Efficacy of Methylphenidate in Patients With Brain Disease: A Systematic Review and Meta-Analysis

Abstract

This systematic review and meta-analysis evaluated the efficacy and safety of methylphenidate in patients with brain disease. A comprehensive search up to November 4, 2024 identified 33 randomized controlled trials involving 1,369 participants with traumatic brain injury (TBI), stroke, Parkinson’s disease (PD), Alzheimer's disease (AD), other dementias, and multiple sclerosis. Methylphenidate was administered at 10–80 mg/day or 0.1–1 mg/kg/day for durations ranging from a single dose to 6 months. Data were synthesized using a random-effects model, with study quality evaluated via the Revised Cochrane Risk of Bias Tool. Methylphenidate significantly improved attention (standardized mean difference [SMD], 0.43; 95% confidence interval [CI], 0.03 to 0.84), particularly in TBI. Motor function improved in stroke populations (mean difference [MD], 0.66; 95% CI, 0.13 to 1.18), while activities of daily living (ADL) significantly improved in stroke and AD (SMD, 0.71; 95% CI, 0.37 to 1.06). Apathy was significantly reduced in AD (SMD, −0.60; 95% CI, −0.95 to −0.26), and depression improved across patients with PD, stroke, and TBI (SMD, −0.50; 95% CI, −0.94 to −0.05). No significant effects were observed for consciousness, global cognition, executive function, fatigue, or quality of life. Side effects were mild, with a slight increase in pulse rate (MD, 0.28; 95% CI, 0.10 to 0.47). In summary, methylphenidate improves attention (TBI), motor function (stroke), ADL (stroke, AD), and mood, especially apathy (AD) and depression, with a favorable safety profile. Its effects appear condition-specific, and further research is needed to confirm long-term efficacy and establish standardized protocols.

Trial Registration

International Prospective Register of Systematic Reviews Identifier: CRD42024563826.

Graphical Abstract

Highlights

• ∙ Methylphenidate improves attention, motor function, apathy, and depression.

• ∙ No significant effects on global cognition, executive function, or quality of life.

• ∙ Mild side effects include increased pulse rate; overall safety profile is favorable.

INTRODUCTION

Methylphenidate is a central nervous system (CNS) stimulant that increases the synaptic and extracellular concentrations of dopamine and norepinephrine by blocking the reuptake of these neurotransmitters. Actions at D1 and α-2 adrenergic receptors are thought to be responsible for the therapeutic effects of methylphenidate on prefrontal cortical regulation of cognitive functions such as working memory and attention [1]. Many studies have shown the positive effects of methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD) [2]; it has also been suggested to improve cognitive functions, such as attention, planning, and memory, in adults with ADHD [3]. Methylphenidate has also been used for cognitive impairment in various neurological conditions [4,5,6] and has been recommended for use in improving attention and working memory, particularly in patients with traumatic brain injury (TBI) [7].

In Korea, methylphenidate has been approved for the treatment of ADHD and narcolepsy by the Korean Ministry of Food and Drug Safety (MFDS). However, the drug has recently garnered attention as a "study-enhancing" medication, which has fueled inappropriate use. In response, the MFDS introduced regulatory measures in 2023, including preemptive alerts to physicians prescribing drugs and stricter prescription criteria to prevent misuse. These include restrictions on off-label use, prescriptions exceeding 3 months, dosages beyond the maximum approved daily limit, and the use of immediate-release formulations for adult patients with ADHD. While these measures aim to curb abuse, they also inadvertently restrict access to neurological patients in rehabilitation who could benefit from their cognition-enhancing effects.

Although previous systematic reviews have investigated the effects of methylphenidate, they were primarily limited to TBI populations [8,9]. This study aimed to systematically evaluate the cognitive, functional, and safety effects of methylphenidate in patients with various brain diseases, including TBI, stroke, Parkinson’s disease (PD), Alzheimer’s disease (AD), other dementias, and multiple sclerosis (MS). To address the heterogeneity of populations and outcomes, the analysis was structured by disease type and outcome domains. By providing disease-specific and domain-focused evidence, this study seeks to support the appropriate and evidence-based use of methylphenidate in neurorehabilitation, while helping to prevent its misuse in populations where efficacy remains unproven.

MATERIALS AND METHODS

This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Supplementary Data 1) [10]. The protocol was registered in the International Prospective Register of Systematic Reviews with the registration number CRD42024563826.

Search strategy

A comprehensive search was conducted across 6 international (MEDLINE, Embase, PubMed Central, Scopus, and Web of Science) and 2 domestic (KoreaMed and KISS) databases to identify relevant studies published from database inception until November 4, 2024. The search strategy included Medical Subject Headings (MeSH) terms and keywords related to “methylphenidate” and “brain diseases.” The details of the search strategy are provided in Supplementary Data 2. No restrictions were imposed on the language or publication status.

Study selection

Studies were included based on the PICOS (Population, Intervention, Comparison, Outcomes, Study design) framework. The target population was comprised of patients diagnosed with brain diseases (TBI, stroke, PD, AD, other dementias (vascular cognitive impairment and frontotemporal dementia), and MS). The intervention group received methylphenidate, whereas the control group received a placebo or standard therapy.

