Ibogaine Background and Potential as a Treatment for Alcohol Use Disorder

By Joseph P. Barsuglia, ... Tanya Calvey, in Progress in Brain Research, 2018

Ibogaine is a primary alkaloid present in the root bark of the Tabernanthe iboga plant, which has an ancient history of ceremonial use in Central Africa. In recent decades, a number of studies have demonstrated the efficacy of ibogaine in treating opioid dependence (Brown and Alper, 2017; Davis et al., 2017; Malcolm et al., 2018; Noller et al., 2018). The treatment response rates to a single administration of ibogaine in recent observational studies with opioid users are promising. Remission statistics range from 75% in a small (n = 14) 1-year observational follow-up study in New Zealand (Noller et al., 2018), to 30–50% in larger observational studies from clinics in Mexico (Brown and Alper, 2017; Davis et al., 2017).

These observational outcomes far surpass general efficacy ranges of widely utilized opioid replacement drugs such as methadone and buprenorphine (average 8–35%) (McCarty et al., 2017; Weiss et al., 2011). Ibogaine demonstrates a spectrum of anti-addictive properties with a number of substances of abuse, including cocaine, amphetamines, nicotine, and alcohol (Brown, 2013; Schenberg et al., 2014). Pharmacological models suggest that ibogaine is a promising therapeutic agent for treating alcohol use disorders; however, to date, no formal studies have examined this specific application in humans.

Ibogaine demonstrates complex, broad, and novel pharmacological mechanisms of action to consider in the potential treatment of alcohol use disorders (Alper, 2001). The alkaloid has low micromolar affinity for μ and κ opioid receptors, σ1 and σ2 receptors, serotonin reuptake transporter (SERT) and dopamine transporter (DAT), and is an N-methyl-d-aspartate (NMDA) and α3β4 nicotinic acetylcholine receptor (nAChR) antagonist that increases glial-derived neurotrophic factor (GDNF) expression and substance P immunoreactivity (Alburges et al., 2000; Brown and Alper, 2017; Jacobs et al., 2007; Lavaud and Massiot, 2017; Mash et al., 1998). Ibogaine is hepatically metabolized by CYP2D6 to an active metabolite, noribogaine, which has a longer duration of action with a documented half-life of 28–49 h in CYP2D6 extensive metabolizers (Glue et al., 2015). Anti-addictive effects on drug craving and improvements in mood persist after the elimination of both ibogaine and noribogaine, suggesting a longer-term neuroadaptive response after ibogaine/noribogaine exposure (Brown and Alper, 2017; Pearl et al., 1997).

Ibogaine demonstrates pre-clinical evidence for treating alcohol abuse through multiple pathways. In rodents, ibogaine reduces alcohol intake in alcohol-preferring rats in preference and relapse paradigms (He, 2005; Rezvani et al., 1995); the anti-addictive effect is theorized to occur in part through upregulation of GDNF in the ventral tegmental area (VTA) (He, 2005). The VTA is a major region implicated in reward neurocircuitry (He and Ron, 2006), and chronic alcohol use inhibits the excitability of VTA neurons (Bailey et al., 1998) and firing rates of dopamine cells in this region (Bailey et al., 2001). The rewarding addictive properties of alcohol are associated with stimulation of dopaminergic and serotonergic systems broadly (Marcinkiewcz et al., 2016). Ibogaine's effect on psychological dependence (craving) with multiple substances of abuse has been attributed to its long-acting effects on DAT and SERT (Rezvani et al., 1995). Individuals with alcohol dependence demonstrate lower baseline availability of SERT in the midbrain compared to controls (Ho et al., 2011), and ibogaine is a noncompetitive inhibitor of SERT (Bulling et al., 2012), shown to increase serotonin in the striatum allegedly through this mechanism (Wei et al., 1998). In rodent models, ibogaine administration increases serotonin and dopamine release in mesolimbic pathways, including the nucleus accumbens, striatum, and the prefrontal cortex (Broderick et al., 1994; Maisonneuve et al., 1992; Wei et al., 1998), which are all prominent regions of therapeutic interest in the treatment of alcohol use disorder (Gilpin and Koob, 2008). The μ opioid receptor has demonstrated a functional role in the rewarding and reinforcing effects of alcohol (Méndez and Morales-Mulia, 2008) as well as craving (Nutt, 2014), and ibogaine binds μ, κ, and δ opioid receptors (Litjens and Brunt, 2016). However, neither ibogaine nor noribogaine activates G-proteins associated with morphine administration, or produces signs and symptoms of opioid intoxication in opioid naïve persons (Antonio et al., 2013).

Therefore, it seems that ibogaine is able to produce a neuroadaptive effect on endogenous opioid systems that reverses opioid tolerance and may be implicated broadly in its “addiction-interrupting” effects with other substances such as alcohol. Additionally, ibogaine is an NMDA antagonist, and drugs with this mechanism, such as ketamine, memantine, or NMDA regulators, such as acamprosate have shown promise in reducing symptoms of alcoholism and cravings (Ron and Wang, 2009). Ibogaine has no affinity for GABA receptors and is not thought to be effective in treating acute alcohol withdrawal syndrome.

In addition to its direct anti-addictive neurobiological properties, ibogaine occasions potent dissociative and waking dream-like (oneiric) states that engender transformative psychological insights (Heink et al., 2017; Schenberg et al., 2017). In individuals with substance use disorders, ibogaine stimulates heightened memory retrieval specifically related to drug abuse, the perception of one's own future with or without drug use, and visions which reveal powerful insights into the psychological factors contributing to the addiction, such as emotionally unresolved personal traumas (Schenberg et al., 2017).

Several studies have shown that lifetime trauma incidence is a primary predictor of developing an addictive disorder (Garami et al., 2018; Konkolÿ Thege et al., 2017; Mandavia et al., 2016), and during ibogaine treatment, individuals with different forms of substance addictions consistently report therapeutic processing of autobiographical imagery, childhood experiences, and evocation of repressed traumatic memories (Davis et al., 2017; Schenberg et al., 2017; Winkelman, 2014).

One study found that the subjective intensity of altered states of consciousness during the ibogaine experience was associated with an individual's ability to make adaptive changes as well as how “changed” a person felt as a result of treatment (Heink et al., 2017). In a retrospective study, ibogaine treatment responders were more likely to report their ibogaine experience as spiritually meaningful, and that they gained insight into the cause of their addiction compared to non-responders (Davis et al., 2017). In addition, ibogaine administration is associated with improvement in mood and anxiety symptoms (Davis et al., 2017; Mash et al., 2001; Noller et al., 2018), which are precipitants and contributors to alcohol-related problems (Allan et al., 2015). Collectively, ibogaine demonstrates multiple potential pharmacological and psychological properties for treating alcohol use disorders.