Arber Ibrahimi
DEFINITION
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.
Mechanisms of action
Despite several years of intensive research, the mechanism of anti-addictive action of ibogaine has not been unequivocally defined. This is perhaps due to the fact that the neurochemical and molecular basis of drug addiction is by itself poorly understood. The recently identified antagonistic activity of ibogaine on N-methyl-D-aspartate (NMDA) receptors as well as its agonist activity at opioid receptors are highly regarded as a possible mechanisms of these anti-addictive actions. However, it should be mentioned that ibogaine interacts with several neurotransmitter systems, including serotonin uptake sites and sigma sites, and that at least some of ibogaine's actions have been attributed to a long-lasting metabolite, possibly O-desmethylibogaine (other names: noribogaine or 12-hydroxyibogamine) for chemical structures.
Several lines of evidence suggest that NMDA receptors are involved in mediating the effects of abused drugs. NMDA antagonists acting at the glutamate, open channel (MK-801) and glycine binding sites suppress symptoms of morphine withdrawal in rodents as well as attenuate drug self-administration, sensitization to the behavioral effects of psychostimulants and rewarding effects of drugs of abuse . Several studies indicate that ibogaine is a competitive inhibitor of [3H]MK-801 or [3H]TCP binding (Ki ~1 mM) to NMDA receptor coupled ion channels . Consistent with these neurochemical studies, ibogaine produced a voltage dependent block of NMDA evoked currents in hippocampal cultures (Ki, 2.3 mM at -60 mV) as well as inhibited glutamate-induced cell death in neuronal cultures, indicating its antagonistic activity at the NMDA receptors. Moreover, in drug-discrimination studies, ibogaine substituted as an interoceptive cue in mice trained to recognize MK-801 (dizocilpine) in a drug discrimination paradigm .
Ibogaine binds to opioid receptors with an affinity of 2-4 M and its metabolite O-desmethylibogaine has an affinity of ~ 1 M . Increasing evidence suggests that agonists can modulate the reinforcing effects of drugs. It has been reported that agonists decrease morphine and cocaine self-administration in rats and attenuate the rewarding effects of both morphine and cocaine in a conditioned place preference paradigm. In addition, agonists were found to prevent sensitization to the conditioned rewarding effects of cocaine . Kappa agonists, as well as an NMDA antagonist, mimic the inhibitory effect of ibogaine on morphine-induced locomotor hyperactivity in rats . The combination of a antagonist and an NMDA agonist has been reported to antagonize ibogaine's effects on nucleus accumbens dopamine release, on morphine-induced hyperactivity, and on morphine self-administration .
Ibogaine has been reported to produce hallucinations or fantasies in man. Several s receptor ligands (e.g. cyclazocine and N-allylnormetazocine [SKF 10,047]) also produce psychotic symptoms in humans while the major effect of s receptor antagonists in humans is attenuation of hallucinations (both drug-induced and illness-related) . Ibogaine inhibited the binding of [3H]pentazocine (a s1 receptor ligand), to high (IC50 ~86 nM) and low (IC50 ~5.6 mM) affinity sites in mouse cerebellum . In other studies, ibogaine had a relatively high affinity for s2 receptors (Ki = 90.4 and 250 nM) and a significantly lower affinity for s1 receptors (Ki = 9310 nM) . Nonetheless, since the physiology and pharmacology of the s receptor is not well understood, the significance of these findings remains unclear.
Clinical studies
Numerous psychotropic actions of ibogaine have been reported. These actions appear to depend on both the dose and setting.
Ibogaine or the total iboga extract (4-5 mg/kg) given orally, elicits subjective reactions which last for approximately 6 hours. Fifty percent of subjects are reported to experience dizziness, incoordination, nausea, and vomiting . Typically in these studies, the drug elicited a state of drowsiness in which the subject did not want to move, open the eyes, or attend to the environment.
