Methylphenidate for children and adolescents with autism spectrum disorder

Nancy Sturman; Laura Deckx; Mieke L van Driel

doi:10.1002/14651858.CD011144.pub2

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Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

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

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Analysis 1.1

Comparison 1 TEACHER rated: high dose versus placebo, Outcome 1 Primary outcome: ADHD symptoms ‐ inattention (same measurement instrument).

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Analysis 1.2

Comparison 1 TEACHER rated: high dose versus placebo, Outcome 2 Primary outcome: ADHD symptoms ‐ hyperactivity (different measurement instrument).

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Analysis 1.3

Comparison 1 TEACHER rated: high dose versus placebo, Outcome 3 Primary outcome: ASD symptoms.

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Analysis 1.4

Comparison 1 TEACHER rated: high dose versus placebo, Outcome 4 Secondary outcome: adverse events.

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Analysis 2.1

Comparison 2 TEACHER rated ‐ sensitivity: correlation 0, Outcome 1 Primary outcome: ADHD symptoms ‐ inattention (same measurement instrument).

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Analysis 2.2

Comparison 2 TEACHER rated ‐ sensitivity: correlation 0, Outcome 2 Primary outcome: ADHD symptoms ‐ hyperactivity (different measurement instrument).

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Analysis 2.3

Comparison 2 TEACHER rated ‐ sensitivity: correlation 0, Outcome 3 Primary outcome: ASD symptoms.

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Analysis 3.1

Comparison 3 TEACHER rated ‐ sensitivity: correlation 0.8, Outcome 1 Primary outcome: ADHD symptoms ‐ inattention (same measurement instrument).

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Analysis 3.2

Comparison 3 TEACHER rated ‐ sensitivity: correlation 0.8, Outcome 2 Primary outcome: ADHD symptoms ‐ hyperactivity (different measurement instrument).

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Analysis 3.3

Comparison 3 TEACHER rated ‐ sensitivity: correlation 0.8, Outcome 3 Primary outcome: ASD symptoms.

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Analysis 4.1

Comparison 4 TEACHER rated ‐ sensitivity: different scales, Outcome 1 Primary outcome: ADHD ‐ hyperactivity.

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Analysis 5.1

Comparison 5 PARENT rated: high dose versus placebo, Outcome 1 Primary outcome: ADHD symptoms (same measurement instrument).

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Analysis 5.2

Comparison 5 PARENT rated: high dose versus placebo, Outcome 2 Primary outcome: ASD symptoms ‐ impaired social interaction.

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Analysis 5.3

Comparison 5 PARENT rated: high dose versus placebo, Outcome 3 Secondary outcome: adverse events.

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Analysis 6.1

Comparison 6 PARENT rated ‐ sensitivity: correlation 0, Outcome 1 Primary outcome: ADHD symptoms (same measurement instrument).

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Analysis 6.2

Comparison 6 PARENT rated ‐ sensitivity: correlation 0, Outcome 2 Primary outcome: ASD symptoms ‐ Impaired social interaction.

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Analysis 7.1

Comparison 7 PARENT rated ‐ sensitivity: correlation 0.8, Outcome 1 Primary outcome: ADHD symptoms (same measurement instrument).

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Analysis 7.2

Comparison 7 PARENT rated ‐ sensitivity: correlation 0.8, Outcome 2 Primary outcome: ASD symptoms ‐ Impaired social interaction.

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Analysis 8.1

Comparison 8 PARENT rated ‐ sensitivity: different scales, Outcome 1 Primary outcome: ADHD ‐ hyperactivity.

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Analysis 9.1

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 1 Primary outcome: ADHD ‐ inattention.

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Analysis 9.2

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 2 Primary outcome: ADHD ‐ hyperactivity.

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Analysis 9.3

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 3 Primary outcome: ASD ‐ impaired social interaction.

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Analysis 9.4

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 4 Primary outcome: ASD ‐ stereotypical behaviours.

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Analysis 9.5

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 5 Primary outcome: ASD ‐ overall ASD.

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Analysis 9.6

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 6 Secondary outcome: adverse events ‐ abdominal discomfort.

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Analysis 9.7

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 7 Secondary outcome: adverse events ‐ reduced appetite.

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Analysis 9.8

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 8 Secondary outcome: adverse events ‐ dizziness.

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Analysis 9.9

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 9 Secondary outcome: adverse events ‐ drowsiness.

