A Retrospective and Current Analysis (1997)
by: Chris Lovett
In our society today, the United States along with many other countries are facing the ever-ubiquitous problem of substance abuse and chemical dependency. While addiction is not a new affliction to mankind, many new therapies and treatments are being developed rapidly as we begin to comprehend more fully the neurochemical bases of the brain and behavior, and the pharmacological actions of many addictive substances. Also, as we gain more knowledge about the mechanisms of action of chemical agents that are capable of treating addiction or alleviating withdrawal symptoms, we gain insight into the very nature of chemical addiction. One of these agents being currently researched along with ketamine and MDMA is Ibogaine, which has been proposed as being effective in treating opiate addiction (Lotsof, 1985), cocaine and amphetamine addiction (Lotsof, 1986), alcohol dependency (Lotsof, 1989), nicotine/tobacco dependency (Lotsof, 1991) and various combinations of these substances (Lotsof, 1992).
Ibogaine (12-methoxyibogamine), the principal indole alkaloid of the Central West African shrub Tabernanthe iboga, has also been known in the past by the tradename Lambarene(TM). Between 1939 and 1966 Lambarene(TM) was marketed in France for its general stimulant effects on the body including fighting fatigue and promoting a sense of well-being. More recently, ibogaine has been known by the tradename Endabuse(TM) as an anti-addictive pharmacological agent. The United States federal government, in response to the resolutions of the World Health Assembly of May 1967 and May 1968, illegalized ibogaine, placing it on the Food and Drug Administration’s Schedule I list of “controlled substances analogous to lysergides and to certain CNS stimulants including LSD, DMT, psilocybin and others. Fortunately, in 1991 the National Institute on Drug Abuse (NIDA) decided to include ibogaine on the list of drugs to be evaluated in the treatment of drug dependency, a decision that has prompted much research in the last few years, although the mechanisms of action still remain evasive and unclear to researchers.
Botanical Origins Ibogaine is obtained most commonly as the principal indole alkaloid from the root bark of Tabernanthe iboga, a shrub indigenous to Central West Africa and particularly Gabon. Henri Baillon of the Museum National d’Histoire Naturelle in Paris established the genus Tabernanthe in 1889, and named the sample which had been brought back from Gabon to France in 1864 by Dr. Griffon du Bellay, a navy surgeon, Tabernanthe iboga (Goutarel, 1992). Tabernanthe is in the Apocynaceae or dogbane family, and ibogaine has also been isolated from Tabernanthe pubescens, Voacanga schweinfurthii and other Voacanga species, ten species of the related Tabernaemontana genus, and is the major alkaloid of the bark of Tabernaemontana crassa. While ibogaine is the principal active alkaloid T. iboga also contains voacangine (carbomethoxy ibogaine), the positional isomer tabernanthine (13-methoxyibogamine) and ibogamine, all of which may contribute to the overall effects of T. iboga (Ott, 1993). In 1901 the principal alkaloid of T. iboga was isolated from the roots of the plant and named Ibogaine by Dybowsky and Landrin (1901).
Religious Uses of Tabernanthe iboga Among the indigenous peoples of Gabon, Africa, the Mitsogho have been using the roots of Tabernanthe iboga, which they call eboka or mbassoka, as part of their Bwiti initiation ritual ever since their migration to the area. The Bwiti ceremony is strictly for males among the Mitsogho, a rite of passage from adolescence to manhood. By chewing the scrapings of the eboka root, the amount used in the ritual containing up to 6.25 grams of ibogaine, the candidate for initiation, or “banzi”, hopes to embark on a spiritual journey coming eventually to the Village of the Bwiti. Here he will encounter Nzamba-Kana, the father of humankind, the first man on Earth, and his wife Disumba, the mother of humankind and the first woman on Earth.
The ritual is preceded by a day of fasting and abstinence from sex, and then begins with the banzi chewing a large amount of root-bark and stems of eboka under the close supervision of his “mother”, a former initiate. The banzi’s skull is struck three times with a hammer to “break open the head” freeing the spirit, and his tongue is pricked with a needle to enable him to relate his visions. After these and other preliminary symbolic rites, the young candidate is led into a temple and placed on the left side, which symbolizes womanhood, darkness and death. About twenty minutes after the eboka begins to be absorbed, the banzi repeatedly and violently vomits, afterwards becoming drowsy and losing motor coordination. The “mother” monitors the pulse and body temperature of the initiate by touch continuously for the first ten hours of the experience until the visionary effects begin to occur.
