MPH Part 2: Dosage, Side Effects, Contraindications

66% of children with ADHD-HI and ADHD-C subtypes require a moderate to high dose.¹²
“The last 10 mg” are particularly important for achieving the optimal effect.³
When adjusting the dosage, therefore, you should not stop increasing the dose too soon. Emotional numbness (“zombie”) is a sign of an overdose.

Adults require a significantly lower dose because the number of DATs (dopamine transporters) decreases with age. The number of DATs is halved in 50-year-olds compared to 10-year-olds; for adults, a starting dose of no more than 5 mg every 3 hours (immediate release) is recommended.

The half-life of MPH is:⁴

• about 2.5 hours for children
• about 3.5 hours for adults

6. MPH Dosage¶

For detailed information on dosing MPH and stimulants, see Dosage of Medications for ADHD

6.1. MPH should not be calculated based solely on weight or age¶

Methylphenidate is not generally dosed “based on body weight.” Some people with ADHD are able to manage with very low doses of MPH (3 to 5 mg every 3 hours). Others require the maximum recommended dose of 1 mg/kg of body weight per day.
The maximum dose of 1 mg/kg of body weight per day applies primarily to children. A comprehensive meta-analysis of 28 cohort studies involving 5,524 children and adolescents up to 18 years of age, in which the appropriate MPH dose was determined in a stepwise manner, reports a range of 0.8 mg/kg/day to 1.8 mg/kg/day.⁵ For people with ADHD who tolerate MPH well but experience only a moderate effect at lower doses, a dosage of more than 1 mg/kg/day may also be tested.⁶

A study reports a wide range of optimal doses (based on OROS-MPH in this case):⁷

• 7.9% with 18 mg
• 29.3% with 36 mg
• 34.4% with 54 mg
• 19.8% with 72 mg
• 8.7% with 90 mg

Another study found the optimal dose of sustained-release MPH for children and adolescents to be:⁸

• 1.5% with 10 mg
• 2.0% with 15 mg
• 16.8% with 20 mg
• 27.7% with 30 mg
• 25.2% containing 40 mg
• 17.8% with 50 mg
• 8.9% with 60 mg

A clinical trial comparing fixed-dose and flexible-dose regimens confirmed the benefits of an individually tailored dose.⁹¹⁰

Blood levels of MPH vary greatly from person to person depending on the dose of MPH taken.¹¹ These individual differences in effect are attributed, among other things, to genetically determined differences in metabolism.¹²¹³

For adults (who weigh more), the required daily dose is generally much lower.

People with the ADHD-I subtype and, to an even greater extent, people with ASD seem to require lower doses particularly often.
We are aware of several cases of people with ADHD for whom a single dose of 1.25 mg of immediate-release MPH is the optimal dosage.

6.2. Daily Coverage MPH¶

It is definitely recommended to use MPH in a way that covers the entire day, but not the late evening and night.

For information on the varying durations of action of the individual MPH medications, see section 7 below.

6.3. Dose Adjustment for Methylphenidate¶

6.3.1. Gradual introduction in small steps¶

It is important to titrate the dose slowly and persistently. In our opinion, the standard titration practice in Germany is significantly too fast.
As a general rule, MPH should be started at a low dose and the dosage increased only gradually. Even if the optimal dosage were known, starting with the optimal dose right away could potentially be too much for the patient¹⁴ and trigger side effects.¹⁵

The dosage should start at 2.5 mg to a maximum of 5 mg every 3–4 hours, and should only be increased to 3 × 5 = 15 mg per day within the first few days. Trials with higher starting doses not only failed to produce better efficacy results but actually yielded worse outcomes, while also resulting in a significantly higher discontinuation rate due to side effects.¹⁵ Others recommend 2.5 to 5 mg twice daily, with a weekly increase of 2.5 to 5 mg.^{616 14 15 17} Since such fine-grained dosing increments do not harm other people with ADHD (but rather help prevent dosage-related side effects),¹⁸ dosing increments in 2.5-mg increments (based on a single immediate-release dose of MPH) should be the gold standard. Kühle agrees.¹⁷ A large meta-analysis points in the same direction.¹⁹ Other sources recommend starting with 1–2 single doses of 5 mg and increasing the single dose weekly in 5-mg increments.²⁰ For the reasons mentioned, we consider these dose increments to be too large.
For people with ADHD for whom even extremely small differences in dosage are critical, a pharmacy in Switzerland offers MPH drops. One drop contains 0.35 mg of MPH. It is manufactured in batches and preserved with E216 and E218.²¹ One person with ADHD reports that dissolving immediate-release MPH in alcohol in such precise amounts that they could be measured drop by drop yielded a comparable result.

• Inform people with ADHD and (informed) third-party observers about the duration of action of the respective medication and the expected rebound effect.
• We consider up-dosing with 2.5 mg per single dose every 5 to 7 days to be appropriate. We now consider dosage increments of 5 mg per dose—which we previously deemed acceptable here—to be too high, because there is a significant proportion of people with ADHD for whom 2.5 mg less would constitute an underdose and 2.5 mg more would constitute an overdose.¹⁷ Even if this represents only a minority of people with ADHD, it would constitute medical malpractice to increase the dose more rapidly, since it is impossible to predict which group a person with ADHD belongs to. See also below: Genetic variants influence MPH dosing.
  The younger a person with ADHD is and the less they notice the MPH dose, the more the dose increments can be increased.
  During the titration process, the dose is increased until the signs of an overdose become more pronounced with each subsequent dose increase. After that, the dose that optimally reduces the symptoms without causing side effects can be determined.
  Unfortunately, there have been cases in which doctors have started treatment with single doses of 15 or 20 mg. We strongly advise against this.
  Even if this were the correct dosage for a few people with ADHD, such a high initial dose would significantly increase their risk of experiencing much more severe side effects in the first few weeks than they would with a slower titration.

