MPH Part 6 - Side Effects, Drug Interactions

10. Side Effects of Methylphenidate¶

When administered at the correct dosage, MPH helps people with ADHD feel that they are much more themselves than before. If a person with ADHD feels that stimulants are making them less like themselves, this is a serious indication of an incorrect dosage, misuse, or misdiagnosis. (ADxS Experience)
Studies on the side effects of ADHD medications should always be examined to determine which doses and which route of administration were used. Of course, stimulants cause side effects at certain doses. Anything that has an effect can also cause side effects. As the dose increases, these side effects naturally increase as well. The dose makes the poison.

A dose-response network meta-analysis of double-blind, fixed-dose RCTs in children and adolescents found that the efficacy of MPH increased up to about 45 mg/day and then plateaued, while the proportion of treatment discontinuations due to adverse effects rose steadily with increasing dose. The estimated discontinuation rate due to side effects was: (network meta-analysis, k = 48 RCTs, N = 4,964, age 5 to 18 years, mean study duration 3.1 weeks, E 1a.)¹

• 8.2% (95% CrI: 2.8 to 21.3%) below 60 mg MPH/day
• 4.8% (95% CrI: 2.2 to 10.6%) below 45 mg MPH/day
• 2.8% (95% CrI: 1.7 to 5.0%) below 30 mg MPH/day
• 1.7% (95% CrI: 1.3 to 2.2%) below 15 mg MPH/day
• 1.2% (95% CI 1.1 to 1.3%) below 5 mg MPH/day
• 1% lower than placebo (pooled discontinuation rate for the placebo arms)

When the benefits and risk of discontinuation were weighed equally, the most favorable MPH dose range was 18 to 46 mg/day (optimum: 30 to 39 mg/day).

10.1. Side Effects¶

10.1.1. No increased rate of serious side effects¶

A Cochrane meta-analysis on MPH in children and adolescents (mean age 9.7 years) found no higher rate of serious side effects with MPH than with placebo (RR = 0.98, 95% CI 0.44 to 2.22). The data set was too small to draw a definitive conclusion. (Meta-analysis [Cochrane], k = 185 RCTs; for this finding, k = 9, n = 1,532; median duration of parallel-group studies 49 days; 96.8% of studies at high risk of bias; GRADE very low, E 1a.)³

The updated version of this Cochrane meta-analysis confirmed the finding: Serious adverse events did not occur more frequently with MPH than with placebo or no treatment (RR = 0.80, 95% CI 0.39 to 1.67, k = 26, n = 3,673; TSA-adjusted RR = 0.91, 95% CI 0.31 to 2.68). The certainty of the evidence was very low. (Cochrane meta-analysis, k = 212 RCTs, N = 16,302, mean treatment duration 28.8 days, 41% of studies fully or partially industry-funded, full text not available to us, E 1a.)⁴

10.1.2. Slightly increased risk of non-serious side effects (+29%)¶

A Cochrane meta-analysis on MPH in children and adolescents (mean age 9.7 years) found 29% more non-serious adverse events in the MPH group than in the placebo group (RR = 1.29, 95% CI 1.10 to 1.51, k = 21, n = 3,132). The most common side effects were loss of appetite (RR = 3.66, k = 16, n = 2,962) and sleep problems (RR = 1.60, k = 13, n = 2,416). ([Cochrane] meta-analysis, k = 185 RCTs; for this finding, k = 21, n = 3,132; 96.8% of the studies had a high risk of bias; E 1a.)³

Mild side effects were more common with MPH than with placebo or no treatment in the following cases:

• Children and adolescents: RR = 1.23 (95% CI 1.11 to 1.37, k = 35, n = 5,342, TSA-adjusted RR = 1.22), primarily sleep problems and loss of appetite. ([Cochrane] meta-analysis, k = 212 RCTs, N = 16,302, mean treatment duration 28.8 days, full text not available to us, E 1a.)⁴
• Adults taking sustained-release MPH: RR = 1.27 (95% CI 1.19 to 1.37, k = 14, n = 4,214) for any adverse event. Serious adverse events were not significantly more common (RR = 1.43, 95% CI 0.85 to 2.43, k = 14, n = 4,078). Discontinuations due to adverse effects were more common (RR = 2.36, 95% CI 1.62 to 3.43, k = 15, n = 3,963). ([Cochrane] meta-analysis, k = 24 RCTs, N = 5,066, median duration 8 weeks, 76% of studies industry-funded, E 1a.)⁵
• Adults taking immediate release MPH: gastrointestinal symptoms (e.g., dry mouth, nausea, abdominal pain) RR = 1.96 (95% CI 1.13 to 2.95) and loss of appetite RR = 1.77 (95% CI 1.06 to 2.96). ([Cochrane] meta-analysis, k = 10 RCTs, N = 497; for this finding, k = 4, n = 203 MPH and 141 placebo, 6 to 18 weeks, E 1a.)⁶

A Cochrane meta-analysis of non-randomized studies in children and adolescents found that, in cohort studies without a control group, 51.2% (95% CI 41.2 to 61.1%) of participants treated with MPH experienced at least one non-serious adverse event, including:

• 31.1% reduction in appetite (95% CI 26.5% to 36.2%, k = 84, n = 11,594)
• 17.9% difficulty falling asleep (95% CI 14.7–21.6%, k = 82, n = 11,507)
• 14.4% headaches (95% CI 11.3–18.3%, k = 90, n = 13,469)
• 10.7% abdominal pain (95% CI 8.6–13.3%, k = 79, n = 11,750)

6.2% (95% CI 4.8% to 7.9%) discontinued treatment due to non-serious adverse events, and 1.2% (95% CI 0.6% to 2.3%, k = 7, n = 1,173). The authors consistently rated the risk of bias in the non-comparative studies as high and the evidence as very low. ([Cochrane] meta-analysis, k = 260 non-randomized studies, including 177 non-comparative cohort studies with N = 2,207,751, ages 3 to 20 years, GRADE very low, E 2b.)⁷

A significant proportion of the side effects reported in studies also occur with placebo (nocebo effect). In the placebo arms of 105 RCTs on ADHD medications, 55.5% of participants reported side effects. The nocebo rate increased with age and duration of treatment and depended on the method used to record side effects. Studies with a high nocebo rate showed a more favorable safety profile for the active ingredient. (Meta-analysis, k = 105 RCTs, n = 8,743 in placebo arms, all ADHD medications, MPH not analyzed separately, full text not available to us, E 1a.)⁸

Among adults, the total number of patients who discontinued treatment was not significantly higher in the MPH group than in the placebo group (OR 1.19, 95% CI 0.82 to 1.74, I² = 64%). After excluding one outlier study, the difference was significant (OR 1.44, 95% CI 1.14 to 1.82). Discontinuations due to adverse events were more common with MPH than with placebo (OR 2.68, 95% CI 1.81 to 3.98, I² = 0%). Under OROS-MPH, overall discontinuations were also significantly more frequent (OR 1.61, 95% CI 1.23 to 2.11). (Meta-analysis, k = 12 RCTs, N = 2,496, 4 to 24 weeks, E 1a.)⁹

10.1.3. No serious side effects with long-term use¶

A systematic review found no serious neuropsychiatric consequences and no severe cardiovascular events associated with long-term MPH use. Blood pressure and heart rate increased slightly. The evidence regarding long-term neuropsychiatric and cognitive effects was rated as limited. (Systematic review, k = 13 [6 systematic reviews, 5 cohort studies, 1 RCT, 1 narrative review], E 2b.)¹⁰ In adolescents and young adults who had been taking sustained-release MPH for at least 2 years, an echocardiographic examination found no impairment of cardiac function. However, systolic blood pressure was higher and BMI was lower than in healthy individuals. Both values were associated with the duration of use. (Cross-sectional study with matched controls, N = 121, n = 70 taking MPH for at least 2 years, n = 51 controls; full text not available to us, E 3.)¹¹

In a 52-week RCT in adults (COMPAS), the following were observed significantly more frequently with flexibly dosed sustained-release MPH (Medikinet retard, mean dose at week 13: 48.8 mg/day) compared with placebo: (RCT, n = 433, of whom 205 were treated with MPH and 209 with placebo; 52 weeks; E 1b.)¹²

• 22% decrease in appetite compared to 3.8%
• 15% compared to 4.8% dry mouth
• 13% compared to 3.3% heart palpitations
• 11% compared to 3.3% agitation
• 10% compared to 2.9% restlessness
• Increased sweating, tachycardia, and weight loss, each occurring in 6.3% of patients compared with 1.9%
• 4.9% versus 1.0% depressive symptoms

Syncope occurred only in the placebo group (2.4% versus 0%). At least one adverse event occurred in 96% of those on MPH and 88% of those on placebo. Serious side effects were rare (7.3% vs. 4.3%) and did not differ significantly between the groups. Over 52 weeks, participants in the MPH group lost an average of 1.2 kg, while those in the placebo group gained 0.3 kg. Clinically relevant ECG changes were very rare in both groups.

In an open-label extension study with OROS-MPH (18 to 90 mg/day, mean 52.8 mg) lasting a mean of 437 days, 10.3% of adults discontinued treatment due to side effects. 81.3% experienced at least one adverse event. None of the serious adverse events (7.7%) were classified as drug-related. Blood pressure and pulse showed little change on average. Elevated individual readings occurred (systolic blood pressure above 140 mmHg in 21.7%, diastolic blood pressure above 90 mmHg in 17.1%, and heart rate above 100/min in 9.2%). In the subsequent randomized withdrawal phase (n = 45), no withdrawal or rebound symptoms were observed after switching to placebo. (Open-label study (extension of an RCT), n = 155, at least 52 weeks, authors employed by the manufacturer, E 2b.)¹³

Of 112 individuals diagnosed as adults and treated with medication, 51% were still taking MPH after an average of 6 years. The most common reasons for discontinuation were lack of efficacy (29%), elevated mood or hypomania (11%), and loss of contact with the prescribing physician (9%). None of the participants with elevated mood or hypomania had bipolar disorder at baseline. While continuing MPH (median current daily dose of 54 mg), the following were reported: (Prospective naturalistic cohort study, n = 112, 6 years, E 2b.)¹⁴

• 28% reduction in appetite
• 24% dry mouth
• 19% each for anxiety/restlessness and increased heart rate
• 17% decrease in libido
• 15% sweating
• 11% depressive mood

10.1.4. Common Side Effects¶

(E 4): Very common (in more than 10% of cases) are: (Product Information, E 4.)¹⁵ * (Narrative Review, E 4.)*¹⁶

• loss of appetite
• Headaches
• Dry mouth (according to the current UK prescribing information, data from adult studies)
• Nervousness
• Insomnia
• Nausea (according to the current UK prescribing information, data from adult studies)

Most side effects occur only shortly after starting the medication and usually subside after a short period of treatment. (Textbook, E 4.)²¹ The temporary sensation of a dry or coated tongue shortly after taking the medication may last a bit longer, but it will almost certainly go away eventually. (ADxS experience)
Tics usually appeared at the start of treatment and often disappeared after about four weeks at a constant dose, though in some cases only after a slight dose reduction. (textbook, secondary citation via Trott and Wirth [2000] on Rapoport [1992], E 4.)²¹ If people with ADHD feel for months that the world is drifting away or that life is becoming monotonous, this is a clear indication of an overdose. (ADxS experience)

A meta-analysis of placebo-controlled RCTs found no increased risk of new or worsened tics with stimulants (RR = 0.99, 95% CI 0.78 to 1.27). Tics were reported in 5.7% (95% CI 3.7 to 8.6%) of patients on stimulants and in 6.5% (95% CI 4.4 to 9.5%) of patients on placebo. For MPH alone, the RR was 1.02 (95% CI 0.78 to 1.33, k = 20). Neither dose nor duration of treatment influenced the risk of tics, even when the analysis was restricted to MPH. In crossover studies, the measured risk of tics was higher than in parallel-group studies. (meta-analysis, k = 22 RCTs, N = 2,385 children, E 1a.)⁴⁵

Emotional Side Effects¶

Emotional side effects changed as follows in children and adolescents treated with MPH compared with placebo: (meta-analysis, k = 45 studies, children and adolescents, E 1a.)⁴⁶

• speaking less: RR = 1.53 (95% CI 1.15 to 2.04, k = 13)
• Apathy (including sedation, emotional numbness, and drowsiness) RR = 1.27 (95% CI 1.03 to 1.58, k = 16)
• Sadness RR = 1.08 (95% CI 0.93 to 1.26, k = 21), not significant
• Irritability RR = 0.86 (95% CI 0.74 to 0.99, k = 31)
• Anxiety RR = 0.81 (95% CI 0.71 to 0.92, k = 21)
• Euphoria RR = 0.77 (95% CI 0.59 to 1.00, k = 7)

In contrast, emotional lability was increased among those taking amphetamines (RR = 3.82). Crying occurred more frequently with higher doses of MPH. Sadness was more common among those taking immediate release MPH than among those taking sustained-release MPH.

Another meta-analysis also found a reduced risk of irritability with MPH (RR = 0.89, 95% CI 0.82 to 0.96, k = 32) and an increased risk with amphetamines (RR = 2.90, 95% CI 1.26 to 6.71, k = 5). (meta-analysis, k = 32 RCTs, N = 3,664 children, full text not available to us, E 1a.)⁴⁷

10.1.5. Pre-existing comorbidities and side effects¶

Emotional side effects (anxiety, sadness, irritability) decreased from baseline in children taking OROS-MPH (18 to 54 mg/day) who had more pronounced pre-existing symptoms of anxiety, depression, or ODD. In children with lower baseline levels, these symptoms remained the same or increased. (RCT [crossover, double-blind, 3 doses and placebo, each for 1 week], n = 171, ages 7 to 11 years, 4 weeks, E 1b.)⁴⁸

Side Effects in Preschoolers¶

Side Effects in Preschoolers

Preschoolers (ages 3 to 5) discontinued MPH treatment due to side effects:

• 11% on immediate release MPH over 1 year (average daily dose most recently 20.5 mg). 30% of parents spontaneously reported moderate to severe side effects (emotional outbursts, difficulty falling asleep, repetitive behaviors or thoughts, loss of appetite, irritability). During the titration phase, decreased appetite, sleep problems, and weight loss were more common than with placebo. During the maintenance phase, sleep problems and loss of appetite persisted, while other side effects decreased. Of the serious adverse events, only one was possibly related to MPH. (RCT with open-label extension [PATS], n = 183, 3 to 5 years, 1 year, E 1b.)⁵⁴
• Approximately 11% experienced weight loss while taking sustained-release MPH (MPH-MLR) over 12 months in 4- to 5-year-olds. 18% lost weight, 18% experienced a decreased appetite, 9% had insomnia, and 6.7% had high blood pressure. Weight and height z-scores decreased significantly, while diastolic blood pressure increased significantly. The side effects were not dose-dependent. (Open-label study, n = 89, ages 4 to under 6 years, 12 months, authors employed by the manufacturer, full text not available to us, E 2b.)⁵⁵
• 0% with immediate release MPH (up to 1.25 mg/kg/day, slow, flexible titration) over 8 weeks. MPH caused more mild adverse events than the two placebo groups (332 versus 235 and 227), but no more moderate or severe ones. Loss of appetite and insomnia were more common with MPH. ECG and laboratory values showed no abnormalities requiring treatment. (RCT, n = 153, 3 to 5 years, 8 weeks, E 1b.)⁵⁶
• 0% at doses below 0.3 and 0.5 mg/kg of MPH twice daily for at least 1 week each. Eight of the 17 behaviors assessed changed, mostly at the higher dose. At doses below 0.5 mg/kg, there was an increase in loss of appetite (81% vs. 25% with placebo), fatigue (66% vs. 13%), and disinterest in others (75% vs. 31%), sadness, and nightmares, while irritability, anxiety, and sleep problems decreased. The number of side effects was higher than is typically reported in school-aged children. Serious side effects occurred in less than 10% of participants, with a frequency similar between the placebo and MPH groups. (RCT [crossover, double-blind], n = 32, mean age 4 years 10 months, 7 to 10 days each, E 1b.)⁵⁷