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Analysis 9.10

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 10 Secondary outcome: adverse events ‐ headache.

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Analysis 9.11

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 11 Secondary outcome: adverse events ‐ anxiety.

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Analysis 9.12

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 12 Secondary outcome: adverse events ‐ depressed mood.

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Analysis 9.13

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 13 Secondary outcome: adverse events ‐ irritability.

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Analysis 9.14

Comparison 9 TEACHER rated ‐ subgroup: doses, Outcome 14 Secondary outcome: adverse events ‐ repetitive movements.

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Analysis 10.1

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 1 Primary outcome: ADHD ‐ inattention.

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Analysis 10.2

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 2 Primary outcome: ADHD ‐ hyperactivity.

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Analysis 10.3

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 3 Primary outcome: ASD ‐ impaired social interaction.

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Analysis 10.4

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 4 Secondary outcome: adverse events ‐ abdominal discomfort.

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Analysis 10.5

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 5 Secondary outcome: adverse events ‐ reduced appetite.

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Analysis 10.6

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 6 Secondary outcome: adverse events ‐ headache.

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Analysis 10.7

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 7 Secondary outcome: adverse events ‐ anxiety.

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Analysis 10.8

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 8 Secondary outcome: adverse events ‐ depressed mood.

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Analysis 10.9

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 9 Secondary outcome: adverse events ‐ irritability.

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Analysis 10.10

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 10 Secondary outcome: adverse events ‐ repetitive behaviours.

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Analysis 10.11

Comparison 10 PARENT rated ‐ subgroup: doses, Outcome 11 Secondary outcome: adverse events ‐ sleep disturbance.

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Summary of findings for the main comparison. High‐dose methylphenidate versus placebo for symptoms of ADHD and ASD as rated by teachers

High‐dose methylphenidate versus placebo for symptoms of ADHD and ASD as rated by teachers
Patient or population: children aged 6 to 18 years with ASD Settings: paediatric or psychiatric outpatient or inpatient units, special education units or classes Rater: teachers, clinicians or programme staff Intervention: high‐dose methylphenidate Comparison: placebo Follow‐up: 1 week Measure of effect: if necessary, we transformed results to ensure that lower scores represented fewer symptoms for all comparisons. We standardised results using standardised mean differences (SMD). As such, results are expressed in standardised units, and a negative SMD represents an improvement in symptoms. As a rough guide, an SMD of 0.20 to 0.49 represents a small effect, 0.50 to 0.79 a moderate effect, and ≥ 0.80 a large clinical effect. We used an SMD of 0.52 as the minimum clinically relevant intertreatment difference.
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with high‐dose methylphenidate	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Primary outcome: ADHD‐like symptoms
Inattention Measured using SNAP‐IV inattention subscale (range 0 to 27)	—	The mean inattention score in the intervention group was 2.72 units lower (5.37 lower to 0.06 lower)	—	51 teachers (2 RCTs)	⊕⊕⊝⊝ Low^a,b	—
Hyperactivity	—	The mean hyperactivity score in the intervention group was 0.78 standard units lower (1.13 lower to 0.43 lower)	—	73 teachers (4 RCTs)	⊕⊕⊝⊝ Low^a,b	—
Impulsivity	See comment		—	36 teachers (1 RCT)	—	Insufficient data to pool results
Primary outcome: core symptoms of ASD
Impaired social interaction	—	The mean impaired social interaction score in the intervention group was 0.51 standard units lower (1.07 lower to 0.05 higher)	—	63 teachers (3 RCTs)	⊕⊝⊝⊝ Very low^a,b,c	—
Impaired communication	See comment		—	24 teachers (1 RCT)	—	Insufficient data to pool results
Stereotypical behaviours	—	The mean stereotypical behaviours score in the intervention group was 0.34 standard units lower (0.84 lower to 0.17 higher)	—	69 teachers (3 RCTs)	⊕⊕⊝⊝ Low^a,b	—
Overall ASD	—	The mean overall ASD score in the intervention group was 0.53 standard units lower (1.26 lower to 0.19 higher)	—	36 teachers (2 RCTs)	⊕⊕⊝⊝ Low^a,b	—
Secondary outcome: rate of adverse effects
Total number of adverse events	See comment		—	79 teachers (1 RCT)	—	Insufficient data to pool results^d
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ADHD: attention deficit hyperactivity disorder; ASD: autism spectrum disorders; CI: confidence interval; SNAP‐IV: Swanson, Nolan and Pelham scale, Fourth Revision;RCT: randomised controlled trial
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one point for limitations in design and implementation. ^bDowngraded one point for imprecision because data came from small studies. ^cDowngraded one point for indirectness of evidence. ^dData on individual adverse events are presented in the text.

