- In adults with ADHD, adding 50 mg naltrexone to long-acting methylphenidate decreased the likeability of methylphenidate during the titration phase of treatment, although not the maintenance phase
- The titration phase appears to be a period of heightened vulnerability to euphoric effects of stimulants
- The findings support the concept of combining an opioid receptor antagonist with a stimulant to reduce abuse potential
Central nervous stimulants are the class of drugs most often prescribed for attention deficit hyperactivity disorder (ADHD), but their use is problematic. Stimulants are often abused because they activate the mu-opioid receptor, which is associated with euphoria. One study estimated that 5-35% of college-age young adults were using stimulants without a prescription.
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In a previous study published in Neuropharmacology, Massachusetts General Hospital researchers found that naltrexone, an opioid antagonist, could block the rewarding effects of methylphenidate in mice. Naltrexone is approved by the FDA for the treatment of opioid use disorder and alcoholism.
In a new study published in the Journal of Clinical Psychiatry, a Mass General team led by Thomas J. Spencer, MD, and Joseph Biederman, MD, has shown that coadministration of naltrexone with a stimulant can attenuate euphoria in young adults with ADHD.
The open-label study conducted between January 2013 and June 2015 involved 37 medication-naive individuals with ADHD, 18 to 30 years old. Subjects were preselected for having experienced euphoria with a test dose of immediate-release methylphenidate (IR-MPH).
The subjects were randomly assigned to receive a daily dose of either placebo or 50 mg naltrexone for six weeks. They all were given a daily dose of the stimulant Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH), also known as Ritalin LA. This long-acting drug contains 50% immediate-release beads and 50% extended-release beads.
During the first three weeks of the study, SODAS-MPH was titrated up to 80 mg/day, and for the next three weeks it was continued at a stable dose (highest tolerated dose ≤80 mg/day).
At week three (after the titration period), subjects were tested to see whether naltrexone was suppressing the euphoria-producing effects of MPH. This consisted of taking a naltrexone dose in the morning but not SODAS-MPH. They then took either placebo or a supratherapeutic dose of IR-MPH (60 mg). The patient then rated the “likeability” of the capsule (euphoric effects) every hour for four hours, using the Liking a Drug Effect Scale of the Drug Rating Questionnaire, Subject version. In the afternoon, they took the opposite capsule (placebo or IR-MPH) and rated its likeability in the same way.
The likeability assessments were repeated at the end of the study, week six. The researchers did two sets of assessments because they suspected a higher risk of euphoric effects during the titration phase, when the dose of SODAS-MPH was being increased.
Reduction in Euphoria
The primary outcome measure was the effect of naltrexone on MPH-induced euphoria at week three. At that time point, ratings of euphoria significantly differed between the IR-MPH and placebo groups (P = .02). Ratings of euphoria were significantly lower when IR-MPH was given in the morning than when it was given in the afternoon (P = .02).
The latter finding is important, the researchers say, because it suggests that the euphoria-blocking effect of naltrexone may be maximally beneficial if naltrexone is given close in time to MPH.
At week six, subjects reported only mild euphoria associated with IR-MPH, which was not significantly more than with placebo. Thus, the titration phase of treatment with SODAS-MPH does appear to be a period of heightened vulnerability.
All subjects in this study were white and were referred for ADHD treatment, the researchers add, and the researchers caution that the findings cannot be generalized beyond such a population.
Future studies should examine whether coadministration of naltrexone reduces euphoria. There is also a need to determine the estimated street value of MPH among patient populations that are more ethnically diverse and among volunteers with substance use disorders not seeking ADHD treatment.
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