The primary outcomes were categorized into the following domains: (1) Level of consciousness (Glasgow Coma Scale [GCS]); (2) Cognition, including global cognitive function (Mini-Mental State Examination [MMSE]), attention capacity (Digit Span Forward), working memory (2-Back Working Memory Task, Paced Auditory Serial Addition Test), focused attention (Gordon Diagnostic System, Continuous Performance Test), divided attention (Trail Making Test Part A), complex attention (Digit Symbol Substitution Test, Symbol Coding Raw Test, Simple Reaction Time), and executive function (Trail Making Test Part B, Delis-Kaplan Executive Function System Verbal Fluency); (3) Motor function (Fugl-Meyer Assessment [FMA], Unified Parkinson’s Disease Rating Scale [UPDRS], Freezing of Gait Questionnaire); (4) Activities of daily living (ADL) (Barthel Index, Functional Independence Measure [FIM]); (5) Quality of life (Korean version of the SmithKline-Beecham Quality of Life Scale, Parkinson’s Disease Questionnaire-39); (6) Mood, assessed through apathy (Apathy Evaluation Scale, Neuropsychiatric Inventory) and depression (Beck Depression Inventory, Hamilton Depression Rating Scale, Geriatric Depression Scale, Zung Self-Rating Depression Scale, Profile of Mood States questionnaire); (7) Fatigue (Fatigue Severity Scale, Mental Fatigue Scale).

The secondary outcomes included adverse events, such as changes in vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate), body weight, and other reported symptoms. Only randomized controlled trials (RCTs) were included. Studies that did not meet these criteria, such as nonhuman studies, cohort studies, and case reports, were excluded. Two independent reviewers (Jong Mi Park and Seo Yeon Yoon) screened the titles, abstracts, and full texts of the studies to ensure eligibility, and disagreements were resolved through discussion.

Data extraction

Data were independently extracted by 2 reviewers (Jong Mi Park and Seo Yeon Yoon) using a standardized extraction form that included variables such as study characteristics (author name, publication year, and sample size), participant demographics (age, sex, and diagnosis), intervention details (methylphenidate dosage, duration, and administration frequency), comparison protocols (placebo or standard therapy), and outcomes (primary and secondary measures, effect sizes, and adverse events). To prevent artificial inflation of the sample size owing to duplicate data, which could narrow confidence intervals (CIs), overestimate statistical power, and decrease statistical accuracy, the outcome with the longest follow-up (FU) duration was extracted when multiple outcomes with different FU durations were reported for the same test. Additionally, different assessment tools, even those that measure the same concept, may evaluate slightly different aspects, increasing the heterogeneity across studies. This could undermine the reliability and generalizability of the results of the meta-analysis. Therefore, when multiple assessment tools were used to evaluate the same outcome, the tool reported in at least 2 or more studies was selected for analysis.

Quality assessment

The quality of the included studies was evaluated using the Revised Cochrane Risk of Bias Tool for Randomized Trials. This tool assesses bias across 5 domains: randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results. For each study, the risk of bias was classified as low, some concerns, or high [11]. Two reviewers (Jong Mi Park and Seo Yeon Yoon) independently assessed the risk of bias, and discrepancies in the assessments were resolved by a third reviewer (Yong Wook Kim).

Statistical analysis

To analyze the data, the mean and standard deviation (SD) of the change from baseline values were initially calculated for the intervention and control groups. When complete data were unavailable, these values were computed in accordance with Section 6 of the Cochrane Handbook (version 6.3). Effect sizes are expressed as mean difference (MD) or standardized mean difference (SMD) with corresponding 95% CI using a random-effects model. Given the diverse geographic and medical backgrounds of the included studies, a restricted maximum likelihood random-effects meta-analysis was employed to account for the substantial heterogeneity. The I² statistic was used to measure heterogeneity, whereas publication bias was evaluated using funnel plots and Egger’s test. As recommended by previous studies, Egger’s test was conducted only for meta-analyses that included 3 or more studies [12,13]. All statistical analyses were performed using Stata software (version 18; Stata Corp., College Station, TX, USA), with significance set at p < 0.05.

RESULTS

Study identification and characteristics

A total of 10,845 records were identified through database and register searches. After removing 836 duplicate records, 10,009 unique records were screened for titles and abstracts. After excluding 9,958 records during this stage, 51 full-text articles were assessed for eligibility. Of these, 25 studies were excluded for the following reasons: insufficient data (n = 10), inappropriate control groups (n = 4), secondary analyses on economic outcomes or response predictors from previously included RCTs (n = 4), imaging-focused studies (n = 3), open-label trial designs (n = 2), and study protocols without reported results (n = 1). Studies excluded due to insufficient data lacked key statistical information (e.g., means, SDs, or change scores), reported outcomes only in graphical format, or did not provide adequate information to estimate effect sizes despite attempts to apply imputation methods. Studies with inappropriate control groups were excluded because they did not include a placebo or standard therapy comparator. Instead, they used active comparators such as other pharmacological agents (e.g., antidepressants or stimulants), or compared different dosing regimens of methylphenidate, which did not align with our predefined PICOS criteria. An additional 7 records were identified through citation searches. Finally, 33 RCTs were included in the review, including studies on TBI (n = 14), stroke (n = 5), PD (n = 4), AD (n = 7), other dementias (n = 2), and MS (n = 1). Fig. 1 shows a flowchart of the general study selection process.

Fig. 1. PRISMA flowchart of screening and selecting the studies.

KISS, Korean studies Information Service System; RCT, randomized controlled trial; TBI, traumatic brain injury; AD, Alzheimer’s disease; PD, Parkinson’s disease; MS, multiple sclerosis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Among the included studies, 1,369 participants (TBI, n = 444; stroke, n = 128; PD, n = 149; AD, n = 584; other dementias, n = 38, and MS, n = 26) were included, with 816 in the intervention group and 820 in the control group. Participants’ ages ranged from 10.7 [14] to 78 years [15], regardless of the type of brain disease. Methylphenidate dosing protocols varied widely. Daily doses ranged from 10 to 80 mg and were administered either as single doses or divided into multiple doses. Weight-based dosing protocols ranged from 0.1 to 1 mg/kg/day, given once or twice daily. In some studies, doses were titrated, starting from 5 mg and increasing to 20 mg/day or starting from 1 mg/kg/day and increasing by 0.25 mg/kg increments per week. Detailed characteristics of the included studies are summarized in Table 1 [4,5,6,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43].

