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66% of ADHD-HI and ADHD-C subtype children require moderate to high dosing.12
The “last 10 mg” are particularly important in order to achieve an optimum effect.3
When adjusting the dosage, the increase in dosage should therefore not be stopped too early. Emotional depletion (“zombie”) is a sign of overdosing.
Adults require a significantly lower dosage, as 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 (immediate release) is recommended.
Methylphenidate is not dosed across the board “according to body weight”. There are people with ADHD 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 meta-analysis of 28 cohort studies on 5524 children and adolescents up to 18 years of age, in which the appropriate MPH dose was determined in stages, reported a range from 0.8 mg / kg / day to 1.8 mg / kg / day.5 In persons with ADHD 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
One study reports a large variability in the optimal dose level (here using OROS-MPH):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:8
1.5 % with 10 mg
2.0 % with 15 mg
16.8 % with 20 mg
27.7 % with 30 mg
25.2 % with 40 mg
17.8 % with 50 mg
8.9 % with 60 mg
A clinical study comparing fixed and flexible dosing confirmed the benefits of an individually adjusted dose.910
Blood levels of MPH vary greatly from individual to individual depending on the dose of MPH taken.11 The individual differences in effect are attributed to genetic differences in metabolization, among other things.1213
For adults (with a higher body weight), the required daily dose is usually significantly lower.
lower dosage for adults
Adults have far fewer dopamine transporters and therefore generally require less MPH than children. A dosage similar to that used in children can therefore already constitute an overdose in adults. Therefore, an even slower dosage in even lower steps (increase 2.5 mg to max. 5 mg immediate release / day, every 4 days) is recommended for adults. An overdose can cause exactly the symptoms that should actually be avoided, as the optimal dopamine level is already exceeded, which causes very similar signal transmission 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).
Persons with ADHD-I presentation and even more ASD sufferers seem to require lower doses particularly frequently.
We know of several cases of affected adults who are optimally dosed with a single dose of 1.25 mg of immediate release MPH.
In any case, it is advisable to use MPH to cover the entire day, but not the late evening and night.
Details
Taking MPH only once (in the morning) for 3 (immediate release) or 6 hours (sustained release) means that the person with ADHD is at the mercy of their stress sensitivity again afterwards. MPH should be used with caution in the last few hours before going to bed. Most people react with sleep problems. For some, however, a quarter to half dose of stimulants enables them to fall asleep because it stops their thoughts from racing. It is possible that a low dose of immediate release stimulants could be helpful for people who already have low arousal. These are people who, for example, find it helpful to have a radio or television playing in the background to help them concentrate better. For others, listening to audio books helps them to fall asleep. People with a high arousal tend to need absolute quiet in order to be able to concentrate.
For the different duration of action of the individual MPH drugs, see below under 7.
Slow and persistent dosing is important. In our opinion, the usual dosing practice in Germany is far too fast.
In principle, MPH should be dosed low at the start of the test and the dosage should only be increased slowly. Even if the optimal dosage were known, an immediate optimal dosage would possibly lead to excessive demands14 and side effects.15
The dosage setting should start with 2.5 mg to a maximum of 5 mg / 3-4 hours, which should only be increased to 3 x 5 = 15 mg / day within the first few days. Tests with higher starting dosages not only produced no better, but even worse efficacy results and at the same time resulted 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.616141517 Since such small dosing increments do not harm other people with ADHD (but on the contrary help to avoid dosing side effects), dosing increments in 2.5 mg steps (based on an immediate release single dose of MPH) should be the gold standard. So does Kühle. A large meta-analysis points in the same direction. Other sources recommend starting with 1-2 single doses of 5 mg and increasing the single dose weekly in 5 mg increments. For the reasons mentioned, we consider these dose increments to be too large.18171920
For people with ADHD for whom even extremely small differences in dose are crucial, a pharmacy in Switzerland offers MPH drops. One drop contains 0.35 mg MPH. It is produced in batches and preserved using E216 and E218.21 A person with ADHD reported that dissolving immediate release MPH in alcohol in such exact quantities that they could be measured out per drop showed a comparable result.
Inform people with ADHD and observing third parties about the duration of action of the respective preparation and the expected rebound.
We consider up-dosing by 2.5 mg per single dose every 5 to 7 days to be sensible. We now consider dosage increments of 5 mg / single dose, as we used to consider acceptable here, to be too high, because there is a relevant proportion of people with ADHD for whom 2.5 mg less means underdosing and 2.5 mg more means overdosing.17 Even if this only represents a minority of people with ADHD, it would be malpractice to increase the dosage more quickly, as it is never possible to predict which group a person with ADHD belongs to. See also below: Gene variants influence MPH dosage.
The younger a person with ADHD is and the less they notice the MPH dose at all, the sooner the dosage increments can be increased.
In the course of adjustment, the dose is increased until the characteristics of an overdose are intensified with the next and subsequent dose increases. The dose that optimally reduces the symptoms without causing side effects can then be determined.
Unfortunately, there are known cases in which doctors have started discontinuation with single doses of 15 or 20 mg. We strongly advise against this.
