Ibogaine as a treatment for substance misuse: Potential benefits and practical dangers

By John Martin Corkery

Excerpt from: Progress in Brain Research, Volume 242, 2018

Abstract

Ibogaine is an indole alkaloid found in the root bark of the Iboga shrub native to west Africa possessing hallucinogenic properties. For centuries it has been used in religious ceremonies and to gain spiritual enlightenment. However, since the early 1960s, its apparent ability to reduce craving for psychoactive substances including alcohol, cocaine, methamphetamine, opiates, and nicotine has led to its use in detoxification treatments.

In many instances, clients receive treatment in non-medical settings, with little by way of robust scientific clinical trials. This chapter provides an overview of the potential benefits that could arise from such research. This is balanced against the serious adverse effects that can occur due to undiagnosed health conditions and/or concomitant use of other drugs. A detailed update is provided of the 33 deaths known to have occurred, including 5 in the UK.

Looking forward, there is a need to develop better opiate detoxification treatment against a background of increasing opioid-related fatalities. A congener of ibogaine, 18-MC, appears to be safer and is to undergo clinical trials. In the meantime, would-be consumers and treatment providers must make more careful, detailed risk-assessments before using ibogaine. Treatment outcomes, including deaths, need to be accurately recorded and published.

Introduction

The Iboga plant Tabernanthe iboga (Apocynaceæ) was first classified 140 years ago, although descriptions of it and samples of it were exhibited in France in the 1860s (Goutarel et al., 1993). In 1905 it was reported that the plant was ascribed stimulatory and even aphrodisiac properties. Its consumption held off fatigue, the need to sleep and provided energy to work. It was stated to have effects like alcohol but without affecting one's reasoning. Too high a dose led to a special type of drunkenness, with a certain degree of muscular contractions and convulsions.

The alkaloid ibogaine was first isolated from the plant and named by Édouard Landrin in 1900, although the first method for its extraction was published the following year (Dybowski and Landrin, 1901). In the immediate period following, Landrin and colleagues conducted extensive animal experiments on ibogaine's effects on the circulatory, respiratory, nervous, and muscular systems. The results of these investigations, together with extensive botanical and chemical descriptions, were published in a monograph (Landrin, 1905). Landrin recorded that the possibility of iboga and ibogaine having potential for use in therapy was being discussed among medical circles. The main uses suggested were as: a neurasthenic, a cardiac regulator, and for stimulating nutrition. However, its abuse by some was noted. Most of these aspects are still a feature of investigations and research today. They provide a frame-work for this chapter.

Iboga is a shrub indigenous to central west Africa, especially Gabon, Cameroon and Congo. The shrub grows up to 1.5–2 m in height, has yellowish or pinkish flowers, and produces sweet pulpy fruits without any psychoactive alkaloids. The root bark contains about 6% of indole alkaloids: these include ibogaine, ibogaline, ibogamine, and tabernanthine (Bruneton, 2009:1177), in the proportions 80%, 15% and 5% respectively for the first three listed (Jenks, 2002). Ibogaine's chemical formula is C20H26N2O; its molecular mass is 310.433 g/mol. It possesses two distinct chiral centers, thereby generating four stereoisomers.

Apart from extraction from the iboga plant, ibogaine hydrochloride can be semi-synthesized from voacangine, another plant alkaloid which acts as a precursor (Jenks, 2002). Total synthesis of ibogaine was first described in a US patent in 1956 (Janot and Goutarel, 1957), and a decade later Büchi et al. (1966) published a detailed paper on its complete synthesis. Over the years, additional methods of synthesis have been achieved (Frauenfelder, 1999).

Ibogaine is a tryptamine. Its action is complex, affecting several different neurotransmitters at the same time. It appears to possess important affinities for N-methyl-d-aspartate (NMDA), kappa-opioid, sigma, and nicotine receptors. Ibogaine's action at the kappa-opioid receptor is likely to contribute to its psychoactive effects (Zubaran et al., 1999). It is thought that the weak agonistic action of ibogaine on the serotonin 5HT2A receptor (Glick and Maisonneuve, 1998; Helsley et al., 1998) may contribute to its hallucinogenic effects (Wei et al., 1998). Dopamine levels are not only lowered by ibogaine, but also its breakdown is enhanced (Glick et al., 2001). Ibogaine may work in reversing the effects of opiates on gene expression, with resulting impacts on neuroreceptors, returning them to a pre-addiction condition (Brackenridge, 2010). Furthermore, addictive loops and pathways in the brain are reversed (He et al., 2005).

