Ibogaine

Ibogaine is a naturally occurring psychoactive substance found in a number of plants, principally in a member of the Apocynaceae family known as iboga (Tabernanthe iboga). A hallucinogen, the substance is banned in some countries; in other countries it is being used to treat addiction to opiates, methamphetamine and other drugs. Derivatives of ibogaine that lack the substance's hallucinogen 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. 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 for dieting. Additionally, Freedom of Information Act documents released in the 1980s show that the U.S. 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, primarily due to the need to conduct the synthesis in an anoxic environment.

While ibogaine's prohibition in the U.S. 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 now used by treatment clinics in 12 countries on six continents to facilitate detoxification and relief of chemical dependence to substances such as methadone, heroin, alcohol, powder cocaine, crack cocaine, and methamphetamine, and to facilitate psychological introspection and spiritual exploration.

Psychoactive effects
At doses of around 1-2 mg/kg of body weight, ibogaine has a mild stimulant effect. Doses of 4 mg/kg or greater can cause a “dream-like” visual phase followed by an introspective phase. Therapeutic doses are typically 10 mg/kg and upwards for psychotherapy use, and 15 mg/kg and upwards for interruption of addiction.

The visual phase is characterized by open-eye visuals, closed-eye visuals, and dreamlike sequences. Objects may be seen as distorted, projecting tracers, or having moving colors or textures. When the eyes are closed, extremely detailed and vivid geometric and fractal visions may be seen. Subjective reports often include a movie-like recollection of earlier life experiences as well as dreamlike sequences with symbolism of one's present or anticipated future. Other effects in the visual phase may include laughing, sensations of euphoria or fear, and temporary short-term memory impairment. The visual phase usually ends after one to four hours, after which the introspective phase begins.

Ibogaine is an oneirophrenic or "remogen" referring to the REM or Rapid Eye Movement normally occurring for brief periods of time during the sleep/dream state. Ibogaine catalyses this state of REM for hours while fully conscious and aware so that memories; life experiences; and issues of trauma can be processed in a subjective manner.

The introspective phase is typically reported to bring elevated mood, a sense of calm and euphoria, and a distinct intellectual and emotional clarity. Subjects often report being able to accomplish deep emotional and intellectual introspection into psychological and emotional concerns. It is also during this period that opioid addicts first notice the absence of withdrawal symptoms or cravings. The duration of the introspective phase is highly variable, usually lasting hours but sometimes lasting days.

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). Ventricular ectopy has been observed in a minority of patients during ibogaine therapy. It has been 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.

There are 12 documented fatalities that have been loosely associated with ibogaine ingestion. Exact determinations of the cause of death have proven elusive due to the quasi-legal status of ibogaine and the unfamiliarity of medical professionals with this relatively rare substance. No autopsy to date has implicated ibogaine as the sole cause of death. Causes given range from significant pre-existing medical problems to the co-consumption of drugs such as opiates which are potentiated by ibogaine. 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 and Earl Grey tea.

Treatment for opioid addiction
The most-studied therapeutic effect of ibogaine is the reduction or elimination of addiction to opioids, but there appears to be no reliable evidence for its safety or effectiveness. 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. However, researchers note that there remains a "need for systematic investigation in a conventional clinical research setting."

Proponents of ibogaine treatment for drug addiction have established formal and informal clinics or self-help groups in Canada, Mexico, the Caribbean, Costa Rica, the Czech Republic, France, Slovenia, the Netherlands, Brazil, South Africa, the United Kingdom and New Zealand, where ibogaine is administered as an experimental compound. 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 therapeutic effect on alcoholism as far back as the 1960s. Both ibogaine and LSD appear to be effective at encouraging introspection and giving the user occasion to reflect on where their addiction came from while also occasioning an intense, transformative experience that can put established patterns of behaviour into perspective; ibogaine has the added benefit of preventing withdrawal effects.

Chronic pain management
In 1957, Jurg Schneider, a pharmacologist at CIBA, 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. Kroupa et al. 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.

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 in 1985. In 1969, Claudio Naranjo was granted a French patent for the use of ibogaine in psychotherapy.

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. (1993). Animal model support for ibogaine claims to treat alcohol dependence were established by Rezvani (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 , as opposed to their salt form, which is stable. The exact methods and quality of the original Indra extraction was never documented, so the real composition of the product remains uncertain.

