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MPH Part 2: Dosage, side effect, contraindications


MPH Part 2: Dosage, side effect, contraindications

66% of ADHD-HI and ADHD-C subtype children require moderate to high dosing.12
In particular, “the last 10 mg” are important to achieve an optimal effect.3
Therefore, when adjusting the dosage, do not stop increasing the dosage too soon. Emptional depletion (“zombie”) is a sign of overdose.

Adults require a significantly lower dosage because the number of DAT (dopamine transporters) decreases with age. The number of DAT is halved in 50-year-olds compared to 10-year-olds. For adults, an initial dosage of max. 5 mg every 3 hours (unretarded) is recommended.

The half-life of MPH is:4

  • for children about 2,5 hours
  • for adults about 3.5 hours

6. Dosage of MPH

6.1. MPH by weight?

Methylphenidate is not dosed across the board “according to body weight”. There are sufferers who manage with very low doses of MPH (3 to 5 mg every 3 hours). Others need the maximum recommended dose of 1 mg/kg body weight per day.
The maximum dose of 1 mg/kg body weight per day applies primarily to children. A comprehensive metastudy of 28 cohort studies of 5524 children and adolescents up to 18 years of age, in which the appropriate MPH dose was determined in a stepwise manner, reported a range of 0.8 mg/kg/day to 1.8 mg/kg/day.5 In affected individuals who tolerate MPH well and achieve only a moderate effect with lower doses, a dosage of more than 1 mg/kg/day can also be tested.6

In adults (with higher body weight), the required daily dose is usually much lower.

lower dosage for adults

Adults have far fewer dopamine transporters and therefore require less MPH than children. A dosage as in children can therefore already represent an overdose in adults. Therefore, an even slower dosage in even lower steps (increase 2.5 mg to max. 5 mg unretarded/day, every 4 days) is recommended for adults. An overdose can cause exactly the symptoms that are supposed to be avoided, as the optimal dopamine level is already exceeded, causing very similar signal transduction problems as the ADHD-typical too low dopamine level. At a higher dosage (over 60 mg / day) individual neurologists report adaptation effects (not statistically proven).

6.2. Daily coverage MPH

In any case, it is recommended to use MPH in such a way that the entire day is covered, but not the later evening and night.


Taking MPH only once (in the morning) for 3 (unretarded) or 6 hours (retarded) causes the sufferer to be at the mercy of his stress sensitivity again afterwards. In the last hours before bedtime, MPH should be used with caution. Most people respond with sleep problems. For some, on the other hand, a quarter to half dose of stimulant just enables them to fall asleep because it shuts off the mind spinning. Potentially, a low dose of unretarded stimulants could be helpful in those individuals who have low arousal anyway. These are people who, for example, find it helpful to have a radio or television on in the background to help them concentrate. For others, listening to audio books helps them to fall asleep. People with a high arousal tend to need absolute quiet to be able to concentrate.

For the different duration of action of the individual MPH drugs, see below under 7.

6.3. Dosage adjustment of methylphenidate

6.3.1. Slow dosing in small steps

Slow and patient dosing is important. In our opinion, the usual dosing practice in Germany is clearly too fast.
In principle, MPH should be dosed low at the beginning of the test and the dosage increased only slowly. Even if the optimal dosage were known, an immediate optimal dosage would possibly cause an overload7 and force side effects.8

The dosage setting should start with 2.5 mg to a maximum of 5 mg / 3-4 hours, which should only be extended to 3 x 5 = 15 mg / day within the first few days. Tests with higher starting dosages produced not only no better, but even worse efficacy results and at the same time caused a significantly higher discontinuation rate due to side effects.8 Others recommend 2.5 to 5 mg twice daily, with a weekly increase of 2.5 to 5 mg.697810
We consider an up-dosing every 5 to 7 days by 2.5 mg per single dose to be reasonable. Dosing increments of 5 mg / single dose, as we used to consider acceptable here, we now consider too high, because there is a relevant proportion of sufferers for whom 2.5 mg less means underdosing and 2.5 mg more means overdosing.10 Even if this represents only a minority of sufferers, it would be malpractice to updose more rapidly, since it can never be predicted to which group a sufferer belongs. See also below: Gene variants influence MPH dosing.
The younger a sufferer is and the less they even notice about the MPH dose, the sooner the up-dose jumps can be increased.
In the course of discontinuation, the dose is increased until the characteristics of overdose are enhanced with the next dose increase and the one after that. Thereafter, the dose that optimally reduces symptoms without causing side effects can be determined.

