The Effects of Naltrexone on Subjective Response to Methamphetamine in a Clinical Sample: a Double-Blind, Placebo-Controlled Laboratory Study

Abstract

Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of 'crave drug,' 'stimulated,' and 'would like drug access,' decreased the the post-MA administration timecourse of 'anxious' and increased ratings of 'bad drug effects,' as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA.

Figure 1

Craving scores (methamphetamine urge questionnaire (MAUQ)), presented with standard errors, following control and methamphetamine (MA) cue exposure during both placebo and naltrexone (NTX) conditions. Analyses revealed a significant medication × trial effect, such that NTX attenuated cue-induced craving for MA as compared with placebo. Asterisks represent planned comparisons; ***p<0.001.

Figure 2

Subjective response scores (drug effects questionnaire (DEQ)), presented with standard errors, at baseline (BA) and change from baseline at 5, 10, 15, 20, 30, 60, 90, and 120 min following methamphetamine (MA) administration, during both placebo and naltrexone (NTX) conditions. Analyses revealed a significant main effect of medication, such that NTX attenuated ratings of ‘stimulated,' ‘crave drug,' and ‘would like drug access,' as compared with placebo.

Figure 3

Subjective response scores (drug effects questionnaire (DEQ)), presented with standard errors, at baseline (BA) and change from baseline at 5, 10, 15, 20, 30, 60, 90, and 120 min following methamphetamine (MA) administration, during both placebo and naltrexone (NTX) conditions. Analyses revealed significant medication × trial effects on ‘feel drug effects' and ‘drug high' as compared with placebo (although no post hoc tests were significant). Further, NTX was associated with lower ‘anxious' ratings from MA administration at later time points and greater ‘bad drug effects' during early time points. Asterisks refer to statistically significant post hoc tests, which were conducted at each time point in trial; *p<0.05, **p<0.01.