Psychedelic Therapy: A Primer for Primary Care Clinicians-Ibogaine.

BACKGROUND: Ibogaine is a plant-derived alkaloid that has been used for thousands of years in rites of passage and spiritual ceremonies in West-Central Africa. In the West, it has primarily been used and studied for its anti-addictive properties and more recently for other neuropsychiatric indications, including post-traumatic stress disorder, depression, anxiety, and traumatic brain injury. AREAS OF UNCERTAINTY: Ibogaine requires careful patient screening and monitoring because of significant safety issues. There is potential for cardiotoxicity (prolonged QT interval); without rigorous screening, fatal arrhythmias may occur. However, preliminary research suggests that co-administration of ibogaine with magnesium may mitigate cardiotoxicity. Additionally, ibogaine may have dangerous interactions with opiates, so patients who receive ibogaine treatment for opioid use disorder must withdraw from long-acting opioids. Other potential concerning effects of ibogaine include rare incidences of mania or psychosis. Anticipated transient effects during ibogaine treatment can include ataxia, tremors, and gastrointestinal symptoms. THERAPEUTIC ADVANCES: Robust effects after a single treatment with ibogaine have been reported. In open-label and randomized controlled trials (RCTs), ibogaine reduces heroin and opioid cravings by upwards of 50%, up to 24 weeks after the treatment. An observational study of 30 Special Operations Forces veterans with mild traumatic brain injury reported that 86% were in remission from post-traumatic stress disorder, 83% from depression, and 83% from anxiety, one month after a single-dose ibogaine treatment. LIMITATIONS: Although there are several observational and open-label studies, there is only a single double-blind, placebo-controlled RCT on ibogaine. More RCTs with large sample sizes must be conducted to support ibogaine's safety and efficacy. CONCLUSIONS: Given the promising preliminary findings, ibogaine could potentially fill a much-needed gap in treatments for challenging conditions, including opioid dependence. Ibogaine's remarkable effects in traditionally treatment-resistant, combat-exposed individuals hints at its potential in broader populations with physical and psychological trauma.

The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients.

OBJECTIVE: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. METHODS: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity. RESULTS: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms. CONCLUSIONS: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.

Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview.

BACKGROUND: There is a growing interest in studying ibogaine (IBO) as a potential treatment for substance use disorders (SUDs). However, its clinical use has been hindered for mainly two reasons: First, the lack of randomized, controlled studies informing about its safety and efficacy. And second, IBO's mechanisms of action remain obscure. It has been challenging to elucidate a predominant mechanism of action responsible for its anti-addictive effects. OBJECTIVE: To describe the main targets of IBO and its main metabolite, noribogaine (NOR), in relation to their putative anti-addictive effects, reviewing the updated literature available. METHODS: A comprehensive search involving MEDLINE and Google Scholar was undertaken, selecting papers published until July 2022. The inclusion criteria were both theoretical and experimental studies about the pharmacology of IBO. Additional publications were identified in the references of the initial papers. RESULTS: IBO and its main metabolite, NOR, can modulate several targets associated with SUDs. Instead of identifying key targets, the action of IBO should be understood as a complex modulation of multiple receptor systems, leading to potential synergies. The elucidation of IBO's pharmacology could be enhanced through the application of methodologies rooted in the polypharmacology paradigm. Such approaches possess the capability to describe multifaceted patterns within multi-target drugs. CONCLUSION: IBO displays complex effects through multiple targets. The information detailed here should guide future research on both mechanistic and therapeutic studies.

Ibogaína: un psicodélico atípico con potencial antiadictivo / Ibogaine: an atypical psychedelic with anti-addictive potential

El trastorno por uso de sustancias es una enfermedad crónica de graves consecuencias. Actualmente, los tratamientos farmacológicos no apuntan a corregir los cambios neurobiológicos generados en el cerebro por el uso crónico de sustancias de abuso, sino que se enfocan principalmente en la atenuación de algunos de los síntomas que padece el consumidor. La ibogaína es un psicodélico atípico que, tanto en estudios observacionales como en ensayos clínicos abiertos, ha mostrado una propiedad antiadictiva que perdura en el tiempo. Sin embargo, su delicado perfil de toxicidad cardíaca, así como su uso en entornos sin adecuadas medidas de seguridad, han limitado su progresión en las investigaciones clínicas. Los efectos antiadictivos de ibogaína han disparado diversas líneas de investigación básica, preclínica y clínica, que buscan confirmar su efectividad, entender sus mecanismos de acción y delimitar su perfil de seguridad. Dada la poca información disponible para los profesionales de salud sobre esta sustancia, esta revisión busca aportar información acerca de su potencial terapéutico, posibles mecanismos de acción y riesgos asociados a su administración.