Unfortunately, there are known cases in which physicians have started the setting with single doses of 15 or 20 mg. Malpractice is still a rather mild term for this.
Even if this were the right dosage for a few sufferers, even for them, such a high initial dosage in the first few weeks would significantly increase the risk of suffering considerably more severe side effect problems than with a slower setting.

6.3.2. No caffeine with MPH dosage

Caffeine (theine is also caffeine), theobromine (dark cocoa), and other stimulants should be avoided at all costs when dosing. Caffeine, which was previously tolerated without problems, can suddenly cause internal tremors and other discomfort when taken concurrently with stimulants, which can then be misinterpreted as a drug side effect. When stimulants are re-dosed, caffeine can trigger a sensation like overdose. Once stimulants are dosed, caffeine can be tried again. Abnormal sensations can then be correctly attributed to caffeine.

6.3.3. No nicotine withdrawal with MPH single-dosing

Nicotine withdrawal started at the same time as dosing can falsify the result. Often, the need for cigarettes decreases by itself with the use of stimulants.
Similarly, restarting a NIcotine intake during stimulant induction should be avoided.

6.3.4. Age-related dosage differences

Because adults have significantly fewer dopamine transporters than children (50-year-olds have only half as many as 10-year-olds,11 a much lower dosage is indicated for adults than for children.

See more at Medication dosage in ADHD.

6.3.5. Gene variants influence MPH levels

A small proportion of affected individuals require a significantly lower dosage of MPH.

The CES1 Gly143Glu polymorphism was found in 5.8% of ADHD sufferers and 4.1% of the population. Among 441 children, no case of CES1 Glu143Glu (homozygous) was found.
CES1 Gly143Glu showed an unchanged reduction in inattention and hyperactivity-impulsivity on MPH.
Carriers of the CES1 143Glu variant (5.56%), required nearly 30% lower MPH doses for symptom reduction.12

For more on the influence of CES1 gene variants on the effect of MPH see Influences on the potency of MPH In the article MPH part 3: degradation, potency.

6.4. Side effects in the setting of methylphenidate

In the first few days, taking the drug can be associated with the feeling as if snow had fallen - everything is packed in absorbent cotton. This (usually very pleasant) impression comes from this reduction in sensory overload and, like most side effects, disappears within a few days.
Rarely, side effects such as headache, sleep problems or others occur. Most side effects subside within the first few weeks after dosing, The risk of such side effects can be significantly reduced by very slow dosing (as described above).8 Headaches can sometimes be reduced or avoided by drinking enough and eating regularly (glucose if necessary). Since stimulants reduce the sense of hunger, this may contribute to reduced fluid and food intake, which may contribute to headache.

One study found that MPH did not cause sleep problems. This could possibly differ from the results of other studies because this study was relatively long, lasting 16 weeks, so that the acclimation side effects were no longer noticeable.13 In contrast, a small study that looked at only 14 days found decreased sleep duration and delayed sleep onset in children treated with sustained-release MPH.14

6.5. Overdose symptoms with MPH

With a suitable dosage of MPH, the ability to concentrate increases and the internal pressure and any hyperactivity that may be present decrease. If the latter increases again with increased dosage, this is a sign that the dosage is too high.
Methylphenidate closes the stimulus filter (which is too wide open in ADHD sufferers). A typical reaction of those affected with a suitable dosage is that they come into their own, that they are more themselves.

If the patient finds that MPH makes him jittery (although neither caffeine (theine is just another name for caffeine) nor theobromine (dark cocoa) is consumed), the dose should still be increased cautiously at first. It has been observed several times that such side effects disappeared after a few days or on the next higher dose. If this shakiness remains, the dosage is too high. The same applies if the concentration becomes too strong, i.e. the stimulus filter is restricted too much. Restricted emotionality (“zombie effects”) is a clear indication of overdose.

A study in monkeys concluded that low doses of MPH reduced impulsivity, while higher doses had a sedative effect.15
This follows empirical experience that ADHD sufferers, especially children, can sometimes appear apathetic under MPH. Following this study, this suggests an overdose.

6.6. Even if MPH is effective, even more so if there is a side effect / nonresponding try different MPH medications

Many sufferers report that they experience side effects with one MPH preparation that they do not experience with another MPH preparation. On this side, reports are known that one MPH preparation (here: Medikinet) had no effect, while another (here: Concerta) responded well.
Other sufferers report experiencing increased aggression in response to one preparation (Concerta in this case), which did not occur with another MPH preparation (Medikinet or unretarded MPH).
Still others feel a stronger rebound effect (increase in agitation the moment the effect wears off) with Medikinet than with other MPH preparations.

The different MPH preparations show very different time courses of drug release .In addition, MPH is embedded in different excipients depending on the manufacturer.
In the case of an existing gluten intolerance, MPH embedded in wheat starch is naturally unsuitable. A comparable situation may arise with regard to lactose intolerance.

