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15. Long-term effects: No habituation effects with MPH¶
A study of people with ADHD who took MPH for 2 years showed a significant worsening of hyperactivity and inattention when MPH was discontinued, which corresponds to a recurrence of the symptoms improved by MPH.1
A placebo-controlled discontinuation trial in persons with ADHD who had taken MPH for over 2 years showed that discontinuation of MPH caused a significant increase in ADHD symptoms.2 Nevertheless, in some persons with ADHD it seems that after some time a continuation of the medication is dispensable, which justifies regular discontinuation attempts.
A meta-analysis of 87 randomized placebo-controlled double-blind studies found no evidence of a decrease in the effect of methylphenidate, amphetamine drugs, atomoxetine or α2 antagonists with prolonged use.3
A meta-analysis found only one RCT comparing the effect of a single dose of MPH with the effect of prolonged use (here: 4 weeks). This RCT found a significant agreement between the effect of a single dose and the effect of prolonged use. This is relevant for the evaluation of studies on the effect of single doses of MPH.4
One study observed a higher increase in dopamine in the ventral striatum (including the nucleus accumbens) in women than in men. The increase in the dorsal striatum was the same.5
17. Areas of application of methylphenidate in relation to other ADHD medications¶
According to the current European consensus, methylphenidate is the first choice of medication for ADHD in children (before amphetamine medication) and the second choice of medication in adults (after amphetamine medication)67
In children who are MPH non-responders, i.e. who do not respond to MPH, the efficacy of amphetamine medication should be tested.
People with ADHD with pronounced dysphoria during inactivity or with comorbid depression benefit particularly from amphetamine medication.
In addition, people with ADHD who require stronger activation may be able to cope better with amphetamine medication.
Highly gifted people are said to respond better to amphetamine medication than to MPH.8
20. MPH medication significantly reduces the risk of addiction¶
The updated European consensus on the diagnosis and treatment of ADHD from 2018 concludes that stimulants significantly reduce the risk of addiction while taking them.12
People with ADHD with comorbid cocaine addiction showed a significant reduction in addictive behavior when treated with stimulants. This corresponded to the reduction in ADHD symptoms.13
The international consensus on screening, diagnosis and treatment of adults with addiction and ADHD recommends treatment with long-acting stimulants with increasing doses up to high doses, in combination with psychotherapeutic treatment.14
A meta-analysis of 6 studies with n = 1,014 test subjects showed a significantly reduced risk of later addiction for participants medicated with stimulants (here: MPH).15 The risk of later addiction, whether to alcohol or other substances, was found to be 1.9 times lower, i.e. almost halved.16
A Swedish cohort study found that 3 years after being prescribed stimulants for ADHD, the risk of an addiction diagnosis was reduced by 31%.17
These findings may be supported by the fact that adolescents with marked novelty-seeking who were found to have reduced BOLD activity in mesolimbic (nucleus accumbens (ventral striatum) and midbrain) and prefrontal cortical (dlPFC) regions during reward anticipation at age 14 were more likely to engage in problematic drug use at age 16.18 This could be interpreted to mean that ADHD medications that increase dopamine and norepinephrine levels, such as MPH or amphetamine medications, directly contribute to lowering the risk of addiction.
ADHD medication reduced the influence of preference for short-term rewards and frustration intolerance on internet addiction.19
One study found no increased addictive affinity in adult rodents as a result of treatment with MPH during adolescence.20 Other studies also found evidence that stimulants do not increase the risk of addiction.21
We believe that the two components of ADHD and addiction can be weighted very differently in different individuals and that the success of drug treatment depends heavily on this different weighting. The setting in which medication takes place and whether or not it is flanked and intensively supported by other measures is therefore likely to play a very important role. The practical experience of one of our advisory boards is that pure substance treatment without intensive, accompanying co-treatment usually only leads to the use of an additional substance.
In addition, a combination of addiction and ADHD often involves other comorbidities such as depression etc., which makes treatment even more difficult, as antidepressants are often no longer effective when many substances are abused. It therefore seems important to us for the success of the treatment that inpatient detoxification and drug abstinence for drug cessation are started in the case of a combination of addiction and ADHD.
“The drug treatment of patients with ADHD who also have substance abuse or dependence should be carried out by a specialist with knowledge of the treatment of ADHD and addiction.”22
Finally, it should be noted that people with ADHD often find it difficult enough to take the stimulants prescribed to them regularly and on time. If stimulants triggered addictive behavior, this would not be the case. In addition, people with ADHD do not wake up in the morning with a “craving” for their medication. However, such cases are not reported.
