MPH Part 3 - Effects on Symptoms

Methylphenidate (MPH) improves the core ADHD symptoms of inattention, hyperactivity, and impulsivity in children, adolescents, and adults. According to a large review of numerous meta-analyses, the effect in children and adolescents was moderate to large during the first 12 weeks, and moderate in adults. Adults themselves rated the effect as less pronounced than the treating clinicians did. For treatment periods of 26 or 52 weeks, there is a lack of high- or moderate-certainty evidence for all ADHD treatments.

In addition to the core symptoms, studies showed improvements in attention, response inhibition (the ability to stop an action once it has begun), reaction time, and memory performance, mostly with small to moderate effects. According to several studies and reviews, improvements on neuropsychological tests and behavioral improvements were barely related.

According to textbooks and studies, MPH is particularly effective in treating hyperactivity, restlessness, and impulsivity. In a meta-analysis, aggressive behavior decreased to a similar extent as the core symptoms. Motivation and drive also improved. MPH also has a positive effect on perception, concentration, attention, handwriting, social skills, academic performance, reading, and math, as well as on emotional lability. However, academic performance improved to a lesser extent than the symptoms. Under real-world conditions and during long-term treatment, some observational studies found no improvement in academic outcomes.

In several studies, the effect on executive functions (planning, directing, and controlling one’s own actions) and working memory in performance tests was minimal, particularly among adults. No effect was found in individual studies on fine motor skills during writing or, following a single dose, on a test for recognizing emotions based on facial expressions around the eyes. The findings regarding Theory of Mind (the ability to infer the thoughts and feelings of others) are therefore contradictory.

Immediate release MPH typically takes effect within 15 to 20 minutes. There are no known cases of a delay of days or weeks before the onset of action. Studies showing improvement at a later stage involved a gradual increase in the dose. The claim that MPH affects attention for only 2 to 3 hours but restlessness for 7 to 8 hours is not supported by the cited sources. In a study on smoking cessation, sustained-release MPH was effective only in cases of more severe ADHD. Creativity in healthy individuals did not change after a single dose of MPH. In one study, children with ADHD who were not taking medication showed greater creativity in open-ended tasks than those who were taking medication.

1. Effect on Symptoms¶

Methylphenidate improves symptoms in children with ADHD: (Narrative review, E 4)¹

• Response time
• Variability in reaction time
• tonic alertness
• phasic alertness
• divided attention
• Flexibility/Shift in Attention/Task Switching
• selective attention
  • Inhibition
  • focused attention
• Task accuracy with respect to
  • Vigilance
  • divided attention
  • Inhibition
  • focused attention
  • Flexibility
  • Integration of sensory information
• Number of omissions and errors of commission on attention tasks

 

1.1. Effects on ADHD Symptoms According to Meta-Analyses¶

 

(E 1a): MPH reduced ADHD symptoms in meta-analyses involving

• For children and adolescents, short-term (up to 12 weeks):
  • an effect size greater than an SMD of 0.75 (95% CI 0.56 to 1.03) across all raters, with moderate to high certainty of evidence. Tolerability was not significantly worse than with placebo, and acceptability was better (RR 1.58, 95% CI 1.35 to 1.85). (Umbrella review, 221 reanalyzed meta-analyses from 47 reports, E 1a.)³
• for 6- to 12-year-olds with non-immediate release MPH (within-group before-and-after effect sizes, Cohen’s d) according to: (meta-analysis, k = 26, E 1a.)⁴
  • Teacher rating (k = 13, n = 588) d = 1.83 (95% CI 1.43 to 2.12)
  • Parental judgment (k = 15, n = 705) d = 1.53 (95% CI 1.23 to 1.82)
• in adults, for short-term use:
  • Clinician’s assessment: SMD 0.50 (95% CI 0.39 to 0.61), moderate certainty of evidence (umbrella review, 221 reanalyzed meta-analyses from 47 reports, E 1a.)³
  • Self-reported outcome: SMD 0.34 (95% CI 0.26 to 0.42), high certainty of evidence. Tolerability was worse than with placebo (RR 0.50, 95% CI 0.36 to 0.69). (umbrella review, 221 reanalyzed meta-analyses from 47 reports, E 1a.)³

For medium- and long-term effects (26 and 52 weeks, respectively), no evidence of high or moderate certainty was found for any treatment. (Umbrella review, 221 reanalyzed meta-analyses from 47 reports, E 1a.)³

(E 1a): Immediate release MPH improved additional areas in 6- to 12-year-olds (within-group before-and-after effect sizes, Cohen’s d) according to: (meta-analysis, k = 26, E 1a.)⁴

• Oppositional behavior and social behavior disorders, as assessed by teachers: d = 1.08 (95% CI 0.77 to 1.39)
• Social behavior in the teacher’s evaluation: d = 1.06 (95% CI 0.69 to 1.43)
• Social behavior as assessed by parents: d = 0.62 (95% CI 0.42 to 0.83)
• Oppositional behavior and social behavior disorders, as assessed by parents: d = 0.61 (95% CI 0.39 to 0.83)
• Academic performance d = 0.33 (95% CI −0.14 to 0.81, not significant)

A systematic review of 28 studies (2015 to 2025) found that MPH improved not only the core symptoms but also executive functions, social cognition, and emotional regulation in children and adolescents. (Systematic review, n = 28, full text not available to us, E 4.)⁵