Autism and Intellectual Disabilities¶

In children with autism (a pervasive developmental disorder), MPH had an effect on ADHD symptoms (ES 0.67, 95% CI 0.08 to 1.27), though this effect was somewhat weaker than in studies of ADHD without autism. * Occurred more frequently with MPH than with placebo (absolute risk difference): (meta-analysis, k = 4 RCTs on MPH, N = 94, E 1a.)*⁵⁸

• Insomnia: 19% (95% CI 2–36%)
• Decreased appetite: 17% (95% CI: 3% to 31%)
• Irritability: 14% (95% CI: 5–24%)
• depressive symptoms: 7% (95% CI 0.4 to 13%)
• social withdrawal 7% (95% CI 0.2 to 15%)

In children with autism and ADHD symptoms, the effect of MPH (sustained release in the morning, immediate release in the afternoon, up to 0.48 mg/kg per morning dose) increased linearly with dose within the range studied. Stereotypies did not increase. Five of 24 children discontinued the afternoon dose due to irritability in the late afternoon or evening; of these, 2 experienced reduced sleep and 2 experienced increased stereotypical behaviors. (RCT, crossover, n = 24, E 1b.)⁵⁹

In children with autism (ages 5 to 13), the only side effect that was significantly more common with MPH (as assessed by parents) in placebo-controlled crossover RCTs was loss of appetite (RR 8.28, 95% CI 2.57 to 26.73, k = 2, n = 74). No study reported severe adverse effects. The evidence on adverse effects was of very low quality, as the studies were short (one week per dose) and excluded children who could not tolerate a test dose of MPH (in the largest study, 16 of 66 children did not receive the maximum dose for this reason). ([Cochrane] meta-analysis, k = 4 RCTs, N = 113, E 1a.)⁶⁰

For children with ADHD and intellectual disability or borderline intelligence:

• Individually titrated, immediate-release MPH (up to 1.5 mg/kg/day) caused the typical side effects of difficulty falling asleep (21% versus 3% with placebo), loss of appetite (15% vs. 2%), and weight loss (−2.7 kg compared to placebo, 95% CI −3.72 to −1.67). Heart rate and blood pressure did not differ significantly from placebo. Five children discontinued treatment due to side effects, all while taking MPH. (RCT, n = 122, IQ 30 to 69, ages 7 to 15, 16 weeks, E 1b.)⁶¹
• Overall discontinuation rates (OR 1.68, 95% CI 0.68 to 4.14, k = 4) and discontinuations due to side effects (OR 4.82, 95% CI 0.98 to 23.63, p = 0.053, k = 4) were not significantly different from those of placebo. After adjusting for publication bias (Trim and Fill), discontinuations due to side effects were significantly more frequent with MPH (OR 5.53, 95% CI 1.33 to 23.07). Seven of the eight studies lasted only 1 to 4 weeks. (meta-analysis, k = 8, n = 242 MPH, n = 181 placebo, E 1a.)⁶²

Substance Use Disorder¶

Adolescents (ages 13 to 18) with ADHD and substance use disorder who continued to use substances for the most part experienced more treatment-related adverse events per person while on OROS-MPH (96% reached 72 mg/day) than while on placebo (2.4, 95% CI 1.9 to 2.9, compared with 1.6, 95% CI 1.3 to 1.9, p = 0.02). Serious adverse events occurred less frequently with OROS-MPH than with placebo (4 versus 7). One of these was attributed to OROS-MPH (a brief inpatient psychiatric evaluation following the ingestion of unknown substances at a rave party). Possible interactions with drugs or alcohol consumed on the same day were reported by 2.8% of participants in the OROS-MPH group and 2.1% in the placebo group. (RCT, n = 303, 16 weeks, E 1b.)⁶³ Higher alcohol and cannabis use at baseline increased the risk of treatment-related adverse events among those receiving OROS-MPH, but not the risk of serious adverse events. The adolescents did not experience more treatment-related adverse events than adults without a substance use disorder (except for nicotine). The adults actually experienced more treatment-related and psychiatric adverse events, regardless of the treatment arm. Adolescents reported depressive feelings more frequently while on OROS-MPH and lost more tablets (on average, about 3 daily doses), regardless of the treatment arm. (Secondary analysis of two RCTs, n = 303 adolescents and n = 255 adults, E 1b.)⁶⁴

10.1.6. Gene variants associated with an increased risk of MPH side effects¶

10.2. Temporary Delay in Height Growth¶

A cross-sectional analysis of the KiGGS data found no increased rate of short stature (height at or below the 3rd percentile) among boys taking MPH. (Cross-sectional study [KiGGS 2003–2006], N = 4,244 boys, n = 118 on MPH, ages 6 to 15 years, E 3.)¹⁷

In a Thai cohort, the z-score did not change significantly with MPH (an average of 14.1 mg/day over 39.4 months) (MD 0.0017, 95% CI −0.0004 to 0.0038). Only weight decreased slightly in the first year and returned to baseline in the second year. (Retrospective cohort study, n = 911, ages 5 to 18 years, MPH as the sole psychotropic medication for at least 1 year, E 2b.)¹⁸ A temporary impairment in height growth is common in childhood ADHD and is regularly made up for during adolescence. This does not appear to be a specific effect of methylphenidate. (Textbook, E 4)²¹ Boys with ADHD were slightly shorter than controls through middle adolescence (age-adjusted z-score 0.21 vs. 0.47), but their height normalized by late adolescence. This was not related to the use of psychotropic medications. (Case-control study, n = 124 boys with ADHD, n = 109 controls, measurement after 4 years of follow-up, E 3.)⁷⁰

Children with ADHD were 3.88 times more likely to have short stature in 4th grade (OR 3.88; 95% CI 1.69 to 8.88) and grew more slowly from kindergarten through 4th grade. Within the ADHD group, a longer duration of medication use was associated with an additional reduction in height gain (β −0.187; 95% CI −0.248 to −0.126). However, the probability of short stature was no higher among children with ADHD who were on medication than among those who were not. The active ingredient was not recorded, and no distinction was made between stimulants and non-stimulants. (cohort study, N = 7,063, n = 298 with ADHD in 4th grade, E 2b)⁷¹

Meta-analyses found a slight reduction in height and weight among children and adolescents treated with MPH:

• Height z-score: MD = −0.13 (95% CI −0.18 to −0.09, k = 20), weight z-score: MD = −0.25 (95% CI −0.36 to −0.15, k = 15), BMI z-score: MD = −0.26 (95% CI −0.32 to −0.20, k = 15). The mean BMI did not change significantly. The decrease in the height z-score was most pronounced with a treatment duration of more than 12 months (MD = −0.19). (Meta-analysis, k = 33 [4 RCTs, 29 cohort studies], N = 4,438, 3 weeks to 5 years, GRADE predominantly low, very low for height, E 2b.)⁷²
• Size z-score: SMD = 0.27 (95% CI 0.16 to 0.38), Weight z-score: SMD = 0.33 (95% CI 0.22 to 0.44) as a decrease before/after treatment over more than 6 months (last measurement at 21 to 72 months; in some cases, MPH and amphetamine were analyzed together). Weight was primarily affected during the first 12 months, and height during the first 24 to 30 months. In the few studies with a control group, weight was reduced (SMD −0.47, 95% CI −0.75 to −0.19, k = 2), while height was not significantly affected (k = 3). Dose (less than vs. 30 mg/day or more), dosage form, age, and prior treatment did not moderate the effects. (meta-analysis, k = 18, N = 4,868, at least 6 months, E 2b.)⁷³

Adult Height and Pubertal Development¶

In the long-term follow-up of the MTA study (primarily immediate-release MPH), young adults who had taken stimulants on a regular basis as children and adolescents were shorter than those with negligible use. The difference was:

• 4.06 cm (−0.66 z-scores) for those with long-term versus negligible use after 16 years (mean age 24.7 years). Those who received long-term treatment were also heavier in adulthood than the control group without ADHD (+7.47 kg). (Cohort study [MTA follow-up], n = 568 with ADHD [53 long-term, 374 inconsistent, 141 with negligible treatment], n = 258 controls, 16 years, E 2b.)⁷⁵
• 2.55 cm (d = 0.42) for those who took the medication consistently versus those who took it inconsistently or not at all. Among those receiving treatment, those who took it consistently were 2.36 cm (d = 0.38) shorter than those who took it inconsistently. The ADHD group as a whole was 1.29 cm shorter than the control group. Lower symptom severity in adulthood was not associated with consistent medication use. (Cohort study [MTA follow-up], n = 515 with ADHD, n = 289 controls, ages 2 to 16, E 2b.)⁷⁶

Group assignment based on duration of use was not randomized but was determined by the participants’ self-selected dosing regimen.

In a nationwide Korean cohort, children and adolescents with ADHD who were treated with MPH were more likely to be overweight or obese in young adulthood (ages 20 to 25) (aOR = 1.60, 95% CI 1.51 to 1.71) and were slightly more likely to have short stature (aOR = 1.08, 95% CI 1.02 to 1.15) than their peers without ADHD. The mean height difference was less than 1 cm (maximum −0.6 cm in females) and was clinically insignificant. Boys who had taken MPH for 1 to 4 years had the highest BMI (26.0). (Retrospective registry cohort study, N = 34,850 [n = 12,866 children aged 6 to 11 years, n = 21,984 adolescents aged 12 to 19 years], E 2b.)⁷⁷
In the European ADDUCE cohort, children and adolescents with and without MPH treatment did not differ in their self-reported Tanner stages of pubertal development after 2 years (e.g., pubic hair OR 1.28, p = 0.16). After 24 months, puberty data were available for only about half of the participants. An Italian subgroup receiving MPH (n = 39; n = 25 after 24 months) showed slightly accelerated bone maturation after 24 months (bone age plus 2.74 years at a chronological age of plus 2.11 years) with a stable predicted adult height. (Prospective cohort study [ADDUCE, 3 cohorts: MPH, ADHD without MPH, controls], N = 1,410, n = 756 on MPH, 2 years, E 2b.)⁷⁸

Breaks in Treatment¶

Children and adolescents who had paused MPH treatment for at least 3 months during a treatment period of at least one year did not differ from those who had received continuous treatment in terms of changes in height, weight, and BMI z-scores. In both groups, height and weight decreased more sharply the younger the children were at the start of treatment. (Retrospective cohort study, n = 432, E 2b.)⁷⁹

Precocious Puberty¶

Premature puberty (pubertas praecox) was more common in children with ADHD than in children without ADHD. MPH did not increase this risk:

• Children with ADHD who were taking MPH had a lower risk of early puberty than children with ADHD who were not taking MPH (aHR 0.63, 95% CI 0.57 to 0.70). The difference was significant among girls (aHR 0.51, 95% CI 0.44 to 0.59) but not significant among boys (aHR 0.91). (Register-based cohort study, N = 3,342,077, n = 186,681 with ADHD, E 2b.)⁸⁰
• ADHD medication (MPH or atomoxetine) did not alter the incidence of central precocious puberty in children with ADHD (register-based cohort study, n = 290,148, 15 years, full text not available to us, E 2b.)⁸¹

A case series described 7 children of normal weight (mean age 8.2 years) who developed central precocious puberty after at least 6 months of MPH treatment (0.5 mg/kg per dose, three times daily). (Case series, n = 7, E 4.)⁸²

10.3. Parkinson’s Disease / Tremors in Older Adults¶

A very comprehensive study analyzed, over a period of about 20 years (1996 to 2016) the likelihood of basal ganglia and cerebellar disorders (Parkinson’s disease, secondary parkinsonism, other degenerative basal ganglia disorders, essential tremor) in people with ADHD, both with and without a known prescription for stimulants. The disorders occurred between the ages of 21 and 66. (cohort study, retrospective, registry data, N = 190,559, n = 31,769 with ADHD, of whom n = 4,960 had a known prescription for stimulants, n = 158,790 matched controls, median follow-up 21 years, E 2b.)⁸³

A German case-control study retrospectively surveyed 88 people with ADHD and 88 matched controls. None of the participants reported having received methylphenidate during childhood, so it was not possible to investigate a link between ADHD and psychostimulants in childhood. People with Parkinson’s disease reported more ADHD symptoms in childhood in retrospect (WURS-k 14.4 vs. 9.8 points, p = 0.01). (case-control study, n = 176, E 3.)⁸⁵

Another cohort study of people with ADHD aged 50 and older found that a prescription for stimulants reduced the risk of Parkinson’s disease by 58% (HR 0.419, 95% CI 0.34 to 0.516). Of the 59,471 individuals treated with stimulants, 131 developed Parkinson’s disease, compared with 272 in the matched group not receiving stimulants. MPH was not analyzed separately from amphetamines. (Cohort study, retrospective, N = 118,942 [59,471 each with and without stimulants, propensity score-matched], up to 30 years, E 2b.)⁸⁶

10.4. Risk of psychosis slightly elevated, if at all¶

The absolute risk of new-onset psychosis while taking ADHD medication depended on the active ingredient. It was:

• in adults hospitalized for a first episode of psychosis or mania within one year of starting medication (registry study, n = 16,125, 1 year, E 2b.)⁸⁹
  • 0.60% less than atomoxetine
  • 0.33% of amphetamine-based medications
  • 0.19% less than methylphenidate
• Among 13- to 25-year-olds with ADHD, for a new episode of psychosis (diagnosis plus prescription of antipsychotics) (cohort study, insurance data, N = 221,846, 143,286 person-years, E 2b.)⁹⁰
  • 0.21% among amphetamine-based medications (HR 1.65, 95% CI 1.31 to 2.09 compared with methylphenidate)
  • 0.10% less than methylphenidate

Reports of psychotic symptoms as adverse effects in 13- to 25-year-olds were 1.6 times more common with amphetamine medications than with methylphenidate (ROR 1.61, 95% CI 1.26 to 2.06); for ADHD as an indication, the rate was 1.9 times higher. For atomoxetine, there was no difference compared to methylphenidate. Reporting rates are not incidence rates. (Pharmacovigilance study, disproportion analysis, n = 13,863 reports, E 3.)⁹¹
Among 13- to 25-year-olds with ADHD who were treated with stimulants, the incidence of psychosis was 2.4 per 1,000 person-years (0.24% per year). (Cohort study, insurance data, N = 221,846, 143,286 person-years, E 2b.)⁹⁰ In the general population aged 18 to 64, the incidence of treated first-episode psychosis was 21.4 per 100,000 person-years (0.0214% per year), and among men aged 18 to 24, it was 61.0 per 100,000 person-years. The age groups and case definitions differ between the two studies. (Incidence study, n = 2,774 first-episode psychoses, 12.9 million person-years, E 2b.)⁹²
The studies do not allow us to conclude whether the increase in the prevalence of psychosis is attributable to the presence of ADHD or to the use of stimulants.
Another study found an 8-fold increased risk among people with ADHD who were taking ADHD medications (0.38% within one year vs. 0.048% per year in the general population aged 18 to 67, RR 7.99, 95% CI 6.06 to 10.54). Half of the people with ADHD (50.8%) had a history of substance use disorder. (registry study, n = 16,125, 1 year, E 2b.)⁸⁹ Since this study compares people with ADHD who are taking medication—rather than people with ADHD and people without medication—to the general population, no reliable conclusions can be drawn regarding the contribution of ADHD medications.