6.3.2. No Caffeine When Taking MPH¶

Caffeine (theine is also caffeine), theobromine (dark cocoa), and other stimulants should be strictly avoided when adjusting the dosage. Caffeine, which was previously tolerated without any problems, can suddenly trigger internal tremors and other discomforts when taken alongside stimulants—symptoms that may then be mistakenly interpreted as side effects of the medication. When first determining the appropriate dosage of stimulants, caffeine can trigger sensations similar to an overdose. Once the dosage of the stimulants has been established, caffeine can be reintroduced. Any adverse sensations can then be correctly attributed to the caffeine.

6.3.3. No nicotine withdrawal with a single dose of MPH¶

Quitting nicotine at the same time as starting the medication may skew the results. Often, the urge to smoke decreases on its own as you take the stimulant.
Similarly, one should avoid resuming nicotine use while titrating the dose of stimulants.

6.3.4. Age-Related Differences in Dosage¶

Since adults have significantly fewer dopamine transporters than children (50-year-olds have only half as many as 10-year-olds;²² ), a much lower dosage is recommended for adults than for children.

For more information, visit ⇒ Dosage of Medications for ADHD.

6.3.5. Gene variants influence MPH levels¶

A small percentage of people with ADHD require a significantly lower dose of MPH.

The CES1 Gly143Glu polymorphism was found in 5.8% of people with ADHD and 4.1% of the general population. Among 441 children, no cases of CES1 Glu143Glu (homozygous) were found.
CES1 Gly143Glu showed an unchanged reduction in inattention and hyperactivity-impulsivity on MPH.
Carriers of the CES1 143Glu variant (5.56%) required MPH doses that were nearly 30% lower to reduce symptoms.²³

Learn more about how CES1 gene variants influence the effects of MPH at Factors Affecting the Potency of MPH in the article “ : MPH Part 3: Metabolism, Efficacy”.

6.4. Side Effects During the Initial Adjustment to Methylphenidate¶

In the first few days, taking the medication may feel as if snow has fallen—as if everything is wrapped in cotton. This sensation (which is usually very pleasant) stems from a reduction in sensory overload and, like most side effects, disappears within a few days.
Others describe the initial effect as the impressive experience of having a clear head for the first time in their lives, with their thoughts no longer racing.

Side effects such as headaches, sleep problems, or others rarely occur. Most side effects subside within the first few weeks after titration. The risk of such side effects can be significantly reduced by a very slow titration (as described above).¹⁵ A study with individually flexible dose adjustment reported a dropout rate due to side effects of 2.3%—well below average²⁴ —compared to studies with fixed dosing regimens, where the rate reached as high as 18.5% in some cases.¹³

To date, no study of adults known to us has explicitly prohibited caffeine consumption during the dosing period. Since caffeine drastically increases the incidence of side effects during the titration phase, the incidence of side effects is likely to decrease significantly compared to the study results if caffeine intake is consistently avoided.

Headaches can sometimes be reduced or prevented by drinking enough fluids and eating regularly (including glucose, if necessary). Since stimulants reduce the feeling of hunger, this can lead to reduced fluid and food intake, which can contribute to headaches.

One study found that MPH did not cause sleep problems. This may differ from the results of other studies because this study lasted a relatively long time—16 weeks—so that the side effects associated with the body’s adaptation to the medication were no longer noticeable.²⁵ In contrast, a small study that lasted only 14 days found reduced sleep duration and delayed sleep onset in children treated with sustained-release MPH.²⁶

A greater increase in blood pressure following the first dose of MPH was associated with greater reduction in ADHD symptoms after 6 months.²⁷

6.5. Symptoms of an MPH Overdose¶

When MPH is administered at the appropriate dose, the ability to concentrate increases, while internal restlessness and any hyperactivity decrease. If these symptoms reoccur at higher doses, it is a sign that the dose is too high.
Methylphenidate closes the stimulus filter (which is too open in people with ADHD). A typical reaction among people with ADHD who are on the right dosage is that they come back to themselves—they feel more like themselves.

If a person with ADHD notices that MPH makes them jittery (even though they are not consuming caffeine [theine is just another name for caffeine] or theobromine [dark cocoa]), they should nevertheless continue to increase the dose cautiously at first. It has been observed on several occasions that such side effects disappeared after a few days or upon moving to the next higher dose. If this jitteriness persists, the dosage is too high. This also applies if concentration becomes too intense—that is, if the stimulus filter is restricted too much. Diminished emotional responsiveness (“zombie effects”) is a clear indication of an overdose.

A study of monkeys concluded that low doses of MPH reduce impulsivity, while higher doses have a sedative effect.²⁸
This is consistent with empirical findings that people with ADHD, particularly children, may sometimes appear apathetic while taking MPH. Based on this study, this suggests an overdose.

In rats, aripiprazole was able to reduce the effects of an MPH overdose.²⁹ This is all the more surprising given that aripiprazole is a potent CES1 inhibitor, which means it reduces the breakdown of MPH.³⁰⁴

6.6. Even if MPH is effective, and especially if there are side effects or a lack of response, try different MPH medications¶

Many people with ADHD report experiencing side effects with one MPH medication that they do not experience with another MPH medication. We are aware of reports that one MPH medication (in this case, Medikinet) had no effect, while another (in this case, Concerta) worked well.
Other people with ADHD report that they experienced increased aggression when taking one medication (in this case, Concerta), which did not occur with another MPH medication (Medikinet or medication with immediate release of MPH).
Still others experience a stronger rebound effect (an increase in restlessness as the drug’s effects wear off) with Medikinet than with other MPH medications.

The various MPH formulations exhibit very different release profiles. In addition, depending on the manufacturer, MPH is incorporated into different excipients.
For individuals with gluten intolerance, MPH embedded in wheat starch is naturally unsuitable. A similar situation may arise with regard to lactose intolerance.

