Naltrexone May Reduce Stimulant-Related Euphoria

Stimulants remain the preferred option for treating attention-deficit/hyperactivity disorder (ADHD), but there are concerns about their potential for misuse. Alternative medications with less addiction potential such as the anti-hypertensive drug guanfacine are available, but clinical research shows that they are not as strong and effective as stimulants.

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A small study published last month in Journal of Clinical Psychiatry suggests that treating ADHD patients with a combination of the opioid blocker naltrexone and methylphenidate could reduce the feelings of euphoria some patients experience when taking stimulants.

Researchers at Massachusetts General Hospital enrolled 37 young adults (aged 18 to 30) with ADHD who reported a feeling of euphoria when taking stimulants. The participants were randomly assigned to take either placebo or 50 mg naltrexone in the morning along with an extended-release methylphenidate formulation taken in the morning and afternoon (up to 80 mg/day).

At baseline and three and six weeks later, the participants were asked to take a drug likeability test, where they answered questions about how good they felt after taking their medications. On the days they were given the drug likeability test, the participants took either an immediate-release methylphenidate pill in the morning or afternoon instead of their regular extended-release medication. Participants took a placebo pill during the other time, so they would not know when they were taking the active dose.

The researchers, led by Thomas Spencer, M.D., the assistant chief of the Pediatric Psychopharmacology Research Program at Mass General, observed that naltrexone significantly reduced the level of “drug liking,” or euphoria, experienced by the participants after taking methylphenidate for three weeks compared with those taking placebo.

At baseline, the participants reported an average methylphenidate liking score of 10 (on a scale of 1 to 29 using the Drug Rating Questionnaire, Subject scale). After three weeks, this score dropped to a 6 among naltrexone users. When the participants took the immediate-release methylphenidate in the morning, coinciding with the naltrexone pill, the average drug liking scores fell to 2.

At the six-week mark, the authors reported that there was no longer any significant difference between the reports of drug liking between the participants in the naltrexone and placebo groups. The authors noted this was not surprising, given that by this time the participants were on stable doses of methylphenidate. Research has shown that stimulants pose the most risk for abuse when introduced abruptly and unevenly, such as the first few weeks of treatment when the optimal dose is being determined.

“It is [also] possible that the experience of euphoria attenuated because the study subjects only had mild euphoria at outset,” Spencer and colleagues wrote. “Our nonsignificant effect for euphoria at week 6 should be viewed with caution due to the possibility of a floor effect, which would have reduced statistical power.”

Blocking euphoria associated with methylphenidate would mean little if naltrexone also blocked the therapeutic effects of methylphenidate. In a separate article in the Journal of Clinical Psychiatry, the authors noted that there were no differences in the clinical efficacy of methylphenidate between participants taking naltrexone or placebo. Both groups had similar declines in their ADHD Investigator Symptom Rating Scale scores over six weeks as well as similar rates of dropout from the study.

“This is a promising approach to make the effects of methylphenidate more specific and personalized to adults with ADHD, [a population] where there is some concern that stimulant-related euphoria will lead to abuse,” said Mark A. Stein, Ph.D., director of the ADHD and Related Disorders Clinic at Seattle Children’s Hospital. Stein noted that this combination approach would not be beneficial in children, as euphoria is seldom reported as a side effect in children taking stimulants; reports of dysphoria, or feeling uneasy, are actually more common.   

“A future step would be to see if it works in a group at risk for substance use disorders, such as adolescents or young adults with history of substance use disorder. It would also be helpful to see if the blocking effect holds for methylphenidate administered other than orally.”

This study was funded by a grant from the U.S. Department of Defense. ■