Another large cohort study suggests a possible slight increase in risk associated with stimulants; it found a significantly increased risk of psychosis in ADHD overall (2.7% vs. 0.4%, OR 6.99; after adjusting for autism and substance abuse, OR 2.57). Each additional 5 prescriptions of stimulants slightly increased this risk by 6% (OR 1.06, 95% CI 1.02 to 1.10), and non-stimulants by 15% (OR 1.15, 95% CI 1.01 to 1.30). The confidence intervals overlapped. The duration of medication was not associated with the risk of psychosis. MPH (prescribed in 70.7% of cases) and amphetamine (1.1%) were not associated with subsequent psychosis when considered individually. In a sibling comparison, the risk of psychosis remained elevated in ADHD (OR 2.95, 95% CI 2.07 to 4.20). (cohort study, n = 18,139 with ADHD, 72,437 controls, sibling comparison, medication analysis n = 13,237, E 2b.)⁹³ Another large study based on the Swedish Health Registry involving 23,898 adolescents and young adults who were new users of methylphenidate (ages 12 to 30) compared the risk of psychosis 12 weeks before and after the start of MPH administration within the same individual and found no significant increase (IRR 1.04, 95% CI 0.80 to 1.34), nor was there a significant increase among those with a history of psychosis (IRR 0.95, 95% CI 0.69 to 1.30). One year after initiation, the risk was 36% lower among individuals with a history of psychosis (IRR 0.64, 95% CI 0.45 to 0.91). (Cohort study, registry data, within-individual design, n = 23,898, E 2b.)⁹⁴ A narrative review suggested a higher risk of psychosis, particularly with high doses of MPH, but acknowledged that the specific dose responsible remains unclear. (Narrative review, k = 24, E 4.)⁹⁵

When taking stimulants, people with ADHD:

• psychotic symptoms: 2.76% (95% CI 0.73 to 9.88, k = 10)
• bipolar disorder: 3.72% (95% CI 0.77 to 16.05, k = 4)
• a psychotic disorder: 2.29% (95% CI 1.52 to 3.40, k = 4)

Psychotic symptoms occurred more frequently with amphetamine medications than with methylphenidate (OR 1.57, 95% CI 1.15 to 2.16, k = 3, n = 231,325). Higher doses of stimulants were associated with more frequent psychotic symptoms. A control group of untreated persons with ADHD was lacking, so it was not possible to distinguish a drug effect from an ADHD effect. Heterogeneity was very high (I² > 95%). (Meta-analysis, k = 16, N = 391,043, predominantly observational studies, E 2b.)⁹⁶

The benefits of treating ADHD (reduction in premature mortality, reduction in the lifetime risk of depression and anxiety disorders, reduction in the risk of substance abuse, etc.) are likely to significantly outweigh the potential risks. (ADxS Assessment)
Learn more about the risks of (untreated) ADHD at ⇒ Consequences of ADHD.

Comparisons within the same person¶

Children and adolescents (ages 6 to 19) in Hong Kong did not have a higher risk of new-onset psychotic events while taking MPH than during periods when they were not taking MPH (IRR 1.02, 95% CI 0.53 to 1.97). In contrast, the risk was significantly increased during the 90 days prior to the start of MPH treatment (IRR 4.64, 95% CI 2.17 to 9.92). The authors attributed this to the symptoms that led to psychiatric evaluation and the initiation of treatment. (Self-controlled case series, N = 20,586 on MPH, n = 103 with a psychotic event, E 2b.)⁹⁷

Even among adults with a history of psychosis, psychotic episodes did not increase in the 6 months following the start of treatment with stimulants or atomoxetine (RR 0.95, 95% CI 0.84 to 1.08). For (dex)methylphenidate (n = 2,378), the RR was 1.07 (95% CI 0.90 to 1.27), 0.76 (95% CI 0.49 to 1.16) for amphetamine medications, and 0.81 (95% CI 0.65 to 1.02) for atomoxetine. The confidence intervals overlapped. (Registry cohort study, within-individual design, n = 3,770, ages 18 to 64, E 2b.)⁹⁸

Hallucinations in Reporting Data and Clinical Trials¶

In the WHO pharmacovigilance database (VigiBase), psychotic symptoms were reported slightly more frequently among 5- to 17-year-olds taking MPH than among those taking other ADHD medications (aROR 1.27, 95% CI 1.15 to 1.40), as were hallucinations (aROR 1.35, 95% CI 1.19 to 1.52). Visual hallucinations were the most common (43.2%). After discontinuing or reducing the dose of MPH, the symptoms resolved in 88.6% of cases; without these measures, they resolved in 12.0%. The comparison group consisted of reports on atomoxetine, clonidine, guanfacine, and tricyclic antidepressants. Reporting rates are not incidence rates. (Pharmacovigilance study, disproportion analysis, n = 1,232 MPH reports of psychotic symptoms, full text not available to us, E 3.)⁹⁹

An analysis by the U.S. Food and Drug Administration (FDA) of 49 randomized controlled trials (RCTs) from the pediatric approval programs for all ADHD medications found 11 cases of psychosis or mania in 743 person-years on the active ingredient and none in 420 person-years on placebo (1.48 events per 100 person-years, 95% CI 0.74 to 2.65). MPH preparations accounted for 5 events in approximately 122 person-years (4 of which occurred with transdermal MPH), while atomoxetine accounted for 4 events in 488 person-years. Among the more than 800 spontaneous reports of psychosis or mania, approximately 90% lacked a corresponding history. In children, visual and/or tactile hallucinations of insects, snakes, or worms were common. (Pooled analysis, k = 49 RCTs, n = 5,717 on active ingredient, n = 3,990 on placebo, mean duration 51 days, and spontaneous reports, all ADHD medications, E 1a.)¹⁰⁰ In the U.S. spontaneous reporting database FAERS, visual hallucinations in 6- to 17-year-olds taking MPH were among the 20 most common adverse events (n = 101 reports, ROR 4.76, 95% CI 3.86 to 5.87). (Pharmacovigilance study, disproportionate risk analysis, n = 8,585 reports, E 3.)¹⁰¹

10.5. Loss of appetite, anorexia nervosa¶

Treatment with MPH increased the risk of loss of appetite by a factor of 5.11 compared with placebo (OR 5.11, 95% CI 1.99 to 13.14). The term “anorexia” here refers to loss of appetite as a side effect, not the eating disorder anorexia nervosa. (meta-analysis, k = 49 [11 RCTs, 38 cohort studies], n = 1,304 MPH and 887 controls [RCTs], n = 5,524 [cohorts], children and adolescents, E 1a.)¹⁰²
According to the prescribing information, current or past anorexia nervosa is a contraindication for methylphenidate. (E 4.)¹⁰³

Among preschool-aged children (up to 6 years old), of all recorded side effects associated with stimulants (MPH in 8 of 9 studies), only decreased appetite was more common than with placebo (OR 2.39), with low to very low quality of evidence. (Meta-analysis, k = 9 RCTs, N = 544, E 1a.)¹⁰⁴

10.6. Seizure threshold, EEG abnormalities¶

Methylphenidate is believed to lower the seizure threshold. This applies to patients with a history of seizures (e.g., those with epilepsy) as well as patients with abnormal EEG findings but no prior history of seizures. In rare cases, MPH may trigger seizures even in the absence of the aforementioned risk factors.

A study of 517 children with ADHD found EEG abnormalities in 273 (52.8%) of them, 39 of which were epileptiform. Children with and without EEG abnormalities exhibited similar patterns of MPH use (initial use, positive response, and continued MPH use). In a follow-up of the 39 children with epileptiform EEG abnormalities and 39 matched controls after 3 years, no new seizures occurred in children without epilepsy or with seizure-free epilepsy. Seizures occurred in only 3 children with drug-resistant epilepsy, and their frequency had not increased. The number of children with epilepsy was small, at 14. (Cohort study, N = 517, n = 78, 3 years, E 2b.)¹⁰⁸

Among 6- to 25-year-olds with no history of seizures or epilepsy, the risk of a seizure was increased in the first 30 days after starting MPH (IRR 4.01, 95% CI 2.09 to 7.68), but not on days 31 through 180 (IRR 1.13, 95% CI 0.56 to 2.25) or with longer-term use (IRR 1.38, 95% CI 0.92 to 2.07). The seizure incidence among MPH users was 4.4 per 10,000 patient-years. No one died from a seizure. 84% of those who experienced their first seizure while taking MPH did not have another seizure. (Self-controlled case series, N = 29,604 on MPH, n = 269 with seizures, mean follow-up 10.7 years, E 2b.)¹⁰⁹

In a randomized controlled trial (RCT), sustained-release MPH (OROS-MPH) did not significantly worsen epilepsy in children with epilepsy and ADHD. However, higher doses were associated with a higher daily risk of seizures (p < 0.001). The seizure rate per 100 days was 0.53 with placebo, 0.52 with 10 or 18 mg, 1.12 with 36 mg, and 2.30 with 54 mg. The evidence was of low certainty. (Cochrane Review, k = 2, including 1 RCT on MPH with n = 33, E 1a.)¹¹⁰

If the frequency of seizures increases or if new seizures occur, methylphenidate should be discontinued. (Professional article; full text not available to us, E 4)¹¹¹

10.7. Exacerbation of existing anxiety disorders, depression, and aggression¶

Comorbid anxiety disorders may worsen with stimulant medication. For adults with ADHD and comorbid anxiety, depression, or addiction, a norepinephrine reuptake inhibitor or an α2A-adrenoceptor agonist may be a suitable alternative to a stimulant. (Textbook, E 4.)¹¹²
According to the prescribing information, MPH may exacerbate existing anxiety, agitation, or tension. Patients should be monitored for new or worsening aggressive behavior. (E 4.)¹⁰³

A small RCT found no acute change in state anxiety following a single dose of MPH (0.3 mg/kg, immediate release). However, children who had received MPH in the first session showed higher state anxiety at the start of the second session, which the authors interpreted as a possible delayed anxiety-inducing effect. (RCT, crossover, double-blind, n = 20, children, single dose, E 1b.)¹¹³

10.8. MPH and Risk of Manic Episodes in Bipolar Disorder¶

A study of 1,043 patients with bipolar disorder found no increased risk of mania after starting MPH treatment. Manic episodes subsequently decreased by 48%, as did depressive episodes and psychiatric hospitalizations. The authors attributed the decline primarily to a regression toward the mean, since manic episodes occurred more frequently approximately 6 months before the start of MPH treatment, rather than to MPH itself. (Registry study, mirror-image design, n = 1,043, 1 year before/after, full text not available to us, E 2b.)¹¹⁴
According to the prescribing information, special caution is warranted in patients with comorbid bipolar disorder due to the potential for triggering mixed or manic episodes. (E 4.)¹⁰³

In adults with bipolar disorder, the risk of mania following the initiation of MPH depended on whether they were also taking mood-stabilizing medication:

• without mood stabilizers (MPH monotherapy, n = 718): HR 6.7 (95% CI 2.0 to 22.4) in the first 3 months and HR 9.7 (95% CI 2.9 to 31.7) in the following 3 months (register-based cohort study, within-individual design, N = 2,307, 6 months, E 2b.)¹¹⁵
• with a mood stabilizer (n = 1,103): HR 0.6 (95% CI 0.4 to 0.9) in the first 3 months (register-based cohort study, within-individual design, N = 2,307, 6 months, E 2b.)¹¹⁵

A replication study using French health insurance data also found more inpatient diagnoses of mania in the 3 months following the start of MPH treatment in patients not taking mood stabilizers (n = 2,745). However, in case-crossover analyses, this difference was no longer significant. The authors considered the natural course of mania to be a possible explanation. With continuous mood-stabilizing treatment (n = 3,526), the risk of mania increased only at MPH doses above 30 mg. (Registry study, self-controlled design, n = 6,271, 6 months before/after, full text not available to us, E 2b.)¹¹⁶

10.9. MPH increases histamine levels¶

We suspect that people with histamine intolerance may have a harder time tolerating ADHD medications. We are not aware of any studies on this topic. (ADxS assessment)
A person with ADHD and histamine intolerance reported that she could not tolerate AMP or sustained-release MPH at all, but was able to tolerate immediate-release MPH in small doses. (ADxS experience)

10.10. Rebound¶

A “rebound” refers to a brief increase in symptoms—which are normally reduced by MPH—at the end of the medication’s effective period. If a dose of MPH lasts about 3 hours, ADHD symptoms may intensify for approximately 20 to 30 minutes at the end of those 3 hours or immediately afterward.
Among 149 hospitalized children (ages 5 to 12) receiving short-acting stimulants (mostly MPH), rebound occurred in 30% after at least one dose, but was severe enough to warrant discontinuation of treatment in only 8.7%. In 21.5%, rebound occurred with only one of several doses. There were no clinical differences between children with and without rebound. (Retrospective cohort study, n = 149, children, nursing assessment: day shift vs. evening shift, E 2b.)¹²¹
Sustained-release stimulants are likely associated with a lower risk of rebound than immediate release stimulants. (Narrative review, E 4.)¹²²
We assume that a rebound is caused by a too rapid decline in dopamine/norepinephrine levels. With medications that exhibit a very slow decline in efficacy, a rebound appears to occur less frequently. (ADxS assessment)

A rebound effect can be avoided by taking the next dose in a timely manner so that there is no gap in medication.
For the last dose of the day, the rebound effect can be mitigated or avoided by taking a much smaller dose than the usual single dose at the time when the next dose would normally be taken.

Among male adolescent drivers with ADHD, driving performance did not deteriorate 16 to 17 hours after taking 72 mg of OROS-MPH, either in the simulator or on the road, compared with placebo. In contrast, when taking sustained release amphetamine salts (30 mg), there were significantly more inattentional errors on the road at midnight than with the placebo (p = 0.04, one-tailed) and than with OROS-MPH (p = 0.008), which could indicate a rebound effect. Driving performance fluctuated two to three times more under amphetamine late in the evening. (RCT [crossover, double-blind, placebo-controlled], n = 19 boys, ages 17 to 19, partially manufacturer-funded, E 1b.)¹²³ In an Italian routine cohort, 1 out of 480 children discontinued MPH treatment during the first week due to rebound. (Retrospective cohort study, n = 480, immediate release MPH, 1 week, E 2b.)²³

Symptoms Following Sudden Discontinuation¶

Case reports described the following after abrupt discontinuation of MPH:

• recurrent acute dystonia (initially affecting the tongue and mouth, followed hours later by the jaw and both legs) in a 6-year-old on the second day after sudden discontinuation of 3 × 10 mg of immediate release MPH while concurrently taking guanfacine, each administered at approximately the usual times. The dystonia resolved with fluid infusion alone. (Case report, n = 1, E 4.)¹²⁴
• Severe vomiting lasting several days, headache, and sensitivity to light in an 11-year-old girl with autism and ADHD following abrupt discontinuation of 36 mg OROS-MPH (case report, n = 1, E 4.)¹²⁵

10.11. MPH and Anesthesia¶

In the case of surgery, in addition to the sometimes significantly increased sensitivity to medications in people with ADHD, the issue of interactions between ADHD medications and anesthetics must also be taken into account.

