Ibogaine

"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)."

"In 1962, the anti-addictive property of ibogaine was inadvertently discovered by 19-year-old heroin addict Howard Lotsof.⁵⁸ Lotsof was part of an experimental group of mostly 20-something Caucasians attending college.⁵⁹ The group, which included seven heroin addicts, shared a common interest in experimenting and subjectively evaluating their experiences with various psychoactive drugs, including Mescaline, LSD, DMT, and psilocybin,⁶⁰ in an effort to determine the psychotherapeutic value of hallucinogenic drugs.⁶¹ As psychedelic drugs were not illegal at the time, Lotsof had access to many of these drugs through his company, S & L Laboratories.⁶² Rather than simply providing the hallucinogenic, euphoriant high the group anticipated, the heroin addicts noticed that ibogaine actually alleviated their craving for heroin.⁶³ Lotsof ceased using heroin, cocaine, and all other drugs during the six months following his initial dose of ibogaine, an effect most members of the group shared.⁶⁴

"In 1986, more than two decades after his initial discovery, Lotsof: [sic] founded NDA International (NDA); obtained patents for the use of ibogaine in treating opiate, cocaine, amphetamines, and alcohol addictions under the name Endabuse; and started unofficially distributing ibogaine to addicts in Holland.⁷⁵"

"All available autopsy, toxicological, and investigative reports were systematically reviewed for the consecutive series of all known fatalities outside of West Central Africa temporally related to the use of ibogaine from 1990 through 2008. Nineteen individuals (15 men, four women between 24 and 54 years old) are known to have died within 1.5-76 h of taking ibogaine. The clinical and postmortem evidence did not suggest a characteristic syndrome of neurotoxicity. Advanced preexisting medical comorbidities, which were mainly cardiovascular, and/or one or more commonly abused substances explained or contributed to the death in 12 of the 14 cases for which adequate postmortem data were available. Other apparent risk factors include seizures associated with withdrawal from alcohol and benzodiazepines and the uninformed use of ethnopharmacological forms of ibogaine."

"Because ibogaine inhibits cardiac ion channels in therapeutic concentrations, the drug is potentially proarrhythmic. The risk of its administration, however, is possibly reduced by the fact that the drug also shows antiarrhythmic properties."

"Within three hours after ingesting a higher dose of ibogaine, the user will enter into the 'acute phase,' typically lasting four to eight hours.⁴² It is during this phase that the user experiences ibogaine’s most intense effects, characterized as the 'panoramic recall of a large amount of material relating to prior life events from long-term memory, primarily in the visual modality,' or the 'waking dream' state.⁴³ If the user is an addict, he or she will usually be taken back to the place and time where the underlying issue leading to the addiction arose, allowing the addict to gain critical insight into the reasons why he or she abuses."

"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."

"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."

"As these researchers point out, and those most familiar with the treatment will testify, ibogaine is not, in general, a 'cure' for drug addiction.¹²² In the majority of cases, however, it does eliminate or substantially decrease signs and symptoms of withdrawal and the individual typically emerges some 36 hours later without physical dependence on the drug.¹²³ 'Ibogaine doesn’t eradicate the underlying causes of addiction, which for many people may take years to understand and come to terms with. Ibogaine is more than a detox, but it’s a catalyst, not a ‘cure.''¹²⁴ Ibogaine creates a 'window of opportunity' where the individual can cognitively choose to take back control of his or her life.¹²⁵"

"Having been discovered by a drug addict, rather than by scientists in a laboratory, ibogaine has been condemned from the very beginning.¹³³ Classified as a Schedule I controlled substance, ibogaine is listed in the same category with the very drugs it counteracts because its hallucinogenic properties arguably outweigh its medicinal value."

"The medical treatment model presently exists mainly in countries adjacent to the US, such as Mexico, where ibogaine is subsumed within a physician’s legal prerogative to prescribe experimental treatment, or Saint Kitts, where the government includes ibogaine in its national formulary and provides specific approval to the clinic there to administer it. The most common setting is a private clinic with less frequent use of hospitals."

"The clinical focus on the treatment of opioid withdrawal distinguishes the ibogaine subculture from subcultures associated with psychedelic or other illegal drugs. The reason for taking ibogaine was more frequently to alleviate the symptoms of opioid withdrawal than to pursue spiritual or psychological goals. In the US, the expansion of the ibogaine subculture coincides temporally with a substantial increase in the public health impact of opioid use disorders (Compton and Volkow, 2006). The incidence of opioid-related deaths in the US doubled between 1999 and 2004 (Fingerhut, 2007), with methadone and oxycodone accounting for most of this increase. In contrast to trends regarding opioids, there was no increase in use of hallucinogen and MDMA among young adults in the US between 2002 and 2005 (Substance Abuse and Mental Health Services Administration, 2006), suggesting that the recent expansion of the ibogaine subculture is not an epiphenomenon of popular interest in psychedelic drugs and the availability of psychoactive substances on the Internet (Schifano et al., 2006)."

"The estimated number of participants in the ibogaine subculture increased fourfold relative to the prior estimate of 5 years earlier, an average yearly rate of growth of approximately 30%."

"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."

"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."

"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)."

"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 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 were therefore interested in identifying the molecular pathway mediating the beneficial actions of Ibogaine on ethanol-drinking behaviors. 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."