Ibogaine

Ibogaine is an indole alkaloid, a long-acting hallucinogen which has gained attention due to its application in the treatment of opioid addiction and similar addiction syndromes. It occurs naturally in a number of dogbane plants, among them above all in Tabernanthe iboga.

Formulations
Ibogaine is commercially produced in 2 forms; the purified crystalline hydrochloride salt and a total alkaloid extract. The hydrochloride salt is favored for research because its composition is standardized, which allows for more consistent results. The total alkaloid extract has about 1/5th the potency of ibogaine hydrochloride and contains all the alkaloids of the Tabernanthe iboga rootbark used in African traditional religion and medicine. In Africa, Tabernanthe iboga is consumed as a stimulant by chewing the rootbark. In Bwiti religious ceremonies, the rootbark is pulverized and swallowed with water to produce intense psychoactive effects.

Voacangine, a close natural analog of ibogaine found in the tree bark of the Voacanga africana tree, is a common ingredient in the semi-synthesis of ibogaine because it is more abundant and easily accessible than iboga rootbark. 

The name "Indra extract" has become synonymous with the total alkaloid extract of iboga rootbark. However, that name actually refers to a particular stock of about 44kg of iboga alkaloids extracted 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 the extract to treat heroin addicts in Christiana, 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. Iboga extracts are still often called called "Indra extract", but it is unclear whether any of them are actually from Waltenburg's original Indra stock, or whether any of that stock is still in existence or viable after over 2 decades. Indole compounds such as ibogaine are susceptible to degradation over time due to indole oxidation.

History
Ibogaine was first isolated from Tabernanthe iboga in 1901 by Dybowski and Landrin and independently by Haller and Heckel in the same year. Samples of the plant were obtained from Gabon, Africa in the mid 1800s where it has been used in initiation rites of the Bwiti religion. The challenging total synthesis was accomplished by G. Büchi in 1966. Since then, several further totally synthetic routes have been developed. The use of ibogaine in treating substance use disorders in human subjects was first proposed by Howard Lotsof in which was awarded in 1985. 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).

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). However, there have been as yet no peer-reviewed studies demonstrating any statistically significant long term improvement following ibogaine administration to humans with drug problems.

Effects
At low doses, ibogaine has a mild stimulant effect. At higher doses, temporary effects include hallucination and ataxia. The most studied long-term therapeutic effect is that ibogaine seems to catalyze partial or complete interruption 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 to other substances such as alcohol, methamphetamine, and nicotine, and may affect compulsive behavioral patterns not involving substance abuse or chemical dependence. Ibogaine has been used as an adjunct to psychotherapy by Claudio Naranjo, documented in his book The Healing Journey.

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 milligrams per kilogram of body weight for minor effect to 30 mg/kg in the cases of strong polysubstance addiction. It is unknown whether doses greater than 30mg/kg in humans produce effects that are therapeutically beneficial, medically risky, or simply prolonged in duration.

Mechanism and Pharmacodynamics
Among recent proposals for ibogaine mechanisms of action is activation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the ventral tegmental area (VTA) of the brain. The work has principally been accomplished in preclinical ethanol research where 40 mg/kg of ibogaine caused increases of RNA expression of GDNF in keeping with reduction of ethanol intake in the rat, absent neurotoxicity or cell death.

Ibogaine is a noncompetitive antagonist at α3β4 nicotinic receptors, binding with moderate affinity. Several other α3β4 antagonists are known, and some of these such as bupropion (Zyban) and mecamylamine have been used for treating nicotine addiction. This α3β4-antagonism correlates quite well with the observed effect of interrupting addiction. Since α3β4 channels and NMDA channels are related to each other and their binding sites within the lumen bind a range of same ligands (e.g. DXM), some "older" sources suggested that ibogaine's anti-addictive properties may be (partly) due to it being an NMDA receptor antagonist. However, ligands, like 18-MC, selective for α3β4- vs. NMDA-channels showed no drop-off in activity.

