Ling et al.’s ‘Sustained‐release methylphenidate in a randomized trial of treatment of methamphetamine use disorder’

Ling et al. 1 evaluated the efficacy of methylphenidate sustained-release (MPH-SR) as a treatment for methamphetamine use disorder. The primary outcome measure, self-reported days of methamphetamine use in the last 30 days of the 10-week trial, was not significantly different between active medication and placebo, although several of the secondary outcomes of methamphetamine use showed a beneficial effect of MPH-SR. The takeaway message might be that the results are equivocal, and stimulant medications are not so promising for treating stimulant use disorders 2. However, we believe that the MPH-SR dose employed in the study, 54 mg/day, was modest, and may not have been high enough to produce an optimal effect. The existing evidence supports the effectiveness of higher stimulant doses for stimulant use disorders. Another study found that an MPH dose of 54 mg/day was effective among amphetamine-dependent patients 3. Higher doses of MPH are often used to treat attention deficit hyperactive disorder (ADHD), and various studies have shown this to be well tolerated 4-6. Notably, in one study when a substantially higher dose of MPH-SR was administered (up to 180 mg) to amphetamine-dependent individuals, MPH-SR was superior to placebo in reducing the proportion of amphetamine-positive urines 7. The same research group did not observe a beneficial effect when lower dosing was used 5. This is consistent with clinical trials in cocaine-dependent patients in whom higher doses of amphetamine were more likely to elicit cocaine abstinence than lower doses or placebo 8, 9. Adequate dosage has been found to be essential for effectiveness of other agonist-replacement strategies for substance use disorders, such as methadone or buprenorphine maintenance. One prominent finding from the Ling et al. 1 study was that baseline methamphetamine use made a difference. Among the subgroup of patients with higher baseline amphetamine use (at least 10 days of use in the prior 30 days), MPH-SR was superior to placebo on the primary outcome measure. Similarly, when our research group evaluated the combination of mixed amphetamine salts-extended release and topiramate for cocaine dependence, this combination out-performed placebo in achieving abstinence for those using for at least 9 days in the month prior to study entry, but not for those using for less than 9 days 9. In psychopharmacology trials medication is often more effective, compared to placebo, among patients with greater severity of illness at baseline 10. This and other trials have shown stimulant medication can be administered safely to patients with stimulant use disorders. However, their effectiveness remains controversial, and there is bias in the field against agonist replacement strategies. For stimulant users with milder severity behavioral therapy alone may be sufficient, and it is noteworthy that the behavioral intervention offered in Ling's trial, voucher incentives plus cognitive behavioral therapy (CBT), represents the state of the art. It may make sense to target stimulant medications towards stimulant users with moderate/high use patterns, as suggested by both Ling et al. 1 and Mariani et al. 9, and with more robust dosing, to determine the clinical utility of this pharmacological approach. F.R.L. currently receives medication from US WorldMed for an ongoing study that is sponsored by the National Institute on Drug Abuse and served as a consultant to GW Pharmaceuticals, Eli Lily, and served on an advisory board to Shire in 2006–07. F.R.L. also serves as a consultant to Major League Baseball, regarding the diagnosis and treatment of ADHD. E.V.N. served on an advisory board for Eli Lily and Company in January 2012. E.V.N. and A.B. receive medication from Alkermes for ongoing studies that are sponsored by the National Institute on Drug Abuse. J.J.M. reports no competing interests and no financial relationships with commercial interests.