Ibogaine is a rainforest indole alkaloid derived from the root of Tabernanthe iboga, a shrub that grows in west central Africa. Ibogaine has long been used by native peoples in low doses to treat illnesses and to combat fatigue. It is used in higher doses for hallucinogenic eligious rituals. The use of iboga (ibogaine andassociated alkaloids) in Bwiti initiation ceremonies has been studied by ethnologists in Gabon (Goutarel, Gollnhofe & Sillans, 1993), Unlike methadone, LAAM, and buprenorphine, ibogaine is not a substitute for narcotics, and it is not addicting (Mash, 1995).
Physiological responses to ibogaine have been examined since the early 1900s. In the 1950s, Ciba-Geigy Pharmaceuticals investigated the antihypertensive properties of ibogaine, but discontinued research because of skepticism over its commercial value (Mash, 1995). Ibogaine was reported as a beneficial adjunct to psychotherapy by Claudio Naranjo (1973), a Chilean psychotherapist and physician. Howard Lotsof, an American filmmaker and political activist, found that ibogaine was particularly useful in treating opiate addiction, based on his own experience and that of his friends since the early 1960s. Over a period from 1985 to 1992, Lotsof received patent rights for use of ibogaine in the treatment of narcotic, stimulant, alcohol, nicotine, and polydrug dependence. Investigations of ibogaine's physiological properties, toxicity, and mechanisms of action for treating drug dependence were prompted by activists' reports that a single dose could virtually eliminate opiate withdrawal and cravings for cocaine and heroin. Lotsof (1995) and others describe the effect ofibogaine as "interrupting" the addiction.
Laboratory studies have determined that ibogaine indeed attenuates opiate withdrawal (Dzoljic, Kaplan, & Dzoljic, 1988; Glick, Rossman, Rao, Maisonneuve, & Carlson, 1992) and reduces morphine self-administration in rats (Glick, Rossman, Steindorf, Maisonneuve, & Carlson, 1992). Using radioligand binding assays, Sweetnam et al. (1995) found that ibogaine interacts at a wide variety of neurotransmitter receptors. These include the mu, delta, kappa, and sigma opioid receptors, as well as dopamine, norepinephrine, and serotonin uptake sites. A possible mechanism for reduced drug craving following ibogaine ingestion relates to its action at opioid receptors, Ibogaine binds weakly to the NMDA receptor, acting asa competitive inhibitor of MK-801 (Mash et al., 1995; Popik, Layer, & Skolnick, 1994). MK-801 is an excitatory amino acid antagonist that has been associated with attenuation of opiate tolerance (Marek, Ben-Eliyahu, Gold, & Liebeskind, 1991; Trujillo & Akil, 1991).
Cocaine self-administration in rodents is also reduced by ibogaine (Cappendijk & Dzoljic, 1993; Sershen, Hashim, & Lajtha, 1993). Animal models show that ibogaine reverses cocaine-induced changes in dopamine levels (Broderick, Phelan, & Berger, 1992; Maisonneuve, Keller, & Glick, 1991; Maisonneuve, Rossman, Keller, & Glick, 1991; Sershen, Hashim, Harsing, & Lajtha, 1992) and reduces motor activity and side effects related to cocaine administration (Broderick, Phelan, Eng, & Wechsler, 1994; Sershen et al., 1992). Multiple administrations over time appear to yield greater reductions in morphine and cocaine self-administration (Cappendijk & Dzoljic, 1993; Glick, Rossman, Steindorf, et al., 1992).
The results of preclinical animal studies thus indicate great promise for the use of ibogaine in treatment of addiction, but official enthusiasm has been tempered by studies indicating selective loss of Purkinje cells in the cerebellar vermis of rats (O'Hearn & Mollive4 1993). However, these findings have not been replicated in primates, and the rodents in O'Hearn and Molliver's research received higher doses than are required for therapeutic effects. The authors propose that the toxicity observed in rats may be caused by release of excitatory amino acids in the inferior medullary olive, rather than by the direct effect of ibogaine itself. This hypothesis is under investigation at Johns Hopkins University. In addition, three deaths among human subjects worldwide have been associated with ibogaine treatment, although the causes of death in these cases appear to have been preexisting health problems and simultaneous use of other drugs. Nonetheless, these reports have added to the concerns of government officials who are skeptical about funding research for a Schedule I hallucinogenic drug to treat drug addiction.
Further studies on the potential neurotoxic properties of ibogaine are warranted. However, the risks of damage must be considered in the context of risks to untreated addicts. Significant numbers of drug addicts die every year from overdose, violence, injection-related health problems, and other risks associated with hard drug use (10 deaths per 1,000 per year among untreated opiate addicts; American Psychiatric Association, 1994a). Other addicts experience physiological damage as a direct result of substance abuse. Although "as little harm as possible" is the goal in treatment development, what is an acceptable level of risk?
Addict self-help groups from the Netherlands, U.S. activists, and physicians who have observed ibogaine treatment sessions have continued to push for research funding and investigation of ibogaine in humans. These activists have seen addicts who received ibogaine treatment and did not experience withdrawal (Lotsof, Della Sera, & Kaplan, 1995), were nolonger interested in using intoxicating substances and also were not chained to maintenance treatment (Lotsof, 1995). In fact, some individuals who underwent ibogaine treatment dramatically changed their lifestyle: They were observed to resume healthy weight, eat better, reduce alcohol consumption, and quit smoking!
Preclinical and clinical trials have begun to establish the safety of ibogaine in human volunteers. The FDA has approved the use of limited doses of ibogaine in research, which may increase if results are encouraging. Mash and colleagues at the University of Miami are, investigating the neurological and neuropsychological effects of ibogaine on drug-dependent male volunteers who received ibogaine treatments in Panama. Preliminary results for six subjects were reported at the Symposium on Maturational Issues in Behavioral Disorders in Maastricht, the Netherlands (Mash, 1995). Participant behavior was assessed before, during, and after treatment on a wide variety of addiction and withdrawal symptom checklists, psychiatric screenings, mood profiles, and neuropsychological tests. Participants were evaluated for cerebellar and extrapyramidal signs by neurological exam.
Ibogaine was not associated with neurobehavioral impairments for the dose range tested. While under the direct influence of ibogaine, participants first exhibited mild tremor and transient ataxia. Next, participants reported vivid visual images that some described as repressed memories. The content of the visual images produced fearful emotions in some participants. Tremors, ataxia, and vivid visual imagery lasted up to 8 hours. Most participants reported a relaxation period 24 hours after ibogaine ingestion, by which time most of the ibogaine was eliminated, as confirmed by blood and urine samples. However, some participants reported mild insomnia for several days. Participants maintained orientation to time and place and showed no amnesia throughout the ibogaine treatment session. Postibogaine neuropsychological testing did not reveal impairments compared to baseline performance. The chronology of participants' experiences correlated with ibogaine blood levels (Mash, 1995).
A specific clinical procedure for ibogaine treatment has been developed by Lotsof (1995). He describes key elements in the treatment setting to minimize participant discomfort, including building trust and maintaining safety. Some participants may feel more comfortable in the presence of former addicts who are experienced with the treatment procedure (Frenken Sc. Nodelman, 1996). An informal self-help network has been providing ibogaine treatments to addicts in Europe since 1987 (Lotsof, 1995).
Ibogaine is particularly appealing to some opiate-dependent individuals because the ibogaine is administered only one to three times. In contrast, methadone, LAAM, and buprenorphine are designed for use as maintenance or tapering drugs, requiring regular administrations. From the limited data available to date, ibogaine appears to show promise for interrupting addiction in healthy, relatively high-functioning individuals (Lotsof, 1995; Lotsof et al., 1995; Sheppard, 1994).
If the results of toxicity studies allow research to continue in humans, treatment-matching methodology will be appropriate to determine participant factors most strongly associated with improvement. For example, are age, socioeconomic status, psychiatric symptoms, motivation, history of drug abuse, and past experience with hallucinogens related to outcome? Are there risks that participants should be aware of? Controlled clinical studies are required to support reports that either single or repeated ibogaine administrations are effective in treating substance use disorders. Deciding upon an appropriate control drug to use in double-blind studies presents significant challenges to researchers. If subjects and attending physicians are aware of the withdrawal attenuation, hallucinogenic effects, and 24- to 36-hour duration of ibogaine, group assignment can easily be ascertained if effects are not comparable to expectations, and the results will thus be rendered invalid. Furthermore, the criteria for success must be assessed in relation to the outcomes that are possible with existing treatments.
Like other pharmacological agents, ibogaine will probably be most successful if its use is coupled with therapy and appropriate psychosocial support. The interruption of addiction that is proposed to result from ibogaine treatment provides an excellent opportunity to introduce psychotherapy, social skills training, occupational guidance, and medical intervention to treat sequelae of drug abuse.
Ibogaine continues to be controversial, despite numerous documented successes. It is unclear why this promising treatment is not slated for more funding when opiate and cocaine addiction are clearly not going away. Perhaps ibogaine's classification as a hallucinogen conjures up images of Timothy Leary's "Tune in, turn on, and drop out" message of the 1960s in the minds of those who oppose its use. Certainly, reports of toxicity in animals are relevant, but if follow-ups of humans treated with ibogaine do not indicate clinically relevant damage, then the benefits seem to outweigh the risks. Although ibogaine probably will not end opiate addiction, it appears that it can provide another much-needed treatment option for opiate-dependent individuals who do not want to become involved in maintenance treatment.
Summary of Harm Reduction Strategies for Opiate Addiction
Methadone maintenance treatment is the best-studied and most successful treatment available to date for opiate addiction. Its success in reducing crime is well documented, which has helped public officials overcome its controversial aspects. LAAM operates similarly to methadone. Although ithas been less thoroughly studied, it appears to have comparable treatment efficacy, and provides participants with a less cumbersome clinic visit schedule because of its longer duration of action. Buprenorphine provides yet another alternative to maintenance and tapering forms of opiate treatment. It is not quite as effective in reducing illicit drug use as methadone but buprenorphine withdrawal appears to be less daunting than,methadone withdrawal for addicts.
Although relatively well studied, all the maintenance drugs remain somewhat controversial, largely because of public discomfort with "replacing one drug with another." In addition, some opiate-dependent individuals feel trapped by their continued physical dependence on the maintenance drug. Treatments that facilitate interruption of addiction by single administrations are appealing to these individuals. Ibogaine has been reported to interrupt the addiction process by attenuating withdrawal and significantly reducing cravings for opiates. However, ibogaine is also very controversial, not only because of possible side effects, but due to its hallucinogenic properties.
Opiate addicts come from many walks of life and cannot all be treated by the same method. A wide variety of strategies must be made available to attract opiate-dependent individuals to treatment, including maintenance, tapering, interruption, and nonpharmacological treatments. Determination of treatment efficacy must be compared to risks incurred without treatment. If a treatment appears to reduce the risks associated with opiate use without introducing serious new risks, that treatment should be made available.
