ADHD: Methylphenidate (Ritalin etc.) is safe and effective for 99% of all people

Great news! In a 2018 review by Storebø et al. it was proven that Methylphenidate was safe and effetive for more than 92.7% of the 2,207.751 participants in their review of 260 studies. The review also showed that 99% did not have any serious adverse events (serious side effects), and 98,8% did not withdraw from using Methylphenidate due to any serious adverse events, and 92.7% did not withdraw from any adverse events.

Storebø, O. J., Pedersen, N., Ramstad, E., Kielsholm, M. L., Nielsen, S. S., Krogh, H. B., … Gluud, C. (2018). Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – assessment of adverse events in non-randomised studies. Cochrane Database of Systematic Reviews, (5).
http://doi.org/10.1002/14651858.CD012069.pub2

Authors’ Key Points

[…] The findings suggest that methylphenidate administration might lead to serious adverse (harmful) events, including death, cardiac problems, and psychotic disorders. About 1 in 100 patients treated with methylphenidate seemed to suffer a serious adverse event. Withdrawal from methylphenidate due to serious adverse events occurred in about 1.2 out of 100 patients treated with methylphenidate. Withdrawal from methylphenidate due to any adverse events occurred in about 7.3 out of 100 patients treated with methylphenidate. We also noted a large proportion of non-serious adverse events. More than half the patients exposed to methylphenidate seemed to suffer one or more adverse events. Withdrawal from methylphenidate due to non-serious adverse events occurred in about 6.2 out of 100 patients exposed to methylphenidate. Withdrawal of methylphenidate for unknown reasons was 16.2 out of 100 patients exposed to methylphenidate. The quality of the evidence and hence the certainty or reliability of the evidence for the comparative studies is very low. The reliability of the evidence for the non-comparative studies is low due to weaknesses in study design. Accordingly, it is not possible to accurately estimate the risks of adverse events in children and adolescents prescribed methylphenidate.[…] Storebø et al. (2018)

ADDspeaker’ Key Points

The findings suggest that methylphenidate administration might lead to serious adverse (harmful) events, including death, cardiac problems, and psychotic disorders in less than 1% of all people using Methylphenidate. and that it is safe and effective for 83,8%, have some non-serious side effects for 6,2% (decreased appetite, abdominal pains, headache, sleep disturbances), and that 1,2% may experience any serious side effects (arrythmia, psychosis, cardiac problems or death). Taking these results into consideration, about 99% of everyone who uses Methylphenidate, are safe and the medication is effective. About 99 in 100 patients treated with methylphenidate seemed to not suffer a serious adverse event. Withdrawal from methylphenidate due to serious adverse events did not occur in about 98.8 out of 100 patients treated with methylphenidate. Withdrawal from methylphenidate due to any adverse events did not occur in about 92,7 out of 100 patients treated with methylphenidate. Less than half the patients exposed to methylphenidate seemed to suffer one or more (non-serious) adverse events. Withdrawal from methylphenidate due to non-serious adverse events did not occur in about 93,8 out of 100 patients exposed to methylphenidate. Withdrawal of methylphenidate for unknown reasons was not seen in 83,8 out of 100 patients exposed to methylphenidate. The quality of the evidence and hence the certainty or reliability of the evidence for the comparative studies is very low, due to using the GRADE systemic interpretations. The reliability of the evidence for the non-comparative studies is low due to weaknesses in study design, due to using the GRADE systemic interpretations. Accordingly, due to using the GRADE systemic interpretations, it is not possible to accurately estimate the risks of adverse events in children and adolescents prescribed methylphenidate.

Author’ conclusion

[…]Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here. Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.[…] Storebø et al. (2018)

[…] Methyphenidiate might be associated with a number of serious adverse events. Methylphenidate produces a large number of other non- serious harmful effects in children and adolescents with ADHD. We suggest that clinicians and parents are alert to the importance of monitoring adverse events in a systematic, meticulous manner. If methylphenidate is to continue to have a place in ADHD treatment in the future, we need to identify subgroups of patients in whom the benefits of methylphenidate outweigh the harms. Just as we need to be able to identify who is likely to benefit from treatment, we also need to be able to identify those who are most at risk of experiencing adverse events. In order to do this, we need to undertake large-scale, high-quality RCTs along with other studies aimed at identifying those who respond and those who do not respond to treatment.[…] Storebø et al. (2018)

ADDspeaker’s conclusion

Methyphenidiate might be associated with a number of serious adverse events, for less than 1% of people who use Methylphenidate. Methylphenidate produces non-serious harmful effects for 1,2% of children and adolescents with ADHD. We suggest that clinicians and parents continue to be alert to the importance of monitoring adverse events in a systematic, meticulous manner. In light of our findings, that 83,8% of people have no adverse events, we support that methylphenidate is to continue to have a place in ADHD treatment in the future, while taking care to identify subgroups of patients in whom the harms of methylphenidate outweigh the benefits . Just as we need to be able to identify who is likely to benefit from treatment, we also need to be able to identify those who are most at risk of experiencing adverse events. In order to do this, we need to undertake large-scale, high-quality RCTs along with other studies aimed at identifying those who respond and those who do not respond to treatment.