If all MPH preparations fail to produce a satisfactory effect (the typical nonresponder rate is just under 30%), medication with amphetamine drugs should always be given. This allows another 70-80% of MPH nonresponders to be satisfactorily medicated, so that the total nonresponder rate of MPH and AMP drops below 10%.
If dysthymia or depression persists despite satisfactory effects of MPH in other respects, a switch to amphetamine medications may also be considered, since these also have a mild serotonergic effect.

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

6.7. Circumstances surrounding the setting and taking

Some sufferers always need their MPH medications at exactly the same time.
Care should be taken to ensure that doses are taken so that the entire day is covered. However, the last doses of the day must be taken at such a time that there is no effect at bedtime.


During the adjustment to MPH, caffeine (coffee, black tea), theobromine (dark cocoa) and alcohol should be completely avoided, as these can intensify the effects of stimulants. Several sufferers report that MPH makes them much more sensitive to such stimulants. A jittery feeling can therefore be triggered by caffeine, whereas the same amount of caffeine had no such effect without MPH. Like antidepressants, MPH often causes mild side effects (dry mouth, etc.) in the first few days or weeks of use, which subside quite soon.

To prevent or alleviate loss of appetite, it is recommended to take it with or after meals.

6.8. Effect on non-affected persons

MPH can also work in non-ADHD sufferers. It can (in small doses) increase attention, just as mild stress increases cognitive performance by slightly raising norepinephrine and dopamine in the PFC.
Higher dosing in unaffected people (like low dosing in people who have already slightly elevated levels of dopamine or norepinephrine) can cause DA and NE levels to become so elevated that this causes ADHD symptoms.
In ADHD, the (tonic) dopamine level in the striatum is too low, which causes quite a few ADHD symptoms. MPH increases the dopamine level in the striatum to the optimal level when dosed correctly. However, if the dopamine level is increased above the optimal level - by overdosing in ADHD sufferers or by taking MPH in healthy people - this triggers the same symptoms as in ADHD, because neurotransmitter communication only functions optimally at the correct neurotransmitter level.16

The dopamine increase on amphetamine administration in the dorsal striatum (but not in the nucleus accumbens) is higher in both male and female rats when they were previously exposed to chronic uncontrollable stress. This may indicate an aberrant dopaminergic response to stimulants (ADHD drugs) in sufferers of chronic stress as well as ADHD.17

7. Retarded or unretarded MPH

Retardation means that a drug has a prolonged mode of action. This is achieved by means of various mechanisms.

Unretarded (“normal”) MPH has a duration of action between 2.5 and 4 hours. The advantage of the short duration of action is a better controllability, because sometimes a little earlier or sometimes a little later, sometimes a little less or a little more can be taken and the daily coverage can be regulated more easily. The disadvantage is that a greater cooperation and discipline of the affected person is required. With ADHD in general and with ADHD-affected children in particular this reliability is not always given. If one only notices that one has to top up because one has just “exploded” again for no adequate reason, or because one has been staring into space for quite some time, a large part of the achievable normalization of life has been missed. In addition, frequent use of medication throughout the day more clearly conveys the feeling of being affected by a disorder. Medications with a long retardation (10-14 hours), which only have to be taken once in the morning, have a much stronger effect on the feeling of normalization in comparison.

Slow-release MPH works for between 4 and 12 hours, depending on the preparation, as the drug capsule slowly releases its active ingredients into the body.
The advantage is that the affected person does not have to remember to take his medication again, the disadvantage is the lack of fine control with regard to the quantity, since the capsules only contain the specified dosages and cannot be divided like tablets, and that after the effect has expired, if there are still a few hours of day left to live, the duration of effect of a capsule may last too long, which can then cause sleep problems.
Retarded preparations may help reduce dysphoria and/or hyperactivity during rebound when the effects of unretarded preparations wear off.6
What fits better, each person concerned must find out for himself.

When dosing, an unretarded form is preferable, provided that dosing is reliable, since tablets can be divided into finer units by partitioning.

The combination of sustained-release preparations (as the standard for the day) with unretarded tablets (for a quicker start in the morning, for supplementation later in the afternoon or evening, and for fine control during increased loads) is permissible.6

For individual sustained-release / non-released MPH preparations, see below.

7.1. Taking with / without food intake

Some preparations (e.g., Medikinet Adult and Medikinet retard) require a food base for ingestion because the sustained-release portion is encased in an acid-resistant membrane and relies on slowed transit (via solid food) through the stomach to the intestine. If transported too quickly into the alkaline region of the duodenum, the sustained-release portion may be released prematurely18, resulting in an excessive and shortened effect.

