Ibogaine

Ibogaine

Clinical data
Routes of administration	oral
ATC code	none
Legal status
Legal status	AU: S4 (Prescription only) CA: Legal US: Schedule I
Pharmacokinetic data
Elimination half-life	2 hours
Identifiers
IUPAC name 12-Methoxyibogamine
CAS Number	83-74-9 Y
PubChem CID	197060
ChemSpider	170667 Y
UNII	3S814I130U
ChEMBL	ChEMBL1215855 Y
CompTox Dashboard (EPA)	DTXSID20894069
ECHA InfoCard	100.001.363
Chemical and physical data
Formula	C20H26N2O
Molar mass	310.433 g/mol g·mol−1
3D model (JSmol)	Interactive image
Melting point	152 to 153 °C (306 to 307 °F)
SMILES O(c1ccc2c(c1)c3c(n2)[C@@H]5C[C@H]4C[C@@H]([C@@H]5N(CC3)C4)CC)C
InChI InChI=1S/C20H26N2O/c1-3-13-8-12-9-17-19-15(6-7-22(11-12)20(13)17)16-10-14(23-2)4-5-18(16)21-19/h4-5,10,12-13,17,20-21H,3,6-9,11H2,1-2H3/t12-,13+,17+,20+/m1/s1 Y Key:HSIBGVUMFOSJPD-CFDPKNGZSA-N Y
(verify)

Ibogaine is a naturally occurring psychoactive substance found in a plant in a member of the Apocynaceae family known as Iboga (Tabernanthe iboga). A hallucinogen with both psychedelic and dissociative properties, the substance is banned in some countries; in other countries it is being used to treat addiction to methadone, heroin, alcohol, cocaine, methamphetamine, and other drugs. Derivatives of ibogaine that lack the substance's hallucinogenic properties are under development.

Ibogaine-containing preparations are used in medicinal and ritual purposes within African spiritual traditions of the Bwiti, who claim to have learned it from the Pygmy peoples. Although it was first commonly advertised as having anti-addictive properties in 1962 by Howard Lotsof, its western use predates that by at least a century. In France it was marketed as Lambarene, a medical drug used as a stimulant. Additionally, the U.S. Central Intelligence Agency (CIA) studied the effects of ibogaine in the 1950s.

Ibogaine is an indole alkaloid that is obtained either by extraction from the iboga plant or by semi-synthesis from the precursor compound voacangine, another plant alkaloid. A full organic synthesis of ibogaine has been achieved. The synthesis process is too expensive and challenging to be used to produce a commercially significant yield. The synthesis was published with U.S. patent 2,813,873 in 1956. The free base has been characterised by X-ray crystallography., while the HBr salt has been characterised also.

While ibogaine's prohibition in several countries has slowed scientific research into its anti-addictive properties, the use of ibogaine for drug treatment has grown in the form of a large worldwide medical subculture. Ibogaine is also used to facilitate psychological introspection and spiritual exploration.

History

It is uncertain exactly how long iboga has been used in African spiritual practice, but its activity was first observed by French and Belgian explorers in the 19th century. The first botanical description of the Tabernanthe iboga plant was made in 1889. Ibogaine was first isolated from T. iboga in 1901 by Dybowski and Landrin and independently by Haller and Heckel in the same year using T. iboga samples from Gabon. In the 1930s, ibogaine was sold in France in 8 mg tablets under the name "Lambarene". The total synthesis of ibogaine was accomplished by G. Büchi in 1966. Since then, several further totally synthetic routes have been developed.

In the early 1960s, anecdotal reports appeared concerning ibogaine's effects. The use of ibogaine in treating substance use disorders in human subjects was first observed by Howard Lotsof in 1962, for which he was later awarded U.S. patent 4,499,096 in 1985.