1.2. Effects on Cognitive Functions¶

(E 1a): MPH improved cognitive function

• According to meta-analyses of placebo-controlled studies, for:
  • chronic administration (at least 1 week) for: (meta-analysis, k = 18, N = 1,667, E 1a.)⁶
    • Attention Hedges g 0.59 (95% CI 0.44 to 0.74)
    • Reaction inhibition: Hedges’ g = 0.37 (95% CI 0.23 to 0.51)
    • Working memory: Hedges’ g = 0.36 (95% CI 0.20 to 0.52)
    • Reaction time: Hedges’ g = 0.34 (95% CI: 0.11 to 0.57)
  • Children and adolescents (ages 5 to 18) for: (meta-analysis, k = 36, E 1a.)⁷
    • SMD for reaction time variability: 0.62 (95% CI: 0.34 to 0.90)
    • non-executive memory SMD 0.60 (95% CI 0.41 to 0.79)
    • Reaction inhibition SMD 0.41 (95% CI 0.27 to 0.55)
    • Executive memory SMD 0.26 (95% CI 0.13 to 0.39)
    • SMD response time 0.24 (95% CI 0.15 to 0.33)
  • People with ADHD aged 4.8 to 50.1 years, regardless of age, for: (METASTUDY, k = 50, N = 1,611, E 1a.)⁸
    • Sustained attention (k = 29, n = 956) ES 0.42 (95% CI 0.26 to 0.59)
    • Reaction inhibition (k = 25, n = 775) ES 0.40 (95% CI 0.22 to 0.58)
    • Working memory (k = 13, n = 559) ES 0.24 (95% CI 0.00 to 0.48), not significant (p = 0.053)
• Based on a systematic review (9 studies on MPH, 1 on lisdexamfetamine) for memory, vigilance, divided attention, phasic and tonic alertness, and focused attention; inconclusive findings for executive functions and academic performance (Systematic review, k = 10, n = 753, full text not available to us, E 2b.)⁹
• in individual studies on:
  • Working memory:
    • Verbal working memory (N-back) performance under MPH was at the same level as that of controls and better than without MPH, with no change in fMRI activation patterns ( , boys) (within-subject study with/without MPH and a control group, fMRI, N = 26, n = 14, Fig. 2b.)¹⁰
    • fewer errors on the backward digit span and arithmetic tasks (WISC-III), Stroop and Trail Making after 3 months of MPH (p ≤ 0.001) in treatment-naive boys with ADHD-C (Controlled longitudinal study, N = 53, n = 23, 3 months, E 2b.)¹¹
    • Visual-spatial working memory and inhibitory control were better after a single dose of MPH than at baseline, after anodal tDCS, and after sham tDCS. A single tDCS session over the left DLPFC was ineffective. (Randomized, sham-controlled, within-subject study, open-label MPH, n = 26, single dose, E 2a.)¹²
  • sustained attention:
    • Reaction time, reaction time variability, and omission errors on the CPT-II improved more significantly with OROS-MPH (mean 52.4 mg) than with atomoxetine (mean 1.4 mg/kg) (p < 0.05). The changes in test performance did not correlate with changes in symptoms. (RCT, double-blind, crossover, n = 102, 4 to 6 weeks each, E 1b.)¹³
  • Reaction selection and inhibition:
    • Greater improvement with OROS-MPH than with atomoxetine (increase in detectability on the CPT: 0.15 vs. 0.06, p < 0.01; Rapid Visual Information Processing: 3.45 vs. 2.22, p < 0.05). Both active ingredients improved executive functions. (Open-label randomized trial, N = 157, n = 79, 3 months, full text not available to us, E 1b.)¹⁴
    • Stroop-5 time and corrections were better with OROS-MPH than with atomoxetine; perseverative errors on the WCST were reduced with OROS-MPH (p = 0.005) (Open-label randomized trial, n = 30, 12 weeks, E 1b.)¹⁵
  • instrumental learning with rewards:
    • More accurate and faster responses with MPH, most pronounced at high doses. The learning curves of children with ADHD were not impaired without MPH compared to controls. (RCT, placebo-controlled, 3-dose crossover, N = 50, n = 23, E 1b.)¹⁶

The expectation of having received MPH did not alter behavior in boys with ADHD; only active MPH (0.3 mg/kg) improved it. The boys attributed their success to their own effort and ability, regardless of medication or expectation. (RCT, balanced placebo design, n = 136, full text not available to us, E 1b.)¹⁷

1.3. One-Year Course of Immediate Release MPH¶

After one year of treatment with immediate release MPH, levels decreased in children and adults (ages 4 to 65) in a Spanish multicenter chart review: (Retrospective observational study, n = 730, 1 year, E 3.)¹⁸

• the CGI severity score from 4.51 to 1.67
• the number of symptoms (DSM-IV-TR) for the mixed type, from 14.62 to 7.70
• the number of symptoms in the predominantly inattentive subtype from 7.90 to 4.34
• the number of symptoms in the predominantly hyperactive-impulsive subtype, from 6.73 to 3.39

86.9% were satisfied or very satisfied after one year; 25.75% reported at least one side effect. At the end of the study, 41.47% were still taking immediate release MPH, on average for 3.8 years. (Retrospective observational study, n = 730, 1 year, E 3.)¹⁸

1.4. Methylphenidate is particularly effective¶

1.4.1. Hyperactivity, Restlessness, and Impulsivity¶

• Hyperactivity (Textbook, E 4)¹⁹

  • Average activity in children, as objectively measured by actigraphy, is reduced compared to placebo, according to: (meta-analysis, k = 8 RCTs, N = 393, E 1a.)²⁰
    • Studies focusing only on daytime activity (k = 3): SMD -0.96 (95% CI -1.23 to -0.70)
    • All studies (k = 8): SMD -0.77 (95% CI -1.16 to -0.38)

• Restlessness (Textbook, E 4)¹⁹

• Impulsivity (Textbook, E 4)¹⁹

  • People with ADHD have reported on forums that MPH is more effective at reducing impulsivity than Vyvanse. (ADxS experience)²¹
  • A study of monkeys (which, by nature, do not have people with ADHD) concluded that low doses of MPH reduced impulsivity, while higher doses had a sedative effect. (animal study, n = 5, macaques, E 2b)²²
    This is consistent with empirical findings that an overdose of MPH can cause apathy.
  • MPH had varying effects on different forms of impulsivity:
    • MPH (0.5 mg/kg) improved response inhibition in 7- to 13-year-old boys with ADHD (shorter stop-signal reaction time, d = 1.54) and response variability, but not reflective impulsivity or decision quality (Information Sampling Task) (double-blind, placebo-controlled RCT, N = 42, n = 21, E 1b.)²³
    • OROS-MPH at the lowest effective dose (average 18 mg) improved choice impulsivity (delay discounting, d = 0.36) and working memory (d = 0.74) in 7- to 12-year-olds, but did not improve time perception. The improvements were not correlated with one another. (double-blind, placebo-controlled crossover study, n = 35, E 1b.)²⁴
    • Low oral doses of MPH (1.5 to 6 mg/kg) reduced the rate of temporal discounting in rhesus monkeys in a dose-dependent manner (less impulsive choice), with the strongest effect observed in one of the most impulsive animals and the weakest in the least impulsive one (animal study, n = 4, rhesus monkeys, E 2b.)²⁵

1.4.2. Aggression, Social Behavior, and Physical Symptoms¶

• (E 2b): Aggressiveness (textbook, E 4)¹⁹ * (open-label longitudinal study (dissertation), n = 24, average duration 5.4 months, E 2b)*²⁸

  • and, in fact, more effective than atomoxetine (open-label randomized trial, N = 160, 24 weeks, E 1b)²⁹
  • Stimulants (MPH in 75% of the studies, mean 22.18 mg/day) reduced aggression-related behavior in children and adolescents with ADHD with effect sizes similar to those observed for core symptoms. Comorbid social behavior disorders reduced the effect on overt aggression. The weighted mean effect size was as follows: (meta-analysis, k = 28, N = 683, E 1a.)³⁰
    • overt aggression in the teacher’s assessment: 1.04 (95% CI 0.79 to 1.32)
    • Total overt aggression: 0.84 (95% CI 0.70 to 1.02)
    • overt aggression as assessed by clinicians: 0.77 (95% CI 0.63 to 0.88)
    • Open aggression in the parental assessment: 0.71 (95% CI 0.42 to 1.15)
    • Total covert aggression (k = 7) 0.69 (95% CI 0.21 to 1.29)
  • MPH (0.3 mg/kg) reduced aggression directly observed during the treatment program in both highly and less aggressively behaved boys with ADHD. MPH had barely any effect on aggressive reactions to provocation in the laboratory or on social information processing. (Placebo-controlled study, n = 26, E 1b.)³¹