On the journey towards the Village of the Bwiti, the banzi passes through four distinct levels or stages, encountering his ancestors along the way who encourage him to go further as he begins realizing that his spiritual substance is timeless, and that the concept of death has no meaning. He feels himself carried by the wind to the infinite Village, while hearing the Ngombi harp which is played throughout the ceremony, representing the link between his village of earthly men and the Village of the Bwiti in the beyond. When he reaches the Village, and encounters Nzamba-Kana and Disumbu, all is suddenly engulfed in intense sparks of light which slowly form into an enormous ball, Kombe, the sun. Kombe questions the banzi, and asks him why he has come. He says,”I am Kombe, the Chief of the World, I am the essential point! This is my wife Ngondi (the moon) and these are my children Minanga (the stars). The Bwiti is everything you have seen with your own eyes,” (Gollnhofer and Sillans, 1983).
The wind then carries the initiate back to his earthly village, where the elders greet him and invite him to take his place on the right side of the temple, the side of men and life. The new initiate will not encounter the Bwiti again until the day of his death, and eboka is not consumed again except for in small doses as a stimulant to aid in hunting.
Eboka is also used in an initiatory rite of the Ombudi order of the Mitsogho, an order of women healers, though they consume much smaller quantities than the Bwiti initiates. Along the coast of Gabon, the Fang people also use Tabernanthe iboga in their own Bwiti initiation rites which are essentially the same as those of the Mitsogho and the ritual language used is Mitsogho. The Fang differ, however, in that they allow women to be initiated, and the have also integrated some elements of Christianity into their syncretic ceremony. During the Fang eboka experience, the initiate may encounter saints, Noah, Jesus Christ, the Virgin Mary, Lucifer and Adam instead of Nzamba-Kana and Disumba as with the Mitsogho (Gollnhofer and Sillans, 1983). This supports my own personal view that when a visionary plant or entheogen such as Tabernanthe iboga is used as a religious sacrament, the effect is strongly culturally-dependent and not just the sum of its chemical alkaloids.
Therapeutic Uses After the isolation of ibogaine from Tabernanthe iboga in 1901 by Dybowsky and Landrin, there was very little research done on the effects of ibogaine other than by a few French pharmacologists including Phisalix, Lambert, Heckel, Pouchet, Chevalier and Closmonil. For approximately the next forty years, little interest was shown in ibogaine and it was regarded as an obscure cardiac stimulant.
Renewed interest in ibogaine occurred in 1939 when Wurman published his Doctorate of Medicine thesis in Paris entitled,”Contribution a l`etude experimentale et therapeutique d`un extrait de Tabernanthe manii d`origine gabonaise,” (Contribution to the experimental and therapeutic study of an extract of T. manii from Gabon). This led to the dry extract of the roots of Tabernanthe manii being prepared in tablet form and given the tradename Lambarene(TM) in honor of Dr. Schweitzer.
Lambarene(TM) was produced in France, and contained about 200mg of extract or 8mg of ibogaine per tablet. The package label described it as: “a neuromuscular stimulant, promoting cell combustions and getting rid of fatigue, indicated in cases of depression, asthenia, in convalescence, infectious diseases, greater than normal physical or mental efforts by healthy individuals. 2-4 tablets daily. Rapid and prolonged action not followed by depression. May be administered to hypertensives.”
Lambarene(TM) was of particular interest to post-World War II athletes and French mountaineers because of its antifatigue properties, and continued to be marketed in France until 1966 when ibogaine was prohibited in France. Since 1989, ibogaine has also been banned by the International Olympic Committee, the International Union of Cyclists and the French State Secretariat for Youth and Sports (Gouteral, 1992).
Ibogaine has also been used as a psychotherapeutic agent as well as a stimulant. Beginning in 1969, Claudio Naranjo, a Chilean physician, while training at the Institute of Personality and Research of U.C. Berkeley, conducted many psychotherapy sessions using ibogaine as a psychological catalyst. He used a dosage of about 200mg-300mg per patient, and termed the state ibogaine brought about as “oneirophrenia” and ibogaine as an “oneirophrenic” substance (Naranjo, 1973).
