Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use

This preprint (2023, v2) animal in vivo and human in vitro study examines a new class of oxa-iboga alkaloids (10 & 40 mg/kg) concerning their effects on opioid addiction in rats and their cardiotoxic effects on human heart cells. In contrast to noribogaine, oxa-iboga analogs exhibited no risk of inducing arrhythmia in adult human primary cardiomyocytes, and oxa-noribogaine induced acute and long-lasting suppression of morphine self-administration in rats in response to both single and repeated dosing regimes.

Abstract

“Introduction: Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities. Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, currently approved medications do not reverse the persistent neurocircuitry and psychological changes that underlie addiction states, highlighting an urgent need for radically different therapeutic approaches. Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt maladaptive habits including opioid use in drug-dependent humans. However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias.

Methods: We introduce a new class of iboga alkaloids – “oxa-iboga” – defined as benzofurancontaining iboga analogs and created via structural editing of the iboga skeleton.

Results: The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in addiction models and no cardiac pro-arrhythmic potential, compared to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine intake after a single dose in rat models of addiction and persistent reduction of morphine intake after a short treatment regimen.

Discussion: Oxa-noribogaine maintains and enhances the ability of iboga compounds to effect lasting alteration of addiction-like states while addressing iboga’s cardiac liability. As such, oxa-iboga compounds represent candidates for a new kind of anti-addiction pharmacotherapeutics.”

Authors: Vaclav Havel, Andrew C. Kruegel, Benjamine Bechand, Scot McIntosh, Leia Stallings, Alana Hodges, Madalee G. Wulf, Melissa Nelson, Amanda Hunkele, Mike Ansonoff, John E. Pintar, Christopher Hwu, Najah Abi-Gerges, Saheem A. Zaidi, Vsevolod Katritch, Mu Yang, Jonathan A. Javitch, Susruta Majumdar, Scott E. Hemby & Dalibor Sames

Summary

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States

The authors of this paper are from Columbia University, Fred Wilson School of Pharmacy, High Point University, Columbia University Irving Medical Center, Memorial Sloan Kettering Cancer Center, University of Health Sciences & Pharmacy at St Louis and Washington University School of Medicine, St Louis, MO 63110, USA.

Abstract

Despite extensive efforts to develop pharmacotherapies for substance use disorders, currently approved medications do not reverse the persistent neurocircuitry and psychological changes that underlie addiction states. We introduce a new class of iboga alkaloids, “oxa-iboga”, which exhibit atypical behavioral features compared to standard kappa psychedelics.

Ibogaine, the major psychoactive alkaloid found in the iboga plant, induces profound psychedelic effects that include dream-like states, panoramic and interactive memory recall, experiences of death and rebirth, confrontation with personal trauma, and loosening of maladaptive habits. Ibogaine has been shown to rapidly interrupt opioid drug dependence.

Ibogaine, an anesthetic psychedelic, has a complex chemical structure and a polycyclic tryptamine system that defines the iboga alkaloids. We have developed a nickel-catalyzed process that enables the preparation of the benzofuran iboga analogs, which show greatly potentiated KOR activity on the iboga pharmacological background.

Oxa-iboga is a novel class of iboga alkaloids discovered by structural editing of ibogaine enabled by efficient de novo chemical synthesis. It is highly potent at the kappa opioid receptor and inhibits the serotonin transporter in humans.

Oxa-iboga analogs are potent KOR agonists in vitro

Noribogaine acts as a KOR partial agonist in a bioluminescence resonance energy transfer (BRET) assay for G protein activation, and substitution of the indole NH group with oxygen dramatically accentuates KOR activity. Oxa-noribogaine is more than tenfold selective for KOR versus MOR and about seven-fold over DOR.

Oxa-iboga compounds largely maintain the 5HT reuptake inhibitory activity with a modest loss of potency as compared to noribogaine, and have a marginal increase in potency at the nicotinic receptors.

Oxa-noribogaine induces potent antinociceptive effects in mice in the tail-flick assay (thermal nociception), and the analgesic effect is lost up to a 10 mg/kg dose in KOR knock-out (KOR-KO) mice, whereas a marginal right shift was observed in MOR knock-out (MOR-KO) mice.

KOR agonists induce dose-dependent hallucinosis in humans, accompanied by sedation and mood worsening in healthy subjects. In mice, oxa-noribogaine does not induce sedation, whereas epi-oxa-noribogaine induces a strong sedative effect at an equianalgesic dose, which is completely reversed by KOR antagonist aticaprant.

Oxa-noribogaine showed no aversion or abuse liability at supra-analgesic doses, and demonstrated no acute depressive-like effects in mice at highly analgesic doses. Its pharmacokinetic profile matched well with the in vivo physiological readouts and in vitro pharmacological parameters.

Oxa-noribogaine is an atypical KOR agonist that provides potent analgesia without the common side effects of kappa psychedelics.

