Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine

Abstract

Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric acid type A (GABAA) receptors (e.g., alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of d-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and “positive” subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone. Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6–7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected. Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like “positive” subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10 mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior.

Buspirone maintenance does not alter the reinforcing, subjective, and cardiovascular effects of intranasal methamphetamine

“…Methamphetamine also produced a constellation of prototypical stimulant-like subjective effects indicative of abuse potential (e.g., Good Effects and Like Drug) and elevated systolic and diastolic blood pressure. These effects are consistent with the type and magnitude of effects typically observed following methamphetamine administration by various routes (e.g., Hart et al, 2001; Kirkpatrick et al, 2012; Marks et al, 2016; Pike et al, 2016; Stoops et al, 2015), but was not impacted by buspirone maintenance.…”

Naltrexone maintenance fails to alter amphetamine effects on intracranial self-stimulation in rats.

“…. Lastly, naltrexone also attenuated the reinforcing effects of methamphetamine in a human laboratory study (Marks et al, 2016), although no effect was observed in another study with a similar experimental design (Stoops, Pike, Hays, Glaser, & Rush, 2015). Overall, these results suggest that naltrexone is less effective, less potent, and less reliable to block abuse-related effects of amphetamine than of -antagonists like morphine.…”

“…Similarly, studies in healthy as well as amphetamine-dependent subjects have reported that naltrexone maintenance decreased subjective effects of amphetamine (Jayaram-Lindstrom, Konstenius, et al, 2008; Jayaram-Lindstrom, Wennberg, Hurd, & Franck, 2004), and decreased metrics of amphetamine use in a placebo-controlled clinical trial (Jayaram-Lindstrom, Hammarberg, Beck, & Franck, 2008). Lastly, naltrexone also attenuated the reinforcing effects of methamphetamine in a human laboratory study (Marks et al, 2016), although no effect was observed in another study with a similar experimental design (Stoops, Pike, Hays, Glaser, & Rush, 2015). Overall, these results suggest that naltrexone is less effective, less potent, and less reliable to block abuse-related effects of amphetamine than of mu agonists like morphine.…”

Maintenance on naltrexone + amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys

“…Moreover, amphetamine’s own abuse liability is another undesirable amphetamine effect, and previous studies have suggested that naltrexone may attenuate abuse-related effects of amphetamine. For example, naltrexone decreased amphetamine self-administration in rhesus monkeys (Jimenez-Gomez et al, 2011), methamphetamine self-administration in a human laboratory study (Marks et al, 2016) and amphetamine use by patients meeting criteria for amphetamine dependence (Jayaram-Lindstrom et al, 2008). These findings suggest that combinations of amphetamine and naltrexone may have lower abuse liability than amphetamine alone.…”