Between 1991 and 2011, against the backdrop of a PR campaign aimed at convincing consumers that opioids were both safe and non-addictive, the U.S. saw a threefold spike in annual opioid prescription rates (from 76 to 219 million). Before long, misuse and addiction had exploded: In 2020, 3 million people in the U.S. have had or currently live with an OUD. The COVID-19 pandemic only deepened the opioid epidemic; overall drug overdoses shot up 30% in a year to 93,000, of which close to 75% involved opioids.
While public opinion has turned against opioids, the crisis of addiction has unfortunately taken on a life of its own, with many turning to street drugs like heroin when unable to access opioid prescriptions. Moreover, current treatment options for all types of addiction are limited and produce variable results, with relapse rates across substance use disorders estimated to be between 40 and 60% (in line with other chronic conditions like hypertension and asthma).
Yet one little known substance has been quietly building a reputation for unprecedented success in treating opioid addiction: Ibogaine.
History
Ibogaine is a naturally occurring psychoactive compound found in the root bark of the African shrub Tabernanthe iboga, as well as other plants in the Apocynaceae family. Although thought to be used for hundreds – if not thousands – of years in ceremonial and spiritual settings in African communities, the first Western reports of ibogaine use came from French and Belgian explorers in the 19th century.
Ibogaine was first isolated from Tabernanthe iboga by Jan Dybowski and Edouard Landrin in 1901, and independently by Haller and Heckel in the same year. George Büchi would go on to synthesize ibogaine in 1966.
Between 1930 and the 1960s, ibogaine – in the form of an extract from the Tabernanthe manii plant – was marketed as Lambarène in France, purporting efficacy as a both a mental and physical stimulant. Although it enjoyed great popularity among athletes in particular, it was withdrawn from the market when all ibogaine containing medicines were declared illegal in France. At the same time, the World Health Assembly classified ibogaine “as a substance likely to cause dependency or endanger human health”, and the United States Food and Drug Administration assigned it Schedule 1 status (indicating no accepted medical use and high potential for abuse).
Yet anecdotal evidence regarding ibogaine’s therapeutic effects began emerging in the 60s as well. In 1962, Howard Lotsof and five friends – all heroin addicts — began experimenting with ibogaine and found both their cravings and withdrawal symptoms to be significantly reduced. Speaking with the New York Times in 1994, he said he was searching for a new high when he took bitter white powder from an exotic West African Shrub: “The next the thing I knew, I was straight.”
How does ibogaine work – and is it safe?
Ibogaine affects a variety of neurotransmitter systems, but appears to have particularly high affinity for the sigma-2 receptor. In humans, ibogaine is metabolized into noribogaine by the cytochrome P450 2D6 enzyme, which is responsible for the metabolization of many other chemicals, raising the risk of dangerous drug interactions.
Noribogaine – like ibogaine – is a weak NMDA receptor antagonist, as well as a moderate k-opioid receptor agonist and weak µ-opioid receptor agonist. Although exact mechanisms for the production of ibogaine’s dissociative psychedelic effects are unclear, it has been speculated that action at the kappa opioid receptor contributes significantly; Additional effects may come from noribogaine’s function as a potent serotonin reuptake inhibitor.
While there have indeed been reports of complications related to ibogaine, most such cases appear to be due to prior medical conditions or drug interaction. Nevertheless, those with any type of heart condition – in particular prolonged QTC Interval or hypertrophic cardiomyopathy – should avoid ibogaine, as this can lead to dangerous reactions.
Critically, as with any potent psychedelic – especially given that ibogaine’s effects may persist for up to 36 hours – an individual seeking treatment should only ever take ibogaine under direct clinical supervision in a controlled environment.
Therapeutic Potential
Shortly after his inadvertent discovery of ibogaine’s anti-addictive properties, Howard Lotsof began working with a Belgian company to produce a tablet form of ibogaine for clinical trials in the Netherlands; he received a US patent for the product in 1985. 3 years later, results from the first placebo-controlled trial were published, demonstrating attenuation of opioid withdrawal in rats. A number of other studies soon followed, corroborating ibogaine’s apparent efficacy in alleviating addiction not just for opioids, but cocaine and alcohol as well.
Phase 1 tests were carried out on a cohort of 33 heroin addicts. Treated with between 6 and 29 mg/kg of ibogaine, 25 showed improvements in the symptoms of opioid withdrawal.
Today, though ibogaine remains illegal in the United States, some countries – including Canada, Mexico, and the United Kingdom – allow its prescription by a clinician for anti-addiction therapy. Nevertheless, due to ongoing prohibition, as well as safety concerns, large scale studies have not been undertaken and there is currently insufficient data to conclusively determine efficacy. Despite this, anecdotal evidence has continued to pour in, strongly suggesting the potential ibogaine may have in treating the increasingly global issue of addiction in all forms.