Naranjo reported that this “oneirophrenia” would last about six hours and that his subjects would experience an enhancement of their fantasies which were rich in Jungian archetypes. These fantasies involved animals, the subject himself, with or without others, and were easily manipulated by both the patient and by the psychotherapist. Naranjo, after conducting over fifty case-studies of the psychotherapeutic use of ibogaine, concluded that ibogaine was a “non-toxic drug that clarifies thoughts and permits a very thorough introspection while preserving the patient’s emotional character which is indispensable for the stimulation of thought and imagination. I doubt that there is anything that can be achieved with a drug that cannot be done without it. However, drugs can be psychological catalysts that make it possible to compress a very lengthy psychotherapeutic process into a shorter time and change its prognosis. Although ibogaine cannot open a door by itself, it can be considered as the oil for its hinges,” (Naranjo, 1969).
Anecdotal Anti-Addictive Reports In 1962, Howard Lotsof and a group of six or seven friends, all of whom were at the time in various stages of addiction to either cocaine or heroin, each took a dose of about 500mg of ibogaine. They then experienced an approximately 36 hour waking dream-state in which childhood memories and formative experiences were relived and re-examined, each of them gaining insights into how their addictive personality traits formed, where their lives went wrong, so to say (Mash, 1997).
Lotsof, along with five of the others who took that initial dose of ibogaine, permanently gave up the use of drugs entirely following this incredible, unexpected experience, amazingly suffering no withdrawal symptoms whatsoever. Lotsof himself rebuilt his life at this point, dedicating himself to curing drug addicts by providing them with ibogaine. He went on to found the New York corporation NDA International, Inc. in 1986, with the purpose of marketing ibogaine hydrochloride under the tradename of Endabuse(TM). Each capsule of Endabuse(TM) contains 1 gram of ibogaine hydrochloride and is used in the rapid interruption of drug and alcohol addiction with virtually no withdrawal symptoms. Lotsof also filed a number of patents between 1985 and 1992 for methods of using ibogaine in treatments to cure the addiction to substances including narcotics (Lotsof, 1985), cocaine and amphetamines (Lotsof, 1986), alcohol (Lotsof, 1989), nicotine (Lotsof, 1991) and combinations of these drugs (Lotsof, 1992).
Between 1988 and 1990, in conjunction with the International Coalition for Addict Self-Help (ICASH) and the Dutch Addict Self-Help (DASH) groups, Lotsof began conducting underground trials in the Netherlands with more than three dozen addicts successfully being treated. Thanks to Lotsof’s inspiration, research has been and continues to be done on ibogaine at Evans University of Rotterdam, at the Addiction Research Foundation in Toronto, at Albany Medical College, N.Y., and through the Committee on Problems of Drug Dependence at the National Institute of Health, Bethesda, Maryland. Very promising treatment of addicts is currently being conducted by Deborah Mash and others, officially outside of the United States, through Healing Visions: Institute for Addiction Recovery, Ltd. In addition to directing this treatment of addicts, Deborah Mash, Professor of Neurology and Molecular and Cellular Pharmacology, along with Dr. Juan Sanchez-Ramos, both of the University of Miami’s School of Medicine, have conducted F.D.A. approved Pre-Clinical and Phase I Human Safety and Efficacy trials funded mostly by the National Institute on Drug Abuse (NIDA) and the Multidisciplinary Association for Psychedelic Studies (MAPS), (Mash, 1997). MAPS: FEATURE: Ibogaine– C. Lovett, Part II ¡¤ To: maps-forum@xxxxxxxx ¡¤ Subject: MAPS: FEATURE: Ibogaine– C. Lovett, Part II ¡¤ From: maps-forum@xxxxxxxx ¡¤ Date: Tue, 5 Aug 1997 23:43:11 -0400 (EDT) ¡¤ Reply-to: maps-forum@xxxxxxxx ¡¤ Sender: owner-maps-forum@xxxxxxxx Ibogaine: A Retrospective and Current Analysis By Chris Lovett For Principles of Pharmacology and Toxicology I, UC Santa Cruz, 1997. Part II
The pharmacology of ibogaine is extremely complex and not very well understood at the moment. It has been shown to affect the neurotransmitters serotonin (5-HT) and dopamine, to act as a competitive antagonist at the MK-801 binding site of the NMDA receptor complex, and to act as an agonist at the kappa and mu opiate receptors. Ibogaine also has various effects with various durations depending on the dosage. In the following table, human dosages are based on a body weight of 50-100 kg:
USAGE DOSE HUMAN DOSAGE(ORAL) EFFECT DURATION Lambarene(TM) 8mg/tablet (0.08-0.04mg/kg) Stimulant 2-6hrs. The Mitsogho 50-150mg (0.5-3mg/kg) Stimulant 4-8hrs. Claudio Naranjo 200-300mg (2-6mg/kg) Oneirophrenic 4-8hrs. Lotsof in 1962 500mg (5-10mg/kg) Anti-addictive 24-30hrs. Endabuse(TM) 1000mg (10-20mg/kg) Anti-addictive 24-30hrs. The Mitsogho 2-6g (40-100mg/kg) Entheogenic 24-36hrs.