Also with other preparations with long-term effect, a food intake before the intake can influence the duration of the effect. In the case of fasting intake, there is an increased risk that the drug without acid-dependent retardation will already have migrated so deeply into the intestine at the time when the effect of the retarded portions is supposed to begin that complete absorption of the active ingredient is no longer guaranteed there.19 The bioavailability of Ritalin LA (whose retardation is not acid-dependent) is also said to be about eleven percent higher when taken after a meal than when taken fasting, so that it is also recommended that Ritalin LA and Ritalin adult be taken with or after a meal.20

8. Carrier substances

  • Ritalin: wheat starch7
  • Medikinet: corn starch7
  • Equasym: lactose (milk sugar)7

9. Effect quality of methylphenidate

Methylphenidate is the drug of choice for children. It combats the symptoms of ADHD significantly better than one year of behavioral therapy. Comparable effects are achieved only after 3 years of behavioral therapy.

Since stimulants produce or increase learning and therapy ability, it makes sense to first work acutely with stimulants in order to create the basis for being able to discontinue them again in parallel by means of behavior therapy and/or neurofeedback.

The mean effect size of MPH in ADHD ranges from 0.9 to 1.3.

For the efficacy of individual medications and forms of treatment, see Effect size of different forms of treatment for ADHDin the chapterTreatment and therapy.

MPH medication in combination with noradrenergic drugs or zinc may further improve the effect. However, a cautious approach is recommended here. It is recommended to consult a physician with experience in ADHD medication.

10. Side effects of methylphenidate

Most side effects occur only for a short time after starting the medication and regularly disappear within the first four weeks. The respective short-term feeling of a dry / furry tongue after taking the medication could last longer.
Tic disorders are observed in overdose. If sufferers feel for months that the world is becoming distant or that life is becoming monotonous, this is also a clear indication of overdose.
At an appropriate dosage, the effect of MPH gives ADHD sufferers the feeling that they are much more themselves than before. Should a sufferer feel that stimulants make them feel less themselves, this is a very serious indication of misdosing, misuse or misdiagnosis.

Several studies stated that adverse reactions to stimulants occur primarily in those with higher anxiety levels and faster reaction times or preexisting comorbidities.2122
No correlation with EEG values was found.22

10.1. Length growth delayed for a short time

Several comprehensive studies failed to find any persistent impairment of length growth in boys with ADHD by MPH.23

A temporary impairment of length growth in the first year of MPH treatment was recovered in the second year.24 Temporary impairment of length growth is common in ADHD in childhood and is regularly recovered in adolescence. This does not appear to be a specific effect of methylphenidate.25 Another study found a 4-fold increased risk of decreased length growth and weight gain in children with ADHD at ages 8 and 10 years. The length of stimulant treatment amplified this risk.26

10.2. Light weight loss

One comprehensive study found a slightly lower BMI in boys with ADHD due to MPH.23 Weight reduction by MPH was only trended and not statistically significant in another study.24 A large meta-analysis of 38 cohort studies of 5524 participants up to 18 years of age found weight loss with an OR of 5.11 compared with placebo.5

10.3. Blood pressure unchanged

A comprehensive study found no impairment of blood pressure in boys with ADHD by MPH.27

10.4. Liver damage not known

There are no known increased reports of liver damage with MPH.28 Liver values should nevertheless always be monitored when discontinuing ADHD medications.

10.5. Reduced risk of stress fractures

MPH use by ADHD sufferers reduced the risk of stress fractures compared with nonaffected individuals (without MPH use).29

10.6. More common mild side effects

A large meta-analysis of 38 cohort studies of 5524 participants up to 18 years of age found the most common side effects to be sleep problems (OR 4.66), weight loss (OR 5.11), abdominal pain (OR 1.9), and headache (in 14% of MPH takers) compared with placebo.5 Sleep problems often result from dosing too late in the day, especially during single-dose administration. Very slow dosing can help avoid side effects. Most of these side effects resolve within the first few weeks.
For some sufferers, administration of a small unretarded dose (1/4 to 1/2 of a single daily dose) helps them fall asleep.6
One study that lasted 16 weeks found that MPH did not cause sleep problems.13 In contrast, a small study that looked at only 14 days found decreased sleep duration and delayed sleep onset in children treated with sustained-release MPH.14 This is consistent with the experience that sleep problems from MPH are possible but are usually only a single-dose side effect. We conclude that in case of sleep problems due to MPH during the first weeks, it might be helpful to shorten the daily coverage. Regardless, slow dosing in increments of max. 2.5 mg / single dose of unretarded MPH is always recommended.

