So how is ibogaine able to affect such a rapid, drastic change in OUD patients, many of whom had previously tried and failed to remain abstinent using the gold-standard opioid agonist treatment? Researchers are still trying to answer that question, with most data supporting a complex blend of pharmacological action, neuroplasticity, and oneirophrenic or holotropic experiences.

Ibogaine exhibits complex pharmacological action at a wide range of neurotransmitter receptors, with a low binding affinity for the serotonin reuptake transporter; sodium channels; nicotinic acetylcholine; N-methyl-D-aspartate (NMDA) glutamate; and kappa-opioid, mu-opioid, and sigma-2 receptors (Brown, 2013). Although it is an agonist for 5-HT_2A, 5-HT3, and muscarinic receptors, ibogaine is also an antagonist for NMDA glutamate and nicotinic acetylcholine receptors. Ibogaine, which is highly lipophilic, therefore, concentrates in the brain and adipose tissue and slowly metabolizes via demethylation to form the active metabolite, noribogaine, which has its own unique pharmacological profile. Noribogaine, with a circulating half-life of 28–49 h, exhibits less affinity for NMDA receptors and a greater affinity for mu-opioid receptors than its parent compound (Mash et al., 2000). This agonism of opioid receptors by noribogaine may contribute to the observed reductions in withdrawals and cravings.

Although noribogaine’s actions at opioid receptors may mediate initial therapeutic effects relating to craving and withdrawal symptoms, they do not fully explain the long-lasting anti-addiction effects often noted after a single session of ibogaine treatment for opioid dependence. It has been postulated that the enduring anti-addictive properties of ibogaine relate instead to a rewiring of neural circuitry associated with addiction. Indeed, both ibogaine and noribogaine increase the glial-derived neurotrophic factor (GDNF) in the ventral tegmental area, which has been shown in preclinical studies to reduce self-administration of alcohol (He et al., 2005). Interestingly, however, 18-methoxycoronardine (18-MC), a structural analog developed to mitigate the negative cardiovascular and hallucinogenic side effects of ibogaine, does not increase the GDNF despite demonstrating efficacy in reducing cocaine and morphine self-administration (Brown, 2013). Noribogaine, but not ibogaine, on the other hand, has been shown to increase dendritic arbor complexity and promote neuritogenesis in cortical neurons in vivo. This rapidly induced neuroplasticity is mediated via the stimulation of TrkB, mTOR, and intracellular 5-HT_2A signaling pathways and is thought to be essential to the therapeutic effects of ibogaine and other psychoplastogens on complex mental health conditions, such as depression and SUD (Ly et al., 2018; Vargas et al., 2023).

Similar to classic psychedelics, the activation of the 5-HT_2A receptors is also thought to be responsible for the hallucinatory effects of ibogaine. The ibogaine experience has been described both as oneirophrenic, or a waking dream-like state, and holotropic, a healing transformation of the consciousness (Underwood et al., 2021). Although Bwiti practitioners describe the ibogaine visionary experience in four phases, current researchers typically identify three distinct stages. The four phases of the Bwiti ibogaine initiation ritual are broken down by the type of vision and its attached significance: 1) random images lacking meaning; 2) fractal animal or natural images; 3) mythical images promoting peace; and 4) encounters with spiritual entities or ancestors. The three stages identified by researchers in conjunction with the treatment for SUD, in contrast, are characterized by both physical and psychological effects: 1) an acute phase defined by ataxia, possible GI distress, and changes in the heart rate while revisiting memories; 2) a reflective phase focusing inward while examining alternative pasts and futures; and 3) a residual stimulation phase with a decreased intensity of visions and a gradual return to the external environment (Alper et al., 2001; Underwood et al., 2021). It is possible that this altered state of consciousness is a necessary component to ibogaine’s anti-addictive therapeutic effects. Although the vast majority of ibogaine patients claim the experience to be both psychologically difficult and physically draining, objective and subjective reports from these same patients describe how it increased empathy, self-reflection, and appreciation, and decreased their feelings of anxiety and depression, improving familial and social relations (Brown and Alper, 2018; Camlin et al., 2018; Davis et al., 2018; Malcolm et al., 2018; Noller et al., 2018; Brown et al., 2019; Wilson et al., 2020). As one patient reflected, “I was also able to begin to see how, because I felt so unlovable, I paid in one way or another for love. I was able to stop that and open myself up to real love for maybe the first time in my adult life” (Brown et al., 2019). Consideration of these reports is increasingly important as researchers develop new compounds based off of hallucinogens, such as 18-MC and tabernanthalog (TBG). Although these novel molecules are showing some promise in preclinical studies regarding neuroplasticity and reduced addiction-seeking behaviors (Brown, 2013; Cameron et al., 2021), the lack of an altered state of consciousness could render them less effective or even completely ineffective when administered to human patients. This is an active area of research that requires further study.