• MPH reduced the intensity of hyperactive boys’ behavior when provoked by peers, but did not significantly increase either global or specific measures of self-control. Cognitive-behavioral training improved self-control more than a control training program. Combining it with MPH did not provide any additional benefit. (Two placebo-controlled, double-blind studies, n = 21 and n = 24, 3 and 5 weeks, respectively; E 1b.)³²

• In a study of children aged 6 to 12 with aggression and ADHD, systematically titrated stimulants, when offered in conjunction with family-based behavioral therapy, eliminated aggression in 63% (96 out of 151) of the participants. (RCT, N = 175, n = 45 randomized, 8 weeks, E 1b.)³³ In children for whom stimulants did not sufficiently reduce aggression, adjunctive treatment with risperidone (effect size 1.3) or valproic acid (effect size 0.9) improved aggression, although risperidone was associated with weight gain.

• socially inappropriate behavior (textbook, E 4)¹⁹

  • Children with ADHD, behavioral problems, and callous-unemotional traits (emotional coldness) exhibited more behavioral problems, disobedience, and rule-breaking under behavioral therapy alone than children without these traits. With additional MPH (0.3 and 0.6 mg/kg twice daily), these differences largely disappeared. (placebo-controlled within-subject study, randomized order of priority, n = 37, 6 weeks, E 1b.)³⁴

• Behavioral problems (as self-reported), and it was more effective than atomoxetine (open-label randomized trial, N = 160, 24 weeks, E 1b.)²⁹

• somatic symptoms, and with better results than atomoxetine (open-label randomized trial, N = 160, 24 weeks, E 1b)²⁹

1.4.3. Motivation and Drive¶

• Motivation through reward (in adults with ADHD, MPH enhanced activation of the ventral striatum in fMRI in response to stimuli signaling a reward) (Double-blind, placebo-controlled fMRI study with a control group, N = 38, n = 18, single dose, E 2a.)³⁵
  • MPH (40 mg single dose) increased the willingness of adults with ADHD to exert greater effort for monetary rewards (Effort Expenditure for Rewards Task) to a greater extent than in controls (group × active ingredient p = 0.001). ADHD severity correlated with the MPH-induced increase in willingness to exert effort, but not with changes in attention performance. (Double-blind, placebo-controlled crossover study with a control group, N = 46, n = 23, E 1b.)³⁶
  • MPH (0.20 to 1.39 mg/kg) increased the breakpoint in a progressive-ratio task among 7- to 12-year-olds with ADHD and reduced both the time between responses and the variability in response times. The pause following the reward (task initiation) did not change. (Study comparing conditions with and without medication, n = 21, E 2b.)³⁷
  • MPH completely prevented effort-induced depletion of regulatory control (ego depletion) in healthy individuals, with a specific effect in the Slow-4 frequency band of reaction times, which is associated with mind wandering (Double-blind, placebo-controlled RCT, N = 108, healthy participants, E 1b.)³⁸

• Drive

• People with ADHD report quite consistently that MPH improves motivation more than AMP (ADxS experience)

1.4.4. Attention Performance and Effects in Adults¶

• Number of omissions and commissions in attention tasks (double-blind, randomized, placebo-controlled crossover study, N = 116, n = 58, E 1b)⁴⁵

• Mind wandering (in adults taking MPH or atomoxetine) (Cross-sectional cohort study, N = 94, n = 54, 3 months, full text not available to us, E 2b.)⁴⁶

MPH is effective in adults: (Narrative review with a structured search, E 4.)⁴⁷

• for the core symptoms of ADHD: SMD 0.49 (95% CI 0.35 to 0.64)
• against accompanying emotional dysregulation: SMD 0.34 (95% CI 0.23 to 0.45) (meta-analysis by Lenzi et al. of 21 placebo-controlled RCTs; secondary citation via Jaeschke et al.)

MPH is thought to be most effective for cognitive ADHD symptoms. Motor and social behaviors may gradually require slightly higher doses. (Narrative review, E 4)⁴⁸

1.5. The Positive Effects of Methylphenidate¶

1.5.1. Perception, Concentration, and Attention¶

• Perception (textbook, E 4)⁴⁹

  • Adults with ADHD had elevated auditory temporal discrimination thresholds, which MPH reduced to the level of non-affected individuals (within-subject study with/without MPH in randomized order of priority and a control group, N = 81, n = 33, E 2b.)⁵⁰

• Concentration (textbook, E 4)¹⁹

  • Many adults report that MPH allows for greater focus than Vyvanse, while Vyvanse makes them feel more relaxed overall and has a more consistent effect (ADxS experience)

• Attention (textbook, E 4)¹⁹

  • Distractibility is reduced, and attention is increased

1.5.2. Motor Skills and Handwriting¶

• motor restlessness (Textbook, E 4)¹⁹

• Typography and Graphic Expression (Textbook, E 4)⁵⁴

  • Handwriting legibility and accuracy were better in hyperactive boys while on MPH than after discontinuation. Writing fluency (speed and acceleration of writing movements) deteriorated while on MPH. Without MPH, writing movements were similar to those of controls. (Controlled study with/without MPH in a balanced order of priority, N = 42, n = 21, E 2b.)⁵⁵
  • MPH improved certain aspects of eye-hand coordination slightly more than placebo. Teacher ratings improved only in the MPH group. (RCT, double-blind, crossover, n = 19, E 1b.)⁵⁶

• Motor Skills

  • In 13 studies, MPH was primarily associated with lower motor variability and greater stability, though the results were inconsistent across tasks and often showed no change in mean performance (Systematic review, k = 13, E 2b.)⁵⁷
  • Stimulants tended to improve balance performance, although the evidence was of low certainty (2 Class II, 2 Class III, and 5 Class IV studies) (Systematic review, k = 9, full text not available to us, E 2b.)⁵⁸

1.5.3. Social Perception, Social Cognition, and Vulnerability¶

• social perceptual ability and facial responsiveness

• social cognition (performance on social cognition tests; according to a review cited there, 10 out of 13 studies showed improved theory-of-mind/mentalization performance and 7 showed improved emotion recognition, predominantly among MPH participants) and social interaction (Narrative review, E 4.)⁶⁰

• A study found that children with ADHD had basal oxytocin levels (in saliva) that were unchanged compared to people without ADHD. After interacting with a parent, oxytocin levels were significantly higher in children without ADHD than in people with ADHD, whose oxytocin levels decreased under placebo. Following a single dose of methylphenidate, oxytocin levels in people with ADHD rose after interaction with a parent, and the difference compared to people without ADHD was no longer present. At the same time, performance on theory-of-mind tasks normalized under MPH. (RCT, N = 90, n = 50, single dose, E 1b.)⁶¹