One study reported a statistically significant increase in intraocular pressure of the left eye only by MPH in ADHD. No change in macular, retinal nerve fiber layer (RNFL), or ganglion cell layer (GCL) thickness was reported.30

10.7. Parkinson / tremor in old age

A very comprehensive study analyzed the likelihood of disorders from the Parkinson’s form group (simple tremor to Parkinson’s disease) in ADHD sufferers with and without stimulant use over decades of life.31

The study is highly interesting in terms of the results:

  1. ADHD increases lifetime likelihood of Parkinson’s(-like) disorder by 2.4-fold
  2. Parkinson’s(-like) disorders even more likely if ADHD sufferers had taken stimulants (6-fold)
  3. Parkinson’s(-like) disorders are 8 times more common in ADHD sufferers who received methylphenidate than in nonaffected individuals

To this end, it should be noted:

  1. The result contradicts a later long-term study (see below).
  2. The correlation is correct
  3. Causality is questionable
    Is Parkinson’s more likely in stimulant users or in more severe ADHD, which is more often treated with stimulants?
    The study design does not permit a statement on this. Other studies will be needed for this.
  4. The increased risk of comorbidity in ADHD is not limited to PD.
    The likelihood of early death is dramatically increased in untreated ADHD: from 0.8% in unaffected individuals to 2.3% in ADHD sufferers, or plus 1.5 percentage points

More revealing are the absolute figures.
Got a disorder of the basal ganglia or cerebellum (a disorder related to Parkinson’s disease (tremor) or Parkinson’s disease)

  • 56 of 24,792 non-ADHD sufferers = 0.23%

    • Of which 26 = 0.1 % with less than 50 years of age
    • Of which 19 = 0.08 % got Parkinson’s disease
  • 104 of 26,809 ADHD sufferers who were not known to be receiving stimulants = 0.39%

    • Of which 69 = 0.26 % with less than 50 years of age
    • Of which 38 = 0.14 % got Parkinson’s disease
  • 62 of 4960 ADHD sufferers known to be receiving stimulants = 1.25%

    • Of which 42 = 0.85 % with less than 50 years of age
    • Of which 19 = 0.38 % got Parkinson’s disease

60% of stimulant takers had received amphetamine medication, 40% methylphenidate. If the risk is 6-fold higher for all stimulant users and 8-fold higher for MPH, which was taken by only 40%, it must therefore be much lower than 4-fold for amphetamine drugs.

This means: the risk for Parkinson’s (related) disorder could be estimated to be

  • 1 % ADHD-HI with amphetamine medication
  • 2 % ADHD-HI with methylphenidate

So one could also - just as correctly - formulate:
The risk of developing Parkinson’s (like) disorder within 20 years is increased by 0.16 percentage points in people who have ADHD (0.16% more people develop Parkinson’s (like) disorder if they have ADHD than if they do not). If amphetamine medications are taken, the increase is increased by 1% points compared to non-affected people; if methylphenidate is prescribed, the risk is increased by 2% points.

Extrapolate that to 100,000 people:

  • 1.5% of 100000 is 1500 additional premature deaths from ADHD
  • 1% of 100000 is 1000 additional sufferers of disorders from the Parkinson’s form group (from a simple tremor to Parkinson’s) on amphetamine medication for ADHD (without knowing if this is due to the severity of the ADHD or the AMP).
  • 2% of 100000 are 2000 additional sufferers of disorders from the Parkinson’s form group (from a simple tremor to Parkinson’s) with methylphenidate in ADHD (without knowing if this is due to the severity of the ADHD or the MPH).

But if someone who has ADHD now has a choice,

  • With untreated ADHD to triple the risk of early death from 0.8% to 2.3% (absolute: plus 1.5 percentage points)
  • What medicines can largely fix
  • Or to accept an increased risk of Parkinson’s disease disorders (from simple tremor to Parkinson’s disease) by a factor of three to eight, but only by 1 to 2 percentage points in absolute terms,

most people would prefer to have a trembling hand when alive than a steady one when dead.

It further follows that if ADHD is treatable with amphetamine medications, they should be preferred over MPH.

Against this background, the formulation of the study results sounds somewhat tendentious or attention-seeking.
The study design would be perfect to show how much higher mortality is with medication. This - much more important question - is not answered, although these data should have jumped out at the authors. Likewise, it is not differentiated that with amphetamine medication the risk was only half as much increased as with methylphenidate, but only the higher number of methylphenidate was mentioned.

