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Baumann MH, Pablo J, Ali SF, Rothman RB, Mash DC. 
“Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine”. 
Alkaloids Chem Biol. 2001;56:79-113.
Drug addiction is a disease that affects millions of people worldwide (1). The severity of the drug addiction problem, coupled with a lack of effective medications, has prompted investigators to explore the plant kingdom as a source of novel therapeutics. One example of a plant-derived compound with potential utility in treating drug addiction is the indole alkaloid, ibogaine (2,3). Ibogaine is found in the roots of the African shrub, Tabernanthe iboga. Historically, native peoples of West Central Africa have used the root bark of this plant as a sacrament in their rituals of initiation into adulthood (4). More recently, ibogaine has gained a reputation as an “addiction interrupter,” based on findings in animals and humans (reviewed in 5,6). In rats, acute administration of ibogaine (40 mg/kg, i.p.) produces long-lasting decreases in the self-administration of cocaine and morphine (7-9, see Glick et al. in this volume). Ibogaine also alleviates symptoms of opioid withdrawal in morphine-dependent rats (10,11) and heroindependent human addicts (12,13, see Alper et al. this volume). These promising findings support the development of ibogaine as a pharmacological adjunct in the treatment of substance use disorders.

Despite extensive investigation, the mechanisms underlying the antiaddictive properties of ibogaine are not fully understood (14,15). Radioligand binding studies show that ibogaine binds with low micromolar (μM) affinity to a number of molecular targets in nervous tissue, resulting in a complex pharmacology (16- 27). Some of these ibogaine binding sites include sigma-2 receptors (16,17), serotonin (5-HT) and dopamine (DA) transporters (18-21), mu- and kappa-opioid receptors (21-24), and NMDA-coupled ion channels (25-27). Biodistribution studies in rats demonstrate that brain concentrations of ibogaine range from 10 to 20 μM when measured 1 hour after acute administration of 50 mg/kg p.o. (21) or 40 mg/kg i.p. (28,29). Thus, the interaction of ibogaine with μM-affinity binding sites may be functionally relevant in vivo. Few studies have been able to attribute in vivo pharmacological effects of ibogaine to activation of specific binding sites. In fact, there is speculation that the key to ibogaine’s antiaddictive potential is related to the simultaneous activation of multiple neurotransmitter systems in the brain (14,15).

An intriguing aspect of ibogaine pharmacology is the long-lasting action of the drug. In rats, a single administration of ibogaine elicits behavioral and neurochemical effects that can last for days (7-9,18,30,31), even though the biological half-life of the drug is only a few hours (32,33). Such observations suggest the possibility that ibogaine is converted to a long-acting metabolite (7- 9). Mash et al. (19) and Hearn et al. (34) provided the first direct evidence for the formation of a major ibogaine metabolite in vivo. These investigators used sensitive analytical methods to identify an O-demethylated metabolite of ibogaine, 10-hydroxyibogamine (noribogaine), in the blood and urine from monkeys and humans treated with ibogaine. Figure 1 shows the chemical structures of ibogaine, noribogaine, and the neurotransmitter serotonin (5- hydroxytryptamine, 5-HT). The methoxy group at the 10-position of ibogaine is converted to a hydroxyl group to form noribogaine. Note the presence of an indole moiety in the structure of the iboga alkaloids and 5-HT. Subsequent pharmacokinetic studies have demonstrated that ibogaine is converted to noribogaine in rats (21,29).
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