Substance use disorder is a chronic disease with severe consequences. Currently, pharmacological treatments do not aim to correct the neurobiological changes generated in the brain by the chronic use of substances of abuse, but rather focus mainly on attenuating some of the user's symptoms. Ibogaine is an atypical psychedelic that has shown long-lasting and interesting antiaddictive properties in both observational studies and open-label clinical trials. However, its delicate profile of cardiac toxicity, as well as its use in settings without adequate safety measures, have limited its progression in clinical research. The anti-addictive effects of ibogaine have triggered diverse scientific research in basic, preclinical, and clinical areas, which seek efficacy confirmation and to fully understand ibogaine´s underlying mechanisms of action and its safety profile. Given that there is little information available to health professionals about ibogaine and its antiaddictive properties, this review aims to provide published data about its therapeutic potential in drug addiction, its mechanisms of action, and risks associated with its administration.

Identifying setting factors associated with improved ibogaine safety: a systematic review of clinical studies.

Ibogaine is a psychoactive alkaloid derived from the west-African shrub Tabernanthe iboga. Western cultures are increasing the interest for the substance due to its claimed anti addictive properties, although the evidence supporting this effect is still preliminary. The use of ibogaine often occurs with no medical supervision in uncontrolled settings, and its use has been associated with several reports of severe adverse events. This review aims to evaluate the clinical studies of ibogaine, with a focus on administration settings, to elucidate specific criteria that may promote safer contexts for ibogaine use. A systematic review of the literature was conducted based on PRISMA guidelines. PubMed, Scielo, ClinicalTrials.gov and Core.ac.uk electronic databases were searched, and clinical studies published until November 17, 2022, were retrieved. The final synthesis included 12 sources. Information about general characteristics of the studies, adverse effects, screening of participants and setting characteristics were summarized and discussed. It is concluded that the use of controlled settings, supported by trained professionals and equipment allowing for rigorous medical, psychiatric, and cardiac monitoring, are essential to promote the safety of patients receiving ibogaine.

A systematic literature review of clinical trials and therapeutic applications of ibogaine.

BACKGROUND: Iboga and its primary alkaloids, ibogaine and noribogaine, have been of interest to researchers and practitioners, mainly due to their putative efficacy in treating substance use disorders (SUDs). For many SUDs, still no effective pharmacotherapies exist. Distinct psychoactive and somatic effects of the iboga alkaloids set them apart from classic hallucinogens like LSD, mescaline, and psilocybin. AIMS: The study team performed this systematic review focusing on clinical data and therapeutic interventions involving ibogaine and noribogaine. METHODS: The team conducted a search for all publications up to December 7, 2020, using PubMed and Embase following PRISMA guidelines. RESULTS: In total, we identified 743 records. In this review, we consider 24 studies, which included 705 individuals receiving ibogaine or noribogaine. This review includes two randomized, double-blind, controlled clinical trials, one double-blind controlled clinical trial, 17 open-label studies or case series (including observational or retrospective studies), three case reports, and one retrospective survey. The published data suggest that ibogaine is an effective therapeutic intervention within the context of SUDs, reducing withdrawal symptoms and craving. Data also point toward a beneficial impact on depressive and trauma-related psychological symptoms. However, studies have reported severe medical complications and deaths, which seem to be associated with neuro- and cardiotoxic effects of ibogaine. Two of these fatalities were described in the 24 studies included in this review. CONCLUSION: Treatment of SUDs and persisting comorbidities requires innovative treatment approaches. Rapid-onset therapies such as the application of ibogaine may offer novel treatment opportunities for specific individuals. Rigorous study designs within medical settings are necessary to warrant safe application, monitoring, and, possibly, medical intervention.

Safety of ibogaine administration in detoxification of opioid-dependent individuals: a descriptive open-label observational study.

