Title

Noribogaine: An active metabolite of the indole alkaloid ibogaine as an anti-addiction pharmacotherapy

Date of Award

2000

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Neuroscience

First Committee Member

Deborah C. Mash, Committee Chair

Abstract

The consequences of drug abuse (e.g. overdoses, and violent crime) continues to increase the burden on an already over-burdened health care system. A non-addicting pharmacological agent in combination with psychotherapy may prove a viable alternative to interdiction of supply and incarceration. Anecdotal reports from addict self-help groups suggest that ibogaine may block opiate withdrawal and reduce drug craving for cocaine and heroin for extended time periods. While ibogaine has diverse CNS effects, the pharmacological targets underlying the physiological and psychological actions of ibogaine are not completely understood. The purported efficacy of ibogaine following single dose administrations has led to the suggestion that a long-acting metabolite of ibogaine may explain in part how the drug reduces craving for psychostimulants and opiates. The purpose of this dissertation was to determine the metabolic disposition of ibogaine, investigate the basis of gender differences in pharmacokinetics, and to determine the mechanism of action of the long-acting metabolite.The results of this dissertation demonstrate that: (1) ibogaine is O-demethylated to noribogaine predominantly by the isozyme CYP2D6; (2) gender differences in behavioral studies following ibogaine administration may be due to the sex hormone-dependent biotransformation of ibogaine to noribogaine; (3) noribogaine acts as a full agonist at the mu opioid receptor likely leading to an alleviation of the symptoms of withdrawal; and (4) preliminary assays using tritiated noribogaine demonstrate multiphasic affinities displaying constants that are in agreement with inhibitory constants from previous studies demonstrating affinities for the 5HT transporter and mu opioid receptor. Taken together, the results of this dissertation indicate that given the long-term presence of noribogaine along with its capacity to reset multiple opioid receptors and block reuptake at the 5HT transporter may explain how only a single dose of ibogaine in humans is able to block withdrawal symptoms and to interrupt psychostimulant and opiate dependence in humans.

Keywords

Biology, Neuroscience; Health Sciences, Rehabilitation and Therapy; Health Sciences, Pharmacology

Link to Full Text

http://access.library.miami.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:9972552