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BACKGROUND: Ayahuasca is a South American plant hallucinogen rich in the psychedelic N,N-dimethyltryptamine and ß-carbolines (mainly harmine). Preclinical and observational studies suggest that ayahuasca exerts beneficial effects in substance use disorders, but these potentials were never assessed in a clinical trial. METHODS: Single-center, single-blind, feasibility, proof-of-concept study, assessing the effects of one dose of ayahuasca accompanied by psychological support (without psychotherapy) on the drinking patterns (primary variable) of 11 college students with harmful alcohol consumption. Secondary variables included safety and tolerability, craving, personality, anxiety, impulsivity, self-esteem, and social cognition. FINDINGS: Ayahuasca was well tolerated (no serious adverse reactions were observed), while producing significant psychoactive effects. Significant reductions in days per week of alcohol consumption were found between weeks 2 and 3 (2.90 ± 0.28 vs 2.09 ± 0.41; P < 0.05, uncorrected), which were not statistically significant after Bonferroni correction. There were no statistically significant effects for other variables, except for a significant reduction in reaction time in an empathy task. CONCLUSIONS: A significant reduction in days of alcohol consumption was observed 2-3 weeks after ayahuasca intake, but this effect did not survive after Bonferroni correction. The lack of significant effects in alcohol use and other variables may be related to the small sample size and mild/moderate alcohol use at baseline. The present study shows the feasibility of our protocol, paving the way for future larger, controlled studies.

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Although several studies have been conducted to elucidate the relationship between psychedelic consumption and cognition, few have focused on understanding the long-term use influence of these substances on these variables, especially in ritualistic contexts.  To verify the influence of ritualistic ayahuasca consumption on the cognition of experienced ayahuasca religious users (> 20 years) and beginners (< 3 years), which participated in rituals of the Centro Luz Divina (CLD), a Santo Daime church in Brazil. Observational, descriptive, and cross-sectional study was carried out in which 48 people participated divided into three groups: (a) experienced ayahuasca users (n = 16), (b) beginner ayahuasca users (n = 16) and (c) control group (n = 16). All groups were matched by sex, age, and education and contained 8 women and 8 men. Cognition was assessed with the WASI (intelligence quotient), Digit Span (verbal working memory), Corsi Block-Tapping Task (visuospatial-related and working memory), Rey-Osterrieth Complex Figure test (visual perception, immediate memory), and Wisconsin Card Sorting and Five Digit Test (executive functions). Groups were homogenous in terms of sociodemographic characteristics, with participants presenting average intellectual performance. There was no evidence of cognitive decline amongst ayahuasca users. The experienced group showed higher scores compared to the less experienced group in the Digit Span and Corsi Block-Tapping tasks, which assess working verbal and visuospatial memories respectively. We confirmed the botanical identities of Psychotria viridis and Banisteriopsis caapi and the presence of the alkaloids both in the plants and in the brew. Short and long-term ayahuasca consumption does not seem to alter human cognition, while long-term use seems to be associated with improvements in aspects of working memory when compared with short-term use.

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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.

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OBJECTIVE: To assess endocannabinoid (anandamide, AEA; 2-arachidonoylglycerol, 2-AG) plasma levels in healthy volunteers and in volunteers with social anxiety disorder (SAD) after a single oral dose of ayahuasca or placebo. METHODS: Post hoc analysis of endocannabinoid plasma levels (baseline, 90 and 240 min after drug intake) from two parallel-group, randomized, placebo-controlled trials. In Study 1, 20 healthy volunteers ingested ayahuasca (average 1.58 mg/ml dimethyltryptamine (DMT)) or placebo, and in Study 2, 17 volunteers with SAD received ayahuasca (average 0.680 mg/ml DMT) or placebo. RESULTS: A significant difference was observed in AEA concentrations in Study 2 after ayahuasca intake (Χ2 (2) = 6.5, p = 0.03, Friedman test), and near significant differences (increases) were observed between baseline and 90 (Z = 0, p = 0.06, Wilcoxon test) and 240 (Z = 10, p = 0.06) minutes after ayahuasca intake. CONCLUSIONS: Although our findings suggest that ayahuasca could modulate AEA levels in SAD patients, the high interindividual variability in both trials and the small samples preclude definitive conclusions. More research with larger samples is needed to better understand the effects of ayahuasca and other hallucinogens in the endocannabinoid system.

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Ayahuasca is a hallucinogenic/psychedelic traditionally used for ritual and therapeutic purposes. One such therapeutic use is related to Substance Use Disorders (SUDs). A previous systematic review of preclinical and human studies published until 2016 suggested that ayahuasca and its alkaloids have therapeutic effects in the treatment of SUDs. To conduct an update of this previous review. A systematic review of quantitative studies which analyzed the effects of ayahuasca and its alkaloids on drug use (primary outcome) and other measures (secondary outcomes) related to SUDs was conducted, including articles from 2016 to 2020. Nine studies (four preclinical, five observational) were included in the review. Preclinical studies in rodents reported reductions in amphetamine self-administration and anxiety, and in alcohol- and methylphenidate-induced conditioned place preference. Observational studies among healthy ritual ayahuasca users and patients with SUDs reported reductions in drug use, anxiety, and depression, and increases in quality of life and well-being. We replicated the findings of the previous review suggesting that ayahuasca and its alkaloids have therapeutic effects in the treatment of SUDs. However, translation of preclinical data to humans is limited, observational studies do not allow us to infer causality, and there is a lack of standardization on ayahuasca doses. Although promising, randomized, controlled trials are needed to better elucidate these results. The PROSPERO ID for this study is CRD42020192046.