Even if this were the right dosage for a few people with ADHD, the risk of suffering considerably more severe side effect problems in the first few weeks with such a high starting dosage would be significantly higher than with a slower adjustment.
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 any problems, can suddenly trigger internal tremors and other symptoms when taken simultaneously with stimulants, which can then be misinterpreted as a side effect of the medication. When new doses of stimulants are taken, caffeine can trigger a sensation similar to an overdose. Once the stimulants have been dosed, caffeine can be tried again. Sensations of discomfort can then be correctly attributed to caffeine.
Nicotine withdrawal started at the same time as dosing can falsify the result. The need for cigarettes often decreases of its own accord after taking stimulants.
Similarly, restarting nicotine intake during stimulant dosing should be avoided.
As 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 indicated for adults than for children.
A small proportion of people with ADHD require a significantly lower dosage of MPH.
The CES1 polymorphism Gly143Glu was found in 5.8% of people with ADHD and 4.1% of the population. No cases of CES1 Glu143Glu (homozygous) were found among 441 children.
CES1 Gly143Glu showed an unchanged reduction in inattention and hyperactivity-impulsivity on MPH.
Carriers of the CES1 143Glu variant (5.56%) required almost 30% lower doses of MPH to reduce symptoms.23
More on the influence of CES1 gene variants on the effect of MPH at Influences on the potency of MPH In the article MPH Part 3: Degradation, potency.
6.4. Side effects when discontinuing methylphenidate¶
In the first few days, taking the medicine can feel like snow has fallen - everything is wrapped in absorbent cotton. This (usually very pleasant) impression is due to the reduction in sensory overload and, like most side effects, disappears within a few days.
Others describe the initial effect with the impressive experience that for the first time in their lives their heads are calm and their thoughts are not racing.
To date, no known study in adults has explicitly prohibited the consumption of caffeine during dosing. Since caffeine drastically increases the rate of side effects during dosing, the rate of side effects should be significantly reduced if caffeine intake is consistently avoided compared to the study results.
Headaches can sometimes be reduced or avoided by drinking enough and eating regularly (possibly glucose). As stimulants reduce the feeling of hunger, this can contribute to reduced fluid and food intake, which can also cause headaches.
One study found that MPH did not cause sleep problems. This could differ from the results of other studies possibly because this study lasted a relatively long 16 weeks, so that the acclimatization side effects were no longer noticeable.24 In contrast, a small study looking at just 14 days found reduced sleep duration and delayed sleep onset in children treated with sustained release MPH.25
With an appropriate dosage of MPH, the ability to concentrate increases and the internal pressure and any hyperactivity present decrease. If the latter increases again when the dosage is increased, this is a sign that the dosage is too high.
Methylphenidate closes the stimulus filter (which is too wide open in people with ADHD). A typical reaction of people with ADHD with the right dosage is that they come to themselves, that they are more themselves.
If the person with ADHD notices that MPH makes them jittery (although neither caffeine (theine is just another name for caffeine) nor theobromine (dark cocoa) is consumed), the dose should still be increased carefully at first. It has been observed several times that such side effects disappear again after a few days or at the next higher dose. If this shakiness persists, the dosage is too high. This also applies if the concentration becomes too high, i.e. the stimulus filter is restricted too far. Restricted emotionality (“zombie effects”) is a clear indication of an overdose.
A study on monkeys concluded that low doses of MPH reduce impulsivity, while higher doses have a sedative effect.26
This follows on from empirical experience that people with ADHD, especially children, can sometimes appear apathetic when taking MPH. Following this study, this indicates an overdose.
6.6. Try different MPH medications even if MPH is effective, especially in the case of side effects / non-responding¶
Many people with ADHD report that they experience side effects with one MPH preparation that they do not experience with another MPH preparation. There are reports on this side that one MPH preparation (here: Medikinet) showed no effect, while another (here: Concerta) responded well.
Other people with ADHD report that they experienced increased aggression with one drug (here: Concerta), which did not occur with another MPH drug (Medikinet or immediate release MPH).
Others experience a stronger rebound effect with Medikinet (increased agitation when the effect wears off) than with other MPH preparations.
The various MPH preparations have very different release times, and MPH is embedded in different carriers depending on the manufacturer.
In the case of an existing gluten intolerance, MPH embedded in wheat starch is naturally unsuitable. The same may apply to lactose intolerance.
If a satisfactory effect is not achieved with all MPH preparations (the typical non-responder rate is just under 30%), medication with amphetamine drugs should always be used. In this way, a further 70 to 80 % of MPH non-responders can be satisfactorily medicated, so that the overall non-responder rate for MPH and AMP falls to below 10 %.
If dysthymia or depression persists despite the satisfactory effect of MPH, a switch to amphetamine medication can also be considered, as 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. Accompanying circumstances of recruitment and intake¶
Some people with ADHD always need their MPH medication at exactly the same time.
Care should be taken to ensure that the entire day is covered. However, the last doses of the day must be taken early enough so that there is no effect at bedtime.
