Research on Ibogaine for Addiction

April 2017 · 11 minute read

Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review

R Mačiulaitis V Kontrimavičiūtė FMM Bressolle V Briedis

First Published March 1, 2008

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Ibogaine is an indole alkaloid derived from the bark of the root of the African shrub Tabernanthe iboga. Psychoactive properties of ibogaine have been known for decades. More recently, based on experimental data from animals and anectodal reports in human, it has been found that this drug has anti-addictive effects. Several patents were published between 1969 and 1995. The pharmacology of ibogaine is quite complex, affecting many different neurotransmitter systems simultaneously. However, the pharmacological targets underlying the physiological and psychological actions of ibogaine are not completely understood. Ibogaine is rapidly metabolized in the body in noribogaine. The purpose of this article was to review data from the literature concerning physicochemical properties, bio-analytical methods, and pharmacology of ibogaine; this article will be focused on the use of this drug as anti-addictive agent.

Fatalities after taking ibogaine in addiction treatment could be related to sudden cardiac death caused by autonomic dysfunction

U. Maas, S. Strubelt

Received 2 February 2006, Accepted 6 February 2006, Available online 15 May 2006

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Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption

Dao-Yao He, Nancy N. H. McGough, Ajay Ravindranathan, Jerome Jeanblanc, Marian L. Logrip, Khanhky Phamluong, Patricia H. Janak and Dorit Ron

Journal of Neuroscience 19 January 2005

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Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.

Effects of ibogaine on acute signs of morphine withdrawal in rats: Independence from tremor

S.D. Glick, K. Rossman, N.C. Rao, I.M. Maisonneuve, J.N. Carlson

Accepted 8 November 1991, Available online 25 November 2002

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Because of the claim that ibogaine suppresses the symptoms of “narcotic withdrawal” in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2–3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal.

Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures.

Mash DC, Kovera CA, Pablo J, Tyndale RF, Ervin FD, Williams IC, Singleton EG, Mayor M.

Ann N Y Acad Sci. 2000 Sep;914:394-401.

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Ibogaine is an indole alkaloid found in the roots of Tabernanthe Iboga (Apocynaceae family), a rain forest shrub that is native to western Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and thirst, and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and opiates. Anecdotal reports attest that a single dose of ibogaine eliminates opiate withdrawal symptoms and reduces drug craving for extended periods of time. The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. The majority of ibogaine biotransformation proceeds via CYP2D6, including the O-demethylation of ibogaine to 12-hydroxyibogamine (noribogaine). Blood concentration-time effect profiles of ibogaine and noribogaine obtained for individual subjects after single oral dose administrations demonstrate complex pharmacokinetic profiles. Ibogaine has shown preliminary efficacy for opiate detoxification and for short-term stabilization of drug-dependent persons as they prepare to enter substance abuse treatment. We report here that ibogaine significantly decreased craving for cocaine and heroin during inpatient detoxification. Self-reports of depressive symptoms were also significantly lower after ibogaine treatment and at 30 days after program discharge. Because ibogaine is cleared rapidly from the blood, the beneficial aftereffects of the drug on craving and depressed mood may be related to the effects of noribogaine on the central nervous system.

Inhibitory effects of ibogaine on cocaine self-administration in rats

Susanne L.T. Cappendijk, Michailo R. Dzoljic

Received 1 February 1993, Revised 9 July 1993, Accepted 14 July 1993, Available online 22 November 2002.

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In order to determine the potential anti-addictive properties of ibogaine, we used the cocaine self-administration model in rats. The results indicate that a single injection of ibogaine (40 mg/kg i.p.) produced a significant decrease of cocaine intake, which remained unaltered for more than 48 h. Since the half-life time of ibogaine is short, this might suggest the involvement of one or several active metabolites of ibogaine in cocaine intake. Repetitive administration of ibogaine on three consecutive days also induced a pronounced decrease of cocaine intake. However, a more prominent inhibitory effect on cocaine intake was observed in animals treated repeatedly with ibogaine (40 mg/kg i.p.), once each week for 3 consecutive weeks. These results indicate that ibogaine or its metabolite(s) is a long-lasting interruptor of cocaine dependence, which supports similar observations from uncontrolled clinical studies.