Table 1. Characteristics of the included studies.

Study		No. of participants (experimental/control)	Age (yr; experimental/control)	Intervention protocol	Control protocol	Follow-up duration	Outcome measure	Main findings
Traumatic brain injury
	Dymowski et al. [16] (2017)	E = 6	E = 35 ± 14.2	Methylphenidate 0.6 mg/kg daily for 7 wk	Placebo	9 mon	1. Attention capacity (Digit Span Forward, Digit Span total)	No significant improvement in attention with methylphenidate. A trend of increased blood pressure observed.
		C = 4	C = 32.5 ± 15.3				2. Attention working memory (Digit Span back word)
							3. Focused attention (simple selective attention task)
							4. Divided attention (TMT-A)
							5. Executive function (TMT-B)
							6. Vital signs (BP, pulse)
	Haddadi et al. [17] (2022)	E = 31	E = 40.1 ± 17.4	Methylphenidate 0.3 mg/kg up to a maximum of 20 mg daily for week	Placebo	1 wk	1. Level of consciousness (GCS)	Methylphenidate group had improved GCS upon discharge, reduced ICU and hospital stay, with no significant difference in delirium or agitation.
		C = 31	C = 33 ± 12.7				2. ICU and hospital stay duration
							3. Delirium (CAM-ICU)
							4. Agitation (RASS)
	Jenkins et al. [18] (2019)	20 (crossover)	E = 40 ± 12	Methylphenidate 0.3 mg/kg twice daily for 2 wk	Placebo	4 wk	1. Divided attention (TMT-A)	Significant improvement in attention with methylphenidate for patients with low caudate dopamine transporter binding. Improvements also noted in apathy and fatigue, no improvement in patients with normal binding levels.
			C = 39 ± 12				2. Executive function (TMT-B)
							3. SPECT dopamine transporter binding
							4. Self and caregiver assessments (apathy, fatigue)
	Kamali et al. [19] (2021)	E = 45	E = 34.2 ± 7.9	Methylphenidate 0.3 mg/kg twice daily (6 AM and 2 PM) for 8 days	Routine ICU drugs without methylphenidate	8 days	1. Level of consciousness (GCS)	Methylphenidate significantly reduced intubation duration and improved consciousness recovery rate No significant difference in APACHE II scores between groups.
		C = 45	C = 34.5 ± 8.3				2. APACHE II
							3. Intubation duration
	Kim et al. [20] (2006)	E = 9	E = 30.1 ± 11.5	Methylphenidate Single dose of 20 mg single dose	Placebo	2 hr	1. Attention working memory (2-back working memory task)	Methylphenidate significantly improved working memory (reaction time and accuracy) compared to placebo. No significant effects observed for visuospatial attention.
		C = 9	C = 38.3 ± 9.8			2 days	2. Visuospatial attention (accuracy, reaction time)
	Kim et al. [21] (2012)	23 (crossover)	34.2 ± 11.5	Methylphenidate 0.3 mg/kg, single dose	Placebo	1 day	1. Perfusion fMRI	Significant improvement in accuracy and reaction time on Visual Sustained Attention Task. Enhanced reaction time on 2-back task. Reduced cerebral blood flow in task-related regions.
							2. Attention working memory (2-back working memory task)
							3. Complex attention test (Visual Sustained Attention Task)
	Kurowski et al. [22] (2019)	26 (crossover)	11.5 ± 2.8	Methylphenidate 1 mg/kg/day for 4 wk	Placebo	8 wk	1. Vital signs (SBP, DBP, pulse)	Methylphenidate included mild weight loss (~1 kg), increased systolic BP (~3–6 points), and mild appetite changes.
							2. Weight
	LeBlond et al. [23] (2019)	26 (crossover)	11.5 ± 2.8	Methylphenidate 1 mg/kg/day for 4 wk	Placebo	4 wk	1. Focused attention (CPT)	Significant improvements in attention. Cognitive performance declined after discontinuation of medication.
						8 wk	2. Executive function (D–KEFS VF)
	Lee et al. [6] (2005)	E = 10	E = 35.3 ± 8.0	Methylphenidate 5–20 mg daily for 4-wk	Placebo	4 wk	1. Global cognition (MMSE)	Methylphenidate significantly reduced depressive symptoms and improved cognitive function and daytime alertness compared to placebo and sertraline.
		C = 10	C = 35.5 ± 7.2				2. Complex attention test (Digit symbol test, recognition reaction time, motor reaction time)
							3. Depression (BDI, HAM-D)
							4. Quality of Life (KvSBQoL)
							5. Leeds Sleep Evaluation Questionnaire
	Mahalick et al. [14] (1998)	14 (crossover)	10.7 ± 2.9	Methylphenidate 0.3 mg/kg twice daily for 2 wk	Placebo	2 wk	1. Focused attention (Gordon Diagnostic System, Ruff 2 & 7 Cancellation Test)	Significant improvement in attention, vigilance, and processing speed with methylphenidate compared to placebo.
	McDonald et al. [24] (2017)	E = 18	E = 43.1 ± 12.3	Methylphenidate 0.1 mg/kg twice daily for 2–4 days, then 0.2 mg/kg twice daily for 2–4 days then 0.3 mg/kg twice daily for the remainder of 6 wk	Placebo	6 wk	1. Focused attention (Gordon Diagnostic System)	Methylphenidate improved attention. Adverse effects included insomnia and headaches.
		C = 18	C = 37.2 ± 12.0				2. Complex attention test (symbol coding raw score)
	Plenger et al. [25] (1996)	E = 10	E = 31.4 ± 17.0	Methylphenidate 0.3 mg/kg twice daily for 30 days	Placebo	30 days	1. Level of Consciousness (GCS)	Significant improvement level of consciousness. Effects not sustained at 90 days. Side effects included insomnia and headache.
		C = 13	C = 26.6 ± 8.7			90 days
	Willmott and Ponsford [26] (2009)	40 (crossover)	26.3 ± 9.1	Methylphenidate 0.3 mg/kg twice daily over 2 wk	Placebo	2 wk	1. Focused attention (simple selective attention task, complex selective attention)	Significant improvement in information processing speed and attention tasks. No effect on working memory or strategic attention.
							2. Complex attention test (Symbol Digit Modalities Task)
							3. Attention working memory (Letter Number Sequencing)
	Zhang and Wang [27] (2017)	E = 18	E = 36.3 ± 10.9	Methylphenidate titrated from 5 mg to 20 mg daily for 30 wk	Placebo	30 wk	1. Global cognition (MMSE)	Methylphenidate significantly reduced mental fatigue and improved cognitive performance on reaction time and memory tasks compared to placebo. Significant reductions in depression scores were also observed. No major safety concerns were noted.
		C = 18	C = 34.9 ± 12.1				2. Complex attention test (Digit symbol test, Choice reaction time)
							3. Depression (BDI, HAM-D)
							4. Vital signs (SBP, DBP, pulse)
							5. Weight
							6. Fatigue (MFS)
Stroke
	Delbari et al. [28] (2011)	E = 19	E = 64.1 ± 10.8	Methylphenidate 17 mg daily combined with 45-min daily physiotherapy for 15 days	Placebo	6 mon	1. Global cognition (MMSE)	Methylphenidate group showed significant improvement in mood at 90 and 180 days, with cognitive improvements.
		C = 20	C = 65.3 ± 9.6				2. Depressio (GDS)
