Research Review: Medications for ADHD Treatment – Efficacy, Side Effects, Safety
A recent and noteworthy research review published in The New England Journal of Medicine summarized main findings over the past decade regarding ADHD medication use, abuse, efficacy, side effects, and safety.
December 18, 2020
The prestigious New England Journal of Medicine recently dedicated significant and noteworthy space to a research review of the pharmacologic treatment for attention deficit hyperactivity disorder (ADHD or ADD)1 from Samuele Cortese, M.D., Ph.D. In the NEJM‘s September issue, Dr. Cortese summarized the most notable findings of the last decade related to use of medications for ADHD, their efficacy, side effects, and safety.
Medication Use in ADHD
Reported in the article was a study of prescription databases that revealed that the prevalence of ADHD medication use increased from 2001 to 2015.2 The average relative percentage increase in the United States was 2.83% per year. Follow-up periods of a systematic review revealed the average length of treatment with stimulants was 136 days in children and 230 days in adults.3 Rate of medication discontinuation were highest among 15- to 21-year-olds. Among the reasons for discontinuation were side effects, perceived lack of effectiveness, dislike of taking medications, and stigma.4
ADHD Medication Efficacy and Effectiveness
According to the article, a meta-analysis of randomized controlled trials (RCTs) demonstrated that medications approved for ADHD more effectively decreased the severity of inattention, hyperactivity, and impulsivity than did placebos. The largest effect sizes were found for amphetamines, followed by methylphenidate.5 At the group level, amphetamines were more efficacious than methylphenidate, atomoxetine, and guanfacine. However, at the patient level, approximately 41% of participants had equally good responses to both amphetamines and methylphenidate.6
Some studies that used a within-person design found that, in periods during which patients were receiving medication, there was a significant decrease in negative outcomes such as “unintentional physical injuries, motor vehicle accidents (among male patients), substance use disorder, and criminal acts, as well as an improvement in academic functioning.”7
A double-blind RCT of medication discontinuation found that participants who had been treated with methylphenidate for an average of 4.5 years and continued taking methylphenidate experienced ongoing benefits related to ADHD symptoms, compared to participants who stopped or switched to a placebo.8
Side Effects and Safety of Medications for ADHD
A meta-analysis of RCTs found that several ADHD medications were linked to higher discontinuation rates due to adverse events, as compared with placebo. Short-term trials have shown significant increases in heart rate or blood pressure in patients with ADHD treated with stimulants or atomoxetine, as compared with placebo.9 Small but persistent increases in blood pressure or heart rate are concerning if sustained over a long period, but a meta-analysis found no significant link between ADHD medication and sudden death, stroke, or myocardial infarction.10
Some within-person studies demonstrated that patients being treated with ADHD medications had a decreased risk for seizures, depression, mania, and suicidality.11
Neurological Effects of ADHD Medication
Across randomized trials, the most consistent benefit of a dose of stimulant medication was enhanced attention control and inhibition.12 Longer-term neurobiologic effects (in patients who received stimulants for more than 6 months) included “activation in the right caudate nucleus that is generally close to normal levels during tasks requiring attention.”13
Nonmedical Use of ADHD Medication
There is little evidence that use of ADHD medications without a prescription improves academic or work performance in those without ADHD. Nonetheless, 58.7% of college students in the United States reported nonmedical use of stimulants on at least one occasion, and 2.1% of adults in the United States reported at least one episode of nonmedical stimulant use.14 Motivation for nonmedical stimulant use included enhancement of academic or work performance, as well as recreational use. Self-medication for undiagnosed ADHD could be another explanation “since persons who engaged in nonmedical use of stimulants reported more symptoms of ADHD than those who did not engage in nonmedical stimulant use.”
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2Raman SR, Man KKC, Bahmanyar S, et al. Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases. Lancet Psychiatry 2018;5:824-35.
3Gajria K, Lu M, Sikirica V, et al. Adherence, persistence, and medication discontinuation in patients with attentiondeficit/hyperactivity disorder — a systematic literature review. Neuropsychiatr Dis Treat 2014;10:1543-69.
4Zetterqvist J, Asherson P, Halldner L, Långström N, Larsson H. Stimulant and non-stimulant attention deficit/hyperactivity disorder drug use: total population study of trends and discontinuation patterns 2006-2009. Acta Psychiatr Scand 2013;128:70-7
5Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry 2018;5:727-38
7Chang Z, Ghirardi L, Quinn PD, Asherson P, D’Onofrio BM, Larsson H. Risks and benefits of attention-deficit/hyperactivity disorder medication on behavioral and neuropsychiatric outcomes: a qualitative review of pharmacoepidemiology studies using linked prescription databases. Biol Psychiatry 2019;86:335-43.
8Matthijssen A-FM, Dietrich A, Bierens M, et al. Continued benefits of methylphenidate in ADHD after 2 years in clinical practice: a randomized placebo-controlled discontinuation study. Am J Psychiatry 2019;176:754-62.
9Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry 2018;5:727-38
11Chang Z, Ghirardi L, Quinn PD, Asherson P, D’Onofrio BM, Larsson H. Risks and benefits of attention-deficit/hyperactivity disorder medication on behavioral and neuropsychiatric outcomes: a qualitative review of pharmacoepidemiology studies using linked prescription data
12Rubia K, Alegria AA, Cubillo AI, Smith AB, Brammer MJ, Radua J. Effects of stimulants on brain function in attentiondeficit/hyperactivity disorder: a systematic review and meta-analysis. Biol Psychiatry 2014;76:616-28.
13Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K. Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring taskspecific, stimulant medication, and age effects. JAMA Psychiatry 2013;70:185-98.
14Faraone SV, Rostain AL, Montano CB, Mason O, Antshel KM, Newcorn JH. Systematic review: nonmedical use of prescription stimulants: risk factors, outcomes, and risk reduction strategies. J Am Acad Child Adolesc Psychiatry 2020;59:100-12.