Ibogaine is a naturally occurring psychoactive substance found in plants in the Apocynaceae family such as Tabernanthe iboga, Voacanga africana and Tabernaemontana undulata. It is a psychedelic with dissociative properties.
Ibogaine is not currently approved for any medical uses in the United States. Preliminary research indicates that it may help with drug addiction; however, there is a lack of data in humans. Its use has been associated with serious side effects and death. It is used as an alternative medicine treatment for drug addiction in some countries. Its prohibition in other countries has slowed scientific research. Ibogaine is also used to facilitate psychological introspection and spiritual exploration. Derivatives of ibogaine that lack the substance's psychedelic properties are under development.
Ibogaine-containing preparations are used for 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 Lambarène and 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. The total synthesis of ibogaine was described in 1956. Structural elucidation by X-ray crystallography was completed in 1960.
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Psychoactive effects
Ibogaine is a psychedelic. The experience of Ibogaine is broken down in two phases, the visionary phase and the introspection phase. The visionary phase has been described as oneirogenic, referring to the dreamlike nature of its psychedelic effects, and lasts for 4 to 6 hours. The second phase, the introspection phase, is responsible for the psychotherapeutic effects. It can allow people to conquer their fears and negative emotions. 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.
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Uses
Medical
Ibogaine is not currently approved for any medical uses. Clinical studies of ibogaine to treat drug addiction began in the early 1990s, but concerns about cardiotoxicity led to termination of those studies. There is currently insufficient data to determine whether it is useful in treating addiction. Nonetheless, some alternative medicine clinics administer ibogaine for this purpose, in what has been called a "vast, uncontrolled experiment."
Religious
In Bwiti religious ceremonies, the root bark is pulverized and swallowed in large amounts to produce intense psychoactive effects.
Adverse effects
Immediate
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 per rectum to avoid nausea and vomiting.
Cardiovascular
Ibogaine causes long QT syndrome at therapeutic doses, apparently by blocking hERG potassium channels in the heart.
Neurotoxicity
Work in the laboratory of Mark Molliver at Johns Hopkins indicated degeneration of cerebellar Purkinje cells observed in rats given substantially larger dosages of ibogaine than those used to study drug self-administration and withdrawal. However, subsequent research found no evidence of neurotoxicity in the primate or mouse at dosages that produced cerebellar degeneration in the rat, and it has been suggested that cerebellar degeneration might be a phenomenon limited to a single species. The FDA was aware of Molliver's work at the time it approved a Phase 1 study in which humans received ibogaine in 1993. Neuropathological examination revealed no evidence of degenerative changes in a woman who had received four separate doses of ibogaine ranging between 10 and 30 mg/ kg over a 15-month interval prior to her death due to a mesenteric artery thrombosis with small bowel infarction 25 days after her last ingestion of ibogaine. A published series of fatalities temporally associated with the ingestion of ibogaine found no evidence suggesting a characteristic syndrome of neurotoxicity.
Interactions
Adverse interactions may occur between ibogaine and psychiatric medications. Some studies also suggest the possibility of adverse interaction with heart conditions.
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 are similarly metabolized by CP450, in particular foods containing bergamottin or bergamot oil, such as grapefruit juice.
Pharmacology
Pharmacodynamics
Ibogaine affects many different neurotransmitter systems simultaneously.
Noribogaine is most potent as a serotonin reuptake inhibitor. It acts as a moderate ?-opioid receptor agonist and weak µ-opioid receptor agonist or weak partial agonist. It is possible that the action of ibogaine 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. Noribogaine is more potent than ibogaine in rat drug discrimination assays when tested for the subjective effects of ibogaine.
Pharmacokinetics
Ibogaine is metabolized in the human body by cytochrome P450 2D6 into noribogaine (12-hydroxyibogamine). 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. After ibogaine ingestion in humans, noribogaine shows higher plasma levels than ibogaine and is detected for a longer period of time than ibogaine.
Chemistry
Ibogaine is a tryptamine. It has two separate chiral centers, meaning that there are four different stereoisomers of ibogaine. These four isomers are difficult to resolve.
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.
Crystalline ibogaine hydrochloride is typically produced by semi-synthesis from voacangine in commercial laboratories.