	Grade et al. [5] (1998)	E = 10	E = 69.8 ± 3.7	Methylphenidate 5–30 mg daily, increased gradually and combined with physical therapy for 3 wk	Placebo	3 wk	1. Global cognition (MMSE)	Methylphenidate group showed improvements in mood, activities of daily living, and motor function compared to placebo. Cognitive outcomes were not significantly different. Minimal side effects were reported.
		C = 11	C = 72.6 ± 3.5				2. Depression (HAM-D, ZDS)
							3. Motor Function (FMA)
							4. Activities of daily living (FIM)
	Lokk et al. [29] (2011)	E = 19	E = 64.1 ± 10.8	Methylphenidate 10 mg daily combined with 45-min daily physiotherapy, 15 sessions over 15 days	Placebo	6 mon	1. Motor Function (FMA)	There were slightly but significant differences in BI and NIHSS compared to placebo at the 6-mon follow-up.
		C = 20	C = 65.3 ± 9.6				2. Activities of daily living (BI)
							3. Stroke Severity (NIHSS)
	Luauté et al. [30] (2018)	E = 13	E = 58.6 ± 5.9	Methylphenidate 10 mg twice daily for 5 days combined with Prism Adaptation therapy for spatial neglect	Placebo combined with Prism Adaptation therapy	45 days	1. Activities of daily living (FIM)	Methylphenidate group showed a significant long-term functional improvement on the FIM, with no serious adverse events.
		C = 8	C = 51.2 ± 11.7				2. Neglect test (line bisection, line cancellation, star cancellation, Albert test)
	Tardy et al. [31] (2006)	8 (crossover)	60.5 ± 9.5	Methylphenidate 20 mg daily for 7 days	Placebo crossover	7 days	1. Motor Function (finger tapping)	Methylphenidate group led to significant motor performance improvement, and heightened cerebral activation in the ipsilesional primary sensorimotor cortex and contralesional premotor cortex. No adverse events reported.
							2. Cerebral activation (fMRI)
Parkinson's disease
	Drijgers et al. [32] (2012)	23 (crossover)	63.9 ± 9.8	Methylphenidate 10 mg daily for 7 days	Placebo	7 days between treatments	1. Complex attention test (Letter Digit Substitution Test)	Methylphenidate improved anhedonia and vigor without significant cognitive changes.
							2. Depression (Profile of Mood States questionnaire)
							3. Fatigue (Profile of Mood States questionnaire)
	Foley [33] (2011)	23 (crossover)	67.6 ± 9.6	Methylphenidate max 80 mg/day divided in 3 doses over 12 weeks	Placebo, with a 3-wk washout period between crossovers	12 wk	1. Motor function (UPDRS)	No significant benefit of methylphenidate on gait, marginal improvement in freezing. Trend for worsening UPDRS and FOGQ scores. Some marginal improvement in depression measures.
							2. Freezing of Gait Questionnaire
							3. Depression (GDS)
	Mendonça et al.[34] (2007)	E = 17	E = 66.3 ± 7.6	Methylphenidate 10 mg 3 times per day for 6 wk	Placebo	6 wk	1. Motor function (UPDRS)	Significant reduction in fatigue scores for methylphenidate group compared to placebo. No change in motor function. Adverse effects more frequent in placebo group.
		C = 17	C = 62.2 ± 10.0				2. Fatigue (FSS)
	Moreau et al. [35] (2012)	E = 35	E = 63 ± 4	Methylphenidate 1 mg/kg per day for 90 days, dose titration over 4 weeks with 0·25 mg/kg increments per week.	Placebo	90 days	1. Complex attention test (Simple reaction time)	Methylphenidate improved gait, reduced freezing in off-levodopa state. Some improvement in UPDRS Motor.
		C = 34	C = 64 ± 5				2. Motor function (UPDRS)
							3. Freezing of Gait Questionnaire
							4. Quality of life (PDQ39)
							5. Vital signs (pulse)
							6. Weight
Alzheimer's disease
	Drye et al. [36] (2013)	13 (crossover)	N/R	Methylphenidate 10 mg twice daily for 3 days them 20 mg twice daily for remaining 6 wk	Placebo + standardized psychosocial intervention	2 wk	1. Global cognition (MMSE)	Methylphenidate showed greater improvement in apathy symptoms compared to placebo.
						4 wk	2. Apathy (AES, NPI-apathy)
						6 wk
	Herrmann et al. [37] (2008)	13 (crossover)	77.9 ± 7.8	Methylphenidate 10 mg twice daily for 2 wk with a 1-wk placebo washout	Placebo crossover	2 wk	1. Global cognition (MMSE)	Methylphenidate led to modest improvement in apathy symptoms compared to placebo. Adverse events were reported, with some requiring discontinuation (delusion, flushing, agitation, restlessness, hallucinations, irregular heart beat).
							2. Apathy (AES, CGI, NPI-apathy)
	Lanctôt et al. [38] (2014)	E = 29	76 ± 8	Methylphenidate 10 mg twice daily for 6 wk	Placebo	6 wk	1. Attention capacity (Digit span forward)	Methylphenidate improved attention (Digit Span forward) compared to placebo.
		C = 31
	Mintzer et al. [4] (2021)	E = 89	76 (median)	Methylphenidate 10 mg twice daily for 6 mon	Placebo + standardized psychosocial intervention	6 mon	1. Global cognition (MMSE)	Methylphenidate showed significant reduction in apathy. No significant effects on cognition or quality of life. Adverse events were minimal.
		C = 91					2. Attention capacity (Digit span forward)
							3. Attention working memory (Digit span back word)
							4. Apathy (NPI-apathy)
	Padala et al. [39] (2018)	E = 30	E = 77.0 ± 7.5	Methylphenidate 10 mg twice daily for 12 wk	Placebo	12 wk	1. Global cognition (MMSE)	Methylphenidate significant reduction in apathy and improvement in functional status and caregiver burden. Notable improvements in cognition and mild adverse events observed.
		C = 29	C = 76.2 ± 8.5				2. Apathy (AES)
							3. Activities of daily living
							4. Vital signs (SBP, pulse)
	Rosenberg et al. [15] (2013)	E = 29	E = 78 ± 8	Methylphenidate 20 mg daily for 6 wk + standardized psychosocial intervention	Placebo + standardized psychosocial intervention	6 wk	1. Apathy (AES, NPI-apathy)	Significant improvement in apathy for methylphenidate group compared to placebo. Adverse events included weight loss > 2% and mild anxiety.
		C = 31	C = 75 ± 9
	Zeng et al. [40] (2024)	E = 98	E = 74.8 ± 6.9	Methylphenidate 20 mg daily for 6 mon	Placebo	6 mon	1. Vital signs (SBP, pulse)	Methylphenidate group showed modest weight loss. Higher incidence of falls in methylphenidate group but no major cardiovascular events.
		C = 101	C = 74.7 ± 6.4
Other dementias
	Leijenaar et al. [41] (2020)	30 (crossover)	67 ± 8	Methylphenidate 10 mg single doses	Placebo	Same day	1. Vital signs (SBP, DBP, pulse)	Methylphenidate increase SBP and pulse.
	Rahman et al. [42] (2006)	8 (crossover)	62.0 ± 10.1	Methylphenidate 40 mg single doses	Placebo	Same day	1. Vital signs (SBP, DBP, pulse)	Methylphenidate increase SBP but not pulse.
MS
	Harel et al. [43] (2009)	E = 14	E = 34.6 ± 10.2	Methylphenidate 10 mg single doses	Placebo	Same day	1. Attention working memory ((PASAT3″, PASAT2″)	Methylphenidate significantly improved attention performance. No adverse effects reported.
		C = 12	C = 40.1 ± 10.5

