; the use of a psychoactive prescription medication or over‐the‐counter medication requiring more than a 28‐day washout period (excluding hormonal contraceptives); participation in a clinical study within 30 days of screening; a drug dependence or substance abuse disorder (excluding SCID‐defined nicotine dependence) within 6 months before screening or a positive urine drug result at screening or baseline (excluding current psychostimulant medications); and a documented allergy, intolerance, or history of nonresponse to MPH or amphetamine."
Interventions	Intervention Characteristics Placebo 25mg SHP465 MAS 50mg SHP465 MAS 75mg SHP465 MAS
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by Shire Development LLC (Lexington, MA). Shire provided funding to CHC for support in writing and editing this manuscript. Country: USA Setting: The study was conducted at 48 sites across the United States. Authors' names: Glen Frick, Brian Yan, Lenard A. Adler Institution: Shire, Lexington, MA, USA; New York University, New York, NY, USA Email: lenard.adler@nyumc.org Address: New York University, School of Medicine, One Park Avenue, 8th Floor, New York, NY 10016, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: computer‐generated two‐part labels were used for blinding, and all treatments were identical in appearance
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: while there was a low overall attrition rate (9%) for the collective randomized participants, there was a discrepancy in attrition due to adverse events between the amphetamine and placebo arms. In the amphetamine arm, 10% of participant withdrawals were due to adverse events, whereas in the placebo arm, only 3% of withdrawals were due to adverse events. Since the reasons for participant dropout were linked to outcomes, we judged this study as having a high risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure was reported

Gasior 2014.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 27 20mg LDX N: 27 50mg LDX N: 27 70mg LDX N: 27 Overall N: 108 Mean Age (years): 27.7 Mean Weight (kg): 78.2 Inclusion criteria: "Healthy men (aged 18–40 y) with regular sleep‐wake habits (eg, routinely spending 6.5 to 8 hours sleeping nightly, not oversleeping by more than 3 hours on weekends) as determined by investigator interviews and confirmed in a screening sleep diary and actigraphy monitoring during the week before randomization." Exclusion criteria: "Excessive sleepiness as defined by a self‐reported Epworth sleepiness scale score at screening of greater than 10; Irregular work hours or routine night‐shift work within 1 month before randomization; Experiencing or having a history of any known/suspected sleep disorder, any disorder associated with EDS, or any diagnosis interfering with assessment of sleepiness were excluded; Study‐related induced sleepiness or abnormal findings on the initial polysomnography (PSG) conducted on day –1 (check‐in); Traveled across 2 or more time zones 2 weeks or less before screening; Current or previous history of serious, severe, or unstable physical or psychiatric illness that may affect sleep or wakefulness; Any medical disorder that may require treatment or make the full completion of the study unlikely or any condition that presented undue risk from lisdexamfetamine dimesylate, armodafinil, or study procedures; Caffeine consumption of more than 400 mg/d for 2 weeks before screening, history (≤6 months before screening) of suspected substance abuse or dependence disorder or positive drug/alcohol screening result, or those who smoked or used nicotine‐containing products; Treated with medications with central nervous system effects within 14 days of check‐in with sedating antihistamines, decongestant sympathomimetics, and/or monoamine oxidase inhibitors."
Interventions	Intervention Characteristics Placebo 20mg LDX 50mg LDX 70mg LDX
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: "The study was funded by Shire Development LLC. Shire Development LLC provided funding for support in writing and editing this manuscript. They were involved in the design, collection, analysis, interpretation, and fact checking of information." Country: USA Setting: The study was conducted at Clinilabs, a Clinical Research Unit in New York, NY. Authors' names: Maria Gasior, Jon Freeman, Gary Zammit, Patricia Donnelly, Joseph Gao, Maria Celeste Ferreira‐Cornwell, Thomas Roth Institution: Shire Development LLC, Clinilabs Inc., Henry Ford Hospital Sleep Center Email: mgasior@shire.com Address: Shire Development LLC, 725 Chesterbrook Blvd, Wayne, PA 19087, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: all randomized participants were included in the safety‐analysis set
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

Ginsberg 2012.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 15 Mean Age (years): 35.3 Male (N): 15 72mg OROS Methylphenidate N: 15 Mean Age (years): 33.5 Male (N): 15 Overall N: 30 Mean Age (years): 34.4 Male (N): 30 Inclusion criteria: To enter the trial, participants had to have confirmed ADHD in accordance with DSM‐IV and to agree not to behave violently during the study. Participants with comorbid disorders such as autism‐spectrum disorder, anxiety and depression could take part if they were considered to be stable at baseline. Previous drug‐elicited episodes of psychosis were not a cause for exclusion, other than chronic psychoses. Concurrent medication not interfering with methylphenidate was permitted for treating comorbid disorders, as long as doses were stable for at least 1 month at baseline. Medications interfering with methylphenidate had to be tapered off before the baseline visit took place. Exclusion criteria: Participants were excluded if they were known to be non‐responsive or intolerant to methylphenidate, or intolerant to lactose. In addition, participants were excluded if they showed evidence of substance misuse up to 3 months before baseline, assessed in urine samples. Intellectual disability, epilepsy, glaucoma, uncontrolled hypertension, angina pectoris, cardiac arrhythmias, cardiac abnormality or a family history of serious cardiac illnesses were exclusion criteria, but hepatitis C without liver insufficiency did not preclude inclusion.
Interventions	Intervention Characteristics Placebo 72mg OROS Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by the Swedish Ministry of Health and Social Affairs and Stockholm County Council, Sweden. Country: Sweden Setting: The study was conducted at Norrtälje Prison, a high‐security prison for long‐term adult male inmates outside Stockholm, Sweden. Authors' names: Ylva Ginsberg, Nils Lindefors Institution: Karolinska Institutet, Stockholm, Sweden Email: ylva.ginsberg@ki.se Address: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: Random number table
Allocation concealment (selection bias)	Low risk	Comment: the random number table was stored in the pharmacy department and was concealed from study staff and participants until completion of the study. The placebo and methylphenidate capsules and packaging were identical in appearance and were coded with a unique randomisation number.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: no attrition in this RCT
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

Green 2011.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 12 Mean Age (years): 11.1 Male (N): 7 Female (N): 5 Mean Daily Dose 15.7mg Methylphenidate N: 22 Mean Age (years): 11.1 Male (N): 13 Female (N): 9 Overall N: 34 Mean Age (years): 11.1 Male (N): 20 Female (N): 14 Inclusion criteria: Children and adolescents with velocardiofacial syndrome and ADHD Exclusion criteria: Not specified
Interventions	Intervention Characteristics Placebo Mean Daily Dose 15.7mg Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by the Basil O'Connor Starter Scholar Research Award of the March of Dimes, NARSAD Young Investigator Award, the Marguerite Stolz Award from the Sackler Faculty of Medicine, and an R01 grant from the National Institute on Drug Abuse (NIDA). Country: Israel Setting: The study was conducted at the Behavioral Neurogenetics Center, Schneider Children’s Medical Center of Israel. Authors' names: Tamar Green, Ronnie Weinberger, Adele Diamond, Michael Berant, Leora Hirschfeld, Amos Frisch, Omer Zarchi, Abraham Weizman, Doron Gothelf Institution: Tel Aviv University, Sackler Faculty of Medicine, Schneider Children’s Medical Center, University of British Columbia, Sheba Medical Center, Felsenstein Medical Research Center, Geha Mental Health Center Email: gothelf@post.tau.ac.il Address: The Child Psychiatry Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer 52621, Ramat Gan, Israel
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	High risk	Comment: this was an open‐label study, and thus the outcome assessor was not blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: no attrition reported
Selective reporting (reporting bias)	Low risk	Comment: blood pressure measurements were reported

Guerdjikova 2016.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 25 Mean Age (years): 36.1 BMI: 38.8 Male (N): 3 Female (N): 22 LDX N: 25 Mean Age (years): 39.2 BMI: 40.8 Male (N): 1 Female (N): 24 Total N: 50 Mean Age (years): 37.7 BMI: 39.8 Male (N): 4 Female (N): 46
Interventions	Intervention Characteristics Placebo Daily Mean Dose 59.6mg of LDX
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Change from baseline Inclusion criteria: "(i) were men or women from 18 to 55 years of age, (ii) met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (A.P.A., 2000) criteria for BED, and (iii) had ≥3 BE days/week for the 2 weeks before receiving study medication." Exclusion criteria: "(i) current anorexia nervosa or bulimia nervosa; (ii) current suicidal ideation or a suicide attempt within the last year as determined by the Columbia‐Suicide Severity Rating Scale (Posner, 2007); (iii) receipt of a psychological or weight loss intervention for BED begun within 3 months of study entry; (iv) a substance use disorder (except nicotine dependence) or stimulant misuse within 6 months of study entry or a lifetime history of psychosis, mania, or hypomania; (v) a clinically unstable medical illness or clinically significant laboratory or electrocardiogram (ECG) abnormalities; (vi) receipt of psychotropic medication (other than hypnotics) within 4 weeks prior to randomization; or (vii) a known allergy to LDX. Women were excluded if they were pregnant, lactating, or if of childbearing potential, not practicing a medically accepted form of contraception."
Identification	Sponsorship source: The study was supported by a grant from Shire, a pharmaceutical firm that produces amphetamine‐based ADHD drugs. Shire also provided the study medication. Country: USA Setting: The study was conducted at the Lindner Center of HOPE, Mason, Ohio. Authors' names: Anna I. Guerdjikova, Nicole Mori, Thomas J. Blom, Paul E. Keck Jr., Stephanie L. Williams, Jeffrey A. Welge, Susan L. McElroy Institution: Lindner Center of HOPE, Mason, Ohio; Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio Email: anna.guerdjikova@lindnercenter.org Address: Lindner Center of HOPE, Research Institute, 4075 Old Western Row Road, Mason, Ohio 45040, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Participants were randomized to receive LDX or placebo in a 1:1 ratio according to computer‐generated coding. Randomization was balanced by use of permuted blocks."
Allocation concealment (selection bias)	Low risk	Quote: "Allocation concealment was achieved by having research pharmacy personnel perform the randomization, package the study medication, and maintain the integrity of the blinded information throughout the trial."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The participants were blinded as to whether they received lisdexamphetamine or placebo.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Results were heavily dependent on assumptions regarding missing data as attrition was high, with 46% of participants withdrawing before study completion.
Selective reporting (reporting bias)	Low risk	Changes in both systolic and diastolic blood pressure are reported outcomes.

Hegerl 2017.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 20 Mean Age (years): 49.1 Male (N): 9 Female (N): 9 40mg Methylphenidate N: 22 Mean Age (years): 43.3 Male (N): 13 Female (N): 11 Overall N: 42 Mean Age (years): 46.1 Male (N): 22 Female (N): 20 Inclusion criteria: "Adult inpatients, competent to agree to study participation and able to give written informed consent. Present with a manic episode according to ICD‐10 criteria (F30.0, F30.1, F31.0 or F31.1), a YMRS sum score of at least 20 and maximally 45 points at screening, a body mass index > 17 and able to swallow tablets thus being able to take the study drugs" Exclusion criteria: "Any other current major psychiatric disorder classified using ICD‐10 criteria with the exception of attention deficit hyperactivity disorder (ADHD) or other hyperkinetic disorders, harmful tobacco use, neurotic, stress‐related and somatoform disorders, behavioral syndromes related to physiological disturbances and physical factors and personality disorders; psychotic features; contraindications for taking methylphenidate (like hypersensitivity to components of this drug, very pronounced anxiety and agitation, ineffective contraception during the conduct of the RCT); severe non‐psychiatric diseases (e.g., metabolic disorders) interfering with the aims of the RCT or with individual safety or compliance, as evaluated by the study investigator; oral intake of MAO‐inhibitors within 14 days, fluoxetine within six weeks and of any other antidepressant drugs or primarily psychotropic substances within one week before study entry; stable treatment with mood stabilizers like lithium, anticonvulsants (e.g. valproate, carbamazepine) or neuroleptics (e.g. risperidone) or benzodiazepines was not an exclusion criterion and was continued; however, patients taking more than two of these substances could not be selected for inclusion; medical history of cardiovascular diseases, serious hypertension, glaucoma and hyperfunction of the thyroid; long QT syndrome or a family history of QT prolongation, sudden cardiac death or other significant inherited cardiovascular disorders; a history of electroconvulsive therapy within the last three months; known alcohol and drug dependency or abuse (except for patients with an abstinence exceeding three months) with sporadic abuse of cannabis not being an exclusion criterion; pregnancy or nursing; concomitant participation in another clinical trial or participation during the 30 days before screening; prior participation in this RCT or suicidality."
Interventions	Intervention Characteristics Placebo 40mg Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by a grant of the Spanish ‘Ministerio de Sanidad, Politica Social e Igualdad’ (Ministry of Health, Social Politics and Equality), EC10‐110, EC10‐297, EC10‐333, and EC10‐064, and by the Instituto de Salud Carlos III of Spain (CIBERSAM), grant 11INT2 which had been provided after a peer‐review process. The funding source had no rule in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the paper for publication. Country: The study was conducted in Belgium, Germany, Hungary and Spain. Setting: The study was conducted across multiple clinical centers in the four countries involved. Authors' names: Ulrich Hegerl, Roland Mergl, Christian Sander, Jens Dietzel, Istvan Bitter, Koen Demyttenaere, Ricardo Gusmão, Ana González‐Pinto, Iñaki Zorrilla, Adriana García Alocén, Victor Perez Solà, Eduard Vieta, Georg Juckel, Ulrich S. Zimmermann, Michael Bauer, Pascal Sienaert, Sónia Quintão, Marc‐Andreas Edel, Csilla Bolyos, Jose Luis Ayuso‐Mateos, Pilar López‐García, Michael Kluge Institutions: University Hospital Leipzig, Semmelweis University, University Psychiatric Center KU Leuven, Instituto de Saúde Pública, Universidad del País Vasco, Hospital del Mar, Technische Universität Dresden, and Universidad Autónoma de Madrid Email: Ulrich.Hegerl@medizin.uni‐leipzig.de Address: Department of Psychiatry and Psychotherapy, University Hospital Leipzig, Semmelweisstr. 10, D‐04103 Leipzig, Germany
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study is double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: of the 42 participants enrolled in the study, 40 were included in the final analysis
Selective reporting (reporting bias)	Low risk	Comment: baseline blood pressure and change from baseline are both reported

Kornstein 2019.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 372 Mean Age (years): 38.2 Male (N): 56 Female (N): 316 Mean Weight (kg): 92.9 Lisdexamfetamine Dimesylate N: 373 Mean Age (years): 37.83 Male (N): 49 Female (N): 324 Mean Weight (kg): 94 Overall N: 745 Mean Age (years): 38.0 Male (N): 105 Female (N): 640 Mean Weight (kg): 93.5 Inclusion criteria: "Men or women (aged 18‐55 years) meeting DSM‐IV‐TR BED criteria, confirmed by the eating disorders module of the Structured Clinical Interview for the DSM‐IV‐TR Axis I Disorders and the Eating Disorder Examination‐Questionnaire; PRotocol‐defined moderate to severe BED (≥ 3 BE days/wk during the 14 days before baseline and CGI‐S scores ≥4 at screening and baseline) and a BMI ranging from 18 to 45 kg/m2." Exclusion criteria: "Current diagnoses of anorexia nervosa or bulimia nervosa (based on the SCID‐I eating disorders module); Comorbid Axis I or Axis II psychiatric disorders controlled with prohibited medications or uncontrolled and associated with significant symptoms; Pregnancy; Psychotherapy or weight loss support for BED (≤3 months of screening); Psychostimulant use for BED (≤6 months of screening); Being considered a suicide risk, having previously attempted suicide, or currently demonstrating active suicidal ideation; Lifetime history of psychosis, mania, hypomania, dementia, or ADHD; History of cardiovascular conditions; Moderate or severe hypertension, resting average SBP >139 mmHg, or average DBP >89 mmHg at screening or baseline; Lifetime history of amphetamine or stimulant abuse; Recent substance abuse or dependence history; Intolerance or hypersensitivity to LDX or related compounds."
Interventions	Intervention Characteristics Placebo Lisdexamfetamine Dimesylate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by Shire Development LLC, a pharmaceutical company that manufactures amphetamine‐based ADHD drugs. Country: USA Setting: The study was conducted across 41 clinical research sites in the United States. Authors' names: Susan L. McElroy, James I. Hudson, Michael T. Morrow, Thomas A. Witte, Stacy L. Ferreira‐Cornwell, Manisha Madhoo, Scott P. Williams, Patrick McDonnell, Jack W. Tiller Institution: Lindner Center of HOPE, University of Cincinnati College of Medicine, Harvard Medical School, Shire Development LLC, Takeda Pharmaceuticals Email: smcelroy@lindnercenter.org Address: Lindner Center of HOPE, 4075 Old Western Row Rd, Mason, OH 45040, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: randomly assigned 1:1
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study is double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: attrition rate not reported
Selective reporting (reporting bias)	High risk	Comment: blood pressure measurements were reported but the dosages administrated were not clearly provided. This study thus has a high risk of reporting bias.