BACKGROUND AND AIMS: Ibogaine is an indole alkaloid used in rituals of the African Bwiti tribe. It is also used in non-medical settings to treat addiction. However, ibogaine has been linked to several deaths, mainly due to cardiac events called torsades des pointes preceded by QTc prolongation as well as other safety concerns. This study aimed to evaluate the cardiac, cerebellar and psychomimetic safety of ibogaine in patients with opioid use disorder. DESIGN: A descriptive open-label observational study. SETTING: Department of psychiatry in a university medical center, the Netherlands. PARTICIPANTS: Patients with opioid use disorder (n = 14) on opioid maintenance treatment with a lasting wish for abstinence, who failed to reach abstinence with standard care. INTERVENTION AND MEASUREMENTS: After conversion to morphine-sulphate, a single dose of ibogaine-HCl 10 mg/kg was administered and patients were monitored at regular intervals for at least 24 hours assessing QTc, blood pressure and heart rate, scale for the assessment and rating of ataxia (SARA) to assess cerebellar side effects and the delirium observation scale (DOS) to assess psychomimetic effects. FINDINGS: The maximum QTc (Fridericia) prolongation was on average 95ms (range 29-146ms). Fifty percent of subjects reached a QTc of over 500ms during the observation period. In six out 14 subjects prolongation above 450ms lasted beyond 24 hours after ingestion of ibogaine. No torsades des pointes were observed. Severe transient ataxia with inability to walk without support was seen in all patients. Withdrawal and psychomimetic effects were mostly well-tolerated and manageable (11/14 did not return to morphine within 24 hours, DOS scores remained below threshold). CONCLUSIONS: This open-label observational study found that ibogaine treatment of patients with opioid use disorder can induce a clinically relevant but reversible QTc prolongation, bradycardia, and severe ataxia.

The adverse events of ibogaine in humans: an updated systematic review of the literature (2015-2020).

CONTEXT: Ibogaine is the main alkaloid of the African shrub Tabernanthe iboga. It produces hallucinogenic and psychostimulant effects, but it is currently known for the anti-addictive properties. Despite the potential therapeutic effects, several cases of fatalities and serious adverse events related to ibogaine/noribogaine use can be found in the literature. Most studies consist in case reports or were conducted under non-controlled settings, so causation cannot be clearly established. OBJECTIVES: To update (2015-2020) the literature on the adverse events and fatalities associated with ibogaine/noribogaine administration. METHODS: Systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Eighteen studies were included in the final selection. Highly heterogeneous results were found in terms of kind of product used or the known dosages. The adverse events were classified in acute effects (< 24 h), mainly cardiac (the most common was QTc prolongation), gastrointestinal, neurological, and clinical alterations, and long-lasting effects (> 24 h), mainly persistent cardiac alterations, psychiatric, and neurological signs. CONCLUSIONS: There is a high need of phase I clinical trials that can describe the safety of different dosages of ibogaine with standardized products. Further research should perform clinical profiling of vulnerable populations, and design effective screening methods and clinical procedures.

A non-hallucinogenic psychedelic analogue with therapeutic potential.

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Ibogaine Consumption With Seizure-Like Episodes, QTc-Prolongation, and Captured Cardiac Dysrhythmias.

BACKGROUND: Ibogaine is a psychoactive indole alkaloid that has been investigated for use as a treatment for opioid addiction. While not commercially available in the United States, it is available via Internet suppliers. Ibogaine use has been associated with significant cardiac and neurologic effects, such as QT-segment prolongation, cardiac dysrhythmias, hallucinations, seizures, and central nervous system depression. We present a case of verified ibogaine exposure with associated QTc prolongation and torsade de pointes with qualitative analysis of the ingested substance, and examine the history, social context, availability, and perceptions of ibogaine's effects and safety. CASE REPORT: A 34-year-old white woman with medical history significant for heroin and cocaine use disorder presented with reported seizures 1 day after ingestion of 2 g ibogaine powder purchased from an Internet supplier. Shortly after ingestion, she experienced hallucinations and was reported by family to have four to five seizure-like episodes, at one point becoming apneic. In the emergency department, she was noted to have QTc prolongation and several episodes of torsade de pointes. Qualitative analysis confirmed the presence of ibogaine in the empty foil packages containing the ingested substance. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As increasing numbers of opioid-dependent patients attempt to curtail their substance use disorders, we anticipate a rise in ibogaine exposures, necessitating awareness by front-line clinicians in recognizing and treating a drug exposure that can rapidly become life-threatening.

La paradoja del iboga: intoxicación por un remedio natural de desintoxicación / The paradox of iboga: intoxication by a natural detoxification remedy

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A Mixed-Method Analysis of Persisting Effects Associated with Positive Outcomes Following Ibogaine Detoxification.