Details
During the adjustment to MPH, caffeine (coffee, black tea), theobromine (dark cocoa) and alcohol should be completely avoided, as these can increase the effect of stimulants. Many people with ADHD report that MPH makes them much more sensitive to such stimulants. A jitteriness can therefore be triggered by caffeine, whereas the same amount of caffeine without MPH had no such effect. Like antidepressants, MPH often causes mild side effects (dry mouth etc.) in the first few days or weeks of taking it, which soon subside.
To prevent or alleviate loss of appetite, it is recommended to take it with or after meals.
MPH can also have an effect on people not suffering from ADHD. It can (in low doses) increase attention, just as mild stress increases cognitive performance by slightly increasing noradrenaline and dopamine in the PFC.
A higher dosage in unaffected people (such as a low dosage in people who already have slightly elevated dopamine or noradrenaline levels) can cause DA and NE levels to become so elevated that ADHD symptoms are induced.
In ADHD, the (tonic) dopamine level in the striatum is too low, which causes a number of ADHD symptoms. MPH increases the dopamine level in the striatum to the optimum level when dosed correctly. However, if the dopamine level is increased beyond the optimal level - by overdosing in people with ADHD 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.27
The increase in dopamine in the dorsal striatum (but not in the nucleus accumbens) following amphetamine administration is higher in both male and female rats if they have previously been exposed to chronic uncontrollable stress. This could indicate a different dopaminergic response to stimulants (ADHD medication) in persons with ADHD and chronic stress.28
There is no explicit restriction on the approval of methylphenidate for the elderly. The MPH product information contains a note that MPH should not be prescribed to older people. There is no such indication for lisdexamfetamine, despite equally inadequate data.
Treatment with MPH at an older age should nevertheless be able to constitute an off-label prescription.29
There are no indications that MPH would cause difficulties in old age.
A small study reports good tolerability in older people with ADHD.30 MPH is also used for age-related depression31
6.10. International guidelines for treatment with methylphenidate¶
“Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents”, guideline of the American Academy of Pediatrics3233
Children, adolescents:
Start: with a low dose, especially in children, as they metabolize the drug more slowly and respond differently to it
Increase in 7-day increments (in urgent cases in 3-day increments)
Goal: Dose with optimal efficacy and minimal side effects.
This guideline does not specify dosage levels.
In treatment-resistant cases also combination medication.
Children, teenagers, adults:34
Start with low doses of medication, slowly increasing the dose until the dose that improves symptoms and functioning and has a good side effect profile is reached.
Joint selection of suitable medication by doctors and people with ADHD / legal guardians.
Individually suitable medication selection
Dose titration under regular medical review of progress in terms of symptoms, functional levels and adverse effects
Optimal dose: Dose at which symptoms are reduced and functional outcomes are improved, with minimal adverse effects
6.10.4. New Zealand: Guidelines of the New Zealand Ministry of Health, 2001¶
The New Zealand guidelines do not appear to be freely available on the Internet. There are only reproductions with unclear copyright.
Children, teenagers and adults:
Dosing starting at the lower end of the dose range (approximately 0.1 to 0.2 mg/kg MPH or 0.05 to 0.1 mg/kg DAMP).
Individual titration as required
Speed of titration according to the intensity of the treatment effect and side effects
Optimal dose: smallest dose for an optimal therapeutic response
Maximum dose:
MPH: 60 mg/day for adolescents and children
AMP: 20 mg/day younger children; 40 mg/day older children
If there is no improvement
Check compliance with the medication regime
Adjust dosage
Change active ingredient
Medication treatment with stimulants (MPH or dextroamphetamine) is the first choice.
Further interventions (including behavioral therapy) only if there is still a need for them after a few months of optimally titrated medication.
Children, teenagers, adults:37
Start with a low dose (0.2 mg/kg/dose for children and adolescents)
Increase until good results are achieved, or adverse effects occur, or maximum dose is reached (0.7 mg/kg/dose for children and adolescents) - whichever occurs first
Children, teenagers, adults:38
Start: low starting dose
Titration: 10 mg titration steps of half-day retarded MPH
Increase until no further clinically significant improvement in symptoms (e.g. at the level of core symptoms, but also in terms of a change in problem behavior) can be achieved and the adverse effects remain tolerable
Goal: lowest possible dosage
The 2009 guideline stated:“For stimulants: No strict correlation between body weight and necessary dose!(evidence level IIa). Always individual titration. The stated mg/kg bw are average values and can be individually under- or exceeded.”39
MPH:
While the guidelines for MPH stipulate dosing in 10 mg titration steps of half-day-retained MPH, we consider half as fast titration to be sensible with Kühle - even if this challenges the persistence of some people with ADHD. For this purpose, immediate release MPH (2.5 mg / single dose) or sustained release MPH (5 mg / single dose, which corresponds to 2 consecutive doses of 2.5 mg immediate release MPH due to the double duration of action) can be used.
6.10.8. Great Britain: BAP Guidelines, 2007, 2014¶
Children, teenagers, adults:4041
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
In treatment-resistant cases also combination medication.
