Physiological and subjective effects of acute intranasal methamphetamine during extended-release alprazolam maintenance

Abstract

Background Medications development for methamphetamine dependence is ongoing, but no widely accepted, effective pharmacotherapy has been identified. Previous studies have demonstrated neurobiological perturbations to central GABAA activity following chronic stimulant use, and that positive modulation of GABAA receptors attenuates the neurochemical and behavioral response to stimulant drugs such as methamphetamine. Therefore, GABAA modulators could be useful as pharmacotherapies for stimulant-use disorders. Methods This study tested the hypothesis that intranasal methamphetamine would be safe and well tolerated during maintenance on extended-release alprazolam (XR), and that the effects of methamphetamine would be attenuated. Eight non-treatment-seeking, stimulant-dependent individuals completed an inpatient experiment in which ascending doses of intranasal methamphetamine (0, 5, 10, 20 and 30 mg) were administered after four days of alprazolam XR maintenance (0 and 1 mg/day). Results Intranasal methamphetamine produced prototypical effects (e.g., increased positive subjective ratings and elevated cardiovascular signs). The combination of intranasal methamphetamine and alprazolam XR was safe and well tolerated. Alprazolam XR produced small, but orderly, reductions in some of the subjective effects of methamphetamine, and performance impairment. Conclusions The present results demonstrate that methamphetamine use during alprazolam XR treatment would not pose a significant safety risk. Given the potential of GABAA positive modulators to manage certain aspects of stimulant abuse and dependence (i.e., drug-induced seizures, anxiety and stress), but the relatively small impact on the acute abuse-related effects of methamphetamine observed here, additional research with GABAA positive modulators is warranted, but should consider their use as an adjunct component of combination behavioral and/or drug treatment.

Methamphetamine self-administration in humans during d-amphetamine maintenance

“…Methamphetamine administered alone dose dependently increased positive subject-rated drug-effects (e.g., Like Drug; Willing to Take Again), which is consistent with the results of previous research (e.g., [21][22][23][24]. d-Amphetamine maintenance attenuated some of the positive subject-rated drug-effects, which is consistent with a previous study that showed 45 mg/day d-amphetamine reduced the subject-rated drug-effects of methamphetamine (8).…”

“…Finally, methamphetamine dose dependently increased systolic blood pressure and d-amphetamine maintenance attenuated these increases, compared to placebo maintenance. These findings are consistent with the results of prior studies that showed intranasal methamphetamine is safe and well-tolerated in a controlled laboratory setting (8,16,17,(22)(23)(24) and that d-amphetamine maintenance reduces some of the cardiovascular effects of methamphetamine (8). The attenuation of cardiovascular effects of methamphetamine during d-amphetamine maintenance may be attributable to participants developing cross-tolerance to the cardiovascular effects of stimulants.…”

Methamphetamine Self-Administration in Humans During d-Amphetamine Maintenance

“…Third, the sample size was relatively small. The sample size was chosen based on other human laboratory studies that tested the behavioral effects of methamphetamine alone and during maintenance on potential medications to treat methamphetamine abuse that detected statistically significant effects (8, 23, 27, 33). This sample size was sufficient to detect changes in the reinforcing effects of cocaine following d -amphetamine maintenance (11).…”

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

“…27 In human laboratory experiments, acute pretreatment with naltrexone 11,28,29 and alprazolam 11,30 reduced the subject-rated effects of d -amphetamine in separate studies. Maintenance on 1 mg/day alprazolam XR also produced a small, but orderly attenuation of some subject-rated effects of methamphetamine 31 , and likewise, maintenance on 50 mg/day naltrexone modestly decreased a subset of “positive” subject-rated drug effects of intravenous methamphetamine 32 , in individuals who met criteria for stimulant-use disorders (but see 33 ).…”

“…Although alprazolam has known abuse potential, 35–37 the prior research described above demonstrated its ability to reduce the abuse-related effects of stimulants, 11,24,27,30,31,38 so it was selected for initial proof-of-concept testing in an attempt to demonstrate the initial efficacy of maintenance on naltrexone and a potent GABA A positive allosteric modulator to attenuate the response to methamphetamine.…”