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Psychedelics or serotonergic hallucinogens are a group of substances that share the agonism of serotonergic 5-HT2A receptors as their main mechanism of action. Its main effects include changes in perception, cognitive process, and mood. Despite being used for centuries by different cultures in ritual contexts, these substances have currently aroused the interest of science and industry for their promising antidepressant, anxiolytic, and anti-addictive effects. Considering this evidence, this article aims to explore some of the possible health policy challenges to integrate these therapeutic tools into broad and heterogeneous health systems. As a main benefit, these substances produce rapid and enduring effects with the administration of single or few doses, which could lead to new treatment possibilities for patients with severe mental disorders resistant to the usual medications. The main challenge is associated with the fact that these substances remain scheduled in most countries and are associated with social stigma related to their recreational use (especially LSD and psilocybin). This situation makes it exceedingly difficult to conduct clinical trials, although international conventions allow such research. Ethically, this could be interpreted as a violation of human rights since thousands of people are prevented from having access to possible benefits. Interestingly, ritual ayahuasca use is more acceptable to the public than the use of psilocybin-containing mushrooms or LSD. The controlled, clinical use of LSD and psilocybin seems to be less criticized and is being explored by the industry. Rigorous scientific evidence coupled with industrial interests (LSD and psilocybin), together with respect for traditional uses (ayahuasca) and international conventions, seems to be the best way for these drugs to be integrated into health systems in the next years. Which highlights the need for an urgent dialogue between science, health system, society, and politics.

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Abstract Background Therapeutic properties of ibogaine in the treatment of addiction are attracting both clinicians and patients to its use. Since ibogaine is not an authorized medicine, the quality of these products is not always known, increasing the probability of adverse reactions. Objective This study collects different types of iboga-derived samples from treatment providers, vendors and online buyers to analyse their content. Methods Analysis of iboga products (n = 16) was performed using gas chromatography and mass spectrometry methods (GC/MS). Products included Iboga root bark, Total Alkaloids (TA), Purified Total Alkaloids (PTA HCl), ibogaine hydrochloride (ibogaine HCl) and one Voacanga africana root bark. Results The content of ibogaine was highly variable, ranging from 0.6% to 11.2% for products sold as iboga root bark, from 8.2% to 32.9% for products sold as TA, 73.7% for one sample sold as PTA and from 61.5% to 73.4% for products sold as ibogaine HCl. One sample did not show any iboga alkaloids. Other alkaloids and unknown substances were found in almost all samples. Discussion The purity of iboga products is highly variable. These results should be taken into consideration by suppliers and users, especially regarding correct dosing to avoid overdose, as well as potential interactions with other substances.

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In a recent issue of the BMC Psychiatry, the evidence of effectiveness of treatments for psychiatric conditions in end-stage cancer patients was reviewed (Johnson, 2018). The review was comprehensive, and included traditional and non-traditional/alternative treatments, including herbal medicines and spirituality. However, evidence showing that classic or serotonergic hallucinogens/psychedelics such as psilocybin and lysergic acid diethylamide (LSD) could be effective treatments for depressive and anxiety disorders in end-stage cancer was not included. In this commentary, we expand the information available on the original article by briefly reviewing data from recent placebo-controlled, double-blind, cross-over clinical trials showing evidence that administration of single (or few) doses of LSD and psilocybin was associated with rapid and sustained reductions in depressive and anxiety symptoms in patients with end-stage cancer and other life-threatening diseases (e.g., Bechterew's disease, Parkinson's disease, Celiac disease). Since these substances seem to produce rapid and sustained therapeutic effects with single (or few) doses and well tolerated, large-scale, prospective, multi-site studies of end-stage cancer and classical/serotonergic hallucinogens/psychedelics should be performed to improve our understanding of the therapeutic potentials of these drugs and their use on clinical practice.

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BACKGROUND: Recognition of emotions in facial expressions (REFE) is a key aspect of social cognition. Anxiety and mood disorders are associated with deficits in REFE, and anxiolytics and antidepressants reverse these deficits. Recent studies have shown that serotonergic hallucinogens (i.e. ayahuasca, dimethyltryptamine, psilocybin, lysergic acid diethylamide [LSD], and mescaline) have anxiolytic and antidepressant properties, but their effects on REFE are not well understood. The purpose of the study was to conduct a systematic review analyzing the effects of serotonergic hallucinogens on REFE in humans. METHODS: Studies published in the PubMed, PsycINFO, and Web of Science databases until 19 October 2018 which analyzed the effects of serotonergic hallucinogens on REFE in humans were included. RESULTS: Of the 62 studies identified, 8 studies were included. Included studies involved the administration of a single or a few doses of LSD or psilocybin, and most trials were randomized and controlled with placebo. LSD and psilocybin reduced the recognition of negative emotions in most studies and modulated amygdala activity to these stimuli, which was correlated with antidepressive effects in patients. Both drugs were well tolerated. CONCLUSIONS: Serotonergic hallucinogens reduced the recognition of negative emotions by modulating amygdala activity. Despite the small sample sizes, results suggest that serotonergic hallucinogens show promising beneficial effects on deficits in REFE.

