Unlicensed Stimulant Doses in Adult ADHD Barely Reduce Symptoms Compared to Licensed Doses

Licensed dosing of stimulants is associated with more reduced symptoms in adults with ADHD than unlicensed dosing, according to a new systematic review meta-analysis led by Luis C. Farhat, MD, of University Hospital in São Paulo, Brazil.¹

To improve patients’ ADHD symptoms, some physicians will prescribe higher doses of stimulants, going above the US Food and Drug Administration (FDA) recommendation. The FDA recommends a maximum of 60 mg per day for the stimulant methylphenidate, but the Consumer Packed Goods (CPG) recommends ≤100 mg per day.²

Due to the conflicting dosing recommendations, investigators of a new analysis studied the dosing levels of 2 stimulants, methylyphenidate and amphetamines. The team identified 47 double-blind, placebo-controlled randomized clinical trials—29 methylphenidate and 18 amphetamines—and examined the data on licensed dosing and unlicensed dosing, particularly looking for the outcomes of ADHD symptom changes, tolerability, and acceptability. The investigators also looked for discontinuation of the stimulants due to adverse effects. The study contained 7714 participants, all >18 years old, with a mean age of 35 years. Over half of the sample (n = 4204 [56%]) were male.¹

“Based on our findings, practitioners should be aware that adults with ADHD may experience the most reductions of symptoms with stimulants at licensed doses and that additional reductions of symptoms with unlicensed doses may be small and possibly non clinically meaningful (eg, less than 10 to 15 ADHD-RS reductions),” the investigators wrote. “However, the tolerability of stimulants may continuously decrease with increments in dose.”

Because of the decrease in tolerability, the investigators think practitioners should prescribe unlicensed doses carefully. The team also noted that some medicines, like mixed amphetamine salts, are licensed doses of extended-release formulations that are similar than other formulations. Thus, sometimes an unlicensed dose is not high.

For methylphenidate, the data showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], −0.23; 95% CI, −0.44 to −0.02). However, the reduction was small, with improvements between 35 – 40 mg per day. Also, with methylphenidate, the increased the risk of adverse events caused some participants to stop taking the stimulants. There no was significant difference in acceptability (1.59; 95% CI,0.93-2.73; P = .09). For heterogeneity, there was low change in ADHD symptoms and acceptability, as well as low-to-moderate tolerability.

As for amphetamines, the data did now show differences between unlicensed and licensed doses (SMD, −0.08; 95% CI, −0.24 to 0.08). There was also a risk of participants stopping taking the stimulants because of adverse events. Like with methylphenidate, amphetamines had no significant association with acceptability (0.81; 95% CI, 0.54 – 1.22; P = .31). For heterogeneity, amphetamine had low tolerability, low-to-moderate acceptability, and moderate to high changes in ADHD symptoms,

The findings highlighted that unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. While Farhat and colleagues believe practitioners can still trial unlicensed doses if needed and tolerated, they emphasized that people should be aware of the low gains in symptom reduction.

“Importantly, because the risk benefits based on averages from our study will not generalize to every patient, our study does not provide evidence that practitioners should not trial unlicensed doses of stimulants in routine clinical practice,” the investigators concluded. “Indeed, individuals differ in their response to these medications and some adults with ADHD may experience larger reductions of symptoms, or less evident adverse events, with unlicensed doses than the average patient as reflected in our findings.”

References

1. ^{Farhat LC, Flores JM, Avila-Quintero VJ, et al. Treatment Outcomes with Licensed and Unlicensed Stimulant Doses for Adults With Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis [published online ahead of print, 2023 Oct 25]. JAMA Psychiatry. 2023;e233985. doi:10.1001/jamapsychiatry.2023.3985}
2. ^{METHYLIN (methylphenidate hydrochloride) oral solution. CII. Food and Drug Administration.chromeextension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021419s010lbl.pdf. Accessed October 31, 2023.}