6.10.9. England and Wales: NICE guidelines, 2016, 2018¶
Children, adolescents:42
Initial treatment starting with low doses
immediate release 5 mg two or three times a day, or
sustained release
Titration depending on symptoms and side effects over 4-6 weeks until dose optimization
Maximum dose: 60 mg/day
Adults:
Initial treatment starting with low doses
immediate release 5 mg three times a day
sustained release: corresponding dose
Titration depending on symptoms and side effects over 4-6 weeks until dose optimization
Maximum dose: 100 mg/day
Children, adolescents:45
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 pm)
Gradual increase by 2.5 to 5 mg per week, depending on clinical response and side effects
Dose range: 0.5 to 2 mg/kg/day
Maximum dose: 60 mg/day
The “Swedish Medical Products Agency ADHD drugs - treatment guide-lines” Do not appear to be publicly available. Reproduced from Huss et al.13
Children, adolescents:
Start with low doses (18 mg for long-acting medication; 5-10 mg for medium-acting medication)
Gradual adjustment (approx. once a week)
Goal: Dose that shows good effect and is 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 (approx. once a week)
Goal: Dose with the best balance between efficacy and side effects
Maximum dose: 80 mg/day
Methylphenidate is the first choice of medication for children. It combats the symptoms of ADHD significantly better than one year of behavioral therapy. Comparable effects are only achieved after 3 years of behavioral therapy.
Since stimulants establish or increase the ability to learn and engage in therapy, it makes sense to initially work acutely with stimulants in order to create the basis for discontinuing them in parallel by means of behavioral therapy and/or neurofeedback.
The mean Effect size of MPH for ADHD is between 0.9 and 1.3.
MPH medication in combination with noradrenergic medication or zinc can further improve the effect. However, a cautious approach is recommended here. It is advisable to consult a doctor with experience in medication for ADHD.
At an appropriate dosage, the effects of MPH give people with ADHD the feeling that they are much more themselves than before. If a person with ADHD feels that stimulants make them feel less like themselves, this is a serious indication of misdosing, misuse or misdiagnosis.
A Cochrane meta-analysis of MPH in children (mean age 9.7 years) found slightly less severe side effects with MPH than with placebo (OR = 0.91, k = 9, n = 1,532).46
10.1.2. Slightly increased risk of mild side effects (+ 29 %)¶
A Cochrane meta-analysis of 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).46
10.1.3. No serious side effects with long-term use¶
A systematic review found no serious side effects of long-term MPH use.47
Common side effects of MPH can include
(Common: occur in 1 to 10 %; 90 to 99 % of people medicated with MPH do not have these side effects)
Affect instability (mood swings)
Aggression
Agitation
Alopecia (hair loss)
Fear
Anorexia (weight loss, lack of weight gain)
One comprehensive study found a slightly lower BMI in boys with ADHD on MPH.48 In another study, the weight reduction due to MPH was only trended and not statistically significant.49 A large meta-analysis of 38 cohort studies on 5524 participants up to 18 years of age found weight loss with an OR of 5.11 compared to placebo.5
abnormal behavior
Arrhythmia (cardiac arrhythmia; heart beats too quickly, too slowly or irregularly)
Arthralgia (joint pain)
Abdominal pain
Depression
Diarrhea
Dyskinesia (disorders of the movement sequence)
Vomiting
Skin rash
Cough
Hypertension (high blood pressure)
A comprehensive study found no adverse effect of MPH on blood pressure in boys with ADHD.50
Stomach complaints
Dry mouth
Nasopharyngitis (inflammation of the nose/throat)
Palpitations (subjective feeling that the heart is beating too fast / too strongly / irregularly)
Pruritus (itching)
psychomotor hyperactivity
frequent signs of overdose
Pyrexia (fever)
Throat and larynx pain
Irritability
Sleep problems
Problems falling asleep
Advice on taking too late in the day
Daytime tiredness
Dizziness
Tachycardia (heart rate over 100 beats / minute)
Nausea
Urticaria (hives)
Growth retardation with prolonged use in children.
Most of the side effects mentioned are non-specific and do not play a major role in practice51
A comparison of the side effects with the package insert for aspirin or SSRI is recommended for classification.
A large meta-analysis of 38 cohort studies involving 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 headaches (in 14% of MPH takers) compared to placebo.5 Sleep problems are often caused by dosing too late in the day, especially when starting dosing. Very slow dosing can help to avoid side effects. Most of these side effects disappear within the first few weeks.
For some people with ADHD, the administration of a small immediate release dose (1/4 to 1/2 of a single daily dose) helps them to fall asleep.6
A study that lasted 16 weeks found that MPH did not cause sleep problems.24 In contrast, a small study that looked at only 14 days found reduced sleep duration and delayed falling asleep in children treated with sustained release MPH.25 This is consistent with the experience that sleep problems are possible with MPH, but are usually only a side effect of dosing. We conclude that in case of sleep problems due to MPH during the first weeks, it might be helpful to shorten the daytime coverage. Regardless of this, slow dosing in increments of max. 2.5 mg / single dose of immediate release MPH is always recommended.
