Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies

Ayahuasca is a traditional Amazonian botanical brew made from Banisteriopsis caapi (rich in b‑carbolines such as harmine, tetrahydroharmine and harmaline) and Psychotria viridis (which contains N,N‑dimethyltryptamine, DMT). The b‑carbolines inhibit monoamine oxidase A (MAO‑A), permitting orally administered DMT to reach the systemic circulation and activate 5‑HT1A/2A/2C receptors in frontal and paralimbic brain regions. Apart from ritual and spiritual uses, anecdotal reports and preliminary studies in consumers and patients have suggested potential therapeutic effects of ayahuasca for substance dependence, anxiety and mood disorders, and safety data from acute administration and long‑term consumer assessments have been broadly reassuring. Dos Santos and colleagues therefore conducted a systematic literature review to collate animal and human studies that evaluated anxiolytic or antidepressive effects of ayahuasca and its main alkaloids (DMT, harmine, THH and harmaline). The review aimed to summarise preclinical and clinical evidence up to 3 April 2015 and to identify gaps that warrant further research, particularly given the need for new treatments that are faster‑acting and have favourable adverse‑effect profiles.

The investigators carried out the review according to PRISMA guidelines. Electronic searches were performed in PubMed (1966 to 3 April 2015), LILACS (1982 to 3 April 2015) and SciELO (1998 to 3 April 2015) using terms for ayahuasca, its alkaloids (dimethyltryptamine, harmine, tetrahydroharmine, harmaline) combined with anxiety/depression‑related keywords. No language restrictions were applied, and reference lists of identified papers were hand‑searched. Predefined inclusion criteria encompassed animal models of anxiety or depression; experimental studies administering ayahuasca to healthy volunteers that used validated scales for anxiety or depressive‑like symptoms; observational studies of ayahuasca consumers assessing anxiety or depressive symptoms with validated instruments; and clinical trials in patients diagnosed with anxiety or depressive disorders using DSM criteria. Eligible article types included journal articles, abstracts, letters, conference abstracts, books and book chapters; case reports, comments and editorials were excluded. Two independent reviewers screened studies, with a third reviewer resolving disagreements. Extracted items included authors, year, design, participant characteristics (species, sample size), intervention (compound, dose), response criteria and outcome measures. For clarity, results were grouped into animal and human studies. The search initially retrieved 514 references (four duplicates removed), 510 abstracts were screened, 21 full texts were reviewed in detail, and all 21 met the established inclusion criteria. The included sample comprised 10 animal studies and 11 human studies (three experimental, seven observational and one clinical trial).