Lasser 2010a.

Study characteristics
Methods	Study design: Randomized double‐blind placebo‐controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics for mixed amphetamine salts (MAS) trial Placebo for MAS XR trial N: 45 Mean Age (years): 39.6 Male (N): 29 Female (N): 16 Mean Weight (lb): 186.3 Mean Height (in): 67.7 20mg MAS XR N: 41 Mean Age (years): 38.9 Male (N): 29 Female (N): 12 Mean Weight (lb): 183.9 Mean Height (in): 68.2 40mg MAS XR N: 42 Mean Age (years): 37.3 Male (N): 25 Female (N): 17 Mean Weight (lb): 185.6 Mean Height (in): 67.5 Inclusion criteria: Met DSM‐IV criteria for a primary diagnosis of ADHD; at least 18 years old. Exclusion criteria: Comorbid psychiatric conditions with significant symptoms, pregnancy, seizures, tic disorders, Tourette’s syndrome, hypertension, cardiac conditions, a positive drug screen, history of substance abuse, or use of any prescription/investigational medication except that used to treat ADHD within 30 days of screening.
Interventions	Intervention Characteristics Placebo 20mg MAS XR 40mg MAS XR
Outcomes	Systolic Blood Pressure Outcome type: Continuous Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The study was funded by Shire Pharmaceuticals. All authors are employees at Shire and own stocks and/or stock options in Shire. Editorial assistance was provided by Health Learning Systems, which was funded by Shire Development Inc. for support in writing and editing. The sponsor was involved in the design, collection, analysis and interpretation. Country: USA Setting: The study took place across multiple clinical research centers (specific locations not specified). Authors' names: R. Lasser, S. Dirks, A. Babcock, A. Adeyi Institution: Shire Development Inc. Email: rlasser@shire.com Address: Shire Development Inc., 725 Chesterbrook Blvd, Wayne, PA 19087, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: In the study, the process of sequence generation was not reported.
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study is double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: study's attrition rate was not reported
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

Lasser 2010b.

Study characteristics
Methods	Study design: Randomized double‐blind placebo‐controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics for lisdexamfetamine trial Lisdexamfetamine (LDX) Placebo N: 62 Mean Age (years): 35.2 Male (N): 32 Female (N): 30 Mean Weight (lb): 181.3 Mean Height (in): 67.9 50mg LDX N: 117 Mean Age (years): 34.2 Male (N): 66 Female (N): 51 Mean Weight (lb): 173.1 Mean Height (in): 67.6 70mg LDX N: 122 Mean Age (years): 35.8 Male (N): 63 Female (N): 59 Mean Weight (lb): 174.3 Mean Height (in): 67.4 Inclusion criteria: Met DSM‐IV criteria for a primary diagnosis of ADHD; at least 18 years old in MAS XR trial; 18 to 55 years of age in LDX trial. Exclusion criteria: Comorbid psychiatric conditions with significant symptoms, pregnancy, seizures, tic disorders, Tourette’s syndrome, hypertension, cardiac conditions, a positive drug screen, history of substance abuse, or use of any prescription/investigational medication except that used to treat ADHD within 30 days of screening.
Interventions	Intervention Characteristics Placebo 50mg LDX 70mg LDX
Outcomes	Systolic Blood Pressure Outcome type: Continuous Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint (last valid post‐baseline measurement) assume most were at 4 weeks. Diastolic Blood Pressure Outcome type: Continuous Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint (last valid post‐baseline measurement) assume most were at 4 weeks. Heart rate Outcome type: Continuous Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint (last valid post‐baseline measurement) assume most were at 4 weeks.
Identification	Sponsorship source: The study was funded by Shire Pharmaceuticals. All authors are employees at Shire and own stocks and/or stock options in Shire. Editorial assistance was provided by Health Learning Systems, which was funded by Shire Development Inc. for support in writing and editing. The sponsor was involved in the design, collection, analysis and interpretation. Country: USA Setting: The study took place across multiple clinical research centers (specific locations not specified). Authors' names: R. Lasser, S. Dirks, A. Babcock, A. Adeyi Institution: Shire Development Inc. Email: rlasser@shire.com Address: Shire Development Inc., 725 Chesterbrook Blvd, Wayne, PA 19087, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Comment: In the study, the process of sequence generation was not reported. However, randomization resulted in exceptionally uneven ratios, with 239/301 randomized subjects receiving LDX. This study thus has a high risk of selection bias.
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study is double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: attrition rate of the study was not reported
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

Lin 2014.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 78 Mean Age (years): 11.4 Male (N): 53 Female (N): 25 36mg OR 54mg OROS MPH N: 36 Mean Age (years): 9.9 Male (N): 27 Female (N): 9 Overall N: 114 Mean Age (years): 10.9 Male (N): 80 Female (N): 34 Inclusion criteria: "Female and male patients ≥ 6 years and < 17 years and 9 months of age at the time of informed consent; Meet DSM‐IV‐TR criteria for ADHD, based on a clinician interview, and confirmed using the K‐SADS‐PL; Have an ADHD‐RS‐IV‐Parent:Inv total score ≥ 1.5 standard deviations above the age and gender norms (at screening and week 0), and have a CGI‐ADHD‐S (Guy 1976) score ≥ 4 (at screening and week 0)" Exclusion criteria: "Body weight < 18 kg or > 75 kg; History of bipolar I or II disorder, or psychosis; Any seizure disorder or pervasive developmental disorder; Presence of motor tics or a diagnosis of Tourette’s syndrome; Marked anxiety, tension, or agitation sufficient to contraindicate treatment with OROS MPH; History of electroencephalographic abnormalities; Clinically significant abnormal electrocardiogram; serious or unstable medical illness; Any medical condition that would increase sympathetic nervous system activity markedly (e.g., catecholamine secreting neural tumor); Requiring the daily use of medications with sympathomimetic activity (e.g., albuterol, pseudoephedrine); Any medical condition that would be exacerbated by an increase in norepinephrine tone; Current or past history of clinically significant hypertension."
Interventions	Intervention Characteristics Placebo 36mg OR 54mg OROS MPH
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: Eli Lilly and Company provided analysis for this study and multiple authors are employees and stockholders for this pharmaceutical company. Countries: USA, Canada, Taiwan, Mexico, Puerto Rico Setting: The study was conducted across 31 investigative sites in five countries: USA (23 sites), Canada (3 sites), Taiwan (3 sites), Mexico (1 site), and Puerto Rico (1 site). Authors' names: Daniel Y. Lin, Christopher J. Kratochvil, Wen Xu, Ling Jin, Deborah N. D’Souza, William Kielbasa, Albert J. Allen Institution: Eli Lilly and Company, University of Nebraska Medical Center, inVentiv Health Company Email: lin_daniel_yen@lilly.com Address: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind (wherein “potentially unblinded patients [are] excluded”), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 210 out of 270 randomized participants completed the trial
Selective reporting (reporting bias)	High risk	Comment: dosages of OROS MPH were not clearly provided and did not indicate which participants took which doses

Martinsson 2003.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 15 Mean Age (years): 68 Female (N): 6 Male (N): 9 Mean Weight (kg): 79 Mean Height (cm): 171 2.5mg/5mg/10mg dextroamphetamine N: 30 Mean Age (years): 67 Female (N): 13 Male (N): 17 Mean Weight (kg): 73.5 Mean Height (cm): 169 Overall N: 45 Mean Age (years): 67.3 Female (N): 19 Male (N): 26 Mean Weight (kg): 75.3 Mean Height (cm): 169.7 Inclusion criteria: "(1) age, 18 to 85 years; (2) clinical diagnosis of acute hemispheric cerebral infarction within the carotid‐supplying area confirmed by excluding hemorrhagic stroke on a CT scan; (3) onset of symptoms 72 hours before the start of treatment; (4) score of 15 on arm, hand, and leg motor items of the Scandinavian Stroke Scale (SSS) or a presumed need for hospital care at the stroke unit for at least 5 days because of other focal neurological symptoms such as aphasia or neglect; (5) symptoms present for 1 hour and still present at the start of treatment; (6) informed consent." Exclusion criteria: "Other serious diseases with short life expectancy or that could interfere with the study protocol; Known ongoing alcohol or drug abuse; No limits set to blood pressure (BP)."
Interventions	Intervention Characteristics Placebo 2.5mg/5mg/10mg dextroamphetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was supported by grants from the Federation of County Councils, Family Janne Elgqvist Foundation, Swedish Association of Neurologically Disabled, Åke Wiberg Foundation, Karolinska Institute, and Swedish Stroke Association. Country: Sweden Setting: The study was conducted at the Department of Neurology, Karolinska Hospital, Stockholm, Sweden. Authors' names: Louise Martinsson, Nils Gunnar Wahlgren Institution: Karolinska Institute, Department of Neurology, Karolinska Hospital Email: louise.martinsson@ks.se Address: Stroke Research Unit, R2:03, Department of Neurology, Karolinska Hospital, S‐171 76 Stockholm, Sweden​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Low risk	Comment: prepared and numbered 45 matching boxes. Participants received boxes in consecutive order. Codes were kept until the end of the trial.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: study started with 45 participants but only 32 completed the study in the end. [(45‐38)/45]*100% = 15.6% of participants were not included in the final analysis. Four participants dropped out before the study started, therefore graded as low risk of bias
Selective reporting (reporting bias)	Low risk	Comment: all blood pressure measurements reported

Mathew 1985.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics 15mg dextroamphetamine sulfate N: 10 Mean Age (years): 28.6 Male (N): 5 Female (N): 5 Hand Preference: all right‐handed Placebo N: 12 Mean Age (years): 27.9 Male (N): 7 Female (N): 5 Hand Preference: all right‐handed Overall N: 22 Mean Age (years): 28.2 Male (N): 12 Female (N): 10 Hand Preference: all right‐handed Inclusion criteria: "Subjects who were found to be physically and mentally healthy by a psychiatrist and not addicted to alcohol or drugs were invited to participate in the present project." Exclusion criteria: Individuals who were suspected of having "addiction potential" (e.g. personality disorders) were excluded.
Interventions	Intervention Characteristics 15mg dextroamphetamine sulfate Placebo
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The source of funding is not reported. Country: USA Setting: The study was conducted at Vanderbilt University, Nashville, TN, USA. Authors' names: Roy J. Mathew, William H. Wilson Institution: Department of Psychiatry, Vanderbilt University Email: Clinic@RoyJMathewMD.com Address: Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: "Assignment to the amphetamine and placebo groups was made on a random basis." No explanation of the random sequence generation is offered and no other mention of randomization is mentioned in this publication.
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: "Neither the subjects nor the CBF technicians were informed about the identity of the drug. However, a physician who knew whether amphetamine or saline was being given was present in the room during the study. His interactions with the subjects and the staff were kept to a minimum." Although the publication does not explicitly mention using a double‐blind design, it appears that the participants are blinded and the key personnel are blinded. Thus, we deemed there to be a low risk of performance bias with respect to blinding.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: “neither the subjects nor the technicians were informed about the identity of the drug. However, a physician who knew whether an amphetamine or saline IV was being given was present in the room during the study”. Since it is unclear who took the blood pressure measurements, it is unclear whether blood pressure outcomes were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: study did not provide the attrition rate
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is fully reported.

Mathew 1989.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 24 Mean Age (years): 31 Male (N): 9 Female (N): 15 15mg dextroamphetamine sulfate N: 24 Mean Age (years): 31.3 Male (N): 10 Female (N): 14 Overall N: 48 Mean Age (years): 31.2 Male (N): 19 Female (N): 29 Inclusion criteria: "Population 1 required a diagnosis of schizophrenia. Population 2 consisted of normal controls with no physical and psychiatric disorders and were medication‐free for a minimum of 1 month before the study." Exclusion criteria: "Unable to comprehend the informed consent form or undergo CBF measurements."
Interventions	Intervention Characteristics Placebo 15mg dextroamphetamine sulfate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: Supported by a grant from the National Institute of Mental Health. Country: USA Setting: Clinical research setting Authors' names: Roy J. Mathew, William H. Wilson Institution: Department of Psychiatry, Vanderbilt University, Nashville, TN, USA Email: Clinic@RoyJMathewMD.com Address: Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: participants were blinded. However, it is unclear whether the research personnel were blinded. Thus, this study has an unknown risk of performance bias.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: study does not state whether it is an open‐label study or whether there is any blinding, so it is unclear whether blood pressure measurements were likely biased by knowledge of treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: no attrition
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

Mattingly 2020.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 43 Mean Age (years): 8.8 Male (N): 29 Female (N): 14 Mean Weight (kg): 36.1 Mean BMI: 19.3 6.25mg SHP465 MAS N: 45 Mean Age (years): 8.8 Male (N): 27 Female (N): 18 Mean Weight (kg): 39.3 Mean BMI: 20.17 Overall N: 88 Mean Age (years): 8.8 Male (N): 56 Female (N): 32 Mean Weight (kg): 37.7 Mean BMI: 19.7 Inclusion criteria: "Boys or nonpregnant girls aged 6–12 years meeting primary DSM‐5 criteria for ADHD based on a detailed psychiatric evaluation using the Mini International Neuropsychiatric Interview version for Children and Adolescents; Baseline ADHD‐Rating Scale, Fifth Edition, Child, Home Version total score ≥ 28 and baseline Clinical Global Impressions‐Severity (CGI‐S) of Illness score ≥ 4; Eligible participants either were not receiving ADHD pharmacotherapy or were not completely satisfied with their current ADHD pharmacotherapy and had been living with the same parent/LAR for ≥ 6 months." Exclusion criteria: "Concurrent chronic or acute illness, disability, or condition that might confound safety assessments, increase participant risk, or prohibit the participant from completing the study; Having a controlled or uncontrolled comorbid Axis I or Axis II psychiatric disorder; Initiating behavioral therapy within 1 month of baseline; Being considered a suicide risk, having made a suicide attempt, or having a history of or currently demonstrating suicidal ideation; Having a family history of sudden cardiac death or ventricular arrhythmia; having high blood pressure (≥ 95th percentile for age, sex, and height) at screening and/or baseline; Having a history of symptomatic cardiovascular disease or other serious cardiac conditions; having a clinically significant electrocardiogram (ECG) or clinical laboratory abnormalities at screening or baseline; Having a height or weight ≤ 5th percentile for age and sex at screening or baseline; having an allergy, hypersensitivity, or intolerance to amphetamine; failure to fully respond to an adequate course of amphetamine therapy; and being unable to swallow a pill or administer the contents of a pill in applesauce due to an allergy to applesauce."
Interventions	Intervention Characteristics Placebo 6.25mg SHP465 MAS
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: "The study was funded by Shire Development LLC, a member of the Takeda group of companies, Lexington, MA. Shire Development LLC, a member of the Takeda group of companies, also provided funding to ICON plc (North Wales, PA) for support in writing and editing this article." Country: USA Setting: The study was conducted at 27 sites in the United States between December 2017 and June 2018. Authors' names: Greg Mattingly, Valerie Arnold, Brian Yan, Ming Yu, Brigitte Robertson Institution: Midwest Research Group, CNS Healthcare, Shire Development LLC Email: greg@mattingly.com Address: Midwest Research Group, 4801 Weldon Spring Parkway, Suite 300, St. Charles, MO 63304, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: low attrition rate
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