If none of the MPH medications produce a satisfactory response (the typical non-responder rate is just under 30%), treatment with amphetamine-based medications should always be initiated. This allows an additional 70 to 80 percent of MPH nonresponders to be successfully treated, thereby reducing the overall nonresponder rate for MPH and AMP to less than 10 percent.
If dysthymia or depression persists despite MPH being otherwise effective, switching to amphetamine-based medications may also be considered, as these also have a mild serotonergic effect.

Antidepressant effects were observed with daily doses of MPH ranging from 10 to 30 mg and daily doses of AMP ranging from 5 to 60 mg.⁶

6.7. Circumstances Surrounding Prescription and Use¶

Some people with ADHD need to take their MPH medication at exactly the same time every day.
Care should be taken to ensure that the medication is taken in such a way that it provides coverage throughout the entire day. However, the last doses of the day must be taken early enough so that the medication’s effects have worn off by bedtime.

6.8. Effect on People Not Affected¶

MPH can also be effective in people who do not have ADHD. It can (at low doses) increase attention, just as mild stress enhances cognitive performance by slightly raising levels of norepinephrine and dopamine in the prefrontal cortex (PFC).
A higher dose in unaffected individuals (such as a low dose in people who already have slightly elevated dopamine or norepinephrine levels) can cause such a significant increase in DA and NE levels that it triggers ADHD symptoms.
In ADHD, the (tonic) dopamine level in the striatum is too low, which causes many ADHD symptoms. When properly dosed, MPH raises dopamine levels in the striatum to the optimal level. However, if dopamine levels are raised beyond the optimal level—due to an overdose in people with ADHD or when MPH is taken by healthy individuals—this triggers the same symptoms as those seen in ADHD, because neurotransmitter communication functions optimally only at the correct neurotransmitter level.³¹

Amphetamine-based medications also have a positive effect (at low doses) on unaffected male mice:³²

• False alarms significantly reduced in both males and females
• Reduced hit rate for females
• As a result, CPT performance improved (only) in males
• Orientation and physical engagement in response to task stimuli are not impaired

6.9. MPH in Old Age¶

There is no explicit restriction on the use of methylphenidate in the elderly. The MPH prescribing information states that MPH should not be prescribed to older adults. In contrast, there is no such statement for lisdexamfetamine, despite the equally insufficient data.
Treatment with MPH in older adults may, however, constitute off-label prescribing.³⁵

There is no evidence to suggest that MPH would cause difficulties in old age.
A small study reports good tolerability among older people with ADHD.³⁶
In addition, MPH is also used to treat depression in older adults.³⁷

6.10. International Guidelines for Treatment with Methylphenidate¶

6.10.1. United States: AAP Guidelines, 2011, 219¶

“Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents,” a guideline from the American Academy of Pediatrics³⁸³⁹

Children, Adolescents:
Start with a low dose, especially in children, since they metabolize the medication more slowly and respond to it differently
Increase in 7-day increments (in urgent cases, in 3-day increments)
Goal: A dose that provides optimal efficacy with minimal side effects.
This guideline does not specify dosage levels.

For treatment-resistant cases, combination therapy may also be used.

6.10.2. Canada: CADDRA Guidelines/CAP Guidelines, 2011¶

Children, Teens, Adults:⁴⁰
Start with low doses of medication and gradually increase the dose until a level is reached that improves symptoms and functional ability and has a good side-effect profile.

6.10.3. Australia: NHMRC Guidelines, 2012, 2023¶

Children, Teens, Adults:⁴¹

Joint selection of appropriate medications by doctors and people with ADHD/guardians.
Personalized Medication Selection
Dose titration with regular medical monitoring of progress regarding symptoms, functional levels, and adverse effects
Optimal dose: The dose that reduces symptoms and improves functional outcomes while minimizing adverse effects

6.10.4. New Zealand: Guidelines from the New Zealand Ministry of Health, 2001¶

The New Zealand guidelines do not appear to be freely available on the Internet. The only versions found have unclear copyright information.

Children, Teens, and Adults:
Start dosing at the lower end of the dosage range (approximately 0.1 to 0.2 mg/kg MPH or 0.05 to 0.1 mg/kg DAMP).
Customized titration as needed
Titration rate based on the intensity of the treatment effect and side effects
Optimal dose: the smallest dose that produces an optimal therapeutic response
Maximum dose:

• MPH: 60 mg/day for adolescents and children
• AMP: 20 mg/day for younger children; 40 mg/day for older children

If there is no improvement

• Check compliance with the medication regimen
• Adjust the dosage
• Change the active ingredient

Treatment with stimulants (MPH or dextroamphetamine) is the first-line treatment.
Additional interventions (including behavioral therapy) should be used only if they are still necessary after several months of optimally titrated medication.

6.10.5. Malaysia: Malaysian Guidelines, 2008, 2020¶

Children, Teens, Adults:⁴²
Start with a dose at the lower end of the dosage range

• 2.5 mg/day for children aged 3–5 years
• 5 mg/day for an 8-year-old
• 10 mg/day for children over 8 years of age

Goal: Maximum effectiveness with minimal side effects
Maximum dose:

• 60 mg/day
• 30 mg/day, for children ages 3–5

6.10.6. Europe: ESCAP Guidelines, 2004¶

Children, Teens, Adults:⁴³
Start with a low dose (0.2 mg/kg per dose for children and adolescents)
Increase the dose until a good result is achieved, adverse effects occur, or the maximum dose is reached (0.7 mg/kg per dose for children and adolescents)—whichever occurs first

6.10.7. Germany: S3 Guideline, 2018¶

Children, Teens, Adults:⁴⁴
Start: low initial dose
Titration: 10 mg titration increments of semi-daily-release MPH
Increase the dose until no further clinically significant improvement in symptoms (e.g., in terms of core symptoms, but also in terms of a change in problem behavior) can be achieved and the adverse effects remain tolerable
Goal: the lowest possible dose

The 2009 guideline stated:“For stimulants: There is no strict correlation between body weight and the required dose!(Evidence level IIa). Always titrate individually. The mg/kg body weight values listed are averages and may be lower or higher depending on the individual.”⁴⁵

MPH:
While the guidelines for MPH recommend titrating the dose in 10-mg increments using semi-daily-release MPH, we agree with Kühle that a titration rate half as fast is appropriate—even if this tests the persistence of some people with ADHD. For this purpose, immediate release MPH (2.5 mg per single dose) or sustained release MPH (5 mg per single dose, which—due to its twice-as-long duration of action—is equivalent to two consecutive doses of 2.5 mg of immediate release MPH) can be used.

