OPEN Foundation

Iboga / Ibogaine

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

Abstract

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.

Knuijver, T., Schellekens, A., Belgers, M., Donders, R., van Oosteren, T., Kramers, K., & Verkes, R. (2022). Safety of ibogaine administration in detoxification of opioid-dependent individuals: a descriptive open-label observational study. Addiction (Abingdon, England), 117(1), 118–128. https://doi.org/10.1111/add.15448

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A non-hallucinogenic psychedelic analogue with therapeutic potential

Abstract

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.

Cameron, L. P., Tombari, R. J., Lu, J., Pell, A. J., Hurley, Z. Q., Ehinger, Y., Vargas, M. V., McCarroll, M. N., Taylor, J. C., Myers-Turnbull, D., Liu, T., Yaghoobi, B., Laskowski, L. J., Anderson, E. I., Zhang, G., Viswanathan, J., Brown, B. M., Tjia, M., Dunlap, L. E., Rabow, Z. T., … Olson, D. E. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842), 474–479. https://doi.org/10.1038/s41586-020-3008-z

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Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies

Abstract

Introduction: Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders.

Objective: To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients’ accounts, and elucidating how these affect the treatment process.

Methods: We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP).

Results: Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses.

Conclusions: This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.

Breeksema, J. J., Niemeijer, A. R., Krediet, E., Vermetten, E., & Schoevers, R. A. (2020). Psychedelic treatments for psychiatric disorders: a systematic review and thematic synthesis of patient experiences in qualitative studies. CNS drugs, 1-22; 10.1007/s40263-020-00748-y

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Ibogaine therapy for addiction: Consumer views from online fora

Abstract

Background Ibogaine is a psychedelic drug used by for-profit clinics and lay-people to treat addiction, despite some reported fatalities and a lack of rigorous clinical research. Little is known about ibogaine therapy from a consumer perspective. Online discussions generate and disseminate information about ibogaine therapy and provide a window into how people understand ibogaine’s risks and uses. We examined views expressed in online fora in order to describe a consumer perspective of ibogaine therapy for addiction, and to elucidate the role of online fora in mediating people’s understanding of, and engagement with ibogaine. Methods We thematically analysed 40 threads comprising posts from 101 individual contributors from two popular online fora; Reddit (n = 20) and Drugs Forum (n = 20). Results Our analysis identified three primary themes: (1) online fora as a resource for do-it-yourself research; (2) the therapeutic interaction in ibogaine therapy, and; (3) therapeutic mechanisms of ibogaine. Online fora were a key resource for information about ibogaine therapy, where personal experiences and evidence-based information were valued. Treatment arrangements, risks, and harm reduction were discussed at length by forum participants. Discussions of therapeutic effects focused on pharmacological mechanisms but positive psychological changes resulting from the psychedelic experience were also reported. Clinic-based treatment was preferred by many forum participants due to safety concerns, but money and time and treatment intent sometimes necessitated lay-administration of ibogaine. Microdosing of ibogaine was also frequently discussed. Conclusion: Online fora appear to have facilitated a sense of community where individuals are held to account for the success of ibogaine therapy. Fora discussions illustrate that neuroscientific explanations of addiction and behaviour have explanatory salience for people involved in ibogaine therapy. Online fora could be used as a platform for clinician and peer-led support and harm-reduction interventions, and for further research monitoring treatment practices and long-term outcomes.

Barber, M., Gardner, J., Savic, M., & Carter, A. (2020). Ibogaine therapy for addiction: Consumer views from online fora. International Journal of Drug Policy83, 102857.; 10.1016/j.drugpo.2020.102857

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Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans

U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-related psychological and cognitive impairment among U.S. Special Operations Forces Veterans.

We conducted a survey of Veterans who completed a specific psychedelic clinical program in Mexico between 2017 and 2019. Questions probed retrospective reports of mental health and cognitive functioning during the 30 days before and 30 days after treatment. A total of 65 people completed treatment during this time frame and were eligible for contact. Of these, 51 (78%) completed the survey and were included in data analyses (mean age = 40; male = 96%; married = 55%; Caucasian/White = 92%; Operation Enduring Freedom/Operation Iraqi Freedom Service = 96%).

