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Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals

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Abstract

Rationale

In laboratory animals, the biological stressor yohimbine (α2-noradrenergic autoreceptor antagonist) promotes drug seeking. Human laboratory studies have demonstrated that psychological stressors can increase drug craving but not that stressors alter drug seeking.

Objectives

This clinical study tested whether yohimbine increases opioid-seeking behavior.

Methods

Ten heroin-dependent, buprenorphine-stabilized (8 mg/day) volunteers sampled two doses of hydromorphone [12 and 24 mg IM in counterbalanced order, labeled drug A (session 1) and drug B (session 2)]. During each of six later sessions (within-subject, double-blind, randomized crossover design), volunteers could respond on a 12-trial choice progressive ratio task to earn units (1 or 2 mg) of the sampled hydromorphone dose (drug A or B) vs money ($2) following different oral yohimbine pretreatment doses (0, 16.2, and 32.4 mg).

Results

Behavioral economic demand intensity and peak responding (O max) were significantly higher for hydromorphone 2 than 1 mg. Relative to placebo, yohimbine significantly increased hydromorphone demand inelasticity, more so for hydromorphone 1-mg units (P max = 909, 3,647, and 3,225 for placebo, 16.2, and 32.4 mg yohimbine doses, respectively) than hydromorphone 2-mg units (P max = 2,656, 3,193, and 3,615, respectively). Yohimbine produced significant but clinically modest dose-dependent increases in blood pressure (systolic ≈ 15 and diastolic ≈ 10 mmHg) and opioid withdrawal symptoms, and decreased opioid agonist symptoms and elated mood.

Conclusions

These findings concur with preclinical data by demonstrating that yohimbine increases drug seeking; in this study, these effects occurred without clinically significant subjective distress or elevated craving, and partly depended on opioid unit dose.

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Acknowledgments

NIH grant R01 DA015462 from the National Institute on Drug Abuse and a State of Michigan grant (Joe Young, Sr. Funds) supported this research. Data for this study were obtained under registered NIH clinical trial NCT00684840. Preliminary data were presented orally at the June 2010 meeting of the College on Problems of Drug Dependence. The authors thank Dr. Carl Christensen for medical screening and monitoring; Ken Bates for recruiting participants; and Debra Kish, Joi Moore, Lisa Sulkowski, and Melissa Williams for experimental data collection and management.

Conflict of interest

The authors declare no conflict of interest with respect to the conduct or content of this work.

Disclosures

Dr. Greenwald has received compensation as a consultant to Reckitt-Benckiser Pharmaceuticals, Inc., the company that markets buprenorphine products. Both Dr. Greenwald and Dr. Steinmiller have received compensation from Titan Pharmaceuticals, Inc., which manufactures a buprenorphine product. Dr. Lundahl has received compensation from Gateway Community Health (Michigan) and the National Football League.

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Authors and Affiliations

  1. Substance Abuse Research Division, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 2761 East Jefferson Ave., Detroit, MI, 48207, USA

    Mark K. Greenwald, Leslie H. Lundahl & Caren L. Steinmiller

  2. Department of Pharmacology, University of Toledo, Toledo, OH, USA

    Caren L. Steinmiller

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  1. Mark K. Greenwald
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  2. Leslie H. Lundahl
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Correspondence to Mark K. Greenwald.

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Greenwald, M.K., Lundahl, L.H. & Steinmiller, C.L. Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals. Psychopharmacology 225, 811–824 (2013). https://doi.org/10.1007/s00213-012-2868-9

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