Based on this review by Storebø et al. (2018), ADDspeaker concludes, in accordance with both the NICE NG87 (2018), and the Updated European Consensus Statement on diagnosis and treatment of ADHD (2018), and Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan, and Cardiovascular Safety of Stimulants in Children with Attention-Deficit/Hyperactivity Disorder: A Nationwide Prospective Cohort Study, which unanimously recommend Methylphenidate as first line in pharmacological treatment of children and adolescents with ADHD.

Table showing comparative effect sizes for ADHD treatment options

BACKGROUND INFORMATION: What is going on?

If you’re confused I really can’t blame you, since the interpretations from Storebø et al. (2018), makes no sense, given that their own findings to a large extent, unequivocally prove that Methylphenidate DO NOT cause any harmful side effects for the vast majority of children, adolescents and adults who use it.

So what is the motive behind their deliberately negative interpretation of their own data? Why du the focus on the insignificant risks of using Methylphenidate, when 99% of people DO NOT risk any serious adverse events? The answer is to be found back in 2015, so let’s dig up some background on Storebø et al. to put the spotlight on what they are trying to achieve.

Going back to the roots …

In 2015, Storebø et al. (2015), published a meta-analysis of the Methylphenidate with the purpose of providing proof, that the current scientific evidence in support of both safety and efficacy of Methylphenidate was of ‘low quality’ and with ‘a risk risk of bias’.

They based this definition of ‘bias’ on a proprietary standard for evaluating quality of scientific studies, called GRADE, which is a method developed by The Cochrane Collaboration, which supposedly stands for “Trusted evidence. Informed decisions. Better health.” according to their website.

In the 2015 study, Storebø et al. (2015) conducted a meta-analysis of 186 studies, where they found that only 19 of them did not seem to be ‘paid for by the pharmaceutical industry’ or ‘violated the double-blind, randomized study design’ or ‘where the findings seemed to be more favorable towards finding less adverse events, when the study was done by scientists who had a connection to the pharmaceutical industry’.

In that study Storebø et al. (2015) conclude, that; […] Methylphenidate use in children and adolescents may improve the symptoms of ADHD, general behaviour, and quality of life. It does not seem to cause an increased risk of serious adverse events in the short term but was associated with a relatively high risks of non-serious adverse events. These findings should be interpreted in the light of several limitations, includ ing the lack of blinding, outcome reporting bias, heterogeneity, and the consequent very low quality of evidence for all outcomes. More long term randomised nocebo tablet (active placebo) controlled clinical trials without risks of bias are necessary to allow firm decisions on methylphenidate treatment in children and adolescents with ADHD. We believe that nocebo controlled trials should be conducted first in adults
with ADHD. […] Storebø et al. (2015)

And they determine, that their findings should result in these implications;

[…] Implications for practice: The results of meta-analyses suggest that methylphenidate may improve teacher reported ADHD symptoms, teacher reported general behaviour, and parent reported quality of life among children and adolescents with a diagnosis of ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non-serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases the risk of serious adverse events.[…] Storebø et al. (2015)

[…] Implications for research: Better designed trials are needed to assess the benefits of methylphenidate. Because of the frequency of non-serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, “nocebo tablet” controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. Such trials ought first to be conducted in adults with ADHD. We also acknowledge that investigators can directly carry out nocebo controlled trials in children and adolescents if they can argue that young people with ADHD are different from adults with the disorder. Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to sex, age, type of ADHD, presence of co-morbidities and dose. Finally, the findings highlight the urgent need for large randomised trials of non-pharmacological treatments.[…] Storebø et al. (2015)

Storebø et al. (2015): Storebø, O. J., Ramstad, E., Krogh, H. B., Nilausen, T. D., Skoog, M., Holmskov, M., … Gluud, C. (2015). Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). The Cochrane database of systematic reviews, (11), CD009885.
doi: https://dx.doi.org/10.1002/14651858.CD009885.pub2

The press release, the frenzy, and the feedback

Following that meta-analysis being published, media from all over the world picked it up, and asked the authors for comments, Storebø et al. was more than happy to elaborate on their findings, and as Storebø OJ himself commented in one article;

[…]The perception has been that there is very good evidence and effect of these medications, so it has been very surprising to find out that the evidence is so uncertain due to the poor quality of the included studies that you can not say anything about effect size.[…] Storebø OJ, MetroXpress (2015) (article have since been taken down)

For further information on Storebø et al. read this article: Nocebo, ADHD and Cochrane

In 2016, Banaschewski et al. replies to Storebø et al. with;

[…] Let us conclude that the Cochrane review by Storebo et al. (2015) is indeed flawed in terms of study selection and risk of bias assessment. We think that the clinical interpretation of the flawedanalysis should not be admissible and lacks careful consideration. […] Banaschewski et al. (2016)

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