Ibogaine was placed in US Schedule 1 in 1967 as part of the US government's strong response to the upswing in popularity of psychedelic substances, though iboga itself was scarcely known at the time. Ibogaine's ability to attenuate opioid withdrawal confirmed in the rat was first published by Dzoljic et al. (1988). Ibogaine's use in diminishing morphine self-administration in preclinical studies was shown by Glick et al. (1991) and ibogaine's capacity to reduce cocaine self-administration in the rat was shown by Cappendijk et al. in 1993. Animal model support for ibogaine claims to treat alcohol dependence were established by Rezvani in 1995.

The name "Indra extract", in strict terms, refers to 44 kg of an iboga extract manufactured by an unnamed European industrial manufacturer in 1981. This stock was later purchased by Carl Waltenburg, who distributed it under the name "Indra extract". Waltenburg used this extract to treat heroin addicts in Christiania, Denmark, a squatter village where heroin addiction was widespread in 1982. Indra extract was offered for sale over the Internet until 2006, when the Indra web presence disappeared. It is unclear whether the extracts currently sold as "Indra extract" are actually from Waltenburg's original stock, or whether any of that stock is even viable or in existence. Ibogaine and related indole compounds are susceptible to oxidation when exposed to oxygen.

An ibogaine research project was funded by the US National Institute on Drug Abuse in the 1990s. The National Institute on Drug Abuse (NIDA) abandoned efforts to continue this project into clinical studies in 1995. Data demonstrating ibogaine's efficacy in attenuating opioid withdrawal in drug-dependent human subjects was published by Alper et al. (1999) and Mash et al. (2000).

Synthesis

One recent total synthesis of ibogaine and related drugs starts with 2-iodo-4-methoxyaniline which is reacted with triethyl((4-(triethylsilyl)but-3-yn-1-yl)oxy)silane using palladium acetate in DMF to form 2-(triethylsilyl)-3-(2-((triethylsilyl)oxy)ethyl)-1H-indole. This is converted using N-iodosuccinamide and then fluoride to form 2-(2-iodo-1H-indol-3-yl)ethanol. This is treated with iodine, triphenyl phosphine and imidazole to form 2-iodo-3-(2-iodoethyl)-1H-indole. Then using 7-ethyl-2-azabicyclo[2.2.2]oct-5-ene and cesium carbonate in acetonitrile the ibogaine precursor 7-ethyl-2-(2-(2-iodo-1H-indol-3-yl)ethyl)-2-azabicyclo[2.2.2]oct-5-ene is obtained. Using palladium acetate in DMF the ibogaine is obtained. If the exo ethyl group on the 2-azabicyclo[2.2.2]octane system in ibogaine is replaced with an endo ethyl then epiibogaine is formed.

Side effects and safety

One of the first noticeable effects of large-dose ibogaine ingestion is ataxia, a difficulty in coordinating muscle motion which makes standing and walking difficult without assistance. Xerostomia (dry mouth), nausea, and vomiting may follow. These symptoms may be long in duration, ranging from 4 to 24 hours in some cases. Ibogaine is sometimes administered by enema to help the subject avoid vomiting up the dose. Psychiatric medications are strongly contraindicated in ibogaine therapy due to adverse interactions. Some studies also suggest the possibility of adverse interaction with heart conditions. In one study of canine subjects, ibogaine was observed to increase sinus arrhythmia (the normal change in heart rate during respiration). It was proposed that there is a risk of QT-interval prolongation following ibogaine administration. This risk was further demonstrated by a case reported in the New England Journal of Medicine documenting prolonged QT interval and ventricular tachycardia after initial use.

Fatalities following ibogaine ingestion are documented in the medical literature. Lethal respiratory and cardiac effects are associated with use. Also, because ibogaine is one of the many drugs that are partly metabolized by the cytochrome P450 complex, caution must be exercised to avoid foods or drugs that inhibit CP450, in particular foodstuffs containing bergamottin or bergamot oil, common ones being grapefruit juice.