Summary of findings for the main comparison. High‐dose methylphenidate versus placebo for symptoms of ADHD and ASD as rated by teachers

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Summary of findings 2. High‐dose methylphenidate versus placebo for symptoms of ADHD and ASD as rated by parents

High‐dose methylphenidate versus placebo for symptoms of ADHD and ASD as rated by parents
Patient or population: Children aged 6 to 18 years with ASD Settings: paediatric or psychiatric outpatient or inpatient units, special education units or classes Rater: parents Intervention: high‐dose methylphenidate Comparison: placebo Follow‐up: 1 week Measure of effect: if necessary, we transformed results to ensure that lower scores represented fewer symptoms for all comparisons. We standardised results using standardised mean differences (SMD). As such, results are expressed in standardised units, and a negative SMD represents an improvement in symptoms. As a rough guide, an SMD of 0.20 to 0.49 represents a small effect, 0.50 to 0.79 a moderate effect, and ≥ 0.80 a large clinical effect. We used an SMD of 0.52 as the minimum clinically relevant intertreatment difference.
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with high‐dose methylphenidate	Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Primary outcome: ADHD‐like symptoms
Inattention Measured using SNAP‐IV inattention subscale (range 0 to 27)	—	The mean inattention score in the intervention group was 3.16 units lower (6.89 lower to 0.57 higher)	—	71 parents (2 RCTs)	⊕⊕⊝⊝ Low^a,b	—
Impulsivity	See comment		—	48 parents (1 RCT)	—	Insufficient data to pool results
Hyperactivity Measured using ABC hyperactivity subscale (range 0 to 48)	—	The hyperactivity score in the intervention group was 6.61 units lower (12.19 lower to 1.03 lower)	—	71 parents (2 RCTs)	⊕⊕⊝⊝ Low^a,b	—
Primary outcome: core symptoms of ASD
Impaired social interaction	—	The impaired social interaction score in the intervention group was 0.21 standard units lower (0.60 lower to 0.18 higher)	—	71 parents (2 RCTs)	⊕⊝⊝⊝ Very low^a,b,c	—
Impaired communication	See comment		—	48 parents (1 RCT)	—	Insufficient data to pool results
Stereotypical behaviours	See comment		—	48 parents (1 RCT)	—	Insufficient data to pool results
Overall ASD	See comment		—	48 parents (1 RCT)	—	Insufficient data to pool results
Secondary outcome: rate of adverse events
Total number of adverse events	See comment		—	108 parents (1 RCT)	—	Insufficient data to pool results^d
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ABC: Aberrant Behavior Checklist; ADHD: attention deficit hyperactivity disorder; ASD: autism spectrum disorders; CI: confidence interval; SNAP‐IV: Swanson, Nolan and Pelham scale, Fourth Revision;RCT: randomised controlled trial
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^a Downgraded one point for limitations in design and implementation. ^b Downgraded one point for imprecision because data came from small studies. ^c Downgraded one point for indirectness of evidence. ^d Data on individual adverse events are presented in the text.

Summary of findings 2. High‐dose methylphenidate versus placebo for symptoms of ADHD and ASD as rated by parents

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Table 1. Instruments used to measure ADHD outcomes

Instrument	Inattention		Impulsivity		Hyperactivity
Instrument	Teacher^a	Parent	Teacher^a	Parent	Teacher^a	Parent
ABC	—	—	—	—	H , Q, R	P , R
ACTeRS	P	P	—	—	P	P
Conners' Global Index	—	—	P	P	P	P
CPRS‐R and CTRS‐R	P	P	—	—	P, Q	P
Conners' Abbreviated Parent/Teacher Questionnaire	—	—	—	—	—	—
SNAP‐IV	P , R	P , R	—	—	P , R	P, R
^a'Teacher' includes clinician and trained observer raters. Letters (H, P, Q, R) indicate those studies that used a particular instrument to rate the particular outcome. Letters in bold and underlined font indicate the instrument we used in our meta‐analysis: H: Handen 2000; P: Pearson 2013; Q: Quintana 1995; R: RUPP 2005. ABC: Aberrant Behavior Checklist; ACTeRS: ADD‐H (Attention deficit disorder ‐ hyperactivity) Comprehensive Teacher Rating Scale; ADHD: attention deficit hyperactivity disorder; CPRS‐R: Conners' Parent Rating Scale ‐ Revised; CTRS‐R: Conners' Teacher Rating Scale ‐ Revised;SNAP‐IV: Swanson, Nolan, and Pelham Questionnaire, Fourth Edition.