A double-blind study of women without ADHD who had undergone gynecological abdominal surgery found that MPH (0.4 mg/kg IV at the end of anesthesia) had no effect on postoperative pain. MPH reduced sedation for up to 30 minutes after surgery and improved respiratory function following halothane anesthesia for up to 180 minutes afterward. Heart rate increased by 18 to 22 beats per minute 5 minutes after administration. Occasional adverse behavioral effects occurred (restlessness and crying in 4 patients; not observed with placebo). (RCT, double-blind, n = 63 women, ages 16 to 70, E 1b.)¹²⁶ Halothane is barely used in Germany today.
A case report described an increased need for sedatives in a 6-year-old boy with Williams syndrome who was taking MPH (2 × 5 mg/day) (oral midazolam, even when combined with ketamine, was insufficient) and a possible delayed interaction with ketamine resulting in severe nausea, vomiting, and dehydration. (case report, n = 1, child, E 4.)¹²⁷

In rats, MPH shortened the time to wake up from isoflurane anesthesia (median 91 seconds instead of 280 seconds) and restored the righting reflex in a dose-dependent manner during continuous isoflurane administration. MPH also increased the minute volume of respiration. The dopamine antagonist droperidol largely reversed these effects. (Animal study, rats, n = 12 per group, MPH 5 mg/kg i.v., E 2b.)¹²⁸ Following a single dose of propofol, MPH shortened the time to wake-up from a median of 735 to 448 seconds. With a continuous propofol infusion, all 6 rats woke up after receiving MPH (median time: 82 seconds). (Animal study, rats, n = 6 per group, MPH 5 mg/kg i.v., E 2b.)¹²⁹

A review article in the field of anesthesiology found that, in cases of long-term, medically prescribed use of amphetamines and amphetamine-like stimulants (including MPH), continuing the medication around the time of surgery posed few problems. Continuing treatment reduces the risk of withdrawal symptoms and stabilizes the patient’s mental and physical condition. (Narrative review, E 4.)¹³⁰ The prescribing information, however, advises against taking MPH on the day of a scheduled surgery (see 11.1.1).

10.12. Other Information on Side Effects of MPH¶

There have been reports of isolated cases of new-onset trichotillomania (hair pulling) associated with the use of stimulants (MPH, lisdexamfetamine, dexamfetamine). In an 8-year-old and a 15-year-old boy, the condition recurred while taking MPH and lisdexamfetamine and resolved after dose reduction, discontinuation, or spontaneously. After switching to atomoxetine and guanfacine, one of the boys experienced no further episodes. (Case series, n = 2, children and adolescents, E 4.)¹³² Trichotillomania is classified in the DSM-5 as a disorder on the obsessive-compulsive spectrum (in the DSM-IV, it was still classified as an impulse control disorder).
A case report described a 12-year-old boy taking sustained-release dexmethylphenidate (up to 30 mg/day) who experienced severe muscle pain and stiffness in his thighs, which resolved several weeks after discontinuation. (Case report, n = 1, child, E 4.)¹³³
A study found that men aged 20 to 40 with ADHD who had taken stimulants long-term (at least 36 prescriptions) over a 5-year period were more likely to be diagnosed with hypogonadism (1.2%) than men with ADHD who were not taking ADHD medication (0.67%, RR 1.78, 95% CI 1.42 to 2.23) or without ADHD (0.68%, RR 1.75, 95% CI 1.39 to 2.19). MPH was not analyzed separately. Dose, hormone levels, and the cause of hypogonadism were unknown. (Retrospective database cohort study, n = 17,224 per group, men, E 2b.)¹³⁴

Compulsive-like symptoms, hair pulling, and skin picking¶

A systematic review identified 22 case reports of stimulant-induced trichotillomania, tactile hallucinations, and delusions of dermatozoa (the belief that one is infested with parasites). Trichotillomania and tactile hallucinations typically affected boys undergoing treatment for ADHD and resolved after discontinuation of treatment. Delusion of parasitic infestation primarily affected adults who had misused or abused substances. (Systematic review, k = 22 case reports, full text not available to us, E 4.)¹³⁵

Individual cases described as having newly developed under MPH:

• Compulsive symptoms (need for symmetry, compulsive checking, organizing) in a 14-year-old 10 days after starting treatment with 15 mg/day, which completely resolved within 2 weeks after discontinuation (Case report and literature review, n = 1, E 4.)¹³⁶
• Skin picking (dermatillomania, compulsive skin picking) with skin lesions that sometimes bled in a 7-year-old during the first week of treatment with sustained-release MPH; the symptoms subsided after discontinuation of the medication and resolved completely only after treatment with citalopram and risperidone (Case report, n = 1, E 4.)¹³⁷

Raynaud’s Syndrome¶

Raynaud’s syndrome (episodic reduced blood flow to the fingers or toes, accompanied by paleness, bluish discoloration, or redness, and sensitivity to cold) has been reported with methylphenidate, (dex)amphetamine, and, less commonly, atomoxetine. A systematic review identified 61 cases, the vast majority of which were from case reports and case series. Most cases were mild and resolved within weeks after discontinuation, dose reduction, or a change in medication. Isolated cases involving an underlying systemic disease led to ulcers, gangrene, and amputation. Of the 28 cases evaluated, an association with the medication was possible in 13 cases, probable in 13, and certain in 2 (Naranjo scale). A causal relationship could not be established due to the lack of controlled studies. The authors recommended monitoring for signs of Raynaud’s syndrome, particularly at the start of treatment and when increasing the dose. (Systematic review, 22 publications, n = 61 cases, full text not available to us, E 4.)¹³⁸

Sexual Function, Hormones, and Testicular Function¶

Sexual Function

A systematic review identified 14 studies on MPH and sexual function, most of which were case reports of poor quality. MPH was found to both reduce libido and cause ejaculatory dysfunction (more commonly in cases of psychiatric comorbidities) as well as improve sexual arousal and function (more likely in cases of preexisting dysfunction or at low doses). (Systematic review, k = 14, E 4.)¹³⁹ Among adults on long-term medication (primarily MPH), 17% reported decreased sexual desire. (Cohort study, n = 112, of whom 57 continued medication, 6 years, E 2b.)¹⁴

Priapism

An FDA safety advisory (December 2013) regarding priapism (painful, prolonged erection) associated with MPH was based on 15 case reports involving male patients (mean age 12.5 years, ranging from 8 to 33 years). Several were hospitalized; two required surgical intervention (shunt or puncture). Prolonged erections and priapism occurred with both immediate release and sustained release formulations, during dose increases, and during discontinuation. Prescribing information and patient information were subsequently updated. Of 6 published MPH cases (5 involving sustained-release MPH), only 3 were painful and only one lasted longer than 4 to 6 hours. (Narrative review, E 4.)¹⁴⁰ In FAERS, priapism in boys taking MPH was a signal (31 reports, plus 6 reports of painful erections). (Pharmacovigilance study, disproportion analysis, n = 8,585 reports, E 3.)¹⁰¹

Hormones

In previously untreated 6- to 12-year-olds, IGF-1, IGFBP-3, prolactin, TSH, T3, T4, and free T4 did not differ from those observed without medication. While on MPH, the children gained less weight (4.2 and 4.1 kg, respectively, compared with 5.6 kg without medication); height gain did not differ between the groups. The MPH dose relative to body weight correlated negatively with height gain (r = −0.33 and −0.32, respectively). (Prospective cohort study, n = 118, 12 months, E 2b.)¹⁴¹ A case report described bilateral gynecomastia (breast enlargement in males) in a 15-year-old while taking OROS-MPH 27 and 36 mg/day with normal prolactin levels, which resolved within one month after discontinuation. (Case report, n = 1, E 4.)¹⁴²

In children with ADHD, MPH (mean daily dose of 18.1 mg) did not alter salivary testosterone levels over a 4-week period. (Non-randomized prospective study with a control group, n = 132 evaluated, 4 weeks, E 2b.)¹⁴³ In a nationwide Taiwanese cohort, boys with ADHD were more likely to have testicular dysfunction than boys without ADHD (0.14% versus 0.06%, aOR 1.95, 95% CI 1.26 to 3.04). MPH use overall (aHR 1.40, 95% CI 0.77 to 2.54) as well as short-term use (up to 365 days, aOR 0.96, 95% CI 0.51 to 1.82) or long-term MPH use (over 365 days, aOR 1.40, 95% CI 0.69 to 2.83) did not significantly increase the risk. (Register-based cohort study, n = 111,754, 12 years, E 2b.)¹⁴⁴ A case report described a 20-year-old man who, after 17 years of MPH use, presented with delayed puberty and low levels of FSH, LH, and testosterone (hypogonadotropic hypogonadism), which improved with hormone replacement therapy. (Case report, n = 1, E 4.)¹⁴⁵

Changes in blood counts and infections associated with MPH:

• Children with ADHD were less likely to develop respiratory tract infections during periods of MPH treatment than during periods without MPH (all respiratory tract infections: RR 0.64, 95% CI 0.61 to 0.68; lower respiratory tract RR 0.36; influenza RR 0.82). (Register-based cohort study with self-controlled case series analysis, n = 85,853 with ADHD, E 2b.)¹⁴⁶

Hair, Teeth, Skin, Blood Count, Stuttering, and Hearing¶

Hair Loss

In a nationwide Taiwanese birth cohort, children with ADHD had an increased risk of alopecia areata (aHR 1.30, 95% CI 1.04 to 1.64). Children with ADHD who were taking MPH (for more than 3 months) did not have an increased risk; rather, they had a non-significantly reduced risk compared to children with ADHD who were not taking MPH (aHR 0.64, 95% CI 0.32 to 1.25). (Cohort study, n = 1,750,456, of whom 90,016 had ADHD, E 2b.)¹⁴⁷

Teeth Grinding, Dental Health, Dry Mouth

Teeth grinding (bruxism) tended to be more common among 5- to 18-year-olds with ADHD who were taking MPH than among those taking atomoxetine or no medication (moderate to severe: 20.7% compared to 11.5% without medication and 8.1% on atomoxetine), but the difference was not statistically significant. The severity of bruxism was associated with the severity of ADHD, particularly with hyperactivity. (Cross-sectional study, n = 181, E 3.)¹⁴⁸ A systematic review found only one study on MPH: Among 10- to 17-year-olds (n = 467, of whom 281 had ADHD), MPH use was associated with questionnaire-assessed sleep bruxism (OR 1.67, 95% CI 1.03 to 2.68). The overall quality of evidence was very low. (Systematic review, k = 5 cross-sectional studies, including 1 on MPH, E 3.)¹⁴⁹

Young adults (Israeli conscripts, ages 18 to 25) with ADHD and MPH were more likely to require dental fillings (24%) than those with untreated ADHD (22%) or without ADHD (17%). The probability increased in a dose-dependent manner (OR 1.006 per additional gram of cumulative MPH dose, 95% CI 1.004 to 1.009, adjusted for, among other factors, ADHD diagnosis, education, and socioeconomic status). Only the need for filling therapy was measured; salivary flow was not recorded. (Retrospective cohort study, n = 213,604, of whom 6,875 were on MPH, E 2b.)¹⁵⁰ Children with ADHD taking MPH, particularly immediate release MPH, had more dental caries, poorer oral hygiene, lower salivary flow, and higher levels of Streptococcus mutans than healthy controls. (Cross-sectional study, n = 99, of whom 49 were on MPH; full text not available to us, E 3.)¹⁵¹

Skin Reactions Associated with the MPH Patch (Transdermal MPH)

With the MPH patch, about half of the 6- to 12-year-olds showed significant redness at the application site, which usually subsided within 24 hours. 1% experienced more severe reactions (significant swelling); none developed blisters or reactions extending beyond the adhesive site. One child (0.3%) was found to have a contact allergy to MPH. (Open-label study, n = 305, 7 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)¹⁵² Over 12 months, reactions at the adhesive site led to study discontinuation in 6.7% of 6- to 12-year-olds. These were mostly mild redness. Only 48% completed the study. (Open-label extension study, n = 326, 12 months, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)¹⁵³ The FDA identified 51 cases of persistent chemical leukoderma (skin depigmentation) under the MPH patch, predominantly at the site of adhesion, with onset ranging from 2 months to 4 years after the start of therapy. No discoloration resolved during follow-up, even after discontinuation. Nineteen cases had been diagnosed as vitiligo. In 2015, the U.S. prescribing information was updated accordingly. (Case series from spontaneous reports, n = 51, E 4.)¹⁵⁴ Redness at the adhesion site was the most frequently reported MPH adverse reaction in FAERS among 6- to 17-year-olds (n = 418). (Pharmacovigilance study, disproportion analysis, n = 8,585 reports, E 3.)¹⁰¹

Complete Blood Count

After 3 months of MPH, white blood cell counts (by 1,350/µl), neutrophil counts, lymphocyte counts, and eosinophil counts increased in 11- to 31-year-olds but remained largely within the normal range. Red blood cell and platelet counts remained unchanged. (cohort study without a control group, n = 64, 3 months, E 2b.)¹⁵⁵ Among hospitalized children and adolescents, neutropenia occurred in 55.2% of those receiving the triple combination of valproate, an antipsychotic, and an ADHD medication (MPH or atomoxetine), in 25% of those receiving valproate and an antipsychotic, with an antipsychotic alone in 12%, and with an antipsychotic and ADHD medication in none of the 19 patients. (Retrospective cohort study, n = 231, E 2b.)¹⁵⁶

Stuttering

In the WHO VigiBase database, MPH was associated with stuttering (17 of 584 reports, ROR 13.9, 95% CI 8.6 to 22.5; for speech disorders overall, ROR 7.3, 95% CI 5.4 to 9.8). Where the course of the condition was reported, stuttering improved after discontinuation or dose reduction. (Pharmacovigilance study, disproportion analysis, n = 2,975 reports of speech disorders, 46 of which were related to MPH, E 3.)¹⁵⁷ In a subsequent analysis of all active ingredients, MPH was the active ingredient most strongly associated with stuttering (27 out of 724 reports, ROR 19.58, 95% CI 13.3 to 28.8). (Pharmacovigilance study, disproportion analysis, n = 724 reports, E 3.)¹⁵⁸ In young men with developmental stuttering, however, a single dose of 20 mg MPH significantly reduced the number of stuttering episodes during reading and speaking compared to baseline (by 46%; under placebo, an increase of 14%), subjectively, the participants did not notice any improvement. (RCT, crossover, n = 15, single dose, E 1b.)¹⁵⁹

Hearing Ability

In children aged 6 to 15, hearing thresholds, speech discrimination, and brainstem audiometry did not change after 3 months of OROS-MPH treatment. (Before-and-after study, n = 30, 3 months, E 2b.)¹⁶⁰ A case report described an 8-year-old girl taking immediate release MPH (5 mg twice daily) who presented with unilateral severe inner-ear hearing loss (approximately 70 dB) accompanied by tinnitus, vertigo, and vomiting, which began approximately 24 hours after the first dose. Despite cortisone and hyperbaric oxygen therapy, her hearing did not improve within 2 months. (case report, n = 1, E 4.)¹⁶¹