Ibogaine (12-methoxyibogamine) is metabolized to its main metabolite noribogaine (O-desmethylibogaine; 12-hydroxyibogamine) (Mash et al., 2001). This occurs principally through O-demethylation by cytochrome P4502D6 (CYP2D6) enzymes, with CYP2C9 and CYP3A4 also making contributions (Gevirtz, 2011; Mash et al., 2001; Obach et al., 1998). The CYP2D6 enzyme makes a significant contribution (30%) to the metabolism of currently used drugs (Zhou, 2009). An important aspect of ibogaine metabolism is that the CYP2D6 cytochrome is subject to polymorphic expression, especially in Caucasians of whom 5–10% lack the gene required for the enzyme's synthesis (Gonzalez and Meyer, 1991).

First pass metabolism is extensive, occurring in the gut wall and liver (Mash et al., 2001). Ibogaine collects at higher levels in fat, consistent with its lipophilic nature, than in the brain or plasma (Hough et al., 1996). It has been suggested, that is following this deposition in fat, that ibogaine is converted into noribogaine on release (Hough et al., 1996, Hough et al., 2000). The mechanisms underlying noribogaine's metabolism are less well understood, but one recent study proposes that glucuronidation may be implicated (Glue et al., 2014).

Oral ibogaine doses of 500–1000 mg (10–25 mg/kg of body weight), levels typically administered to treat drug dependence (Alper, 2001; Mash et al., 1998, Mash et al., 2000) yield peak plasma levels around 11 μg/mL some 2 h after ingestion, with more than 90% being eliminated after 24 h (Alper et al., 2012; Mash et al., 1998, Mash et al., 2000, Mash et al., 2001). Single oral doses of 20 mg/kg (1400 mg/70 kg) ibogaine given to two adult males yielded mean blood concentrations of ibogaine and noribogaine of 0.91 and 0.67 mg/L at 4 h, 0.27 and 1.0 mg/L at 12 h, and 0.15 and 0.80 mg/L at 19 h (Borgusz et al., 1998). The plasma half-life of ibogaine appears to range between about 4 and 8 h. Noribogaine appears to have a longer half-life (Chèze et al., 2008; Maciulaitis et al., 2008). Ibogaine concentrations in whole blood samples of humans after single oral 500–1000 mg doses (Mash et al., 1998, Mash et al., 2000), and in an ibogaine intoxication (Kontrimaviciūte et al., 2006b), have yielded values of 1–10 μg/mL (3–30 μM). Considering that these measurements represent total drug concentrations, and that ibogaine's human plasma protein binding is about 65% (Koenig et al., 2013), it has been estimated that the free plasma concentrations achieved in these studies were 1–11 μM (Koenig et al., 2013).

In terms of its action on neurotransmitters, noribogaine acts as a potent serotonin reuptake inhibitor, a moderate kappa-opioid receptor agonist (Maillet et al., 2015) and a weak (Maillet et al., 2015) or a partial mu-opioid receptor agonist (Antonio et al., 2013). It possesses an opiate replacement aspect like compounds such as methadone (Baumann et al., 2001a, Baumann et al., 2001b; Mash et al., 1995; Zubaran et al., 1999). Noribogaine appears to have stronger subjective effects compared to ibogaine (Zubaran et al., 1999).

Noribogaine not only shows higher plasma levels than ibogaine after consumption but is also detectable for a longer time, peaking about 2.5 h after ingestion around 1 μg/mL, and not declining significantly within 24 h (Mash et al., 1998, Mash et al., 2000, Mash et al., 2001). Its half-life in human plasma has been estimated as being 28–49 h (Glue et al., 2014).

A heaped teaspoon of iboga root bark produces a pleasant euphoric effect. An ibogaine dose of 5 mg/kg bodyweight appears to have minor effects, largely stimulatory. At doses of 10 mg/kg or more a visual phase lasting 1–4 h, followed by an introspective stage is experienced. The latter may last from several hours to days; and it is during this period that opioid addicts first become aware of a lack of craving and withdrawal symptoms. During Bwiti initiation rites 50–100 g is typically consumed, but occasionally even more (up to 200 g).