Therapeutic uses

Treatment for opioid addiction

The most-studied therapeutic effect of ibogaine is the reduction or elimination of addiction to opioids. An integral effect is the alleviation of symptoms of opioid withdrawal. Research also suggests that ibogaine may be useful in treating dependence on other substances such as alcohol, methamphetamine, and nicotine and may affect compulsive behavioral patterns not involving substance abuse or chemical dependence. Researchers note that there remains a "need for systematic investigation in a conventional clinical research setting."

Many users of ibogaine report experiencing visual phenomena during a waking dream state, such as instructive replays of life events that led to their addiction, while others report therapeutic shamanic visions that help them conquer the fears and negative emotions that might drive their addiction. It is proposed that intensive counseling, therapy and aftercare during the interruption period following treatment is of significant value. Some individuals require a second or third treatment session with ibogaine over the course of the next 12 to 18 months. A minority of individuals relapse completely into opiate addiction within days or weeks. A comprehensive article (Lotsof 1995) on the subject of ibogaine therapy detailing the procedure, effects and aftereffects is found in "Ibogaine in the Treatment of Chemical Dependence Disorders: Clinical Perspectives". Ibogaine has also been reported in multiple small-study cohorts to reduce cravings for methamphetamine.

There is also evidence that this type of treatment works with LSD, which has been shown to have a therapeutic effect on alcoholism. Both ibogaine and LSD appear to be effective for encouraging introspection and giving the user occasion to reflect on the sources of their addiction, while also producing an intense, transformative experience that can put established patterns of behaviour into perspective; ibogaine has the added benefit of preventing withdrawal effects.

Shredded bark of tabernanthe iboga for consumption. Contains ibogaine.

Chronic pain management

In 1957, Jurg Schneider, a pharmacologist at CIBA, now Novartis, found that ibogaine potentiates morphine analgesia. Further research was abandoned, and no additional data was ever published by Ciba researchers on ibogaine–opioid interactions. Almost 50 years later, Patrick Kroupa and Hattie Wells released the first treatment protocol for concomitant administration of ibogaine with opioids in human subjects, indicating ibogaine reduced tolerance to opioid drugs. They published their research in the Multidisciplinary Association for Psychedelic Studies Journal demonstrating that administration of low-"maintenance" doses of ibogaine HCl with opioids decreases tolerance. It should be noted however, that the potentiation action of ibogaine may make this a very risky procedure.

Psychotherapy

Ibogaine has been used as an adjunct to psychotherapy by Claudio Naranjo, documented in his book The Healing Journey. He was awarded CA 939266  in 1974.

Formulations

In Bwiti religious ceremonies, the root bark is pulverized and swallowed in large amounts to produce intense psychoactive effects. In Africa, iboga root bark is sometimes chewed, releasing small amounts of ibogaine to produce a stimulant effect. Ibogaine is also available in a total alkaloid extract of the Tabernanthe iboga plant, which also contains all the other iboga alkaloids and thus has only about half the potency by weight as standardized ibogaine hydrochloride.

Currently, pure crystalline ibogaine hydrochloride is the most standardized formulation. It is typically produced by semi-synthesis from voacangine in commercial laboratories. Ibogaine has two separate chiral centers, meaning that there are four different stereoisomers of ibogaine. These four isomers are difficult to resolve.

A synthetic derivative of ibogaine, 18-methoxycoronaridine (18-MC), is a selective α3β4 antagonist that was developed collaboratively by the neurologist Stanley D. Glick (Albany) and the chemist Martin E. Kuehne (Vermont). This discovery was stimulated by earlier studies on other naturally occurring analogues of ibogaine such as coronaridine and voacangine that showed these compounds also have anti-addictive properties.

Psychoactive effects

Ibogaine is a hallucinogen. The experience of Ibogaine is broken down in two phases; the visionary phase comes first, then the introspection phase.