At the dosages listed above, ibogaine has been found to be relatively non-toxic, about as much so as aspirin or quinine, with a wide therapeutic range of 10-50mg as a stimulant, and 300-1000mg as an oneirophrenic or anti-addictive (Dhahir, 1971).
Synthesis and Properties The synthesis of ibogaine and ibogamine was first elucidated by G. Buchi et al. (1966) at the Massachusetts Institute of Technology. They prepared both ibogamine and 12-methoxy ibogamine in the form of their racemates, starting with nicotinamide and proceeding through a 13-step sequence involving an isoquinuclidone intermediate. The correct structure of ibogaine was established by M Bartlett et al. (1958), through chemical studies and x-ray crystallography. The physical properties of ibogaine are as follows:
12-methoxyibogamine: C20H26N2O. Molecular Weight 310.438. C 77.38%, H 8.44%, N 9.02%, O 5.15%. Alkaloid Melting Point@xxxxxx: 152-153 C; HCl salt: 299-300 C (decomposes). pKa: 8.1 in methylcellosolve. The isolated alkaloid is a solid at room temperature consisting of small, red prismatic needles forming from an ethanol solvent. It is practically insoluble in water; soluble in ethanol, ether, chloroform, acetone and benzene. The HCl salt is a crystalline solid at room temperature. It is soluble in water, methanol and ethanol; slightly soluble in acetone and chloroform; practically insoluble in ether. The amount of ibogaine found in Tabernanthe iboga is as follows: root(1.27%), root-bark(2-6%), stems(1.95%) and leaves (0.35%). (Merck, 1996).
Toxicity LD50s are as follows (compare with usage table above): Rat (ORAL): 482 mg/kg Rat (INTRAGASTRIC): 327 mg/kg Rat (INTRAPERITONEAL): 145 mg/kg Guinea Pig (INTRAPERITONEAL): 82 mg/kg
Chronic toxicity studies were done by H. Dhahir in his Ph.D. Thesis (1971), and his findings, as follows, are from his experiments with rats. Ibogaine was administered for 30 days at a dosage of 10 mg/kg intraperitoneally each day, with no damage found to the liver, kidneys, heart or brain. 40 mg/kg was administered each day for 12 days with no damage found to the liver, kidneys, heart or brain. Dhahir contrasted these results with the fact that serotonin is very toxic at dosages four times lower, causing severe kidney damage. He concluded that ibogaine was a relatively non-toxic alkaloid with a wide therapeutic range of 10-50mg as a stimulant and 300-1000mg as a psychotherapeutic agent (Dhahir, 1971).