TMT, Trail Making Test; BP, blood pressure; GCS, Glasgow Coma Scale; ICU, intensive care unit; CAM-ICU, Confusion Assessment Method for the intensive care unit; RASS, Richmond Agitation-Sedation Scale; SPECT, single-photon emission computed tomography; APACHE II, Acute Physiology and Chronic Health Evaluation II; fMRI, functional magnetic resonance imaging; SBP, systolic blood pressure; DBP, diastolic blood pressure; CPT, continuous performance test; D–KEFS VF, Delis-Kaplan executive function system Verbal Fluency; MMSE, Mini-Mental State Examination; BDI, Beck Depression Inventory; HAM-D, Hamilton Depression Rating Scale; KvSBQoL, Korean version of SmithKline-Beecham Quality of Life Scale; MFS, Mental Fatigue Scale; GDS, Geriatric Depression Scale; ZDS, Zung self-rating Depression Scale; FMA, Fugl-Meyer Assessment; FIM, Functional Independence Measure; BI, Barthel Index; NIHSS, National Institute of Health Stroke Scale; AES, Apathy Evaluation Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; FOGQ, The Freezing of Gait Questionnaire; FSS, Fatigue Severity Scale; PDQ39, Parkinson’s Disease Questionnaire-39; NPI, Neuropsychiatric Inventory; CGI, Clinical Global Impression; PASAT, Paced Auditory Serial Addition Test; N/R, not reported.

Assessment of risk and publication biases

Of the 33 included RCTs, 27% (9 RCTs) were assessed as having a low risk of bias and 73% (24 RCTs) had some concerns. All trials employed an appropriate randomization process; therefore, the risk of improper randomization was low. However, there were concerns about the risk of selective reporting of results due to missing outcome data and lack of prior protocol registration. Supplementary Fig. 1 shows a traffic light diagram for each study included in the evaluation. Supplementary Fig. 2 shows a funnel plot of publication bias for each meta-analysis. As shown in Table 2, we used Egger’s test to test for publication bias. Most analyses showed no significant publication bias, except for depression (p = 0.007) and systolic blood pressure (p = 0.005).