The visionary phase has been described as oneirogenic and lasts for 4 to 6 hours. The second phase, the introspection phase, is responsible for the psychotherapeutic effects of ibogaine. It can allow people to conquer their fears and negative emotions.

Ibogaine has been referred to as an oneirogen, referring to the dreamlike nature of its hallucinogenic effects. Ibogaine catalyzes an altered state of consciousness reminiscent of dreaming while fully conscious and aware so that memories, life experiences, and issues of trauma can be processed.

Pharmacology

Ki-values in μM (a smaller value demonstrates higher binding affinity)

Receptor	Ibogaine	Noribogaine
κ-opioid	2.2	0.61
μ-opioid	2.0	0.68
δ-opioid	>10	5.2
NMDA	3.1	15
5-HT2A	16	>100
5-HT2C	>10	>10
5-HT3	2.6	>100
σ1	2.5	11
σ2	0.4	19

The pharmacology of ibogaine is quite complex, affecting many different neurotransmitter systems simultaneously. Because of its fairly low potency at any of its target sites, ibogaine is used in doses anywhere from 5 mg/kg of body weight for a minor effect to 30 mg/kg in the cases of strong polysubstance addiction. It is unknown whether doses greater than 30 mg/kg in humans produce effects that are therapeutically beneficial, medically risky, or simply prolonged in duration. In animal neurotoxicity studies, there was no observable neurotoxicity of ibogaine at 25 mg/kg, but at 50 mg/kg, one-third of the rats had developed patches of neurodegeneration, and at doses of 75 mg/kg or above, all rats showed a characteristic pattern of degeneration of Purkinje neurons, mainly in the cerebellum. While caution should be exercised when extrapolating animal studies to humans, these results suggest that neurotoxicity of ibogaine is likely to be minimal when ibogaine is used in the 10–20 mg/kg range typical of drug addiction interruption treatment regimes, and indeed death from the other pharmacological actions of the alkaloids is likely to occur by the time the dose is high enough to produce consistent neurotoxic changes.

Pharmacodynamics

The general structure of tryptamines.

Ibogaine is a tryptamine. Because of the ibogaine molecule's tryptamine core, ibogaine acts as an agonist (binds to the receptor and triggers a response) for the 5-HT_2A receptor. However what makes ibogaine's pharmacodynamic properties and subjective experience unique from that of other psychedelic tryptamines and serotonergic psychedelics is that it also acts as an antagonist (blocks agonists' effects) of the NMDA receptor set and an agonist for the κ-opioid receptor set.

Metabolites

Ibogaine is metabolized in the human body by cytochrome P450 2D6, and the major metabolite is noribogaine (12-hydroxyibogamine). Noribogaine is most potent as a serotonin reuptake inhibitor and acts as a moderate κ-opioid receptor antagonist and weak µ-opioid receptor full agonist and therefore, also has an aspect of an opiate replacement similar to compounds like methadone. It is possible that this action of noribogaine at the kappa opioid receptor may indeed contribute significantly to the psychoactive effects attributed to ibogaine ingestion; Salvia divinorum, another plant recognized for its strong hallucinogenic properties, contains the chemical salvinorin A which is a highly selective kappa opioid agonist. Both ibogaine and noribogaine have a plasma half-life of around two hours in the rat, although the half-life of noribogaine is slightly longer than that of the parent compound. It is proposed that ibogaine is deposited in fat and metabolized into noribogaine as it is released. Noribogaine shows higher plasma levels than ibogaine and may accordingly be detected for longer periods of time than ibogaine. Noribogaine is also more potent than ibogaine in rat drug discrimination assays when tested for the subjective effects of ibogaine.

Legal status

Ibogaine and its salts are regulated by the U.S. Controlled Substances Act, as a Schedule I-controlled substance, along with other psychedelics such as DMT and mescaline. Ibogaine is not the subject of any regulation in Canada or in Mexico.

