MAPS: ibogaine literature review

[Jon Freedlander <jfreed1@xxxxxxxx>]

hello everyone,

the following is a term paper i wrote for my addictions class last
semester...i thought some of you might find it interesting, so here it is
=)

Ibogaine: A Review of Contemporary Literature
By,
Jonathan Freedlander
PSYC 485 - Prof. John Allen, PhD
University of Maryland, Baltimore County

Introduction and History:

     Banzie (the members of the Bwiti, properly, "those of the chapel")
     ...say that eboga [sic] enables a man or woman to return to infancy
     and to birth - to life in the womb...by returning initiates to the
     uterine condition, a condition in any case very close to life in
     the land of the dead [and so] restores them to their own integrity
     - their pristine conditions. (Fernandez, 1982).

	Ibogaine is a naturally occurring indole alkaloid found in a
variety of tropical shrubs of the Tabernanthe genus, the most well
known of which is Tabernanthe iboga (Shulgin and Shulgin, 1977). In the
western world, extracts of iboga root, which contain some 12 known
active alkaloids, including ibogaine, have been used medicinally for
over a century (Popik, and Skolnick, 1999). Ibogaine was first extracted
from the iboga root in 1901 by Dybowsky and Landrin (Goutarel,
Gollnhofer, and Sillans , 1993), though its chemical structure was not
determined until 1957 (Taylor, 1965). Complete synthesis of ibogaine
from nicotinamide is possible by way of a 13 or 14 step process;
however, this process is rarely used as a source of ibogaine, as
extraction from the root is a considerably less work intensive means of
obtaining the compound, and there are no known advantages to the
synthetic method (Shulgin and Shulgin, 1977).
	The root of the Tabernathe iboga has been used for centuries by
various indigenous cultures of western Africa, as first reported by
French and Belgian explorers in the nineteenth century (Popik and
Skolnick, 1999). Depending on the specific culture, the root is either
chewed whole, or prepared in a mixture, with or without other
psychoactive ingredients (Fernandez, 1982). These cultures use the iboga
root as a catalyst for spiritual discovery, primarily involved in Bouti
initiation rites. In these rites, the initiate must venture into the
spiritual world, guided by those already initiated, in a complex ritual
that is centred around the effects of ingestion of the iboga root. The
effects of the ingested root propagate a voyage of self-discovery, which
is heavily imbued with Jungian archetypes, involving a return to the
womb and a journey through the domain of the tribal ancestors (Goutarel,
Gollnhofer, and Sillans, 1993). Other preparations of the iboga root in
smaller quantities are also used throughout western Africa as a
stimulant, particularly before a hunt, and as an aphrodisiac (Lotsof,
Della Sera, and Kaplan, 1995).
	Ibogaine was first introduced to the Western public in France in
the 1930's, in the form of Lambarene, an extract of the Tabernathe manii
plant. It was described as a mental and physical stimulant and contained
about 8 mg of ibogaine (Popik and Skolnick, 1999).  The drug was
"...indicated  in cases of depression, asthniea, in convalescence,
infectious disease, [and]  greater than normal physical or mental
efforts by healthy individuals," and aroused a great deal of interest
amoung post-war athletes. Eventually, Lambarene disappeared from the
market, and the sale of ibogaine was prohibited in 1966 (Goutarel,
Gollnhofer, and Sillans, 1993).
	In the 1960's, a Chilean psychiatrist named Clauido Naranjo began
experiments to study the potential of ibogaine as a catalyst for the
psychotherapeutic process. He found through case studies that, with a
dosage range of between 3 and 5 mg/kg, ibogaine elicits an oneirogenic
condition which facilitates long term memory retrieval and closure of
unresolved emotional conflicts (Naranjo, 1974). The word "oneirogen"
(from the Greek, meaning "dream") is used rather than "hallucinogen" in
referring to ibogaine's psychological effects, because ibogaine is not
truly psychomimetic; it does not produce loss of consciousness or any
formal deterioration of thought (Goutarel, Gollnhofer, and Sillans,
1993).
	Naranjo noted, as did ethnographers who have studied the cultures of
western Africa, that the imagery produced by ibogaine is largely Jungian
in content. That is, it involves archetypes common to all humans,
imagery that provides the basis for the human psyche. In a therapy
session, this archetypal imagery is used as a medium for mitigating
emotional insight in relation to memories most significant to the
individual's condition (Naranjo, 1974). Indeed, from a psychological
perspective, it would seem as though this relationship is likely to be a
primary factor in ibogaine's therapeutic effects.
	Ibogaine was first reported to be effective in treating chemical
addictions by H. S. Lotsof, when he introduced Endabuse (NIH 10567)
(Popick and Glick 1996). He began studying the effects of ibogaine in
treating individuals with addictive disorders with a series of focus
group experiments in the early 1960's (Lotstof, Della Sera, and Kaplan,
1995). In 1985, Lotsof patented Endabuse for use in the interruption of
opiate dependence disorders (U.S. patent 4,499,096), in 1986 for use in
cocaine dependence disorders (U.S. patent 4,587,243), and in 1992 for
poly-drug use dependence disorders (U.S. patent 5,152,994) (Lotsof,
Della Sera, and Kaplan, 1995). Lotsof also developed a specific
procedure for the use of Endabuse (aptly named the Lotsof ProcedureTM),
which involves comprehensive short and long term physical, psychiatric,
psychological, and social care of the patient (Lotsof, 1994).