• Short-term MPH administration (up to 6 months) improved overall social functioning—as assessed by parents, teachers, or peers—and some components of theory of mind in 6- to 14-year-olds. The effect on nonverbal responses (emotional facial expressions) remained unclear. (Systematic review, k = 15, E 2b.)⁶²

• Among 7- to 16-year-olds treated with OROS-MPH, the following improvements were observed after 24 weeks: (Open-label randomized trial, N = 168, n = 83, 24 weeks, E 1b.)⁶³

  • School-related factor in the parental judgment: Cohen’s d = -0.82
  • School performance in self-assessment: Cohen’s d = -0.66
  • Peer relationships, as assessed by parents: Cohen’s d = -0.50
  • Peer relationships in self-evaluation: Cohen’s d = -0.25

• Empathy increased with MPH in children with ADHD with comorbid ODD (p = 0.003) and without ODD (p = 0.002). Only in the group without ODD did the increase in empathy correlate with symptom improvement (p = 0.015). (Open-label longitudinal study, n = 52, 12 weeks, Phase 2b.)⁶⁴

• Affective and cognitive empathy improved with MPH treatment in treatment-naive 6- to 17-year-olds. Only affective empathy was associated with improvements in inattention. (Naturalistic longitudinal study, n = 61, 6 months, E 2b.)⁶⁵

• In healthy women, a single dose of MPH (20 mg) doubled the degree of conformity to group judgments following moderate social conflict, but not following major conflict (RCT, n = 38, single dose, E 1b.)⁶⁶

• Rejection Sensitivity (Sensitivity to Rejection)
  Almost all of the people with ADHD we surveyed reported an improvement in their rejection sensitivity (which nearly every person with ADHD we surveyed experiences) as a result of MPH. A few people with ADHD reported that their rejection sensitivity worsened while taking MPH. One of these people with ADHD later turned out to be a non-responder for MPH who achieved better results with an amphetamine-based medication. (ADxS experience)

1.5.4. Time Processing, Academic Performance, and Executive Functions¶

• Time Processing

  • MPH reduced the variability in time production in 8- to 12-year-olds with ADHD in a dose-dependent manner (moderate to large effects). Reward and response cost had similar effects; MPH did not further enhance their effects. (RCT, placebo-controlled, crossover study with 3 doses, N = 50, n = 23, E 1b.)⁶⁷

• Academic performance

  • Academic performance and emotional well-being among MPH responders improved over a 2-year period across all treatment groups and remained stable. Intensive multimodal psychosocial adjunctive treatment did not provide any additional benefit compared to MPH alone. (RCT, n = 103, 2 years, E 1b.)⁶⁸
  • School grades improved after 6 months only with MPH alone (from 3.73 to 4.44, p = 0.0088) and behavior (3.80 to 4.60, p = 0.011) improved after 6 months only with MPH alone; this was not the case with parent training or its combination with MPH (RCT, n = 28, 6 months, E 1b.)⁶⁹
  • At an MPH dose of 0.3 mg/kg, the majority of measures of output, accuracy, efficiency, learning acquisition, effort, and self-correction improved both in the laboratory and in the classroom (RCT, double-blind, placebo-controlled, n = 16, E 1b.)⁷⁰
  • Academic performance improved in 61 to 66% of Taiwanese children (Chinese: p = 0.013; math: p = 0.004), and behavior improved in 68 to 78%. Neuropsychologically, only perseverative errors showed improvement (p = 0.022). (Open-label longitudinal study, n = 19, 16 weeks, E 2b.)⁷¹
  • OROS-MPH improved inattention/hyperactivity in Chinese schoolchildren (IOWA score decreased from 10.0 to 3.8, p < 0.0001), digit span, Stroop, WCST, coding, and teacher-rated academic performance (p < 0.0001) (Open-label longitudinal study with a control group, N = 194, n = 153, 12 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)⁷²

• Read

  • According to a meta-analysis for: (meta-analysis, k = 34, E 1a.)⁷³
    • Reading speed (reading tasks completed, k = 5) SMD 0.47 (95% CI 0.30 to 0.64)
    • Reading accuracy (k = 9) +6.2% (95% CI -0.9 to 13.4), not significant
  • MPH improved reading (more words read correctly) more significantly in children with ADHD and dyslexia than in children with ADHD alone or dyslexia alone, without eliminating the reading disorder (Open-label controlled study, N = 43, n = 24, at least 3 months, E 2a.)⁷⁴
  • MPH improved language processing tests, but not reading aloud (RCT, double-blind, crossover, n = 9, E 1b.)⁷⁵

• mathematical skills

  • According to a meta-analysis for: (meta-analysis, k = 34, E 1a.)⁷³
    • Computing productivity (k = 17) +7.8% (95% CI 4.3 to 11.2)
    • Computational accuracy (k = 29) +3.0% (95% CI 1.2 to 4.8)
  • Based on laboratory school studies involving 9- to 12-year-olds who received individually adjusted doses of OROS-MPH, 4 hours after administration (PERMP), for:
    • correctly solved math problems (n = 71) Cohen’s d 1.5 (RCT, double-blind, crossover, N = 78, n = 71, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)⁷⁶
    • completed math problems (n = 71) Cohen’s d 1.4 (RCT, double-blind, crossover, N = 78, n = 71, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)⁷⁶
    • correctly solved math problems (n = 68) Cohen’s d 1.2 (RCT, double-blind, crossover, n = 68, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)⁷⁷
    • Math problems solved (n = 68) Cohen’s d 1.2 (RCT, double-blind, crossover, n = 68, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)⁷⁷
  • The improvement in math performance under MPH was mediated by the child’s self-perceived competence as assessed by the parents (p < 0.01), not by cognitive functions (p = 0.082 to 0.641) or motivation to learn (p = 0.199 to 0.865), which MPH did not alter (RCT, double-blind, crossover, N = 130, n = 63, 7 days, manufacturer-funded, E 1b.)⁷⁸
  • MPH (0.3 mg/kg) accelerated arithmetic responses without a simultaneous second task. Under simultaneous dual-task conditions, MPH improved calculation accuracy at the expense of speed on the secondary task (redistribution of available capacity) (RCT, double-blind, placebo-controlled, crossover, n = 13, E 1b.)⁷⁹

• Children with ADHD showed reduced difficulties with arithmetic while taking MPH (0.3 to 0.5 mg/kg), a finding that was only detected through a combination of three neuropsychological tests. The individual tests distinguished people with ADHD (without medication) from people without ADHD. (Controlled longitudinal study, N = 42, n = 20, E 2b.)⁸⁰

• (E 1b): Academic performance and classroom behavior in:

  • Children: positive effects with linear dose-response curves (0.15, 0.3, and 0.6 mg/kg) on reading comprehension, math performance (quantity and accuracy), disruptive behavior and task-related behavior; only a marginal linear trend was observed in the acquisition of right-hand writing (RCT, double-blind, crossover, n = 29, E 1b.)⁸¹
  • Adolescents: positive effects on the quality of class notes, test and worksheet scores, written expression, teacher evaluations, and classroom behavior. The greatest improvement was usually observed between the placebo and the 10 mg dose (twice daily plus 5 mg in the afternoon, averaging 0.18 mg/kg per dose). Many adolescents did not benefit from higher doses; an increase from 20 to 30 mg tended to result in a deterioration rather than a significant improvement (RCT, double-blind, crossover, n = 45, 6 weeks, E 1b.)⁸²