There has only been one study conducted which has found toxicity or neurotoxicity of any form. This was done by O’Hearn and Molliver (1993) using repeated dosages of 100 mg/kg intraperitoneally on rats, which is near the LD50 for rats (i.p.), and above the LD50 for guinea pigs (i.p.). Also, since these doses were administered intraperitoneally, the drug is not subject to the first-pass effect, which I will discuss shortly, as it would be when given orally in a therapeutic setting. They found degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis. This was associated with loss of the microtubule-associated protein (MAP 2) and calbindin. However, similar neurotoxicity studies were done by Molinari, Maisonneuve and Glick (1996), in which no toxicity or neurotoxicity was found whatsoever. This supports the findings by Sanchez-Ramos and Mash (1994), who conducted Pre-Clinical studies in which African Green monkeys were given 5-25 mg/kg orally for four consecutive days and no neurotoxicity was found.
Pharmacokinetics and Biotransformation There is very little pharmacokinetic data available at this time regarding the adsorption, distribution and elimination of ibogaine in the body. What research has been done mostly addresses how the anti-addictive effects of ibogaine persist for so long in the body, when the half-life according to Dhahir (1971) is only 1 hour. Two types of results have been found to account for this. First, L. Hough, S. Pearl and S. Glick (1996) hypothesize that ibogaine’s long acting effects are due to its persistence in body fat, the drug being slowly released over time. One hour after injecting rats (i.p.) with a dosage of 40 mg/kg, they found ibogaine levels to be 106 ng/ml in blood plasma and 11,308 ng/g in fat tissue. After twelve hours, the levels were 20 ng/ml in blood plasma and 700 ng/g in fat.
Deborah Mash et al. (1995), however, believe that the long-term action of ibogaine is due to its principal metabolite 12-hydroxyibogamine, also called noribogaine. In their study they found that both ibogaine and noribogaine act as competitive antagonists at the MK-801 binding site of the NMDA receptor complex, which may be a cause of ibogaine’s ability to interrupt drug-seeking behavior.
What is also known about the adsorption of ibogaine, is that when administered orally, it is subject to a substantial first-pass effect, being rapidly metabolized by the liver (Hough et al., 1996). Thus, the bioavailability of ibogaine is diminished when administered orally than when administered intraperitoneally, and this effect is reflected in the rat LD50s. Another established property of ibogaine relating to its pharmacokinetic effects is that it has a heptane/water partitioning coefficient of 28 (Zetler et al., 1972). This is not surprising, based on the high adipose-tissue solubilities observed by Hough et al. As is readily apparent, many more pharmacokinetic studies need to be conducted on ibogaine before we begin to understand the action of this highly complex drug.
Pharmacodynamics As with the pharmacokinetics of ibogaine, very little is understood currently about its complex mechanisms of action. There has been a prolific amount of research in the last few years on ibogaine, and various neurotransmitter and receptor systems have been identified as being involved in its mechanisms, including dopamine, serotonin, the NMDA receptor complex and the mu and kappa opiate receptors.
Ibogaine’s binding competitively to the MK-801 binding site of the NMDA receptor complex has been shown to suppress morphine withdrawal and dependency in rats, (Trujillo et al., 1991) and (Popik et al., 1995). This action has also been shown to interact with the kappa opiate receptor in inhibiting opiate dependency (Glick et al., 1996). Mash et al. (1995) found that the principal metabolite of ibogaine, noribogaine, also acts antagonistically at the MK-801 binding site. Ibogaine’s action as an agonist of kappa and mu opiate receptors has also been demonstrated by Glick et al. (1995) to be effective in inhibiting morphine and cocaine self administration in rats. Ibogaine’s action on the dopaminergic system has also been studied, with activity being observed in various brain regions, but not generally in the nucleus accumbens, a supposed site of the neural basis of addiction. Ibogaine has been found to affect dopamine transporters in an unknown way, decreasing extracellular dopamine levels in the striatum, increasing levels in the frontal cortex, and leaving the levels in the nucleus accumbens unchanged (Ali et al., 1996). As evidence of a direct anti-addictive effect, Maisonneuve et al. (1992) have found ibogaine’s effect on the dopaminergic system to inhibit the activity of morphine-preferring rats.
Finally, ibogaine affects the serotonin transporters causing an elevation in serotonin levels. Mash et al. (1995) found this to be true of noribogaine as well. In addition, both ibogaine and noribogaine have been found to inhibit serotonin re-uptake in rats, which has been linked to an attenuation of alcohol consumption in rats that preferred alcohol (Rezvani et al., 1995) and (Rezvani and Mash et al., 1995).