Despite the large numbers of patients seeking ibogaine treatment for SUDs like OUD, its status as a Schedule I drug in the United States has hindered the ability of researchers to properly study its efficacy and safety and to create guidelines for its use. Ibogaine, while non-addictive and generally considered safe in the doses utilized for SUD treatment, does have known adverse and potentially dangerous side effects. It is known to inhibit cardiac hERG potassium channels, leading to QT interval prolongation and an increased risk for potentially fatal arrhythmias, including torsades de pointes (TdP) (Koenig and Hilber, 2015; Luz and Mash, 2021). The IC₅₀ concentration for hERG channels is approximately four times greater than the estimated therapeutic levels of ibogaine. However, one must consider that ibogaine is metabolized to noribogaine primarily by cytochrome P450 2D6 (CYP2D6) enzymes, which not only plays an important role in terms of drug–drug interactions but also in terms of genetic variations. For instance, approximately 10% of the Caucasian population lacks CYP2D6, which could significantly put them more at risk for adverse cardiovascular effects due to unexpectedly high plasma levels of ibogaine (Koenig and Hilber, 2015).

Since the beginning of the “vast uncontrolled experiment” of patients flocking to (mostly) unregulated clinics for ibogaine treatment, at least 32 ibogaine-related deaths have been reported (Luz and Mash, 2021). Although most of the reported fatalities were attributed to the aforementioned adverse cardiovascular effects, it is important to note that they also occurred in unsafe and unregulated settings with improper medical screening and dosing along with a lack of suitable medical care on site for monitoring and emergencies. In response to these severe and potentially dangerous side effects, guidelines for the use of ibogaine to treat SUDs have been published (Dickinson et al., 2016). These days, despite the continued lack of federal regulation, most providers understand the importance of careful patient screening for medical (e.g., EKG and liver function) and psychiatric exclusion criteria prior to treatment, as well as the proper monitoring and availability of medical assistance during and after treatment. Utilizing this careful approach, a recent study by Knuijver et al. was able to demonstrate that, while ibogaine treatment for OUD may produce clinically relevant bradycardia, QTc prolongation, and severe ataxia, these side effects were all manageable and reversible (Knuijver et al., 2022).

Further research is necessary before ibogaine treatment for SUDs in general or OUD, specifically, can be approved and made available to the American public, but it is undeniable that this unique, holotropic psychoplastogen holds promise for those suffering from these conditions. As previously mentioned, researchers are attempting to synthesize ibogaine analogs (18-MC and TBG) with improved safety profiles, but, to date, there has only been a single human trial with either of these compounds (NIH, 2023). There are currently two clinical trials in the recruiting stages for ibogaine for the treatment of opioid withdrawal and detoxification (Table 2). It will be extremely interesting to see if the non-hallucinogenic analogs produce the same efficacy as their hallucinogenic counterpart and if a regulated study design can mitigate any adverse effects of ibogaine itself.