• Executive functions in daily life (Parental Assessment, BRIEF2): After 8 weeks of treatment with 18 mg/day of sustained-release MPH, boys showed improvements in inhibition, self-monitoring, flexibility, emotional control, initiative, working memory, planning and organization, task monitoring, and organization of materials (p < 0.05). In a Go/NoGo task, reaction times decreased (p = 0.002) and accuracy increased (p = 0.009) (Open-label pre-post study, n = 26, 8 weeks, E 2b.)⁸³

• Executive functions on the Wisconsin Card Sorting Test (children with mixed-type symptoms who had not previously received treatment): OROS-MPH improved more domains than atomoxetine; both improved perseveration as well as conceptual learning and reasoning (Open-label randomized controlled trial, n = 43, up to 20 weeks, E 1b.)⁸⁴

1.5.5. Emotional and Psychological Symptoms¶

• Anxiety (Open-label longitudinal study (doctoral dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

• Tension (Open-label longitudinal study (doctoral dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

• Borderline traits (Open-label longitudinal study (doctoral dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

• Depression (Open-label longitudinal study (doctoral dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

  • Stimulant treatment was associated with a lower risk of depression in children and adolescents (RR 0.80, 95% CI 0.72 to 0.89) (Meta-analysis, k = 33, full text not available to us, E 2b.)⁸⁵

• emotional lability (Open-label longitudinal study (doctoral dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

  • In adults, according to a meta-analysis of double-blind RCTs, the effect is about half as strong as that on core ADHD symptoms (SMD -0.8, 95% CI -1.07 to -0.53) for: (meta-analysis, k = 9 RCTs, E 1a.)⁸⁶
    • Stimulants (k = 6) SMD -0.57 (95% CI -0.80 to -0.34)
    • Stimulants and atomoxetine (k = 9) SMD -0.41 (95% CI -0.57 to -0.25)
    • Atomoxetine (k = 3) SMD -0.21 (95% CI -0.34 to -0.08)
  • In adults, according to a systematic review, in 13 of 14 controlled trials (MPH, atomoxetine, lisdexamfetamine). The effect on emotional behavior for MPH ranged from 46 to 110% of the effect on non-emotional ADHD symptoms (atomoxetine 56 to 129%, lisdexamfetamine 36 to 96%). (Systematic review, k = 14, full text not available to us, E 1a.)⁸⁷
  • in children and adolescents in individual studies for:
    • MPH: Cohen’s d = -1.46; atomoxetine: d = -0.93, with no significant difference between groups. The effect remained significant after adjusting for symptom improvement and was associated with increased connectivity between the amygdala and the orbitofrontal and cingulate cortex. (RCT, N = 152, n = 76, 4 weeks at a stable dose, full text not available to us, E 1b.)⁸⁸
    • DR/ER-MPH (taken in the evening) improved the emotional lability subscale of the CGI-P from 5.3 to 1.3 (p < 0.0001) in an open-label study and, in the RCT, compared to placebo (3.11 vs. 4.08, p = 0.0053) in 6- to 12-year-olds (post hoc analysis of two Phase 3 studies, N = 117 in the open-label study, n = 161 in the RCT, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)⁸⁹
    • MPH responders (73.3%, 22 out of 30) with emotional dysregulation showed improvement in this area, with a Hedges’ g of 2.62. The severity of emotional dysregulation correlated with ODD symptoms, but not with core ADHD symptoms. (Open-label study, n = 30, 10 weeks, full text not available to us, E 2b.)⁹⁰
    • In patients with comorbid DMDD, OROS-MPH improved self-reported irritability (Cohen’s d = 0.57) as well as emotional lability, negative affect, and anger. Irritability improved in 71%, worsened in 19%, and remained unchanged in 10%. (Open-label study, n = 22, 4 weeks, Phase 2b.)⁹¹
    • Among adolescents, DERS scores for impulsivity (15.9 to 14.2, p < 0.01) and total scores (88.4 to 82.4, p < 0.05) decreased after 6 months of MPH treatment. In cases of comorbid ODD and self-harm, some scores remained elevated. (Prospective open-label follow-up study, n = 82, 6 months, E 2b.)⁹²

• Emotional symptoms in adults treated with sustained-release MPH (50% immediate release, 50% sustained release, up to 60 mg/day; mean daily dose at week 24 was 41.2 mg and 0.55 mg/kg, respectively). The difference compared to placebo was significant starting in week 5 and remained stable through week 24. The effect sizes were as follows: (RCT, n = 363, 24 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)⁹³

  • Obsessive-compulsive symptoms (SCL-90-R):
    • 0.46 (per-protocol)
    • 0.30 (ITT)
  • emotional dysregulation (as assessed by others, WRAADDS-EDS):
    • 0.42 (per-protocol)
    • 0.37 (ITT)
  • emotional lability (self-reported, CAARS-ELS):
    • 0.35 (per-protocol)
    • 0.3 (ITT)
  • Problems with self-concept decreased more significantly than with the placebo. Anxiety, depression, anger/hostility, phobic anxiety, paranoid thinking, and psychoticism did not improve.

• Life dissatisfaction (Open-label longitudinal study (doctoral dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

• Negative outlook on life (Open-label longitudinal study (dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

• psychotic phenomena (Open-label longitudinal study (doctoral dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

• social introversion (open-label longitudinal study (doctoral dissertation), n = 24, average duration of 5.4 months, E 2b)²⁸

• Uncertainty (Open-label longitudinal study (doctoral dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

• Compulsivity (Open-label longitudinal study (doctoral dissertation), n = 24, mean duration 5.4 months, E 2b)²⁸

• Inner emptiness/boredom (Open-label longitudinal study, n = 30, 3 months, E 2b)⁹⁴

1.6. Limited Effect of Methylphenidate¶

• Delay aversion (in adults): no improvement in performance tests; improvement observed only in self-reports (Open-label, non-randomized longitudinal study with healthy controls, N = 84, n = 42, 6 weeks, E 2b.)⁹⁵
• Executive functions (in adults): no improvement on performance tests; improvement observed only in self-reports (Open-label, non-randomized longitudinal study with healthy controls, N = 84, n = 42, 6 weeks, E 2b.)⁹⁵
• Spatial working memory (children ages 7 to 14): Task accuracy remained unchanged with D-MPH, improved with the combination of D-MPH and guanfacine, and worsened with guanfacine alone (RCT, n = 172, 8 weeks, E 1b.)⁹⁶

1.7. No effect of methylphendiate¶

• Reading the Mind in the Eye (in children, after a single dose). This test measures theory of mind. (Open-label study, n = 25, single dose, E 2b.)¹⁰⁹

• Fine motor skills (handwriting) (Non-randomized controlled trial, n = 58, 8 weeks, E 2a)¹¹⁰

• Facial emotion recognition (children and adolescents, ages 7 to 14): a trend toward improvement, though not statistically significant, on the Frankfurt Facial Emotion Recognition Test (FEFA) (double-blind, placebo-controlled crossover study, non-randomized, n = 21, E 2a.)¹¹¹

1.8. Do stimulants have different time-dependent effects on symptoms?¶

A publication by a renowned researcher claims that there are different time-response and dose-response curves for the motor and cognitive effects of stimulants. (Narrative review, E 4)¹¹² While the effect on motor activity lasts 7 to 8 hours, the effect on attention is said to last only 2 to 3 hours. However, the cited sources do not substantiate this claim. Nor do they align with empirical experience from practice.

