What We Have Gained from Ibogaine: α3β4 Nicotinic Acetylcholine Receptor Inhibitors as Treatments for Substance Use Disorders

Summary & key facts

Researchers reviewing ibogaine and its chemical relatives say these drugs point to a new way to treat substance use disorders by blocking a brain receptor called α3β4 nicotinic acetylcholine receptor (nAChR). Animal studies found ibogaine and some derivatives reduced self-use of drugs like morphine, cocaine, alcohol, and nicotine. But ibogaine can cause serious heart and psychological side effects, so scientists are trying to make safer α3β4-targeting compounds. The idea is promising, but stronger clinical trials and better-tolerated drugs are still needed.

Key facts:

• Ibogaine has been studied for decades as a possible treatment for substance use disorders, with an early clinical test in 1955 and five related patents issued between 1985 and 1992.
• Preclinical (animal) studies reported that ibogaine reduced self-administration of morphine, cocaine, alcohol, and nicotine in rats.
• Ibogaine and its major metabolite noribogaine block hERG heart channels and can cause QT interval prolongation that may last over a week and can progress to acute heart failure or cardiopulmonary arrest.
• Derivatives such as coronaridine and 18-methoxycoronaridine (18-MC) reduced drug self-administration in rats but caused less tremoring or neurotoxicity than ibogaine in those animal studies.
• Inhibition of α3β4 nAChRs is described in the paper as a probable mechanism for the anti-addictive effects of ibogaine and some derivatives, rather than a proven clinical cure.
• The α3β4 nAChR subtype is concentrated in the medial habenula–interpeduncular nucleus (MHb–IPN) pathway, which connects to the brain’s dopamine reward area (ventral tegmental area), a circuit linked to addiction.
• Human brains express 11 neuronal nAChR subunits (eight α-subunits and three β-subunits), and genetic variations in α3β4-related genes have been linked to higher risk for tobacco and alcohol problems in some studies.

Abstract

For decades, ibogaine─the main psychoactive alkaloid found in Tabernanthe iboga─has been investigated as a possible treatment for substance use disorders (SUDs) due to its purported ability to interrupt the addictive properties of multiple drugs of abuse. Of the numerous pharmacological actions of ibogaine and its derivatives, the inhibition of α3β4 nicotinic acetylcholine receptors (nAChRs), represents a probable mechanism of action for their apparent anti-addictive activity. In this Perspective, we examine several classes of compounds that have been discovered and developed to target α3β4 nAChRs. Specifically, by focusing on compounds that have proven efficacious in pre-clinical models of drug abuse and have been evaluated clinically, we highlight the promising potential of the α3β4 nAChRs as viable targets to treat a wide array of SUDs. Additionally, we discuss the challenges faced by the existing classes of α3β4 nAChR ligands that must be overcome to develop them into therapeutic treatments.

Topics

Chemical synthesis and alkaloids Neurotransmitter Receptor Influence on Behavior Nicotinic Acetylcholine Receptors Study

Categories

Biochemistry, Genetics and Molecular Biology Life Sciences Molecular Biology

Tags

Acetylcholine receptor Addiction Alkaloid Biochemistry Chemistry Drug Drugs of abuse In vitro Mechanism of action Medicine Neuroscience Nicotine Nicotinic acetylcholine receptor Nicotinic agonist Pharmacology Psychology Receptor Stereochemistry