As a dissociative anesthetic and analgesic, ketamine works by inhibiting open NMDA receptors in a non-competitive manner, which is considered to play a role in its utility in both depression and SUDs (Franks and Lieb, 1994; Naughton et al., 2014; Strasburger et al., 2017). NMDA normally serves as a binding site for glutamate. Glutamate dysfunction is thought to be one of the pathways involved in SUDs and other neuropsychiatric disorders. Addiction research has shown that metabotropic glutamate receptor 2 (mGlu2), which is abundant in the mesocorticolimbic system, medial PFC, and the nucleus accumbens (nAC), has a reduced function in response to prolonged exposure to drugs, such as alcohol, resulting in altered reward pathways and increased drug-seeking behaviors (Domanegg et al., 2023). Utilizing compounds with NMDA receptor antagonist activity, such as ketamine or ibogaine, works to restore the potential glutamate imbalance and produce synaptic improvements, ultimately allowing one to learn new behaviors (Browne and Lucki, 2013; Strasburger et al., 2017). The rapidity and relatively long-term efficacy of ketamine for depression (and potentially SUDs) have been linked, like ibogaine/noribogaine and classic psychedelics, to a rapid synthesis of brain- and/or glial-derived growth factors along with the activation of the mTOR signaling pathway, leading to synaptogenesis (Li et al., 2010; Autry et al., 2011; Ly et al., 2018; Aleksandrova and Phillips, 2021). In addition to ketamine’s activity at NMDA receptors, recent studies have shown that its activation of µ-opioid receptors, in particular, may be essential to its initial antidepressant effects (Heifets et al., 2021). Although a recent clinical trial investigating the effects of ketamine on precipitated opioid withdrawal (NCT00300794, Table 2) may help answer whether this opioid activity assists with craving and withdrawal symptoms similar to ibogaine, this is an active area of research. Interestingly, other NMDA antagonists that have been developed in order to treat depression, similar to ketamine, without either the opioid or hallucinogenic activity, have not shown as much efficacy in either neurogenesis or long-lasting symptom reduction (Autry et al., 2011; Browne and Lucki, 2013). As with both ibogaine and classic psychedelics, ketamine pharmacology is complex, interacting with multiple neurotransmitters and receptors (Kohrs and Durieux, 1998; Udesky et al., 2005; Mion and Villevieille, 2013; Pacheco Dda et al., 2014). Additionally, similar to the other psychoplastogens discussed here, researchers are still unable to determine how much of ketamine’s efficacy in depression (and possibly SUDs) is reliant on the hallucinogenic and psychotherapeutic components of ketamine-assisted psychotherapy. In Krupitsky’s two-year follow-up study, it was noted that high-dose ketamine, while significantly improving heroin abstinence rates and decreasing cravings, also increased non-verbal emotional attitudes, as compared with a low dose (Krupitsky et al., 2002). Interestingly, both low and high doses improved patients’ symptoms of anxiety, depression, and anhedonia, while increasing their spirituality. Additionally, a study of the effects of ketamine on motivation to quit and cue-induced cravings in cocaine-dependent individuals found that ketamine significantly enhanced motivation for changing problematic behaviors (Dakwar et al., 2014). This is particularly notable as these patients were only subject to a short mindfulness exercise prior to treatment, as opposed to a full psychotherapy session. Moving forward, it is imperative that researchers seeking to develop new compounds, whether to improve safety or to eliminate the altered states of consciousness from the equation, thoroughly investigate the activity of these older medicines. If researchers can identify the pharmacological action and chemical moiety responsible for the enhanced motivation seen in ketamine, for example, it will ensure that this aspect of the potential therapeutic effect can be incorporated into the new compound or can at least be methodically studied by alternate incorporation and removal.

Despite the lower potency and shorter half-life when compared to its parent drug PCP, ketamine is still used recreationally as well to produce feelings of weightlessness, out-of-body experiences, and visions (Curran and Morgan, 2000). Interestingly, regardless of this fact, unlike ibogaine and classic psychedelics, ketamine is a Schedule III drug in the United States. Therefore, it has some advantages, in terms of our knowledge, of the safety profile and clinical guidelines as compared with other psychoplastogens (Sanacora et al., 2017; Cohen et al., 2018; Schwenk et al., 2018). Although it remains to be determined what the ideal dose of ketamine for OUD would be, the known side effects of doses currently used in treating depression include transient cardiovascular alterations, such as an increased heart rate and blood pressure, mild respiratory depression, and dissociative or hallucinogenic effects (Mion and Villevieille, 2013; Sanacora et al., 2017). Several clinical trials of ketamine for OUD alone and with comorbid depression are already underway (Table 2). The results of these trials will help further establish the safety and efficacy of this potential treatment, and hopefully pave the way for future research and trials with other psychoplastogens.

As with ibogaine, LSD, psilocybin, and ayahuasca each exhibit their own unique pharmacological profile, interacting with a wide variety of neurotransmitters and receptors within the brain. They are typically classed together, however, as they are all 5-HT_2A receptor agonists, and as such, they produce an altered state of consciousness together with rapid neuroplasticity. As potent psychoplastogens, LSD, psilocin (the active metabolite of psilocybin), and N-N-dimethyltryptamine (DMT; the main psychoactive component of ayahuasca) have all been shown to increase structural and functional neuritogenesis, spinogenesis, and synaptogenesis within cortical neurons (Ly et al., 2018; Shao et al., 2021; Olson, 2022). This effect, purportedly driven by intracellular 5-HT_2A receptors and mTOR and TrkB signaling pathways, appears to be both rapid and persisting (Shao et al., 2021; Vargas et al., 2023). This psychoplastogen effect could account for the reported long-lasting efficacy of these compounds, as noted after only one to three doses. Additionally, as with ketamine, psychedelics may restore glutamate transmission in the PFC. In the case of 5-HT_2A agonists, it has been found that 5-HT_2A and mGlu2 are capable of regulating each other’s downstream signaling pathways via monovalent crosstalk or heteromer formation (Duman et al., 2021). One theory for neuroplastic-induced efficacy with regards to SUDs is a top–down approach, wherein changes to the PFC via neurogenesis, increasing mGlu2 and decreasing 5-HT_2A, leads to increased inhibitory control and decreased stress reactivity within dorsal raphe nuclei and the extended amygdala with a subsequent decreased stress response and stress-induced neurodegeneration at the hypothalamus–pituitary–adrenal axis (Urban et al., 2023). The neuroplastic changes in the PFC may additionally signal to the ventral tegmental area and the nAC to decrease corticoaccumbal transmission, thereby reducing impulsivity and drug-seeking behaviors.