6.10.8. United Kingdom: BAP Guidelines, 2007, 2014¶

Children, Teens, Adults:⁴⁶⁴⁷
Titration to the optimal dose over a period of 4 to 6 weeks
Maximum dose:

• 60 mg/day for adolescents and children
• 100 mg/day for adults

For treatment-resistant cases, combination therapy may also be used.

6.10.9. England and Wales: NICE Guidelines, 2016, 2018¶

Children, adolescents:⁴⁸
Initial treatment starting with low doses

• 5 mg (immediate release) two or three times a day, or
• sustained release

Titration based on symptoms and side effects over 4–6 weeks until the dose is optimized
Maximum dose: 60 mg/day

Adults:
Initial treatment starting with low doses

• 5 mg of immediate release medication three times a day
• sustained release: corresponding dose

Titration based on symptoms and side effects over 4–6 weeks until the dose is optimized
Maximum dose: 100 mg/day

6.10.10. Scotland: SIGN Guidelines, 2009¶

This guideline was withdrawn in 2019. Readers are referred to the 2018 NICE guideline instead.⁴⁹

Children, Adolescents:⁵⁰
Structured Titration Protocol for Determining the Optimal Drug Dose

6.10.11. Spain: Spanish Guidelines, 2010¶

Children, Adolescents:⁵¹
Start with low doses of immediate release MPH (2.5 or 5 mg depending on weight; 2 to 3 times a day, no later than 5:00 p.m.)
Gradual increase of 2.5 to 5 mg per week, depending on clinical response and side effects
Dosage range: 0.5 to 2 mg/kg/day
Maximum dose: 60 mg/day

6.10.12. Sweden: Swedish Guidelines (2016)¶

The “ “ document, “Swedish Medical Products Agency ADHD drugs – treatment guidelines” ( ), does not appear to be publicly available. Reproduced from Huss et al.¹³

Children, Adolescents:
Start with low doses (18 mg for long-acting medications; 5–10 mg for medium-acting medications)
Gradual adjustment (about once a week)
Goal: A dose that is effective and well tolerated

Adults:
Clinicians are advised to start treatment with a low dose and gradually increase it (usually weekly) to a dose that provides the best balance between efficacy and side effects (maximum dose up to 80 mg/day).
Start with low doses
Gradual adjustment (about once a week)
Goal: A dose that provides the best balance between efficacy and side effects
Maximum dose: 80 mg/day

7. Sustained release or immediate release MPH¶

This section has been moved to Sustained-Release MPH, Sustained-Release Techniques in the post MPH Part 3: Retardation

8. Carriers¶

• Ritalin: wheat starch¹⁴
• Medikinet: Cornstarch¹⁴
• Equasym: Lactose (milk sugar)¹⁴

9. Efficacy of Methylphenidate¶

Methylphenidate is the choice of medication for children. It is significantly more effective at alleviating the symptoms of ADHD than one year of behavioral therapy. Comparable results are not achieved until after 3 years of behavioral therapy.

Since stimulants establish or enhance the ability to learn and undergo therapy, it makes sense to start by using stimulants on an acute basis while, at the same time, using behavioral therapy and/or neurofeedback to lay the groundwork for eventually tapering off their use.

The average effect size of MPH for ADHD ranges from 0.9 to 1.3.

For information on the effectiveness of individual medications and treatment options, see ⇒ Effect sizes of various ADHD treatmentsin the chapter⇒ Treatment and Therapy.

MPH medication, when combined with noradrenergic medications or zinc, can further enhance its effectiveness. However, a cautious approach is recommended in this case. It is advisable to consult a doctor with experience in treating ADHD with medication.

10. Side Effects of Methylphenidate¶

When administered at the appropriate 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.
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 is effective can also cause side effects. As the dose of medication increases, these side effects naturally increase as well.The dose makes the poison.
While even low doses of medication offer slight benefits for people who are not affected, higher doses are, by their very nature, harmful.⁵²

,

10.1. Side Effects¶

10.1.1. No serious side effects (-9%)¶

A Cochrane meta-analysis of MPH in children (mean age 9.7 years) found slightly fewer serious adverse effects with MPH than with placebo (OR = 0.91, k = 9, n = 1,532).⁵³

10.1.2. Slightly increased risk of mild side effects (+29%)¶

A Cochrane meta-analysis on MPH in children (mean age 9.7 years) found slightly more mild side effects with MPH than with placebo (OR = 1.29, k = 21, n = 3,132).⁵³

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

A systematic review found no serious side effects associated with long-term use of MPH.⁵⁴ Long-term use did not cause any cardiovascular problems.⁵⁵

10.1.4. Common Side Effects¶

Most side effects occur only briefly after starting the medication and typically disappear within the first four weeks. The temporary sensation of a dry or coated tongue shortly after taking the medication may last a little longer, but it will almost certainly go away eventually.
Tic disorders are observed in cases of overdose. If people with ADHD feel for months that the world is slipping away or that life is becoming monotonous, this is also a clear indication of overdose.