The increase in risk for disorders from the Parkinson’s form circle (from a simple tremor to Parkinson’s disease) by chronically overdosed MPH could result from an increased production of quinones and a decrease in glutathione (GSH, γ-L-glutamyl-L-cysteinylglycine).32 Chronic administration of 10 mg MPH/kg (approximately 10 times the maximum therapeutic amount in humans) promoted a loss of dopaminergic cells in the substantia nigra.33 Loss of dopaminergic cells could explain parkinsonian symptoms. This also suggests that high doses of MPH should be avoided if possible.

A German study found no evidence for a correlation of Parkinson’s disease and use of psychostimulants such as methylphenidate in childhood.34

Another long-term study found that in ADHD, stimulant prescriptions reduced the risk of Parkinson’s disease by 60%35

10.8. Psychosis risk slightly increased?

According to a very large study, the risk of developing psychosis is lower for ADHD sufferers taking MPH (0.10%) than for those treated with amphetamine medications (0.21%).36 While ADHD sufferers treated with stimulants have 2.4 psychosis cases per 1000 person-years (0.24%), the figure is 0.0214% over the entire population.37 The studies do not allow us to determine whether the increase in psychosis prevalence is due to the presence of ADHD or to the administration of stimulants. However, the doubling of risk with amphetamine medications over MPH preparations suggests that this is the case.

Another large study based on the Swedish health register with 23,898 adolescents and young adults with ADHD compared the risk of psychosis before and after MPH administration and found only a non-significant increase of 4% in the risk of psychosis with methylphenidate.38 This is consistent with another large cohort study that generally found a significantly increased risk of psychosis in ADHD. Stimulants increased this risk very slightly further (6%), while the increase from non-stimulants was almost three times higher than from stimulants, at 15%.39

The benefits of treating ADHD (reducing premature mortality, reducing lifetime risk of depression and anxiety disorders, reducing risk of addiction, etc.) significantly outweigh the potential risk.
More on the risks of (untreated) ADHD at Consequences of ADHD.

10.9. Seizure threshold lowered

Methylphenidate is said to be able to lower the seizure threshold. This applies to patients with a history of seizures (e.g. epileptics) as well as to patients with abnormalities in the EEG without previous seizures. Rarely, MPH is said to be able to trigger seizures even without the aforementioned previous risks.
Methylphenidate should be discontinued if seizure frequency increases or if new seizures occur.19

10.10. Stimulation of existing anxiety disorders, depression, aggression

Comorbid anxiety disorders, depression, and aggression may be exacerbated by stimulants because anxiety and moods are regulated by dopaminergic activity of the ventromedial PFC in conjunction with the limbic system. In these cases, norepinephrine reuptake inhibitors or α2A-adrenoceptor agonists are recommended instead.40
One (quite small) study found no short-term change in state anxiety with a single dose of MPH, but did find evidence of possible long-term worsening.41

10.11. MPH and mania risk in bipolar disorder

One study found that MPH was not associated with an increased risk of mania in patients with bipolar disorder. After MPH treatment, manias decreased by 50%. Depressive episodes and psychiatric admissions also decreased.42

10.12. MPH increases histamine

MPH increases histamine,43 as do all other known ADHD medications:

  • Atomoxetine
  • Amphetamine
  • Modafinil
  • Nicotine
  • Caffeine

Therefore, people with histamine intolerance often have problems by taking ADHD medications.
One ADHD sufferer with histamine intolerance reported that she could not tolerate AMP and sustained-release MPH at all, but could tolerate sustained-release MPH in small doses.

10.13. No increased cardiovascular risks

The hypothesis that methylphenidate would cause increased cardiac problems was not confirmed.44 Changes in EEG values were not found.22 A metastudy found slightly increased values below statistical significance.45

An initial study of n = 564 subjects, which had suggested an increased cardiac death rate in children taking MPH, was refuted by a large number of other studies, including a large study of n = 241,417 children medicated with MPH.46 One very large study found no increased risks of serious cardiovascular events such as stroke, myocardial infarction, or arrhythmia for MPH among 2,566,995 children.47
There are also studies that even confirm a reduced risk of cardiac death under MPH, which is explained by the medical care provided to those affected.

In adults, cardiovascular problems from MPH are said to be possible.48

One study found no significant change in heart rate, QRS, QT, QTc, and QTd interval in ECGs by MPH.
Tp-Te intervals and Tp-Te/QTc ratios were slightly increased after treatment with MPH but within normal values.49

10.14. Rebound

Rebound is the term used to describe a brief increase in symptoms that are actually reduced by MPH at the end of the medication’s effective period. If an MPH dose is effective for around 3 hours, ADHD symptoms may increase at the end of the 3 hours or immediately afterwards for around 20 to 30 minutes.
Rebound is reported more frequently and more clearly with unretarded MPH than with retarded MPH.50
Rebound is thought to be caused by a too rapid decline in dopamine / norepinephrine action levels. Rebound seems to occur less frequently with drugs that show a very slow decline in effect.