Pharmacodynamics :

	Ibogaine's physiological actions are particularly complex, and are
still far from being fully understood. Structurally, ibogaine is a
derivative of serotonin (Dhahir, 1971). It has specific affinities for
many binding sites within the CNS, including NMDA
(N-methyl-D-aspartate), kappa, opioid, sigma, and nicotinic receptors
(Alper et al, 1999). It is known to act on many different
neurotransmitter systems, sometimes in seemingly paradoxical ways
(Popick and Glick,  1996), and does not appear to be a conventional
dopamine or opioid agonist or antagonist or and amine uptake inhibitor
(Alper et al, 1999). Noribogaine (12-hydroxyibogamine) is a metabolite
of ibogaine created by the activity of liver enzymes, and is thought to
be responsible for at least some of ibogaine's psychological effects,
which goes to further complicate the study of ibogaine's
pharmacodynamics (Mash et al, 2000).
	It has long been thought that dopaminergic pathways are involved in
the reinforcement effects of addictive drugs, and ibogaine has been
shown to have some unusual effects on this system. Ibogaine does not
appear to affect binding at dopamine receptors, nor does it seem to
consistently affect dopamine transport systems. However, under certain
experimental conditions, ibogaine results in a reduction of dopamine
concentrations and an increase in dopamine metabolites DOPAC
(dihydroxyphenyl-acetic acid) and HVA (homovanilic acid) (Popick and
Skolnik, 1999). Noribogaine is likely to be involved, at least in part,
in ibogaine's dopaminergic effects, particularly that of reduced
dopamine turnover for an extended period of time after administration;
however, this relationship remains unclear (Mash et al, 2000).
	Like dopamine pathways, NDMA receptors have often been sighted as
neural components implicated in addictive disorders. Ibogaine acts as an
NDMA antagonist, a competitive inhibitor of [3H]MK-801 or [3H]TCP
binding at receptor coupled NMDA ion channels (Sweetnam et al, 1995). In
support of these findings, ibogaine produces a voltage dependent block
of NDMA invoked currents in hippocampal cultures, and inhibits
glutamate-induced cell death in neuronal cultures (Popik et al, 1995).
NDMA antagonists acting at the glutamate, open channel, and glycine
binding sites have been shown to suppress symptoms of morphine
withdrawal in rodents, and attenuate drug self-administration (Trujillo
and Akil, 1991).
	Ibogaine binds only mildly to opioid receptors, though its
metabolite noribogaine has a considerably higher affinity for opioid
receptor binding (Popick and Glick, 1996).  Ibogaine has been reported
not to affect [3H]carfentanil or [3H]enkephalin binding at mu or delta
opioid receptors (Popick and Skolnick, 1999); however, Sweetnam et al
(1995) demonstrated that it does inhibit radioligand binding to mu
opioid receptors. In addition, ibogaine has been shown to inhibit other
compounds from binding at opioid sites, including naloxone, an opioid
antagonist (Popick and Skolnick, 1999). This may be related to the
phenomena of reduced opiate withdrawal symptoms seen in addicts treated
with ibogaine.
	As is the case with many tryptamines, ibogaine's effects on the
serotonergic system are particularly complex. It has no effect on
[3H]serotonin binding (Popick and Skolnick, 1999) and does not displace
ligands acting at 5-HT1a, 5-HT1b, 5-HT1c, 5-HT1d, 5-HT2, or 5-HT3
receptors (Deecher et al, 1992). However, ibogaine does inhibit binding
of 5-HT1a, 5-HT2a, and 5-HT3 ligands with low affinity (Repke et al) and
inhibits radioligand binding to 5-HT2 and 5-HT3 receptors (Sweetnam et
al, 1995). Furthermore, ibogaine's effects on the serotonergic system may
have a role in its regulation of dopamine release (Popick and Skolnik,
1999). Clearly, there is need for much more research on ibogaine's effects
on the serotonergic system, and on its pharmacodynamics in general.