The review identified a heterogeneous but consistent body of evidence suggesting anxiolytic and antidepressive effects for ayahuasca and its alkaloids across species and study types. Overall, 21 studies met inclusion criteria: 10 animal studies (including work on harmaline, harmine and one study of ayahuasca) and 11 human studies (three experimental, seven observational and one clinical trial). Animal findings: Harmaline produced dose‑dependent effects in mice on tests of anxiety‑like behaviour. Lower doses (5–10 mg/kg) increased anxiety in the elevated plus maze, whereas a higher dose (20 mg/kg) showed anxiolytic effects; in the marble burying test, doses of 5–7.5 mg/kg increased marble burying, reported in the paper as consistent with anxiolytic activity in that OCD‑related model. Harmine showed antidepressant‑like effects across several paradigms: in forced swim tests (FST) in mice and rats, intraperitoneal harmine (5–15 mg/kg) dose‑dependently reduced immobility and increased active behaviours. Chronic harmine (5–15 mg/kg/day for 14 days) also reduced immobility and altered swimming/climbing behaviours, and higher doses increased hippocampal BDNF levels. In chronic mild stress (CMS) models, harmine (commonly 15 mg/kg/day for 7 days in reported studies) reversed stress‑induced anhedonia (measured by sucrose/sweet food consumption), normalised adrenal gland hypertrophy and adrenocorticotropic hormone (ACTH) changes, and adjusted BDNF levels. Several studies reported harmine‑related reductions in lipid and protein oxidation and increases in antioxidant enzyme activity (superoxide dismutase and catalase) in prefrontal cortex and hippocampus. Effects on cellular energy metabolism were reported: harmine altered creatine kinase activity and increased activity of mitochondrial respiratory chain complex I (and, in some cases, complex IV) in specific brain regions depending on dose and treatment duration. A single animal study of orally administered ayahuasca (5 mg/kg) decreased immobility in the rat FST, while lower (2.5 mg/kg) and higher (10 mg/kg) doses had no significant effects. Human experimental studies involving DMT and ayahuasca reported mood and anxiety‑related changes. In an open‑label intramuscular DMT trial (0.7 mg/kg) with 15 healthy volunteers, 93% reported feelings of relaxation. A double‑blind, placebo‑controlled study administering intravenous DMT (0.04–0.4 mg/kg) to 15 volunteers found that a low non‑hallucinogenic dose (0.05 mg/kg) produced relaxation in some participants. Oral DMT at 25 mg was reported as non‑active, whereas smoked DMT at that dose produced strong psychoactive effects and increased positive mood in a small sample of six volunteers. Observational studies of ayahuasca consumers generally reported reduced psychopathology and improvements in wellbeing. First‑time ritual participants (n=28) were assessed before and 1–2 weeks after participation and showed reduced psychiatric symptoms with increased serenity; a 6‑month follow‑up of 23 of these participants reported sustained reductions in psychiatric symptoms and improved confidence and optimism. Cross‑sectional studies of experienced users (examples include a 15‑person Unia˜o do Vegetal cohort with ≥10 years use, a 40‑person adolescent Santo Daime group, a 32‑person North American Santo Daime sample with long‑term use, and a larger study with 127 long‑term religious members with a 1‑year follow‑up) consistently found no increase in psychiatric or neurocognitive problems and frequently reported reduced anxiety and depressive symptoms and better neuropsychological performance. One double‑blind, placebo‑controlled ritual study administering questionnaires 1 hour after ingestion in experienced Santo Daime members reported reduced panic and hopelessness after ayahuasca, with no change in state or trait anxiety. Clinical trial data: The single clinical trial included was an open‑label pilot by the review team in which six inpatients with recurrent depression received a single dose of ayahuasca. Depressive symptoms measured with the Hamilton Rating Scale for Depression (HAM‑D), the Montgomery–Åsberg Depression Rating Scale (MADRS) and the anxious‑depression subscale of the Brief Psychiatric Rating Scale (BPRS) were significantly reduced at 1, 7 and 21 days post‑dose compared with baseline. The investigators subsequently reported further work with a larger patient sample including single photon emission computed tomography (SPECT) assessments that they stated showed similar positive effects, although detailed results of that study are not provided in the extracted text.

Dos Santos and colleagues conclude that, despite the limited number of studies and substantial heterogeneity, the literature converges on anxiolytic and antidepressive effects for ayahuasca and its alkaloids across animal models, experimental human studies and observational assessments of users, with preliminary clinical evidence from a small open‑label trial in depressed patients. The authors note that rodent studies consistently show effects for harmine, harmaline and ayahuasca in behavioural models of anxiety and depression, and that experimental human data with DMT and observational work in long‑term ritual users align with reductions in anxiety and depressive symptoms and increases in positive mood or wellbeing. Mechanistically, the review highlights serotonergic receptor agonism at 5‑HT1A/2A/2C as a plausible common pathway, given these receptors' roles in emotional processing and regulation of brain‑derived neurotrophic factor (BDNF) and inflammatory processes. The authors also emphasise non‑serotonergic mechanisms, particularly for harmine: modulation of mitochondrial function, cellular energy homeostasis and oxidative stress markers, and GABA A receptor involvement suggested by some animal studies. Neuroimaging and connectivity data are discussed with caution; acute ayahuasca has been reported to reduce default mode network (DMN) activity, and structural differences (cortical thinning in the posterior cingulate cortex) have been observed in regular users, but changes in DMN–task‑positive network connectivity after ayahuasca were not consistently found. The review acknowledges important limitations. Most evidence derives from rodent studies, human experimental studies were small and often not primarily designed to assess anxiolytic or antidepressive effects, observational studies are vulnerable to confounding by religious affiliation and associated lifestyle factors, and only a single small open‑label clinical trial exists. Heterogeneity of doses, compounds, designs and outcome measures further complicates interpretation. The authors therefore characterise the human evidence as preliminary and call for more rigorous clinical trials to replicate and extend these findings, while noting the potential of ayahuasca‑related compounds as sources of faster‑acting treatments for anxiety and depressive disorders.