McElroy 2014.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 14 Mean Age (years): 43.1 Male (N): 5 Female (N): 9 Mean Weight (kg): 96.4 LDX N: 11 Mean Age (years): 42.9 Male (N): 3 Female (N): 8 Mean Weight (kg): 98.7 Overall N: 25 Mean Age (years): 43 Male (N): 8 Female (N): 17 Mean Weight (kg): 97.4 Inclusion criteria: "(i) Male or female between 18 and 55 years of age, inclusive; (ii) Had bipolar I or II disorder according to the DSM‐IV‐TR; (iii) Currently experiencing a major depressive episode that was inadequately responsive to adequate mood stabilizer and/or antipsychotic therapy, with or without concomitant antidepressant therapy, received for at least 4 weeks." Exclusion criteria: "Showed clinically significant signs of suicidality; Had a DSM‐IV‐TR diagnosis of substance abuse or dependence (except nicotine dependence) within 6 months before randomization; Had a baseline Young Mania Rating Scale score of at least 8, or had a lifetime history of stimulant‐induced mania; Clinically unstable medical disease; History of a structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormality, coronary artery disease, stroke, or other serious cardiovascular problems; an ECG with significant arrhythmias or conduction abnormalities; Uncontrolled hypertension (>160/100) or tachycardia (heart rate >110); Narrow angle glaucoma; Tourette’s syndrome; Current use of a monoamine oxidase inhibitor; Women who were pregnant, lactating, or of childbearing potential and not using adequate contraceptive measures."
Interventions	Intervention Characteristics Placebo LDX
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by Shire Development LLC, a pharmaceutical company that manufactures amphetamine‐based ADHD drugs. Country: USA Setting: The study was conducted at Lindner Center of HOPE, Mason, Ohio. Authors' names: Susan L. McElroy, Brian E. Martens, Nicole Mori, Thomas J. Blom, Leah S. Casuto, John M. Hawkins, Paul E. Keck Jr. Institution: Lindner Center of HOPE, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine Email: susan.mcelroy@lindnercenter.org Address: Lindner Center of HOPE, 4075 Old Western Row Road, Mason, OH 45040, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: randomized to receive LDX or placebo in a 1:1 ratio according to computer‐generated coding
Allocation concealment (selection bias)	Low risk	Comment: research pharmacy performed the randomization, packaged the study medication, and maintained the integrity of the blinded information throughout the trial
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 22 out of 25 randomized participants completed the trial.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure measurements were provided

McElroy 2015.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 63 Mean Age (years): 38 Male (N): 14 Female (N): 49 Mean Weight (kg): 96.8 Mean Height (m): 1.68 BMI: 34.3 30mg lisdexamfetamine dimesylate N: 66 Mean Age (years): 38.4 Male (N): 9 Female (N): 57 Mean Weight (kg): 98.5 Mean Height (m): 1.67 BMI: 35 50mg lisdexamfetamine dimesylate N: 65 Mean Age (years): 39.6 Male (N): 15 Female (N): 50 Mean Weight (kg): 100.6 Mean Height (m): 1.69 BMI: 35.2 70mg lisdexamfetamine dimesylate N: 65 Mean Age (years): 38.6 Male (N): 10 Female (N): 55 Mean Weight (kg): 98.4 Mean Height (m): 1.68 BMI: 35 Overall N: 259 Mean Age (years): 38.7 Male (N): 48 Female (N): 211 Mean Weight (kg): 98.7 Mean Height (m): 1.68 BMI: 34.8 Inclusion criteria: "Adults (aged 18‐55 years) who met the DSM‐IV‐diagnostic criteria for BED were eligible. The diagnosis was confirmed using the eating disorders module (module H) of the Structural Clinical Interview for DSM‐IV‐TR Axis I Disorders and the Eating Disorder Examination Questionnaire. Additional eligibility criteria included a body mass index of at least 25 and no greater than 45 (calculated as weight in kilograms divided by height in meters squared)." Exclusion criteria: "Current bulimia nervosa, anorexia nervosa, ADHD, or another psychiatric disorder; lifetime history of bipolar disorder or psychosis or other conditions that may confound efficacy and safety assessments; a total Montgomery‐Åsberg Depression Rating Scale (MADRS) score of at least 18 at screening or baseline visits; psychological or weight‐loss interventions initiated within 3 months of screening; use of a psychostimulant within the prior 6 months; and a personal or family history of cardiovascular disease that could increase vulnerability to the sympathomimetic effects of psychostimulants. Any adult with a recent history of suspected substance abuse or a lifetime history of psychostimulant abuse and/or dependence. Prior (within the past 30 days) or current therapy with investigational compounds, sedatives, anxiolytics, antipsychotics, antidepressants, norepinephrine reuptake inhibitors, sedative‐hypnotics, benzodiazepines, antihistamines (centrally and peripherally acting), herbal preparations, over‐the‐counter medications, and weight‐reducing agents and prior (within the past 60 days) or current therapy with psychostimulants."
Interventions	Intervention Characteristics Placebo 30mg lisdexamfetamine dimesylate 50mg lisdexamfetamine dimesylate 70mg lisdexamfetamine dimesylate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: This study was supported by Shire Development, LLC, including funding to Scientific Communications & Information and Complete Healthcare Communications, Inc, for support in writing and editing the manuscript. The funding source was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Country: USA Setting: The study was conducted at 30 sites in the United States. Authors' names: Susan L. McElroy, James I. Hudson, James E. Mitchell, Denise Wilfley, M. Celeste Ferreira‐Cornwell, Joseph Gao, Jiannong Wang, Timothy Whitaker, Jeffrey Jonas, Maria Gasior Institution: Lindner Center of HOPE, Harvard Medical School, Neuropsychiatric Research Institute, Washington University, Shire Pharmaceuticals Email: susan.mcelroy@lindnercenter.org Address: Lindner Center of HOPE, 4075 Old Western Row Road, Mason, OH 45040, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Low risk	Comment: participants were randomized using an interactive voice‐response system/interactive web‐response system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: only one person's data out of 260 participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	Comment: blood pressure was reported

McElroy 2016a.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 185 Mean Age (years): 38.7 Male (N): 32 Female (N): 153 Mean Weight (kg): 93.05 57.6mg LDX N: 181 Mean Age (years): 37.1 Male (N): 22 Female (N): 159 Mean Weight (kg): 94.75 Overall N: 366 Mean Age (years): 38 Male (N): 54 Female (N): 312 Mean Weight (kg): 94 Inclusion criteria: Presence of a binge eating frequency of ⩾3 binge eating days/week for 2 consecutive weeks before baseline and a Clinical Global Impressions‐Severity score at screening and baseline of ⩾ 4; BMI ⩾18 and ⩽45. Exclusion criteria: Current anorexia nervosa or bulimia nervosa; comorbid current psychiatric disorders; psychotherapy or weight loss support for BED ⩽ 3 months before screening; psychostimulant use for fasting or dieting for BED ⩽ 6 months before screening; Montgomery–Åsberg Depression Rating Scale total score ⩾ 18 at screening; being considered a suicide risk by the investigator, having previously made a suicide attempt, or currently demonstrating active suicidal ideation; lifetime histories of psychosis, mania, hypomania, dementia, or attention‐deficit/hyperactivity disorder; histories of symptomatic cardiovascular disease, structural cardiac or heart rhythm abnormalities, cardiomyopathy, or coronary artery disease; moderate or severe hypertension, resting average sitting systolic blood pressure 4139 mm Hg, or average diastolic blood pressure 489 mm Hg at screening or baseline (mild, controlled hypertension was not exclusionary); a clinically significant electrocardiogram (ECG) at screening or baseline; lifetime amphetamine or stimulant abuse/dependence histories; recent history of substance abuse/dependence (except nicotine); and having known/ suspected intolerance or hypersensitivity to LDX or related compounds.
Interventions	Intervention Characteristics Placebo 57.6mg LDX
Outcomes	Systolic Blood Pressure Outcome type: ContinuousOutcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: ContinuousOutcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: Clinical research was funded by the sponsor, Shire Development LLC. The lead author is a consultant to and has received grant support from Shire. Shire provided funding to Complete Healthcare Communications for support in writing and editing this manuscript. The sponsor was involved in the design, collection, management, analysis, interpretation, and fact checking of the data. Country: The study was conducted across multiple sites (specific locations not provided). Setting: The study was a multicenter, randomized, double‐blind, placebo‐controlled trial involving clinical research centers. Authors' names: Susan L McElroy, James Hudson, M Celeste Ferreira‐Cornwell, Jana Radewonuk, Timothy Whitaker, Maria Gasior Institution: Lindner Center of HOPE, Harvard Medical School, Neuropsychiatric Research Institute, Washington University, Shire Pharmaceuticals Email: susan.mcelroy@lindnercenter.org Address: Lindner Center of HOPE, 4075 Old Western Row Road, Mason, OH 45040, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Judgement Comment: The study did not describe the sequence generation process and it is thus unknown. The study therefore carries an unknown risk of bias.
Allocation concealment (selection bias)	Low risk	Judgement Comment: Randomization schedule was assigned by an interactive web response system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Judgement Comment: Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement Comment: Given that this study is double‐blind, it is unlikely that blood pressure measurements are biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Judgement Comment: In Study 1, 82% of randomized subjects completed the double‐blind treatment. In Study 2, 76% of randomized subjects completed the double‐blind treatment.
Selective reporting (reporting bias)	Unclear risk	Judgement Comment: Blood pressure measurements changes from baseline at Week 12 (or end treatment) were provided. However, blood pressure measurements at the follow up visits are not provided. Due to the lack of complete information and data, this study has an unknown risk of reporting bias.

McElroy 2016b.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 187 Mean Age (years): 37.6 Male (N): 24 Female (N): 163 Mean Weight (kg): 92.7 56.9mg LDX N: 192 Mean Age (years): 38.5 Male (N): 27 Female (N): 165 Mean Weight (kg): 94.3 Overall N: 379 Mean Age (years): 38 Male (N): 51 Female (N): 328 Mean Weight (kg): 93.5 Inclusion criteria: "Presence of a binge‐eating frequency of ⩾3 binge eating days/week for 2 consecutive weeks before baseline and a Clinical Global Impressions‐Severity score at screening and baseline of ⩾ 4; BMI ⩾18 and ⩽45." Exclusion criteria: "Current anorexia nervosa or bulimia nervosa; comorbid current psychiatric disorders; psychotherapy or weight loss support for BED ⩽ 3 months before screening; psychostimulant use for fasting or dieting for BED ⩽ 6 months before screening; Montgomery–Åsberg Depression Rating Scale total score ⩾ 18 at screening; being considered a suicide risk by the investigator, having previously made a suicide attempt, or currently demonstrating active suicidal ideation; lifetime histories of psychosis, mania, hypomania, dementia, or attention‐deficit/hyperactivity disorder; histories of symptomatic cardiovascular disease, structural cardiac or heart rhythm abnormalities, cardiomyopathy, or coronary artery disease; moderate or severe hypertension, resting average sitting systolic blood pressure 4139 mm Hg, or average diastolic blood pressure 489 mm Hg at screening or baseline (mild, controlled hypertension was not exclusionary); a clinically significant electrocardiogram (ECG) at screening or baseline; lifetime amphetamine or stimulant abuse/dependence histories; recent history of substance abuse/dependence (except nicotine); and having known/ suspected intolerance or hypersensitivity to LDX or related compounds."
Interventions	Intervention Characteristics Placebo 56.9mg LDX
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: "Clinical research was funded by the sponsor, Shire Development LLC. The lead author is a consultant to and has received grant support from Shire. Shire provided funding to Complete Healthcare Communications for support in writing and editing this manuscript. The sponsor was involved in the design, collection, management, analysis, interpretation, and fact checking of the data." Country: The study was conducted across multiple sites (specific locations not provided). Setting: The study was a multicenter, randomized, double‐blind, placebo‐controlled trial involving clinical research centers. Authors' names: Susan L McElroy, James Hudson, M Celeste Ferreira‐Cornwell, Jana Radewonuk, Timothy Whitaker, Maria Gasior Institution: Lindner Center of HOPE, Harvard Medical School, Neuropsychiatric Research Institute, Washington University, Shire Pharmaceuticals Email: susan.mcelroy@lindnercenter.org Address: Lindner Center of HOPE, 4075 Old Western Row Road, Mason, OH 45040, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Low risk	Comment: randomization schedule was assigned by an interactive web response system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "In Study 1, 82% of randomized subjects completed the double‐blind treatment. In Study 2, 76% of randomized subjects completed the double‐blind treatment."
Selective reporting (reporting bias)	Unclear risk	Comment: blood pressure measurements changes from baseline at Week 12 (or end of treatment) were provided. However, blood pressure measurements at the follow‐up visits are not provided. Due to the lack of complete data and information, this study has an unknown risk of reporting bias.

Medori 2008.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 96 Mean Age (years): 34.5 Male (N): 59 Female (N): 37 18mg Prolonged‐Release Methylphenidate N: 101 Mean Age (years): 34.2 Male (N): 58 Female (N): 43 36mg Prolonged‐Release Methylphenidate N: 102 Mean Age (years): 33.8 Male (N): 46 Female (N): 56 72mg Prolonged‐Release Methylphenidate N: 102 Mean Age (years): 33.6 Male (N): 55 Female (N): 47 Overall N: 401 Mean Age (years): 34.2 Male (N): 218 Female (N): 183 Inclusion criteria: "Adult men and women with a diagnosis of ADHD according to the criteria of DSM‐IV; age 18 to 65 years; chronic course of ADHD symptomatology from childhood to adulthood with some symptoms present before age 7 years, as determined by investigators following the CAADID interview; and CAARS total score of ≥ 24 at screening." Exclusion criteria: "History of poor response or intolerance to methylphenidate; Diagnosed with any current clinically unstable psychiatric condition (e.g., acute mood disorder, bipolar disorder, acute obsessive‐compulsive disorder) or with substance use disorder (abuse/dependence) according to DSM‐IV criteria within the last 6 months; Family history of schizophrenia or affective psychosis; Serious illnesses (e.g., hepatic or renal insufficiency or significant cardiac, gastrointestinal, psychiatric, or metabolic disturbances); Hyperthyroidism, myocardial infarction, or stroke within 6 months of screening; History of seizures, glaucoma, or uncontrolled hypertension."
Interventions	Intervention Characteristics Placebo 18mg Prolonged‐Release Methylphenidate 36mg Prolonged‐Release Methylphenidate 72mg Prolonged‐Release Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by Janssen Pharmaceuticals, a Belgian pharmaceutical company. Country: The study was conducted in 13 European countries. Setting: The study was conducted at 51 investigator sites across Europe. Authors' names: Rossella Medori, J. Antoni Ramos‐Quiroga, Miguel Casas, J.J.S. Kooij, Asko Niemelä, Götz‐Erik Trott, Emma Lee, Jan K. Buitelaar Institution: Janssen‐Cilag EMEA, Universitat Autònoma de Barcelona, Oulu University Hospital, University Medical Center St Radboud, Karakter Child and Adolescent Psychiatry University Center Email: rmedori@jacde.jnj.com Address: Janssen‐Cilag EMEA, Reiffeisenstrasse 8, 41470 Neuss, Germany​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: Computer‐generated randomization
Allocation concealment (selection bias)	Unclear risk	Comment: The method of concealment was not described in the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: Given that this study is double‐blind, it is unlikely that blood pressure measurements are biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 365 (91%) of randomized patients completed the 5‐week double‐blind study period.
Selective reporting (reporting bias)	Low risk	Comment: Blood pressure is reported

Mitchell 2021.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 44 Mean Age (years): 38.2 BMI: 24.8 Male (N): 12 Female (N): 32 80‐180mg MDMA N: 46 Mean Age (years): 43.5 BMI: 26.0 Male (N): 19 Female (N): 27 Overall N: 90 Mean Age (years): 40.9 BMI: 25.4 Male (N): 31 Female (N): 59 Inclusion criteria: "The criteria for inclusion consisted of meeting the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM‐5) criteria for current PTSD with a symptom duration of ≥6 months at screening (as assessed with the Mini International Neuropsychiatric Interview (MINI) for DSM‐5), and a CAPS‐5 total severity score of ≥35 at baseline." Exclusion criteria: "Exclusion criteria consisted of primary psychotic disorder, bipolar I disorder, dissociative identity disorder, eating disorders with active purging, major depressive disorder with psychotic features, personality disorders, current alcohol and substance use disorders, pregnancy or lactation, and any medical condition that could make receiving a sympathomimetic drug harmful due to increased blood pressure and heart rate, including uncontrolled hypertension, history of arrhythmia, or marked baseline prolongation of QT and/or QTc interval. Participants with other mild, stable, chronic medical problems (for example, type 2 diabetes mellitus or well‐controlled hypertension) were eligible for enrollment if the site physician, clinical investigator and medical monitor agreed that the condition would not increase the risk associated with MDMA administration."
Interventions	Intervention Characteristics Placebo 80‐180mg MDMA
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: This study was not funded by a private pharmaceutical company. The study was funded by the Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)(3) non‐profit research and educational organization. Country: The study was conducted across multiple sites in the USA, Canada, and Israel. Setting: The study was conducted at 15 sites, including institutional and private clinics. Authors' names: Jennifer M. Mitchell, Michael Bogenschutz, Alia Lilienstein, Charlotte Harrison, Sarah Kleiman, Kelly Parker‐Guilbert, Marcela Ot’alora G., Wael Garas, Casey Paleos, Ingmar Gorman, Christopher Nicholas, Michael Mithoefer, Shannon Carlin, Bruce Poulter, Ann Mithoefer, Sylvestre Quevedo, Gregory Wells, Sukhpreet S. Klaire, Bessel van der Kolk, Keren Tzarfaty, Revital Amiaz, Ray Worthy, Scott Shannon, Joshua D. Woolley, Cole Marta, Yevgeniy Gelfand, Emma Hapke, Simon Amar, Yair Wallach, Randall Brown, Scott Hamilton, Julie B. Wang, Allison Coker, Rebecca Matthews, Alberdina de Boer, Berra Yazar‐Klosinski, Amy Emerson, Rick Doblin Institution: University of California San Francisco, New York University Grossman School of Medicine, MAPS Public Benefit Corporation, University of Wisconsin School of Medicine and Public Health, British Columbia Centre on Substance Use, Chaim Sheba Medical Center, and others Email: jennifer.mitchell@ucsf.edu Address: Department of Neurology, University of California San Francisco, San Francisco, CA, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was stratified by site and occurred following enrollment confirmation (after preparatory visits). Randomization was managed via an interactive web randomization system— ITClinical IWRS, version 11.0.1 (ITClinical, LDA)—based on a centralized randomization schedule developed by an independent third‐party vendor to maintain blinding
Allocation concealment (selection bias)	Low risk	Participants, site staff and the sponsor were blinded to participant group assignment until after the database was locked.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	This is a double‐blind study wherein study outcomes "were assessed by a centralized pool of blinded, independent diagnostic assessors"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Given that this study was double‐blind and blood pressure was assessed “by a centralized pool of blinded, independent diagnostic assessors”, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Out of 91 enrolled participants, 79 participants completed the third experimental session (~87%).
Selective reporting (reporting bias)	Low risk	Both SBP and DBP values were reported