Table 1. Instruments used to measure ADHD outcomes

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Table 2. Instruments used to measure ASD outcomes

Instrument	Impaired social interaction		Impaired communication		Stereotypical behaviours		Overall ASD
Instrument	Teacher ^a	Parent	Teacher ^a	Parent	Teacher ^a	Parent	Teacher ^a	Parent
ABC	H	P	H	P	H , Q	P	—	—
ACTeRS	P	P	—	—	—	—	—	—
CARS	—	—	—	—	—	—	H	—
CYBOCS	—	—	—	—	R	—	—	—
CPRS‐R and CTRS‐R	P	P	—	—	—	—	—	—
Iowa CTRS	H	—	—	—	—	—	—	—
Social communication questionnaire	—	—	—	—	—	—	—	P
SNAP‐IV	R	R	—	—	—	—	—	—
Clinician Global Impression ‐ Severity	—	—	—	—	—	—	P	—
^a'Teacher' includes clinician and trained observer raters; Letters (H, P, Q, R) indicate the studies which used a particular instrument to rate the particular outcome. Letters in bolded and underlined font indicate the instrument we used in our meta‐analysis: H: Handen 2000; P: Pearson 2013; Q: Quintana 1995; R: RUPP 2005; ABC: Aberrant Behavior Checklist; ACTeRS: ADD‐H (Attention deficit disorder ‐ hyperactivity) Comprehensive Teacher Rating Scale; ASD: autism spectrum disorders; CARS: Child Autism Rating Scale; CPRS‐R: Conners' Parent Rating Scale ‐ Revised; CTRS‐R: Conners' Teacher Rating Scale ‐ Revised; CYBOCS: Children's Yale‐Brown Obsessive Compulsive Scales;Iowa CTRS: Iowa Conners' Teacher Rating Scale; SNAP‐IV: Swanson, Nolan, and Pelham Questionnaire, 4th Edition.

Table 2. Instruments used to measure ASD outcomes

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Comparison 1. TEACHER rated: high dose versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD symptoms ‐ inattention (same measurement instrument) Show forest plot	2		Mean Difference (Random, 95% CI)	‐2.72 [‐5.37, ‐0.06]

2 Primary outcome: ADHD symptoms ‐ hyperactivity (different measurement instrument) Show forest plot	4		Std. Mean Difference (Random, 95% CI)	‐0.78 [‐1.13, ‐0.43]

3 Primary outcome: ASD symptoms Show forest plot	4		Std. Mean Difference (Random, 95% CI)	Subtotals only

3.1 Impaired social interaction	3		Std. Mean Difference (Random, 95% CI)	‐0.51 [‐1.07, 0.05]
3.2 Stereotypical behaviours	3		Std. Mean Difference (Random, 95% CI)	‐0.34 [‐0.84, 0.17]
3.3 Overall ASD	2		Std. Mean Difference (Random, 95% CI)	‐0.53 [‐1.26, 0.19]
4 Secondary outcome: adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Gastrointestinal effects: abdominal discomfort	2	69	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.16]
4.2 Gastrointestinal effects: reduced appetite	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.43, 4.12]
4.3 General physical adverse effect: dizziness	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.06, 5.18]
4.4 General physical adverse effect: drowsiness	2	69	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.47, 8.55]
4.5 General physical adverse effect: headache	2	69	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.16]
4.6 Psychological effects: anxiety	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.47, 2.18]
4.7 Psychological effects: depressed mood	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.37, 3.79]
4.8 Psychological effects: irritability	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.29, 2.27]
4.9 Repetitive behaviours: repetitive movements or tics	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.21, 1.57]

Comparison 1. TEACHER rated: high dose versus placebo

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Comparison 2. TEACHER rated ‐ sensitivity: correlation 0

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD symptoms ‐ inattention (same measurement instrument) Show forest plot	2		Mean Difference (Random, 95% CI)	‐2.55 [‐5.15, 0.06]