At therapeutic levels, ibogaine is said to have an active window of 24–48 h. However, the levels of “therapeutic” doses appear to range from 5–8 up to 15–20 mg/kg, the latter being recommended by Lotsof and Wachtel (2003). A dose of up to 30 mg/kg may be used for cases with strong polysubstance dependencies (Chèze et al., 2008).

The chief mood-raising effects of ibogaine usually become apparent a day or so after administration, when the tissue concentrations of the chemical have fallen to minimal levels; this effect can persist from days to weeks afterward when its metabolites are no longer measurable; this may be due to its deposition in fat tissues (Hough et al., 2000; Paškulin et al., 2006).

Root bark or root cortex is dried and then rasped or ground up; it is consumed as it is, washed down with water or occasionally made into a tea or an infusion. Iboga can be purchased in its natural state, as a powder, or as an extract by mail-order or, more commonly in recent years, via the Internet. Pure crystalline ibogaine hydrochloride is the most standardized formulation available from commercial laboratories, typically produced by semi-synthesis from voacangine, or from nicotinamide using a multi-step process (Maciulaitis et al., 2008). Seeds and plants are also offered for sale, as well as tinctures.

There is a danger in not knowing what you are taking, as with other psychoactive substances. Counterfeit iboga or mislabeling of products as iboga is possible, and consumption can even lead to death (Gicquel et al., 2016). In April 2017, a postal package from Brazil was intercepted in Slovenia which was found to hold three plastic containers with a total of 182 mL of clear liquid which contained ibogaine, voacangine, and amyrin (EMCDDA-EDND, 2018).

The variation in products and prices can be illustrated by the following examples advertised on-line in May 2018. Root bark was available as powder: 5 g for £ 23, 25 g for £ 75, through to 100 g for £ 246; 20 g for US$ 89 or 40 g for US$ 165; 20 g for € 105; 100 g for € 400; 5 g for € 17 through to 250 g for € 750; wholesale 5 kg was offered for £ 8190. Root bark shavings were offered: 5 g for £ 20 through to 250 g for £ 495. Root bark capsules cost the following: 35 capsules for € 70; 15 capsules (5 g) for € 20 through to 750 capsules (250 g) for € 825; 22 (23 mg) capsules (5 g) for £ 27 through to 440 capsules (100 g) for £ 261; 2 × 35 capsules for US$ 129 through to 10 × 35 capsules for US$ 475. Iboga is also available as Total Alkaloid (TA) extract: 1 g for € 75; 0.5 g for £ 54 through to 10 g for £ 720; 2 g for US$ 72 through to 10 g for US$ 535.

Ibogaine HCl is available: 15 g for € 255; 2 g for US$ 430 through to 10 g for US$ 1650. 50 mL bottles of iboga tincture were advertised for € 65. In many cases, these prices are considerably higher than in 2010, when the author undertook a similar snapshot of Internet prices. What is worth noting is the removal of a page advertising ibogaine HCl on a site aimed at UK customers; this may be a result of the coming into force of the Psychoactive Substances Act 2016 (see below).

Mindful of the uncertain and varying legal status of iboga and ibogaine in different jurisdictions, dealers advertising these products resort to using forms of wording that attempt to avoid breaking the laws in different parts of the world. Many state that customers must be aged 18 years or over. A typical disclaimer is: “Note: We sell Iboga for botanical research and educational purposes only. Our products are not meant for consumption.” Another supplier mixes their message by stating: “All iboga products on the site are sold as botanical samples, not for human consumption. However, for education purposes we provide information regarding dosage.” The same site then goes on to remind customers that: “It is important to recognise the difference between recreational and therapeutic iboga….” Another variation to be found is: “None of our products are sold or intended for the purpose of human consumption or cosmetic use…. Our products are delivered with no expressed or implied usage for any purpose. We do not provide nor communicate about usage of our products.”