10.1.5. Side effects, primarily in cases of comorbid anxiety or other comorbidities¶

Several studies have found that side effects from stimulants occur primarily in people with ADHD and higher anxiety levels, or those with preexisting comorbidities.⁶¹⁶²
No correlation with EEG readings was found.⁶²

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

An increased risk of certain MPH side effects was found in association with specific gene variants:⁶³

• Loss of appetite: CES1*G
• Buccal-lingual movements: 1065G
• Diastolic blood pressure: ADRA2A Mspl C/C-GC
• Emotionality: DAT1*9/9
• Irritability: SNAP25 T1065G
• Plucking: DRD47/DRD44
• social withdrawal: DRD47/DRD44
• Somatic symptoms: DAT1*10/10
• Tics: 5-HTTLRPS/LL/L, and SNAP25 T1065G
• Sadness: CES1*rsl12443580
• autonomic symptoms: 5-HTTLPR

10.2. Growth in height temporarily delayed¶

Several comprehensive studies found no evidence that MPH causes long-term impairment of height growth in boys with ADHD.⁵⁶

A temporary impairment in height growth during the first year of MPH treatment was made up for in the second year.⁵⁷ 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.⁶⁴

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 taking 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)⁶⁵

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

A very comprehensive study analyzed the likelihood of Parkinson’s-related disorders (ranging from simple tremor to Parkinson’s disease) in people with ADHD, both with and without stimulant use, over the course of decades.⁶⁶

The increased risk of Parkinson’s-related disorders (ranging from simple tremor to Parkinson’s disease) caused by chronic MPH overdose could result from increased production of quinones and a reduction in glutathione (GSH, γ-L-glutamyl-L-cysteinylglycine).⁶⁷ Chronic administration of 10 mg MPH/kg (approximately 10 times the maximum therapeutic dose in humans) promoted a loss of dopaminergic cells in the substantia nigra.⁶⁸ A loss of dopaminergic cells could explain Parkinson’s symptoms. This, too, suggests that high doses of MPH should be avoided whenever possible.

A German study found no evidence of a correlation between Parkinson’s disease and the use of psychostimulants such as methylphenidate during childhood.⁶⁹

Another long-term study found that, in people with ADHD, stimulant medication reduced the risk of Parkinson’s disease by 60%.⁷⁰

10.4. The risk of psychosis is, at most, slightly elevated¶

According to a very large study, the risk of developing psychosis among people with ADHD who take MPH is 0.10%, which is lower than that of those treated with amphetamine medications (0.21%).⁷¹ Another study found a similar ratio.⁷²
While people with ADHD who are treated with stimulants have 2.4 cases of psychosis per 1,000 person-years (0.24%), the rate for the general population is 0.0214%.⁷³
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 medication (0.34% vs. 0.048%).⁷⁴ Since this study compares people with ADHD who are taking medication—rather than people with ADHD and no medication—to the general population, no reliable conclusions can be drawn regarding the contribution of ADHD medications. The absolute risk of a first hospitalization due to psychosis or mania upon starting medication was dependent on the active ingredient:

• Atomoxetine: 0.60% (highest)
• Amphetamine-based medications: 0.33%
• Methylphenidate: 0.19%

Another large cohort study points to a possible slight increase in risk associated with stimulants; the study found a significantly increased risk of psychosis in individuals with ADHD in general. Stimulants increased this risk very slightly (6%), while the increase associated with non-stimulants—at 15%—was nearly three times as high as that associated with stimulants.⁷⁵ Another large study based on the Swedish Health Registry, involving 23,898 adolescents and young adults with ADHD, compared the risk of psychosis before and after methylphenidate (MPH) administration and found only a 4% increase in the risk of psychosis associated with methylphenidate, which was not statistically significant.⁷⁶ If anything, higher doses of MPH appear to increase the risk of psychosis.⁷⁷

The benefits of treating ADHD (reduced premature mortality, reduced lifetime risk of depression and anxiety disorders, reduced risk of substance use disorders, etc.) are likely to far outweigh the potential risks.
Learn more about the risks of (untreated) ADHD at ⇒ Consequences of ADHD.

10.5. Increased Risk of Anorexia¶

Treatment with MPH increases the risk of anorexia by a factor of 4.66.⁷⁸
Therefore, people with ADHD should not be treated with stimulants.

In an RCT, MPH significantly reduced levels of the “hunger neuropeptide” NPY—which regulates food intake and alleviates anxiety and stress—by 21%.⁷⁹

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 who have not previously experienced seizures. In rare cases, MPH may trigger seizures even in the absence of the aforementioned risk factors.

A study involving n = 478 participants found EEG abnormalities in 273 (52.8%) of them. Children with and without EEG abnormalities exhibited similar patterns of MPH use (initial use, positive response, and continued MPH use). A follow-up examination of n = 39 people with ADHD who had EEG abnormalities found no increase in seizures after 3 years of MPH use. Seizures occurred in only 3 children with drug-resistant epilepsy, and their frequency had not increased. In cases of comorbid epilepsy and EEG abnormalities, the risk of seizures remained unchanged with MPH use.⁸⁰

If the frequency of seizures increases or if new seizures occur, methylphenidate should be discontinued.⁸¹

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

Comorbid anxiety disorders, depression, and aggression can be exacerbated by stimulants, as anxiety and mood are regulated by dopaminergic activity in the ventromedial prefrontal cortex (PFC) in conjunction with the limbic system. In these cases, norepinephrine reuptake inhibitors or α2A-adrenoceptor agonists are recommended instead.⁸²
A (fairly small) study found no short-term change in state anxiety following a single dose of MPH, but did find evidence of a possible long-term worsening.⁸³

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

A study found that MPH was not associated with an increased risk of mania in patients with bipolar disorder. Following MPH treatment, the incidence of mania decreased by 50 percent. Depressive episodes and psychiatric hospitalizations also decreased.⁸⁴

10.9. MPH increases histamine levels¶

MPH increases histamine levels, as do⁸⁵ and all other known ADHD medications:

• Atomoxetine
• Amphetamine
• Modafinil
• Nicotine
• Caffeine

As a result, people with histamine intolerance often experience problems when taking ADHD medications.
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.

