Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine’s putative anti-addictive activity

This in vitro (cells) study (1995) on ibogaine revealed the mechanisms of action to be at the mu, delta, kappa, opiate, serotonin 2 and 3, muscarinic 1 and 2 receptors, and de dopamine, norepinephrine, and serotonin reuptake sites. Ibogaine also interacted with NMDA associated and sodium ion channels.

Abstract

“The indole alkaloid ibogaine (NIH 10567, Endabuse) is currently being examined for its potential utility in the treatment of cocaine and opioid addiction. However, a clearly defined molecular mechanism of action for ibogaine’s putative anti-addictive properties has not been delineated. Radioligand binding assays targeting over 50 distinct neurotransmitter receptors, ion channels, and select second messenger systems were employed to establish a broad in vitro pharmacological profile for ibogaine. These studies revealed that ibogaine interacted with a wide variety of receptors at concentrations of 1–100 µM. These included the mu, delta, kappa, opiate, 5HT₂, 5HT₃, and muscarinic_{1 and 2} receptors, and the dopamine, norepinephrine, and serotonin uptake sites. In addition, ibogaine interacted with N-methyl-D-aspartic acid (NMDA) associated ion and sodium ion channels as determined by the inhibition of [³H]MK-801 and [³H]bactrachotoxin A 20-α-benzoate binding (BTX-B), respectively. This broad spectrum of activity may in part be responsible for ibogaine’s putative anti-addictive activity.”

Authors: P. M. Sweetnam, J. Lancaster, Adele Snowman, J. L. Collins, S. Perschke, C. Bauer & J. Ferkany

SUmmary

The indole alkaloid ibogaine was studied for its potential utility in the treatment of cocaine and opioid addiction. The study revealed that ibogaine interacted with a wide variety of receptors, ion channels, and select second messenger systems.

Introduction

Indolealkylamines are centrally active compounds that produce stimulatory and anxiogenic effects in animals. Ibogaine, an indole alkyl amine derivative, has been shown to elicit both actions in man and may have therapeutic potential in the treatment of opiate addiction, stimulant abuse, and ethanol dependence.

Ibogaine interacts with many different receptor systems, including serotonergic, dopaminergic, muscarinic, opiate, and amino acid-ergic systems. This study suggests that any one or combination of these activities may be involved in ibogaine’s putative therapeutic action.

Radiotigand binding assays

Ibogaine was tested for its effect on the D2, D3 and D4 receptors using rat forebrain membranes and human receptor clones. The effects of ibogaine were determined by either liquid scintillation or gamma spectrometry.

Initial inhibitory binding determinations were performed in duplicate using freshly prepared ibogaine solution. Concentration-response studies were performed using triplicate tubes and run on 3 different days using different tissue preparations.

Results

Ibogaine inhibited binding at several bioaminergic receptors, including the dopamine uptake site, serotonin and norepinephrine reuptake sites, and 5HT2 and 5HT3 receptors. Ibogaine did not inhibit binding at the 5HTI receptor at concentrations as high as 1 mM.

Ibogaine inhibits the binding of several neurotransmitter reuptake sites, including dopamine, norepinephrine, and serotonin, as well as several serotonin receptor subtypes. Ibogaine does not inhibit the binding of serotonin to the 5HT1 receptor subtypes.

Ibogaine inhibits the opioid subtype receptor binding assays, and displaces [3H]DTG binding to the putative sigma receptor, which is thought to play a potential role in the etiology of psychosis.

We employed several radioligand binding assays to investigate the inhibitory amino acid-ergic receptors, in particular the GABAA receptor complex. Ibogaine did not inhibit any of the classic competitive excitatory amino acid receptor binding sites.

Ibogaine is both a weak M1 and M2 agent as determined by its ability to displace [3H]pirenzepine binding from bovine striatal membranes and [3H]AF- Fig. 3 A and B Ibogaine inhibits binding of [3H]BTX-B to voltage dependent sodium channels and [3H]saxitoxin to sodium site 1 in the rat brain.

Discussion

Ibogaine is an inhibitor of 14 receptors in the central nervous system, including opioid receptor subtypes, catecholamine uptake sites, several serotonin receptor subtypes, and two distinct ion channels. It is nonselective at muscarinic and muscarinica binding sites, and subtype-selective at alpha adrenergic receptors.

Preliminary pharmacokinetic studies with ibogaine revealed that micromolar activity may be important with this compound. This was an important factor in determining the initial screening concentration used (10 gM) and percent binding inhibition (approximately 30%).

Opiate and cocaine abuse studies often center around the ability of compounds to influence dopaminergic synaptic function. Ibogaine’s proposed therapeutic utility may result from interaction with receptors that directly comprise these synapses or those receptors “upstream” or “downstream” which can modulate their function.

Ibogaine inhibits the binding of the cocaine analog WIN-35,248 to the dopamine uptake site, but does not increase dopamine levels through the blockade of dopamine uptake.

Ibogaine interacts at the 5HT2 receptor, and its potential 5HT3 activity may be important in the treatment of cocaine abuse. Zaclopride has been shown to partially block morphine-induced mesolimbic dopamine function and cocaine-induced locomotion, but ondansetron does not appear to modulate the discriminative or reinforcing stimulus of cocaine.

Ibogaine displaced binding to kappa and mu opioid receptors in the low gM range, and this may be a result of procedural differences in the assays employed in each study.

Ibogaine has been reported to attenuate morphine self-administration following acute administration, possibly due to its ability to induce whole body tremors/shakes. However, radioligand binding assays confirmed previous studies which could not find evidence to support such a mechanism of action.

Ibogaine inhibited both [3H]MK-801 and [3H]TCP binding to the ion channel associated with the MK-801 and TCP receptors.

The NMDA receptor may be important for several reasons, including the ability of NMDA receptor antagonists to attenuate or reverse the development of tolerance, dependence or hyperalgesia to repeated administration of various opiates in rodents. However, ibogaine may also have untoward effects through an interaction with the NMDA receptor.

We report a different receptor binding profile from several previous studies. The most notable differences are summarized in Table 3.

Ibogaine interacts with receptor types associated with opiate and cocaine abuse, as well as those only now being linked to addiction and tolerance. Its receptor profile is similar to that of cocaine, suggesting that numerous but distinct molecular mechanisms performing in concert are involved in substance abuse and chronic drug treatment.