Methylphenidate (MPH) is one of the most widely-prescribed medications for children. Given that ADHD frequently persists over a large part of an individual’s lifespan, any side effects of medication initiated during childhood may well be compounded over time. With funding from the European Union, a recently released review of the evidence looked for possible adverse neurological and psychiatric outcomes.

From the outset, the international team recognized a challenge: “ADHD severity may be an important potential confounder as it may be associated with both the need for long-term MPH therapy and high levels of underlying neuropsychiatric comorbidity.” Their searches found a highly heterogeneous evidence base, which made meta-analysis inadvisable. For example, only 25 of 39 group studies reported the presence or absence of comorbid psychiatric conditions, and even among those, only one excluded participants with comorbidities. Moreover, in only 24 of 67 studies was the type of MPH used (immediate or extended-release) specified. The team, therefore, focused on laying out an “evidence map” to help determine priorities for further research.

The team found the following breakdown for specific types of adverse events:

• Low mood/depression. All three noncomparative studies found MPH safe. Two large cohort studies, one with over 2,300 participants, the other with 142,000, favored MPH over the non-stimulant atomoxetine. But many other studies, including a randomized controlled trial (RCT), had unclear results. Conclusion: “the evidence base regarding mood outcomes from long-term MPH treatment is relatively strong, includes two well-powered comparative studies, and tends to favor MPH.”
• Anxiety. Here again, all three noncomparative studies found MPH safe. But only two of seven comparative studies favored MPH, with the other five having unclear results. Conclusion: “while the evidence with regard to anxiety as an outcome of long-term MPH treatment tends to favor MPH, the evidence base is relatively weak.”
• Irritability/emotional reactivity. A large cohort study with over 2,300 participants favored MPH over atomoxetine. Conclusion: “the evidence base … is limited, although it includes one well-powered study that found in favor of MPH over atomoxetine.”
  Suicidal behavior/ideation. There were no noncomparative studies, but all five comparative studies favored MPH. That included three large cohort studies, with a combined total of over a hundred thousand participants, that favored MPH over atomoxetine. Conclusion: “the evidence base … is relatively strong, and tends to favor MPH.”
• Bipolar disorder. A very large cohort study, with well over a quarter-million participants, favored MPH over atomoxetine. A much smaller cohort study comparing MPH with atomoxetine, with less than a tenth the number of participants, pointed toward caution. Conclusion: “the evidence base … is limited and unclear, although it includes two well-powered studies.”
• Psychosis/psychotic-like symptoms. By far the largest study, with over 145,000 participants, compared MPH with no treatment and pointed toward caution. A cohort study with over 2,300 participants favored MPH over atomoxetine. Conclusion: “These findings indicate that more research is needed into the relationship between ADHD and psychosis, and into whether MPH moderates that risk, as well as research into individual risk-factors for MPH-related psychosis in young people with ADHD.”
• Substance use disorders. A cohort study with over 20,000 participants favored MPH over anti-depressants, anti-psychotics, and no medication. Other studies looking at dosages and durations of treatment, age at treatment initiation, or comparing with no treatment or “alternative” treatment, all favored MPH with the exception of a single study with unclear results. Conclusion: “the evidence base … is relatively strong, includes one well-powered study that compared MPH with antipsychotic and antidepressant treatment, and tends to favor MPH.”
• Tics and other dyskinesias. Of four noncomparative studies, three favored MPH, the other, with the smallest sample size, urged caution. In studies comparing with dexamphetamine, pemoline, Adderall, or no active treatment, three had unclear results and two pointed towards caution. Conclusion: “more research is needed regarding the safety and management of long-term MPH in those with comorbid tics or tic disorder.”
• Seizures or EEG abnormalities. With one exception, the studies had small sample sizes. The largest, with over 2,300 participants, compared MPH with atomoxetine, with inconclusive results. Two small studies found MPH safe, one had unclear results, and two others pointed towards caution. Conclusion: “While the evidence is limited and unclear, the studies do not indicate evidence for seizures as an AE of MPH treatment in children with no prior history … more research is needed into the safety of long-term MPH in children and young people at risk of seizures.”
• Sleep Disorders. All three noncomparative studies found MPH safe, but the largest cohort study, with over 2,300 participants, clearly favored atomoxetine. Conclusion: “more research is needed into the relationship between ADHD, sleep, and long-term MPH treatment.”
• Other notable psychiatric outcomes. Two noncomparative studies, with 118 and 289 participants, found MPH safe. A cohort study with over 700 participants compared with atomoxetine, with inconclusive results. Conclusion: “there is limited evidence regarding long-term MPH treatment and other neuropsychiatric outcomes and that further research may be needed into the relationship between long-term MPH treatment and aggression/hostility.”

Although this landmark review points to several gaps in the evidence base, it mainly supports prior conclusions of the US Food and Drug Administration (FDA) and other regulatory agencies (based on short-term randomized controlled trials) that MPH is safe for the treatment of ADHD in children and adults. Give that MPH has been used for ADHD for over fifty years and that FDA monitors the emergence of rare adverse events, patients, parents, and prescribers can feel confident that the medication is safe when used as prescribed.

REFERENCES:
Helga Krinzinger, Charlotte L Hall, Madeleine J Groom, Mohammed T Ansari, Tobias Banaschewski, Jan K Buitelaar, Sara Carucci, David Coghill, Marina Danckaerts, Ralf W Dittmann, Bruno Falissard, Peter Garas, Sarah K Inglis, Hanna Kovshoff, Puja Kochhar, Suzanne McCarthy, Peter Nagy, Antje Neubert, Samantha Roberts, Kapil Sayal, Edmund Sonuga-Barke , Ian C K Wong , Jun Xia, Alexander Zuddas, Chris Hollis, Kerstin Konrad, Elizabeth B Liddle and the ADDUCE Consortium, “Neurological and psychiatric adverse effects of long-term methylphenidate treatment in ADHD: A map of the current evidence,” Neuroscience and Biobehavioral Reviews (2019) DOI: https://doi.org/10.1016/j.neubiorev.2019.09.023