Table 2. A summary of all the results of the meta-analysis.

Outcome	Categories	Effect size (95% CI)	p value	I2 statistic (%)	Egger p value
Consciousness	Level of consciousness (GCS)	MD, 0.51 (−0.76, 1.78)	0.43	91.23	0.774
Cognition	Global cognitive function (MMSE)	MD, 0.22 (−0.43, 0.88)	0.51	88.26	0.665
	Attention	SMD, 0.43 (0.03, 0.84)	0.04	82.80	0.101
	Executive Function	SMD, 1.62 (−0.65, 3.89)	0.16	91.21	0.304
Motor	FMA	MD, 0.66 (0.13, 1.18)	0.01	0.0	N/A
	UPDRS	MD, −0.30 (−0.80, 0.20)	0.24	56.15	0.467
	Freezing of Gait	MD, 0.17 (−0.20, 0.54)	0.36	0.0	N/A
Activities of daily living		SMD, 0.71 (0.37, 1.06)	< 0.001	0.0	0.497
Quality of life		SMD, 0.17 (−0.25, 0.58)	0.43	0.0	N/A
Mood	Apathy	SMD, −0.60 (−0.95, −0.26)	< 0.001	49.55	0.201
	Depression	SMD, −0.50 (−0.94, −0.05)	0.03	64.82	0.007
Fatigue		SMD, −0.21 (−0.82, 0.39)	0.49	62.54	0.177
Side Effects	Pulse	MD, 0.28 (0.10, 0.47)	< 0.001	0.0	0.785
	SBP	MD, 0.22 (−0.06, 0.49)	0.13	32.00	0.005
	DBP	MD, 0.21 (−0.17, 0.60)	0.28	0.0	0.116
	Weight	MD, −0.22 (−0.56, 0.13)	0.22	0.0	0.240

Values in bold represent statistically significant findings with p values less than 0.05.

CI, confidence interval; MD, mean difference; SMD, standardized mean difference; GCS, Glasgow Coma Scale; MMSE, Mini-Mental State Examination; N/A, not applicable; FMA, Fugl-Meyer Assessment; UPDRS, Unified Parkinson’s Disease Rating Scale; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Effects of methylphenidate

Level of consciousness and cognition

Level of consciousness, assessed by the GCS, did not show a statistically significant improvement (MD, 0.51; 95% CI, −0.76 to 1.78; p = 0.43; I² = 91.23%) (Fig. 2A). Global cognitive function, as measured by the MMSE, also did not show significant changes (MD, 0.22; 95% CI, −0.43 to 0.88; p = 0.51; I² = 88.26%) (Fig. 2B). However, the attention domain demonstrated significant improvement with methylphenidate use (SMD, 0.43; 95% CI, 0.03 to 0.84; p = 0.04; I² = 82.89%) (Fig. 2C). In subgroup analysis by disease, patients with TBI showed significant improvement in the attention domain with methylphenidate use (SMD, 0.30; 95% CI, 0.06 to 0.54; p = 0.01; I² = 0%), whereas there were no significant changes in patients with AD, MS, and PD. Changes in executive function with methylphenidate use did not reach statistical significance (SMD, 1.62; 95% CI, −0.65 to 3.89; p = 0.16; I² = 91.21%) (Fig. 2D).

Fig. 2. Meta-analysis of the effects of methylphenidate on consciousness and cognition. (A) Level of consciousness (GCS). (B) Global cognition (MMSE). (C) Attention. (D) Executive function.

GCS, Glasgow Coma Scale; MD, mean difference; CI, confidence interval; TBI, traumatic brain injury; REML, restricted maximum likelihood; MMSE, Mini-Mental State Examination; AD, Alzheimer’s disease; SMD, standardized mean difference; MS, multiple sclerosis; PD, Parkinson’s disease.

Motor function

Significant improvements were observed on motor function evaluated with the FMA in patients with stroke (SMD, 0.66; 95% CI, 0.13 to 1.18; p = 0.01; I² = 0%) (Fig. 3A). In contrast, assessments using the UPDRS in patients with PD did not demonstrate significant changes (MD, −0.30; 95% CI, −0.80 to 0.20; p = 0.24; I² = 56.15%) (Fig. 3B). Similarly, no significant improvements in Freezing of Gait were observed in patients with PD (MD, 0.17; 95% CI, −0.20 to 0.54; p = 0.36; I² = 0%) (Fig. 3C).

Fig. 3. Meta-analysis of the effects of methylphenidate on motor function. (A) FMA. (B) UPDRS. (C) Freezing of Gait.

FMA, Fugl-Meyer Assessment; MD, mean difference; CI, confidence interval; REML, restricted maximum likelihood; UPDRS, Unified Parkinson’s Disease Rating Scale; PD, Parkinson’s disease.

ADL and quality of life

The meta-analysis revealed significant improvements in ADL in patients with AD and stroke (SMD, 0.71; 95% CI, 0.37 to 1.06; p < 0.001; I² = 0%) (Fig. 4A). In contrast, quality of life did not demonstrate significant improvements (SMD, 0.17; 95% CI, −0.25 to 0.58; p = 0.43; I² = 0%) (Fig. 4B).

Fig. 4. Meta-analysis of the effects of methylphenidate on activities of daily living and quality of life. (A) Activities of daily living. (B) Quality of life.

SMD, standardized mean difference; CI, confidence interval; AD, Alzheimer’s disease; REML, restricted maximum likelihood; PD, Parkinson’s disease; TBI, traumatic brain injury.

Mood and fatigue

Apathy was notably reduced in patients with AD (SMD, −0.60; 95% CI, −0.95 to −0.26; p < 0.001; I² = 49.55%) (Fig. 5A). Similarly, depression was significantly improved in patients with PD, stroke, and TBI (SMD, −0.50; 95% CI, −0.94 to −0.05; p = 0.03; I² = 64.82%) (Fig. 5B). In contrast, the effects of methylphenidate on fatigue were not statistically significant (SMD, −0.21; 95% CI, −0.82 to 0.39; p = 0.49; I² = 62.54%) (Fig. 5C).

