REVIEW OF: Farhat C et al, JAMA Psychiatry 2024;81(2):157–166

STUDY TYPE: Meta-analysis and network meta-analysis of randomized controlled trials

Finding the right stimulant doses for adult ADHD can be challenging. Practice guidelines—and patients—sometimes suggest exceeding the FDA’s approved max doses of 60 mg daily for methylphenidate and 40 mg daily for amphetamine-dextroamphetamine. This study aimed to assess the effectiveness and safety of these higher, unlicensed doses.

The researchers included a total of 47 randomized controlled trials (29 tested methylphenidates; 18 tested amphetamines) with 7,714 participants (mean age 35 years, 56% male, 87% self-identified as White). They calculated standardized mean difference (SMD) in ADHD symptoms over the course of the studies. They also determined the mean dose associated with 50% and 95% (ED50, ED95) of a maximum change in symptoms when compared to placebo, and odds ratio (OR) of discontinuation. They then conducted a network meta-analysis of methylphenidates and amphetamines separately, comparing placebo, licensed, and unlicensed doses of stimulants.

For methylphenidates, the study showed that while increasing doses generally led to better symptom management, the benefits significantly diminished for doses above 40 mg daily: The ED50 was 25 mg daily, and the ED95 was 72.5 mg daily. The higher doses provided a small benefit above maximal licensed doses (SMD -0.23; p=0.03) but were associated with decreased tolerability compared to licensed doses (OR 2.02; p=0.01). Likewise, for amphetamines, there was an initial, sharp decrease in symptoms with increased doses, followed by minimal improvements beyond 35 mg daily (ED50 12.5 mg daily, ED95 30 mg daily).

CARLAT TAKE

While higher-than-normal stimulant doses may slightly reduce ADHD symptoms in adults, they often come with side effects. Rather than pushing the doses of stimulants higher and higher, try augmenting standard doses with exercise, a healthy diet, treating comorbid conditions, cognitive behavioral therapy, and nonstimulant medications.