The antiaddictive effects of ibogaine : A systematic literature review of human studies

Rafael G. DOS SANTOS, José Carlos BOUSO and Jaime E. C. HALLAK

Journal of Psychedelic Studies, 2017, 1, (1), pp. 20–28

DOI: 10.1556/2054.01.2016.001

 

Background and aims : Ibogaine is a naturally occurring hallucinogenic alkaloid with a therapeutic potential for reducing drug craving and withdrawal. To the best of our knowledge, no systematic review was previously performed assessing these effects. Thus, we conducted a systematic literature review of human studies assessing the antiaddictive effects of ibogaine.

Methods : Papers published up to July 2, 2016 were included from PubMed, LILACS, and SciELO databases following a comprehensive search strategy and a pre-determined set of criteria for article selection. Results: Two hundred and fifty-nine studies were identified, of which eight met the established criteria. Seven studies were open-label case series with ibogaine and one study was a randomized, placebo-controlled clinical trial with noribogaine. Case series suggest that a single dose or a few treatments with ibogaine may significantly reduce drug withdrawal, craving, and self-administration in dependent individuals lasting from 24 h to weeks or months. No significant effects of noribogaine on opiate/opioid withdrawal were observed in the clinical trial.

Conclusions : Considering the necessity of new drugs that may produce fast-acting and sustained effects in opiate/ opioid and cocaine dependence, the potential beneficial effects of ibogaine/noribogaine should be further investigated in controlled trials.

Keywords : ibogaine, noribogaine, substance use disorders, dependence, withdrawal

 

