Background: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients ( n = 28) and healthy controls ( n = 45). Aims: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale. Results: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed ( rho = –0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation ( rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed. Conclusions: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.

Rationale Major depressive disorder is one of the leading global causes of disability, for which the classic serotonergic psychedelics have recently reemerged as a potential therapeutic treatment option. Objective We present the first meta-analytic review evaluating the clinical effects of classic serotonergic psychedelics vs placebo for mood state and symptoms of depression in both healthy and clinical populations (separately). Results Our search revealed 12 eligible studies (n = 257; 124 healthy participants, and 133 patients with mood disorders), with data from randomized controlled trials involving psilocybin (n = 8), lysergic acid diethylamide ([LSD]; n = 3), and ayahuasca (n = 1). The meta-analyses of acute mood outcomes (3 h to 1 day after treatment) for healthy volunteers and patients revealed improvements with moderate significant effect sizes in favor of psychedelics, as well as for the longer-term (16 to 60 days after treatments) mood state of patients. For patients with mood disorder, significant effect sizes were detected on the acute, medium (2–7 days after treatment), and longer-term outcomes favoring psychedelics on the reduction of depressive symptoms. Conclusion Despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms.

Ayahuasca is a traditional plant decoction containing N,N-dimethyltryptamine (DMT) and various β-carbolines including harmine, harmaline, and tetrahydroharmine, which has been used ceremonially by Amazonian Indigenous groups for healing and spiritual purposes. Use of the brew has now spread far beyond its original context of consumption to North America, Europe, and Australia in neo-shamanic settings as well as Christian syncretic churches. While these groups have established their own rituals and protocols to guide use, it remains unknown the extent to which the use of traditional or non-traditional practices may affect drinkers’ acute experiences, and longer term wellbeing and mental health outcomes. Hence, this study aimed to provide the first detailed assessment of associations between ceremony/ritual characteristics, additional support practices, motivations for drinking, and mental health and wellbeing outcomes. The paper uses data from a large cross-sectional study of ayahuasca drinkers in more than 40 countries who had used ayahuasca in various contexts (n = 6,877). It captured detailed information about participant demographics, patterns and history of ayahuasca drinking, the setting of consumption, and ritualistic practices employed. Current mental health status was captured via the Kessler 10 psychological distress scale and the mental health component score of the SF-12 Health Questionnaire, while reported change in prior clinically diagnosed anxiety or depression (n = 1276) was evaluated using a (PGIC) Patient Global Impression of Change tool. Various intermediate outcomes were also assessed including perceived change in psychological wellbeing, number of personal self-insights attained, and subjective spiritual experience measured via the spirituality dimension of the Persisting Effects Questionnaire (PEQ) and Short Index of Mystical Orientation. Regression models identified a range of significant associations between set and setting variables, and intermediate and final mental health and wellbeing outcomes. A generalized structural equation model (GSEM) was then used to verify relationships and associations between endogenous, mediating and final outcome variables concurrently. The present study sheds new light on the influence of ceremonial practices, additional supports and motivations on the therapeutic effects of ayahuasca for mental health and wellbeing, and ways in which such factors can be optimized in naturalistic settings and clinical studies.

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The medical use of psychedelic substances (e.g. psilocybin, ayahuasca, lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine) is attracting renewed interest, driven by a pressing need for research and development of novel therapies for psychiatric disorders, as well as promising results of contemporary studies. In this Viewpoint, we reflect upon the ‘Clinical Memorandum on Psychedelics’ recently released by the Royal Australian and New Zealand College of Psychiatrists and note subsequent developments including the application for down-scheduling of psilocybin and 3,4-methylenedioxymethamphetamine presently being considered by the Therapeutic Goods Administration and approvals for access via the Special Access Scheme. We suggest that this field is worthy of rigorous research to assess potential benefits, address safety parameters and clarify therapeutic mechanisms. To this end, we outline recent research findings, provide an overview of current knowledge relating to mechanisms of action and discuss salient aspects of the psychedelic-assisted psychotherapy treatment model. The sum of this research points towards medicinal psychedelics as a potential new class of psychiatric treatments when used within a medically supervised framework with integrated psychotherapeutic support. However, before widespread translation into clinical use can occur, appropriately designed and sufficiently powered trials are required to detect both potential positive and negative outcomes. Unique safety and regulatory challenges also need to be addressed. As for any new medical therapy, psychedelic research needs to be conducted in a rigorous manner, through the dispassionate lens of scientific enquiry. Carte blanche availability to practitioners, without specific protocols and appropriate training, would be potentially harmful to individuals and detrimental to the field.