2 Primary outcome: ADHD symptoms ‐ hyperactivity (different measurement instrument) Show forest plot	4		Std. Mean Difference (Random, 95% CI)	‐0.70 [‐1.07, ‐0.33]

3 Primary outcome: ASD symptoms Show forest plot	4		Std. Mean Difference (Random, 95% CI)	Subtotals only

3.1 Impaired social interaction	3		Std. Mean Difference (Random, 95% CI)	‐0.44 [‐0.99, 0.11]
3.2 Stereotypical behaviours	3		Std. Mean Difference (Random, 95% CI)	‐0.24 [‐0.71, 0.23]
3.3 Overall ASD	2		Std. Mean Difference (Random, 95% CI)	‐0.56 [‐1.28, 0.17]

Comparison 2. TEACHER rated ‐ sensitivity: correlation 0

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Comparison 3. TEACHER rated ‐ sensitivity: correlation 0.8

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD symptoms ‐ inattention (same measurement instrument) Show forest plot	2		Mean Difference (Random, 95% CI)	Subtotals only

2 Primary outcome: ADHD symptoms ‐ hyperactivity (different measurement instrument) Show forest plot	4		Std. Mean Difference (Random, 95% CI)	Subtotals only

3 Primary outcome: ASD symptoms Show forest plot	4		Std. Mean Difference (Random, 95% CI)	Subtotals only

3.1 Impaired social interaction	3		Std. Mean Difference (Random, 95% CI)	‐0.53 [‐1.09, 0.02]
3.2 Stereotypical behaviours	3		Std. Mean Difference (Random, 95% CI)	‐0.37 [‐0.87, 0.14]
3.3 Overall ASD	2		Std. Mean Difference (Random, 95% CI)	‐0.53 [‐1.25, 0.20]

Comparison 3. TEACHER rated ‐ sensitivity: correlation 0.8

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Comparison 4. TEACHER rated ‐ sensitivity: different scales

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD ‐ hyperactivity Show forest plot	4		Std. Mean Difference (Random, 95% CI)	Subtotals only

1.1 ABC	3		Std. Mean Difference (Random, 95% CI)	‐0.75 [‐1.21, ‐0.29]
1.2 SNAP	2		Std. Mean Difference (Random, 95% CI)	‐0.65 [‐1.12, ‐0.19]
1.3 Conners' Rating Scale ‐ Revised	2		Std. Mean Difference (Random, 95% CI)	‐0.87 [‐1.26, ‐0.48]

Comparison 4. TEACHER rated ‐ sensitivity: different scales

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Comparison 5. PARENT rated: high dose versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD symptoms (same measurement instrument) Show forest plot	2		Mean Difference (Random, 95% CI)	Subtotals only

1.1 Inattention	2		Mean Difference (Random, 95% CI)	‐3.16 [‐6.89, 0.57]
1.2 Hyperactivity	2		Mean Difference (Random, 95% CI)	‐6.61 [‐12.19, ‐1.03]
2 Primary outcome: ASD symptoms ‐ impaired social interaction Show forest plot	2		Std. Mean Difference (Random, 95% CI)	‐0.21 [‐0.60, 0.18]

3 Secondary outcome: adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Gastrointestinal effects: abdominal discomfort	2	164	Risk Ratio (M‐H, Random, 95% CI)	4.30 [0.91, 20.34]
3.2 Gastrointestinal effects: reduced appetite	2	164	Risk Ratio (M‐H, Random, 95% CI)	8.28 [2.57, 26.73]
3.3 General physical adverse effect: headache	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.87 [0.10, 33.86]
3.4 General physical effect: sleep disturbance	2	164	Risk Ratio (M‐H, Random, 95% CI)	3.51 [0.59, 20.82]
3.5 Psychological effects: anxiety	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.22, 5.79]
3.6 Repetitive behaviours: general	2	164	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.43, 1.75]
3.7 Psychological effects: irritability	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.25, 6.36]
3.8 Psychological effects: depressed mood	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.05, 62.33]

Comparison 5. PARENT rated: high dose versus placebo

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Comparison 6. PARENT rated ‐ sensitivity: correlation 0

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD symptoms (same measurement instrument) Show forest plot	2		Mean Difference (Random, 95% CI)	Subtotals only