One study reported a statistically significant increase in intraocular pressure of only the left eye due to MPH in ADHD. A change in the thickness of the macular, retinal nerve fiber layer (RNFL) or ganglion cell layer (GCL) was not reported.52
Most side effects only occur shortly after starting the medication and regularly disappear within the first four weeks. The short-term feeling of a dry / furry tongue shortly after taking the medication may last longer, but it goes away quite reliably at some point.
Tic disorders are observed with overdoses. If people with ADHD have the feeling for months that the world is moving away or that life is becoming monotonous, this is also a clear indication of overdose.
10.1.5. Side effects primarily with comorbid anxiety or other comorbidities¶
Several studies have found that adverse reactions to stimulants occur primarily in people with ADHD with higher anxiety levels and faster reaction times or pre-existing comorbidities.5354
No correlation with EEG values was found.54
Several comprehensive studies have found no persistent impairment of length growth in boys with ADHD by MPH.48
A temporary impairment of longitudinal growth in the first year of MPH treatment was recovered in the second year.49 Temporary impairment of longitudinal growth is common in ADHD in childhood and is regularly recovered in adolescence. This is apparently not a specific effect of methylphenidate.55 Another study found a 4-fold increased risk of reduced length growth and weight gain in children with ADHD at ages 8 and 10. The length of stimulant treatment increased this risk.56
A very comprehensive study analyzed the probability of disorders from the Parkinson’s disease spectrum (simple tremor to Parkinson’s disease) in people with ADHD with and without stimulant use over decades of their lifetime.57
The results of the study are extremely interesting:
ADHD increases the lifetime likelihood of Parkinson’s (-like) Disorder by 2.4 times
Parkinson’s (-like) disorders are even more likely if the persons with ADHD had taken stimulants (6-fold)
Parkinson’s (-like) disorders are 8 times more common in persons with ADHD who were given methylphenidate than in non-affected persons
It should be noted:
The result contradicts a later long-term study (see below).
The correlation is correct
Causality is questionable
Is Parkinson’s more likely in stimulant users or in more severe ADHD, which is more commonly treated with stimulants?
The study design does not allow a statement on this. Other studies will be needed for this.
The increased risk of comorbidity in ADHD is not limited to Parkinson’s.
The probability of early death is drastically increased with untreated ADHD: from 0.8% for people without ADHD to 2.3% for people with ADHD, i.e. plus 1.5 percentage points
The absolute figures are more revealing. Disorder of the basal ganglia or cerebellum (a disorder related to Parkinson’s (tremor) or Parkinson’s disease) got
56 of 24,792 non-ADHD persons with ADHD = 0.23 %
Of which 26 = 0.1 % with less than 50 years
Of which 19 = 0.08 % developed Parkinson’s disease
104 of 26,809 persons with ADHD who were not known to be receiving stimulants = 0.39 %
Of which 69 = 0.26 % with less than 50 years
Of which 38 = 0.14 % developed Parkinson’s disease
62 of 4960 persons with ADHD who were known to be receiving stimulants = 1.25%
Of which 42 = 0.85 % with less than 50 years
Of which 19 = 0.38 % developed Parkinson’s disease
60% of stimulant users had taken amphetamines and 40% had taken 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 significantly lower than 4-fold for amphetamine drugs.
This means that the risk of Parkinson’s (related) Disorder could be estimated to be
1 % for ADHD, treated with amphetamine medication
2 % for ADHD, treated with methylphenidate
One could also - just as correctly - formulate this:
The risk of developing a Parkinson’s (related) Disorder within 20 years is increased by 0.16 percentage points in people who have ADHD (0.16% more people develop a Parkinson’s (related) Disorder if they have ADHD than if they do not). If amphetamine medication is taken, the increase is 1 percentage point higher compared to those who are not affected; if methylphenidate is prescribed, the risk is increased by 2 percentage points.
If you convert that to 100,000 people:
1.5% of 100,000 are 1500 additional premature deaths due to ADHD
1% of 100000 is 1000 additional people with ADHD (from a simple tremor to Parkinson’s) on amphetamine medication for ADHD (without knowing whether this is due to the severity of the ADHD or the AMP).
2% of 100000 is 2000 additional people with ADHD (from a simple tremor to Parkinson’s) on methylphenidate for ADHD (without knowing whether this is due to the severity of the ADHD or the MPH).
But if someone who now has ADHD has a choice,
With untreated ADHD tripled the risk of early death from 0.8% to 2.3% (absolute: plus 1.5 percentage points)
What medication can largely remedy
Or to accept an increased risk of Parkinson’s type disorders (from a simple tremor to Parkinson’s disease) by a factor of three to eight, but in absolute terms only by 1 to 2 percentage points,
most people would prefer to have a trembling hand when alive than a steady one when dead.
It also follows that if ADHD is treatable with amphetamine medications, these should be preferred over MPH.
Against this background, the wording 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. However, this - much more important - question is not answered, even though this data should have really jumped out at the authors. Similarly, no differentiation is made between the fact that the risk was only half as high with amphetamine medication as with methylphenidate, but only the higher figure for methylphenidate was mentioned.
