Clinical Question

Are amphetamines safe and effective in adults with attention-deficit/hyperactivity disorder (ADHD)?

Evidence-Based Answer

Amphetamines provide a clinician-rated 30% or greater reduction in ADHD symptoms when compared with placebo (number needed to treat = 5).¹ (Strength of Recommendation: B, based on inconsistent or limited-quality patient-oriented evidence.)

Practice Pointers

ADHD is a neurodevelopmental disorder with a mean onset at six years of age. Approximately one-third of affected children will carry the disorder into adulthood; the current prevalence of ADHD in U.S. adults is 4.4%.² ADHD symptoms present differently in adults than in children. Hyperactivity and impulsivity in adults often appear as restlessness, talkativeness, and emotional dysregulation (i.e., irritability, emotional lability, and emotional reactivity). Inattention manifests similarly in childhood and adulthood. The use of amphetamines for the treatment of adult ADHD has increased, and this Cochrane review analyzed their safety and effectiveness.¹

The review included 19 randomized controlled trials (2,521 adults with ADHD) comparing dextroamphetamine, lisdexamfetamine (Vyvanse), or mixed amphetamine salts with placebo. Studies lasted on average 5.3 weeks (range: one to 20 weeks), with only three studies (N = 542) lasting more than eight weeks. The participants had a mean age of 35.3 years, and most (57.2%) were men; 78.8% had combined-type ADHD. The primary outcome was the severity of ADHD symptoms, assessed by clinicians or participants using the standardized ADHD Rating Scale-IV (ADHD-RS-IV). Secondary outcomes included clinical impressions of ADHD symptom severity and improvement at study end based on the Clinical Global Impression Severity and Impression Scales (CGI-S and CGI-I, respectively); percentage of participants with a 30% reduction in ADHD symptoms (measured by the ADHD-RS-IV) and/or a CGI-I score of 1 or 2; global functioning based on the CGI-S; symptoms of depression and anxiety per standardized instruments chosen by the individual study; treatment adherence; and adverse effects. The review had several limitations: no study had a low risk of bias, 16 of the 19 studies were funded by pharmaceutical companies, there was attrition bias because adverse effects of amphetamines may have been present, and the reviewers were to rule out carryover effects in studies with a crossover design.¹

Low- to very low-quality evidence demonstrated that amphetamines, as a group, were effective in reducing the severity of ADHD symptoms as rated by clinicians (standardized mean difference [SMD] = −0.90; 95% CI, −1.04 to −0.75; P < .00001; 13 studies; 2,028 participants) and participants (SMD = −0.51; 95% CI, −0.75 to −0.28; P < .000021; six studies; 120 participants) using the ADHD-RS-IV. Not all amphetamines performed equally. Lisdexamfetamine (SMD = −1.06; 95% CI, −1.26 to −0.85; seven studies; 896 participants) and mixed amphetamine salts (SMD = −0.80; 95% CI, −0.93 to −0.66; five studies; 1,083 participants) reduced clinician-rated severity of symptoms, whereas dextroamphetamine did not. The review also found that dextroamphetamine and lisdexamfetamine, but not mixed amphetamine salts, significantly reduced participant-rated severity of ADHD symptoms compared with placebo (dextroamphetamine: SMD = −0.77; 95% CI, −1.14 to −0.40; two studies; 35 participants; lisdexamfetamine: SMD = −0.33; 95% CI, −0.65 to −0.01; three studies; 67 participants; and mixed amphetamine salts: SMD = −0.45; 95% CI, −1.02 to 0.12; one study; 18 participants).¹

Amphetamines were not effective at improving global functioning based on the CGI-S Scale or at reducing symptoms of depression and anxiety (based on various standardized instruments used across different studies). Low vs. high dose (low dose defined as less than 16 mg per day for dextroamphetamine, 53.4 mg per day for lisdexamfetamine, and 50 mg per day for mixed amphetamine salts), type of formulation (immediate or sustained release), and the presence of a comorbidity (drug-use disorder or depression) did not affect the severity of ADHD symptoms as assessed by clinicians or participants. A meta-analysis of 17 studies (N = 2,409) found a greater risk of dropout from any adverse effect with amphetamines than with placebo (relative risk = 2.69; 95% CI, 1.63 to 4.42), although withdrawal by participants treated with amphetamines was considered low at 7.6% (placebo drop-out rate was 2.4%).¹ Adverse effects leading to withdrawal included anxiety, depressed mood, nausea/vomiting, headache, fatigue, insomnia, increased blood pressure, flushing, and affective dullness.^3–9 Most reported adverse effects were considered mild to moderate.

The National Institute for Health and Care Excellence (NICE) guidelines for managing adult ADHD recommend implementing environmental modifications initially, and offering medications such as lisdexamfetamine or methylphenidate (Ritalin) only in a shared decision-making model with routine follow-up.¹⁰ When adults are taking amphetamines, it is recommended that weight, heart rate, blood pressure, and sleep patterns be monitored with every medication change and every six months because of potential cardiovascular events. This Cochrane review supports the NICE guidelines.^1,10

The practice recommendations in this activity are available at http://www.cochrane.org/CD007813.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army Medical Department or the U.S. Army Service at large.