Between 1967 and 1970 the World Health Assembly classified ibogaine with hallucinogens and stimulants as a “substance likely to cause dependency or endanger human health.” It was banned in 1989 by the International Olympics Committee as a potential doping agent (Goutarel et al., 1993), although it is not on the list of prohibited substances maintained by the World Anti-Doping Agency.

Ibogaine and its salts are controlled in the USA as Schedule 1 substances. Ibogaine remains unapproved there for any therapeutic use, including treatment of addiction, due to its cardiovascular, hallucinogenic, and neurotoxic side-effects; and the paucity of efficacy and safety data relating to humans. Health Canada added ibogaine and its salts, derivatives or analogs to the Human and Veterinary Prescription Drug List in May 2017 (Health Canada, 2017). It is illegal to import it into Australia without a license. Ibogaine was included in the New Zealand national formulary in February 2010 as a non-approved prescription medicine. In early 2016, Sao Paulo state in Brazil legislated so that ibogaine could be used on prescription.

Several European countries, including Belgium, Denmark, Finland, Hungary, Norway, Poland, Romania, Sweden, Switzerland and Turkey, have banned the sale and possession of ibogaine. The French agency responsible for health (AFSSAPS) included T. iboga, ibogaine, and its analogs in the Schedule of illicit substances in March 2007 (Chèze et al., 2008). In Germany it is unregulated, but pharmacy rules can be used to regulate it for medical use.

In the UK, ibogaine is not controlled under either the Misuse of Drugs Act 1971 or the Medicines Act 1968. However ibogaine, and its metabolite noribogaine, is regarded by the Medicines and Healthcare products Regulatory Agency (MHRA) as a medicinal herb and would require a marketing authorization for sale as a medical treatment (personal communication from MHRA, May 17, 2018). This means it is exempted from regulation under the Psychoactive Substances Act 2016, if being used by “healthcare professionals acting in the course of their duty” or employed in approved scientific research. But, if ibogaine is being provided purely for its psychoactive properties prosecutions could be sought. If doctors prescribe unlicensed medicines, they need to satisfy themselves that there is sufficient safety evidence for the medicines in question. According to a senior consultant addiction psychiatrist, while it is theoretically possible to prescribe ibogaine, “it is an experimental drug so is not recommended as a treatment” (Prof. Colin Drummond, chair of the Addictions Faculty at the Royal College of Psychiatrists, quoted in Hannaford, 2017). It is possible that the enactment of the 2016 Act has led to would-be UK-resident clients going overseas to receive treatment (Hannaford, 2017).

A range of “scenes” associated with the use of ibogaine have been suggested. For example, Alper et al. (2008) describe a “medical subculture” comprising several different “scenes,” but which are distinct from the traditional Bwiti religion in west Africa: “medical model,” “lay provider/treatment guide,” “activist/self-help,” and “religious/spiritual”; in reality, these are different types of medical “providers.”

These scenes could be conceived of as laying in a continuum from the religious and spiritual (metaphysical) domains, through the “psychonaut” experience to the “medical.” This is the broad approach adopted in this chapter, with most emphasis given to the “medical” scenarios. However, it should be made clear that the distinctions between these constituencies can be very blurred and overlap. These three main arenas in which iboga and ibogaine are employed are inter-connected being rooted in the psychoactive properties of ibogaine.

One could further perceive the growing interest in ibogaine and its parent plant (iboga) as merely being part of a much larger paradigm of “natural cures and remedies” and, in particular, the medicalization in the last decade or so of psychedelics. Very serious advances are beginning to be made, after a hiatus of 40–50 years, into the potential of both natural psychedelics and hallucinogens (such as ibogaine, ayahuasca and peyote) and synthetic substances (such as LSD and MDMA); for an example see Winkelman (2014).

The growth of interest in iboga and ibogaine, as well as in the latter's use in drug treatment can be illustrated through using Google Trends, a publicly available web facility of Google Inc., based on Google Search. It presents information on the frequency of particular search terms entered into Google Search relative to the total search-volume across various regions of the world, and in various languages. This facility can be helpful in undertaking health-related research (Nuti et al., 2014) and has been used to track interest in drugs, for example, cannabis (Cavazos-Rehg et al., 2015), synthetic cannabinoids (Curtis et al., 2015), captagon (Al-Imam et al., 2017), fentanyl (Quintana et al., 2017), and novel psychoactive substances (Young et al., 2015).