10.13. Cardiovascular risks: serious events are rare; a slight increase in risk is possible¶

The hypothesis that methylphenidate causes an increased incidence of serious heart problems was not confirmed. (Textbook; full text not available to us; E 4.)¹⁶²

Cardiovascular Events and Diseases¶

Observational studies found the following among ADHD medications:

• an increased risk of

  • sudden unexplained death among 7- to 19-year-olds taking stimulants (MPH in all 10 cases, 1.8% of the 564 sudden deaths compared with 0.4% of the 564 passengers killed in traffic accidents): OR 7.4 (95% CI 1.4 to 74.9) (case-control study, n = 1,128, E 3.)¹⁶³
  • Cardiac arrhythmias within the first 7 days after the initial dose of atomoxetine: aIRR 6.22 (95% CI 1.90 to 20.35); upon repeated administration, aIRR 3.23 (95% CI 1.58 to 6.64) (Self-controlled case series, n = 27,531; full text not available to us; E 2b.)¹⁶⁴
  • Cardiovascular events in the first 6 months after starting MPH treatment in 12- to 60-year-olds: IRR 1.41 (95% HDI 1.09 to 1.88) compared with 1.18 in matched controls. The probability of a risk increase of at least 10% was 70%, compared with 49% in the controls. There was barely any evidence of a risk increase of 20% or more. No differences were observed between individuals with and without a history of cardiovascular disease. (Register-based cohort study, N = 252,382, 6 months, E 2b.)¹⁶⁵
  • Cardiovascular diseases in people aged 6 to 64; significant only at moderate doses starting at 1.5 times the defined daily dose (for MPH, 45 mg/day or higher): (Case-control study, embedded in a registry cohort, N = 278,027, n = 62,060, up to 14 years, E 3.)¹⁶⁶ * (News article, E 4.)*¹⁶⁷
    • High blood pressure after more than 5 years of ADHD medication: AOR 1.80
    • Lisdexamfetamine after 2 to 3 years: AOR 1.23 (95% CI 1.05 to 1.44)
    • MPH after 3 to 5 years: AOR 1.20 (95% CI 1.10 to 1.31)
    • MPH after more than 5 years: AOR 1.19 (95% CI 1.08 to 1.31)
    • Atomoxetine only in the first year: OR 1.07 (95% CI 1.01 to 1.13)
    • Use of ADHD medications per year: OR 1.04 (95% CI 1.03 to 1.05)

• no significantly increased risk of

  • Sudden cardiac death or ventricular arrhythmias in 3- to 17-year-olds taking amphetamine, atomoxetine, or MPH: HR 1.60 (95% CI 0.19 to 13.60); for MPH alone, HR 2.63 (95% CI 0.29 to 23.69). Due to the small number of events, a relative increase in risk could not be definitively ruled out. (cohort study, n = 241,417 new users, median follow-up while on medication 60 to 91 days, manufacturer-funded, E 2b.)¹⁶⁸
  • Cardiovascular diseases associated with stimulants: RR 1.24 (95% CI 0.84 to 1.83). A slightly increased risk of cardiac arrest and tachyarrhythmias (RR 1.60, 95% CI 0.94 to 2.72) could not be ruled out. (Meta-analysis, k = 19, N = 3,931,532, median 1.5 years, E 2b.)¹⁶⁹
  • Stroke, heart attack, or severe cardiac arrhythmias in children and adolescents with ADHD taking stimulants or atomoxetine: OR 1.08 (95% CI 0.78 to 1.49) (Case-control study, embedded in registry cohorts, N = 2,566,995, n = 2,046, author(s) employed by the manufacturer [Roche], E 3.)¹⁷⁰
  • Cardiac arrhythmias or heart failure associated with MPH in a predominantly working-age adult population (Self-controlled case series, n = 27,531; full text not available to us, E 2b.)¹⁶⁴

• a reduced risk of

  • Severe cardiovascular events among 3- to 18-year-olds taking MPH over a median period of approximately 7 years: HR 0.85 (95% CI 0.72 to 0.99); borderline HR 0.83 (95% CI 0.69 to 1.00) for treatment lasting at least 180 days (Register-based cohort study, N = 224,732, median 7.2 to 7.5 years, E 2b.)¹⁷¹

  • Heart attack, sudden cardiac death, or stroke in 25- to 64-year-olds currently taking MPH compared with those who took it in the past: RR 1.07 (95% CI 0.86 to 1.34) (Retrospective cohort study, N = 443,198, n = 150,359 users of ADHD medications, median 1.3 years, E 2b.)¹⁷²

  • Cardiac events (angina pectoris, arrhythmia, or transient ischemic attack requiring emergency department visit or hospitalization) in 6- to 21-year-olds with no known cardiovascular risk factors who are currently taking stimulants: aOR 0.69 (95% CI 0.42 to 1.12), cardiac symptoms (tachycardia, palpitations, syncope): aOR 1.18 (95% CI 0.89 to 1.59). MPH did not differ significantly from amphetamine (events: aOR 2.14, 95% CI 0.82 to 5.63; symptoms: aOR 1.08, 95% CI 0.66 to 1.79) (Retrospective cohort study, N = 171,126, E 2b.)¹⁷³

  • Cardiac-related emergency department visits among 3- to 20-year-olds using amphetamine salts compared with MPH: HR 1.01 (95% CI 0.80 to 1.28) (Retrospective cohort study, N = 30,576, n = 18,238 MPH, n = 12,338 amphetamine, E 2b.)¹⁷⁴

Insert the following items as additional items in the existing list:

under “an increased risk of”:

• Cardiac arrhythmias in children and adolescents with ADHD while taking MPH: RR 1.41 (95% CI 1.21 to 1.63), though rates were similar even before starting MPH (RR 1.50, 95% CI 1.15 to 1.96). A family history of cardiovascular disease did not alter the risk. (Self-controlled case series, n = 2,493, Taiwan; full text not available to us; E 2b.)¹⁷⁵

under “no significantly increased risk of”:

• ischemic heart disease (RR 0.86, 95% CI 0.49 to 1.50) and cerebrovascular disease (RR 0.79, 95% CI 0.45 to 1.39) with MPH in children and adolescents, even in cases of a family history of cardiovascular disease or congenital heart defects (Self-controlled Case Series, n = 2,493, Taiwan, full text not available to us, E 2b.)¹⁷⁵
• Heart attacks among MPH users, predominantly older adults (mean age at MPH initiation: 58 to 70 years; MPH use was independent of an ADHD diagnosis): The risk was highest in South Korea and Taiwan before MPH initiation (IRR 3.17 and 1.97, respectively) and was barely increased or decreased, respectively, during treatment (South Korea IRR 1.05, 95% CI 1.00 to 1.11; Taiwan: IRR 0.72, 95% CI 0.65 to 0.80). The authors found no causal association but recommended monitoring for cardiac events during the first 2 to 8 weeks after starting MPH. In Hong Kong (n = 30), all values were significantly elevated. (Self-controlled case series, n = 2,618 with myocardial infarction, South Korea, Taiwan, Hong Kong, E 2b.)¹⁷⁶

The suspicion of an increased risk of cardiac death associated with MPH, which was derived from a case-control study, has not been confirmed by larger studies. (Book chapter; full text not available to us; E 4.)¹⁷⁷ A reduced risk could be due to closer medical monitoring of patients receiving treatment. (ADxS assessment)

Blood Pressure, Heart Structure, and ECG¶

Late adolescents and young adults who had taken sustained-release MPH for at least 2 years showed no echocardiographic evidence of impaired cardiac function compared with healthy controls. However, systolic blood pressure was elevated and increased with duration of use. The lateral left ventricular E’ value was lower but remained within the normal range. (Cross-sectional study with a control group, n = 121; full text not available to us, E 3.)¹⁷⁸

Further long-term echocardiographic follow-up studies conducted under MPH revealed:

• No increase in left ventricular mass was observed in 12- to 25-year-olds after more than 2 years of MPH treatment compared with people with ADHD who had never been treated with MPH. Systolic blood pressure and heart rate were slightly elevated during the day but not at night. Blood pressure readings in the hypertensive range were observed in 12.2% versus 9.6% (overlapping confidence intervals). Dose and duration of treatment were not associated with left ventricular mass or blood pressure (cross-sectional study with a control group [ADDUCE], n = 233, over 2 years, E 3.)¹⁷⁹
• No changes in cardiac structure or systolic function were observed in children (mean age 9 years) over a 2-year period of stimulant treatment (92% MPH, the remainder lisdexamfetamine; mean dose 0.9 mg/kg/day). Systolic blood pressure increased by 3.7 mmHg; diastolic blood pressure increased non-significantly by 2 mmHg, regardless of dose or active ingredient. Two parameters of diastolic function (isovolumetric relaxation time, deceleration time) were prolonged, with no evidence of reduced left ventricular compliance (Prospective cohort study without a control group, n = 73, 2 years, E 2b.)¹⁸⁰
• No differences in echocardiogram, ECG, cardiac muscle biopsies, and cardiac inflammatory markers in rhesus monkeys after 5 years of continuous MPH administration (2.5 mg/kg twice daily, corresponding to therapeutic plasma levels in children, or 12.5 mg/kg) (Randomized controlled animal study, rhesus monkeys, n = 28, 5 years, E 2b.)¹⁸¹
• No differences, adjusted for confounding factors, in carotid intima-media thickness or epicardial adipose tissue were observed between MPH-treated and untreated children and adolescents. Periaortic adipose tissue was thicker in the untreated group. Within the MPH group, the dose correlated with the thickness of the epicardial and periaortic adipose tissue (cross-sectional study, n = 130, full text not available to us, E 3.)¹⁸²

Children with ADHD treated with MPH had higher systolic blood pressure percentiles and higher plasma nitrite levels than untreated children with ADHD. (Cross-sectional study with a control group, n = 85, E 3.)¹⁸³ * (E 2b): Large registry studies in adults also found a slightly increased cardiovascular risk associated with ADHD medications, including MPH, particularly for high blood pressure. (Registry cohort study, N = 252,382, 6 months, E 2b.)¹⁶⁵ * (Case-control study, embedded in a registry cohort, N = 278,027, n = 62,060, up to 14 years, E 3.)¹⁶⁶

10.14. No cases of liver damage have been reported¶

From 2006 to May 2016, the BfArM’s spontaneous reporting database contained 60 suspected cases of liver damage associated with MPH. A causal relationship was probable in 9 cases and possible in 11 cases, including one case of fulminant hepatitis, one case of enlargement of a benign liver tumor, and 18 cases of reversible elevations in liver enzymes. The authors assessed MPH as well-tolerated by the liver. In cases of liver disease or other risk factors, they recommended regular monitoring of liver function tests. (Analysis of spontaneous reports, n = 60; full text not available to us; E 4.)¹⁸⁹

From 2012 to May 2025, the European pharmacovigilance database EudraVigilance recorded 181 reports of liver and biliary disorders associated with MPH, including 47 cases of drug-induced liver injury (DILI), 20 cases of jaundice, and 9 cases of hepatitis. Liver and biliary disorders were reported significantly more frequently with atomoxetine than with MPH (RR 2.41, 95% CI 2.11 to 3.11), and drug-induced liver injury was reported 6.4 times more frequently (RR 6.42, 95% CI 4.45 to 9.06). Under MPH, liver damage was reported more frequently in individuals under 18 years of age than in adults (RR 2.27, 95% CI 1.21 to 4.25). Reporting rates are not incidence rates. (Pharmacovigilance study, disproportion analysis, n = 421 reports, of which 181 were related to MPH, E 3.)¹⁹⁰

10.15. No known serious long-term side effects from MPH at the usual dosage¶

The animal studies known to us to date that reported harmful effects of long-term MPH administration predominantly used doses significantly above the therapeutic range. (ADxS assessment.) Such studies are common and useful for determining the limits of an active ingredient’s tolerability. However, they say nothing about the risks associated with long-term use at standard therapeutic doses.
By comparison, humans need 30 to 40 ml of water per kilogram per day (2 to 3 liters). However, water can be fatal if more is consumed in a short period of time than the kidneys can excrete (water intoxication with hyponatremia). (Case report, n = 1, E 4.)¹⁹¹ Thus, even with water, the dose determines whether it is harmful. (ADxS assessment.)

Long-term studies in humans¶

A large-scale, long-term study of MPH over a 2-year period in children and adolescents with ADHD found the following in the MPH group compared to people with ADHD who were not receiving medication: (Prospective naturalistic controlled cohort study, n = 1,410, 2 years, E 2b.)¹⁹²

• no significant impairment of growth
• Slower weight gain during the first 6 months; no differences thereafter; BMI remained unchanged at all times
• no increase in psychosis-like symptoms
• a more significant improvement in mood after 24 months
• Greater reduction in dyskinesias after 6 and 12 months
• a smaller decrease in tics after 12 months compared to without MPH
• a slight increase in blood pressure (systolic from 108 to 113 mmHg, diastolic from 65 to 67 mmHg) and heart rate (from 80 to 83 beats per minute)
• No increase in nicotine, alcohol, or marijuana use after adjustment
• After adjustment, no significant differences in suicidal thoughts and suicidal behavior

A population-based cohort study using data from Danish registries of patients who had continuously taken either Medikinet® MR or Concerta® for an extended period (at least 12 months) between 1995 and 2018 found the following regarding (severe) adverse events documented in the hospital: (register-based cohort study, n = 3,704, at least 12 months, manufacturer-funded, authors employed by the manufacturer, E 2b.)¹⁹³

• no cases of cerebral arteritis
• No cases of priapism
• No cases of sudden death with Medikinet® MR (fewer than 5 cases with Concerta®)
• No statistically significant differences in risk between Medikinet® MR and Concerta®

The Brain and the Dopamine System¶

A study in rhesus monkeys found that 6 months after the end of a 12-year long-term administration of MPH (twice daily, 5 days a week, at 2.5 mg/kg per dose with plasma levels in the clinical range, or 12.5 mg/kg per dose with 5to 10 times higher plasma levels) found no changes in striatal VMAT2 and D2/5-HT2 receptor binding or in cerebral glucose metabolism (PET). (Animal study, n = 18, rhesus monkeys, 12 years old, Phase 2b.)¹⁹⁴

During an 8-year course of MPH administration (twice daily, 5 days a week, increasing to 2.5 and 12.5 mg/kg per dose, respectively), a PET study in young male rhesus monkeys found no significant change in striatal VMAT2 binding or D2/5-HT2 receptor binding. VMAT2 binding tended to be lower in both dose groups, but the difference was not statistically significant. (Animal study, rhesus monkeys, 8 years, full text not available to us, E 2b.)¹⁹⁵

One year of treatment with sustained-release MPH (an average of 5.9 to 6.8 mg/kg/day) at doses that produced serum levels within the therapeutic range for children (an average of 10.7 to 13.6 ng/ml) did not alter the availability of dopamine transporters (DAT) or D2/D3 receptors (PET) in young rhesus monkeys and did not affect growth. After discontinuation (washout phase of 3 to 5 months), D2/D3 receptor availability decreased more slowly than in control animals. Susceptibility to cocaine self-administration was not increased. (Animal study, n = 16, rhesus monkeys, 1 year, E 2b.)¹⁹⁶