Oxa-noribogaine induces potent analgesia in the mouse tail-flick test, is KOR dependent, and causes no sedation at a high analgesic dose, in contrast to epi-oxa-noribogaine which is profoundly sedative. e, f, Sedation of epi-oxa-noribogaine is KOR-driven, g, mice do not develop conditioned place preference or aversion, h, no pro-depressive-like effects were detected using the forced swim test after oxa-noribogaine administration (30 min post administration).

noribogaine reaches high brain concentrations in mice 30 min after injection.

Ibogaine has been associated with severe cardiac side effects, most notably cardiac arrhythmias and sudden death. Noribogaine, with its long circulation and large exposure, appears to be the culprit of cardiac risks.

Preclinical assessment of cardiotoxicity of novel compounds is complicated by species differences in cardiac ion channel expression and pharmacology. A state-of-the-art assay with high predictive validity of clinical cardiac effects was used to assess the cardiotoxicity of iboga alkaloids in adult human primary cardiomyocytes.

Based on available clinical data, we tested noribogaine in the clinically relevant concentration range (0.1-10 mM).

Noribogaine showed a concentration-dependent pro-arrhythmia risk in the human cardiomyocyte assay, whereas oxa-noribogaine showed no pro-arrhythmic potential at any of the concentrations tested. Oxa-noribogaine has a large margin of safety with respect to pro-arrhythmia risk.

Human primary cardiomyocytes were used to test the effects of oxa-iboga analogs on arrhythmia. The results showed that oxa- and epi-oxa-noribogaine had no effect on arrhythmia.

To assess the therapeutic potential of oxa-noribogaine, we used a widely used model of opioid use disorder and other SUDs, the rat intravenous self-administration (SA) paradigm. Noribogaine was used as the standard because it is the dominant and long circulating molecular species after ibogaine’s administration in both humans and rats.

Noribogaine suppressed responding to morphine in the session following administration, and a partial but statistically significant suppression of morphine intake on days 2 and 3, returning to baseline responding on days 4 and 5. Oxa-noribogaine induced a stronger and longer-lasting suppression of morphine intake than morphine, and this suppression was morphine-specific from day 3 onward. A single 10 mg/kg dose of oxa-noribogaine induced a selective acute suppression of operant behavior driven by morphine-related reward without affecting behavior motivated by natural rewards.

The long-term effects of oxa-noribogaine were examined by repeated dosing, dose tapering, and long-term post-treatment effects. The experimental design was guided by the clinical experience with ibogaine.

Overall, oxa-noribogaine significantly reduced morphine SA across all sessions and led to a progressive decrease of morphine intake despite the dose tapering. Individual responses varied, with some subjects showing high and lasting response to a single reset dose, while others required multiple doses.

Oxa-noribogaine induces acute and long-lasting suppression of morphine self-administration in rats. The dose of oxa-noribogaine that induces the strongest suppression is 40 mg/kg, and the repeated dosing regimen significantly reduces morphine self-administration across sessions.

Oxa-noribogaine increases its suppression efficacy on days after its administration, enabling dose tapering.

Discussion

Currently approved medications for treatment of SUDs do not reverse or weaken the persistent negative alterations in neurocircuitry and psychological states that underlie addiction. Ibogaine may be a promising new kind of drug that can induce profound and lasting interruption of addiction states in drug dependent human and animal subjects.

The iboga system provides a rich discovery platform for ibogaine-based compounds. Oxa-iboga compounds accentuate KOR agonistic activity, enhance therapeutic-like activity in models of OUD, and address cardiotoxicity, in comparison to noribogaine.

Preclinical studies of ibogaine and 18-methoxycoronaridine for SUD have shown that ibogaine and noribogaine are superior in terms of efficacy and duration of effect on morphine intake, and thus ibogaine may be a superior iboga candidate for SUD treatment.

A compound called PNU-22394A has been tested in rats for opioid use disorder, but showed no lasting effect beyond the acute and non-selective suppression of heroin and sucrose intake. The compound is structurally and pharmacologically related to lorcaserin, a drug that generated excitement in SUD research prior to its market withdrawal.

Oxa-iboga compounds, which act as potent KOR agonists, exhibit atypical behavioral features compared to standard kappa psychedelics. These compounds maintain and enhance the ability of iboga compounds to effect lasting alteration of addiction-like states while addressing iboga’s cardiac liability.

Acknowledgements

This work was supported by Columbia University, The High Point University, the National Institute on Drug Addiction (NIDA) of the National Institute of Health (NIH), the Hope for Depression Research Foundation (J. A. Javitch) and AnaBios Corporation.

Author contributions

D.S. conceptualized and supervised the work, V.H. performed scale-up synthesis, A.C.K. carried out early synthetic work and supervised initial pharmacological characterization and data interpretation, and B.B. performed mice experiments. S.M. and L.S. performed self-administration and conditioned place preference experiments, A.H. trained rats for self-administration studies and conducted food maintained responding experiments, M.G.W. and M.N. performed BRET functional assays, A.H. performed opioid binding assays, C.H. performed serotonin transporter inhibition assays, and M.A. performed cardiotoxicity studies.