Derivatives
A synthetic derivative of ibogaine, 18-methoxycoronaridine (18-MC), is a selective ?3?4 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.
Natural occurrence
Ibogaine occurs naturally in iboga root bark. 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.
History
The use of iboga in African spiritual ceremonies was first reported 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. Complete synthesis of ibogaine was accomplished by G. Büchi in 1966. Since then, several other synthesis methods have been developed.
From the 1930s to 1960s, ibogaine was sold in France in the form of Lambarène, an extract of the Tabernanthe manii plant, and promoted as a mental and physical stimulant. The drug enjoyed some popularity among post World War II athletes. Lambarène was withdrawn from the market in 1966 when the sale of ibogaine-containing products became illegal in France.
In the late 1960s the World Health Assembly classified ibogaine as a "substance likely to cause dependency or endanger human health," the U.S. Food and Drug Administration (FDA) assigned it Schedule I classification, and the International Olympic Committee banned it as a potential doping agent.
Anecdotal reports concerning ibogaine's effects appeared in the early 1960s. Its anti-addictive properties were discovered accidentally by Howard Lotsof in 1962, at the age of 19, when he and five friends--all heroin addicts--noted subjective reduction of their craving and withdrawal symptoms while taking it. Further anecdotal observation convinced Lotsof of its potential usefulness in treating substance addictions. He contracted with a Belgian company to produce ibogaine in tablet form for clinical trials in the Netherlands, and was awarded a United States patent for the product in 1985. The first objective, placebo-controlled evidence of Ibogaine's ability to attenuate opioid withdrawal in rats was published by Dzoljic et al. in 1988. Diminution of morphine self-administration was reported in preclinical studies by Glick et al. in 1991. Cappendijk et al. demonstrated reduction in cocaine self-administration in rats in 1993, and Rezvani reported reduced alcohol dependence in three strains of "alcohol preferring" rats in 1995.
As the use of ibogaine spread, its administration varied widely; some groups administered it systematically using well developed methods and medical personnel, while others employed haphazard and possibly dangerous methodology. Lotsof and his colleagues, committed to the traditional administration of ibogaine, developed treatment regimens themselves. In 1992, Eric Taub brought ibogaine to an offshore location close to the United States, where he began providing treatments and popularizing its use. In Costa Rica Lex Kogan, another leading proponent, joined Taub in systematizing its administration. The two men established medically monitored treatment clinics in several countries.
In 1981 an unnamed European manufacturer produced 44 kg of iboga extract. The entire stock was purchased by Carl Waltenburg, who distributed it under the name "Indra extract" and used it in 1982 to treat heroin addicts in Christiania, Denmark, a squatter village where heroin addiction was widespread. Indra extract was available for sale over the Internet until 2006, when the Indra web presence disappeared. Various products are currently sold in a number of countries as "Indra extract", but it is unclear if any of them are derived from Waltenburg's original stock. Ibogaine and related indole compounds are susceptible to oxidation over time.
The National Institute on Drug Abuse (NIDA) began funding clinical studies of ibogaine in the United States in the early 1990s, but terminated the project in 1995. Data demonstrating ibogaine's efficacy in attenuating opioid withdrawal in drug-dependent human subjects was published by Alper et al. in 1999. A cohort of 33 patients were treated with 6 to 29 mg/kg of ibogaine; 25 displayed resolution of the signs of opioid withdrawal from 24 hours to 72 hours post-treatment, but one 24-year-old female, who received the highest dosage, died. Mash et al., (2000) using lower oral doses (10-12 mg/kg) in 27 patients, demonstrated significantly lower objective opiate withdrawal scores in heroin addicts 36 hours after treatment, with self-reports of decreased cocaine and opiate craving and alleviated depression symptoms. Many of these effects appeared sustainable over a one-month post-discharge follow-up.
Society and culture
Legal status
The Global Ibogaine Therapy Alliance publish a map of ibogaine legal status in various countries around the world.
Brazil
On 14 January 2016, Ibogaine was legalized for prescription use in São Paulo, Brazil, with this legalization to extend to the rest of the country in a few months.
Canada
Ibogaine was unregulated in Canada in 2009. Then Health Canada added ibogaine to the Prescription Drug List (PDL) in 2017.