In adults with ADHD, one year of MPH treatment (approximately 1 mg/kg/day) increased DAT availability in the ventral striatum by an average of 24% (PET, 24 hours after the last dose). In the caudate nucleus and putamen, it did not change significantly over time but was higher after one year than in untreated controls. The authors speculated that such upregulation could reduce efficacy and exacerbate symptoms outside the active period. (Prospective cohort study with a control group, n = 29, 1 year, Phase 2b.)¹⁹⁷

Reproduction and Fertility¶

A study in rats that received 5 mg/kg/day of MPH for 30 days during adolescence found increased sperm DNA damage, a 40% reduction in early embryo quality, and fewer live offspring in the adult animals. (Animal study, Wistar rats, 30 days, full text not available to us, E 2b.)²⁰² Furthermore, the study involved Wistar rats, which do not exhibit dopamine deficiency. (ADxS assessment)
A study in adult BALB/c mice found that doses of 20 mg/kg/day and 40 mg/kg/day of MPH were associated with reduced testosterone levels, decreased sperm production, and weight loss, which the authors interpreted as a possible indication of toxicity. (Animal study, BALB/c mice, n = 24, full text not available to us, E 2b.)²⁰³ BALB/c mice are a widely discussed but controversial animal model for ASD. During development (days 3 to 30), they exhibited regionally varying dopamine levels: less dopamine in the striatum on day 30 and more dopamine in the cerebellum on day 3 compared to C57BL/6J mice. (Animal study, mice, E 2b.)²⁰⁴ It is well known that stimulants reduce appetite. The fact that dopamine-increasing active ingredients are harmful in organisms that do not exhibit reduced dopamine levels is not surprising but rather to be expected. (ADxS Assessment)
A case-control study of men (ages 21 to 31) with hyperactivity found no statistically significant difference in sperm count among former methylphenidate users, but did find a significant difference in sperm motility and abnormalities compared to non-users. According to the authors, sperm count was also altered in current users. The p-values reported in the abstract are partially contradictory. (case-control study, n = 150, full text not available to us, E 3.)²⁰⁵

A systematic review of animal studies on ADHD medications found that, in two studies, MPH caused a delay in vaginal opening (a sign of puberty; by 4.0 days in one study, 95% CI 2.5 to 5.6) and a halving of the number of estrus cycles; two other studies found no difference. In male rats, only minor differences in sperm quality were observed. The adverse effects usually improved after a treatment-free period and were less severe when treatment was started later. The studies were predominantly of low quality. (Systematic review, k = 17, of which 9 on MPH, animal studies, E 2b.)²⁰⁶

In young rats (5 mg/kg/day MPH administered orally starting on day 21 of life), puberty occurred earlier in males and later in females. The testes, epididymis, vas deferens, and ovaries showed tissue changes, and estradiol levels in the females decreased. After 30 days without MPH, the changes resolved. (Animal study, Sprague-Dawley rats, up to 70 days; full text not available to us; E 2b.)²⁰⁷

Genotoxicity and Cancer Risk¶

A small study found that, after 3 months of MPH at a therapeutic dose (20 to 54 mg/day) a 3-fold increase in chromosomal aberrations, a 4.3-fold increase in sister chromatid exchanges, and a 2.4-fold increase in micronuclei in blood lymphocytes. (Pre-post study without a control group, n = 12, 3 months, E 2b.)²⁰⁸ Chromosomal aberrations are considered markers of an increased risk of cancer.

Follow-up studies using the same or similar measures found no increase in genetic damage associated with MPH in:

• 109 children (ages 6 to 12), randomized to receive sustained-release MPH (usually 30 to 40 mg/day) plus behavioral therapy or behavioral therapy alone; after 3 months (chromosomal aberrations p = 0.53, micronuclei p = 0.28, sister chromatid exchanges p = 0.81) (Open-label RCT, n = 109, 3 months, manufacturer-funded, authors employed by the manufacturer, E 1b.)²⁰⁹
• 25 children receiving MPH (average dose 31.8 mg/day or 0.92 mg/kg/day) and 22 children receiving amphetamine salts after 3 months (Randomized open-label study comparing MPH with amphetamine, pre-post comparison, n = 47, 3 months, Phase 2b.)²¹⁰
• Children and adolescents after 1, 3, and 6 months of MPH (micropellets, initial sample n = 38) as well as 9 children who had been taking MPH for 6 months to 2 years (prospective cohort study, n = 47, up to 2 years, E 2b.)²¹¹
• 21 children and adolescents exposed to MPH for more than 12 months (mean 0.80 mg/kg/day) and 31 children after 3 months, compared with 23 healthy controls, measured as micronuclei in blood lymphocytes and oral mucosal cells (Prospective cohort study with a healthy control group, n = 70, over 12 months, E 2b.)²¹² and after 12 months in 12 children (average 0.51 mg/kg/day) (Overview with new follow-up data, n = 12, 12 months, E 2b.)²¹³
• 12 children (mean 0.54 mg/kg/day) and 7 adults (mean 0.92 mg/kg/day) after 3 months (micronuclei, sister chromatid exchanges, chromosomal aberrations) (Prospective pre-post study, n = 19, 3 months, E 2b.)²¹⁴
• 23 adults with ADHD who had been taking MPH for 2 to 15 years, either currently or in the past, compared to 19 people with ADHD who had not taken MPH or had taken it for less than 12 months, and 28 healthy individuals (micronuclei in blood lymphocytes) (cross-sectional study with a control group, n = 70, E 3.)²¹⁵

A review of animal and human studies conducted worldwide since 2005 found no evidence in any of the studies of an increase in genetic damage caused by MPH. (Review, E 4.)²¹⁶

Registry studies found no overall increased risk of cancer among MPH users:

• Among 35,400 individuals who had received MPH before the age of 20, there were 23 cases of cancer compared with an expected 20.4 (SMR 1.13, 95% CI 0.72 to 1.70). The rate was elevated for lymphocytic leukemia (SMR 2.64, 95% CI 1.14 to 5.20, 8 cases). The authors considered a chance finding possible for 18 of the cancer types examined. (Register-based cohort study, n = 35,400, median follow-up 4.5 years, E 2b.)²¹⁷
• Among 21,186 Danish patients with ADHD (of whom 7,418 were treated with MPH alone), with average follow-up periods ranging from 1.3 to 10.8 years, none of the ADHD medications was a risk factor for cancer in the Cox regression analysis (MPH HR 0.74, 95% CI 0.25 to 2.14). A higher dose across all medications (years in defined daily doses) was associated with a slightly increased risk (HR 1.07, 95% CI 1.04 to 1.10), which the authors interpreted as a potentially artificial post-hoc finding. (Register-based cohort study, n = 21,186, up to age 17, E 2b.)²¹⁸
• MPH use was not associated with an increased risk of colorectal cancer in people with ADHD (register-based cohort study, N = 3,192, n = 798 with ADHD, 13 years, E 2b.)²¹⁹

In the carcinogenicity study conducted by the U.S. National Toxicology Program (2 years of MPH in the diet; rats: 4 to 47 mg/kg/day, mice 5 to 67 mg/kg/day), an increased incidence of benign liver tumors was observed in mice at the highest dose, and hepatoblastomas were observed in male mice. In rats, no increase in tumors was observed; instead, there was a decrease in mammary fibroadenomas. MPH was not mutagenic in the Salmonella mutagenicity test. (Animal study, n = 50 per dose, sex, and species; rats and mice; 2 years; E 2b.)²²⁰

10.16. Reduced Risk of Stress Fractures¶

Young adults (Israeli conscripts, ages 18 to 25) with ADHD and the highest MPH exposure (over 180 tablets) had a lower risk of stress fractures after adjustment than those without ADHD (women: OR 0.09, 95% CI 0.01 to 0.40, p = 0.02; men OR 0.49, 95% CI 0.19 to 1.01, p = 0.08, not significant). Untreated people with ADHD had an increased risk (men OR 1.66, 95% CI 1.41 to 1.95; women OR 1.33, 95% CI 1.07 to 1.63). (Retrospective cohort study, n = 682,110, E 2b.)²²¹

The overall risk of bone fractures was also reduced with MPH:

• A 32% to 41% lower risk of fracture (IRR 0.59 to 0.68) during various treatment periods compared with the 6 months prior to the start of MPH in 5- to 24-year-olds. During these 6 months prior to treatment initiation, the risk was elevated compared with the remainder of the untreated period (IRR 1.27, 95% CI 1.05 to 1.53); however, it was not significantly reduced under MPH compared to this period (IRR 0.75 to 0.87). A systematic review of 8 observational studies found a 39% to 74% lower risk in treated ADHD compared to untreated ADHD, particularly among males and with longer-term treatment (systematic review and self-controlled case series study, k = 8, n = 2,023, E 2b.)²²²
• A 23% lower risk of fracture (HR 0.77, 95% CI 0.63 to 0.94) among children who took MPH for more than 180 days compared with children with ADHD who did not take MPH. For durations ranging from 1 to 180 days, there was no significant difference (HR 1.18, 95% CI 0.98 to 1.43) (register-based cohort study, n = 6,201, E 2b.)²²³

Depending on the study, bone density did not change or changed only slightly under MPH:

• 10 boys who had been taking low-dose MPH (an average of 10 mg/day, approximately 0.5 mg/kg/day) showed no difference in bone density or bone turnover in the lumbar spine and femoral neck compared with 10 healthy control children (cross-sectional study with a control group, n = 20, E 3.)²²⁴
• In children aged 4 to 9 years taking stimulants (primarily MPH, at an average of 0.91 mg/kg/day), the height- and sex-adjusted Z-scores for bone density (−0.41) and bone mineral content (−0.55) decreased over a 3-year period. Bone turnover was reduced after 3 months and returned to normal after 3 years. There was no difference between MPH and dexamfetamine (Prospective cohort study, n = 34, 3 years, E 2b.)²²⁵

A meta-analysis of animal studies in rats found that MPH had adverse effects on bone morphology and mechanical strength, particularly at higher doses and with longer-term administration. The risk of bias in the studies ranged from unclear to high. (Meta-analysis of animal studies, k = 8, rats, full text not available to us, E 2b.)²²⁶

10.17. Reduced risk of type 2 diabetes during the first 3 years of use¶

Overall, ADHD medications were associated with a roughly 20% reduced risk of type 2 diabetes in adults during the first 3 years of cumulative use (OR 0.79 and 0.80, respectively). With methylphenidate, the risk was reduced by 23% (OR 0.77) for use up to 1 year and by 15% (OR 0.85) for use from 1 to 3 years; after more than 3 years, there was no longer any difference. (Nested case-control study in a registry cohort, N = 138,778, n = 14,036, E 3.)²²⁷ Long-term use of atomoxetine for more than 3 years increased the risk by 44%. Lisdexamfetamine had no effect.

11. Interactions and Contraindications¶

As with any medication, there are also contraindications for MPH.
Taking this medication without first consulting a doctor is risky.

(E 4): Methylphenidate is metabolized primarily by carboxylesterase 1 (CES1) and not to a clinically relevant extent by the cytochrome P450 system. CYP inducers and inhibitors are therefore unlikely to significantly affect MPH levels. (Professional article in Apothekerzeitschrift; full text not accessible to us, E 4.)¹¹¹ * (E 4.)*²²⁸ Nevertheless, MPH may inhibit the metabolism of some other active ingredients (see 11.1.2). Caution is therefore advised when administering medications with a narrow therapeutic range concomitantly. (E 4.)²²⁸

11.1. Interactions Between Methylphenidate and Other Medications¶

11.1.1. MPH enhances the effects of other medications or substances¶

Caffeine, Alcohol, and Cannabis¶

• Caffeine can have a more intense effect
  Caffeine should be strictly avoided, especially when titrating the dose of stimulants (e.g., MPH). Stimulants often cause caffeine—even in doses that were previously tolerated without issue—to trigger internal tremors. This can be mistakenly interpreted as a (side) effect of the stimulants. (Experience with ADHD and SAD)

• Alcohol
  A systematic review found that taking therapeutic doses of ADHD medications along with alcohol resulted in only a minimal increase in side effects and no serious Consequences from combining them with alcohol or other drugs. (Systematic review, k = 20, no meta-analysis, E 4.)²³²

  • Alcohol can exacerbate the CNS side effects of MPH. High concentrations of alcohol can shift the release profile of extended-release formulations toward that of a rapid-release formulation. (E 4.)²²⁸
  • Alcohol (0.6 g/kg) increased the maximum d-MPH concentration following Retard-MPH by 27 to 35 percent, presumably through inhibition of carboxylesterase 1 (CES1). Alcohol also enhanced the subjective stimulant effects of MPH (“stimulated,” “high”), but not the sensation of intoxication. (RCT, crossover, 4-arm, n = 14 healthy adults, single dose, E 1b.)²³³

• Alcohol (0.6 g/kg) 30 minutes before or after immediate release MPH (0.3 mg/kg) increased the maximum d-MPH concentration by approximately 40% (from 15.3 to 21.5 and 21.4 ng/mL, geometric mean ratio of 1.37 and 1.39, respectively) and the AUC by approximately 25% (ratio of 1.27 and 1.23, respectively). This resulted in the formation of the transesterification product l-ethylphenidate. Despite lower d-MPH levels, women reported a stronger stimulant effect than men. (RCT, crossover, 3-arm, n = 20 healthy participants, single dose, E 1b.)²³⁴

• Cannabis (THC)
  THC (10 mg orally) and MPH (10 or 40 mg) caused an additive increase in heart rate (peak value of 89.1 beats per minute with THC alone, 95.9 and 102.0, respectively, with THC plus 10 or 40 mg MPH). One subject developed persistent tachycardia exceeding 100 beats per minute after receiving 40 mg MPH plus THC. Only 40 mg of MPH had a blood pressure-raising effect, with no interaction with THC. (RCT, double-blind, crossover, 6 sessions, n = 16 healthy adults with occasional cannabis use, single doses, E 1b.)²³⁵

Sympathomimetics, blood pressure-raising agents, and anesthetic gases¶

• All sympathomimetics (Statement by the Expert Panel, E 4)²³⁶ can be potentiated by MPH.
  Active ingredients affected:

  • α-Sympathomimetics (Statement by the Expert Panel, E 4)²³⁶
    • Naphazoline
    • Tetryzoline
    • Tramazoline
    • Xylometazoline
    • Oxymetazoline
    • Phenylephrine
    • Metaraminol
  • β-sympathomimetics (Statement by the Expert Panel, E 4)²³⁶
    • Fenoterol
    • Orciprenaline
  • Catecholamines and mixed α/β sympathomimetics
    • Adrenaline
    • norepinephrine
    • Dopamine
    • Dopamine derivatives
      • Dobutamine
      • Dopexamine
    • Etilefrine
    • Oxilofrin
  • indirect sympathomimetics
    • Amezinium methyl sulfate
    • Norephedrine

• Blood pressure-raising agents (professional article in a pharmacists’ journal; full text not available to us, E 4)¹¹¹
  According to the prescribing information, caution is advised with active ingredients that can also raise blood pressure. (E 4.)²²⁸

• Halogenated anesthetic gases

  • may cause blood pressure spikes in patients taking methylphenidate. (Professional article in Apothekerzeitschrift; full text not available to us, E 4)¹¹¹ During surgery, blood pressure and heart rate may rise suddenly. For scheduled surgical procedures, methylphenidate should not be administered on the day of surgery. (E 4.)²²⁸