The increase in the risk of Parkinson’s type disorders (from a simple tremor to Parkinson’s disease) due to chronic overdose of MPH could result from an increased production of quinones and a decrease in glutathione (GSH, γ-L-glutamyl-L-cysteinylglycine).58Chronic 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.59 A loss of dopaminergic cells could explain Parkinson’s symptoms. This also indicates that high doses of MPH should be avoided if possible.
A German study found no evidence of a correlation between Parkinson’s disease and the use of psychostimulants such as methylphenidate in childhood.60
Another long-term study found that stimulant prescriptions for ADHD reduced the risk of Parkinson’s disease by 60%61
According to a very large study, the risk of developing psychosis is lower for people with ADHD taking MPH (0.10%) than for those treated with amphetamine medication (0.21%).62 While people with ADHD treated with stimulants have 2.4 cases of psychosis per 1000 person-years (0.24%), the figure for the population as a whole is 0.0214%.63 The studies do not allow any statement to be made as to whether the increase in the prevalence of psychosis is due to the existence of ADHD or to the administration of stimulants. However, the doubling of the risk due to amphetamine medication compared to MPH preparations indicates this.
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 in the risk of psychosis due to methylphenidate at 4%.64 This is in line with another large cohort study, which found a significantly increased risk of psychosis in ADHD in general. Stimulants further increased this risk very slightly (6%), while the increase of 15% for non-stimulants was almost three times as high as for stimulants.65 If anything, high doses of MPH appear to increase the risk of psychosis.66
The benefits of treating ADHD (reduction in premature mortality, reduction in lifetime risk of depression and anxiety disorders, reduction in risk of addiction, etc.) significantly outweigh the potential risk.
More about the risks of (untreated) ADHD at ⇒ Consequences of ADHD.
Treatment with MPH increases the risk of anorexia by 4.66 times.67
Treatment with stimulants should therefore be avoided in people with ADHD with anorexia tendencies.
Methylphenidate is said to be able to lower the seizure threshold. This applies to patients with an existing history of seizures (e.g. epileptics) as well as patients with abnormalities in the EEG without previous seizures. In rare cases, MPH can trigger seizures even without the aforementioned previous risks.
If the frequency of seizures increases or if new seizures occur, methylphenidate should be discontinued.68
10.7. Stimulation of existing anxiety disorders, depression, aggression¶
Comorbid anxiety disorders, depression and aggression can be exacerbated by stimulants, as anxiety and moods are regulated by the dopaminergic activity of the ventromedial PFC in conjunction with the limbic system. In these cases, noradrenaline reuptake inhibitors or α2A-adrenoceptor agonists are recommended instead.69
One (quite small) study found no short-term change in state anxiety with a single dose of MPH, but did find evidence of a possible long-term worsening.70
One study found that MPH was not associated with an increased risk of mania in patients with bipolar Disorder. After MPH treatment, mania decreased by 50 %. Depressive episodes and psychiatric admissions also decreased.71
MPH increases histamine,72 as do all other known ADHD medications:
Atomoxetine
Amphetamine
Modafinil
Nicotine
Caffeine
Therefore, people with histamine intolerance often have problems due to taking ADHD medication.
A person with ADHD with histamine intolerance reported that she could not tolerate AMP and sustained release MPH at all, but could tolerate immediate release MPH in small doses.
A rebound is a short-term increase in symptoms that are actually reduced by MPH at the end of the medication’s effective period. If a dose of MPH works for around 3 hours, ADHD symptoms may increase for around 20 to 30 minutes at the end of the 3 hours or immediately afterwards.
Rebound is reported more frequently and more clearly with immediate release MPH than with sustained release MPH.73
We assume that a rebound is caused by too rapid a decline in dopamine/noradrenaline levels. A rebound seems to occur less frequently with drugs that show a very slow decline in effect.
A rebound can be avoided by taking the follow-up dose in good time so that no drug-free period remains.
In the case of the last daily dose, the rebound should be mitigated or avoided by taking a much smaller dose than the usual single dose at the time when the subsequent dose would otherwise be taken.
In the case of surgery, in addition to the sometimes significantly increased (drug) sensitivity of people with ADHD, the question of cross-effects of ADHD drugs with anesthetics must also be considered.
A double-blind study from 1980 found no change in postoperative pain with MPH. Methylphenidate shortened postoperative sedation by up to 30 minutes and improved respiratory function by up to 180 minutes with halothane anesthesia.74 Halothane is no longer used today.
One case study reports a reduced response to sedatives and increased side effects due to MPH.75
One study reports a correlation between attention problems and postoperative delirium.76
Individual cases of trichotillomania (pulling out hair) have been reported.77 Trichotillomania is a specific form of impulse control disorder.