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 duration of action. If a dose of MPH lasts about 3 hours, ADHD symptoms may intensify at the end of those 3 hours or immediately afterward for about 20 to 30 minutes.
Rebound is reported more frequently and more pronounced with immediate release MPH than with sustained release MPH.⁸⁶
We assume that a rebound effect is caused by a too rapid decline in dopamine and norepinephrine levels. With medications that show a very slow decline in effectiveness, a rebound effect appears to occur less frequently.

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.

10.11. MPH and Anesthesia¶

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

A double-blind study from 1980 found that MPH had no effect on postoperative pain. Methylphenidate shortened postoperative sedation by up to 30 minutes and improved respiratory function by up to 180 minutes under halothane anesthesia.⁸⁷ Halothane is no longer used today.
A case study reports a reduced response to sedatives and increased side effects associated with MPH.⁸⁸

A study reports a correlation between attention problems and postoperative delirium.⁸⁹

10.12. Other Information on Side Effects of MPH¶

There have been reports of isolated cases of trichotillomania (hair pulling).⁹⁰ Trichotillomania is a specific type of impulse control disorder.
A study reports muscle pain and stiffness as a possible side effect of MPH.⁹¹
A study reports a twofold increase in the rate of testosterone deficiency among adults with ADHD after 5 years of stimulant use (1.2%) compared to people with ADHD who do not take stimulants (0.67%) or people without ADHD (0.68%).⁹²

10.13. No increased cardiovascular risks¶

The hypothesis that methylphenidate causes an increased risk of heart problems was not confirmed.⁹³ No changes in EEG readings were observed.⁶² A meta-analysis found slightly elevated values that were below the level of statistical significance.⁹⁴

An initial study involving n = 564 people with ADHD, which had suggested an increased rate of cardiac death among children taking MPH, was refuted by a number of other studies, including a large study involving n = 241,417 children taking MPH.⁹⁵ A very large study involving 2,566,995 children found no increased risk of serious cardiovascular events—such as stroke, heart attack, or cardiac arrhythmias—associated with MPH.⁹⁶ A third large registry study involving n = 224,732 individuals also found no increased long-term cardiovascular risks associated with MPH. In fact, the risk rates were reduced by 15%.⁹⁷
There are also studies that even confirm a reduced risk of sudden cardiac death among people with ADHD who use MPH, which could be explained by the medical care these people receive.

Several studies found that MPH did not cause any significant changes in heart rate, QRS, QT, QTc, or QTd intervals on ECGs.
The Tp-Te intervals and the Tp-Te/QTc ratios were slightly elevated after treatment with MPH, but remained within the normal range.⁹⁸ Children with ADHD showed significantly prolonged P-wave dispersion, Tp-Te interval, Tp-Te dispersion, and Tp-Te/QT and Tp-Te/QTc ratios. In addition, nearly half of the patients had QTc values of 460 ms or more. These parameters were not associated with either the MPH dose or the duration of treatment.⁹⁹ The QTc interval and fQRS-T angle were significantly higher in both medication-naive and medication-treated people with ADHD than in the healthy control group. However, the QTc interval and fQRS-T angle did not differ between people with ADHD who are medication-naive and people with ADHD who are medication-treated. Both the QTc interval and the fQRS-T angle correlated with the severity of ADHD symptoms.¹⁰⁰

One study found no increased risk of cardiac arrhythmias associated with methylphenidate. In contrast, an increased risk of cardiac arrhythmias was found for atomoxetine for 7 days following the first exposure to atomoxetine (aIRR 6.22) and for subsequent exposures (aIRR 3.23).¹⁰¹
A 14-year study found a 4% increase in the risk of cardiovascular problems for each year of use of stimulants (methylphenidate, amphetamine-based medications) and, to a slightly lesser extent, the non-stimulant atomoxetine.¹⁰²

A cohort study of n = 252,382 participants with an average age of 20 years found a posterior probability of a 10% or greater increased risk of cardiovascular events of 70% among individuals who received MPH, compared with 49% among the matched controls. No difference in risk was found between individuals with and without a history of cardiovascular disease.¹⁰³
Long-term use did not cause any cardiovascular problems.¹⁰⁴

In adults, MPH may be associated with cardiovascular problems.¹⁰⁵

10.14. No known liver damage¶

There are no known reports of increased incidence of liver damage associated with MPH.¹⁰⁶ However, liver function tests should always be monitored when adjusting ADHD medication doses.

10.15. No Long-Term Adverse Effects of MPH¶

The reports we have seen to date regarding the harmful effects of long-term MPH use are all based on massive overdoses. 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.
As a point of reference: Humans need 30 to 40 ml of water per kilogram per day (2 to 3 liters). However, drinking 3 liters of water at once or 5 liters of water in a day can already be fatal. Accordingly, even doubling the amount of water consumed can have fatal consequences for humans.

A large-scale, long-term study of MPH conducted over a 2-year period in children with ADHD found that in the MPH group:¹⁰⁷

• no significant impairment of growth
• slight weight loss during the first 6 months, which then stopped
• No change in terms of psychosis, depression, dyskinesia, or tics
• slightly elevated blood pressure and heart rate
• preventive effects with regard to addiction and suicide
  • significantly higher nicotine and marijuana use in the non-MPH group
  • a significantly increased risk of suicide in the non-MPH group

A population-based cohort study using data from Danish registries on patients who had continuously taken either Medikinet® MR or Concerta® over a prolonged period (i.e., ≥ 12 months) between 1995 and 2018 found that:¹⁰⁸

• no cases of cerebral arteritis
• No cases of priapism
• No cases of sudden death associated with Medikinet® MR
• No statistically significant differences in risk between Medikinet® MR and Concerta®

A study of primates found no changes in brain parameters 6 months after the completion of a 12-year long-term administration of MPH.¹⁰⁹

In a study of adult rats administered 15 to 20 times the standard daily dose of the drug over the long term, damage to the morphology and function of the cerebellum was observed.¹¹⁰ This is to be expected at such a dosage.