MAO inhibitors, St. John’s wort, and dopaminergic active ingredients¶

• Monoamine oxidase inhibitors (MAOIs)

  • (E 4): MPH is contraindicated during treatment with nonselective, irreversible MAO inhibitors and for at least 14 days after discontinuation of these agents, due to the risk of a hypertensive crisis. Selective or reversible MAO inhibitors (moclobemide, selegiline, rasagiline, linezolid) are not explicitly contraindicated but require caution (see below). (E 4.)²²⁸ * (E 4.)²³⁷ * (Specialized article in Apothekerzeitschrift; full text not available to us; E 4.)¹¹¹
    • Tranylcypromine
      MPH should be avoided for up to 14 days after taking tranylcypromine (professional article in a pharmacy journal; full text not available to us, E 4)²³⁸

• St. John’s Wort
  A pharmacy journal described St. John’s wort as an MAOI. (Technical article in a pharmacy journal; full text not accessible to us, E 4)²³⁹ St. John’s wort extract, however, inhibited MAO-A only in vitro at very high concentrations (significantly only at 10⁻³ mol/l, at 10⁻⁴ mol/l, at most 39%); ex vivo, no significant MAO inhibition was observed in rats even after 300 mg/kg of extract. St. John’s wort is therefore not an MAO inhibitor in the clinical sense. (In vitro and animal study, rat brain homogenate and rats ex vivo, single dose, E 2b.)²⁴⁰
  An analysis of pediatric adverse event reports assessed an interaction between St. John’s wort and MPH as likely in one case and as possible in another. In the probable case (a 15-year-old taking 20 mg of Ritalin daily), restlessness, crying, aggression, and difficulty concentrating occurred a few hours after starting St. John’s wort; these symptoms subsided after discontinuation and recurred upon resuming the herb. The authors cited inhibition of P-glycoprotein by St. John’s wort as a possible mechanism. (Analysis of FDA spontaneous reports, n = 23 reports, of which 5 were evaluable, E 4.)²⁴¹

• All centrally acting dopaminergic and noradrenergic active ingredients (professional article in a pharmacists’ journal; full text not available to us, E 4)¹¹¹
  Blood pressure should be monitored closely here.
  MPH may interact pharmacodynamically with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants). (E 4.)²²⁸
  Examples:

  • selective or reversible MAO inhibitors
    • Moclobemide
    • Linezolid
    • Selegiline
    • Rasagiline
  • Levodopa
  • other Parkinson’s medications
  • centrally acting α2 agonists, e.g.,
    • Clonidine
      Serious adverse reactions, including sudden deaths, have been reported when used concomitantly with MPH. The safety of combining MPH with clonidine or other centrally acting α2-agonists has not been systematically studied. (E 4.)²²⁸
    • Methyldopa

  In a 16-week study of children with ADHD (clonidine up to 0.6 mg/day, MPH up to 60 mg/day), there was no interaction between clonidine and MPH on ECG and other cardiovascular parameters. Bradycardia (heart rate below 60 beats per minute on the ECG) occurred more frequently with clonidine (17.5% vs. 3.4%). Moderate or severe adverse effects were more common with clonidine (79.4% vs. 49.2%), but did not lead to more study discontinuations. *(RCT, double-blind, 4-arm, n = 122, 16 weeks, E 1b.)*<span data-footnote="" data-raw="[Daviss WB, Patel NC, Robb AS, McDermott MP, Bukstein OG, Pelham WE Jr, Palumbo D, Harris P, Sallee FR (2008): Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis. J Am Acad Child Adolesc Psychiatry. 2008 Feb;47(2):189-198. doi: 10.1097/chi.0b013e31815d9ae4. PMID: 18182964.](https://pubmed.ncbi.nlm.nih.gov/18182964/)"></span>
- Guanfacine
  In 7- to 14-year-olds, dexmethylphenidate (sustained release, 5 to 20 mg/day) increased heart rate, blood pressure, and QTc interval, guanfacine (immediate release, 1 to 3 mg/day) lowered heart rate and blood pressure. With the combination, only diastolic blood pressure increased (from 64.4 to 67.5 mmHg). Heart rate, systolic blood pressure, and QTc interval remained unchanged. No serious cardiovascular events occurred over the course of one year. *(RCT, double-blind, 3-arm, n = 207, 8 weeks plus 12 months of open-label continuation, E 1b.)*<span data-footnote="" data-raw="[Sayer GR, McGough JJ, Levitt J, Cowen J, Sturm A, Castelo E, McCracken JT (2016): Acute and Long-Term Cardiovascular Effects of Stimulant, Guanfacine, and Combination Therapy for Attention-Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol. 2016 Dec;26(10):882-888. doi: 10.1089/cap.2015.0264. PMID: 27483130; PMCID: PMC5178010.](https://pmc.ncbi.nlm.nih.gov/articles/PMC5178010/)"></span>

11.1.2. Inhibition of the metabolism of other medications by MPH¶

There are reports that MPH may inhibit the metabolism of coumarin-type anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and certain antidepressants (tricyclic antidepressants and SSRIs). When starting or discontinuing MPH, it may be necessary to adjust the dosage of the active ingredients and to monitor their plasma levels. (E 4.)²²⁸

An analysis of 38 interaction reports involving 25 medications found that methylphenidate was primarily involved in pharmacokinetic interactions that suggested inhibition of cytochrome P450 enzymes, whereas dextroamphetamine and pemoline were more frequently associated with pharmacodynamic interactions. According to the published data, psychostimulants could be safely combined with most drug classes; absolute contraindications were rare. (Review, k = 38 reports, E 4.)²⁴²

• Anticonvulsants (Industry Forum report on a workshop held by the manufacturer Medice, E 4.)²⁴³
  MPH can inhibit the metabolism of some anticonvulsants, thereby increasing their blood levels. (Expert Panel Statement, E 4.)²³⁶ The available data are inconsistent. In an on/off study, no effect was observed for phenobarbital (n = 10) or phenytoin (n = 11). For primidone, one of two case reports described a significantly reduced clearance. (Systematic review, case reports, case series, and small studies, E 4.)²⁴⁴

  • Phenobarbital (Expert Panel Statement, E 4)²³⁶ * (Systematic review, case reports, case series, and small studies, E 4)*²⁴⁴
  • Phenytoin (Expert Panel Statement, E 4)²³⁶ * (Systematic review, case reports, case series, and small studies, E 4)*²⁴⁴
  • Primidone (Statement by the Expert Panel, E 4)²³⁶

• Valproic acid
  Two children (ages 4 and 6) taking valproic acid developed severe dyskinesias (primarily mouth and tongue movements) and bruxism, which lasted up to 14.5 hours. The authors suspected that valproic acid had caused elevated MPH levels or an additive dopaminergic effect and advised caution with this combination. (case series, n = 2, E 4.)²⁴⁵

• tricyclic antidepressants (professional article in a pharmacists’ journal; full text not available to us, E 4)¹¹¹ , e.g.:

  • Amitriptyline (Statement by the Expert Panel, E 4)²³⁶
  • Imipramine (Statement by the Expert Panel, E 4)²³⁶
    MPH can significantly inhibit the metabolism of imipramine. In a case series, imipramine levels rose significantly. The authors advised against combining MPH with imipramine and, as a precaution, also with amitriptyline and clomipramine, since these are metabolized in the same way. (Systematic review, case reports, case series, and small studies, E 4.)²⁴⁴
    Symptoms of an interaction with imipramine include: (Expert Panel Statement, E 4.)²³⁶
    • Confusion and agitation
    • Mood instability
    • Irritability and aggression
    • Psychotic symptoms

• Phenylbutazone (Butazolidin) (Statement by the Expert Panel, E 4)²³⁶
  Phenylbutazone is a nonsteroidal anti-inflammatory drug that is rarely used today. The current prescribing information no longer mentions phenylbutazone. (E 4.)²²⁸

• Anticoagulants (blood-thinning medications) (Expert Panel Statement, E 4)²³⁶

  • oral coumarin-type anticoagulants, e.g., phenprocoumon, warfarin
    Fluctuations in efficacy due to interaction with methylphenidate are possible here. Close monitoring of coagulation parameters is therefore recommended when starting or discontinuing methylphenidate. (Professional article in a pharmacy journal; full text not available to us, E 4)¹¹¹ MPH likely inhibits its metabolism (in one case report, the half-life of ethylbiscoumacetate was prolonged). (Systematic review, case reports, case series, and small studies, E 4.)²⁴⁴

MPH may reduce the effectiveness of other medications¶

• Antihypertensive drugs (professional article in a pharmacy journal; full text not available to us, E 4)¹¹¹ , e.g.:
  • ACE inhibitors
  • Angiotensin receptor blockers
  • Diuretics
  • Calcium channel blockers
  • Beta-blockers

MPH may reduce the blood pressure-lowering effect of antihypertensive drugs. (E 4.)²²⁸

11.1.3. Changes in the Effects of MPH Caused by Other Medications¶

Proton pump inhibitors¶

Medikinet Adult is contraindicated when the gastric pH is above 5.5 and when proton pump inhibitors, H2 blockers, or antacids are taken, as this can cause the entire amount of active ingredient to be released more rapidly. (E 4.)²²⁸ The release of methylphenidate from Ritalin Adult, on the other hand, is pH-independent. Nevertheless, antacids may reduce the absorption of Ritalin Adult. (Professional article in Apothekerzeitschrift; full text not accessible to us, E 4)¹¹¹

Stomach pH can be increased by:

• Proton pump inhibitors, e.g.,
  • Pantoprazole
  • Omeprazole
• H2 antagonists, e.g.,
  • Ranitidine
  • Famotidine
• Antacids

Enzyme Inducers¶

Potent enzyme inducers lower MPH levels a few weeks after initiation and raise them a few weeks after discontinuation. The authors recommended avoiding the combination of potent inducers with MPH whenever possible. The drugs affected are: (Systematic review, case reports, case series, and small studies, E 4.)²⁴⁴

• Carbamazepine
  Carbamazepine induced dose-dependent MPH clearance. In two case reports, ADHD symptoms worsened after the addition of carbamazepine. In one case, 1,000 mg/day of carbamazepine reduced the MPH level by half; in the other, MPH was no longer detectable. Since MPH is not significantly metabolized via cytochrome P450, the authors suspected induction of P-glycoprotein.
  • Two case reports suggest that the MPH dose may need to be at least doubled when high-dose carbamazepine is administered concurrently
• Phenobarbital, phenytoin, and rifampin may

Dopamine antagonists¶

Dopamine antagonists such as antipsychotics (E 4.)²²⁸ or metoclopramide (prokinetic) (professional article in Apothekerzeitschrift; full text not accessible to us, E 4)¹¹¹ can interact pharmacodynamically with MPH and counteract its effects.

Switching, changing the dose, or missing a dose of MPH while taking antipsychotics (especially risperidone) can trigger acute hyperkinetic movement disorders, primarily acute dystonia. An analysis of the FDA adverse event database and the literature identified 36 such cases, 23 of which involved MPH. In 53% of cases, symptoms appeared within 24 hours of the medication change. The most common trigger with MPH was a missed or intentionally skipped dose of MPH while the risperidone dose remained unchanged. The U.S. prescribing information for MPH and risperidone was subsequently updated. (Analysis of spontaneous reports and case reports, n = 36 cases, E 4.)²⁴⁶ In the WHO pharmacovigilance database, 19.3% of reports regarding the MPH plus risperidone combination involved movement disorders, compared with 5.9% for MPH alone and 15.7% for risperidone alone. The likelihood of reporting movement disorders was 3.8 times higher with the combination than with MPH alone (ROR 3.80, 95% CI 3.16 to 4.58) compared to MPH alone and 1.3 times higher (ROR 1.28, 95% CI 1.07 to 1.54) compared to risperidone alone. In 7 of 13 published case reports, the movement disorders occurred during tapering of risperidone or when switching to MPH; in 4 cases, they occurred after missed or omitted MPH doses. (Pharmacovigilance analysis, n = 25,556 reports, and review of case reports, k = 13, E 4.)²⁴⁷

Additional pharmacological findings¶

CBD (cannabidiol, 2 × 750 mg/day for 3 days) had only a negligible effect on the Cmax and AUC of a single dose of MPH (10 mg) (+8% and +9%, respectively), even though CBD is a CES1 inhibitor. (RCT, crossover, placebo-controlled, n = 12 healthy subjects, single dose of MPH, E 1b.)²⁴⁸

In vitro, aripiprazole, perphenazine, thioridazine, and fluoxetine strongly inhibited carboxylesterase 1 (CES1), the primary metabolizing enzyme of MPH. In mice, aripiprazole (10 mg/kg, single dose) increased plasma levels of total MPH and, in particular, of the less active l-MPH. Inhibition of d-MPH metabolism in vitro required concentrations (IC50 58 to 65 µM) that are far higher than the typical plasma levels of these active ingredients (at most about 1.5 µM). Due to higher concentrations in the liver, the authors nevertheless considered an interaction possible for aripiprazole, thioridazine, and fluoxetine, but not for perphenazine. (In vitro and animal study, CES1-expressing cell lines, mice, n = 5 per group, E 2b.)²⁴⁹ Whether this inhibition is clinically relevant in humans has not been investigated.

11.1.4. No Increased Risk of Side Effects from MPH + SSRI¶

A study of adults with ADHD found no disadvantages to taking MPH and SSRIs together compared to MPH alone. Taking SSRIs with MPH halved the risk of headaches (HR 0.50). (Cohort study, registry data from South Korea, N = 17,234, propensity score matching, E 2b.)²⁵² According to the prescribing information, MPH may inhibit the metabolism of SSRIs. (E 4.)²²⁸

Individual case reports have described serotonin syndrome following the addition of MPH to sertraline in a 14-year-old girl (sertraline 150 mg/day, MPH 18 mg/day for 2 days, 7 days on a ventilator, recovery without sequelae) (Case report, n = 1, E 4.)²⁵³ , in an 18-year-old with depression who had been taking paroxetine 20 mg and MPH 10 mg for one month, with an additional manic episode (the authors also considered paroxetine alone as a possible cause) (Case report, n = 1, E 4.)²⁵⁴ and in a 62-year-old woman with treatment-resistant depression 5 days after adding 10 mg of MPH to 100 mg of sertraline (resolution within 10 days after discontinuation). (Case report, n = 1, E 4.)²⁵⁵

11.2. BMI and Blood Pressure¶

Methylphenidate slightly increased systolic blood pressure in children and adolescents (SMD 0.25), but did not affect diastolic blood pressure or heart rate. (Meta-analysis, k = 18, of which 10 were on MPH, N = 5,837, E 1a.)²⁵⁶

MPH increased compared with placebo after a median of 7 weeks: (network meta-analysis, k = 102 RCTs, N = 22,702; full text not available to us, E 1a.)²⁵⁷

• in children and adolescents
  • diastolic blood pressure by 2.42 mmHg (95% CI 1.69 to 3.15)
  • systolic blood pressure by 1.81 mmHg (95% CI 1.05 to 2.57)
• in adults
  • heart rate by 4.37 beats per minute (95% CI 3.16 to 5.59)
  • systolic blood pressure by 1.66 mmHg (95% CI 0.38 to 2.93)
  • diastolic blood pressure by 1.60 mmHg (95% CI 0.29 to 2.91)

MPH did not raise blood pressure or heart rate any more than atomoxetine or viloxazine. The authors recommended monitoring blood pressure and heart rate with any ADHD medication, not just stimulants.