Mooney 2015.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 21 Mean Age (years): 46.4 Male (N): 17 Female (N): 4 70mg LDX N: 22 Mean Age (years): 45.1 Male (N): 18 Female (N): 4 Overall N: 43 Mean Age (years): 45.7 Male (N): 35 Female (N): 8 Inclusion criteria: "(a) treatment‐seeking; (b) between 18 and 65 years of age; (c)in generally good psychiatric and medical health with a normal electrocardiogram and no history of heart disease; and (d) cocaine‐dependent at time of intake by Diagnostic and Statistical Manual of Mental Disorders‐IV (DSM‐IV) criteria." Exclusion criteria: "(a) DSM‐IV diagnoses for current psychotic disorders, mood disorders (except substance‐induced depression), anxiety disorders, ADHD, and other current substance dependence (except marijuana and nicotine dependence); (b) alcohol dependence (with or without physiological dependence); (c) current use of any prescription medications contraindicated by dextroamphetamine;(d) currently pregnant or nursing; (e) current elevation of liver enzyme levels above twice normal limits; (f) existing cardiovascular disease as determined by physician, and ECG evaluation; (g) history of significant acute or chronic physical illness precluding participation; and (h) history of hyperthyroidism, glaucoma, or seizures"
Interventions	Intervention Characteristics Placebo 70mg LDX
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The study was supported by funding from the National Institute on Drug Abuse (NIDA) and NIH grants. Country: USA Setting: The study was conducted at the Ambulatory Research Center, a component of the Department of Psychiatry at the University of Minnesota. Authors' names: Marc E. Mooney, David V. Herin, Sheila Specker, David Babb, Frances R. Levin, John Grabowski Institution: Department of Psychiatry, University of Minnesota, New York State Psychiatric Institute & Columbia University Email: moon0078@umn.edu Address: Department of Psychiatry, University of Minnesota, F282/2A West, 2450 Riverside Avenue, Minneapolis, MN 55454‐1495, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 27/43 randomized participants completed the trial. That is a completion rate of less than 64%. This study thus has a high risk of attrition bias.
Selective reporting (reporting bias)	High risk	Comment: baseline blood pressure is not reported and the change in blood pressure is not reported. There are blood pressure measurements, but it is unclear when exactly during the trial this measurement was taken. Due to the lack of comprehensive information and data, this study has a high risk of attrition bias.

Newcorn 2008.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 74 Mean Age (years): 10.1 Male (N): 55 Female (N): 19 Osmotically Released Methylphenidate N: 220 Mean Age (years): 10.2 Male (N): 156 Female (N): 64 Overall N: 294 Mean Age (years): 10.2 Male (N): 211 Female (N): 83 Inclusion criteria: "Patients were children and adolescents, ages 6 to 16 years, who met the DSM‐IV criteria for ADHD, any subtype, as determined by clinical history and confirmed by a semistructured interview, the Schedule for Affective Disorders and Schizophrenia for School Aged Children—Present and Lifetime Version (KSADS‐PL); Symptom severity at entry was required to be at least 1.5 standard deviations above the U.S. age and gender norms as assessed by the ADHD Rating Scale‐IV." Exclusion criteria: "Seizures, bipolar disorder, a psychotic illness, or a pervasive developmental disorder or who were taking concomitant psychoactive medications; Anxiety and tic disorders; Treated previously with an adequate trial of methylphenidate or amphetamine and either did not experience at least some improvement in ADHD signs and symptoms (nonresponders) or had intolerable adverse events."
Interventions	Intervention Characteristics Placebo Osmotically Released Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by Eli Lilly and Company. The first author has financial relationships with both Shire Pharmaceutical and Eli Lilly. Country: USA Setting: The study was conducted at 20 sites in the United States. Comments: 2 participants in the methylphenidate arm were discontinued due to "Sponsor's decision". Authors' names: Jeffrey H. Newcorn, Christopher J. Kratochvil, Albert J. Allen, Charles D. Casat, Dustin D. Ruff, Rodney J. Moore, David Michelson Institution: Department of Psychiatry, Mount Sinai Medical Center, University of Nebraska Medical Center, Lilly Research Laboratories, Behavioral Health Center Email: Jeffrey.Newcorn@mssm.edu Address: Department of Psychiatry, Mount Sinai Medical Center, Box 1230, One Gustave L. Levy Place, New York, NY 10029, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study did not describe the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment was not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind (wherein drug and placebo were both “overencapsulated for blinding purposes”), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 178 out of 516 randomized participants completed the trial, which is a 34% completion rate. Due to the low completion rate and high attrition rate, the study has a high risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: change in blood pressure was reported

Newcorn 2017a.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 91 Mean Age (years): 14.8 Male (N): 61 Female (N): 30 Mean Weight (kg): 61.05 47.3mg LDX or OROS‐MPH N: 368 Mean Age (years): 14.7 Male (N): 244 Female (N): 124 Mean Weight (kg): 62 Overall N: 459 Mean Age (years): 14.7 Male (N): 305 Female (N): 154 Mean Weight (kg): 61.8 Inclusion criteria: "Weigh > 79.5 lb; DSM‐IV‐TR primary ADHD diagnosis; Baseline ADHD‐RS‐IV total score ≥ 28; Screening and baseline blood pressure values that did not exceed the 90th percentile for age, sex, and height based on CDC guidelines; Not be completely satisfied with their current ADHD therapy, as judged by the investigator at the baseline assessment." Exclusion criteria: "Current comorbid Axis I or II psychiatric diagnosis (except oppositional defiant disorder, which was allowed), with significant symptoms requiring treatment or contraindicating lisdexamfetamine or OROS‐MPH treatment; Considered a suicide risk by the investigator, had previously made a suicide attempt, or were currently demonstrating active suicidal ideation; Underweight or overweight based on CDC body mass index standards for age and sex; Medical or psychiatric condition that could confound safety assessments or increase participant risk; Personal or family cardiovascular history or a clinically significant ECG finding; History of suspected substance abuse or dependence (excluding nicotine) or a lifetime history of amphetamine, cocaine, or stimulant abuse and/or dependence; Concomitant use of medications with central nervous system effects that could potentially affect study performance; Documented allergy or hypersensitivity to amphetamine or methylphenidate; Prior failed response to methylphenidate or amphetamine therapy; Participation in another clinical study within 30 days before screening."
Interventions	Intervention Characteristics Placebo 47.3mg LDX or OROS‐MPH
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The clinical research was funded by Shire Development LLC (Lexington, MA, USA). Country: The study was conducted across multiple sites in the United States and Europe. Setting: The study was conducted at 70 U.S. clinical sites and 77 clinical sites across the U.S., Canada, and Europe. Authors' names: Jeffrey H. Newcorn, Peter Nagy, Ann C. Childress, Glen Frick, Brian Yan, Steven Pliszka Institution: Icahn School of Medicine at Mount Sinai, Vadaskert Child and Adolescent Psychiatry Hospital and Outpatient Clinic, Center for Psychiatry and Behavioral Medicine, Shire Development LLC, University of Texas Health Science Center Email: jeffrey.newcorn@mssm.edu Address: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, Box 1230, New York, NY 10029‐6574, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: participants were randomized (2:2:1) using an interactive web‐response system (IWRS) to once‐daily lisdexamfetamine, OROS‐ MPH, or placebo
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind (wherein both participants and investigators were blinded), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: number of participants who completed the flexible dose study: (68+155+157)/464 = 82%. Number of participants who completed the forced dose study: (97+181+186)/549 = 84%
Selective reporting (reporting bias)	Low risk	Comment: blood pressure change from baseline at last on‐treatment assessment is reported

Newcorn 2017b.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 91 Mean Age (years): 14.8 Male (N): 61 Female (N): 30 Mean Weight (kg): 61.05 47.3mg LDX or OROS‐MPH N: 368 Mean Age (years): 14.7 Male (N): 244 Female (N): 124 Mean Weight (kg): 62 Overall N: 459 Mean Age (years): 14.7 Male (N): 305 Female (N): 154 Mean Weight (kg): 61.8 Inclusion criteria: "Weigh > 79.5 lb; DSM‐IV‐TR primary ADHD diagnosis; Baseline ADHD‐RS‐IV total score ≥ 28; Screening and baseline blood pressure values that did not exceed the 90th percentile for age, sex, and height based on CDC guidelines; Not be completely satisfied with their current ADHD therapy, as judged by the investigator at the baseline assessment." Exclusion criteria: "Current comorbid Axis I or II psychiatric diagnosis (except oppositional defiant disorder, which was allowed), with significant symptoms requiring treatment or contraindicating lisdexamfetamine or OROS‐MPH treatment; Considered a suicide risk by the investigator, had previously made a suicide attempt, or were currently demonstrating active suicidal ideation; Underweight or overweight based on CDC body mass index standards for age and sex; Medical or psychiatric condition that could confound safety assessments or increase participant risk; Personal or family cardiovascular history or a clinically significant ECG finding; History of suspected substance abuse or dependence (excluding nicotine) or a lifetime history of amphetamine, cocaine, or stimulant abuse and/or dependence; Concomitant use of medications with central nervous system effects that could potentially affect study performance; Documented allergy or hypersensitivity to amphetamine or methylphenidate; Prior failed response to methylphenidate or amphetamine therapy; Participation in another clinical study within 30 days before screening."
Interventions	Intervention Characteristics Placebo 47.3mg LDX or OROS‐MPH
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The clinical research was funded by Shire Development LLC (Lexington, MA, USA). Country: The study was conducted across multiple sites in the United States and Europe. Setting: The study was conducted at 70 U.S. clinical sites and 77 clinical sites across the U.S., Canada, and Europe. Authors' names: Jeffrey H. Newcorn, Peter Nagy, Ann C. Childress, Glen Frick, Brian Yan, Steven Pliszka Institution: Icahn School of Medicine at Mount Sinai, Vadaskert Child and Adolescent Psychiatry Hospital and Outpatient Clinic, Center for Psychiatry and Behavioral Medicine, Shire Development LLC, University of Texas Health Science Center Email: jeffrey.newcorn@mssm.edu Address: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, Box 1230, New York, NY 10029‐6574, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: participants were randomized (2:2:1) using an interactive web‐response system (IWRS) to once‐daily lisdexamfetamine, OROS‐ MPH, or placebo
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind (wherein both participants and investigators were blinded), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: number of participants who completed the flexible dose study: (68+155+157)/464 = 82%. Number of participants who completed the forced dose study: (97+181+186)/549 = 84%
Selective reporting (reporting bias)	Low risk	Comment: blood pressure change from baseline at last on‐treatment assessment is reported

Nordin 2013.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Overall N: 12 Mean Age (years): 25 Males (N): 12 Mean Weight (kg): 78 Inclusion criteria: No information Exclusion criteria: No information
Interventions	Intervention Characteristics 20mg dextroamphetamine Placebo
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The study was sponsored by AstraZeneca R&D Neuroscience. Country: Sweden Setting: The study was conducted at the Department of Diagnostic Medical Physics, Karolinska University Hospital, Stockholm, Sweden, and through a collaboration with AstraZeneca R&D Neuroscience. Authors' names: Love Engström Nordin, Tie‐Qiang Li, Jacob Brogren, Patrik Johansson, Niclas Sjögren, Kristin Hannesdottir, Charlotta Björk, Märta Segerdahl, Danny J.J. Wang, Per Julin Institution: Karolinska University Hospital, Karolinska Institutet, AstraZeneca R&D Neuroscience, University of California Los Angeles (UCLA) Email: love.engstrom‐nordin@karolinska.se Address: Department of Diagnostic Medical Physics, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: participants were randomly assigned.
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: blood pressure measurements were taken for each participant.
Selective reporting (reporting bias)	Low risk	Comment: all blood pressure measurements illustrated.

Paterson 1999.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 21 Mean Weight (kg): 78.8 Mean Daily Dose 22.9mg dextroamphetamine N: 24 Mean Weight (kg): 74.6 Overall N: 45 Mean Age (years): 35.5 Males (N): 27 Females (N): 18 Mean Weight (kg): Inclusion criteria: "Presence of at least four inattentive and/or five hyperactive symptoms during the previous 6 months." Exclusion criteria: "Insufficient ADHD score, or comorbidity for other major psychiatric disorders, including a history of current substance abuse; Organic disorders that would contraindicate the use of dexamphetamine; Illicit substance abuse."
Interventions	Intervention Characteristics Placebo Mean Daily Dose 22.9mg dextroamphetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The study was supported by a research grant from the Health Department of Western Australia and by Sigma Pharmaceuticals, which provided the dexamphetamine and placebo tablets. Country: Australia Setting: The study was conducted in a private practice setting with two psychiatrists in Western Australia. Authors' names: Roger Paterson, Charles Douglas, Joachim Hallmayer, Michael Hagan, Zyron Krupenia Institution: Hollywood Specialist Centre, Health Department of Western Australia, University of Western Australia, Graylands Hospital Centre for Clinical Research in Neuropsychiatry Email: 37reception@gmail.com Address: Suite 37, Hollywood Specialist Centre, 95 Monash Avenue, Nedlands, Western Australia 6009, Australia​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: sequence generation process is not described
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 45/51 people analyzed = 88%
Selective reporting (reporting bias)	Low risk	Comment: mean systolic and diastolic blood pressure at entry and 6 weeks, by treatment group, is reported

Patkar 2006.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 30 Mean Daily Dose 34.2mg Extended‐release Methylphenidate N: 30 Overall N: 60 Mean Age (years): 48.5 Inclusion criteria: men and women aged 18 to 65 years with treatment‐resistant depression (TRD) Exclusion criteria: "any Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition psychotic disorder; serious suicide risk; substance abuse in the previous 12 months; history of hypersensitivity to methylphenidate; treatment with antipsychotics, monoamine oxidase inhibitors, or anticonvulsants in the previous 4 weeks; patients with unstable medical disorders, history of Tourette disorder; and pregnancy."
Interventions	Intervention Characteristics Placebo Mean Daily Dose 34.2mg Extended‐release Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The study was supported by an investigator‐initiated grant through McNeil Specialty and Consumer Pharmaceuticals. Country: USA Setting: The study was conducted at two sites in the United States. Authors' names: Ashwin A. Patkar, Prakash S. Masand, Chi‐Un Pae, Kathleen Peindl, Christa Hooper‐Wood, Paolo Mannelli, Patrick Ciccone Institution: Duke University Medical Center, Kangnam St. Mary’s Hospital (Catholic University of Korea), McNeil Specialty and Consumer Pharmaceuticals Email: ashwin.patkar@duke.edu Address: Duke University Medical Center, Suite 700, 4323 Ben Franklin Blvd, Durham, NC 27704, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: sequence generation process is not described
Allocation concealment (selection bias)	Low risk	Comment: method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 83% completed the study
Selective reporting (reporting bias)	Low risk	Comment: blood pressure was reported