An ibogaine research project was funded by the US National Institute on Drug Abuse in the early 1990s. The National Institute on Drug Abuse (NIDA) abandoned efforts to continue this project into clinical studies in 1995, citing other reports that suggested a risk of brain damage with extremely high doses and fatal heart arrhythmia in patients having a history of health problems, as well as inadequate funding for ibogaine development within their budget. However, NIDA funding for ibogaine research continued in indirect grants often cited in peer-reviewed ibogaine publications.

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).

In addition, after years of work and a number of significant changes to the original protocol, on August 17, 2006, a MAPS-sponsored research team received "unconditional approval" from a Canadian Institutional Review Board (IRB) to proceed with a long-term observational case study that will examine changes in substance use in 20 consecutive people seeking ibogaine-based therapy for opiate dependence at the Iboga Therapy House in British Columbia, Canada.

Formulations
In Bwiti religious ceremonies, the rootbark is pulverized and swallowed in large amounts to produce intense psychoactive effects. In Africa, iboga rootbark is sometimes chewed, which releases 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 one-fifth the potency by weight as standardized ibogaine hydrochloride.

Currently, pure crystalline ibogaine hydrochloride is the most standardized formulation. It is typically produced by the semi-synthesis from voacangine in commercial laboratories. Ibogaine has two separate chiral centers which means 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.

Pharmacology
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.

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- 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 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 therefore 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. Noribogaine differs from ibogaine in that it contains a hydroxy instead of a methoxy group at the 12 position.

Legal status
Ibogaine has been placed in the strictest drug prohibition schedules in the United States and a handful of other countries. Canada and Mexico both allow ibogaine therapy facilities to operate and contribute to further understanding of the detoxification and therapeutic process that ibogaine has the potential to facilitate.

Ibogaine and its salts were regulated by the U.S. Food and Drug Administration in 1967 pursuant to its enhanced authority to regulate stimulants, depressants, and hallucinogens granted by the 1965 Drug Abuse Control Amendments (DACA) to the Federal Food, Drug, and Cosmetic Act. In 1970, with the passage of the Controlled Substances Act, it was classified as a Schedule I-controlled substance in the United States, along with other psychedelics such as DMT and mescaline. Since that time, several other countries, including Sweden, Denmark, Belgium, and Switzerland, have also banned the sale and possession of ibogaine. Although illegal in these countries, ibogaine has been used by hundreds of drug dependents in the United States and abroad. Howard Lotsof, a pioneer in bringing awareness to ibogaine's success in helping long-time drug dependents to quit their addiction, and others have been offering willing persons the treatment. In the Czech Republic and Slovenia, taking advantage of less prohibitive legal systems, ibogaine has been applied to people coming from the U.S. and other countries seeking a safe haven.

Ibogaine is not the subject of any regulation in Canada. In Sweden, a non-profit foundation was formed in early 2006 to address the issue of providing ibogaine for addiction interruption within established drug treatment care.

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 was being 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.

Ibogaine has been the subject of several full-length documentary films including Detox or Die in 2004, by director David Graham Scott a feature film aired by the BBC, documenting Scott's own drug addiction and ibogaine treatment. Ibogaine Rite of Passage, directed by Ben Deloenen in 2005, with Howard Lotsof and Patrick K. Kroupa which focused on both native Bwiti ritualistic use of ibogaine as well as modern science and treatment clinics. In 2007 filmmaker Magnolia Martin directed Facing the Habit documenting a one-time millionaire and former stockbroker whose life spiraled out of control due to heroin addiction traveling to Mexico to receive ibogaine treatment. In 2009 a feature documentary I'm Dangerous with Love by filmmaker Michel Negroponte, covered the work of Dimitri Mugianis and his long-running underground ibogaine treatment for heroin addiction.

In addition to documentaries, ibogaine has played a central role in the plot-lines of several episodes of television programs, including:

The X-Files: Via Negativa, Season 8, Episode 7 (2000) C.S.I.: Getting Off, Season 4, Episode 16 (2004) Law & Order Special Victims Unit: Users, Season 11, Episode 7 (2009) Nikita: Echoes, Season 1, Episode 16 (2011)