A study of rats that received 5 mg/kg/day—five times the maximum daily dose typically used in humans—during puberty found impaired sperm quality in the adult animals.¹¹¹ Furthermore, the rats used in the study were Wistar rats, which do not have a dopamine deficiency.
A study in Balb/c mice (an animal model for ASD), which also show no dopamine deficiency but rather a dopamine excess¹¹², found that MPH impaired sperm quality. This study also speculated on the potential toxicity of MPH based on weight loss in the animals at doses of 20 mg/kg and 40 mg/kg MPH, which are equivalent to a therapeutic dose.¹¹³ It is well known that stimulants reduce appetite. The fact that dopamine-increasing active ingredients have adverse effects in organisms that do not have reduced dopamine levels is not surprising but rather to be expected.
In people with ADHD, no statistically significant difference in sperm count was found after taking methylphenidate; however, a significant difference was observed in sperm motility and abnormalities.¹¹⁴

In one study, monkeys were given 2.5 mg/kg or 12.5 mg/kg of MPH twice daily. 12.5 mg/kg twice daily is about 25 times the maximum dose typically recommended for humans and, in our view, represents a drug dose rather than a medicinal dose.
Apart from a temporary decrease in motivation after MPH administration ended (and even that occurred only at the “drug dose”), no negative effects were observed.¹¹⁵
At a dose of 12.5 mg/kg twice daily, there was also a marked decline in cognitive performance, as would be expected with such an overdose.¹¹⁶

10.16. Reduced Risk of Stress Fractures¶

The use of MPH by people with ADHD reduced the risk of stress fractures compared to people with ADHD (who did not take MPH).¹¹⁷

10.17. Reduced Risk of Type 2 Diabetes¶

Methylphenidate reduced the risk of type 2 diabetes by 20% during the first 3 years of use.¹¹⁸ 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 contraindications for MPH as well.
Taking this medication without first consulting a doctor is risky!

Methylphenidate is metabolized independently of the cytochrome P450 system, so there is only a very low potential for pharmacokinetic interactions.⁸¹

11.1. Interactions Between Methylphenidate and Other Medications¶

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

• 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 any problems—to trigger internal tremors. This can be mistakenly interpreted as a (side) effect of the stimulants.
  A very high dose of caffeine (many times higher than therapeutic levels) administered over several days reduced the efficacy of MPH in rats, and vice versa. This confirms that MPH and caffeine have common,¹¹⁹¹²⁰ but not identical¹²¹ mechanisms of action.

• Alcohol
  A comprehensive meta-analysis found little evidence that ADHD medications, when combined with alcohol or other drugs, have any particular negative effects.¹²²

  • When consumed with MPH, alcohol can have a more intense effect
  • Alcohol consumed while taking MPH can increase MPH levels¹²³

• All sympathomimetics¹²⁴ can be potentiated by MPH.
  Active ingredients affected:

  • α-sympathomimetics¹²⁴
    • Naphazoline
    • Tetryzoline
    • Tramazoline
    • Xylometazoline
    • Oxymetazoline
    • Phenylephrine
  • β-sympathomimetics¹²⁴
    • Fenoterol
    • Orciprenaline
    • Catecholamine-derivatives
      • Adrenaline
      • norepinephrine
      • Amezinium methyl sulfate
      • Etilefrine
      • Metaraminol
      • Norephedrine
      • Oxilofrin
      • Dopamine
      • Dopamine derivatives
        • Dobutamine
        • Dopexamine

• Monoamine oxidase inhibitors (MAOIs)

  • Monoamine oxidase inhibitors (MAOIs) should not have been taken during the 14 days prior to taking MPH. Taking MAOIs and methylphenidate at the same time can have consequences for blood pressure.¹²⁵⁸¹
    • St. John’s wort is an MAOI¹²⁶ and also inhibits COMT.
      There are concerns that St. John’s wort may interact with MPH.¹²⁷
    • Tranylcypromine
      MPH should be avoided for up to 14 days after taking tranylcypromine¹²⁸

• blood pressure-raising agents⁸¹

• Halogenated anesthetic gases

  • may cause spikes in blood pressure in patients taking methylphenidate⁸¹ In cases of scheduled surgical procedures, methylphenidate should not be administered on the day of surgery.

• All centrally acting dopaminergic and noradrenergic active ingredients⁸¹
  Blood pressure should be monitored closely here.
  Examples:

  • Moclobemide
  • Linezolid
  • Selegiline
  • Rasagiline
  • Levodopa
  • other Parkinson’s medications
  • centrally acting α2 agonists, e.g.,
    • Clonidine
    • Methyldopa