Documentary films about ibogaine therapy

Detox or Die (2004)

Directed by David Graham Scott. David Graham Scott begins videotaping his heroin-addicted friends. Before long, he himself is addicted to the drug. He eventually turns the camera to himself and his family. After 12 years of debilitating, painful dependence on methadone, Scott turns to ibogaine. Filmed in Scotland and England, and broadcast on BBC One as the third installment in the documentary series One Life.

Ibogaine: Rite of Passage (2004)

Directed by Ben Deloenen. Cy a 34 year old heroin addict undergoes ibogaine treatment with Dr Martin Polanco at the Ibogaine Association, a clinic in Rosarito Mexico. Deloenen interviews people formerly addicted to heroin, cocaine, and methamphetamine, who share their perspectives about ibogaine treatment. In Gabon, a Babongo woman receives iboga root for her depressive malaise. Deloenen visually contrasts this Western, clinical use of ibogaine with the Bwiti use of iboga root, but emphasizes the Western context.

Facing the Habit (2007)

Directed by Magnolia Martin. Martin's subject is a former millionaire and stockbroker who travels to Mexico for ibogaine treatment for heroin addiction.

Tripping in Amsterdam (2008)

In this short film directed by Jan Bednarz, Simon "Swany" Wan visits Sara Glatt's iboga treatment center in Amsterdam. Current TV broadcast the documentary in 2008, as part of their "Quarter-life Crisis" programming roster.

I'm Dangerous with Love (2009)

Directed by Michel Negroponte. Negroponte examines Dimitri Mugianis's long, clandestine career of treating heroin addicts with ibogaine.

In popular culture

In 1972, journalist Hunter S. Thompson accused Democratic candidate Edmund Muskie of being addicted to ibogaine in a satirical piece while covering the Wisconsin primaries of the 1972 U.S. Presidential primaries for Rolling Stone magazine. Many readers, and even other journalists, did not realize that Thompson's assertion was facetious. The claim was completely unfounded, and Thompson himself is documented in the movie Gonzo: The Life and Work of Dr. Hunter S. Thompson discussing the self-fabricated joke of Muskie's alleged ibogaine use and his surprise that anyone actually believed the claim. The original piece appeared in a slightly different form in Fear and Loathing on the Campaign Trail '72.

In 2012, National Geographic Channel aired on January 15 an episode titled "Hallucinogens" as an episode of Drugs, Inc.. The episode featured Ibogaine along with other hallucinogens.

Ibogaine factors into the stories of these television drama episodes:

• "Via Negativa". The X-Files. Season 8. Episode 7. 17 December 2000. Fox Broadcasting Company. {{cite episode}}: Unknown parameter |episodelink= ignored (|episode-link= suggested) (help); Unknown parameter |serieslink= ignored (|series-link= suggested) (help)
• "Getting Off". CSI: Crime Scene Investigation. Season 4. Episode 16. 26 February 2004. CBS. {{cite episode}}: Unknown parameter |serieslink= ignored (|series-link= suggested) (help)
• "Users". Law & Order: Special Victims Unit. Season 11. Episode 7. 4 November 2009. NBC. {{cite episode}}: Unknown parameter |serieslink= ignored (|series-link= suggested) (help)
• "Echoes". Nikita. Season 1. Episode 16. 24 February 2011. The CW Television Network. {{cite episode}}: Unknown parameter |serieslink= ignored (|series-link= suggested) (help)

See also

• Coronaridine
• Tabernanthine

References

Further reading

• Pinchbeck, Daniel (2002). Breaking Open the Head: A Psychedelic Journey into the Heart of Contemporary Shamanism. Broadway Books. ISBN 0-7679-0742-6.
• Daniel Pinchbeck,"Ten Years of Therapy in One Night", The Guardian UK (2003), describes Daniel's second journey with Iboga facilitated by Dr. Martin Polanco at the Ibogaine Association in Rosarito, Mexico.