Another meta-analysis found a greater increase in heart rate among children and adolescents receiving MPH, as well as among adults (adults: SMD 2.04, 95% CI 0.92 to 3.15) and systolic blood pressure (adults SMD 1.40, 95% CI 0.62 to 2.18) with MPH compared to placebo, with no difference between age groups. Cardiac events were no more frequent with MPH than with placebo. (meta-analysis, k = 22, N = 46,107, E 1a.)²⁵⁸

In contrast, a cross-sectional analysis of the KiGGS data found no adverse effects of MPH on blood pressure in boys with ADHD; however, only 118 of the boys had taken MPH. (Cross-sectional study, population-based survey, n = 4,244, of whom 118 were taking MPH, E 3.)²⁰
For patients at risk of high blood pressure, it is therefore necessary to weigh the extent to which the potential risk of a medication-induced increase in blood pressure outweighs the potential benefit of lower blood pressure resulting from reduced stress sensitivity. (ADxS assessment)

A greater increase in blood pressure 45 minutes after the first single dose of MPH (0.3 mg/kg, immediate release) was associated with a greater reduction in ADHD symptoms after 6 months. A greater increase in systolic blood pressure was associated with a greater reduction in inattention (4.2% additional explained variance), while a greater increase in diastolic blood pressure was associated with a greater reduction in hyperactivity and impulsivity (5.2%). (Retrospective cohort study (chart review), n = 171, 6 months, preprint version reviewed, E 2b.)²⁵⁹

Over the long term, new MPH users (mean age 13.7 years, with no prior cardiovascular disease) had a higher risk of cardiovascular disease than matched non-users over an average of 4 years (adjusted HR 2.37, 95% CI 2.21 to 2.54; after calibration for residual bias, HR 1.85, 95% CI 1.55 to 2.22). High blood pressure was the most common diagnosis. The absolute risk remained low (2.3 versus 0.7 cases per 1,000 person-years). The controls were not selected based on ADHD status. Therefore, an influence of ADHD itself cannot be ruled out. (Cohort study, registry data from France, N = 848,864, n = 212,216 new users of MPH, mean 4 years, evidence level 2b.)²⁶⁰

11.3. Taking MPH During Pregnancy¶

Studies on the use of MPH during pregnancy found that, with regard to the offspring,

• Weight

  • (E 2b): unchanged (registry study, Denmark, N = 989,932 pregnancies, n = 186 exposed (MPH or ATX), E 2b)²⁶¹ * (Cohort study, Medicaid registry data, N = 1,461,493 unexposed, 1,515 MPH, 3,331 AMP, 453 ATX, E 2b.)*²⁶²
  • unchanged among amphetamine mixed salts (no MPH study) (Retrospective cohort study, n = 53 exposed, 2:1 matched, E 2b.)²⁶³

• A slightly increased risk of preeclampsia (RR 1.29) associated with stimulant use (AMP or MPH) during pregnancy; however, there was no increased risk of placental abruption or preterm birth. Continuing use during the second half of pregnancy increased the risk of preterm birth (RR 1.30). These effects were primarily attributable to amphetamine. For MPH, an increased risk of preeclampsia was observed only when taken for more than 60 days. The absolute risks were so low that the authors did not recommend discontinuing stimulant use during pregnancy. (Cohort study, Medicaid registry data, N = 1,461,493 unexposed, 1,515 MPH, 3,331 AMP, 453 ATX, E 2b.)²⁶² Atomoxetine did not show these slight increases in risk.

• Risk of Miscarriage Due to ADHD Medications During Pregnancy

  • doubled (OR 2.07, 95% CI 1.51 to 2.84) among pregnancies exposed to MPH, modafinil, or atomoxetine compared with all unexposed pregnancies. When limited to women diagnosed with ADHD (OR 1.69, 95% CI 0.79 to 3.61) and when compared with the woman’s other pregnancies (OR 1.30, 95% CI 0.69 to 2.47), the risk was not significantly increased. (Registry study, Denmark, N = 1,054,494 pregnancies, n = 480 exposed, E 2b.)²⁶⁴

  • A 1.5-fold increase was observed among mothers taking MPH or atomoxetine, but also among untreated mothers with ADHD, which suggests that ADHD itself plays a role (register-based study, Denmark, N = 989,932 pregnancies, n = 186 exposed (MPH or ATX), E 2b.)²⁶¹

  • not statistically significantly altered by methylphenidate and atomoxetine (OR 1.15) (Meta-analysis, k = 10 observational studies, N = 16,621,481, of whom 30,830 had ADHD, E 2b.)²⁶⁵

  • A 1.55-fold increase in the risk of MPH use among pregnant women with ADHD (aOR 1.55, 95% CI 1.35 to 1.79). For ADHD medications overall, the risk increased with dose (lowest dose tertile aOR 1.14, 95% CI 0.91 to 1.42; highest tertile aOR 2.11, 95% CI 1.71 to 2.60). Filled prescriptions may not reflect actual medication use (case-control study, registry data from Norway, n = 2,993 cases, n = 10,305 controls, full text not available to us, E 3.)²⁶⁶

• nearly doubled (adjusted HR 1.98, 95% CI 1.23 to 3.20) following MPH exposure in a prospective study, in which previous miscarriages were also a predictor. The authors considered it possible that the underlying disease might have played a role. (Cohort study, prospective, n = 382 MPH-exposed and 382 control pregnancies, E 2b.)²⁶⁷

• Apgar score below 10

  • twice as common among those treated with MPH or atomoxetine (registry study, Denmark, N = 989,932 pregnancies, n = 186 exposed (MPH or ATX), Category 2b.)²⁶¹

• Malformations

  • slightly increased risk of severe malformations (OR 1.26, 95% CI 1.05 to 1.51) and heart malformations (OR 1.59, 95% CI 1.02 to 2.49, NNH 159) associated with MPH use in early pregnancy (scoping review with meta-analysis, k = 4 cohort studies, n = 2,831 exposed, 2,950,526 controls, E 2b.)²⁶⁸

  • not statistically significantly increased by methylphenidate and atomoxetine (OR 1.14; 95% CI 0.83 to 1.55) (Meta-analysis, k = 10 observational studies, N = 16,621,481, E 2b.)²⁶⁵

  • No increased risk (prevalence ratio 0.8, 95% CI 0.3 to 1.8; congenital heart defects 0.9, 95% CI 0.2 to 3.0) following MPH use in the first trimester. A more than twofold increase in risk is unlikely. (cohort study, Danish registry data, n = 222 exposed, 2,220 matched controls, E 2b.)²⁶⁹

  • No increased risk. (cohort study, prospective registry, N = 1,988, n = 48 MPH/Dex-MPH, full text not available to us, E 2b)²⁷⁰

  • a slightly increased risk of congenital heart defects following MPH use in the first trimester (pooled RR 1.28, 95% CI 1.00 to 1.64), no significant association for malformations overall (aRR 1.11, 95% CI 0.91 to 1.35). Amphetamines did not increase the risk of congenital heart defects (aRR 0.96, 95% CI 0.78 to 1.19) or total congenital malformations (aRR 1.05, 95% CI 0.93 to 1.19) (Cohort study, registry data, N = 1,813,894 pregnancies in the U.S. and 2,560,069 in the Nordic countries, E 2b.)²⁷¹

• No increased risk of major malformations (2.4% vs. 3.4%) or heart defects (0.8% each) following MPH exposure during organogenesis (weeks 4 through 13 of pregnancy) (Cohort study, prospective, 4 teratology information centers, n = 382 MPH-exposed pregnancies and 382 control pregnancies, E 2b.)²⁶⁷

• no increased risk of malformations overall (PR 1.04, 95% CI 0.70 to 1.55), but possibly for heart defects (PR 1.65, 95% CI 0.89 to 3.05, not significant, 12 cases, NNH 92) and for ventricular septal defects (PR 2.74, 95% CI 1.03 to 7.28) following MPH exposure in the first trimester. Prenatally diagnosed malformations were also included. (Registry study, Denmark, N = 364,012 pregnancies, n = 473 MPH-exposed, E 2b.)²⁷²

• Congenital heart defects following MPH exposure: borderline, not significantly increased (RR 1.27, 95% CI 0.99 to 1.63) (Meta-analysis, k = 8 cohort studies; for congenital heart defects associated with MPH, n = 2,541 exposed individuals, E 2b.)²⁷³

• No differences in Apgar scores or ultrasound-detected malformations at 20 weeks between continuing and discontinuing MPH (cohort study, retrospective, Netherlands, 2005–2020, full text not available to us, E 2b.)²⁷⁴

• ADHD symptoms

  • ADHD-like behavior (hyperactivity, impulsivity) in mice following prenatal MPH administration (2.5, 7.5, or 15 mg/kg/day orally throughout gestation), which was suppressed by MPH and atomoxetine
  • Dose-dependent reductions in the expression of the D2 receptor and dopamine transporter genes in the striatum of these mice (significant individually only for the D2 receptor gene at doses below 15 mg/kg), as is common in ADHD animal models (Animal study, mice, oral, throughout gestation, n = 35 to 42 male offspring per dose group, E 2b.)²⁷⁵ This is plausibly consistent with the model of brain development disorders caused by a dopamine deficiency (e.g., genetically inherited or due to chronic stress) or an excess of dopamine (e.g., due to stimulant administration in non-affected individuals). (ADxS Assessment) More on this at ⇒ Brain Developmental Disorder and ADHD in the chapter “ ” ⇒ Etiology.
  • No increased risk of ADHD or other neurodevelopmental disorders associated with MPH or AMP use during pregnancy. The initially observed increased risk of ADHD associated with MPH (HR 1.43), after adjustment, disappeared when more stringent controls were applied for maternal ADHD. (Cohort study, U.S. claims data, N = approximately 4.28 million, n = 1,123 MPH-exposed, E 2b.)²⁷⁶

• neurodevelopmental disorders

  • Risk unchanged (HR 0.95) following exposure to MPH, amphetamines, or atomoxetine, compared with children of mothers who discontinued the medication before conception (register-based study, Sweden, with meta-analysis, N = 861,650 children of 572,731 mothers, 2008 to 2017, E 2b.)²⁷⁷

A systematic review found that in 7 out of 12 cohort studies (2019 to 2024, 10 of which included MPH) found no significant harms associated with ADHD medication during pregnancy for either the mother or the child; 3 studies showed evidence of harms (including preeclampsia); and 2 studies indicated benefits of continuing treatment. A significantly increased risk of birth defects was observed only for modafinil. The authors generally considered the benefits of continuing effective ADHD medication to outweigh the risks. (Systematic review, n = 12, without meta-analysis, E 4.)²⁷⁸

MPH During Breastfeeding¶

MPH passes into breast milk only in small amounts. The relative infant dose (the proportion of the mother’s weight-based dose that the infant receives through breast milk) was:

• 0.7% (mean) among 3 mothers under 35 taking 35 to 80 mg MPH/day (secondary citation from De Hondt et al. 2024, E 4.)²⁷⁹
• 0.2% in a mother taking less than 36 mg of sustained-release MPH per day (milk concentration 7.9 ng/mL in the 4th week after birth, 6.5 hours after administration; infant not exclusively breastfed; normal development at 6 months) (Case series, n = 2, including 1 with MPH, E 4.)²⁸⁰
• 0.16% when the mother takes less than 15 mg of immediate release MPH per day (Secondary citation from De Hondt et al. 2024, E 4.)²⁷⁹

In the few reported cases of breastfed infants, no side effects were observed, and development was normal. In the authors’ own case report, MPH was not detectable in either the mother’s breast milk or the infant’s blood at doses of up to 72 mg MPH/day, and the infant developed normally until the age of one year. (Systematic review including the authors’ own case report, 1 case report, and 1 case series with n = 3 on breastfeeding, E 4.)²⁸¹ In a mother with narcolepsy, resuming MPH 13 weeks after birth (initially 3 × 10 mg/day, later 36 mg of sustained release) did not reduce the amount of expressed milk (751 ± 228 ml/day before, 822 ± 177 mL/day afterward), and the child grew normally. (Case report, n = 1, E 4.)²⁸² Long-term data on the development of breastfed children are lacking.

11.4. Contraindications according to the prescribing information¶

According to the prescribing information, methylphenidate is contraindicated in the following cases: (E 4.)²²⁸ * (professional article in Apothekerzeitschrift; full text not available to us, E 4)*¹¹¹

• Glaucoma

  In children and adolescents, MPH tended to slightly reduce intraocular pressure, though not significantly (Hedges’ g −0.162, 95% credibility interval −0.407 to 0.084). (Bayesian meta-analysis, k = 22, of which 8 were on MPH, N = 293,228 users of psychotropic medications, E 2b.)³⁵ Among predominantly adult first-time users (mean age 45 years), regular MPH use was associated with a slightly increased risk of open-angle glaucoma (aIRR 1.23, 95% CI 1.05 to 1.44, mean follow-up duration 1.8 years). An increased risk of angle-closure glaucoma was found for atomoxetine and amphetamine, but not for MPH. (Cohort study with embedded case-control analysis, USA, N = 240,257 first-time users, 1,159 cases of glaucoma, E 3.)³⁴

• Pheochromocytoma

• Hyperthyroidism

• Thyrotoxicosis

• severe depression

• Suicidal tendencies

• Anorexia nervosa or anorexic disorders

• Psychoses or psychotic symptoms, e.g.,

  • Schizophrenia

• severe affective disorders

  • Mania
  • severe, poorly controlled bipolar I disorder

• psychopathic or borderline personality disorders

• pre-existing cardiovascular diseases, e.g.,

  • severe hypertension
  • Heart failure
  • peripheral arterial disease
  • Angina pectoris
  • hemodynamically significant congenital heart defects
  • Cardiomyopathies
  • Myocardial infarction
  • potentially life-threatening arrhythmias
  • Channelopathies

  In children and adolescents with ADHD, MPH was not associated with ischemic heart disease (RR 0.86, 95% CI 0.49 to 1.50) or cerebrovascular disease (RR 0.79, 95% CI 0.45 to 1.39). A family history of cardiovascular disease did not alter the risk. Arrhythmias were more common among those taking MPH (RR 1.41, 95% CI 1.21 to 1.63), but this was also the case in the period before starting MPH (RR 1.50, 95% CI 1.15 to 1.96). A congenital heart defect increased the risk of arrhythmia only in the period prior to starting MPH (RR 3.19). (Self-controlled case series, Taiwan registry data, n = 2,493, full text not available to us, E 2b.)¹⁷⁵

• pre-existing cerebrovascular diseases, e.g., cerebral aneurysms, vascular abnormalities—including vasculitis—or stroke

• Treatment with nonselective, irreversible MAO inhibitors (up to 14 days after discontinuation)

• marked gastric acidosis (pH above 5.5) and when taking H2 blockers, antacids, or proton pump inhibitors (Medikinet Adult)

The MSD Manual lists methylphenidate among the substances with toxic pulmonary effects that can cause the following conditions:

• Asthma (E 4.)²⁸³
• Interstitial pneumonia or fibrosis (E 4.)²⁸³

According to the prescribing information, asthma and interstitial lung diseases are not contraindications.