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.

• Authors: Thomas J Spencer, Pradeep Bhide, Jinmin Zhu, Stephen V Faraone, Maura Fitzgerald, Amy M Yule, Mai Uchida, Andrea E Spencer, Anna M Hall, Ariana J Koster, Leah Feinberg, Sarah Kassabian, Barbara Storch, Joseph Biederman
• Journal: The Journal of clinical psychiatry (J Clin Psychiatry) 2018 Mar/Apr Vol. 79 Issue 2 ISSN: 1555-2101 [Electronic] United States
• PMID: 29617066 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © Copyright 2018 Physicians Postgraduate Press, Inc.

Chemical References

• Central Nervous System Stimulants
• Narcotic Antagonists
• Methylphenidate
• Naltrexone

Topics

• Adolescent
• Adult
• Attention Deficit Disorder with Hyperactivity (drug therapy)
• Central Nervous System Stimulants (administration & dosage, adverse effects)
• Double-Blind Method
• Drug Administration Schedule
• Drug-Related Side Effects and Adverse Reactions (drug therapy)
• Euphoria (drug effects)
• Female
• Humans
• Male
• Methylphenidate (administration & dosage, adverse effects)
• Naltrexone (administration & dosage, pharmacology)
• Narcotic Antagonists (administration & dosage, pharmacology)
• Treatment Outcome
• Young Adult