Rebound can be avoided by taking the follow-up dose in a timely manner so that no drug-free period remains.
For the last daily dose, it should be possible to mitigate or avoid rebound by taking a much smaller dose than the usual single dose at the time the subsequent dose would otherwise be taken.

10.15. Long-term effects of MPH

The reports known to us to date on the harmful effects of long-term use of MPH are all based on massive overdosage. Such studies are useful in exploring the limits of tolerability of an active ingredient. However, they say nothing about the dangers of long-term use in doses that are customary for medications.
To put this into perspective, humans need 30 to 40 ml of water per kg and day (2 to 3 liters). however, 3 liters of water at once or 5 liters of water a day can already have lethal effects. Accordingly, even a doubling of the administration of water can have lethal effects in humans.

With long-term administration of 15 to 20 times the daily dose used as a drug, one study found damage to cerebellar morphology and function in adult rats51

A study in rats given 5 mg/kg/day during puberty, five times the maximum daily dose used in humans, found impaired sperm quality in the adult animals.52 Moreover, these were Wistar rats, rats that are not deficient in dopamine.
In hyperactivity sufferers, no statistically significant difference in sperm count was found after methylphenidate use, but a significant difference was found in sperm motility and abnormality53

In one study, monkeys received 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 dosage usually recommended for humans and, in our view, represents a drug dose rather than a medication dose.
Except for a temporary reduction in motivation after the end of MPH administration (again, only at the “drug dose”), no negative effects were found 54
Twice 12.5 mg/kg/day also showed marked deterioration in cognitive performance, as expected with such overdoses.55

A study in primates found no change in brain parameters 6 months after cessation of 12 years of long-term administration of MPH.56

10.16. Other MPH side effects

Isolated cases of trichotillomania (pulling out hair) have been reported.57 Trichotillomania is a specific form of impulse control disorder.

One study reported muscle pain and stiffness as a possible side effect of MPH.58

11. Interactions and contraindications

As with any drug, there are contraindications to MPH.
Taking it without prior medical consultation is risky!

Methylphenidate is metabolized independently of the cytochrome P450 system, so there is very little potential for pharmacokinetic interactions.19

11.1. Interactions of methylphenidate with other medications

11.1.2. Enhanced effect of other drugs / substances by MPH

  • Caffeine can act more intensively
    Caffeine should be strictly avoided, especially when taking stimulants (e.g. MPH). Stimulants often cause caffeine in doses that were previously tolerated without problems to now trigger an inner tremor. This can be mistakenly interpreted as a (side) effect of the stimulants.
    A very high caffeine dose (tens of times above drug level) over several days decreased the efficacy of MPH in rats, and vice versa. This confirms that MPH and caffeine have common5960 but not identical61 mechanisms of action.

  • Alcohol
    An extensive meta-analysis found little evidence that ADHD medications would register particular negative effects when combined with alcohol or other drugs.62

    • Taken together with MPH, alcohol can have a more intense effect
    • Alcohol taken together with MPH may increase MPH levels63
  • All sympathomimetics64 can be enhanced by MPH.
    Active ingredients concerned:

  • Monoamine oxidase inhibitors (MAOIs)

    • Monoamine oxidase inhibitors (MAOIs) should not have been taken in the 14 days preceding MPH intake. Simultaneous use of MAOIs and methylphenidate may cause a sudden increase in blood pressure.6519
      • St. John’s wort is an MAOI66 and also inhibits COMT.
        With respect to St. John’s wort, there are suspected interactions with MPH.67
      • Tranylcypromine
        MPH should be avoided until 14 days after taking tranylcypromine19
  • Antihypertensive agents19

  • Halogenated anesthetic gases

    • Can trigger blood pressure spikes in patients taking methylphenidate.19 For planned surgical procedures, methylphenidate should not be used on the day of surgery.
  • All central dopaminergic and noradrenergic agents19
    In this case, blood pressure should be monitored closely.