Platz 2005.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 13 10mg dextroamphetamine N: 18 Overall N: 31 Inclusion criteria: "(a.) mild arm paresis and met the treatment criteria for the Arm Ability training, i.e. Motricity Index [3] arm score < 100, shoulder abduction and elbow flexion > MRC 3, thumb‐index opposition > MRC 2, selective finger movements and precision grip persevered, no more than mild hypesthesia, no position sense deficit; (b.) acute stroke occurred between 3 weeks and 6 months ago." Exclusion criteria: "Major cognitive deficit that prevented adequate participation in study (e.g. aphasia, apraxia, neglect, concentration and memory deficits); Peripheral neurological deficits that affected arm motor control; Pregnancy or breast feeding; Severe hypertension not controlled by medication (systolic blood pressure ≥ 170 mm HG, diastolic blood pressure ≥ 110 mmHG), tachycardia (≥ 100 bpm); Myocardial infarct or angina pectoris within the last 4 weeks; Decompensated cardiac insufficiency; Current medication with any MAO‐inhibitor, alpha‐adrenergic agonist or antagonist; Intracerebral haemorrhage within the last 3 months; Untreated hyperthyroidism; Phaeochromozytoma; Glaucoma; Bladder failure (retention); Psychosis; Epilepsy or history of epileptic seizure and epileptic discharges in EEG."
Interventions	Intervention Characteristics Placebo 10mg dextroamphetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The project was supported by the BMBF (German Federal Minister for Education and Research). Country: Germany Setting: The study was conducted at three departments of neurological rehabilitation: Charité – Universitätsmedizin Berlin, Neurologisches Zentrum (Segeberger Kliniken, Bad Segeberg), and Neurologisches Rehabilitationszentrum (NRZ) in Magdeburg, Germany. Authors' names: T. Platz, I.‐H. Kim, U. Engel, C. Pinkowski, C. Eickhof, M. Kutzner Institution: Charité – Universitätsmedizin Berlin, Neurologisches Zentrum Segeberger Kliniken, Neurologisches Rehabilitationszentrum Magdeburg Email: tplatz@zedat.fu‐berlin.de Address: Klinik Berlin, Kladower Damm 223, 14089 Berlin, Germany
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: computerised random‐number generator
Allocation concealment (selection bias)	Low risk	Comment: study pharmacy determined placebo and treatment group on the list and stored the list outside the study centres
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind and measures were “taken by a (central) rater who was blinded for the type of medication”, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 26/31 randomized participants completed the study
Selective reporting (reporting bias)	Low risk	Comment: blood pressure is reported

Press 2021.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 8 Mean Age (years): 75.5 Male (N): 6 Female (N): 2 30mg Methylphenidate N: 7 Mean Age (years): 76.9 Male (N): 4 Female (N): 3 Overall N: 15 Mean Age (years): 76.2 Male (N): 10 Female (N): 5 Inclusion criteria: male and female participants aged 65 years and older. Exclusion criteria: "Active or unstable medical condition (such as heart failure, symptomatic ischemic heart disease or a recent myocardial infarction, cardiac arrhythmia, advanced renal failure, poorly controlled hypertension with measurements above 160/100 mmHg, hepatic cirrhosis, glaucoma, hyperthyroidism, anxiety neurosis, schizophrenia, or current neuroleptic treatment); a diagnosis of dementia, those with a family history or diagnosis of Tourette syndrome, a diagnosis of seizure disorder, or the presence of motor tics.; subjects who had taken monoamine oxidase inhibitors in the previous 14 days, or one of the following compounds during the last month: bupropion, carbamazepine, phenobarbital, primidone, phenytoin, tricyclic antidepressants, selective serotonin reuptake inhibitors, memantine, acetylcholine esterase inhibitors, loflupane, dicumarol, tyrosine, warfarin; a known allergy to methylphenidate; visual or hearing impairment that would not allow for adequate cognitive evaluation."
Interventions	Intervention Characteristics Placebo 30mg Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: This study was supported by a research grant from the Israeli Ministry of Health. Country: Israel Setting: The study was conducted at the Department of Geriatrics, Soroka Medical Center, and at the Unit for Community Geriatrics, Ben‐Gurion University of the Negev, Beer‐Sheva, Israel. Authors' names: Yan Press, Boris Punchik, Ella Kagan, Alexander Berzak, Tamar Freud, Tzvi Dwolatzky Institution: Ben‐Gurion University of the Negev, Soroka Medical Center, Clalit Health Services, Rambam Health Care Campus Email: yanp@bgu.ac.il Address: Department of Geriatrics, Soroka Medical Center, Beer‐Sheva, Israel
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was completed using a random number generator
Allocation concealment (selection bias)	Unclear risk	The method of allocation concealment is not specified.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	This is a double‐blind study wherein “the researchers were blinded to the allocation between groups until the study was completed. The study drug or placebo were dispensed as identical capsules by the pharmacy in the clinic where the study was performed”.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Given that this study was double‐blind (wherein “researchers were blinded to the allocation between groups until the study was completed”), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Out of 17 participants enrolled in the study, “the final statistical analysis included 15 subjects, seven in the active MPH group and eight in the placebo group”.
Selective reporting (reporting bias)	High risk	There is a possibility of selective outcome reporting for blood pressure measurement. Methylphenidate was given for three days, with increasing doses each day. However, blood pressure comparisons were only made as same‐day comparison (e.g. before and after the first dose) and not across days, nor was there reporting of the overall change in blood pressure. It is stated that “None of the changes in blood pressure over time and between groups reached statistical significance” referencing Table 4, but this table does not show the overall change in blood pressure nor the statistics behind this.

Retz 2012.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 78 Mean Age (years): 38.2 Male (N): 44 Female (N): 34 Mean Weight (kg): 82.9 Mean Daily Dose 66mg MPH ER N: 84 Mean Age (years): 36.6 Male (N): 32 Female (N): 52 Mean Weight (kg): 73.8 Overall N: 162 Mean Age (years): 37.4 Male (N): 76 Female (N): 86 Mean Weight (kg): 78.2 Inclusion criteria: ADHD; 18 or older Exclusion criteria: "WURS‐k scores < 30; Low intelligence (IQ 85), dementia, schizophrenia, bipolar disorder, current major depression, acute anxiety disorders and other unstable psychiatric conditions or serious medical illness; Drug or alcohol dependence during the 6 months before screening; Pregnant or nursing women; Body Mass Index 20 or body weight 130 kg; Treated with any psychopharmacological drug in addition to study medication."
Interventions	Intervention Characteristics Placebo Mean Daily Dose 66mg MPH ER
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The trial was funded by Medice, Germany, which is a corporate pharmaceutical company. Medice's ADHD drugs for both adults and the pediatric population constitute a significant portion of their product line, which may pose a conflict of interest. Country: Germany Setting: The study was conducted across 10 sites in Germany. Authors' names: Wolfgang Retz, Michael Rösler, Claudia Ose, André Scherag, Barbara Alm, Alexandra Philipsen, Roland Fischer, Richard Ammer Institution: Saarland University Hospital, University of Essen, Central Institute of Mental Health Mannheim, University Medical Center Freiburg, Medice GmbH & Co. KG Email: wolfgang.retz@uks.eu Address: Neurocentre, Saarland University Hospital, Bdg. 90.3, D‐66421 Homburg/Saar, Germany​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: "Randomisation was performed by Medice’s Galenic Department which included the generation of the randomisation list and the preparation of emergency envelopes". The study "used block randomisation with a block size of 4. The block size was not mentioned in the investigational plan or the consent given to patients."
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: study used a double‐blind design, so there is a low risk of performance bias due to blinding practices.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: only 7/162 participants discontinued. Given the low attrition rate, there is little incomplete outcome data which could lead to an attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure measurements reported.

Richards 2017.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 78 Mean Age (years): 43.7 Male (N): 25 Female (N): 53 Mean Weight (kg): 82.1 Mean BMI: 28.2 10mg LDX N: 77 Mean Age (years): 39.1 Male (N): 24 Female (N): 53 Mean Weight (kg): 83.5 Mean BMI: 29.1 30mg LDX N: 76 Mean Age (years): 43.4 Male (N): 24 Female (N): 52 Mean Weight (kg): 80.9 Mean BMI: 28.3 50mg LDX N: 78 Mean Age (years): 43.8 Male (N): 25 Female (N): 53 Mean Weight (kg): 81.8 Mean BMI: 29 70mg LDX N: 80 Mean Age (years): 41.5 Male (N): 27 Female (N): 53 Mean Weight (kg): 81.9 Mean BMI: 28.7 Overall N: 389 Mean Age (years): 42.3 Male (N): 125 Female (N): 264 Mean Weight (kg): 82.0 Mean BMI: 28.7 Inclusion criteria: "Men or nonpregnant/non‐nursing women (18–65 years) with a primary diagnosis of nonpsychotic MDD, as defined by the Structured Clinical Interview for DSM Disorders–Clinical Trial version (SCID‐CT), that lasted for at least eight weeks before screening and who had a lead‐in baseline MADRS total score ⩾24; Able to provide written informed consent before completing any study‐related procedures and willing and able to fully comply with study procedures." Exclusion criteria: "Nonresponse (⩾6 weeks of treatment at the maximum tolerated adult dose approved for MDD) to the current MDD episode with two or more antidepressant monotherapies or to an approved augmentation treatment; Lifetime history of treatment‐resistant depression; Hospitalization within the last 12 months for the current MDD episode; Received electroshock therapy for the current depressive episode within three months of lead‐in baseline; Current comorbid psychiatric disorder either controlled with prohibited medications or uncontrolled and associated with significant symptoms; Any symptom that contraindicated LDX treatment or could confound clinical assessments at screening; Current or lifetime history of ADHD; First‐degree relative with bipolar I disorder; Chronic or acute illness or unstable medical condition that could confound safety assessments or lead to increased risk to the participant or difficulty complying with study procedures; Suicide risk; History of symptomatic cardiovascular disease, advanced atherosclerosis, a cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or any condition affecting cardiac performance; History of moderate to severe hypertension; Clinically significant ECG or laboratory abnormality at screening; family history of sudden cardiac death or ventricular arrhythmia; History of seizures, tic disorders, or a current diagnosis and/or family history of Tourette syndrome; History (⩽6 months) of suspected abuse or dependence disorder (excluding nicotine); Lifetime history of amphetamine, cocaine, or other stimulant abuse and/or dependence; Had used within 30 days of screening any other medication (including ADHD medication and over‐the‐counter herbal or homoeopathic preparations) with central nervous system effects that could affect the condition being studied or the action, absorption, or disposition of LDX or the clinical laboratory assessments; Known or suspected intolerance, hypersensitivity, or contraindication to LDX or the assigned antidepressant."
Interventions	Intervention Characteristics Placebo 10mg LDX 30mg LDX 50mg LDX 70mg LDX
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: Shire Development LLC (Lexington, MA, USA) provided funding to Complete Healthcare Communications, LLC for support in writing and editing this manuscript. Country: The study was conducted across 76 sites in five countries (USA, Argentina, Chile, Australia, and the UK). Setting: The study was a randomized, placebo‐controlled, double‐blind, dose‐ranging trial conducted at clinical research centers across the listed countries. Comment: Shire Pharmaceuticals is a biotechnology company that manufactures a variety of drugs with amphetamines, notably their ADDERALL XR® tablets. Shire Pharmaceuticals LLC paid a fine of $56.5 million in 2014 due to violating the False Claims Act by promoting its drugs for the treatment of ADHD. Authors' names: Cynthia Richards, Dan V. Iosifescu, Rajnish Mago, Elias Sarkis, James Reynolds, Brooke Geibel, Matthew Dauphin Institution: Shire Development LLC, New York University School of Medicine, Thomas Jefferson University, Sarkis Family Psychiatry Email: jmr19438@gmail.com Address: Shire Development LLC, 1 Waukegan Road, Chicago, IL 60064, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: sequence generation process is not described.
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment is not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: trial used a double‐blind study design, wherein participants and personnel should both be blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: low attrition rate in this trial so there is a low risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure measured and reported in this study.

Roache 2000.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 29 Mean Age (years): 35.5 Male (N): 83 Female (N): 17 45mg Methylphenidate N: 28 Mean Age (years): 36 Male (N): 75 Female (N): 25 Overall N: 57 Mean Age (years): 35.7 Male (N): 158 Female (N): 42 Inclusion criteria: None mentioned Exclusion criteria: None mentioned
Interventions	Intervention Characteristics Placebo 45mg Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by NIDA Grant DA‐9262 (to Dr. Grabowski). The National Institute on Drug Abuse is a government organization, and there does not appear to be any pharmaceutical or industry sponsorship for this study. Country: USA Setting: The study was conducted at the Substance Abuse‐Medications Development Research Center, Department of Psychiatry & Behavioral Sciences, University of Texas Houston Health Science Center, Houston, Texas. Authors' names: John D. Roache, John Grabowski, Joy M. Schmitz, Daniel L. Creson, Howard M. Rhoades Institution: University of Texas Houston Health Science Center Email: roache@uthscsa.edu Address: Department of Psychiatry, University of Texas‐Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229‐3900
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Twenty‐nine subjects were randomly assigned to receive placebo and 28 received methylphenidate". However, the method of random sequence generation is not specified.
Allocation concealment (selection bias)	Unclear risk	Comment: method for allocation concealment is not specified.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: main study was conducted under "double‐blind conditions".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: no attrition/withdrawal.
Selective reporting (reporting bias)	Low risk	Comment: change in blood pressure was reported

Rosler 2009.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 118 Mean Age (years): 33.8 Male (N): 58 Female (N): 60 Mean Weight (kg): 77.3 Mean Daily Dose 41.2mg MPH ER N: 241 Mean Age (years): 35.2 Male (N): 120 Female (N): 119 Mean Weight (kg): 78 Overall N: 359 Mean Age (years): 34.7 Male (N): 178 Female (N): 179 Mean Weight (kg): 77.8 Inclusion criteria: ADHD; > 18 years. Exclusion criteria: "Individuals with low intelligence (IQ < 85), schizophrenia, bipolar disorder, acute depressive episode, acute anxiety disorders and other unstable psychiatric conditions or serious medical illness; Drug or alcohol dependence during the preceding 6 months; Pregnant or nursing women; Participated in a previous drug trial in the last 30 days and individuals treated with any psychopharmacologicaldrug in addition to study medication."
Interventions	Intervention Characteristics Placebo Mean Daily Dose 41.2mg MPH ER
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The trial was funded by Medice, Germany, which is a corporate pharmaceutical company. Medice's ADHD drugs for both adults and the pediatric population constitute a significant portion of their product line, which may pose a conflict of interest. Country: Germany Setting: 28 study centres across Germany Authors' names: Michael Rösler, Roland Fischer, Richard Ammer, Claudia Ose, Wolfgang Retz Institution: Saarland University Hospital Email: michael.roesler@uniklinik‐saarland.de Address: Neurocenter, Saarland University Hospital, 66421, Homburg/Saar, Germany
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: sequence generation process not described
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: Rosler 2009 used a double‐blind design.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: only 249/359 randomized participants completed study. With less than 70% of participants staying until the end of the trial, there may be a high risk of bias in terms of incomplete outcome data due to the large rate of attrition. 13% of the amphetamine participants who withdrew cited adverse effects, compared to only 8% of the placebo participants who withdrew citing adverse events as the reason for premature termination.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure measurements were reported.

