ibogaine neurotoxicity

Boris Leshinsky bleshins at bigpond.net.au
Fri Aug 12 00:09:52 EDT 2005


I just looked this up for myself, and here's what I found.

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the following from 
http://userpages.umbc.edu/~jfreed1/Ibogaine.html

...
   Of more importance to the general population than these isolated incidents, are recent reports of ibogaine neurotoxicity. There are, however, some discrepancies among these reports. Dhahir (1971) found no pathological changes in the liver, kidney, heart or brain of the rat following chronic intraperitoneal ibogaine administration (10 mg/kg for 30 days, and 40 mg/kg for 12 days.) Likewise, Sanchez-Ramos and Mash (1994) found no evidence of gross pathology in African green monkeys given ibogaine in oral doses of 5 – 25 mg/kg for four consecutive days.

    In higher doses, though, ibogaine has been shown to cause definitive neurotoxic effects. At a single intraperitoneal dose of 100 mg/kg, ibogaine was shown to cause marked degeneration of Purkinje cells and activation of microglia in discrete radial bands of the rat cerebellar cortex (O’Hearn and Molliver, 1997). In support of these findings, Xu et al (2000) found that degeneration of Purkinje cells was visible at intraperitoneal doses beginning at 75 mg/kg, showing increasing damage at 100 mg/kg. This study revealed that the neurotoxicity of ibogaine is dose-dependent, a finding also supported by other investigations (Molinari, Maisonneuve, and Glick, 1996).

    O’Hearn and Molliver (1997) propose that ibogaine is not directly toxic to Purkinje cells, but rather causes Purkinje cell degeneration through sustained activation of the olivocerebellar projection. Scallet et al (1996) reported that activation of serotonin receptors in the forebrain is the initial site of ibogaine neurotoxicity. Cortifugal axons could then stimulate the inferior olive and its excitotoxic climbiner-fiber pathway to the cerebellum (Xu et al, 2000). This lends support to O’Hearn and Molliver’s theory of trans-synaptic excitoxicity mediated by the olivocerebllar projection.

    In light of these findings, a number of researchers have recently been studying the effects of a synthetic congener of ibogaine, 18-methoxycoronaradine, more commonly known as 18-MC. Similar to ibogaine, 18-MC decreases levels of extracellular dopamine in the nucleus accumbens (Szumlinksi, Maisonneuve, and Glick, 2000). Likewise, 18-MC has similar effects to ibogaine on the attenuation of morphine and cocaine self-administration (Glick et al, 1996) and alcohol intake (Rezvani et al, 1997). However, unlike ibogaine, 18-MC is non-tremorigenic, does not induce brachycardia, nor does it cause damage to Purkinje cells, or the brain in general (Glick et al, 1996; Molinari, Maisonneuve, and Glick, 1996; Glick, Maisonneuve, and Szumlinski, 2000). FDA protocol studies of human toxicity had been approved and were underway at the University of Miami, under the direction of neurologist Deborah Mash, but the trials were discontinued due to lack of funding. However, should future studies deem ibogaine too hazardous for clinical use, 18-MC could represent a viable alternative.
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Summary on Ibogaine Neurotoxicity from the Ibogaine Dossier:
http://www.ibogaine.org/neurotoxicity.html

IBOGAINE NEUROTOXICITY

Michael Bosman
Editor, The Ibogaine Dossier (retired)

Revised August 26, 2001
Howard S. Lotsof
Ibogaine Consultant

Concern has been expressed regarding ibogaine neurotoxicity.