The rumors that ADHD medications would trigger addictive behavior are simply a consequence of insufficient knowledge of the differences between drug and medication. Doctors who spread such misconceptions harm their patients and risk medical malpractice claims if damage results from such advice that is contrary to the guidelines.
There are a large number of methylphenidate preparations.
Although they all contain the same active ingredient, people with ADHD respond differently to them. Individual means that some people tolerate preparation A very well and it works well, while preparation B barely works and has unpleasant side effects, while for others the effect is exactly the opposite.23
A solid MPH medication regimen should therefore always include taking different preparations, even if one preparation is already effective and has no unpleasant side effects. This is because it is only possible to determine whether another preparation works significantly better after it has been tested.
Depending on the preparation, a high-fat food intake before / during ingestion can delay or accelerate the maximum effect and reduce or increase the intensity of the effect.23 We have no concrete data on this for the preparations available in Europe.
One (only) pharmacy in Switzerland produces MPH drops. These are even easier to dose, so that even people with ADHD who require very low doses, such as young children, can adjust the dosage precisely. Ryffel reports on one application.2728
The course of the effect curve differs considerably depending on the MPH preparation.
22. Drug level curves of various MPH preparations¶
The temporal progression of drug levels of different MPH preparations can be depicted and compared in drug curves.3637
A graph illustrates the course of the active ingredient levels of:38
Concerta
Ritalin Adult / LA
Medikinet adult
MPH immediate release
A graph illustrates the different active ingredient levels of Equasym with and without food intake.39
The Ratiopharm prescribing information compares the drug level profile of methylphenidate Ratiopharm 40 mg with Ritalin LA.40
This shows that even bioequivalent preparations do not have completely identical effect level curves.
The information for healthcare professionals from Novartis compares the drug level profile of Ritalin LA 40 mg with Ritalin immediate release 2 x / day.41
23. Abuse by pupils and students during examination phases¶
Studies show that ADHD medication can only slightly improve cognitive performance, e.g. attention, in people without ADHD. An increase in academic performance was not observed in people without ADHD42
Due to the inverted-U profile of the effects of dopamine, an increase in dopamine levels in non-affected people (based on an optimal average level) is generally detrimental. At most, severe chronic stress, which lowers dopamine levels, can lead to a dopamine deficiency in non-affected individuals, for which ADHD medication also helps non-affected individuals. We believe it is possible that this could be the case in exam situations. For example, there is ample evidence of abuse of stimulants by non-affected students in exam situations. Meanwhile, there are no reports of voluntary sustained use after exams have ended by people with ADHD who are not affected by ADHD. (In fact, students who misuse stimulants for exam periods have higher than average ADHD symptoms43.)
24. Preparations with the same active ingredient, pharmacies and discount agreements in Germany¶
The individual preparations often differ in terms of bioavailability, effect, duration of action and side effects, even at the same dose.
It often takes a long time to find the right individual preparation and the right dosage for the patient. If a preparation is replaced due to a discount agreement, this can have significant consequences for the therapy, including discontinuation of therapy.
Against this background, the inclusion of stimulants on the substitution exclusion list is urgently required.
Methylphenidate-containing drugs can lead to a false positive laboratory value for amphetamines, especially in immunoassay methods.44
26. Different MPH preparations have different individual effects - despite having the same active ingredient¶
The fact that methylphenidate preparations can have very different effects on different individuals has not yet been scientifically substantiated, but has been recognized beyond doubt empirically.45 We suspect a connection with the different active (time) profiles and various fillers.
We know people with ADHD who reacted with aggression to one MPH preparation and responded excellently to another preparation - and other people with ADHD who reacted to the two preparations with exactly the opposite reaction.
The phenomenon is widely known in forums for people with ADHD and the testing of various MPH preparations is regularly recommended by people with ADHD.
However, since the approval of Vyvanse Adult in May 2019, methylphenidate is increasingly being replaced by Vyvanse in adults. In adults, amphetamine medication is the first choice of medication over methylphenidate.
A detailed graphic and explanatory presentation of the pathway of action of methylphenidate can be found at www.pharmgkb.org.46 Another comprehensive description of methylphenidate can be found at drugbank.com.47
