The Mixed Opioid Receptor Antagonist Naltrexone Mitigates Stimulant-Induced Euphoria: A Double-Blind, Placebo-Controlled Trial of Naltrexone

Abstract

Objective: Supratherapeutic doses of methylphenidate activate μ-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed μ-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 ~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) (χ² = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (χ² = 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.

Trial registration: ClinicalTrials.gov identifier: NCT01673594.

© Copyright 2018 Physicians Postgraduate Press, Inc.

Figures

Figure 1.

CONSORT diagram.

Figure 2a.

Poisson regression model predicting liking a drug effect at Week 3 controlling for baseline euphoria: the MPH x naltrexone interaction (N=31). *There is a significant interaction between MPH and naltrexone (p=0.02).

Figure 2b.

Poisson regression model predicting liking a drug effect at Week 3: the MPH x naltrexone x session interaction (N=31). *There is a significant interaction between MPH, naltrexone, and session (p=0.02).

Figure 3.

Correlation between MPH associated euphoria and MPH associated dysphoria by hour.

Figure 4.

Poisson regression model predicting liking from the MPH x time interaction (Week 6 vs. Week 3 vs. Baseline) (N=31). *There is a significant interaction between MPH and time (p=0.03). Week 3 significantly differs from baseline (p=0.04) and Week 6 significantly differs from Week 3 (p=0.02).