Girls responded better than boys 1.5 hours after taking sustained-release MPH medications (Concerta, Equasym XL/Metadate CD) and worse 12 hours after taking them, regardless of the medication, placebo values, or comorbid anxiety. (Secondary analysis of a double-blind crossover RCT, N = 184, n = 48 girls, 1 week per phase, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)¹¹³

1.9. Latency period until the effect sets in¶

Immediate-release methylphenidate usually takes effect within 15 to 20 minutes.
The extensive body of scientific literature and empirical evidence do not indicate any latency period in the sense of a multiple of the number of doses or days until the effect is observed.

One study reported that, in children with ADHD taking methylphenidate, ADHD symptoms improved—as measured by the Clinical Global Impression-Severity Scale (CGI-S)—only at the second follow-up visit after 12 weeks (CGI-S score decreased from 5.09 to 4.80) and not as early as the first follow-up visit after 4 weeks. The mean daily dose was 9.07 mg at baseline and 17.17 mg after 12 weeks. (Retrospective observational study, N = 431, n = 105, 12 weeks, E 2b.)¹¹⁴

The time to onset of effect varied depending on the function and measured parameter for:

• Attention and working memory: Attention deficits in children who had never taken stimulants (mixed type) normalized to control levels after the first dose of OROS-MPH, while working memory normalized only after one month of daily administration (pilot study with a control group, N = 23, n = 12, 1 month, E 2b.)¹¹⁵
• Clinical response (CGI-I equal to or less than 2): with OROS-MPH after 7 weeks, with atomoxetine after 13 weeks (p < 0.001), with comparable response rates (OROS-MPH 77.27%, atomoxetine 76.19%) (Open-label randomized controlled trial, n = 43, up to 20 weeks, Phase 1b.)⁸⁴

(E 2b): The response to a single initial dose of MPH predicted the response at 4 weeks and 2 months, respectively (see 5.6). (Double-blind, placebo-controlled study, N = 52, n = 46, 4 weeks, E 2b.)¹¹⁶ * (Placebo-controlled single-dose study, n = 60, 2 months, manufacturer-funded, E 2b.)*¹¹⁷

1.10. MPH and Smoking Cessation¶

It has been reported that sustained-release MPH contributed positively to nicotine abstinence/smoking abstinence, but only in more severe cases of ADHD, whereas in milder cases of ADHD, a paradoxical worsening occurred, which, however, remitted after discontinuation of the medication. (Secondary analysis of an RCT, N = 134, E 1b)¹¹⁸ This should be viewed in light of the fact that nicotine, as a stimulant, serves as a form of self-medication for ADHD, even though smoking involves using nicotine as a drug, whereas only nicotine patches or nicotine lozenges act as medication.
Furthermore, the results of this study, viewed in the context of the Inverted-U Theory—which posits that moderate neurotransmitter levels facilitate optimal brain function— whereas both reduced and elevated neurotransmitter levels cause nearly identical symptoms, suggest an overdose in the participants with milder ADHD symptoms (which indicates a lesser deficiency of dopamine and norepinephrine) and a paradoxical reaction.

1.11. MPH and Creativity¶

A study found no change (neither improvement nor impairment) in convergent or divergent creativity in healthy adults following a single dose of 20 mg MPH, regardless of ADHD traits or working memory. (Double-blind, randomized, placebo-controlled crossover study in healthy participants, n = 48, single dose, E 1b.)¹¹⁹ Another study found increased creativity in open-ended (divergent) creativity tests among unmedicated children with ADHD compared to medicated children with ADHD (primarily MPH, some atomoxetine) and non-people with ADHD. (Cross-sectional study, N = 86, n = 43, E 3.)¹²⁰

 

2. Differences in the Effects of Methylphenidate and Amphetamine-Based Medications¶

2.1. Brain Metabolism Under the Influence of Methylphenidate and D-Amphetamine¶

A single dose of methylphenidate (0.35 mg/kg) significantly altered regional cerebral glucose metabolism in five regions of the brain in adults with ADHD. Regions with a high effect size showed increases, including the left frontal (anterior and posterior) and parietal regions, as well as decreases, including the anterior medial frontal, parietal, and left parieto-occipital regions. Global brain metabolism remained unchanged. (Open-label pre-post study, n = 14, single dose, E 2b.)¹²³ After at least 6 weeks of treatment, methylphenidate altered metabolism in only 2 of 60 brain regions. (Open-label pre-post study, N = 37, n = 19, at least 6 weeks, E 2b.)¹²⁴

In contrast, a single dose of D-amphetamine (0.25 mg/kg) significantly altered regional metabolism in 7 regions. Regions with a large effect size showed increases, among others, in the right caudate nucleus (part of the striatum) and decreases, among others, in the right Rolandi region and in anterior frontal regions. (Open-label pre-post study, n = 13, single dose, E 2b.)¹²³ After at least 6 weeks of treatment, D-amphetamine did not alter either global or regional brain metabolism. (Open-label pre-post study, N = 37, n = 18, at least 6 weeks, E 2b.)¹²⁴

The sample sizes (n) used to examine these findings were very small, ranging from 13 to 19 participants per active ingredient. Sample sizes that are too small carry a significant risk of producing misleading results.
For more information, visit ⇒ Studies show—sometimes nothing at all.

