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Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine

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Abstract

The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. Ibogaine undergoes first pass metabolism and isO-demethylated to 12-hydroxyibogamine (12-OH ibogamine). Radioligand binding assays were conducted to identify the potency and selectivity profiles for ibogaine and 12-OH ibogamine. A comparison of 12-OH ibogamine to the primary molecular targets identified previously for ibogaine demonstrates that the metabolite has a binding profile that is similar, but not identical to the parent drug. Both ibogaine and 12-OH ibogamine demonstrated the highest potency values at the cocaine recognition site on the 5-HT transporter. The same rank order (12-OH ibogamine > ibogaine), but lower potencies were observed for the [3H]paroxetine binding sites on the 5-HT transporter. Ibogaine and 12-OH ibogamine were equipotent at vesicular monoamine and dopamine transporters. The metabolite demonstrated higher affinity at the kappa-1 receptor and lower affinity at the NMDA receptor complex compared to the parent drug. Quantitation of the regional brain levels of ibogaine and 12-OH ibogamine demonstrated micromolar concentrations of both the parent drug and metabolite in rat brain. Drug dependence results from distinct, but inter-related neurochemical adaptations, which underlie tolerance, sensitization and withdrawal. Ibogaine’s ability to alter drug-seeking behavior may be due to combined actions of the parent drug and metabolite at key pharmacological targets that modulate the activity of drug reward circuits.

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Authors and Affiliations

  1. Department of Neurology (D4-5), University of Miami School of Medicine, P.O. Box 016960, 33101, Miami, FL, USA

    Julie K. Staley, Qinjie Ouyang, John Pablo & Deborah C. Mash

  2. Metro-Dade County Medical Examiners Department, 1 Bob Hope Road, 33136, Miami, FL, USA

    W. Lee Hearn

  3. Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, P.O. Box 016960, 33101, Miami, FL, USA

    Donna D. Flynn & Deborah C. Mash

  4. Clinical Psychopharmacology Section, Intramural Research Program, National Institute of Drug Abuse/National Institutes of Health, Addiction Research Center, 21224, Baltimore, MD, USA

    Richard B. Rothman

  5. Section on Drug Design and Synthesis, Laboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland, USA

    Kenner C. Rice

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  1. Julie K. Staley
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  2. Qinjie Ouyang
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Staley, J.K., Ouyang, Q., Pablo, J. et al. Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine. Psychopharmacology 127, 10–18 (1996). https://doi.org/10.1007/BF02805969

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  • DOI: https://doi.org/10.1007/BF02805969

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