    • Moclobemide
    • Linezolid
    • Selegiline
    • Rasagiline
    • Levodopa
    • Other parkinsonian drugs
    • Centrally acting α2-agonists, e.g.
      • Clonidine
      • Methyldopa

11.1.3. Inhibition of metabolism of other drugs by MPH

  • Anticonvulsants68
    • Phenobarbital6469
    • Phenytoin6469
    • Primidone64
    • Carbamazepine
      • 2 Anecdotal reports suggest that at least a doubling of the MPH dose may be required if high-dose carbamazepine is given at the same time69
    • Rifampin possibly69
      MPH reduces the effect of anticonvulsants64
      Anticonvulsants reduce MPH blood levels after a few weeks69
  • Tricyclic antidepressants19, e.g.:
    • Amitriptyline64
    • Imipramine64
      Methylphenidate enhances the effect of imipramine,69 while imipramine simultaneously enhances the effect of MPH. Therefore, particularly cautious dosing of imipramine is recommended with concomitant MPH administration.
      Symptoms are:
      • Confusion and agitation
      • Mood instability
      • Irritability and aggressiveness
      • Psychotic symptoms
  • Phenylbutazone (butazolidine)64
    Phenylbutazone is a nonsteroidal anti-inflammatory drug rarely used today.
  • Anticoagulants (blood clotting inhibitors)64
    • Oral anticoagulants of the coumarin type, e.g. phenprocoumon, warfarin
      Variations in effect are possible here due to interaction with methylphenidate. Mechanism is unknown. Close monitoring of coagulation parameters is therefore recommended when starting and stopping methylphenidate.19
  • Antihypertensives19, e.g.:
    • ACE inhibitors
    • Angiotensin receptor blocker
    • Diuretics
    • Calcium channel blocker
    • Beta-blocker
  • Metoclopramide (prokinetic, dopamine antagonist)19

11.1.4. Changes in the effect of MPH due to other drugs

An elevated gastric pH of 5.5 or higher can accelerate / increase the release of the active ingredient of the sustained-release portions of Medikinet adult. The release of methylphenidate from Ritalin adult, however, is pH-independent. With Ritalin adult, a reduction in absorption by antacids is nevertheless possible.19

The stomach pH can be increased by:

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

Chronic oral MPH alone produced in the striatum of rats a tendency to70

  • Increased dynorphin expression
  • Increased substance P expression
  • Unchanged enkephalin expression.

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

MPH and fluoxetine together caused

  • Strongly increased dynorphin expression
  • Strongly increased substance P expression
  • Increased enkephalin expression.

11.2. MPH and blood pressure

Methylphenidate may increase blood pressure in children.

In children with ADHD, blood plasma levels of nitric oxide appear elevated and of asymmetric dimethylarginine (ADMA) decreased. ADMA inhibits the blood pressure elevating effect of nitric oxide. With MPH ingestion, plasma nitric oxide levels further increased. This could possibly be due to decreased inhibition of nitric oxide by ADMA with MPH administration and could be a cause of the blood pressure elevating effect of MPH.48
In contrast, a comprehensive study found no impairment of blood pressure by MPH in boys with ADHD.27
In patients at risk for hypertension, it is therefore necessary to weigh the extent to which the possible risk of a drug-induced increase in blood pressure outweighs the possible benefit of reduced blood pressure due to decreased sensitivity to stress.

11.3. MPH intake during pregnancy

One study found no decreased weight of newborns of mothers with ADHD who took amphetamine medications during pregnancy.71 This is consistent with results from a large cohort study of MPH use during pregnancy.72
Another study comprehensive study found a slight reduction in birth weight and a slight increase in the risks of preeclampsia, placental abruption, or preterm birth with stimulant use (AMP or MPH) in pregnancy, but this was so small that the authors did not recommend discontinuing stimulant use in pregnancy.73 Atomoxetine did not show these slight increases in risk.
A Danish cohort study found a doubled risk of miscarriage with stimulant use during pregnancy.74
Another Danish cohort study found a very small increase in malformations in children born to mothers who had taken MPH in the first trimester of pregnancy. The authors described the risk increase as not relevant.75

A meta-analysis of 4 cohort studies found a small but statistically significant increase in the risk of malformations and cardiac malformations in children whose mothers had taken MPH in early pregnancy.76

A study in mice found increased ADHD symptoms in offspring by MPH administration during pregnancy. A 2.5- to 15-fold dosage (compared to the usual maximum drug level) caused decreased expressions of the D2 receptor and dopamine transporter genes common in ADHD.77 This is plausibly consistent with the model of brain developmental disorders caused by a deficiency of dopamine (e.g., genetically inherited or due to chronic stress) or an excess of dopamine (e.g., due to stimulant administration in unaffected individuals). For more, see Brain development disorder and ADHD In the chapter Emergence.

12. Possible contraindications

Caution should be exercised in the use of methylphenidate with19

  • Glaucoma
  • Hyperthyroidism
  • Thyrotoxicosis
  • Severe depression
  • Psychoses, e.g.
    • Schizophrenia
    • Mania
    • Bipolar disorder type I
  • Cardiomyopathies
    • Especially severe arrhythmias
  • Asthma78
  • Interstitial pneumonia or fibrosis78

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