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Ibogaine

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Ibogaine
Ibogaine
Chemical name (IUPAC) 10-Methoxyibogamine
Chemical name (CAS) 12-Methoxyibogamine
CAS number 83-74-9
Chemical formula C20H26N2O
Molecular mass 310.44 g/mol
Ibogaine (structural formula)
Ibogaine is an indole alkaloid, a strong 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.

Contents

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.C. Frauenfelder (1999) [Doctoral Thesis, page 24] (pdf) The use of ibogaine in treating substance use disorders in human subjects was first proposed by Howard Lotsof in an US Patent awarded in 1985. US Patent # 4,499,096 (1985) [link] Ibogaine's ability to attenuate opioid withdrawal confirmed in the rat was first published by Dzoljic et al. (1988).E.D. Dzoljic et. al. (1988): ["Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats"] Arch. Int. Pharmacodyn. Ther. 294, 64-70 Ibogaine's use in diminishing morphine self-administration in preclinical studies was 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).

Scientific data demonstrating ibogaine's efficacy in attenuating opioid withdrawal in drug dependent human subjects was published by Alper et al. (1999) Alper et al. (1999) ["Treatment of acute opioid withdrawal with ibogaine."] Am J Addict. 1999 Summer;8(3):234-42 (pdf) and Mash et al. (2000). D.C. Mash, et al. (2000). [Ibogaine: Complex Pharmacokinetics, Concerns for Safety, and Preliminary Efficacy Measures] (pdf). Neurobiological Mechanisms of Drugs of Abuse Volume 914 of the Annals of the New York Academy of Sciences, September 2000.

Effects

It has been observed that ibogaine serves to interrupt 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 some of whose work was published in The Healing Journey.C. Naranjo. The Healing Journey. [Chapter V, Ibogaine: Fantasy and Reality, 197-231, Pantheon Books, Div. Random House,ISBN 0394488261, New York (1973)]

Pharmacology

The pharmacology of ibogaine is quite complex, affecting many different neurotransmitter systems simultaneously.P. Popik, P. Skolnick (1998). Pharmacology of Ibogaine and Ibogaine-Related Alkaloids. [The Alkaloids 52, Chapter 3, 197-231, Academic Press, Editor: G.A. Cordell] K.R. Alper (2001). Ibogaine: A Review. [The Alkaloids 56, 1-38, Academic Press] (pdf) Because of its fairly low potency at any of its target sites, ibogaine is used in large doses of hundreds of milligrams up to one gram.

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 tagmental 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.Dao-Yao He, Nancy N.H. McGough, Ajay Ravindranathan, Jerome Jeanblanc, Marian L. Logrip, Khanhky Phamluong, Patricia H. Janok and Dorit Ron. Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption. Journal of Neuroscience 25(3) (2005): 619–628.

Ibogaine is a noncompetitive antagonist (channelblocker) at α3β4 nicotine 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.

It is suspected that ibogaine's actions on the dopaminergic, opioid, and glutamatergic systems are also involved in its anti-addictive effects. Many users of ibogaine report "seeing" similar phenomena, 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 drive their addiction. Additionally, those treated with ibogaine report an immediate cessation of opioid withdrawal signs.

Some sources suggested that ibogaine's anti-addictive properties may be partly due to it being an NMDA receptor antagonist, as other NMDA antagonists such as ketamine have been used to treat amphetamine addiction. Ibogaine is a weak 5HT2A receptor agonist#redirect and a sigma2 receptor agonist.Mach RH, Smith CR, Childers SR. Ibogaine possesses a selective affinity for sigma 2 receptors. Life Sciences. 1995;57(4):PL57-62.

Metabolites

Ibogaine is rapidly metabolized in the human body by cytochrome P450 2D6. Effects after ibogaine treatment lasting longer than 48 hours are therefore not likely to be caused by the initial administration of ibogaine itself. The main metabolite in humans is noribogaine (12-hydroxyibogamine) which contains a phenolic hydroxy instead of a methoxy group. 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.Lindsay B. Hough, Sandra M. Pearl and Stanley D. Glick. Tissue Distribution of Ibogaine After Intraperitoneal and Subscutaneous Administration. Life Sciences 58(7) (1996): 119–122. Noribogaine throws higher plasma levels than ibogaine and may therefore be detected for longer periods of time than ibogaine. The metabolite is somewhat more active at several receptors and transporters. Noribogaine is most potent as a serotonin reuptake inhibitor and as κ and µ-opioid receptor full agonist and therefore may act as an opiate replacement similar to compounds like methadone. Noribogaine is also more potent than ibogaine in rat drug discrimination assays when tested for the subjective effects of ibogaine.

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).Christopher J. Pace, Stanley D. Glick, Isabelle M. Maisonneuve, Li-Wen Heb, Patrick A. Jokiel, Martin E. Kuehne, Mark W. Fleck. Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration. European Journal of Pharmacology 492 (2004): 159–167.

Usage

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, followed by intensive counseling and therapy during the interruption period. Some patients require a second or third session over the course of the next 12 to 18 months to completely rid themselves of opiate addiction. 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".H.S. Lotsof (1995). [Ibogaine in the Treatment of Chemical Dependence Disorders: Clinical Perspectives] (Originally published in MAPS Bulletin (1995) V(3):19-26)

In 1957, Jurg Schneider, a pharmacologist at CIBA, found that ibogaine potentiates morphine analgesia Jurg Schneider (assignee: Ciba Pharmaceuticals), Tabernanthine, Ibogaine Containing Analgesic Compositions. [US Patent No. 2,817,623 (1957)] (pdf). 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 drugsPatrick K. Kroupa, Hattie Wells (2005): [Ibogaine in the 21st Century. Multidisciplinary Association for Psychedelic Studies. Volume XV, Number 1: 21-25] (pdf). 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.

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.

The drug is experimental and controversial, and isolated cases of fatal cardiac arrhythmias during treatment are proposed to have occurred. In such cases there has yet to be a firmly established causal link between mortality and ibogaine administration, because it is unclear whether or not other drugs (such as heroin) were co-administered against indication by the patient himself and because the autopsies have not been conclusive. Arrhythmias have been observed in EKGs to appear at the point of conversion from ibogaine to noribogaine.

Research

An ibogaine research project was funded by the US National Institute on Drug Abuse in the early 1990's. 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.

Legal status

In 1966 ibogaine 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. [Stiftelsen Iboga´s web site]

See also

External links

Media Appearances

References

 

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