Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview

Introduction

Ibogaine (IBO), the principal alkaloid of Tabernanthe iboga, has attracted attention as a potential treatment for substance use disorders (SUDs) because preclinical studies report reductions in drug self-administration and relapse for substances including cocaine, ethanol, nicotine and opioids. Human data are limited: case reports and observational series suggest therapeutic effects that can outlast IBO and noribogaine (NOR) pharmacokinetics, and a single randomised, placebo-controlled trial of a T. iboga extract reported prolonged psychoactive effects and reduced cocaine cravings, but cardiac monitoring was not reported. Safety concerns—most notably QT interval prolongation linked to inhibition of hERG channels and rare fatalities—have impeded clinical development, prompting efforts to develop non-hallucinogenic, less cardiotoxic analogues (for example, tabernanthalog). Pharmacokinetic differences between IBO and its main active metabolite NOR (NOR has a substantially longer half-life) have led to suggestions that NOR contributes importantly to prolonged therapeutic and adverse effects. Ona and colleagues set out to update and synthesise the pharmacological targets of IBO and NOR and to discuss how these multi-target actions could underlie putative anti-addictive effects. Rather than seeking a single ‘‘key target’’, the paper frames IBO/NOR activity within a polypharmacology perspective, aiming to map principal receptor and transporter interactions and to consider how combined actions across systems might produce synergistic benefits relevant to different classes of addictive drugs.