Simonoff 2013.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 61 Mean Age (years): 11.5 Male (N): 40 Female (N): 21 Mean Weight (kg): 40.99 Mean Daily Dose 49.6mg dextroamphetamine N: 61 Mean Age (years): 10.8 Male (N): 45 Female (N): 16 Mean Weight (kg): 41.31 Overall N: 122 Mean Age (years): 11.2 Male (N): 85 Female (N): 37 Mean Weight (kg): 41.15 Inclusion criteria: 7–15 years of age; Diagnosis of ICD‐10 hyperkinetic disorder; Full‐scale IQ of 30–69. Exclusion criteria: "Current stimulant use; Use of neuroleptic medication in the last 6 months; History of a sensitivity reaction to stimulant medication; Diagnosis of a dementing disorder; Epilepsy with daily seizures; Psychotic, bipolar, severe obsessive‐compulsive disorder or severe Tourette syndrome; Household resident with a current substance abuse disorder."
Interventions	Intervention Characteristics Placebo Mean Daily Dose 49.6mg dextroamphetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: This study is funded by The Health Foundation, formerly the PPP Foundation, and sponsored by King’s College, but study design, data collection, analysis and writing were fully independent of the funding body. Country: United Kingdom Setting: Participants were recruited through clinical referrals and community screening across the southeast of England and all assessments were completed by trial team members based at the Institute of Psychiatry. Authors: Emily Simonoff, Eric Taylor, Gillian Baird, Sarah Bernard, Oliver Chadwick, Holan Liang, Susannah Whitwell, Kirsten Riemer, Kishan Sharma, Santvana Pandey Sharma, Nicky Wood, Joanna Kelly, Ania Golaszewski, Juliet Kennedy, Lydia Rodney, Nicole West, Rebecca Walwyn, Fatima Jichi. Institution: Department of Child and Adolescent Psychiatry, King’s College London, Institute of Psychiatry, London, UK; Guy’s & St Thomas’ NHS Foundation Trust, London, UK; South London & Maudsley NHS Foundation Trust, London, UK; Department of Biostatistics, King’s College London, Institute of Psychiatry, London, UK Email: simonoff@kcl.ac.uk Address: Emily Simonoff, Department of Child and Adolescent Psychiatry, King’s College London, Institute of Psychiatry, DeCrespigny Park, London SE5 8AF, UK
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: "The first 15 participants were allocated with simple randomization. Thereafter, allocation was stratified by source of referral (clinical referral or community screening) and ID (full‐scale IQ score <50 or ≥50) with computer‐generated probabilistic minimization." This method of random sequence generation poses a low risk of selection bias.
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment is not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: study used a double‐blind design.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: "Sixteen withdrew from the trial before week 16; 5 of the withdrawals, all on active medication, were due to adverse events". Overall 122 participants were enrolled so a withdrawal of 16 participants can still be considered a low rate of attrition which should only pose a low risk of attrition bias with respect to incomplete outcome data.
Selective reporting (reporting bias)	Low risk	Comment: baseline and week 16 blood pressure were both reported. Although specific dosages were not reported for each treatment group, there does not seem to be a significant risk of reporting bias.

Spencer 2008.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 135 Mean Age (years): 37 Male (M): 67 Female (N): 68 Mean Weight (lb): 177.8 Mean Daily Dose 51.7mg MAS N: 137 Mean Age (years): 36.1 Male (M): 69 Female (N): 68 Mean Weight (lb): 180.4 Overall N: 272 Mean Age (years): 36.5 Male (M): 136 Female (N): 136 Mean Weight (lb): 179.1 Inclusion criteria: "Men or nonpregnant/nonlactating women between 18 and 55 years; Meet DSM‐IV‐TR criteria for primary ADHD diagnosis; Satisfactory medical assessment with no clinically significant or relevant abnormalities; baseline ADHD RS‐IV score ≥ 24; Provide informed consent." Exclusion criteria: "BMI < 18.5 kg/m2; Morbid Obesity; Comorbid psychiatric diagnosis with significant symptoms; Seizure history; Tic disorder; Diagnosis or family history of Tourette’s syndrome; Current chronic or acute illness or unstable medical condition; Mental retardation; Known cardiac structural abnormality or other cardiac condition that could affect cardiac performance; Clinically significant ECG or laboratory abnormalities at screening; Used psychotropic medications that require more than a 28‐day washout period; History of controlled or uncontrolled hypertension or a resting, sitting SBP > 139mmHg or DBP >89mmHg at screening; Allergy, intolerance, or nonresponse to methylphenidate or amphetamines; Drug dependence of substance use disorder (excluding nicotine) within 6 months before screening; Positive urine drug test result at screening or baseline; Participation in another investigational trial within 30 days of screening; Pregnancy or lactation; Concomitant use of psychoactive medications that could interfere with efficacy, safety, or tolerability of triple‐bead MAS."
Interventions	Intervention Characteristics Placebo Mean Daily Dose 51.7mg MAS
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by Shire Development LLC. Shire Pharmaceuticals is a biotechnology company that manufacturers a variety of drugs with amphetamines, notably their ADDERALL XR® tablets. Shire Pharmaceuticals LLC paid a fine of $56.5 million in 2014 due to violating the False Claims Act with promoting its drugs for the treatment of ADHD. Country: The study was conducted across multiple sites in the United States. Setting: The study was conducted at 39 sites in the United States. Authors' names: Thomas J. Spencer, Lenard A. Adler, Richard H. Weisler, Sharon H. Youcha Institution: Massachusetts General Hospital, Harvard Medical School, New York University School of Medicine, Duke University Medical Center, Shire Development LLC Email: spencer@helix.mgh.harvard.edu Address: Massachusetts General Hospital, Pediatric Psychopharmacology Research Unit, 55 Fruit St., Warren 705, Boston, MA 02114, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: randomization via a centralized interactive voice response system.
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: study used "double‐blind treatment".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: 170/272 randomized subjects completed the study. With nearly 40% of the initial study participants withdrawing, this poses a high risk of bias for the loss of outcome data (i.e. not getting after‐treatment blood pressure readings for almost 40% of participants). Out of the discontinued participants from the amphetamine arm, 17% cited adverse events as the reason compared to only 6% of the discontinued placebo participants citing adverse as the reason. It is unclear whether these adverse events were linked to a cardiac cause or a blood‐pressure related cause.
Selective reporting (reporting bias)	Low risk	Comment: change in blood pressure reported.

Sprigg 2007.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 16 Mean Age (years): 73 Male (N): 4 Female (N): 12 Dextroamphetamine N: 17 Mean Age (years): 69 Male (N): 11 Female (N): 6 Overall N: 33 Mean Age (years): 70.9 Male (N): 15 Female (N): 18 Inclusion criteria: "Previously independent (modified Rankin score <3) adult patients with recent ischaemic stroke (3–30 days postictus) and motor weakness (arm and leg components of Scandinavian Stroke Scale < 6) were identified and enrolled from Nottingham City Hospital. Patients were recruited as early as possible after 3 days once they had become clinically stable." Exclusion criteria: "Contraindications to amphetamine, including intracerebral haemorrhage, ischaemic heart disease, uncontrolled hypertension (4160/100 mm Hg), thyrotoxicosis and history of seizures; patients with dementia, coma or pregnancy were also excluded."
Interventions	Intervention Characteristics Placebo Dextroamphetamine
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: The study was supported by BUPA Foundation and The Hypertension Trust. No company manufacturing amphetamine or developing it for stroke was involved in the conception, execution, analysis, or interpretation of the study. Country: United Kingdom Setting: The study was conducted at Nottingham City Hospital, University of Nottingham, United Kingdom. Authors' names: N. Sprigg, M.R. Willmot, L.J. Gray, A. Sunderland, V. Pomeroy, M. Walker, P.M.W. Bath Institution: University of Nottingham, St George's Hospital Medical School, Nottingham City Hospital Email: philip.bath@nottingham.ac.uk Address: Division of Stroke Medicine, University of Nottingham, Nottingham City Campus, Nottingham, NG5 1PB, UK
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: sequence generation process not described.
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind (wherein “All clinical measurements were performed blinded to treatment assignment”), it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: 29/33 participants had full clinical assessment performed
Selective reporting (reporting bias)	High risk	Comment: full clinical assessment done at 90 days but no blood pressure measurements or other clinical measurements are given past Day 4.

Weisler 2017.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 89 Mean Age (years): 34.5 Male (N): 42 Female (N): 47 Mean Weight (kg): 82.82 BMI: 28.11 12.5mg SHP465 Mixed Amphetamine Salts N: 92 Mean Age (years): 33 Male (N): 57 Female (N): 35 Mean Weight (kg): 84.04 BMI: 27.93 37.5mg SHP465 Mixed Amphetamine Salts N: 90 Mean Age (years): 32.4 Male (N): 51 Female (N): 39 Mean Weight (kg): 83.94 BMI: 27.78 Overall N: 271 Mean Age (years): 33.3 Male (N): 150 Female (N): 121 Mean Weight (kg): 83.6 BMI: 27.9 Inclusion criteria: "Men and non‐pregnant women (aged 18–55 years) meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for a primary ADHD diagnosis and having ADHD Rating Scale with Adult Prompts (ADHDRS‐AP) total scores C28 at baseline were enrolled. Eligible participants had satisfactory medical assessments with no clinically significant abnormalities and they were either not currently on ADHD therapy or they reported that they were not completely satisfied with any aspect, including issues related to efficacy and tolerability, of their current ADHD therapy." Exclusion criteria: "Comorbid psychiatric diagnosis that was controlled with prohibited medications or uncontrolled and associated with significant symptoms that contraindicated SHP465 MAS treatment or could confound study assessments. Considered a suicide risk, had previously made a suicide attempt, or were currently demonstrating active suicidal ideation (those with intermittent passive suicidal ideation could be included based on investigator judgment). BMI) <18.5 kg/m2 (underweight) or ≥ 40 kg/m2 (very severely obese) at screening; a history of moderate‐to‐severe hypertension, SBP >139 mmHg, or average sitting DBP> 89 mmHg; use of combination antihypertensive medications (participants with well‐controlled mild hypertension on a single antihypertensive agent could participate); a known history of symptomatic cardiovascular issues or serious cardiac problems; a known family history of sudden cardiac death or ventricular arrhythmia; a clinically significant electrocardiogram; a documented allergy, a hypersensitivity, or an intolerance to amphetamine or any excipient in SHP465 MAS; a failure to respond to an adequate course of amphetamine therapy (to ensure that response to treatment is not artificially reduced by the inclusion of non‐responders); a history of suspected substance abuse or dependence disorder (excluding nicotine) based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria; a lifetime history of amphetamine, cocaine, or other stimulant abuse and/or dependence; and participation in a clinical study within 30 days before screening. Prohibited medications were psychostimulants and amphetamine‐like agents, centrally or peripherally acting antihistamines (non‐sedating antihistamines were permitted), investigational compounds, clonidine and guanfacine, and herbal preparations. Additional medications prohibited were combination anti‐hypertensives (use of a single antihypertensive was permitted if the same dose had been used for at least 3 months before screening), sedatives, anxiolytics, antipsychotics, monoamine oxidase inhibitors, antidepressants, selective noradrenaline reuptake inhibitors, and noradrenaline reuptake inhibitors. Participants requiring or anticipating the need to take medications with central nervous system effects or who were taking monoamine oxidase inhibitors were excluded (stable bronchodilator inhaler use was not exclusionary)."
Interventions	Intervention Characteristics Placebo 12.5mg SHP465 Mixed Amphetamine Salts 37.5mg SHP465 Mixed Amphetamine Salts
Outcomes	Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by Shire Development LLC (Lexington, MA, USA). Shire Development LLC provided funding to Complete Healthcare Communications, LLC (Chadds Ford, PA, USA) for support in writing and editing this manuscript and provided payment for open‐access fees for this publication. The sponsor was involved in the study design, data collection and analysis, and data interpretation. The sponsor was also involved in the writing of the manuscript and in the decision to submit the article for publication. Country: USA Setting: The study was conducted in outpatient clinical settings across 43 U.S. sites. Authors' names: Richard H. Weisler, Michael Greenbaum, Valerie Arnold, Ming Yu, Brian Yan, Margo Jaffee, Brigitte Robertson Institution: Duke University Medical Center, University of North Carolina at Chapel Hill, Capstone Clinical Research Center, CNS Healthcare, Shire Development LLC Email: rweisler@aol.com Address: Duke University Medical Center, 700 Spring Forest Road, Suite 125, Raleigh, NC 27609, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: Participants "were randomized 1:1:1 to placebo or forced‐dose SHP465 MAS (12.5 or 37.5 mg/day) for 4 weeks" but the method of random sequence generation was not specified.
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment not specified.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: double‐blind study wherein "The investigators, the investigators’ staff, and the participants were blinded to the treatment assignment".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: low overall attrition rate (<15%) among participants in this study. There was similar overall attrition in the placebo and amphetamine arms (12% for placebo, 15% for amphetamine), with minimal withdrawals due to adverse events.
Selective reporting (reporting bias)	Low risk	Comment: baseline blood pressure and mean change in blood pressure were reported.

Westover 2013.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 115 Mean Age (years): 36.8 Male (N): 70 Female (N): 45 Daily Dose 72 mg of OROS Methylphenidate N: 115 Mean Age (years): 37.2 Male (N): 62 Female (N): 53 Inclusion criteria: Current smoking status and a diagnosis of ADHD. Exclusion criteria: "Persons with BP >135/85 mm Hg or a HR >90 bpm on three consecutive pre‐randomization visits were excluded. Later, exclusion criteria were changed to only requiring two consecutive pre‐randomization visits with elevated measures, and BP >130/80 mm Hg or HR >88 bpm for participants 40–55 years old. Other exclusion criteria included current DSM‐IV diagnosis of substance abuse/dependence, positive urine toxicology screen, ADHD treatment with stimulants in the past 30 days, and medical conditions deemed unsafe (e.g. uncontrolled hypertension)."
Interventions	Intervention Characteristics Placebo Daily Dose 72 mg of OROS Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Partially reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: "Funding to support this study was received from NIH/NIDA Clinical Trials Network: North Texas Node (3U10DA020024‐01S1), NIH CTSA Grant UL1RR024982, and the O'Brien Kidney Center. These funding organizations had no role in the design and conduct of the study or preparation of the manuscript.” Country: USa Setting: The study was conducted at the Department of Psychiatry and Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, and affiliated sites. Authors' names: Arthur N. Westover, Paul A. Nakonezny, Theresa Winhusen, Bryon Adinoff, Wanpen Vongpatanasin Institution: University of Texas Southwestern Medical Center, VA North Texas Health Care System, University of Cincinnati College of Medicine Email: arthur.westover@utsouthwestern.edu Address: Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	There is treatment randomization but the method of randomization is not described.
Allocation concealment (selection bias)	Unclear risk	The method of allocation concealment is not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	This is a double‐blind trial.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The majority of participants (230 of the original 255) were analyzed.
Selective reporting (reporting bias)	Low risk	Blood pressure measurements at different weeks are reported.

Whiting 2008.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics 10 mg dextroamphetamine N: 19 Age (years): 23 Placebo N: 18 Age (years): 23.44 Overall N: 37 Age (years): 18‐34 Males (n): 11 Females (n): 26 Inclusion criteria: No inclusion criteria provided Exclusion criteria: Participants that were pregnant or any psychiatric, neurological, cardiac, metabolic, degenerative, or motor disorders or diseases.
Interventions	Intervention Characteristics 10 mg dextroamphetamine Placebo
Outcomes	Systolic Blood Pressure Outcome type: Continuous Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint Diastolic Blood Pressure Outcome type: Continuous Reporting: Fully reported Unit of measure: mmHg Data value: Endpoint
Identification	Sponsorship source: This research is not industry‐sponsored but instead supported by a University of Queensland Research and Development awarded to Copland, Chalk, and Chenery. Country: Australia Setting: The study was conducted at the Division of Speech Pathology, School of Health and Rehabilitation Sciences, University of Queensland, Australia. Authors' names: Emma Whiting, Helen J. Chenery, Jonathan Chalk, Ross Darnell, David A. Copland Institution: University of Queensland Email: d.copland@uq.edu.au Address: Division of Speech Pathology, School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, Queensland, Australia
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: "Individuals were randomly assigned to the dexamphetamine and placebo groups using a between subjects study design" but the method for random sequence generation is not described.
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment method is unknown.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: study used a double‐blind design while "[acknowledging] that, due to the nature of dexamphetamine, participants may not have been performing in a fully blinded manner". However, this is the case with all placebo‐controlled randomized studies testing amphetamines. Since the study was double‐blinded, we judged this category as having a low risk of bias.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: blood pressure measured for all participants.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure measurements are reported.

