Ayahuasca is a hallucinogenic decoction used as a traditional medicine in several Amazonian regions. The ritualistic use of ayahuasca has spread throughout many countries, making it necessary to study its risks and benefits. Two sub-studies were designed for this investigation. In sub-study 1, a psychiatric interview and a battery of questionnaires were administered to subjects (n = 40) before their first ayahuasca use. Two follow-ups were conducted at 1 and 6 months. In sub-study 2, the same interview and battery of questionnaires were administered to long-term ayahuasca users (n = 23) and their scores were compared with those of the ayahuasca-naïve group. In the first assessment, nearly half (45%) of the naïve users were found to meet the diagnostic criteria for a psychiatric disorder. After the ayahuasca use, more than 80% of those subjects showed clinical improvements that persisted at 6 months. The questionnaires showed significant reductions in depression and psychopathology. Regarding substudy 2, long-term users showed lower depression scores, and higher scores for self-transcendence and quality of life, as compared to their peers in sub-study 1. Further controlled and observational naturalistic studies assessing the eventual risks and potential benefits of ayahuasca are warranted.Ayahuasca is a psychoactive beverage that results from the decoction of Banisteriopsis caapi and Psychotria viridis, plants rich in β-carbolines (harmine or tetrahydroharmine, among others) and N,N-dimethyltryptamine (DMT), respectively. DMT is a partial agonist of serotonin (5-HT) receptors 1 , but it can interact with other receptors as well (for a review see Carbonaro & Gatch 2 ). The hallucinogenic effects are primarily caused by the combination of the monoamine-oxidase A (MAO-A) inhibiting properties of β-carbolines and DMT, which results in the oral bioavailability of the latter 3 .Ayahuasca has been traditionally used in several communities of the Amazonia, but in recent decades its use has spread throughout the world 4 , first to urban areas of Brazil, where syncretic religions such as Santo Daime, União do Vegetal and Barquinha were established 5 , and then to other contexts, including several countries of the world where ayahuasca retreat centers have been developed and/or neoshamanic groups exist 6,7 .Concurrent with this increased public interest in ayahuasca ceremonies, there has been major interest from the academic and biomedical fields regarding its potential health effects 8,9 . Data from observational studies suggest that ayahuasca and its active ingredient DMT may have anxiolytic properties 10,11 . Furthermore, it has not been associated with increased psychopathology or with impairments in neuropsychological functioning 12,13 . An open-label clinical study found significant therapeutic benefits among patients with treatment-resistant major depressive disorder (MDD) after the administration of a single dose of ayahuasca 14,15 . Additionally, one randomized, placebo-controlled clinical trial was recently publish...

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The number of patients using cannabis for therapeutic purposes is growing worldwide. While research regarding the treatment of certain diseases/disorders with cannabis and cannabinoids is also expanding, only a few longitudinal studies have assessed the mid‐term impacts of medical cannabis use on psychological variables and quality of life (QoL). The aim of the study was to assess the psychological safety and QoL of patients with chronic diseases who self‐medicate with cannabis over time. We recruited patients with various chronic diseases who use cannabis and collected data regarding patterns of cannabis use as well as mental health, personality and QoL. Participants were followed‐up at baseline, 4, 8 and 12 months. Hair analysis was conducted to confirm the presence of cannabinoids. Personality assessment showed a consistent decrease in self‐transcendence and self‐directedness scores. Neither cognitive nor psychopathological deterioration was found. There were also no variations in QoL. Mid‐term use of medical cannabis seems to show adequate tolerability regarding cognitive and psychopathological abilities, and it may help patients with chronic diseases to maintain an acceptable QoL.

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: In drug development, the creation of highly selective ligands has been unsuccessful for the treatment of central nervous system disorders. Multi-target ligands, from the polypharmacology paradigm, are being proposed as treatments for these complex disorders, since they offer enhanced efficacy and a strong safety profile. Natural products are the best examples of multi-target compounds, so they are of high interest within this paradigm. Additionally, recent research on psychoactive drugs of natural origin, such as ayahuasca and cannabis, has demonstrated promising therapeutic potential for the treatment of some psychiatric and neurological disorders. In this text, we describe how research on psychoactive drugs can be effectively combined with the polypharmacology paradigm, providing ayahuasca and cannabis research as examples. The advantages and disadvantages are also discussed.

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 (Χ 2 (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.

Background In recent decades, ritualistic use of ayahuasca has spread throughout the world. Retrospective studies have suggested a good psychological safety profile, but prospective studies involving ceremony ayahuasca-naive participants are lacking. Methods We conducted the study using a subsample from a previous study, for which first-time ceremony ayahuasca participants were recruited. The subsample consisted of 7 subjects who experienced acute and challenging psychological reactions. The semistructured Mini-International Neuropsychiatric Interview and psychometric questionnaires were administered before participants attended the ayahuasca ceremony and at 1 and 6 months after exposure. Subjective experiences were also recorded. Results Seven subjects from a sample of 40 reported having experienced intense challenging psychological effects during the ayahuasca ceremony. Four of those 7 subjects met the diagnostic criteria for 1 or more psychiatric disorder before the ayahuasca ceremony. One month after the ceremony, 2 of those subjects no longer showed psychiatric symptoms, whereas the symptoms of the other 2 were reduced considerably. Those results persisted at the 6-month follow-up. Inappropriate setting/context (poor guiding skills and screening) contributed to some of the challenging reactions. Most of the participants (6 of 7) did not take ayahuasca again during the study period. Conclusions Based on the cases reported here, we suggest that although it is possible that participating in ayahuasca ceremonies may entail acute psychological negative reactions, those challenging experiences can also have positive long-term effects. Prospective research on the safety profile of ayahuasca and how it is affected by the context of different practices and safety strategies is therefore necessary.