Anti-addictive Properties:

	As mentioned earlier, ibogaine was first introduced by H.S. Lotsof
as an aide in breaking the addictive cycle. This claim has been
supported by numerous empirical and clinical studies. Ibogaine has been
shown to attenuate signs of morphine withdrawal in rats (jumping,
rearing, digging, head hiding, chewing, teeth chattering, writhing, and
penile licking), and to reduce self-administration of heroin, morphine,
and cocaine (Glick, Rossman, and Steindorf, 1991). Similar results have
been seen in experiments examining ibogaine's effects on morphine
addicted rats and monkeys (Alper et al, 1999). Ibogaine has also been
shown to reduce cocaine-induced motor stimulation in the mouse (Lotsof,
Della Sera, and Kaplan, 1995).
	In humans, administration of ibogaine resulted in fewer
self-reported cravings for both heroin and cocaine addicts, and reduced
self-reported depressive symptoms (Mash et al, 2000). Sheppard (1994)
found that ibogaine treatment seems to remove an addicted individuals
desire to seek and use opiates, and that after treatment, several
subjects who did use heroin again found the experience to be
unsatisfying. Additionally, multiple reports have sighted that ibogaine
reduces or eliminates opiate withdrawal symptoms within 1 to 2 hours
with a complete resolution of symptoms within 24 to 48 hours (Alper et
al, 1999). Judd (1994) observed that ibogaine has significant advantages
over traditional treatment methods with respect to what she considers
the three major obstacles in addiction treatment; fear of
detoxification, lack of insight, and the inability of addicts to control
their urges to use drugs.
	It is important to note that when using ibogaine in the treatment
of addictive disorders, the methods involved are considerable different
than those used in conventional addiction treatments. Often, only one
treatment of ibogaine is necessary to break the addictive pattern, while
sometimes multiple treatments are needed (Goutarel, Gollnhofer, and
Sillans, 1993). In any case, ibogaine treatment involves a more intimate
relationship between the patient and the clinician (or, more
appropriately, the team of clinicians), involving a greater level of
trust and compassion than is generally seen in typical addiction
counseling (Lotsof, 1994). This is due to the deeply personal nature of
the ibogaine experience, and the fact that at the dosage commonly used
for addiction treatment ibogaine's psychotropic effects last
approximately 24 - 38 hours (Sheppard, 1994).
Conclusion and Commentary:
	Ibogaine represents a truly novel approach to the treatment of
addictive disorders; one which involves a more holistic approach,
involving simultaneous treatment from  physiological, psychological, and
even sociological perspectives. Though clinical research on this
compound's anti-addictive properties is still in its infancy, at this
stage there is significant evidence to suggest that ibogaine has the
potential to address many obstacles that often prevent the successful
treatment of addictions. As one patient stated, "ibogaine is a much more
humane and dignified approach to detox [sic]" (Judd, 1994). If this
notion proves to be true, ibogaine therapy would be a major step forward
for addiction treatment, which at it's present state (particularly in
the United States) is at best often ineffectual, and at worst seriously
degrading to the addicted individual.
	This is not to insult the dedicated work of countless researchers
and therapy providers, but is rather a statement to illustrate our current
lack of understanding of the addictive process in general, and more
specifically, the insurmountable difficulties that current approaches to
addiction treatment inherently possess. With standard addiction
treatment models, it typically takes 4 to 7 attempts on the part of the
patient to reach sobriety, or even temporary abstinence ( Anderson,
1996). If ibogaine does prove to be safe and effective after further
rigorous clinical investigations, and the previous findings are proven
stable in their repeatability, ibogaine will truly represent the next
step in the ever-present dilemma of the chemical addiction phenomenon.