However, an intra-peritoneal dose of 40 mg/kg for 12 days, or 10 mg/kg for 30 days caused no significant pathologic findings in rat heart, liver, kidneys, and brain. (Dhahir 1971) No neurotoxicity was observed after 5-25 mg/kg ibogaine for 4 days per os in African green monkeys. (Sanchez-Ramos 1994)

While O'Hearn and Molliver describe that ibogaine and harmaline have selective neurotoxic effects, leading to degeneration of Purkinje cells in the cerebellar vermis, (O'Hearn 1993a, 1993b) Molinari et al. subsequently report that ibogaine induced neurotoxicity is dose-dependent, not causing pathological changes at therapeutic doses in the rat. (Molinari 1996)

Glick shows that 18-methoxy-coronaridine, a novel, synthetic iboga alkaloid congener, mimics ibogaine's effects on drug self-administration without evidence of cerebellar toxicity at a high dose (100 mg/kg). (Glick 1996) Popik states that ibogaine exhibits neuroprotective properties in cultures of cerebellar granule cell neurons. (Popik 1995)

Further, to the matter of neurotoxicity, Helsley shows no significant differences in Purkinje cell numbers between ibogaine and control groups (Helsley 1997) while Xu in work jointly performed at the University of Arkansas for Medical Sciences and the Division of Neurotoxicology, National Center for Toxicological Research, an FDA laboratory showed no neurotoxicity above controls at human therapeutic doses of 25 mg/kg of ibogaine in the rat. (Xu 2000)
Literature

   1. Methods for the detection and determination of ibogaine in biological materials. Dhahir, H.I., Jain, N.C. and Forney, R.B. J Forensic Sci 16:103-108, 1971.
   2. Ibogaine research update: phase I human study. Sanchez-Ramos, J. and Mash, D.C. Multidisciplinary Association for Psychedelic Studies 4:11, 1994.
   3. Ibogaine induces glial activation in parasagittal zones of the cerebellum. O'Hearn, E., Long, D.B. and Molliver, M.E. Neuroreport 4:299-302, 1993.
   4. Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. O'Hearn, E. and Molliver, M.E. Neuroscience 55:303-310, 1993.
   5. Ibogaine neurotoxicity: a re-evaluation. Molinari, H.H., Maisonneuve, I.M. and Glick, S.D. Brain Res 737:255-262, 1996.
   6. 18 Methoxycoronaridine, a Nontoxic Iboga Alkaloid Congener: Effects on Morphine and Cocaine Self Administration and on Mesolimbic Dopamine Release in Rats. Glick, S.D., Kuehne, M.E., Maisonneuve, I.M., Bandarage, U.K. and Molinari, H.H. Brain Res 719:29-35, 1996.
   7. NMDA Antagonist Properties of the Putative Antiaddictive Drug, Ibogaine. Popik, P., Layer, R.T., Fossom, L.H., et al. J Pharmacol Exp Ther 275:753-760, 1995.
   8. Effects of Chronic Ibogaine Treatment on Cerebellar Purkinje Cells in the Rat. Helsley, S., Dlugos C.A., Pentney R.J., Rabin R.A., Winter J.C. Brain Reseach 759(2):306-308, 1997.
   9. A Dose-Response Study of Ibogaine-Induced Neuropathology in the Rat Cerelellum. Xu Z., Chang L.W., Slikker W. Jr., Ali S.F., Rountee R.L., Scallet A.C. Toxicol Sci 57(1):95-101,2000. 


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and from http://www.ibogainetreatment.com FAQ:

Toxicity:

Medication Development of Ibogaine as a Pharmacotherapy for Drug
Dependence,Deborah C. Mash, Craid A. Kovera, Billy E. Buck, Michael D. Norenberg,
Paul Shapshak W. Lee Hearn and Juan Sanchez-Ramos, (1998) Ann. NY AScad Sci,
844:274-291.

"...toxicological studies conducted in primates have demonstrated that
oral ibogaine administration, given at doses (5 x 25 mg kg) recommended for
the treatment of cocaine and opiate dependence appear to be safe and free of
behavioral or cerebellar toxicity."

In the same paper the authors discuss the autopsy of a patient dying of
natural causes who had received four ibogaine treatments of between 10
mg/kg and 29 mg/kg. "There were no degenerative changes seen in the
cerebellum; cerebellar Purkinje cells were normal and there was no evidence of any
significant cytopathology or neurodegeneration in any other brain area

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