Germany
Ibogaine is unregulated in Germany, but for medical use it can be regulated by the pharmacy rules (AMG).
New Zealand
Ibogaine was gazetted in New Zealand in 2009 as a non-approved prescription medicine.
Norway
Ibogaine is illegal in Norway (as are all tryptamine derivatives).
Sweden
Ibogaine is schedule I in Sweden.
United Kingdom
As of January 2017 in the United Kingdom, ibogaine was an unlicensed medical product.
United States
Ibogaine is classified as a Schedule I-controlled substance in the United States, and is not approved there for addiction treatment (or any other therapeutic use) because of its hallucinogenic, neurotoxic, and cardiovascular side effects, as well as the scarcity of safety and efficacy data in human subjects.
Treatment clinics
Ibogaine treatment clinics have emerged in Mexico, Canada, the Netherlands, South Africa, and New Zealand, all operating in what has been described as a "legal gray area". Costa Rica also has treatment centers, most notably one run by Lex Kogan, a leading proponent of ibogaine. Covert, illegal neighborhood clinics are known to exist in the United States, despite active DEA surveillance. While clinical guidelines for ibogaine-assisted detoxification were released by the Global Ibogaine Therapy Alliance in 2015, addiction specialists warn that the treatment of drug dependence with ibogaine in non-medical settings, without expert supervision and unaccompanied by appropriate psychosocial care, can be dangerous -- and, in approximately one case in 300, potentially fatal.
Media
Documentary films
Detox or Die (2004)
Ibogaine: Rite of Passage (2004)
Facing the Habit (2007)
Tripping in Amsterdam (2008)
I'm Dangerous with Love (2009)
"Hallucinogens" (2012)
"Addiction" (2013)
"The Ibogaine Safari" (2014)
Print media
While in Wisconsin covering the primary campaign for the United States presidential election of 1972, gonzo journalist Hunter S. Thompson submitted a satirical article to Rolling Stone accusing Democratic Party candidate Edmund Muskie of being addicted to ibogaine. Many readers, and even other journalists, did not realize that the Rolling Stone piece was facetious. The ibogaine assertion, which was completely unfounded, did a significant amount of damage to Muskie's reputation, and was cited as a factor in his loss of the nomination to George McGovern. Thompson later said he was surprised that anyone believed it. The article is included in Thompson's post-election anthology, Fear and Loathing on the Campaign Trail '72 (1973).
Author and Yippie Dana Beal co-wrote the 1997 book The Ibogaine Story.
American author Daniel Pinchbeck wrote about his own experience of ibogaine in his book Breaking Open the Head (2002), and in a 2003 article for The Guardian titled "Ten years of therapy in one night".
Television drama
Ibogaine factors into the stories of these episodes from television drama series:
- "Via Negativa". The X-Files. Season 8. Episode 7. 17 December 2000. Fox Broadcasting Company.
- "Getting Off". CSI: Crime Scene Investigation. Season 4. Episode 16. 26 February 2004. CBS.
- "Users". Law & Order: Special Victims Unit. Season 11. Episode 7. 4 November 2009. NBC.
- "Echoes". Nikita. Season 1. Episode 16. 24 February 2011. The CW Television Network.
- "One Last Time". Homeland (TV series). Season 3. Episode 9. 24 November 2013. Showtime.
- "Bon Voyage". Graceland (TV series). Season 3. Episode 7. 6 August 2015. USA Network.
Radio
- "Sink or Swim. Act Two. I'm Not A Doctor But I Play One At The Holiday Inn.". This American Life. Episode 321. 1 December 2006. -- A former heroin addict realizes that he wants to help other addicts kick their habits. The problem is, he wants to do this using a hallucinogenic drug - ibogaine - that is completely illegal, and which requires medical expertise he doesn't have.
Research
Addiction treatment
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.
Chronic pain management
In 1957, Jurg Schneider, a pharmacologist at CIBA (now a division of Novartis), found that ibogaine potentiated morphine analgesia. 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 that ibogaine reduced tolerance to opioid drugs. Their paper in the Multidisciplinary Association for Psychedelic Studies Journal demonstrated that administration of low "maintenance" doses of ibogaine HCl with opioids decreases tolerance, but noted that ibogaine's potentiating action could make this a 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 patent CA 939266 in 1974.
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