Fig. 5. Meta-analysis of the effects of methylphenidate on mood and fatigue. (A) Apathy. (B) Depression. (C) Fatigue.

SMD, standardized mean difference; CI, confidence interval; AD, Alzheimer’s disease; REML, restricted maximum likelihood; PD, Parkinson’s disease; TBI, traumatic brain injury.

Side effects of methylphenidate

This meta-analysis assessed the side effects of methylphenidate, focusing on vital signs and other adverse events. A statistically significant increase in pulse rate was observed (MD, 0.28; 95% CI, 0.10 to 0.47; p < 0.001; I² = 0%) (Fig. 6A). However, changes in systolic blood pressure (MD, 0.22; 95% CI, −0.06 to 0.49; p = 0.13; I² = 32.00%) (Fig. 6B) and diastolic blood pressure (MD, 0.21; 95% CI, −0.17 to 0.60; p = 0.28; I² = 0%) (Fig. 6C) were not statistically significant. In terms of weight, no significant changes were detected (MD, −0.22; 95% CI, −0.56 to 0.13; p = 0.22; I² = 0%) (Fig. 6D). Adverse events reported across the studies included mild gastrointestinal discomfort, insomnia, and appetite suppression; however, no serious adverse events were identified.

Fig. 6. Meta-analysis of the side effects of methylphenidate. (A) Pulse. (B) Systolic blood pressure. (C) Diastolic blood pressure. (D) Weight.

CI, confidence interval; AD, Alzheimer’s disease; REML, restricted maximum likelihood; PD, Parkinson’s disease; TBI, traumatic brain injury.

A summary of all results from the meta-analyses is presented in Table 2.

DISCUSSION

This systematic review and meta-analysis evaluated the efficacy and safety of methylphenidate in patients with various brain diseases. The study found significant improvements in specific areas, such as attention, motor function, ADL, and mood, particularly apathy and depression. However, there were no significant effects on consciousness, global cognitive function, executive function, fatigue, or quality of life. In addition, although significant side effects, such as increased pulse rate, were observed, other side effects, such as changes in blood pressure or body weight, were not reported. These findings suggest that methylphenidate may offer several potential benefits in the treatment of patients with various brain diseases.

Methylphenidate is a CNS stimulant mainly used to treat ADHD [44]. Owing to its immediate onset of action and mild side effects compared to other stimulants or antidepressants [45,46], methylphenidate has also been used in patients with brain diseases to treat a wide range of symptoms, including cognitive and motor function and mood [4,5,6,15,35]. Regarding cognition, methylphenidate has been recommended in previous systematic reviews to improve attention and working memory in TBI [7,47]. For other brain diseases, its cognitive effect has been less studied than that of TBI, and the results are somewhat controversial [4,5,35]. In our meta-analysis, attention was improved with methylphenidate use, and the effects were significant only in patients with TBI, which is consistent with previous studies [47]. The frontostriatal circuit plays critical roles in attention, organization, planning, motivation, and motor control. In patients with TBI, cerebral hemorrhage usually occurs in the frontal lobes, resulting in attention deficits. This anatomical brain region appears to be associated with the effects of methylphenidate in the TBI population. Another reason could be a decline in striatal dopamine availability with age [48], as elderly individuals with reduced dopamine transporter availability have a reduced response to methylphenidate [49]. Among the studies included in this meta-analysis, the mean age of the TBI population was > 20 years less than that of the patients with other brain diseases.

In contrast, global cognitive and executive functions did not show significant changes in this meta-analysis. Previous studies have shown that methylphenidate significantly improves the MMSE score, a global assessment of cognitive function, in patients with end-stage cancer with hypoactive delirium [50], but has little effect on the MMSE score in patients with AD [15]. Methylphenidate has also demonstrated selective effects on executive function in conditions such as ADHD [51] and TBI [23], primarily through enhanced dopaminergic activity and improved prefrontal-striatal connectivity. However, few studies have specifically assessed executive function in stroke and AD populations, limiting the ability to draw definitive conclusions regarding its efficacy in these groups. Moreover, global cognition and executive function have been investigated less frequently than attention, and findings in these areas remain inconsistent. As a result, only a limited number of relevant studies were eligible for inclusion in this meta-analysis, thereby reducing the statistical power to detect significant effects. Another possible reason for this is the association between aging and dopamine transporter availability, considering that more than half of the studies assessing global cognitive function included patients with AD and stroke. Thus, both age- and disease-related declines in dopaminergic function may contribute to the limited ability to respond to methylphenidate. Further assessment of dopamine transporter availability may be useful for predicting the response to methylphenidate in various brain diseases.

Although only amantadine has been recommended for patients with disorders of consciousness (DOC) [52], other pharmacological agents, including methylphenidate, may still be used in practice. However, our meta-analysis did not show any significant effects of methylphenidate on consciousness. Only 3 studies were included in the meta-analysis, all of which evaluated the level of consciousness using the GCS [17,19,25]. The Coma Recovery Scale–Revised (CRS-R) is widely used to assess recovery from DOC during rehabilitation. Surprisingly, no controlled trial has used CRS-R to determine the effects of methylphenidate. In nearly all clinical and research contexts, the initial severity of TBI is measured using the GCS; however, this may not accurately reflect the level of consciousness [53]. The GCS, while excellent for initial trauma assessment and acute care situations, lacks the depth needed to monitor recovery in patients with severe neurological impairment [53]. The CRS-R evaluates multiple domains, including auditory, visual, and motor functions as well as oromotor function, arousal, and communication [54]. It can measure subtle changes in consciousness in patients with DOC and has been associated with functional outcome [54,55]. Therefore, future studies with longer FU durations using the CRS-R are recommended to determine the effects of methylphenidate in patients with DOC.