We examined persisting effects, self-perceived challenges, and potential benefits associated with positive outcomes following ibogaine detoxification using data collected as part of a larger online retrospective study of 73 patients who received treatment for chronic opioid use in Mexico between 2012 and 2015. A mixed-methods design was used comparing treatment responders versus non-responders, as well as content coding of themes from open-ended questions. Most participants reported positive persisting effects of ibogaine detoxification (e.g., enhanced personal sense of gratitude and authenticity, and meaning and appreciation for life). Compared to non-responders, treatment responders endorsed greater persisting changes in their ability to tolerate difficult/painful feelings, capacity for coping with stress, and reduced unhealthy anger. Treatment responders reported greater change in subjective levels of inner peace, joy, feelings of love/openheartedness, and experiences of sacredness in life. Qualitative analyses revealed that treatment responders reported a heightened sense of spiritual awareness and greater connection to their intra-/interpersonal relationships after ibogaine detoxification. Notable challenges of ibogaine detoxification included psychological and health-related difficulties during treatment and challenges with post-treatment integration. Findings highlight the persisting effects associated with positive response to ibogaine detoxification and possible post-treatment needs (i.e., more integration/aftercare resources). Future research using rigorous experimental designs is needed.

Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes.

BACKGROUND: Ibogaine is a monoterpene indole alkaloid used in medical and nonmedical settings for the treatment of opioid use disorder. Its mechanism of action is apparently novel. There are no published prospective studies of drug use outcomes with ibogaine. OBJECTIVES: To study outcomes following opioid detoxification with ibogaine. METHODS: In this observational study, 30 subjects with DSM-IV Opioid Dependence (25 males, 5 females) received a mean total dose of 1,540 ± 920 mg ibogaine HCl. Subjects used oxycodone (n = 21; 70%) and/or heroin (n = 18; 60%) in respective amounts of 250 ± 180 mg/day and 1.3 ± 0.94 g/day, and averaged 3.1 ± 2.6 previous episodes of treatment for opioid dependence. Detoxification and follow-up outcomes at 1, 3, 6, 9, and 12 months were evaluated utilizing the Subjective Opioid Withdrawal Scale (SOWS) and Addiction Severity Index Composite (ASIC) scores, respectively. RESULTS: SOWS scores decreased from 31.0 ± 11.6 pretreatment to 14.0 ± 9.8 at 76.5 ± 30 hours posttreatment (t = 7.07, df = 26, p < 0.001). At 1-month posttreatment follow-up, 15 subjects (50%) reported no opioid use during the previous 30 days. ASIC Drug Use and Legal and Family/Social Status scores were improved relative to pretreatment baseline at all posttreatment time points (p < .001). Improvement in Drug Use scores was maximal at 1 month, and subsequently sustained from 3 to 12 months at levels that did not reach equivalence to the effect at 1 month. CONCLUSION: Ibogaine was associated with substantive effects on opioid withdrawal symptoms and drug use in subjects for whom other treatments had been unsuccessful, and may provide a useful prototype for discovery and development of innovative pharmacotherapy of addiction.

Examination of the Phenomenology of the Ibogaine Treatment Experience: Role of Altered States of Consciousness and Psychedelic Experiences.

Psychedelic drugs have historically been used for ritualistic purposes and to help individuals gain insight. Ibogaine, a naturally occurring psychoactive substance, has been reported to have anti-addictive properties that aid in the treatment of substance use disorders. An online survey obtained retrospective data from individuals who used ibogaine in the past. Individuals who used ibogaine tended to describe thematically similar experiences post-treatment. This study adds to the literature by using the 5d-ASC, a psychometrically sound measure of altered states of consciousness (ASCs), to examine the ASCs induced by ibogaine and discusses the demographic characteristics of those who seek ibogaine treatment (N = 27). The study also examined several aspects of ibogaine treatment experience, including reasons for seeking treatment, course of treatment, and treatment outcome. Results indicated a positive correlation between the various dimensions of the ASCs and the outcome (ability to make changes in one's life, cravings, and how changed the person was as a result of ibogaine treatment). While this study is limited in generalizability due to high attrition and low sample size, it deepens the understanding of the phenomenological experience of ibogaine and explores the possible utility of ibogaine in the treatment of substance use disorders.

Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and Cmax and was slowly eliminated (mean t1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues.