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Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users

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Abstract

Rationale

Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds.

Objectives

The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone.

Methods

Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected.

Results

Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone.

Conclusions

The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration.

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Conflict of interest

This research and the preparation of the manuscript were supported by NIDA grant R01 DA025591 to CRR, T32DA035200 to CRR and KRM, and K02 DA031766 to JAL. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflicts of interest relevant to this research.

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Authors and Affiliations

  1. Department of Psychology, University of Kentucky College of Arts and Sciences, 110 Kastle Hall, Lexington, KY, 40506-0044, USA

    Katherine R. Marks, William W. Stoops & Craig R. Rush

  2. Department of Behavioral Science, University of Kentucky College of Medicine, 110 Medical Behavioral Science Building, Lexington, KY, 40536-0086, USA

    Joshua A. Lile, William W. Stoops & Craig R. Rush

  3. Department of Psychiatry, University of Kentucky College of Medicine, 3470 Blazer Parkway, Lexington, KY, 40509-1810, USA

    Craig R. Rush

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  1. Katherine R. Marks
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  2. Joshua A. Lile
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  4. Craig R. Rush
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Correspondence to Craig R. Rush.

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Fig 1

(Supplementary material) Mean peak subject ratings for oral d-amphetamine on the items Irregular/Heart Racing, Nervous/Anxious, and Shaky/Jittery from the Drug Effect Questionnaire following administration of d-amphetamine and the four pretreatment conditions. An asterisk indicates a significant difference from the corresponding d-amphetamine dose under the placebo pretreatment condition. Other details are as in Fig. 1 (DOC 83 kb)

Fig. 2

(Supplementary material) Mean digits attempted and completed during the DSST following administration of d-amphetamine and the four pretreatment conditions. Other details are as in Figs. 1 and 2 (DOC 68 kb)

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Marks, K.R., Lile, J.A., Stoops, W.W. et al. Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users. Psychopharmacology 231, 2741–2750 (2014). https://doi.org/10.1007/s00213-014-3449-x

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