One study reported muscle pain and stiffness as a possible side effect of MPH.78
One study reported a doubled rate of testosterone deficiency in adult persons with ADHD after 5 years of stimulant use (1.2%) compared to persons with ADHD without stimulant use (0.67%) or non-stimulant use (0.68%).79
The hypothesis that methylphenidate would cause increased heart problems was not confirmed.80 Changes in EEG values were not found.54 A meta-analysis found slightly increased values below statistical significance.81
An initial study with n = 564 people with ADHD, which had suspected an increased cardiac death rate in children taking MPH, was refuted by a large number of other studies, including a large study with n = 241,417 children taking MPH.82 A very large study found no increased risk of serious cardiovascular events such as stroke, heart attack or cardiac arrhythmia for MPH among 2,566,995 children.83
There are also studies that even confirm a reduced risk of cardiac death under MPH, which can be explained by the medical care provided to people with ADHD.
Several studies found no significant change in heart rate, QRS, QT, QTc and QTd interval in ECGs due to MPH.
The Tp-Te intervals and Tp-Te/QTc ratios were slightly increased after treatment with MPH, but within normal values.84 Children with ADHD showed significantly prolonged P-wave dispersion, TpTe interval, TpTe dispersion, and TpTe/QT and TpTe/QTc ratios. In addition, almost half of the patients had QTc values of 460 ms or more. These parameters were neither associated with the MPH dose nor with the duration of treatment.85
One study found no increased risk of cardiac arrhythmias for methylphenidate. However, an increased risk of cardiac arrhythmia was found for atomoxetine for 7 days after the first exposure to atomoxetine (aIRR 6.22) and for subsequent exposure (aIRR 3.23).86
A study over 14 years found a 4% increase in the risk of cardiovascular problems for each year of taking stimulants (methylphenidate, amphetamine drugs) and, to a lesser extent, for the non-stimulant atomoxetine.87
A cohort study of n = 252,382 with an average age of 20 years found a posterior probability of at least 10% increased risk of cardiovascular events of 70% in people receiving MPH compared to 49% in matched controls. There was no difference in risk between people with and without a history of cardiovascular events.88
In adults, cardiovascular problems are said to be possible due to MPH.89
The reports known to us to date on the harmful effects of long-term use of MPH are all based on massive overdoses. Such studies are usually useful to test the limits of the tolerability of an active ingredient. However, they say nothing about the dangers of long-term use at normal doses.
To put this into perspective: humans need 30 to 40 ml of water per kg per day (2 to 3 liters). however, 3 liters of water at once or 5 liters of water per day can already have a lethal effect. This means that even doubling the amount of water given to humans can have fatal effects.
A large-scale, long-term study of MPH over 2 years in children with ADHD found in the MPH group:91
no significant impairment of growth
slight weight loss in the first 6 months, which then subsided
no change in relation to psychosis, depression, dyskinesia, tics
slightly elevated blood pressure and pulse
preventive effect in relation to addiction and suicide
significantly increased nicotine and marijuana use in the non-MPH group
significantly increased suicidal tendencies in the non-MPH group
A study in primates found no change in brain parameters 6 months after the end of 12 years of long-term administration of MPH.92
A study in adult rats found damage to the morphology and function of the cerebellum after long-term administration of 15 to 20 times the usual daily dose.93 This is as expected for such doses.
A study on rats that received 5 mg/kg/day, five times the maximum daily dose normally given to humans during puberty, found that sperm quality was impaired in the adult animals.94 These were also Wistar rats, i.e. rats that do not have a dopamine deficiency.
No statistically significant difference in sperm count was found in people with ADHD after taking methylphenidate, but there was a significant difference in sperm motility and abnormality95
In one study, monkeys were given 2.5 mg/kg or 12.5 mg/kg MPH twice daily. 12.5 mg/kg twice daily is around 25 times the maximum dose usually recommended for humans and, in our view, represents a drug dose rather than a medication dose.
Apart from a temporary reduction in motivation after the end of MPH administration (again, only with the “drug dose”), no negative effects were found 96
At twice 12.5 mg/kg/day, there was also a significant deterioration in cognitive performance, as would be expected with such an overdose.97
As with any medication, there are also contraindications for MPH.
Taking it without prior medical consultation is risky!
Methylphenidate is metabolized independently of the cytochrome P450 system, so that there is only a very low potential for pharmacokinetic interactions.68
11.1. Interactions of methylphenidate with other medications¶
11.1.1. Enhanced effect of other drugs / substances due to MPH¶
Caffeine can have a more intensive effect
Caffeine should be strictly avoided, especially when taking stimulants (e.g. MPH). Stimulants often cause caffeine in doses that were previously tolerated without any problems to now trigger inner tremors. This can be wrongly interpreted as a (side) effect of the stimulants.
A very high dose of caffeine (tens of times above drug level) over several days reduced the efficacy of MPH in rats, and vice versa. This confirms that MPH and caffeine have common,99100 but not identical101 mechanisms of action.
Alcohol
A comprehensive meta-analysis found little evidence that ADHD medication in combination with alcohol or other drugs would have any particular negative effects.102
When taken together with MPH, alcohol can have a more intensive effect
Alcohol taken together with MPH can increase MPH levels103
All sympathomimetics104 can be strengthened by MPH.
People with ADHD:
No monoamine oxidase inhibitors (MAOIs) should have been taken in the 14 days prior to taking MPH. Taking MAOIs and methylphenidate at the same time can result in a sudden increase in blood pressure.10568
St. John’s wort is a MAOI106 and also inhibits COMT.