1.1 Inattention	2		Mean Difference (Random, 95% CI)	‐3.11 [‐6.84, 0.62]
1.2 Hyperactivity	2		Mean Difference (Random, 95% CI)	‐6.44 [‐10.00, ‐0.89]
2 Primary outcome: ASD symptoms ‐ Impaired social interaction Show forest plot	2		Std. Mean Difference (Random, 95% CI)	Subtotals only

Comparison 6. PARENT rated ‐ sensitivity: correlation 0

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Comparison 7. PARENT rated ‐ sensitivity: correlation 0.8

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD symptoms (same measurement instrument) Show forest plot	2		Mean Difference (Random, 95% CI)	Subtotals only

1.1 Inattention	2		Mean Difference (Random, 95% CI)	‐3.18 [‐6.91, 0.56]
1.2 Hyperactivity	2		Mean Difference (Random, 95% CI)	‐6.67 [‐12.25, ‐1.08]
2 Primary outcome: ASD symptoms ‐ Impaired social interaction Show forest plot	2		Std. Mean Difference (Random, 95% CI)	Subtotals only

Comparison 7. PARENT rated ‐ sensitivity: correlation 0.8

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Comparison 8. PARENT rated ‐ sensitivity: different scales

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD ‐ hyperactivity Show forest plot	2		Std. Mean Difference (Random, 95% CI)	Subtotals only

1.1 ABC	2		Std. Mean Difference (Random, 95% CI)	‐0.60 [‐1.04, ‐0.16]
1.2 SNAP	2		Std. Mean Difference (Random, 95% CI)	‐0.53 [‐1.04, ‐0.03]

Comparison 8. PARENT rated ‐ sensitivity: different scales

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Comparison 9. TEACHER rated ‐ subgroup: doses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD ‐ inattention Show forest plot	2		Std. Mean Difference (Random, 95% CI)	Subtotals only

1.1 Low dose	2		Std. Mean Difference (Random, 95% CI)	‐0.28 [‐0.61, 0.05]
1.2 Medium dose	2		Std. Mean Difference (Random, 95% CI)	‐0.46 [‐0.89, ‐0.04]
1.3 High dose	2		Std. Mean Difference (Random, 95% CI)	‐0.38 [‐0.75, ‐0.02]
2 Primary outcome: ADHD ‐ hyperactivity Show forest plot	4		Std. Mean Difference (Random, 95% CI)	Subtotals only

2.1 Low dose	2		Std. Mean Difference (Random, 95% CI)	‐0.40 [‐0.77, ‐0.03]
2.2 Medium dose	3		Std. Mean Difference (Random, 95% CI)	‐0.55 [‐1.00, ‐0.10]
2.3 High dose	4		Std. Mean Difference (Random, 95% CI)	‐0.78 [‐1.13, ‐0.43]
3 Primary outcome: ASD ‐ impaired social interaction Show forest plot	3		Std. Mean Difference (Random, 95% CI)	Subtotals only

3.1 Low dose	2		Std. Mean Difference (Random, 95% CI)	‐0.30 [‐0.59, ‐0.02]
3.2 Medium dose	3		Std. Mean Difference (Random, 95% CI)	‐0.44 [‐0.94, 0.06]
3.3 High dose	3		Std. Mean Difference (Random, 95% CI)	‐0.51 [‐1.07, 0.05]
4 Primary outcome: ASD ‐ stereotypical behaviours Show forest plot	3		Std. Mean Difference (Random, 95% CI)	Subtotals only

4.1 Medium dose	2		Std. Mean Difference (Random, 95% CI)	‐0.23 [‐0.43, ‐0.03]
4.2 High dose	3		Std. Mean Difference (Random, 95% CI)	‐0.34 [‐0.84, 0.17]
5 Primary outcome: ASD ‐ overall ASD Show forest plot	2		Std. Mean Difference (Random, 95% CI)	Subtotals only

5.1 Medium dose	2		Std. Mean Difference (Random, 95% CI)	‐0.52 [‐1.20, 0.17]
5.2 High dose	2		Std. Mean Difference (Random, 95% CI)	‐0.54 [‐1.26, 0.19]
6 Secondary outcome: adverse events ‐ abdominal discomfort Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Medium dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 High dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.16]
7 Secondary outcome: adverse events ‐ reduced appetite Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Medium dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.75, 2.20]
7.2 High dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.43, 4.12]
8 Secondary outcome: adverse events ‐ dizziness Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 Medium dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.01, 4.06]
8.2 High dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.06, 5.18]
9 Secondary outcome: adverse events ‐ drowsiness Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 Medium dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.05, 32.89]
9.2 High dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.47, 8.55]
10 Secondary outcome: adverse events ‐ headache Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 Medium dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10.2 High dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.16]
11 Secondary outcome: adverse events ‐ anxiety Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11.1 Medium dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.10, 4.46]
11.2 High dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.47, 2.18]
12 Secondary outcome: adverse events ‐ depressed mood Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