Nevertheless, as it is with ibogaine, it is currently not possible to separate the known pharmacological effects from the psychological effects caused by psychedelics, producing altered states of consciousness. Although each of the psychedelics produce their own unique “trips” in terms of duration, physical side effects, and hallucinatory manifestations, the impact of the experience on the user tends to be profound and, for the most part, highly beneficial. Higher psychedelic doses, mystical-type experiences, and greater personal insights are all correlated with a more favorable outcome (Argento et al., 2019; Garcia-Romeu et al., 2019; Hamill et al., 2019). Indeed, even when controlling the intensity of the drug’s effects, mystical-type subjective effects have been found in some studies to be “necessary” for the enduring beneficial efficacy of the drug (Garcia-Romeu et al., 2014; Yaden and Griffiths, 2021). In the psilocybin tobacco cessation study, the authors likened the effect of the mystical experience to an “inverse PTSD-like experience,” in which a singular event was capable of causing lasting behavioral and likely biological benefits to the patients, with one patient stating that it left them “feeling complete as a person and physically part of all things” (Garcia-Romeu et al., 2014). It should be noted that the studies investigating these drugs for changes in mental health or addiction nearly always involve a strong psychotherapeutic component, whether in the form of a religious ceremony or Western psychotherapy. Indeed, ritual users, such as those who partake of ayahuasca as a sacrament in the Uniao do Vegetal (UDV) church, acknowledge that, for them, the two cannot be separated (Grob et al., 1996). Ayahuasca served as a catalyst for change in their lives, but the ritual and community helped solidify their resolutions and outlook on life. Similarly, post-treatment psychotherapy employed by modern researchers serves to help patients integrate the visionary experience into their lives moving forward.

Despite multiple recent clinical trials demonstrating the efficacy of classic psychedelics for a number of neuropsychiatric conditions, these compounds remain as Schedule I drugs. Therefore, there are no set clinical guidelines with regards to patient exclusion criteria, dosing, administration, or medical monitoring, although individual states are beginning to establish these details (OHA, 2023). Likewise, the FDA recently released a draft of the guidelines for the industry to address the necessary and complicated components of conducting clinical investigations with psychedelic drugs (FDA, 2023). Nevertheless, 5-HT_2A agonists are generally considered safe and non-addictive. DMT has been shown to increase the heart rate, blood pressure, and anxiety, but these adverse events are mild and self-limited (D'Souza et al., 2022). Ayahuasca, which contains monoamine oxidase inhibitors, harmine and harmaline, in addition to DMT, causes similar short-term cardiovascular responses as DMT alone, along with typically inducing nausea and vomiting shortly after ingestion (Hamill et al., 2019). The emesis portion of the ayahuasca experience is often portrayed as a “cleansing” to prepare the participant for the visions to come. Adverse events reported with psilocybin include headache, nausea, dizziness, and a transient increase in BP and HR, but, as with ayahuasca and DMT, these are self-limited (Goodwin et al., 2022). A recent clinical trial of LSD for anxiety reported mild and transient adverse events during treatment, including anxiety, nausea, and headache (Holze et al., 2023). Overall, the adverse effects of psychedelics tend to be mild and transitory, while the positive benefits to neuropsychiatric disorders and a general outlook on life are rapid and long-lasting. To date, despite the potential, there have been no published results of clinical trials on classic psychedelics for the treatment of OUD, although three trials involving psilocybin and one of MDMA are in the initial and recruiting phases (Table 2). The results of these trials will hopefully add to the growing evidence of the safety and efficacy of classic psychedelics for the treatment of not only neuropsychiatric disorders and substance abuse but also of the person as a whole. Indeed, a couple of these trials (NCT05242029 and NCT05585229) are notable in the sense that they are investigating the potential of psilocybin in patients who are currently using OATs for OUD. Although many patients who seek out treatments like ibogaine, ketamine, or psychedelics for OUD do so because they have found OATs to either be ineffectual or too difficult to adhere to, it is possible that the combination of therapy may be synergistic pharmacologically or that psychoplastogens may enhance the motivation of patients to adhere to the regimen of OATs. On the other hand, the use of these compounds may assist patients in transitioning off of OATs. This is an interesting concept requiring further study.