Journal
JOURNAL OF CLINICAL PSYCHIATRY
Volume 79, Issue 2, Pages -Publisher
PHYSICIANS POSTGRADUATE PRESS
DOI: 10.4088/JCP.17m11609
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Funding
- Department of Defense in Fort Detrick, Maryland [W81XWH-12-1-0510]
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Objective: Supratherapeutic doses of methylphenidate activate mu-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed mu-opioid antagonist, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential in subjects with attention-deficit/hyperactivity disorder (ADHD). Methods: We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate (January 2013 to June 2015). Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH) was administered twice daily, was titrated to similar to 1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with an oral test dose of 60 mg of immediate-release methylphenidate (IR-MPH). The primary outcome measure was Question 2 (Liking a Drug Effect) on the Drug Rating Questionnaire, Subject version, which was assessed after oral test doses of 60 mg of IR-MPH were administered after the third and sixth weeks of treatment with SODAS-MPH. Results: Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS-MPH and randomized to naltrexone 50 mg/d or placebo. Thirty-one subjects completed through week 3, and 25 completed through week 6. Naltrexone significantly diminished the euphoric effect of IR-MPH during the heightened-risk titration phase (primary outcome; first 3 weeks) (chi(2) = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (chi(2) = 0.22, P = .64) of SODAS-MPH treatment. Conclusions: Preclinical findings are extended to humans showing that naltrexone may mitigate stimulant-associated euphoria. Our findings provide support for further studies combining opioid receptor antagonists with stimulants to reduce abuse potential.
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