Sweetman et al. (1995) perhaps best sums up the state of our knowledge of the pharmacodynamics of ibogaine by suggesting that multiple mechanisms of action are responsible for ibogaine’s inhibitory effects on substance addiction. As can be inferred from the ever expanding supply of scientific data, the pharmacodynamics of ibogaine, and its principal metabolite noribogaine, are very complex, effecting multiple sites simultaneously, and a full understanding of their actions may not be possible with our current knowledge of neuroscience and its accepted mechanisms of action for chemicals that affect it. MAPS: FEATURE: Ibogaine– C. Lovett, Part III ¡¤ To: maps-forum@xxxxxxxx ¡¤ Subject: MAPS: FEATURE: Ibogaine– C. Lovett, Part III ¡¤ From: maps-forum@xxxxxxxx ¡¤ Date: Tue, 5 Aug 1997 23:50:03 -0400 (EDT) ¡¤ Reply-to: maps-forum@xxxxxxxx ¡¤ Sender: owner-maps-forum@xxxxxxxx Ibogaine: A Retrospective and Current Analysis By Chris Lovett For Principles of Pharmacology and Toxicology I, UC Santa Cruz, 1997. Part III
Last year, in 1996, Deborah Mash and Juan Sanchez-Ramos received F.D.A. approval for the next step of ibogaine research: Phase I human safety trials, evaluating the use of ibogaine in treating cocaine abusers. Unfortunately, the National Institute on Drug Abuse decided in August, 1996 to reject their application for funds, so currently their research is on hold. They have been partially supported by organizations like the Multidisciplinary Association for Psychedelic Studies (MAPS), and the Heffter Research Institute, but these organizations are very small and severely limited in funds.
Ibogaine is also almost impossible to find on the black-market. Perhaps this is because members of the larger underground power-structures in our country that have interests in the vast money-generating power of addictive drugs such as heroin and cocaine, as well as the legal corporations with vested interests in the alcohol and tobacco industries, do not want addiction to be cured. It would be bad for business! Not to mention all those high-level, high-paying bureaucratic positions as well as the laboring police forces that depend on the “War on Drugs” for an occupation. If there were not victims of drug-addiction to apprehend and condemn, or “dangerous” substances to write new laws about, to classify into arbitrary lists, to conduct demographic studies in relation to, and to use as a bludgeoning tool to promote genocide among the peoples of inner-city ghettos, what would our government do with itself? Probably shift its efforts towards increasing our nuclear weapons production, no doubt.
But if the government or any mysterious underground power structures are really factors in the delay in the legalization of ibogaine for anti-addictive use, is only speculation at best, paranoia at worst. What is important is that addicts are being treated by Deborah Mash and others, officially outside of the United States. In addition, Howard Lotsof’s NDA International, Inc. has been manufacturing Endabuse(TM) capsules, also outside of the United States, preparing for what seems to be the imminent legalization of ibogaine for therapeutic use.
There exists no reason why further steps in drug-development for F.D.A. approval of ibogaine should be prevented. There has been no toxicity shown in any pre-clinical animal studies using dosages within the proposed therapeutic index, even at its upper limit, and the F.D.A. has given approval to continue with Phase I human safety trials. Perhaps the reason why the NIDA decided not to fund these trials is that ibogaine’s mechanisms of action are still poorly understood. If this is the case, then the NIDA is forgetting a fundamental principle of scientific research. All models, including models of drug-action, are only models. These models only approximate truth, approximate reality. Just because we cannot find the correctly shaped model to depict the mechanisms of ibogaine does not mean that it is dangerous. It means perhaps our model-based representations of reality are beginning to fail us. Our limits of understanding are beginning to exceed our limits to construct representational models. We are in need of a new paradigm or meta-paradigm to conceptualize within, perhaps one that does not take as an inherent principle the concepts of physicality and reductionism. This is the root of the fear surrounding ibogaine, not fear of the compound, but fear of our own conceptual limits. Perhaps with a new world-view, a new paradigm within which we can conceptualize the workings of ibogaine and many other elusive concepts, this extremely non-toxic spiritual salve which is ibogaine can be used to heal and relieve those people experiencing the pain from within that is the cause of addiction.
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