References:

	Alper, K., Lotsof, H., Frenken G., Luciano, D., and Bastiaans, J.
(1999).  "Treatment of Acute Opioid Withdrawal with Ibogaine". The
American Journal on Addictions, Vol. 8, pp 234 - 242.
	Anderson, C. (1998). "Ibogaine Therapy in Chemical Dependency and
Posttraumatic Stress Disorder: A Hypothesis Involving the Fractal Nature
of Fetal REM Sleep and Interhemispheric Reintegration".  MAPS:
Multidisciplinary Association for Psychedelic Studies, Vol. 8.
	Deecher, D., Teitler, M., Soderlund, D., Bornman, W., Kuehne, M.,
and Glick, S. (1992). "Mechanisms of Action of Ibogaine and Harmaline
Congeners Based on Radioligand Binding Studies". Brain Research, Vol.
571, pp 242 - 247.
	Dhahir, H. (1971). "A Comparative Study on the Toxicity of Ibogaine
and Serotonin." Thesis, PhD. In Toxicology, Indiana University.
	Fernandez, J, Bwiti: an Ethnography of the Religious Imagination in
Africa. Princeton University Press, Princeton, NJ, 1982.
	Glick, S., Rossman, K., and Steindorf, S. (1991). "Effects and
After-Effects of Ibogaine on Morphine Self-Administration in Rats".
European Journal of Pharmacology, Vol. 195, pp 341 - 345.
	Goutarel, R., Gollnhofer, O., and Sillans, R. (1993).
"Pharmacodynamics and Therapeutic Actions of Iboga and Ibogaine".
Psychedelic Monographs and Essays, Vol. 6, pp 71 - 111.
	Judd, B. (1994). "Ibogaine, Psychotherapy, and the Treatment of
Substance-Related Disorders". 8th International Conference on Drug
Related Harm, Washington, D.C.
	Lotsof, H. (1994). "Ibogaine in the Treatment of Chemical
Dependence Disorders: Clinical Perspectives (A Preliminary Review)".
	Lotsof, H., Sera, E., and Kaplan, C. (1995). "Ibogaine in the
Treatment of Narcotic Withdrawal". 37th International Congress on
Alcohol and Drug Dependence, U. of CA, San Diego.
	Mash, D., Kovera, C., Pablo, J., Tyndale, R., Ervin, F., Williams,
I., Singleton, E., and Mayor, M. (2000). "Ibogaine: Complex
Pharmokinetics, Concerns for Safety, and Preliminary Efficacy Measures".
Neurobiological Mechanisms of Drugs of Abuse, Vol. 914, pp 394 - 401.
	Naranjo, C. The Healing Journey. Pantheon Books, New York, 1974.
	Popick, P. and Glick, S. (1996). "Ibogaine, A Putatively
Anti-Addictive Alkaloid". Drugs of the Future, Vol. 21, pp 1109 - 1115.
	Popick, P. and Skolnick, P. (1999). "Pharmacology of Ibogaine and
Ibogaine-Related Alkaloids". The Alkaloids, Vol. 52, pp 197 - 231.
	Popick, P., Layer, R., Fossom, L., Benveniste, M., Getter-Douglas, B.,
Witkin, J., and Skolnick, P. (1995). "NMDA Antagonist Properties of the
Putative Anti-Addictive Drug, Ibogaine".  Journal of Pharmacology and
Experimental Therapeutics, Vol. 275, pp 753 - 760.
	Repke, D., Artis, D., Nelson, J., and Wong, E. (1994). "Abbreviated
Ibogaine Congeners. Synthesis and Reactions of Tropan-3-yl-and-3indoles.
Investigation of an Unusual Isomerization of 2-substituted Indoles Using
Computational and Spectroscopic Techniques". Journal of Organic
Chemistry, Vol. 59, pp 2164 - 2171.
	Sheppard, S. (1994). "A Preliminary Investigation of Ibogaine: Case
Reports and Recommendations for Further Study". Journal of Substance
Abuse Treatment, Vol. 11, pp 379 - 385.
	Shulgin, A. and Shulgin, A. TiKHAL: The Continuation (Tryptamines I Have
Known and Loved), Transform Press, 1977.
	Sweetnam, P., Lancaster, J., Snowman, A., Collins, J., Pershcke, S.,
Bauer, C., and Ferkany, J. (1995). "Receptor Binding Profile Suggests
Multiple Mechanisms of Action are Responsible for Ibogaine's Putative
Anti-Addictive Activity". Psychopharmacology, Vol. 118, pp 369 - 376.
	Taylor, W. (1965). "Ibogaine: Chemistry and Physiology". The Alkaloids,
Vol. 8, pp 203 - 227.
	Trujillo, K. and Akil, H. (1995). "Excitatory Amino Acids and Drugs of
Abuse: A Role for NMDA Receptors in Drug Tolerance, Sensitisation, and
Physical Dependence". Drug and Alcohol Dependence, Vol. 38, pp


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