With regard to St. John’s wort, there are suspected interactions with MPH.107
Tranylcypromine MPH should be avoided for up to 14 days after taking tranylcypromine108
Can trigger blood pressure spikes in patients taking methylphenidate68 Methylphenidate should not be used on the day of surgery for planned surgical procedures.
All centrally dopaminergic and noradrenergic active ingredients68
Blood pressure should be closely monitored in this case.
Examples:
Moclobemide
Linezolid
Selegiline
Rasagiline
Levodopa
Other Parkinson’s remedies
Centrally acting α2 agonists, e.g.
Clonidine
Methyldopa
11.1.2. Inhibition of the metabolism of other drugs by MPH¶
2 individual case reports indicate that at least a doubling of the MPH dose may be necessary if high doses of carbamazepine are given at the same time110
Rifampin possibly110 MPH reduces the effect of anticonvulsants104 Anticonvulsants reduce the MPH blood level after a few weeks110
Imipramine104
Methylphenidate enhances the effect of imipramine,110 while imipramine also enhances the effect of MPH. Therefore, a particularly cautious dosage of imipramine with simultaneous MPH administration is recommended.
Symptoms are:
Confusion and agitation
Mood instability
Irritability and aggressiveness
Psychotic symptoms
Phenylbutazone (Butazolidine)104
Phenylbutazone is a non-steroidal anti-inflammatory drug that is rarely used today.
Oral anticoagulants of the coumarin type, e.g. phenprocoumon, warfarin
Fluctuations in effect are possible here due to interaction with methylphenidate. The mechanism is unknown. Close monitoring of coagulation parameters is therefore recommended when starting and stopping methylphenidate.68
11.1.3. Changes in the effect of MPH due to other medications¶
An increased gastric pH above 5.5 can accelerate / increase the release of the sustained release components of Medikinet adult. The release of methylphenidate from Ritalin adult, however, is pH-independent. Nevertheless, a reduction in absorption is possible with Ritalin adult due to antacids.68
The stomach pH value can be increased by:
Proton pump inhibitors, e.g.
Pantoprazole
Omeprazole
H2 antagonists (although less likely), e.g.
Ranitidine
Famotidine
Antacids
Chronic oral MPH alone produced a tendency in the striatum of rats to111
Increased dynorphin expression
Increased substance P expression
Unchanged enkephalin expression.
Oral fluoxetine alone did not change the expression of these genes.
MPH and fluoxetine together caused
Strongly increased dynorphin expression
Strongly increased substance P expression
Increased enkephalin expression
Oxytocin potentiates MPH-induced stimulation of tonic (extracellular) dopamine firing, probably by modulating dopamine receptor signaling pathways. Oxytocin did not affect MPH-induced dopamine reuptake or MPH-induced phasic dopamine firing.112
Methylphenidate can increase blood pressure in children.
In children with ADHD, blood plasma levels of nitric oxide appear to be increased and asymmetric dimethylarginine (ADMA) decreased. ADMA inhibits the blood pressure-increasing effect of nitric oxide. When MPH was taken, plasma nitric oxide levels increased further. This could possibly be due to a reduced inhibition of nitric oxide by ADMA during MPH administration and could be a cause of the blood pressure increasing effect of MPH.89
In contrast, a comprehensive study found no adverse effect of MPH on blood pressure in boys with ADHD.50
Patients at risk of high blood pressure should therefore weigh up 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 reduced sensitivity to stress.
One study found no reduced weight in newborns of mothers with ADHD who took amphetamine medication during pregnancy.113 This is consistent with results from a large cohort study of MPH use during pregnancy.114
Another comprehensive study found a slight reduction in birth weight and a slight increase in the risks of pre-eclampsia, placental abruption or premature birth with stimulant use (AMP or MPH) during pregnancy, although this was so small that the authors did not recommend discontinuing stimulant use during pregnancy.115 Atomoxetine did not show these slight increases in risk.
A Danish cohort study found a doubled risk of miscarriage when taking stimulants during pregnancy.116
Another Danish cohort study found a very small increase in malformations in children of mothers who had taken MPH in the first trimester of pregnancy. The authors described the increase in risk as not relevant.117 A smaller study found no increased risk.118
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 mother had taken MPH in early pregnancy.119
A study in mice found increased ADHD symptoms in offspring due to MPH administration during pregnancy. A 2.5 to 15-fold dosage (compared to the usual maximum drug level) caused reduced expressions of the D2 receptor and dopamine transporter genes, which are common in ADHD.120 This is plausibly consistent with the model of brain development disorders caused by a lack of dopamine (e.g. genetically inherited or due to chronic stress) or an excess of dopamine (e.g. due to stimulant administration in non-affected individuals). More on this at ⇒ Brain development disorder and ADHD In the chapter ⇒ Development.
A cohort study found no increased risk of ADHD or other neural development disorders from MPH or AMP use during pregnancy. The increased ADHD risk initially found was due to the mothers’ ADHD on closer examination.121
Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber) hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 213, mit weiteren Nachweisen ↥