The psychoactive properties of ibogaine and related compounds were studied in detail by Naranjo , who explored the possibility of using ibogaine to facilitate psychotherapy. He used the term "oneirophrenia" to describe the ibogaine-induced state. Such an "oneirophrenic" state differs from the psychotomimetic state by the absence of all psychotic symptoms, yet having in common the prominence of primary process thinking. Naranjo, observing at least 40 sessions conducted with 30 patients, reported that the psychic state produced by ibogaine might be described as similar to a dream state without loss of consciousness. Thus, at doses of 4-5 mg/kg, subjects experienced an enhancement of fantasy without experiencing changes in the perception of the environment, delusions, depersonalization, or formal alterations of thinking. Ibogaine's fantasies were reported as rich in archetypal contents, involving animals and/or the subject himself with or without other individuals. The fantasies evoked by ibogaine were easy to manipulate by both the subjects and the psychotherapist. The patients were able to respond to the questions of the therapists. It was concluded that ibogaine could act as a psychological catalyst which could compress a long psychotherapeutic process into a shorter time .
No double-blind, placebo controlled clinical trials with ibogaine in the treatment of drug addiction have been conducted. Such studies are obviously needed.
Conclusions
The preclinical pharmacological effects of ibogaine may be summarized as follows: a decrease in self-administration of psychostimulants, morphine and alcohol, reduction of morphine withdrawal syndrome, a decrease in locomotor activity, memory retrieval facilitation, cardiovascular effects and tremor. Ibogaine decreases the hypermotility and dopamine turnover elicited by stimulants in male mice and rats, but has opposite effects in female rats. Neurochemical effects of ibogaine on mesolimbic and mesocortical dopamine systems can be summarized as follows: high doses decrease extracellular dopamine concentrations and increase concentrations of dopamine metabolites; low doses do not affect dopamine concentrations but decrease dopamine metabolite concentrations. Ibogaine may also affect the activity of voltage-dependent sodium channels, opioid k, s and NMDA receptors, and serotonin transporters . In addition, high doses of ibogaine appear to be toxic to Purkinje cells in the rat cerebellum. In humans, it has been reported that ibogaine reduces craving and attenuates opioid dependence. Ataxia, nausea, vomiting and hypertension have also been observed. It also has been reported that ibogaine will produce tremors, hallucinations or "fantasies" and apprehension, increase strength and appetite, and possibly increase libido.
The pharmacological profile of ibogaine, including its putative "anti-addictive" effects, is likely to result from actions at multiple loci. For example, the effects of ibogaine on voltage-dependent sodium channels could explain its tremorigenic actions, while an anti-cholinesterase activity may explain its effects on blood pressure as well as stimulation of digestion and appetite. The neurochemical basis for the putative "anti-addictive" actions of ibogaine remains unclear. Based on its neurochemical profile, ibogaine may produce "anti-addictive" actions through multiple effects at k receptors,s receptors, or serotonin transporters . Alternatively, ibogaine, or an unidentified active metabolite might act at pathways which have not been previously linked to addictive processes.
While these hypotheses all merit further investigation, at present, there are converging lines that link the NMDA-antagonist action of ibogaine to its putative "anti-addictive" properties. NMDA antagonists (acting at either glutamate, glycine, polyamine, or, open channel site) attenuate morphine withdrawal, attenuate drug self-administration, the sensitization to the behavioral effects of psychostimulants and rewarding effects of drugs of abuse .
From the reports of human heroin addicts who have taken ibogaine, it appears that several features of the ibogaine experience are important in interrupting addiction. Thus, Dutch addicts who used ibogaine described the experience as having a dream with full consciousness, together with anxiety and the recall of memories . After this experience, the addicts did not feel compelled to use heroin. While these insights are intriguing, they are at present without heuristic value. Further studies are required to determine the importance of such experiences in the treatment of drug abuse. In conclusion, the claimed "anti-addictive" properties of ibogaine require rigorous validation in humans, after careful assessment of its neurotoxic potential. It remains to be established if an ibogaine metabolite, producing less side effects, could be of therapeutic value.