In our meta-analysis, improvements in FMA in the stroke population and ADL in the AD and stroke populations were noted. However, the mean FMA improvement (MD, 0.66) did not exceed the minimum clinically important difference (MCID) thresholds (12.4 for subacute stroke, 3.5 for chronic stroke) [56,57], suggesting limited direct clinical relevance. Given the concurrent improvements in apathy (AD) and depression (stroke, TBI, and PD), these functional gains may be mediated by mood enhancement rather than neuromotor recovery alone. Previous studies support this interpretation: remission of post-stroke depression is associated with up to 2.5 times greater improvements in ADL [58], and in one study, improvement in depression showed a strong correlation with ADL gains measured by the Barthel Index (r = 0.925) [59]. Additionally, psychosocial participation has been shown to mediate over 80% of motor and 70% of cognitive recovery in neurorehabilitation [60]. The observed ADL improvement (SMD, 0.71) likely reflects not only physical capacity but also increased motivation and emotional readiness. For example, reduced apathy in AD may promote greater engagement in daily activities. At the neurobiological level, methylphenidate enhances dopaminergic activity in prefrontal-striatal circuits involved in both motivation and motor planning [61], potentially counteracting depression-related dopamine depletion that impairs motor learning [62]. Mood-focused interventions have also been shown to enhance motor recovery through increased frontal lobe activation. These results suggest that functional gains in FMA and ADL are more likely attributable to the combined effects of mood improvement and active participation in rehabilitation, rather than to isolated neuropharmacological effects on motor pathways.

Regarding side effects, only increased pulse rate was statistically significant; however, considering the absolute value of 0.28, it might be negligible in clinical practice.

Recently, the Korean MFDS initiated regulatory measures for methylphenidate use in 2023 and established strict prescription criteria to prevent misuse. Consequently, methylphenidate use in neurorehabilitation is limited. Methylphenidate has been widely used in brain diseases, particularly TBI and stroke, mainly for cognition and mood. In this systematic review, although there were some studies on the TBI population, there were only a limited number of studies on stroke populations. The small number of studies may have contributed to the non-significant findings in patients with stroke. In addition, the heterogeneity of the included studies, including drug dosage, duration of use, and outcome measures, made it difficult to perform a subgroup analysis and to define the target population that may benefit from methylphenidate. More clinical trials in stroke patients are needed, and studies predicting the response to methylphenidate using an assessment of dopamine transporter availability are needed to elucidate the pathophysiology and define target populations.

This study has several notable advantages. First, this is one of the few meta-analyses to comprehensively assess the effects of methylphenidate on a wide range of brain disorders. By including a wide range of outcomes, from cognitive and motor functions to mood and ADL, it provides a holistic understanding of the drug’s effects. Second, careful selection of assessment tools and a focus on outcomes with strong FU data minimized potential bias and improved the generalizability of the results. Third, in addition to its efficacy, this study systematically evaluated the side effects of methylphenidate, providing a balanced perspective of its benefits and risks.

Despite its strengths, this study had several limitations. The first limitation is that despite finding statistically significant improvements, no analysis was performed to determine whether the level was at least equal to the MCID. Although the MCID could not be identified in the meta-analysis of various assessment tools, the same assessment tools showed smaller values than the MCID. Future studies should incorporate MCID evaluations to provide a better clinical context for methylphenidate’s efficacy. Second, high heterogeneity was observed in many of the analyzed outcomes, particularly in cognitive domains such as attention and executive function, which may have reduced the precision of the effect estimates. The variability in the administration protocols and duration of methylphenidate use across studies likely contributed to this heterogeneity. Furthermore, even when the same outcome was assessed, different measurement instruments may have evaluated slightly different aspects, increasing the heterogeneity in cognitive assessments. Large-scale studies with standardized protocols and consistent assessment tools are required to address this issue. Third, the limited sample sizes of certain subgroups, such as those with MS and other dementias, may have reduced the statistical power to detect significant effects. Small sample sizes restricted the generalizability of the findings and may contribute to inconclusive results in these specific populations. Fourth, many of the studies included in this analysis had FU periods ≤ 7.5 months, but most had FU periods < 2 months, which may not have been long enough to fully understand the long-term efficacy and safety of methylphenidate in neurologically affected populations. Long-term studies are required to fully understand the sustained benefits and potential risks of this intervention. Fifth, while Egger’s test indicated no significant publication bias for most outcomes, significant results for depression and systolic blood pressure suggested potential reporting biases that could overestimate treatment effects in these domains. This finding highlights the importance of cautious interpretation and the need for further studies to confirm these findings.

This systematic review and meta-analysis demonstrated that methylphenidate has variable effects depending on the type of brain disease. In TBI, attention improved significantly; in stroke and AD, gains were observed in ADL, though the improvement in motor function among stroke patients did not reach the MCID. Apathy was reduced in AD, and depression improved in PD, stroke, and TBI. However, no significant effects were observed in consciousness, global cognitive function, executive function, fatigue, or quality of life. Although the drug showed a favorable safety profile with no serious adverse events, a slight increase in pulse rate was noted. Future research should focus on larger long-term studies with standardized protocols and include MCID thresholds to ensure clinically meaningful results. These findings will help optimize the use of methylphenidate in patients with various brain diseases.

SUPPLEMENTARY MATERIALS

Supplementary Data 1

PRISMA 2020 checklist

Supplementary Data 2

Search strategy

Supplementary Fig. 1

Risk of bias in the included studies assessed using the Cochrane Risk of Bias 2.0 Tool.

Supplementary Fig. 2

Funnel plot to detect publication bias.