INTRODUCTION

Ibogaine is a naturally occurring indole alkaloid derived from the root barks of Tabernanthe iboga, a plant native to western Central African countries such as Gabon and Cameroon, where it has been used traditionally by the Pygmies and other African ethnic groups for several centuries, and more recently, as a sacrament in initiatory rites and for social cohesion in the Bwiti religion (Alper, 2001; Alper, Lotsof, & Kaplan, 2008; Brown, 2013; Mash et al., 1998). Although T. iboga contains several other alkaloids, ibogaine is considered to be the main psychoactive substance present in this plant. The mechanism of action of ibogaine – and its O-demethylated active metabolite noribogaine – is poorly understood and considered to involve antagonism of the N-methyl-D-aspartate (NMDA) glutamate receptor and α3β4 nicotinic acetylcholine receptor, inhibition of the serotonin (5-HT) reuptake transporter and dopamine release, agonism of the σ2 receptor, κ- and μ-opioid receptors, M1/2 muscarinic receptor, and 5-HT2A receptors [similar to classic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT)], and enhancement of glial cell line-derived neurotrophic factor (GDNF) (Alper, 2001; Alper et al., 2008; Brown, 2013; Donnelly, 2011; Lotsof & Alexander, 2001; Mash et al., 1998). In the 1960s, Lotsof et al. showed that ibogaine could reduce heroin withdrawal (Alper, 2001; Alper et al., 2008; Brown, 2013; Donnelly, 2011; Lotsof & Alexander, 2001; Mash et al., 1998). On the basis of the initial observations and several treatments provided in non medical contexts, Lotsof et al. proposed ibogaine as a new method to treat dependence to opiates/opioids (morphine, heroin, and methadone), stimulants (nicotine, cocaine, amphetamine, and methamphetamine), and ethanol and acquired several patents for such uses (United States patents: US 4499096 1985, 4587243 1986, 4857523 1989, 5026697 1991, and 5152995 1992). It has been estimated that more than 3,400 people have been treated with ibogaine for drug dependence in clinics around the world, mainly in countries such as The Netherlands, the United States, Mexico, and Brazil (Alper, 2001; Alper et al., 2008; Brown, 2013; Donnelly, 2011). In the context of drug dependence treatment, ibogaine is usually ingested orally in the form of extracts/hydrochloride (HCl) in doses ranging from 4 to 25 mg/kg (Alper, 2001;
Alper et al., 2008; Brown, 2013; Donnelly, 2011; Forsyth et al., 2016; Glue, Lockhart, et al., 2015; Glue,Winter, et al., 2015; Lotsof & Alexander, 2001; Mash et al., 1998). About 1 hr after oral administration, subjects experience decreased muscular coordination, increased sensitivity to light and
sound, nausea and vomiting if they move, and visual effects that the ibogaine supporters refer to them as “oneirogenics” (similar to dreams). These visual effects are sustained for around 4–8 hr and are followed by a contemplative state of 12–24 hr in which lucid dreaming may occur accompanied by the emergence of autobiographical memories. Insomnia and increased energy may be present for 72 hr following ibogaine intake (Alper, 2001; Alper et al., 2008; Brown, 2013; Donnelly, 2011; Forsyth et al., 2016; Glue, Lockhart, et al., 2015; Glue, Winter, et al., 2015; Lotsof & Alexander, 2001; Mash et al., 1998). Lower oral doses of ibogaine (20 mg) and noribogaine (3–60 mg) were administered to healthy male volunteers in recent open-label (ibogaine) and double-blind, placebo-controlled (noribogaine) studies, and both drugs were found to be safe and well tolerated (Forsyth et al., 2016; Glue, Lockhart, et al., 2015; Glue, Winter, et al., 2015). At this dose levels, subjects did not experience the above-mentioned psychoactive effects,
reporting basically transient nausea, gastrointestinal symptoms, and dizziness. Ibogaine administration has been associated with several fatalities (>25 cases), which appear to involve increases in cardiac arrhythmias, previous cardiovascular diseases, and use of opiates/opioids or other drugs during the acute effects of ibogaine (Alper, 2001; Alper, Staji´c, & Gill, 2012; Brown, 2013; Koenig & Hilber, 2015; Litjens & Brunt, 2016; Meisner, Wilcox, & Richards, 2016). Ibogaine intake has also been associated with psychosis (Houenou, Homri, Leboyer, & Drancourt, 2011), mania (Marta, Ryan, Kopelowicz, & Koek, 2015), and seizures (Breuer et al., 2015). However, most of these cases happened in uncontrolled/
non-medical settings, using unknown doses of ibogaine of variable purity. When administered in more
controlled/supervised contexts, to individuals without previous cardiovascular diseases or under the acute effects of drugs, ibogaine appears to be relatively safe (Alper, 2001; Alper et al., 2008, 2012; Brown, 2013; Donnelly, 2011; Forsyth et al., 2016; Glue, Lockhart, et al., 2015; Glue, Winter, et al., 2015; Koenig & Hilber, 2015; Lotsof & Alexander, 2001; Mash et al., 1998; Meisner et al., 2016). However, sudden deaths and fatalities with unknown causes have also been reported, and ibogaine should be administered only after a complete medical screening and with a rigorous cardiovascular monitoring (Alper, 2001; Alper et al., 2012; Brown, 2013; Koenig & Hilber, 2015; Litjens & Brunt, 2016; Meisner et al., 2016). Animal studies showed that ibogaine is neither reinforcing nor aversive, and that this alkaloid reduces opiate/ opioid (morphine and heroin), cocaine, and ethanol selfadministration (Alper, 2001; Alper et al., 2008; Belgers et al., 2016; Brown, 2013; Donnelly, 2011; Frenken, 2001; Lotsof & Alexander, 2001; Mash et al., 1998). Animal studies also reported that noribogaine reduces nicotine and amphetamine self-administration (Alper, 2001; Alper et al., 2008; Belgers et al., 2016; Brown, 2013; Donnelly, 2011; Frenken, 2001; Lotsof & Alexander, 2001; Mash et al., 1998). A recent meta-analysis of animal studies reported that the most significant effects of ibogaine in reducing drug self-administration were observed in the first 24 hr after its administration, and these effects were sustained for more than 72 hr (Belgers et al., 2016). Moreover, several case reports described significant reductions in drug (mostly heroin, methadone, and cocaine) craving and withdrawal symptoms within 1–2 hr after oral administration of single or few doses of ibogaine, followed by complete cessation of the opiate/opioid withdrawal syndrome within 24–48 hr and significant reductions or even total cessation of substance use weeks to months (or longer) following ibogaine intake (Alper, 2001; Alper et al., 2008; Brown, 2013; Donnelly, 2011; Frenken, 2001; Lotsof & Alexander, 2001; Mash et al., 1998). These data from human case reports are in line with animal studies (Belgers et al., 2016). Although some reviews analyzing the antiaddictive effects of ibogaine in humans were published, these were narrative and non-systematic reviews (Alper, 2001; Alper et al., 2008; Brown, 2013; Donnelly, 2011; Mash et al., 1998), and the most recent of them was published 3 years ago (Brown, 2013). To the best of our knowledge, no systematic review analyzing the antiaddictive effects of ibogaine in humans was previously performed. Therefore, considering the apparent increase in ibogaine use and its possible toxic and therapeutic effects (Alper et al., 2008), this study aimed to conduct a systematic literature review of human studies that investigated the antiaddictive effects of ibogaine or of its main active metabolite, noribogaine.

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