Wigal 2017.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 43 Mean Age (years): 9.3 Male (N): 23 Female (N): 20 33mg/day MPH ERCT (extended‐release chewable tablet) N: 42 Mean Age (years): 9.9 Male (N): 30 Female (N): 12 Overall N: 85 Mean Age (years): 9.6 Male (N): 53 Female (N): 32 Inclusion criteria: "Eligible subjects were males and females 6–12 years of age with a diagnosis of ADHD." Exclusion criteria: "Current primary psychiatric diagnosis of severe anxiety disorder, conduct disorder, pervasive developmental disorder, eating disorder, obsessive‐compulsive disorder, major depressive disorder, bipolar disorder, or other psychiatric disorder, substance abuse disorder, or a personal or family history of Tourette’s syndrome; Clinically significant or severe medical illness or condition, including seizure disorder, cardiac disorders or conditions (including severe hypertension), untreated thyroid disease, or a history of HIV or hepatitis B or C infections; Clinically significant abnormal laboratory results or a positive test for illicit drug use at screening; History of hypersensitivity or lack of efficacy to MPH. Psychotropic agents were prohibited. Sedative hypnotics were prohibited within 24 hours before the screening, except sedative‐hypnotics that had been prescribed as sleep aids (at bedtime only) for at least 30 days before the baseline visit."
Interventions	Intervention Characteristics Placebo 33mg/day MPH ERCT
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: The study was funded by NextWave Pharmaceuticals, a subsidiary of Pfizer Inc. Pfizer produces an amphetamine‐based medication used to treat ADHD. Country: USA Setting: The study was conducted at six U.S. sites. Authors' names: Sharon B. Wigal, Ann Childress, Sally A. Berry, Heidi Belden, Faith Walters, Phillip Chappell, Nancy Sherman, John Orazem, Donna Palumbo Institution: AVIDA Inc., Center for Psychiatry and Behavioral Medicine Inc., Tris Pharma Inc., Pfizer Inc. Email: drsharon@avidainc.com Address: AVIDA Inc., 1600 Dove Street, Suite 305, Newport Beach, CA 92660, USA​
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: "Subjects were randomly assigned (1:1) to receive either MPH ERCT, at their optimal open‐label dose (20–60 mg/ day), or placebo daily for 1 week. Randomization was conducted according to a fixed schedule using a permuted block design stratified by clinical site." The permuted block design is adequate for a low risk of selection bias.
Allocation concealment (selection bias)	Low risk	Comment: "The randomization code was maintained centrally by the clinical supply group, and the study team and investigator site personnel were blinded throughout the study." Given this blinding of study personnel, there should be a low risk of selection bias with respect to allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: a "double‐blind" trial.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: "86 were randomly assigned to treatment (placebo, n = 44; MPH ERCT, n = 42). A total of 85 subjects received at least one dose of double‐blind study medication and had at least one postbaseline efficacy evaluation and were included in the randomized safety population and ITT population. One subject assigned to placebo discontinued the study during the double‐blind treatment period (lost to follow‐up)." This is a very low attrition rate.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure change is reported.

Winhusen 2010.

Study characteristics
Methods	Study design: Randomized controlled trial Study grouping: Parallel group
Participants	Baseline Characteristics Placebo N: 128 Mean Age (years): 37.5 Male (N): 67 Female (N): 61 72mg OROS Methylphenidate N: 127 Mean Age (years): 38.1 Male (N): 77 Female (N): 50 Overall N: 255 Mean Age (years): 37.8 Male (N): 144 Female (N): 111 Inclusion criteria: "Interested in quitting smoking; Between 18 and 55 years of age; In good physical health as determined by a medical history, electrocardiogram, and vital signs; Meet DSM‐IV criteria for ADHD as assessed by the Adult Clinical Diagnostic Scale version 1.2, have a DSM‐IV ADHD Rating Scale (ADHDRS) total score >22; Smoke at least 10 cigarettes per day (CPD), have a CarbonMonoxide (CO) level ≥8 ppm, have smoked cigarettes for at least 3 months." Exclusion criteria: "Vital signs criterion cut‐off was 135/85 mmHg for blood pressure and 90 bpm for heart rate for the first 143 participants randomized into the trial (for participants 40 or older, new cut‐offs were 130/80 mmHg and/or a HR > 88 bpm for the remainder of the trial); Significant suicidal/homicidal risk; Used tobacco products other than cigarettes in the past week, had a positive urine screen for anillicit drug, or met DSM‐IV criteria for: current abuse or dependence for any psychoactive substance other than nicotine, current major depression, any anxiety disorder except specific phobias, antisocial personality disorder, or a lifetime diagnosis of bipolar disorder orpsychosis; History of narrow angle glaucoma or seizure disorder, tics, or a family history of Tourette’s syndrome; Had been treated for ADHD with psychomotor stimulants or had used smoking cessation counseling programs or medications within the last 30 days; Currently taking a medication that could adversely interact with OROS‐MPH, had a known allergy to OROS‐MPH, or had been a non‐responder to a reasonable course of MPH treatment; Pregnant or breastfeeding or unwilling to use an adequate method of birth control."
Interventions	Intervention Characteristics Placebo 72mg OROS Methylphenidate
Outcomes	Systolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline Diastolic Blood Pressure Outcome type: Continuous Outcome Reporting: Fully reported Unit of measure: mmHg Data value: Change from baseline
Identification	Sponsorship source: "This study is supported by the following grants from the National Institute on Drug Abuse: U10‐DA015831 and K24 DA022288 to Harvard University (Dr Weiss); U10‐DA013035 to New York State Psychiatric Institute (Dr. Nunes); U10‐DA013046 to New York University (Dr. Rotrosen); U10‐DA013036 to Oregon Health and Science University (Dr. McCarty); U10‐DA013732 to the University of Cincinnati (Dr. Somoza). The study medication and matching placebo were provided by McNeil Consumer & Specialty Pharmaceuticals at no cost." Country: USA Setting: The study was conducted at six clinical sites, including two ADHD clinics, two smoking cessation clinics, and two substance‐abuse community treatment programs, in the USA. Authors' names: Theresa M. Winhusen, Eugene C. Somoza, Gregory S. Brigham, David S. Liu, Carla A. Green, Lirio S. Covey, Ivana T. Croghan, Lenard A. Adler, Roger D. Weiss, Jeffrey D. Leimberger, Daniel F. Lewis, Emily M. Dorer Institution: University of Cincinnati, Veterans Affairs Medical Center, National Institute on Drug Abuse, Kaiser Permanente, Columbia University, Mayo Clinic, New York University, Harvard Medical School, Duke Clinical Research Institute Email: winhusen@carc.uc.edu Address: Department of Psychiatry, University of Cincinnati College of Medicine, 3210 Jefferson Avenue, Cincinnati, OH 45220, USA
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: random sequence was generated by computer randomization.
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: study employed a double‐blind design where both participants and personnel were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: given that this study was double‐blind, it is unlikely that blood pressure measurements were biased by knowledge of the treatment group.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: approximately 84% of participants completed the 11‐week active treatment period. No participant discontinued due to an adverse event. Since a large majority of participants completed the trial in its entirety, there is a lower risk of attrition bias.
Selective reporting (reporting bias)	Low risk	Comment: blood pressure measurements were reported.

ADHD: attention deficit hyperactivity disorder; AISRS: Adult ADHD Self‐Report Scale; BED: binge‐eating disorder; BMI: body mass index; bpm/BPM: beats per minute; DBP: diastolic blood pressure; DSM: Diagnostic and Statistical Manual of Mental Disorders; ECG: electrocardiogram; ICD: International Classification of Diseases; IR: immediate release; LDX: lisdexamfetamine; MAS: mixed amphetamine salts; MDMA: methylenedioxymethamphetamine; MPH: methylphenidate; OROS: osmotic release oral system; SBP: systolic blood pressure; XR: extended release; YMRS: Young Mania Rating Scale

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Adler 2020	Ineligible comparison: no placebo arm
Alcorn 2020	Insufficient information available (paper does not specify randomization or random allocation to the experimental methylphenidate or parallel placebo group, or how many participants were allocated to each arm). We contacted authors but did not receive a response.
Anderer 2002	Ineligible design: not a randomized controlled trial (RCT)
Angrist 2001	Ineligible study design: review article, not a primary study
Arnold 2005	Ineligible study design: all participants received d‐methylphenidate in the first six weeks of this trial before randomization to methylphenidate and placebo; not a randomized placebo‐controlled trial for the full length of the trial.
Bawden 1997	Ineligible study design: placebo‐controlled case study, not an RCT
Becker 2016	Ineligible outcomes: did not measure blood pressure
Berry 2022	No report of baseline or endpoint blood pressure measurements. We contacted the authors but did not receive a response.
Biederman 2005	Ineligible design: not a randomized controlled trial
Boileau 1976	Ineligible design: not a randomized controlled trial
Bolin 2016	Ineligible study design: all participants received a placebo and a dose of d‐amphetamine and phendimetrazine in random order (cross‐over study)
Booij 2016	Ineligible outcomes: study tested exposure to D‐amphetamine and measured “physiological induces of stress [including] heart rate”, but did not measure nor report on blood pressure.
Brams 2012	Ineligible study design: all participants were administered lisdexamfetamine dimesylate prior to randomization to lisdexamfetamine dimesylate and placebo. Therefore, not the entirety of this trial was a randomized controlled trial.
Bray 2004	Absolute changes in blood pressure were not provided as an outcome. We contacted authors to request blood pressure measurements but received no response.
Brown 1984	Ineligible design: not a randomized controlled trial
Bruera 2006	Ineligible outcomes: blood pressure was not measured nor reported
Buitelaar 2009	The initial five weeks of this study included randomization to a methylphenidate arm or placebo. However, no blood pressure measurements were provided to identify the change in blood pressure between baseline and week five. We contacted authors who informed us that "these were data from an industry registration study (i.e. of Janssen)." Therefore, the study authors do not have access to these data.
Butter 1975	No blood pressure measurements provided. We could not obtain current contact information for study authors.
Caldwell 1996	Ineligible study design: “each participant received … dextroamphetamine during one period, and placebo capsules during the other period”.
Caldwell 1997	Ineligible study design: all participants received amphetamine “on Dexedrine days” and placebo “on placebo days”; not a randomized controlled trial
Cardenas 2002	Ineligible outcomes: study did not report any blood pressure measurements (e.g. baseline, post‐treatment or any overall change in blood pressure). We contacted study authors to request blood pressure measurements, but received no response.
Chandler 1980	Ineligible study design and outcomes: participants underwent each experimental condition (i.e. placebo and amphetamine); study only reported baseline blood pressure and not blood pressure measurements after intervention.
Chapotot 2003	Ineligible outcomes: study did not report blood pressure measurements. We contacted study authors to request these data, but received no response.
Childress 2020	Dose‐optimization study; not a placebo‐controlled study
Childress 2021	Blood pressure not reported as an outcome
Childs 2016	Ineligible study design and intervention type: study used a “within‐subjects design” and was not an RCT. In addition, to "facilitate blinding, participants were informed that they might receive a placebo, stimulant (e.g. amphetamine)" or other drug types, but amphetamine was not actually given as a treatment arm.
Ching 2022	Did not report blood pressure measurements
Cohen 1971	Ineligible study design: double‐blind cross‐over trial
Connor 2005	Did not report blood pressure measurements. We contacted study authors, but the missing information could not be retrieved.
Cooper 2005	Ineligible study design: a "within‐subject" design
Cossu 2019	Case study, not a randomized controlled study
DeWit 2000	This citation refers to a conference abstract. The subsequent published study was a within‐subject design, not a randomized controlled trial.
Ding 2009	Conference abstract only
Donner 2007	Ineligible study design: large, non‐comparative, non‐placebo‐controlled trial
Dursteler‐MacFarland 2013	Blood pressure was not measured as an outcome
Fallu 2006	Ineligible study design: uncontrolled trial
Findling 2008	Not a placebo‐controlled RCT design: all “subjects were titrated to [various dosages of] LDX [lisdexamfetamine]”
Findling 2010	Blood pressure measurements not provided as a study outcome
Findling 2013	Findling 2013 was excluded after full‐text review because “Regardless of prior treatment in the antecedent study, all participants began this open‐label study with a 30 mg/day dose of LDX [lisdexamfetamine]” This does not meet the review's inclusion criterion requiring random allocation to the experimental amphetamine or a parallel placebo group for the entirety of the study.
Focken 1984	Blood pressure not a measured outcome
Froehlich 2014	Ineligible study design: study utilized a cross‐over design (“Participants underwent a 4‐week within‐subject, randomized, double‐blind, crossover trial”)
Gadow 2011	Not an RCT: “All participants received placebo and three doses of methylphenidate”
García Ron 2022	Ineligible study design: “Interventional, prospective, longitudinal and comparative study with a crossover design”
Gasior 2017	Ineligible study design: not an RCT; the authors cited study limitations as “the study attrition rate and the lack of a placebo control group”.
Gladstone 2006	Involved randomization to the rehabilitation or no‐rehabilitation treatment arms. However, it is unclear whether the allocation to amphetamine and placebo was through a randomized process. Furthermore, no blood pressure measurements were provided. We contacted authors for clarification, but received no response.
Goldstein 2018	Blood pressure was not a measured outcome
Goodman 2017	No blood pressure measurements provided
Grade 1998	Ineligible outcomes: RCT design, but full‐text review revealed there were no blood pressure measurements reported at any point in the study
Hamilton 1983	Ineligible study design: “treatments were all administered to all subjects” and there was no reference to randomization
Hammerness 2009	Not a placebo‐controlled randomized trial
Heil 2002	Not a placebo‐controlled randomized trial: “Each participant was exposed to the six drug conditions”.
Hermens 2007	Ineligible design: study employed a 'within‐subject' design
Hudson 2017	Ineligible design: all participants participated in an open‐label phase where they were administered lisdexamfetamine, an amphetamine; participants were not randomized to placebo or lisdexamfetamine for the entirety of the study.
Huss 2014	Blood pressure measurements were not reported. We contacted authors for clarification, but received no response.
ISRCTN77940178	Blood pressure outcomes were not available. We requested blood pressure data from study authors but did not receive a response.
Jordan 1998	Ineligible design: all participants received the experimental intervention (amphetamine) and placebo
Kasparbauer 2016	Ineligible outcomes: no measurement of blood pressure
Kelly 2005	Ineligible design: "double‐blind, randomized, placebo controlled, 3‐period crossover study"
Keser 2017	Ineligible design: "crossover, placebo‐controlled, and double‐blinded design"
Killgore 2008	Ineligible outcomes: did not measure blood pressure
Kis 2020	Although participants were randomly assigned to either placebo or amphetamines, all participants also received a form of psychological intervention. As outlined in our protocol, participants in both the experimental and control arms could receive standard medical therapy for existing comorbid conditions. However, since psychological intervention was not administered before the trial began, this could introduce a confounding variable.
Kurlan 2002	Ineligible outcomes: did not measure blood pressure
Lane 2014	Not randomized: across several testing days, participants in this trial were administered both placebo and amphetamine
Langenecker 2020	Ineligible outcomes: did not measure blood pressure
Larsson 1988	Ineligible design: authors did not indicate whether randomization was part of the trial design in their methods. We could not obtain the study authors' contact information to seek clarification.
Linssen 2011	Ineligible design: although “the order of the treatments was randomized”, each participant received both amphetamine and placebo during different periods of the trial.
Maayan 2009	Ineligible design: all received amphetamine; no randomization to treatment arms
Martin 2014	Ineligible outcomes: study did not report baseline or post‐treatment blood pressure or change in blood pressure
McDonald 2017	Study did not report baseline or post‐treatment blood pressure or change in blood pressure. We contacted authors to request data but received no response.
McIntyre 2013	Ineligible design: no placebo arm
McKetin 1999	Ineligible study design
Mendonca 2007	Blood pressure was not measured as an outcome
Mintzer 2021	Incomplete outcome data due to only reporting baseline blood pressure data and no further blood pressure measurements. We contacted study authors but did not obtain the necessary data.
Moreau 2012	Study did not report final blood pressure, nor change in blood pressure measurements. We contacted authors to request data but did not receive a response.
Morrow 2015	Study did not measure blood pressure as an outcome.
Murray 2021	Not an RCT: placebo and drug were "distinctly colored to enable subjects’ choice of preferred capsule"
NCT00249353	Blood pressure measurements were not reported in this publication. We contacted the study authors but did not obtain the requested blood pressure data.
NCT00914095	Randomization was not part of the study design in this clinical trial.
NCT01099059	Ineligible study design. The study has only parallel drug arms and no placebo arm.
NCT01244269	No results or papers from this trial have been published thus far. The study has been terminated. We contacted the trial investigator but were unable to obtain any relevant data.
NCT04283604	In this clinical trial, “the study will be divided into two sub studies… In the first session, all participants will undergo motor tests, in the same conditions. In the second session, half of ADHD participants (25) will be asked to take their regular MPH treatment, before the session.” This trial is excluded for two reasons: no randomization to amphetamine or placebo; trial uses 'Crossover Assignment' as an intervention model.
NCT04283877	No results or papers from this trial have been published thus far. We contacted the trial investigator but were unable to obtain any relevant data.
NTR6140	No results or papers from this trial have been published thus far. We contacted the trial investigator but were unable to obtain any relevant data.
Olfson 2012	Ineligible design: did not randomly assign participants
Olson 2003	Ineligible outcomes: study did not measure blood pressure
Palumbo 2008	Ineligible outcomes: study did not measure blood pressure
Peled‐Avron 2021	Ineligible outcomes: study did not report blood pressure measurements
Porges 1981	Ineligible design: "The order of the drug treatment was randomized" within subjects, i.e. a 'within‐subject' design and not an RCT
Rahman 2006	Ineligible design: double‐blind, placebo‐controlled cross‐over study
Richards 2016	Ineligible study design. As outlined in our protocol, participants in both the experimental and control arms could receive standard medical therapy for existing comorbid conditions. However, in this trial, participants entered an 8‐week, single‐blind lead‐in phase during which they were randomly assigned to one of four different antidepressant medications. After this phase, they were then randomized to receive either amphetamine or placebo. Since participants were not receiving these antidepressant treatments prior to the trial, Richards 2016 was excluded for not aligning with our study design criteria.
Roelands 2008	Ineligible design: cross‐over study: “The treatment was randomized and administered in double‐blind crossover manner.”
Rothenhausler 2000	Not a randomized placebo‐controlled trial
Rush 2002	In Rush 2002, “The order of drug administration was random except that each volunteer received each training condition, 150 mg cocaine and placebo, at least twice.” Due to the lack of randomization to experimental and control groups, Rush 2002 does not fit the criteria of being an RCT.
S'Jongers 1969	Ineligible outcomes: study did not report blood pressure as an outcome, and we were unable to contact the authors to clarify whether blood pressure was ever measured.
Schepers 2019	Ineligible study design: not an RCT; study used "dose order counterbalanced across subjects"
Schrantee 2016	Ineligible outcomes: study did not measure blood pressure
Sevak 2009	Not an RCT: “All subjects completed two sampling sessions to acquaint them with the drug effects” wherein all the participants were administered amphetamines.
Sharma 1990	Not an RCT: "Placebo and methylphenidate days were randomized and separated by a minimum of 48 hours." The order in which placebo or treatment was administered was randomized, but the allocation to placebo or treatment group itself was not randomized.
Shiels 2009	Ineligible design: no randomization to the amphetamine group and control/placebo
Shim 2022	Ineligible design: “active‐controlled trial” rather than placebo‐controlled study design
Sonde 2007	Ineligible outcomes: blood pressure was not measured
Spencer 2005a	Ineligible outcomes: study did not measure blood pressure
Spencer 2005b	Ineligible design: study used a parallel design, not a randomized controlled design
Szobot 2003	Ineligible outcomes: study did not measure blood pressure
Takahashi 2014	Ineligible outcomes: study did not measure blood pressure
Tannock 1995	Ineligible outcomes: study did not measure blood pressure
Tidey 2000	Ineligible design: no randomization to an amphetamine arm and a placebo arm
Tiihonen 2007	Ineligible outcomes: study did not measure blood pressure
Treig 2003	Ineligible outcomes: study did not measure blood pressure
Trivedi 2013	Ineligible design. As outlined in our protocol, participants in both the experimental and control arms could receive standard medical therapy for existing comorbid conditions. However, in the lead‐in phase of this trial, all participants were administered a non‐amphetamine drug (escitalopram). Since participants were not receiving escitalopram as standard medical therapy prior to the trial, this trial was excluded for not aligning with our study design criteria.
Van Kammen 1977	Ineligible outcomes: study did not measure blood pressure
Van Ruitenbeek 2021	Ineligible design: all participants underwent the Maastricht Acute Stress Test aimed at activating the human stress system, which likely confounded blood pressure measurements.
Walker‐Batson 1995	Ineligible outcomes: study did not measure blood pressure
Wardle 2013	Not an RCT
Weisler 2009	Ineligible design: “open‐label, multicenter, single‐arm study” and therefore not an RCT.
Weyandt 2018	Ineligible design: “This pilot study employed a double‐blind, placebo‐controlled, within‐subjects crossover design”.
Wigal 2004	Ineligible outcomes: study did not report baseline blood pressure, final blood pressure or an overall change in blood pressure. We emailed authors for clarification, but received no response.
Wigal 2015	Ineligible outcomes: study did not measure blood pressure
Wilens 2003	Not an RCT: participants “received once‐daily OROS MPH [osmotic release oral system methylphenidate] in this multicenter, open‐label, nonrandomized study”.
Wilens 2005a	Ineligible outcomes: we contacted authors to request blood pressure measurements but were unable to retrieve missing information
Wilens 2005b	Ineligible design: “three trials were completed in a crossover design with a 1‐ to 2‐week washout between treatments.” Cross‐over studies are excluded from this review.
Yarosh 2015	Ineligible outcomes: no reporting of baseline blood pressure, final blood pressure or an overall change in blood pressure. We contacted study authors for data but did not receive a response.
Zahn 1980	Ineligible outcomes: study did not measure blood pressure
Zahn 1981	Ineligible outcomes: study did not measure blood pressure
Zheng 2011	Not an RCT (no randomization)