A preliminary investigation of ibogaine: Case reports and recommendations for further study

Sheppard SG.

J Subst Abuse Treat. 1994 Jul-Aug;11(4):379-85.

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A naturally occurring substance, ibogaine, was taken by seven individuals who were addicted to opiates. Ibogaine, an alkaloid with psychotropic effects at doses of 200-300 mg and above, was taken in single doses of 700-1800 mg by the subjects in the study. At the end of the 24-38-hr psychoactive period induced by the drug at these doses, none of the subjects displayed significant opiate withdrawal symptoms. At the lowest dose of 700 mg, one subject recontinued his drug abuse after 2 days; of the remaining six individuals who took 1,000 mg or above, two relapsed after a number of weeks, one reverted to intermittent heroin use, and three appear to have remained drug-free 14 weeks or more after undergoing this experimental treatment. Ibogaine may be of value in the present and could serve as a model for the development of improved agents for the treatment of substance abuse in the future.

Ibogaine fails to reduce naloxone-precipitated withdrawal in the morphine-dependent rat.

Sharpe, Lawrence G.; Jaffe, Jerome H.

September 1990

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Because of anecdotal reports in which ibogaine eliminates opioid withdrawal symptoms in humans, we studied this phenomenon in the rat model. Ibogaine (5,10, 20 and 40 mg kg-1, s.c.) was administered 15min before naloxone (0.5 mg kg-1, s.c.) in morphine dependent rats (3 days after the s.c. implantation of a 75 mg morphine pellet). Of the 12 withdrawal signs scored, the only significant changes observed after ibogaine (compared with vehicle control) was a decrease in grooming (10 mg kg-1) and an increase in teeth chatter (5 mg kg-1). In spite of ibogaine’s apparent interaction with several neurotransmitter receptor systems, it does not alleviate opioid withdrawal in this animal model at non-tremor-igenic (5 and 10 mg kg-1) or tremorigenic (20 and 40 mg kg-1) doses.

Effects of ibogaine on naloxone-precipitated withdrawal in morphine-dependent mice

B. Francés, R. Gout, J. Cros, JM Zajac

First published: November 1992

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Summary— In naive mice, ibogaine at a tremorigenic dose (30 mg/kg, ip), did not produce antinociception but did potentiate the antinociceptive potency of morphine in the tail-flick test. In morphine-dependent mice, ibogaine did not eliminate withdrawal symptoms but significantly increased the number of repetitive vertical jumps induced by naloxone, whatever the duration of the chronic morphine treatment. By comparison, repetitive jumping induced by α-napthoxyacetic acid (α-NOAA), a non-convulsant drug which induced jumping without affecting other morphine-withdrawal signs, was not significantly modified by ibogaine. These results indicate that while acute antinociceptive effects of morphine are modulated by ibogaine, this drug, shown to alleviate opiate dependence in man, does not attenuate in mice opioid withdrawal manifestations.

Treatment of acute opioid withdrawal with ibogaine.

Alper KR, Lotsof HS, Frenken GM, Luciano DJ, Bastiaans J.

Am J Addict. 1999 Summer;8(3):234-42.

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Ibogaine is an alkaloid with putative effect in acute opioid withdrawal. Thirty-three cases of treatments for the indication of opioid detoxification performed in non-medical settings under open label conditions are summarized involving an average daily use of heroin of .64 +/- .50 grams, primarily by the intravenous route. Resolution of the signs of opioid withdrawal without further drug seeking behavior was observed within 24 hours in 25 patients and was sustained throughout the 72-hour period of posttreatment observation. Other outcomes included drug seeking behavior without withdrawal signs (4 patients), drug abstinence with attenuated withdrawal signs (2 patients), drug seeking behavior with continued withdrawal signs (1 patient), and one fatality possibly involving surreptitious heroin use. The reported effectiveness of ibogaine in this series suggests the need for systematic investigation in a conventional clinical research setting.

Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats.

Dzoljic ED, Kaplan CD, Dzoljic MR.

Arch Int Pharmacodyn Ther. 1988 Jul-Aug;294:64-70.

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Ibogaine, an indole alkaloid, administered intracerebroventricularly 4-16 micrograms, attenuated a naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats. It appears that ibogaine has a more consistent effect on certain selective withdrawal signs related to the locomotion. This might explain an attenuating effect of ibogaine on some withdrawal signs. However, due to complex interaction of ibogaine with serotonin and other neurotransmitter systems, the mechanism of ibogaine antiwithdrawal effect remains unknown and requires further elucidation.

Interactions between ibogaine, a potential anti-addictive agent, and morphine: an in vivo microdialysis study

Maisonneuve IM, Keller RW Jr, Glick SD.

Eur J Pharmacol. 1991 Jun 18;199(1):35-42.

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Ibogaine, an indolalkylamine, has been claimed to be effective in abolishing drug craving in heroin and cocaine addicts. The present study used in vivo microdialysis to determine the effects of ibogaine on extracellular levels of dopamine (DA) and its metabolites and the effects of ibogaine pretreatment on morphine stimulation of brain DA systems. Acutely, ibogaine (40 mg/kg i.p.) decreased extracellular DA levels in the striatum, increased them in the prefrontal cortex and had no significant effects in the nucleus accumbens. Nineteen hours after ibogaine injection. DA levels were still decreased in the striatum and the metabolite levels were lower in all three regions. When injected 19 h prior to a morphine challenge (5 mg/kg i.p.), ibogaine (40 mg/kg, i.p.) prevented the rise in DA levels in all three regions normally observed after a morphine injection. A high dose of morphine (30 mg/kg i.p.), administered alone, produced no increase in extracellular DA levels; it is therefore unclear whether ibogaine antagonized or potentiated the effects of the lower dose of morphine. Regardless of the nature of this interaction, it appears that ibogaine affects brain DA systems for a period of time that exceeds its elimination from the body and, during this time, alters the responses of these systems to morphine.

Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine’s putative anti-addictive activity

Sweetnam PM, Lancaster J, Snowman A, Collins JL, Perschke S, Bauer C, Ferkany J.

Psychopharmacology (Berl). 1995 Apr;118(4):369-76.

The indole alkaloid ibogaine (NIH 10567, Endabuse) is currently being examined for its potential utility in the treatment of cocaine and opioid addiction. However, a clearly defined molecular mechanism of action for ibogaine’s putative anti-addictive properties has not been delineated. Radioligand binding assays targeting over 50 distinct neurotransmitter receptors, ion channels, and select second messenger systems were employed to establish a broad in vitro pharmacological profile for ibogaine. These studies revealed that ibogaine interacted with a wide variety of receptors at concentrations of 1-100 microM. These included the mu, delta, kappa, opiate, 5HT2, 5HT3, and muscarinic1 and 2 receptors, and the dopamine, norepinephrine, and serotonin uptake sites. In addition, ibogaine interacted with N-methyl-D-aspartic acid (NMDA) associated ion and sodium ion channels as determined by the inhibition of [3H]MK-801 and [3H]bactrachotoxin A 20-alpha-benzoate binding (BTX-B), respectively. This broad spectrum of activity may in part be responsible for ibogaine’s putative anti-addictive activity.

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See also

Ibogaine in the treatment of chemical dependence disorders: clinical perspectives, 1995

100 years of ibogaine: neurochemical and pharmacological actions of a putative anti-addictive drug., 1995