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Abstract Background Ayahuasca is a psychoactive ethnobotanical concoction that has been used for decades by indigenous groups of the Northwestern Amazon and by syncretic religious organizations for ritual and therapeutic purposes. In the last two decades, it is being used worldwide in evolving practices. Ayahuasca seem to therapeutic effects, but controlled studies are lacking. Moreover, its safety and toxicity are not completely understood. Objectives To present an overview of the effects of ayahuasca based on the most recent human studies. Methods Narrative review. Results Ayahuasca administration in controlled settings appears to be safe from a subjective and physiological perspective, with few adverse reactions being reported. More frequent adverse reactions occur in non-controlled settings. Prolonged psychotic reactions are rare and seem to occur especially in susceptible individuals. Ayahuasca showed antidepressive, anxiolytic, and antiaddictive effects in animal models, observational studies, and in open-label and controlled studies. Discussion Ayahuasca administration in controlled settings appear to be safe. Moreover, ayahuasca seem to have therapeutic effects for treatment-resistant psychiatric disorders that should be further investigated in randomized controlled clinical trials. However, medical complications and cases of prolonged psychotic reactions have been reported, and people with personal or family history of psychotic disorders should avoid ayahuasca intake.

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Ayahuasca is an Amazonian psychoactive plant beverage containing the serotonergic 5-HT(2A) agonist N,N-dimethyltryptamine (DMT) and monoamine oxidase-inhibiting alkaloids (harmine, harmaline and tetrahydroharmine) that render it orally active. Ayahuasca ingestion is a central feature in several Brazilian syncretic churches that have expanded their activities to urban Brazil, Europe and North America. Members of these groups typically ingest ayahuasca at least twice per month. Prior research has shown that acute ayahuasca increases blood flow in prefrontal and temporal brain regions and that it elicits intense modifications in thought processes, perception and emotion. However, regular ayahuasca use does not seem to induce the pattern of addiction-related problems that characterize drugs of abuse. To study the impact of repeated ayahuasca use on general psychological well-being, mental health and cognition, here we assessed personality, psychopathology, life attitudes and neuropsychological performance in regular ayahuasca users (n = 127) and controls (n = 115) at baseline and 1 year later. Controls were actively participating in non-ayahuasca religions. Users showed higher Reward Dependence and Self-Transcendence and lower Harm Avoidance and Self-Directedness. They scored significantly lower on all psychopathology measures, showed better performance on the Stroop test, the Wisconsin Card Sorting Test and the Letter-Number Sequencing task from the WAIS-III, and better scores on the Frontal Systems Behavior Scale. Analysis of life attitudes showed higher scores on the Spiritual Orientation Inventory, the Purpose in Life Test and the Psychosocial Well-Being test. Despite the lower number of participants available at follow-up, overall differences with controls were maintained one year later. In conclusion, we found no evidence of psychological maladjustment, mental health deterioration or cognitive impairment in the ayahuasca-using group.

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Ayahuasca is a psychoactive beverage used for magico-religious purposes in the Amazon. Recently, Brazilian syncretic churches have helped spread the ritual use of ayahuasca abroad. This trend has raised concerns that regular use of this N,N-dimethyltryptamine-containing tea may lead to the medical and psychosocial problems typically associated with drugs of abuse. Here we assess potential drug abuse-related problems in regular ayahuasca users. Addiction severity was assessed using the Addiction Severity Index (ASI), and history of alcohol and illicit drug use was recorded. In Study 1, jungle-based ayahuasca users (n=56) were compared vs. rural controls (n=56). In Study 2, urban-based ayahuasca users (n=71) were compared vs. urban controls (n=59). Follow-up studies were conducted 1 year later. In both studies, ayahuasca users showed significantly lower scores than controls on the ASI Alcohol Use, and Psychiatric Status subscales. The jungle-based ayahuasca users showed a significantly higher frequency of previous illicit drug use but this had ceased at the time of examination, except for cannabis. At follow-up, abstinence from illicit drug use was maintained in both groups except for cannabis in Study 1. However, differences on ASI scores were still significant in the jungle-based group but not in the urban group. Despite continuing ayahuasca use, a time-dependent worsening was only observed in one subscale (Family/Social relationships) in Study 2. Overall, the ritual use of ayahuasca, as assessed with the ASI in currently active users, does not appear to be associated with the deleterious psychosocial effects typically caused by other drugs of abuse.

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