Characteristics of ongoing studies [ordered by study ID]

ACTRN12614000654651.

Study name	The Impact of Dexamphetamine Treatment for Obesity on Executive Function: A Double‐Blind Randomised Controlled Pilot Study
Methods	Randomised controlled trial (RCT)
Participants	Adults aged 18–70 years with a body mass index of 25–60 that met the criteria for nocturnal respiratory support for obstructive sleep apnea (OSA)
Interventions	Dextroamphetamine vs control
Outcomes	Executive function measures
Starting date
Contact information	Antoinette Poulton, Melbourne School of Psychological Sciences, University of Melbourne, Parkville, VIC 3052, Australia
Notes

ACTRN12617000657325.

Study name	Randomised, double‐blind, placebo controlled trial of lisdexamfetamine for the treatment of methamphetamine dependence
Methods	RCT
Participants	The target sample is 180 participants with methamphetamine dependence of ≥ 2 years, using ≥ 14 days out of the previous 28, who have previously attempted but not responded to treatment for methamphetamine use.
Interventions	15‐week intervention of dextroamphetamine vs control
Outcomes	Change from baseline in days of methamphetamine use by self‐report for the last 28 days at week 13 and urinalysis confirmation of methamphetamine use
Starting date
Contact information	Nadine Ezard, University of New South Wales, Randwick, New South Wales, Australia
Notes

ACTRN12618000629235.

Study name	Acute methamphetamine and alcohol usage alters gaze behaviour during driving: a randomised, double‐blind, placebo‐controlled study
Methods	RCT
Participants	20 healthy adults
Interventions	Methamphetamine vs control
Outcomes	Executive function measures
Starting date
Contact information	Amie Hayley, Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC, Australia
Notes

D'Aiello 2022.

Study name	Comparing the Effect of Methylphenidate and Anodal tDCS [transcranial direct current stimulation] on Inhibitory Control and Working‐Memory in Children and Adolescents with Attention Deficit/Hyperactivity Disorder: A Study Protocol for a Randomized, within‐Subject Trial
Methods	RCT
Participants	Children and adolescents diagnosed with severe ADHD
Interventions	Methylphenidate vs control
Outcomes	Executive function measures
Starting date
Contact information	Barbara D’Aiello, Child and Adolescent Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
Notes

Haggarty 2022.

Study name	Dose Dependent Effects of Acute Methamphetamine on EEG Alpha Power, Self‐Reported Stimulation and Blood Pressure in Healthy Adults
Methods	RCT
Participants	Healthy volunteers aged 18 to 35
Interventions	Methamphetamine vs control
Outcomes	Level of alpha frequency power
Starting date
Contact information	Connor Haggarty, University of Chicago, Chicago, Illinois, USA
Notes

ISRCTN14910154.

Study name	Stimulant medication for ADHD and tics ‐ understanding response versus non‐stimulants
Methods	RCT
Participants	Children and young people (6 to 16 years old) with ADHD and tics will be recruited in England.
Interventions	Methylphenidate vs control
Outcomes	Executive function measures
Starting date
Contact information	Chris Hollis, Institute of Mental Health, University of Nottingham Jubilee Campus, Nottingham NG7 2TU, United Kingdom
Notes

NCT02979327.

Study name	Cardiovascular effects of Adderall in healthy adults
Methods	Double‐blind, randomized, cross‐over design
Participants	Inclusion criteria Adults 18 years of age and older Healthy people without known cardiovascular disease, thyroid disease or documented mental health illness On no medications No prior history of regular amphetamine use, and non‐prescription stimulants Nonsmokers Exclusion criteria Known cardiovascular disease, thyroid disease History of psychotic disorders/mental health illness, including but not limited to anxiety, depression, bipolar disorder; history of substance abuse or dependence Currently taking medications Prior history of regular amphetamine use, or non‐prescription stimulants Smokers Pregnant Known lactose intolerance (due to presence of lactose in the prepared medication) Family history of sudden cardiac death
Interventions	Experimental arm 1: "Participants will receive an Adderall capsule at the first study visit, then a Placebo capsule at the second study visit." Experimental arm 2: "Participants will receive a Placebo capsule at the first study visit, then an Adderall capsule at the second study visit."
Outcomes	Primary: SBP, DBP, mean arterial pressure (MAP), heart rate Secondary: plasma norepinephrine All outcomes to be measured at baseline and 3 hours
Starting date	01 June 2018
Contact information	Anna Svatikova, MD, Mayo Clinic
Notes

NCT04885257.

Study name	Methylphenidate for PTSD and stroke veterans
Methods	Randomized, double‐blind, placebo‐controlled, parallel‐group trial Masking: quadruple blind: participant, care provider investigator, outcomes assessor
Participants	Inclusion criteria Male or female US military veteran; signed informed consent Criterion A Index Trauma(s) resulting in PTSD (post‐traumatic stress disorder) occurred during adulthood prior to stroke CAPS‐5 (Clinician‐Administered PTSD Scale for DSM‐5) past week total score = 23 at baseline visit Willing to refrain from antipsychotics, mood stabilizers, stimulants, and any formulation of methylphenidate (MPH) First‐ever symptomatic ischemic stroke radiologically verified, occurring within past 1 to 12 months Females of child‐bearing potential (i.e. not postmenopausal or surgically sterile) must be using a medically acceptable method of birth control and should not be pregnant nor have plans for pregnancy or breastfeeding during the study Exclusion criteria Moderate to severe cognitive impairment (Montreal Cognitive Assessment score < 16/30) Poor pre‐stroke baseline function of a modified Rankin score > 2 Presence of any standard MRI contraindications Current diagnosis of DSM‐5‐defined bipolar disorder I, schizophrenia, schizoaffective disorder, obsessive‐compulsive disorder, or major depressive disorder with psychotic features (MINI) Diagnosis of moderate or severe substance use disorder (except for caffeine and nicotine) during the preceding 3 months Patients who utilize alcohol or cannabis but do not meet criteria for moderate or severe disorder are permitted at the discretion of the investigator Participants must agree to abstain from illicit drugs during the study Increased risk of suicide that necessitates inpatient treatment or warrants additional therapy excluded by the protocol; and/or intensity of suicidal ideation (Type 4 or Type 5) or any suicidal behavior in the past 3 months on Columbia Suicide Severity Rating Scale (C‐SSRS) Use of any investigational drug, MPH formulation, antipsychotics, mood stabilizers, monoamine oxidase inhibitors, stimulants or any medication known to be a potent (strong) cytochrome P450 subtype 3A4 inhibitor within 2 weeks of baseline Treatment with evidence‐based trauma‐focused therapy for PTSD within two weeks of baseline (if participant is receiving therapy, he/she must complete treatment prior to entering study) Supportive psychotherapy in process at time of Screening may be continued during the study. History of moderate or severe traumatic brain injury (TBI) as defined by the Ohio State University TBI Identification Method Based on investigator's clinical judgment, history of mild TBI is not excluded Any clinically significant, uncontrolled, or medical/surgical condition or laboratory abnormality that would contraindicate use of MPH Severe allergic reaction, bronchospasm, or hypersensitivity to any MPH formulation Litigating for compensation for a psychiatric disorder. Veterans who are in the process of applying for or receiving VA service‐connected disability are eligible Current enrollment in another intervention trial for PTSD or stroke Persons imprisoned, diagnosed with terminal illness, or require surrogate for consent
Interventions	Placebo control arm: people with both PTSD and recent history of stroke. The frequency will be up to twice a day, with oral dosing. Methylphenidate active arm: people with both PTSD and recent history of stroke. The oral dosing maximum will be up to 20 mg twice daily.
Outcomes	CAPS‐5 (Clinician‐Administered PTSD Scale); modified Rankin scale
Starting date	14 January 2022
Contact information	Chen Lin, MD, Birmingham VA Medical Center, Birmingham (AL)
Notes	Study sponsor: Veterans' Affairs Office of Research and Development

NTR4653.

Study name	Predicting the wide ranging effects of enhancing dopamine on cognition
Methods	A "within‐subject, double‐blind, placebo‐controlled, design"; "non‐randomized"; "open: masking not used"
Participants	Inclusion criteria: "Healthy volunteers between 18 and 45 years of age" Exclusion criteria: "Neuropsychiatric disorders; history of drug abuse; heart problems"
Interventions	"All subjects will visit the Donders Centre for Cognitive Neuroimaging (DCCN) for two testing sessions that will last between 5 and 6 hours. On study day one, 50 subjects will receive oral capsules of 20mg methylphenidate and 50 subjects will receive oral placebo capsules. On study day two subjects will receive the capsule (methylphenidate or placebo) that they did not receive on study day one...." "On study day one participants will first undergo a medical screening interview to ensure that they do not meet any of the exclusion criteria. Subjects will then complete a baseline measure of working memory, receive one oral capsule of either 20mg MPH or placebo, rest for approximately 1.5 hours, and then complete the battery of cognitive tests. On study day two, subjects will complete the same procedure, but without the medical screening interview; in this session subjects will receive the capsule (methylphenidate or placebo) that they did not receive on study day one."
Outcomes	"Social Learning (Beta value for personal learning) Social Learning (Win‐stay, lose‐shift behaviour) Social Learning (Perseveration) Working memory (Accuracy and reaction time) Motivation x activation reinforcement learning task (Pavlovian bias) Probabilistic reversal learning (Lose‐switch, win‐stay behaviour) Probabilistic reversal learning (Perseveration) Pavlovian to Instrumental Transfer (Vigour changes upon Pavlovian stimuli) Demand selection task task (Bias towards easy/difficult condition)"
Starting date	14 April 2014
Contact information	Radboud Universiteit Nijmegen, Kapittelweg 29, Nijmegen 6525 EN, the Netherlands
Notes	"Primary sponsor: Radboud Universiteit Nijmegen" "Source(s) of monetary or material Support: Veni grant, Human Frontiers; James McDonnell Foundation; Donders Centre for Cognitive Neuroimaging Principal Investigator Budget"

ADHD: attention‐deficit hyperactivity disorder; DBP: diastolic blood pressure; MAP: mean arterial pressure; RCT: randomized controlled trial; SBP: systolic blood pressure

Differences between protocol and review

Subgroup analyses

Many included studies did not separate the data in a way that would enable us to perform a subgroup analysis. Of the five planned subgroup analyses indicated in the study protocol (Chan 2020), we were able to compare (1) participants under age 18 versus participants aged 18 and older; and (2) studies of shorter duration (≤ four weeks) versus those of longer durations (> four weeks to < eight weeks; and ≥ eight weeks). Too few included studies provided the relevant separate data needed to complete subgroup analysis for the rest of the planned subgroups (i.e. men versus women; hypertensive participants versus non‐hypertensive participants; high dosage versus low dosage).

Sensitivity analyses

We were able to perform all sensitivity analyses outlined in the protocol, with additional analyses included either by our initiative or in response to reviewers' comments, as follows.

• As noted in Characteristics of included studies, 37 of 56 included studies (66%) were sponsored by pharmaceutical companies producing amphetamines at the time the studies were conducted. To assess the effect of industry sponsorship, we added a post hoc sensitivity analysis excluding pharmaceutical industry‐sponsored studies.

• We added a sensitivity analysis excluding studies shorter than seven days' duration to assess the effects of amphetamines over a longer duration.

• We added a sensitivity analysis excluding studies that measured blood pressure more than 24 hours after the final amphetamine/placebo dose, as measurements taken beyond this window may not accurately capture peak blood pressure effects.

• Following a reviewer’s comment regarding 3,4‐methylenedioxymethamphetamine (MDMA)’s off‐label status, we conducted a sensitivity analysis excluding the one included study which administered MDMA.

Contributions of authors

Magnus Chan: lead role in searching for, identifying and assessing studies meeting the review's inclusion/exclusion criteria, and in data extraction and analysis.

Jocelyn Chan: second review author in verifying trials meeting inclusion/exclusion criteria, and in data extraction and analysis.

James (Jim) Wright: senior review author, formulated the idea for the review.

All review authors were involved in writing the review.

Sources of support

Internal sources

• University of British Columbia, Canada

  Infrastructure support

External sources

• BC Ministry of Health Grant to the Therapeutics Initiative, Canada

  Salary support

Declarations of interest

Magnus Chan: nothing to declare.

Jocelyn Chan: nothing to declare.

James M Wright: JMW is a Cochrane editor but was not involved in the editorial process of this review.

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