Euphoria associated with the stimulant methylphenidate may be mitigated by co-administration of naltrexone in patients with attention-deficit/hyperactivity disorder (ADHD), according to a study published in the Journal of Clinical Psychiatry.

Methylphenidate has been shown to bind to μ-opioid receptors, and to elicit conditioned place preference when administered at supratherapeutic doses in animal studies — an effect that was blocked by the mixed opioid receptor antagonist naltrexone.2

In this double-blind placebo-controlled randomized trial ( identifier: NCT01673594) conducted over a 6-week period, 37 adult patients with ADHD (age 18 to 30; medication-naïve) who experienced euphoria after a 60-mg test dose of immediate-release methylphenidate were enrolled.

Study participants were randomly assigned to receive 50 mg naltrexone or placebo daily in addition to Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH; titration at approximately 1 mg/kg/day for 3 weeks; continuation for another 3 weeks; twice daily). Abuse liability was evaluated with a “likeability assessment” (primary outcome; Drug Rating Questionnaire-Subject version [DRQ-S]) after a single supratherapeutic dose (60 mg) of immediate-release methylphenidate followed by placebo (or vice versa) at baseline and at 3 and 6 weeks. When likability was assessed, study participants were administered naltrexone, but not SODAS-MPH.

A total of 31 individuals were evaluated at the 3-week follow-up (naltrexone: n=15; mean age, 25.1; 40% men; placebo: n=16; mean age, 24.4; 50% men). There were 25 patients who completed the study.

Study participants treated with naltrexone vs placebo had lower drug-liking (euphoria) during the 3-week titration but not during the maintenance phase, as assessed with question 2 of the DRQ-S (titration phase: 𝛘2 = 5.07; P =.02) The effect of naltrexone in diminishing “drug liking” was more pronounced when immediate-release methylphenidate  was administered in the morning vs the afternoon (𝛘2 = 5.20; P =.02), suggesting a greater effect when administered closer in time to the stimulant bolus.

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Study strengths included translation from animal to human models, use of a double-blind setup, and use of an enriched patient sample sensitive to stimulant-induced euphoria. Study limitations included not accounting for naltrexone’s effects on polysubstance users and an inability to generalize findings to younger or non-white populations.

During the titration phase of SODAS-MPH administration — believed to represent a period of higher vulnerability — naltrexone mitigated stimulant-induced euphoria. “These findings could lead to the development of a non-addictive form of stimulant treatment for ADHD, which could facilitate access to an effective ADHD treatment,” concluded the study authors.

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  1. Spencer TJ, Bhide P, Zhu J, et al. The mixed opioid receptor antagonist naltrexone mitigates stimulant-induced euphoria: a double-blind, placebo-controlled trial of naltrexoneJ Clin Psychiatry. 2018;79(2):17m11609. doi:10.4088/jcp.17m11609
  2. Zhu J, Spencer TJ, Liu-chen LY, Biederman J, Bhide PG. Methylphenidate and μ opioid receptor interactions: a pharmacological target for prevention of stimulant abuse. Neuropharmacology. 2011;61(1-2):283-292.