12.1 Medium dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.46, 2.26]
12.2 High dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.37, 3.79]
13 Secondary outcome: adverse events ‐ irritability Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

13.1 Medium dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.54, 1.70]
13.2 High dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.29, 2.27]
14 Secondary outcome: adverse events ‐ repetitive movements Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

14.1 Medium dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.30, 1.85]
14.2 High dose	2	69	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.21, 1.57]

Comparison 9. TEACHER rated ‐ subgroup: doses

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Comparison 10. PARENT rated ‐ subgroup: doses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome: ADHD ‐ inattention Show forest plot	2		Std. Mean Difference (Random, 95% CI)	Subtotals only

1.1 Low dose	2		Std. Mean Difference (Random, 95% CI)	‐0.27 [‐0.58, 0.03]
1.2 Medium dose	2		Std. Mean Difference (Random, 95% CI)	‐0.49 [‐0.85, ‐0.13]
1.3 High dose	2		Std. Mean Difference (Random, 95% CI)	‐0.51 [‐1.15, 0.14]
2 Primary outcome: ADHD ‐ hyperactivity Show forest plot	2		Std. Mean Difference (Random, 95% CI)	Subtotals only

2.1 Low dose	2		Std. Mean Difference (Random, 95% CI)	‐0.35 [‐0.55, ‐0.14]
2.2 Medium dose	2		Std. Mean Difference (Random, 95% CI)	‐0.67 [‐1.01, ‐0.33]
2.3 High dose	2		Std. Mean Difference (Random, 95% CI)	‐0.60 [‐1.04, ‐0.16]
3 Primary outcome: ASD ‐ impaired social interaction Show forest plot	2		Std. Mean Difference (Random, 95% CI)	Subtotals only

3.1 Low dose	2		Std. Mean Difference (Random, 95% CI)	‐0.15 [‐0.33, 0.04]
3.2 Medium dose	2		Std. Mean Difference (Random, 95% CI)	‐0.17 [‐0.37, 0.03]
3.3 High dose	2		Std. Mean Difference (Random, 95% CI)	‐0.21 [‐0.60, 0.18]
4 Secondary outcome: adverse events ‐ abdominal discomfort Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Low dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.73 [0.29, 10.34]
4.2 Medium dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	4.51 [0.98, 20.67]
4.3 High dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	4.30 [0.91, 20.34]
5 Secondary outcome: adverse events ‐ reduced appetite Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Low dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	3.41 [0.91, 12.78]
5.2 Medium dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	10.00 [3.14, 31.82]
5.3 High dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	8.28 [2.57, 26.73]
6 Secondary outcome: adverse events ‐ headache Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Low dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.77 [0.31, 9.94]
6.2 Medium dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	2.29 [0.55, 9.58]
6.3 High dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.87 [0.10, 33.86]
7 Secondary outcome: adverse events ‐ anxiety Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Low dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.45, 3.52]
7.2 Medium dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.46, 3.58]
7.3 High dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.22, 5.79]
8 Secondary outcome: adverse events ‐ depressed mood Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 Low dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.22, 4.42]
8.2 Medium dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	2.30 [0.39, 13.42]
8.3 High dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.05, 62.33]
9 Secondary outcome: adverse events ‐ irritability Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 Low dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.30, 5.83]
9.2 Medium dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.77 [0.23, 13.47]
9.3 High dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.25, 6.36]
10 Secondary outcome: adverse events ‐ repetitive behaviours Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 Low dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.54, 1.66]
10.2 Medium dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.55, 2.62]
10.3 High dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.43, 1.75]
11 Secondary outcome: adverse events ‐ sleep disturbance Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11.1 Low dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	2.94 [0.44, 19.64]
11.2 Medium dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	5.10 [0.71, 36.68]
11.3 High dose	2	164	Risk Ratio (M‐H, Random, 95% CI)	3.51 [0.59, 20.82]

Comparison 10. PARENT rated ‐ subgroup: doses

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