DARK Classics in Chemical Neuroscience: Ibogaine

This literature review (2018) of the history of ibogaine looks back at the early use, pharmacological studies, and subsequent clinical trials that investigate this compound for the treatment of mental health disorders.

Abstract

“The West African iboga plant has been used for centuries by the Bwiti and Mbiri tribes to induce hallucinations during religious ceremonies. Ibogaine, the principal alkaloid responsible for iboga’s psychedelic properties, was isolated and sold as an antidepressant in France for decades before its adverse effects precipitated its removal from the market. An ibogaine resurgence in the 1960s was driven by U.S. heroin addicts who claimed that ibogaine cured their opiate addictions. Behavioral pharmacologic studies in animal models provided evidence that ibogaine could blunt self-administration of not only opiates but cocaine, amphetamines, and nicotine. Ibogaine displays moderate-to-weak affinities for a wide spectrum of receptor and transporter proteins; recent work suggests that its actions at nicotinic acetylcholine receptor subtypes may underlie its reputed antiopiate effects. At micromolar levels, ibogaine is neurotoxic and cardiotoxic and has been linked to several deaths by cardiac arrest. Structure–activity studies led to the isolation of the ibogaine analog 18-methoxycoronaridine (18-MC), an α3β4 nicotinic receptor modulator that retains ibogaine’s anticraving properties with few or no adverse effects. Clinical trials of 18-MC treatment of nicotine addiction are pending. Ibogaine analogs may also hold promise for treating anxiety and depression via the “psychedelic-assisted therapy” approach that employs hallucinogens including psilocybin and methylenedioxymethamphetamine (“ecstasy”).”

Authors: Michael J. Wasko, Paula A. Witt-Enderby & Christopher K. Surratt

Summary

■ INTRODUCTION

As science and medicine advanced, many drugs were created that greatly improved general health. However, the misuse and abuse of medications has led to a significant societal burden, and the current opioid abuse epidemic has led to a public health emergency.

The Schedule I drug ibogaine was marketed in France under the trade name Lambarene for over 40 years, and was used to detoxify morphine addicts at the Addiction Research Center federal facility in Lexington, Kentucky in 195512.

Howard Lotsof, a teenage New York City heroin addict, encountered ibogaine in 1962 and experienced several hours of vivid hallucinations and a panoramic life review. After taking ibogaine, Lotsof immediately abstained from heroin and became the leading advocate for ibogaine as an FDA-approved medical treatment for opiate addiction.

Buchi and co-workers achieved a total synthesis of ibogaine in 1966, beginning with reduction of N-benzyl-3-cyanopyridinum bromide using aqueous NaBH4. This resulted in isoquinuclidine S1-4, which was then hydrolyzed with concentrated HCl to yield primary amide S1-5. Ibogaine (1) was synthesized by hydrolysis of 6NH2SO4, followed by acetylation with acetic anhydride, and hydrogenolysis to provide the HCl salt of secondary amine S110. Ibogaine (1) and its C4 epimer, S1-15, were then readily separable.

In 2012, ibogaine was synthesized from 4-methoxy-2-iodaniline (S2-1), using triethylchlorosilane (TESCI) and imidazole, followed by silyl deprotection with TBAF to yield 5-methyoxy-2-iodotryptol S2-4 and subsequent iodination to form S2-5 and S2-6.

■ MANUFACTURING INFORMATION

Ibogaine is a compound classified as Schedule I by the Drug Enforcement Administration (DEA), and a Schedule I DEA license is required for a researcher to obtain the drug. The drug is synthesized-to-order via the National Institute on Drug Abuse (NIDA) Drug Supply Program.

■ DRUG METABOLISM

Ibogaine was found in adipose tissue at 100-fold higher levels than plasma after 1 h, suggesting first-pass metabolism by the liver. The half-life of ibogaine is 2 h in rats, 7 h in humans.

