(ibogaine - action and research history) "Ibogaine, a natural alkaloid extracted from the root bark of the African shrub Tabernanthe Iboga, has attracted attention because of its reported ability to reverse human addiction to multiple drugs of abuse, including alcohol. Human anecdotal reports assert that a single administration of ibogaine reduces craving for opiates and cocaine for extended periods of time and reduces opiate withdrawal symptoms (Sheppard 1994; Mash et al., 1998; Alper et al., 1999). Studies also suggest that ibogaine attenuates drug- and ethanol induced behaviors in rodents. For example, ibogaine reduces operant self-administration of heroin in rats, as well as naloxone precipitated withdrawal in morphine-dependent rats (Glick et al., 1992; Dworkin et al., 1995). Administration of ibogaine decreases cocaine-induced locomotor activity and reduces cocaine self-administration in rats (Cappendijk and Dzoljic, 1993) and mice (Sershen et al., 1994). Rezvani et al. (1995) reported that ibogaine reduces ethanol self-administration in alcohol-preferring selected lines of rats;"

(ibogaine - basic research) "18-MC [18-methoxycoronaridine], a novel iboga alkaloid congener, reduces intravenous methamphetamine and nicotine self-administration in rats. These and previous results with morphine, cocaine and alcohol indicate that 18-MC warrants further development as a potential treatment for multiple forms of drug addiction."

(ibogaine - basic research) "Studies also suggest that ibogaine attenuates drug- and ethanol-induced behaviors in rodents. For example, ibogaine reduces operant self-administration of heroin in rats, as well as naloxone-precipitated withdrawal in morphine-dependent rats (Glick et al., 1992; Dworkin et al., 1995). Administration of ibogaine decreases cocaine-induced locomotor activity and reduces cocaine self-administration in rats (Cappendijk and Dzoljic, 1993) and mice (Sershen et al., 1994)."

(ibogaine - basic research results) "Based on anecdotal reports in humans, ibogaine has been claimed [1] to be effective in interrupting dependence on opioids, stimulants, alcohol and nicotine. Preclinical studies in rats have supported these claims: ibogaine has been reported to decrease the i.v. self-administration of morphine [2] and cocaine [3] and the oral intake of alcohol [4] and nicotine [5]. However, studies in rats have also raised concerns regarding potential adverse effects of ibogaine; most notably, high doses have been shown to be neurotoxic to the cerebellum [6,7]."

(ibogaine - basic research results) "Ibogaine is a natural alkaloid reported to reverse the adverse actions of multiple drugs of abuse including opiates, psychostimulants, nicotine and alcohol in humans, as well as in rodent models (Popik et al., 1995; Mash et al., 1998; Glick & Maisonneuve, 2000; Alper et al., 2008; Maciulaitis et al., 2008). Despite its attractive properties, Ibogaine can induce severe side-effects such as hallucinations, whole-body tremors and ataxia that may be related to neurotoxicity in the cerebellum and dysregulation of the cardiovascular system (O'Hearn & Molliver, 1993; Popik et al., 1995; Maas & Strubelt, 2006; Maciulaitis et al., 2008). We previously demonstrated that systemic administration of low non-toxic doses of Ibogaine in rats reduces ethanol self-administration and relapse (He et al., 2005). ... We found that Ibogaine increased GDNF [glial cell line-derived neurotrophic factor] expression resulting in the activation of the GDNF pathway (He et al., 2005). Importantly, we showed that the actions of Ibogaine to reduce ethanol intakewere localized to the VTA [ventral tegmental area], and that infusion of anti-GDNF neutralizing antibodies into the VTA attenuated the Ibogaine-mediated decrease in ethanol self-administration (He et al., 2005). Together, these results suggest that the desirable actions of this drug are mediated, as least partially, by GDNF. A potential strategy to overcome these undesirable actions of Ibogaine is the use of derivatives that share only its valuable actions. In this regard, the main metabolite of Ibogaine, noribogaine, and 18-methoxycoronaridine (18-MC) a synthetic congener, may have promising profiles. Noribogaine has been shown to induce a long-lasting reduction in morphine and cocaine, but notwater, self-administration in rats (Glick et al., 1996b), and 18-MC was found to reduce morphine, psychostimulant and nicotine self-administration, as well as ethanol intake in rodents, without affecting water consumption (Rezvani et al., 1997; Maisonneuve & Glick, 2003). Importantly, in contrast to Ibogaine, noribogaine and 18-MC have no tremorigenic effects (Glick et al., 1996b; Baumann et al., 2001; Maisonneuve & Glick, 2003), and no evidence of cerebellar toxicity was found for 18-MC in rats, even after administration of a high dose (Glick et al., 1996a). Taken together, these data suggest that Ibogaine derivatives may be an effective treatment of addiction and safer than the parent compound. However, it should be noted that it is currently unknown whether the desirable actions of noribogaine and 18-MC are mediated by GDNF."

(ibogaine side effects) "Although ibogaine has been reported to effectively reduce drug cravings and withdrawal symptoms in addicts (Sheppard, 1994), its tremorigenic, hallucinogenic, neurotoxic, and cardiovascular side effects (see Alper, 2001) have prevented its approval as a treatment for addiction. On the other hand, 18-methoxycoronaridine, although not yet tested in humans, has no apparent side effects in rats, presumably because it is more selective pharmacologically than ibogaine."

(ibogaine side effects) "Despite its attractive properties, ibogaine is not approved as an addiction treatment because of the induction of side effects such as hallucinations. In addition, ibogaine at high doses causes degeneration of cerebellar Purkinje cells (O'Hearn and Molliver, 1993, 1997) and whole-body tremors and ataxia (Glick et al., 1992; O'Hearn and Molliver, 1993) in rats."

(GDNF and ibogaine in addiction treatment) "In summary, repeated administration of drugs of abuse and alcohol induces a common pattern of changes in gene expression and protein levels selectively in the VTA [ventral tegmental area]. A subset of these changes is reversed by intra-VTA GDNF [glial cell line-derived neurotrophic factor], as are some of the drug-induced behavioral effects. Endogenous GDNF systems appear to inhibit drug related behaviors, while repeated drug administration appears to inhibit GDIVF signaling itself. Based on these studies, we propose that GDNF is an endogenous anti-addiction agent. This possibility is directly supported by the finding that the activity of the anti-addiction drug, ibogaine, on alcohol consumption is mediated via increased expression of GDNF in the midbrain and the subsequent activation of the GDNF pathway."