2.2. Comparison of Mechanisms of Action and Efficacy¶

Amphetamine acted independently of neuronal firing rate, displaced intraneuronal catecholamine stores, delayed reuptake, and inhibited degradation by MAO. MPH acted in a firing-rate-dependent manner and via the reuptake transporters, increasing extracellular norepinephrine and dopamine (including outside the cortex) but to an extent nearly as great as that of D-amphetamine. (Narrative review, manufacturer-funded, E 4.)¹²⁸

(E 2b): In animal and in vitro studies, MPH and amphetamine differed in terms of

• the source of the released dopamine:
  • Amphetamine released newly synthesized, cytoplasmic dopamine in the rat striatum (DOPAC decreased); MPH increased dopamine without altering DOPAC (animal study, microdialysis, rats, E 2b.)¹²⁹
  • Amphetamine (10⁻⁵ M) released dopamine, p-tyramine, and m-tyramine to the same extent in striatal slices. MPH released the tyramines to a similar extent, but released only very little dopamine. Reserpine enhanced dopamine release induced by MPH, but not that induced by amphetamine. Amphetamine inhibited the uptake of all three amines more strongly than MPH. (In vitro study, striatal slices, rats, E 2b.)¹³⁰
  • Nomifensine enhanced dopamine release induced by MPH and other non-amphetamine stimulants, but inhibited dopamine release induced by amphetamine (in vitro study, striatal sections, rats; full text not available to us, E 2b.)¹³¹
  • In SHR, amphetamine may have triggered the release of dopamine from large dense-core vesicles. Increased dopamine synthesis and release in the nucleus accumbens of SHRs could explain the stronger effect of MPH on dopamine release in SHRs compared to WKys. (Narrative review, E 4.)¹³²
• the extent of the increase in dopamine:
  • Extracellular dopamine in the striatum of rats (microdialysis) according to: (animal study, rats, baboons, E 2b.)¹³³
    • Amphetamine (2.5 mg/kg i.p.) +1,398 ± 272%
    • MPH (5 mg/kg i.p.) +360 ± 31%
  • synaptic dopamine (decrease in [11C]-raclopride binding on PET) in rats and baboons, according to: (animal study, rats, baboons, E 2b.)¹³³
    • Amphetamine in rats (2.5 mg/kg i.p.) 25 ± 4%
    • MPH in baboons (1.0 mg/kg IV) 25 ± 7%
    • Amphetamine in baboons (0.5 mg/kg i.v.) 24 ± 4%
    • MPH in rats (5 mg/kg i.p.) 21 ± 4%
  • synaptic dopamine in the human striatum (decrease in [11C]-raclopride binding on PET) according to: (meta-analysis, k = 92, N = 1,640, E 2b.)¹³⁴
    • oral MPH 11.5%
    • Amphetamine 10.9%
    • Ketamine 9.8%
    • Alcohol 4.8%
    • cognitive tasks 2.7%
• binding to trace amine-associated receptor 1 (TAAR1). Most amphetamines activated TAAR1 in rats and mice at physiologically relevant concentrations; MPH showed no affinity for TAAR1. (In vitro study, HEK293 cells expressing human, rat, and mouse TAAR1, E 2b.)¹³⁵
• the effects of repeated administration. Amphetamine (0.5 to 4 mg/kg) led to sensitization of motor activation over 7 days, while MPH (20 mg/kg) led to tolerance. MPH at doses of 1 and 5 mg/kg had no motor effect even after 7 days. (Animal study, rats, 7 days, E 2b.)¹³⁶

Psychostimulants increased synaptic dopamine levels more in the putamen and ventral striatum than in the caudate nucleus. MPH-induced dopamine release decreased with age. (Meta-analysis, k = 92, N = 1,640, E 2b.)¹³⁴ Only a few studies, predominantly animal experiments, were available on the molecular mechanisms of action of MPH and lisdexamfetamine in ADHD. (Narrative review with structured search, manufacturer-funded, E 4.)¹³⁷

(E 1a): In meta-analyses, amphetamine-based medications showed greater effect sizes on ADHD symptoms compared to placebo than MPH. The effect size was

• for children and adolescents with:
  • Lisdexamfetamine SMD −1.28 (95% CI −1.84 to −0.71) (meta-analysis, k = 28 RCTs, E 1a.)¹³⁸
  • Amphetamine-based medications (all ADHD symptoms) SMD 1.03 (meta-analysis with meta-regression, k = 23 RCTs, manufacturer-funded, E 1a.)¹³⁹
  • Amphetamines (clinician assessment) SMD −1.02 (95% CI −1.19 to −0.85) (Network meta-analysis, k = 133 RCTs, N = 10,068 children and adolescents in the efficacy analysis, E 1a.)¹⁴⁰
  • MPH (teacher rating) SMD −0.82 (95% CI −1.16 to −0.48). No valid teacher-reported comparison was available for amphetamines. (network meta-analysis, k = 133 RCTs, N = 10,068 children and adolescents in the efficacy analysis, E 1a.)¹⁴⁰
  • MPH (clinician assessment) SMD −0.78 (95% CI −0.93 to −0.62) (Network meta-analysis, k = 133 RCTs, N = 10,068 children and adolescents in the efficacy analysis, E 1a.)¹⁴⁰
  • MPH preparations (all ADHD symptoms) SMD 0.77 (meta-analysis with meta-regression, k = 23 RCTs, manufacturer-funded, E 1a.)¹³⁹
  • MPH SMD −0.75 (95% CI −0.98 to −0.52) (meta-analysis, k = 28 RCTs, E 1a.)¹³⁸
• in adults for:
  • Lisdexamfetamine SMD −0.89 (95% CI −1.09 to −0.70) (meta-analysis, k = 20 RCTs, E 1a.)¹⁴¹
  • Amphetamines (clinician assessment) SMD −0.79 (95% CI −0.99 to −0.58) (Network meta-analysis, k = 133 RCTs, N = 8,131 adults in the efficacy analysis, E 1a.)¹⁴⁰
  • Mixed amphetamine salts: SMD −0.64 (95% CI −0.83 to −0.45) (meta-analysis, k = 20 RCTs, E 1a.)¹⁴¹
  • MPH SMD −0.50 (95% CI −0.58 to −0.41) (meta-analysis, k = 20 RCTs, E 1a.)¹⁴¹
  • MPH (clinician assessment) SMD −0.49 (95% CI −0.64 to −0.35) (Network meta-analysis, k = 133 RCTs, N = 8,131 adults in the efficacy analysis, E 1a.)¹⁴⁰

In direct comparisons (clinician assessment), amphetamines, modafinil, atomoxetine, and MPH were superior in children and adolescents (SMD −0.46 to −0.24) and in adults (SMD −0.94 to −0.29). Taking efficacy and tolerability into account, the authors recommended MPH as the first-line treatment for children and adolescents and amphetamines for adults, since amphetamines were less well tolerated in children and adolescents (OR 2.30, 95% CI 1.36 to 3.89) and MPH only in adults (OR 2.39, 95% CI 1.40 to 4.08) were less well tolerated than placebo. (Network meta-analysis, k = 133 RCTs, N = 24,642, of which n = 18,199 were included in the efficacy analysis, E 1a.)¹⁴⁰ After adjusting for design characteristics, the advantage of amphetamine preparations over MPH preparations remained significant (p = 0.008), as did the advantage after correcting for publication bias (amphetamine SMD from 1.10 to 0.99, MPH from 0.79 to 0.72). (Meta-analysis with meta-regression, k = 23 RCTs, manufacturer-funded, E 1a.)¹³⁹

(E 1a): In direct comparative studies, amphetamine-based medications were found to be superior to MPH