It is suspected that ibogaine's actions on the opioid and glutamatergic systems are also involved in its anti-addictive effects. Persons treated with ibogaine report a cessation of opioid withdrawal signs generally within an hour of administration.

Ibogaine is a weak 5HT2A receptor ligand and a sigma2 receptor agonist.

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 moderate κ- and weak µ-opioid receptor full agonist and has therefore also an aspect of an opiate replacement similar to compounds like methadone. Both ibogaine and noribogaine have a plasma half-life of approximately thirty minutes. It is proposed that ibogaine is deposited in fat and metabolized into noribogaine as it is released. Noribogaine throws 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 phenolic hydroxy instead of a methoxy group at the 12 position.

Analogs & Derivatives
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).

Addiction Interruption
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 drug. Although the full nature of Ibogaine is still emerging, it appears that the most effective treatment paradigm involves visionary doses of ibogaine of 10 to 20 mg/kg, producing an interruption of opiate withdrawal and craving. 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 and therapy during the interruption period following treatment is of significant value. Some patients require a second or third treatment session with ibogaine over the course of the next 12 to 18 months as it will provide a greater efficacy in extinguishing the opiate addiction or other drug dependence syndrome. A minority of patients 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".

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 (MAPS) Journal demonstrating that administration of low "maintenance" doses of ibogaine HCl with opioids decreases tolerance.

Degenerative neural diseases
Substances that promote the expression of GDNF, such as ibogaine, are known to provide benefit in treating neurodegenerative diseases such as Parkinson's disease. Other ligands in the GDNF family may hold promise for treating related neurodegenerative diseases such as ALS and Alzheimer's disease.

Side effects
At therapeutic doses, ibogaine has an active window of 24 to 48 hours, is often physically and mentally exhausting and produces ataxia for as long as twelve hours, in some cases even longer. Nausea that may lead to vomiting is not uncommon throughout the experience. Such unpleasant symptoms tend to reduce the attractiveness of ibogaine as a recreational drug at therapeutic doses, however, at lower doses ibogaine is known to have stimulant effects. Some users administer ibogaine by enema in order to avoid nausea.

In one study using dogs as the subject, ibogaine has been 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 theoretical risk of QT-interval prolongation following ibogaine administration, but no actual occurrence of this phenomenon has been published to date. 

There are 8 documented fatalities that have been loosely associated with ibogaine ingestion. . Autopsies have failed to implicate ibogaine as the sole cause of death due to some patients having significant pre-existing medical problems, and some patients surreptitiously consuming other drugs such as heroin against medical indications during or after ibogaine treatment.

Research
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 continues in indirect grants often cited in peer reviewed ibogaine publications.

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 addiction treatment for opiate dependence at Iboga Therapy House in Vancouver.

Legal status
Ibogaine and its salts were regulated by the 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 LSD and mescaline. Since that time, several other countries, including Sweden, Denmark, Belgium, and Switzerland, have also banned the sale and possession of ibogaine.

In early 2006, the creation of a non-profit foundation addressing the issue of providing ibogaine for the purpose addiction interruption within establishment drug treatment care was formed in Sweden.

References in popular media
Ibogaine was the topic of one show in the American public radio series This American Life, Week of December 1, 2006. The show called "Sink or Swim" documented the story of a former addict who opened an underground addiction treatment service using Ibogaine.

Other fanciful/fictionalized mentions of ibogaine:
 * The X-Files, Season 8, Episode 7, "Via Negativa". Originally aired: 12/17/2000. Summary: a serial killer/cult leader uses Ibogaine to astral-project and kill his victims.
 * CSI, Season 2, Episode 4, "Getting Off". Originally aired: 1/1/2004. Summary:  An underground ibogaine treatment provider is murdered by dealers of morphine and cocaine.

There is also an allegation from infamous gonzo journalist Hunter S Thompson that United States Democratic Party presidential hopeful Edmund Muskie used ibogaine during his 1972 campaign. This is also voiced in 1972 articles in Rolling Stone magazine. Thompson also claims to have used ibogaine himself.