Notably, some have questioned the official stance of NIDA and the DEA, which describe Ibogaine as having high abuse potential. Those who have experience treatments regularly describe the experience as among the most challenging of their lives. In an interview with VICE, David Graham Scott described the experience thusly:
“I had an intense visionary experience. There were a lot of time-traveling aspects to it; I was manning a spacecraft going into this grid-like pattern in space. There was a lot to do with evolution too but I can’t remember a lot of it because it was so bizarre and chaotic. Sometimes it was beyond me—I knew it was telling me something but I couldn’t understand it. There were also continual black wavy lines in front of your eyes which made it difficult to see easily. It’s not an easy ride by any means—it’s a heavy, heavy trip (…) Some of the visions were very enlightening but I saw a lot of very disturbing things. Ibogaine has got very little potential as a drug of abuse because not many people would want to do it on a regular basis.”
Moreover, case series and preclinical studies lend further weight to ibogaine’s potential efficacy in treating addiction disorders, as well as for alleviating withdrawal symptoms during detox for heroin, cocaine, and other amphetamines. Additionally, two recent studies sponsored by the Multidisciplinary Association of Psychedelic Studies (MAPS) have corroborated these findings, with cessation or reduced opioid use evident for up to 12-months after treatment. Notably, however, one patient died while under medical supervision.
Finally, the largest observational study of ibogaine’s potential benefits to-date reported that of 88 subjects interviewed, 80% stated that treatment either reduced or eliminated their withdrawal symptoms. At the time of the survey, which took place more than 6-months after treatment, 41% reported total abstinence; and though 70% of the sample eventually reported a relapse following treatment, 48% of those reported decreased use and 11% eventually achieved abstinence. Interestingly, those that responded to the treatment, reported their ibogaine experiences as more spiritually meaningful, mirroring similar findings with psilocybin.
Conclusion
In short, while hurdles remain, ibogaine represents among the most promising treatments for opioid use disorder and other substance abuse disorders. Although its mechanism of action is not fully understood, the strength of anecdotal evidence and the fact ibogaine doesn’t rely on opioid agonism – unlike maintenance treatments with drugs like methadone and buprenorphine – means it represent an entirely new approach to treatment. Encouragingly, clinical trials for ibogaine for alcohol use disorder are underway in Brazil, with more on the horizon.
Critically, ibogaine may be most effective when paired with other types of care. As one participant in the 2017 MAPS study noted, “Iboga could give an opiate addict several months to half a year of freedom from craving, and a period of time in which to get their life together and learn to face things straightforwardly, directly and honestly. Iboga will not do the work for you.”
As with other psychedelics, it’s important not to view ibogaine as a panacea. More often than not, while most patients experience significant reductions in their symptoms, these eventually return, even if at reduced intensity. Because of this, adjuncts like behavioural therapies (e.g. cognitive behavioural therapy) may be necessary to help individuals cope with life stressors and renewed cravings in a healthy way.
Nevertheless, while therapeutic protocols and follow-up treatments are still being developed and clinically verified, what’s clear is that we cannot remain passive in the face of a crisis that claims more than 90 lives a day.
“There have been claims by the government that there’s a high potential for abuse and no medical use and claims from ibogaine advocates that one dose is a miracle cure,” said Rick Doblin, Executive Director of MAPS. “We’re trying to gather some scientific evidence to better evaluate it.”
And as the weight of anecdotal and preclinical evidence mounts, researchers and drug developers will need to expand the size and improve the quality of clinical trials to demonstrate to regulators (especially the US FDA, given that the opioid epidemic is a uniquely American problem) that the benefits of ibogaine outweigh the risks.
Noribogaine
Noribogaine (or 12-hydroxyibogamine) is the principal psychoactive metabolite of the ibogaine. It is thought to be involved in the antiaddictive effects of ibogaine-containing plant extracts, such as the Tabernanthe iboga of Africa.
Much like its parent compound, noribogaine is a potent serotonin reuptake inhibitor, but does not affect the reuptake of dopamine. Unlike ibogaine, noribogaine does not bind to the sigma-2 receptor. Similarly to ibogaine, noribogaine acts as a weak NMDA receptor antagonist and binds to opioid receptors. It has greater affinity for each of the opioid receptors than does ibogaine.
Therefore, noribogaine may have a role as maintenance therapy following initial treatment with ibogaine rather than as a stand-alone drug for acute detoxification. Under these circumstances, the absence of oneirophrenic or hallucinogenic effects would be a key advantage relative to ibogaine, as it would potentially provide for office or even home use of the drug. Therefore, noribogaine offers additional upside potential beyond ibogaine itself.
DemeRx is currently developing ibogaine and noribogaine for the treatment of opioid use disorders.