Medication Development of Ibogaine as a Pharmacotherapy for Drug Dependence^a

Abstract

The potential for deriving new psychotherapeutic medications from natural sources has led to renewal interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger 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 cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine-dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration-time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.

Glial Cell Line-derived Neurotrophic Factor Reverses Ethanol-mediated Increases in Tyrosine Hydroxylase Immunoreactivity via Altering the Activity of Heat Shock Protein 90

“…Ibogaine is reported to reverse phenotypes associated with addiction to multiple drugs of abuse, including alcohol, in humans (24,25), and various studies including ours also suggest that ibogaine attenuates drug-and ethanol-mediated behaviors in rodents (1, 26 -28). We identified GDNF in the VTA as the mediator of the ability of ibogaine to decrease ethanol consumption as inhibition of GDNF signaling in the VTA by delivery of anti-GDNF neutralizing antibodies attenuated the action of ibogaine to decrease ethanol intake (1).…”

Intoxication mortelle à l’iboga: quantification de l’ibogaïne et de l’ibogamine dans des racines d’ibogaet dans des prélèvementspost-mortempar CPG-SM/SM

“…À ce jour, il n'existe pas d'explication concluante quant à la cause de ces décès. Certains auteurs mettent en cause la neurotoxicité cérébelleuse de l'ibogaïne principalement observée sur les rats [1,8], d'autres suspectent une dérégulation du système nerveux autonome combinée à un stress psychologique à l'origine d'un arrêt cardiaque soudain Tableau II. Concentrations mesurées des différents composés analysés, dans les échantillons post-mortem de la victime (ng mL -1 ).…”

“…À ce jour, dix-huit décès liés à une ingestion d'ibogaïne ont pu être documentés [1,[5][6][7][8][9][10][11][12]. À la fin des années 60, la World Health Assembly classe l'ibogaïne dans les drogues hallucinogènes et stupéfiantes en tant que substance potentiellement addictive ou dangereuse pour la santé humaine [1].…”

Tripping up addiction: the use of psychedelic drugs in the treatment of problematic drug and alcohol use

“…Over the past three decades, ibogaine has received interest as a possible anti-craving and antiwithdrawal aid for drug addiction, primarily opiate and cocaine addictions (15). In the mid-1990s, the National Institute on Drug Abuse (NIDA) began a programme of research into ibogaine's potentially therapeutic effects in drug addiction (16), although this was prematurely disbanded due to concerns over potential harms. Despite this, "alternative" ibogaine treatment centres are used by people with addictions around the world (17)(18)(19) and it is estimated that over 3,000 people have taken ibogaine, chiefly as a treatment for drug addiction (18) Zealand (24,25).…”

“…These results and ongoing studies are promising, but properly controlled experimental research is much needed. Importantly, there have been some well-reported fatalities associated with ibogaine use, specifically a woman from the Netherlands, whose death contributed to the closure of the NIDA-funded research in the 1990s (14,16). This may be due to the tradition of using ibogaine during opioid withdrawal -where there is extreme physiological reactions that might exacerbate ibogaine toxicity.…”