Results indicated significant and very large reductions in retrospective report of suicidal ideation (p < .001; d = −1.9), cognitive impairment (p < .001; d = −2.8), and symptoms of posttraumatic stress disorder (p < .001; d = −3.6), depression (p < .001; d = −3.7), and anxiety (p < .001; d = −3.1). Results also showed a significant and large increase in retrospective report of psychological flexibility (p < .001; d = 2.9) from before-to-after the psychedelic treatment. Increases in the retrospective report of psychological flexibility were strongly associated with retrospective report of reductions in cognitive impairment, and symptoms of posttraumatic stress disorder, depression, and anxiety (rs range −0.61 to −0.75; p < .001). Additionally, most participants rated the psychedelic experiences as one of the top five personally meaningful (84%), spiritually significant (88%), and psychologically insightful (86%) experiences of their lives.
Limitations: Several limitations should be considered including the retrospective, self-report, survey design of the study, and the lack of randomization and blinding, thus making these finding preliminary.

U.S. Special Operations Forces Veterans may have unique treatment needs because of the sequela of problems associated with repeated trauma exposure and the nature of the exposure. Psychedelic-assisted therapy with these under-researched psychedelics may hold unique promise for this population. However, controlled studies are needed to determine whether this treatment is efficacious in relieving mental health and cognitive impairment among U.S. Special Operations Forces Veterans.

Davis, A. K., Averill, L. A., Sepeda, N. D., Barsuglia, J. P., & Amoroso, T. (2020). Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans. Chronic Stress4, 2470547020939564; 10.1177/2470547020939564
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Spotlight commentary: REBUS and the anarchic brain

Abstract

In ‘REBUS and the Anarchic Brain: Towards a Unified Model of the Brain Action of Psychedelics’, Carhart-Harris and Friston offer an important analysis of what the predictive processing framework has to offer our understanding of psychedelic experiences, providing an invaluable ground for psychedelic psychiatry. While applauding this, we encourage paying greater attention to contextual factors shaping extreme experiences and their sequalae, and suggest that the authors’ comparisons with certain non-psychedelic altered states may overlook more informative parallels that can be drawn elsewhere. Addressing both points will prove fruitful, ultimately, in identifying the mechanisms of action of greatest interest in psychedelic experiences.
Carhart-Harris, R. L., & Friston, K. J. (2019). REBUS and the anarchic brain: toward a unified model of the brain action of psychedelics. Pharmacological reviews71(3), 316-344., https://doi.org/10.1093/nc/niaa007
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Mystical Experiences in Retrospective Reports of First Times Using a Psychedelic in Finland

Abstract

Despite their acutely inebriating and sometimes unpleasant effects, some people report positive changes in life satisfaction, well-being, or mental health after taking psychedelic drugs. One explanation may be the ability of psychedelics to trigger mystical-type experiences. We examined the validity, reliability, and factor structure of a novel Finnish translation of the Revised Mystical Experiences Questionnaire (MEQ30) among 288 people retrospectively reporting on their first time using a psychedelic. We found evidence for internal consistency reliability and preliminary evidence for criterion and discriminant validity of the Finnish MEQ30. A four-factor structure with factors for mystical qualities, positive mood, transcendence, and ineffability had the best, fair to reasonable fit to the data. MEQ30 scores and having a full mystical experience were highly associated with describing the experience as mystical, spiritual, or religious, and as personally significant, and somewhat associated with the experience being sad or difficult. Mystical experiences were especially associated with positive changes in relationships with nature and oneself and in creativity. Mystical experiences were more common with larger doses. Increasing research suggests mystical-type experiences to relate to positive changes after taking psychedelics. The Finnish MEQ30 is able to tap into relevant information about this aspect of people’s psychedelic experiences.
Kangaslampi, S., Hausen, A., & Rauteenmaa, T. (2020). Mystical Experiences in Retrospective Reports of First Times Using a Psychedelic in Finland. Journal of Psychoactive Drugs, 1-10. https://doi.org/10.1080/02791072.2020.1767321
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A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats

Abstract

Anecdotal reports and open-label case studies in humans indicated that the psychedelic alkaloid ibogaine exerts profound antiaddictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite, noribogaine, in substance-use-disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose- and time-dependence) induced by the acute ibogaine and noribogaine administration in rats using the forced swim test (FST, 20 and 40 mg/kg i.p., single injection for each dose). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine’s FST effect was short-lived (30 min) and correlated with high brain concentrations (estimated >8 μM of free drug), while the ibogaine’s antidepressant-like effect was significant at 3 h. At this time point, both ibogaine and noribogaine were present in rat brain at concentrations that cannot produce the same behavioral outcome on their own (ibogaine ∼0.5 μM, noribogaine ∼2.5 μM). Our data suggests a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine.
Rodríguez, P., Urbanavicius, J., Prieto, J. P., Fabius, S., Reyes, A. L., Havel, V., … & Carrera, I. (2020). A Single Administration of the Atypical Psychedelic Ibogaine or its Metabolite Noribogaine Induces an Antidepressant-like Effect in Rats. ACS Chemical Neuroscience., https://doi.org/10.1021/acschemneuro.0c00152
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Hallucinogens and Their Therapeutic Use: A Literature Review

Abstract

The exploration of possible therapeutic benefits of hallucinogenic substances has undergone a revitalization in the past decade. This literature review investigated the published literature regarding the psychotherapeutic uses of hallucinogens in psychiatric disorders. The results showed that a variety of substances have been evaluated in the treatment of psychiatric disorders, including ayahuasca, ibogaine, ketamine, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, and psilocybin. The conditions treated ranged from depression to autism, with the largest volume of research dedicated to substance use disorders. The majority of studies that were reviewed demonstrated significant associations with improvement in the conditions investigated. However, it was difficult to draw definitive conclusions as most studies suffered from small sample sizes, inconsistent measures, and poor study design. To properly assess the risks and potential benefits of hallucinogens in psychiatric treatment, there is a need for well designed, standardized studies that demonstrate the impact of hallucinogenic substances on psychiatric conditions.

BEGOLA, M. J., & SCHILLERSTROM, J. E. (2019). Hallucinogens and Their Therapeutic Use: A Literature Review. Journal of Psychiatric Practice®25(5), 334-346., 10.1097/PRA.0000000000000409
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Emotional breakthrough and psychedelics: Validation of the Emotional Breakthrough Inventory

Abstract

Background: Psychedelic therapy is gaining recognition and the nature of the psychedelic experience itself has been found to mediate subsequent long-term psychological changes. Much emphasis has been placed on the occurrence of mystical-type experiences in determining long-term responses to psychedelics yet here we demonstrate the importance of another component, namely: emotional breakthrough.
Methods: Three hundred and seventy-nine participants completed online surveys before and after a planned psychedelic experience. Items pertaining to emotional breakthrough were completed one day after the psychedelic experience, as were items comprising the already validated Mystical Experience Questionnaire and the Challenging Experience Questionnaire. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores were used to predict changes in well-being (Warwick-Edinburgh Mental Wellbeing Scale) in a subsample of 75 participants with low well-being baseline scores (⩽45).
Results: Factor analyses revealed six emotional breakthrough items with high internal consistency (Cronbach’s alpha=0.932) and supported our prior hypothesis that emotional breakthrough is a distinct component of the psychedelic experience. Emotional breakthrough scores behaved dose-dependently, and were higher if the psychedelic was taken with therapeutic planning and intent. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores combined, significantly predicted subsequent changes in well-being (r=0.45, p=0.0005, n=75), with each scale contributing significant predictive value. Emotional breakthrough and Mystical Experience Questionnaire scores predicted increases in well-being and Challenging Experience Questionnaire scores predicted less increases.
Conclusions: Here we validate a six-item ‘Emotional Breakthrough Inventory’. Emotional breakthrough is an important and distinct component of the acute psychedelic experience that appears to be a key mediator of subsequent longer-term psychological changes. Implications for psychedelic therapy are discussed.

Keywords: Psychedelics; catharsis; emotion; therapy.
Roseman, L., Haijen, E., Idialu-Ikato, K., Kaelen, M., Watts, R., & Carhart-Harris, R. (2019). Emotional breakthrough and psychedelics: validation of the emotional breakthrough inventory. Journal of Psychopharmacology33(9), 1076-1087., https://doi.org/10.1177/0269881119855974
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