Fig. 1 shows that since 2004 to May 2018, Internet searches using Google for “ibogaine” have been relatively stable, whereas Fig. 2 shows that searches for “ibogaine treatment” have shown a steady increase over the same timeframe. It is unlikely the growth in the ibogaine subculture can be ascribed to the “epiphenomenon” of the availability of psychoactive substances on the Internet or popular interest in psychedelics (Schifano et al., 2006).

Ibogaine is a tryptamine possessing psychedelic properties, including that of disassociation. This psychoactive aspect is probably fundamental to the first domain—religious experience. Belgian and French explorers in central west Africa first came across and reported the use of T. iboga in spiritual ceremonies in the 19th century. At the time, some of these were described as initiation rites into fetishes, that today we would more correctly call animist or cultic religious traditions. This involved the preparation of a potion, either the raw material or an infusion, by a shaman who administered it to the neophyte or initiate. “Soon all the nerves would jangle in an extraordinary fashion. An epileptic madness would seize him during which trance, he would utter words, which heard by the initiates, had a prophetic sense and proved that the fetish lived in him” [author's translation] (cited in Landrin, 1905).

Such religious use is primarily associated with the Bwiti tribe of Gabon, who are said to have inherited knowledge about the psychoactive properties of its roots from the Pygmies of central Africa. In their ceremonies, which have probably been conducted for centuries, the thin roots of the iboga plant are cut into small pieces and chewed (Landrin, 1905) or the bark of the root is crushed or ground and swallowed with water (Jenks, 2002). Higher doses generate its psychoactive effects, including hallucinations and the facilitation of communion with the spirits of the ancestors in rites of passage. Ibogaine ingestion in a religious context allows a bonding across time and space between consumers and their ancestors and fellow community members through a shared common experience of a distinctive system of belief and consciousness (Fernandez, 1982; Fernandez and Fernandez, 2001). For detailed examples of such ceremonies see Goutarel et al. (1993).

Two phases are commonly described in respect of the religious/spiritual dimension. An initial “visionary” phase, lasting for up to 4 or 6 h, is characterized by dream-like psychedelic experiences of consciousness, described as oneirogenic, a state similar that found in REM sleep. This followed by an “introspection” phase in which allows spiritual insight and self-exploration.

Both phases or aspects are also represented within the experiences of modern shamans—“psychonauts” (“sailors of the mind/soul”). A recent paper (Orsolini et al., 2017) outlined how the term “psychonaut” was first used to describe those who took psychoactive substances to acquire more knowledge of the “inner universe” while dealing with religious questions (Jünger, 1970). To achieve the state of a psychonaut it is appropriate to experiment with drugs (Carroll, 1987). Thus, psychonauts are regarded as akin to traditional shamans (Labate and Jungaberle, 2011); “new/virtual shamans” (Orsolini et al., 2015); “chaos magickians” [sic] (Booth, 2000); and “techno-shamans” (Orsolini et al., 2017). Today, we have e-psychonauts, who like the shamans of old, have beliefs and goals more often to do with the achievement of altered states of consciousness rather than for recreational purposes. Within such communities, the use of psychedelics provides a special, “ritual” form of bonding, with some evidence that such drug users have a greater concern for others compared to other substance users and drug-naïve individuals (Orsolini et al., 2017).

Medical Uses

Ibogaine appears to have a range of healing properties, from the religious and spiritual to the physical and psychological. Here, again, there is likely to be cross-over between these domains. Not only do the Bwiti also use iboga/ibogaine for religious purposes but also for medicinal purposes, e.g. infertility. In the Congo the fresh or dried root is marinated in palm wine for a few hours, before being taken out and the liquid used as an aphrodisiac (Bouquet, 1969:67). Iboga root is also used...

Risks

It has been calculated there were 3414 treatment episodes using ibogaine between 1989 and 2006, presumably outside of west Africa. During this period 11 fatalities were recorded (including at least 3 where the medical examiner identified anatomically, pre-existing medical conditions and where ibogaine was not cited as contributing to death). These figures give a ratio of 1 ibogaine-related death to every 427 treatment episodes (Alper et al., 2008)...