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

• Anticonvulsants¹²⁹
  • Phenobarbital¹²⁴¹³⁰
  • Phenytoin¹²⁴¹³⁰
  • Primidone¹²⁴
  • Carbamazepine
    • Two case reports suggest that the MPH dose may need to be at least doubled when high-dose carbamazepine is administered concurrently¹³⁰
  • Rifampin, possibly¹³⁰
    MPH reduces the effectiveness of anticonvulsants¹²⁴
    Anticonvulsants reduce blood levels of MPH after a few weeks¹³⁰
• tricyclic antidepressants⁸¹, e.g.:
  • Amitriptyline¹²⁴
  • Imipramine¹²⁴
    Methylphenidate enhances the effects of imipramine,¹³⁰ while imipramine, in turn, enhances the effects of MPH. Therefore, particular caution is advised when dosing imipramine in combination with MPH.
    Symptoms include:
    • Confusion and agitation
    • Mood instability
    • Irritability and aggression
    • Psychotic symptoms
• Phenylbutazone (Butazolidin)¹²⁴
  Phenylbutazone is a nonsteroidal anti-inflammatory drug that is rarely used today.
• Anticoagulants (blood-thinning medications)¹²⁴
  • oral coumarin-type anticoagulants, e.g., phenprocoumon, warfarin
    Fluctuations in efficacy due to interaction with methylphenidate are possible. The mechanism is unknown. Close monitoring of coagulation parameters is therefore recommended when starting or discontinuing methylphenidate.⁸¹
• Antihypertensive drugs⁸¹, e.g.:
  • ACE inhibitors
  • Angiotensin receptor blockers
  • Diuretics
  • Calcium channel blockers
  • Beta-blockers
• Metoclopramide (prokinetic, dopamine antagonist)⁸¹

11.1.3. Changes in the effects of MPH caused by other medications¶

An elevated stomach pH of 5.5 or higher may accelerate or increase the release of the sustained-release components of Medikinet Adult. The release of methylphenidate from Ritalin for Adults, on the other hand, is pH-independent. Nevertheless, antacids may reduce the absorption of Ritalin for Adults.⁸¹

Stomach pH can be increased by:

• Proton pump inhibitors, e.g.,
  • Pantoprazole
  • Omeprazole
• H2 antagonists (although less likely), e.g.,
  • Ranitidine
  • Famotidine
• Antacids

Chronic oral administration of MPH alone produced a tendency toward […]. in the striatum of rats¹³¹

• increased dynorphin expression
• increased substance P expression
• unchanged enkephalin expression.

Oral fluoxetine alone did not alter the expression of these genes.

MPH and fluoxetine, when used together, caused

• a significant increase in dynorphin expression
• significantly increased Substance P expression
• increased enkephalin expression

Oxytocin potentiates the MPH-induced stimulation of tonic (extracellular) dopamine firing, likely by modulating dopamine receptor signaling pathways. Oxytocin did not affect either MPH-induced dopamine reuptake or MPH-induced phasic dopamine firing.¹³²

CBD (cannabidiol) had only a negligible effect on MPH levels and AUC, even though CBD is a CES1 inhibitor.¹³³

11.1.4. No interactions between MPH and SSRIs¶

A study of n = 17,234 adults found no adverse effects associated with taking MPH and SSRIs together. Taking SSRIs with MPH reduced the risk of headaches.¹³⁴

11.2. BMI and Blood Pressure¶

Methylphenidate can raise blood pressure in children.

In children with ADHD, blood plasma levels of nitric oxide appear to be elevated, while those of asymmetric dimethylarginine (ADMA) appear to be reduced. ADMA inhibits the blood pressure-raising effect of nitric oxide. When MPH was administered, plasma nitric oxide levels increased further. This could possibly be due to reduced inhibition of nitric oxide by ADMA during MPH administration and may represent a cause of MPH’s blood pressure-raising effect.¹⁰⁵
In contrast, a comprehensive study found that MPH did not adversely affect blood pressure in boys with ADHD.⁵⁸
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 sensitivity to stress.

A greater increase in blood pressure upon the first dose of methylphenidate was associated with a greater reduction in ADHD symptoms after 6 months.²⁷

11.3. Taking MPH During Pregnancy¶

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

• Weight
  • unchanged¹³⁵¹³⁶
  • slightly reduced¹³⁷
• Risks of preeclampsia, placental abruption, or preterm birth associated with the use of stimulants (AMP or MPH) during pregnancy; however, these risks were so low that the authors did not recommend discontinuing stimulant use during pregnancy.¹³⁷ Atomoxetine did not show these slight increases in risk.
• Risk of miscarriage due to stimulants during pregnancy
  • not statistically significantly altered by methylphenidate and atomoxetine (meta-analysis, k = 10, n = 16,621,481)¹³⁸
  • doubled¹³⁹
• Malformations
  • very slight increase (not significant)¹⁴⁰
  • No increased risk.¹⁴¹
  • slightly increased (meta-analysis, k = 4) risk of birth defects and heart defects associated with taking MPH during early pregnancy¹⁴²
  • Not statistically significantly increased by methylphenidate and atomoxetine (+14%) (meta-analysis, k = 10, n = 16,621,481)¹³⁸
• ADHD symptoms
  • increased in a study of mice
  • Reduced expression of the D2 receptor and dopamine transporter genes—as is common in ADHD—at doses 2.5 to 15 times higher than the usual maximum drug level¹⁴³. This is plausibly consistent with the model of brain development disorders, which are caused by a dopamine deficiency (e.g., genetically inherited or due to chronic stress) or an excess of dopamine (e.g., from stimulant use in non-affected individuals). More on this at ⇒ Brain Developmental Disorder and ADHD In the chapter “ ” ⇒ Etiology.
  • There is no increased risk of ADHD or other neurodevelopmental disorders associated with taking MPH or AMP during pregnancy. Upon closer examination, the initially observed increased risk of ADHD was found to be attributable to the mothers’ own ADHD.¹⁴⁴
• neurodevelopmental disorders
  • Risk unchanged (Swedish cohort study, n = 861,650 children of n = 572,731 mothers from 2008 to 2017)¹⁴⁵

11.4. Possible Contraindications¶

Caution is advised when using methylphenidate in the following cases:⁸¹

• Glaucoma
• Hyperthyroidism
• Thyrotoxicosis
• severe depression
• Psychoses, e.g.,
  • Schizophrenia
  • Mania
  • Bipolar Disorder Type I
• Cardiomyopathies
  • particularly severe arrhythmias
• Asthma¹⁴⁶
• Interstitial pneumonia or fibrosis¹⁴⁶