Methoxycoronaridine is metabolized to 18-hydroxycoronaridine by CYP2C19, and ibogaine has a plasma concentration of 700 to 1000 ng/mL and a brain concentration of 143 170 ng/g 3 h after infusion. Noribogaine has a high brain penetration rate.

■ STRUCTURE−ACTIVITY RELATIONSHIPS (SAR)

Ibogaine is the most abundant of approximately 80 structurally similar alkaloids found in the Tabernanthe iboga plant. The synthesis and pharmacologic screening of chemical congeners led to the development of 18-methoxycoronaridine (18-MC), a less toxic antiaddictive compound, that retains efficacy in rodent models of inhibiting morphine and cocaine administration.

■ PHARMACOLOGY

Ibogaine triggers its curious effects at the molecular level through binding to many target proteins, with no clear receptor preference. Its active metabolite noribogaine displays sub-micromolar opiate receptor (KOP) affinity and partial agonism.

Ibogaine and noribogaine were effective in decreasing morphine self-administration in rats. They bind to the opiate receptor in the low- and sub-micromolar range, respectively, and have an effect dependent on the assay and model used.

Ibogaine and noribogaine have a similar affinity for the dopamine transporter to amphetamine, although ibogaine binds to and stabilizes the inward-facing transporter conformation in the “alternating-access” mechanism, which is different from that of amphetamine and cocaine. Ibogaine and analogs serve as DAT and SERT “pharmacochaperones”, stabilizing the tertiary structure of the transporter and allowing misfolded mutant versions to refold into functional transporters.

Ibogaine’s action at NMDA receptors may contribute to its analgesic and anti-reinforcing properties. Interestingly, 18-MC has little or no NMDA receptor activity.

Ibogaine, a noncompetitive antagonist at several nicotinic acetylcholine receptors, is thought to have antiaddictive properties via its actions at the nicotinic acetylcholine receptor. Ibogaine and its derivatives have been shown to inhibit nicotine administration in rodent models.

Although ibogaine appears promising in animal models of addiction, it has remained controversial due to life-threatening, dose-dependent adverse effects. Ibogaine has been associated with neurotoxicity in rodents, but the dose used clinically is well below the doses used to cause neuronal toxicity in preclinical settings.

Ibogaine has been associated with nausea, ataxia, headache, nosebleed, seizures, prolongation of the QTc interval, and cardiovascular problems. Pre-existing heart conditions may have contributed to ibogaine’s lethality in 12 of 14 cases with sufficient autopsy data.

Ibogaine triggers hallucinations of 24 h or more. The effects gradually decrease during the following 8 20 h, and it takes 1 3 days to perceive a full return to normal consciousness.

■ HISTORY AND IMPORTANCE IN NEUROSCIENCE

Howard Lotsof advocated for ibogaine’s use in treating opiate addiction, and Stanley Glick and colleagues conducted experiments on rats to test the hypothesis. Ibogaine was found to decrease morphine and cocaine self-administration, water bar presses, and dopamine release in the nucleus accumbens. Noribogaine inhibits nicotine consumption by rats, and decreases food intake by 23%, providing the rationale for assessing 18-MC as an antiobesity candidate.

■ CONCLUSION

The legendary street drug ibogaine is a double-edged sword that can cause cardiovascular damage, neurotoxicity, and even death. The search for an analog that retains the positive aspects of ibogaine but lacks its adverse effects led to the discovery of 18-methoxycoronaridine.

Ibogaine, noribogaine, 18-MC, and other analogs bind to multiple receptor and transporter proteins, but the nicotinic acetylcholine receptor subtypes may be the target.

In the view of the authors, ibogaine’s simultaneous actions at multiple receptors creates the observed behavioral profile.

Ibogaine was once used to treat depression, but was discarded. Ketamine, psilocybin, LSD, and MDMA are now being investigated for treating depression and severe anxiety disorders.

A 19-year-old New York City addict’s curiosity and tenacity launched a worldwide fascination with a hallucinogen that reputedly cured him of his opiate addiction.