• A slight advantage for mixed amphetamine salts (Adderall) over immediate release MPH, as measured by the (meta-analysis, k = 4, manufacturer-funded, E 1a.)¹⁴²
  • Overall p-value: SMD 0.52 (p = 0.007)
  • Clinician’s assessment: SMD 0.37 (p = 0.001)
  • Parental rating: SMD 0.28 (p = 0.037)
  • pooled overall effect: SMD 0.25 (95% CI 0.12 to 0.39); after adjustment for publication bias: SMD 0.12 (p = 0.04)
  • Teacher rating: SMD 0.13 (not significant)
• for lisdexamfetamine (30 to 70 mg/day) compared with OROS-MPH (18 to 54 mg/day) in 6- to 17-year-olds, a 5.6-point (95% CI −8.4 to −2.7) greater reduction in the ADHD-RS-IV (−24.3 vs. −18.7, placebo −5.7) and a 17.4 percentage point (95% CI 5.0 to 29.8) higher proportion of CGI-I responders (NNT 6) (post-hoc analysis of an RCT, N = 336, n = 317, 7 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)¹⁴³
• for lisdexamfetamine versus OROS-MPH in 13- to 17-year-olds: (Two RCTs, N = 1,013, 6 and 8 weeks, respectively; manufacturer-funded; author(s) employed by the manufacturer; E 1b.)¹⁴⁴
  • For the fixed-dose group (70 mg vs. 72 mg/day): ES −0.33 (p = 0.0013), CGI-I improvement 81.4% vs. 71.3%
  • No significant difference with flexible dosing (ES −0.20, p = 0.0717); CGI-I improvement of 83.1% versus 81.0%
• For mixed amphetamine salts, an effect across the entire spectrum of improvement; for MPH, a clear effect in the “slightly improved” and “much improved” categories, but not in the “greatly improved” category. Both prevented deterioration. (Reanalysis of an RCT, N = 58, manufacturer-funded, E 1b.)¹⁴⁵
• No significant difference between MPH (mean 40 mg) and D-amphetamine (mean 20 mg) in children with minimal cerebral dysfunction. Both were superior to placebo and caffeine. (Double-blind crossover study, n = 18, E 2a.)¹⁴⁶
• An improvement in arithmetic accuracy was observed only with D-amphetamine, while both active ingredients improved the number of reading and arithmetic tasks completed and reading accuracy (boys with ADHD, school setting) (Double-blind, placebo-controlled crossover study, n = 33, 11 weeks, E 1b.)¹⁴⁷

Both classes of stimulants are considered highly effective. If the response is inadequate, switching to a different class of stimulants may improve the individual’s response. (Narrative review; authors employed by the manufacturer; E 4.)¹⁴⁸

In healthy adults, MPH slightly improved cognitive performance (SMD 0.21, p = 0.0004), particularly recall (SMD 0.43), sustained attention (SMD 0.42), and inhibitory control (SMD 0.27), whereas D-amphetamine showed no significant effects. (Meta-analysis, k = 47, of which MPH k = 24 and D-amphetamine k = 10, E 1a.)¹⁴⁹

(E 2b): In animal studies on attention and impulsivity, the following was found for amphetamine and MPH

• Improved attentional performance (5-Choice Serial Reaction Time Task) only at high stimulus frequencies (amphetamine 0.03 to 0.3 mg/kg, MPH 1 to 6 mg/kg). Amphetamine increased premature responses (motor impulsivity) but reduced false positives in the Go/NoGo task. The effect of MPH on impulsivity was inconsistent and depended on the baseline level. (animal study, Long-Evans rats, E 2b.)¹⁵⁰
• Improved accuracy was observed only in inattentive mice (amphetamine 0.5 mg/kg, MPH 2 mg/kg). Premature responses increased with amphetamine 1 mg/kg and MPH 0.5 mg/kg. (Animal study, C57Bl/6J mice, E 2b.)¹⁵¹
• more responses following the stop signal and significantly more premature responses (stop-signal abandonment), while atomoxetine slightly improved stop accuracy and reduced premature responses (animal study, n = 8, rats, E 2b.)¹⁵²
• higher-risk choices (amphetamine 0.25 mg/kg, MPH 3.0 mg/kg) (animal study, n = 8, rats, E 2b.)¹⁵³

2.3. Direct Comparisons in Children and Individual Response¶

(E 1b): In direct crossover comparisons among children, methylphenidate and D-amphetamine were equally effective on a group basis; however, on an individual basis, one of the two stimulants was often superior or better tolerated in the following cases:

• Efficacy: MPH and D-amphetamine were significantly more effective than placebo and caffeine in 6 evaluations; there was no difference between them. Of 26 responders, 12 responded best to D-amphetamine, 10 to MPH, and 1 to caffeine. Six children each responded only to one of the two stimulants (double-blind crossover study, n = 29, E 2a.)¹⁵⁴
• Response rate (CGI): D-amphetamine 88%, MPH 79%, at least one of the two 96% (boys in a day clinic, wide dose range up to an average of 2.5 mg/kg/day MPH) (Double-blind crossover study, n = 48, 9 weeks, E 1b.)¹⁵⁵
• Attention and activity: both stimulants showed comparable effects relative to placebo in the computer-based CPT with motion tracking and in teacher ratings (ages 9 to 14) (secondary analysis of an RCT, crossover design, n = 36, 6 weeks, E 2b.)¹⁵⁶
• Side effects: similar profiles across groups; more severe insomnia with D-amphetamine. In 7 (39%) of 18 children who responded to both stimulants, the side effects of the two stimulants differed in a clinically relevan * Ly (RCT, crossover, N = 36, n = 34, 6 weeks, E 1b.)*¹⁵⁷

(E 1b): Methylphenidate and amphetamine-based medications reduced ADHD symptoms to a comparable degree in:

• Children and adolescents taking sustained-release dexmethylphenidate (10 to 30 mg) and sustained-release mixed amphetamine salts (10 to 30 mg). At the highest dose, 79% and approximately 80%, respectively, showed a reliable improvement (ADHD-RS-IV). The dose was a stronger determinant of response than the class of stimulants. Hyperactivity/impulsivity improved significantly, while inattention improved only moderately in a dose-dependent manner. Decreased appetite and insomnia increased with dose for both active ingredients. (double-blind crossover RCT, N = 65, n = 56, 8 weeks, manufacturer-funded, E 1b.)¹⁵⁸
• Children and adolescents (ages 4.5 to 16.4) who have never taken stimulants and are taking immediate-release methylphenidate and immediate-release dexamfetamine. (Open-label RCT, n = 100, 12 months, E 1b.)¹⁵⁹

After 12 months, the following participants were still taking the assigned medication: (Open-label RCT, n = 100, 12 months, E 1b.)¹⁵⁹

• Methylphenidate 68% (34 out of 50)
• Dexamfetamine 56% (28 out of 50, p = 0.15)

Weight loss after 3 months was as follows: (Open-label RCT, n = 100, 12 months, E 1b.)¹⁵⁹

• Dexamfetamine 1.44 kg (SD 2.42)
• Methylphenidate 0.31 kg (SD 0.97, p = 0.005)