Anti-inflammatory activity of ayahuasca and its implications for the treatment of neurological and psychiatric diseases

Neuroinflammation is described as a central pathogenic process in many neurological and psychiatric conditions, including depression, anxiety, cognitive disorders and neurodegenerative diseases. The introduction frames inappropriate or chronic activation of inflammatory processes in the central nervous system (CNS) — involving cells such as microglia, astrocytes and circulating immune mediators — as a contributor to neuronal dysfunction and disease. Because many current pharmacotherapies do not explicitly target neuroinflammatory mechanisms, the authors present the search for agents with anti-neuroinflammatory properties as a key therapeutic priority. Goulart Da Silva and colleagues position ayahuasca, an Amazonian botanical decoction traditionally used in ritual and therapeutic contexts, as a candidate due to accumulating evidence that its active constituents (β-carbolines and tryptamines) produce both psychotropic and anti-inflammatory effects. The paper reports a narrative review of preclinical and clinical findings addressing ayahuasca's anti-inflammatory activity and discusses the implications of those effects for treating neurological and psychiatric disorders. The authors state that relevant literature was identified via searches of PubMed and Medline covering studies from recent decades.

This paper is presented as a narrative review rather than a systematic review or meta-analysis. The extracted text states that scientific articles from recent decades were obtained through searches on PubMed and Medline, but it does not specify exact search dates, search terms, inclusion or exclusion criteria, or whether any formal screening or quality assessment was performed. Consequently, the review synthesises heterogeneous evidence drawn from in vitro experiments, animal studies, human observational reports, and clinical trials, without a described risk-of-bias appraisal or prespecified protocol. The authors integrate data across multiple experimental modalities: molecular and cellular studies (including brain organoids and human immune cells), animal behavioural and toxicology experiments, and human studies ranging from observational evaluations of religious use to randomised clinical trials in people with treatment-resistant depression. Where tables are referenced in the text (for summaries of animal, in vitro and human studies), the extracted material here does not reproduce those tables; methodological details contained solely in them are therefore not available in the provided text.

Constituent pharmacology and the need for combined plants: The review reiterates that ayahuasca is typically prepared from Psychotria viridis (source of DMT) together with Banisteriopsis caapi (source of β-carbolines such as harmine). Orally administered DMT is rapidly degraded by monoamine oxidase (MAO) in the gut and liver; β-carbolines act as reversible MAO-A inhibitors, permitting DMT to reach systemic circulation and the CNS and thereby exert pharmacological actions. Properties of β-carbolines (B. caapi): These alkaloids, derived from tryptophan, have multiple actions beyond MAO-A inhibition. The authors describe antioxidant activity, interaction with GABAA benzodiazepine sites (reported as inverse agonism, with dose-dependent anxiogenic or anxiolytic effects), and engagement with serotonergic and dopaminergic receptors. Harmine is reported to have moderate affinity for 5-HT2A receptors and low affinity for 5-HT2C, and to increase electrically evoked dopamine efflux in the nucleus accumbens in rodent models. Properties of tryptamines (P. viridis): DMT is highlighted as a low-molecular-weight indolic alkaloid that readily crosses the blood–brain barrier. Its pharmacology includes agonism at 5-HT1A (linked to anxiolytic and antidepressant-like effects) and 5-HT2A (linked to hallucinogenic effects and, with longer-term stimulation, increased expression of brain-derived neurotrophic factor, BDNF). The authors note that 5-HT2A activation can engage mTOR signalling and that DMT also interacts with the sigma-1 receptor (σ1R), implicated in intracellular calcium signalling and neuroplasticity. 5-MeO-DMT, a related dimethyltryptamine, is discussed as an endogenous regulator of inflammation and immune homeostasis acting through serotonergic receptors and σ1R. Pharmacokinetic observations from the extracted text report that intravenously administered DMT yields peak blood levels and subjective effects within about 2 minutes and declines to negligible levels by 30 minutes, while oral administration within ayahuasca shows a later peak effect (around 107 minutes) and an apparent half-life of about 259 minutes. Anti-inflammatory and neuroprotective findings: In vitro studies using human monocyte-derived dendritic cells found that dimethyltryptamines blocked inflammatory release of cytokines and chemokines. Experiments with 45-day human brain organoids treated for 24 hours with 5-MeO-DMT demonstrated formation of new dendritic spines and upregulation of proteins involved in protrusion formation, microtubule dynamics and cytoskeletal reorganisation. Those organoid data are reported to show downregulation of NFAT and NF-κB pathways via modulation of toll-like receptors and G-protein-coupled receptors, consistent with an anti-inflammatory effect. Additional organoid studies treated with DMT reportedly increased expression of synaptic proteins and reduced expression of proteins linked to inflammation, degeneration and brain injury, suggesting potential neuroprotective actions. Human studies cited in the text reported higher BDNF levels in volunteers treated with ayahuasca compared with placebo. Neuroinflammation as a disease mechanism: The review summarises literature linking chronic neuroinflammation to a range of disorders — including depression, anxiety disorders, Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischaemia and ALS — and identifies proinflammatory cytokines such as IL-1β, IL-6 and TNF-α as implicated biomarkers. The authors highlight parallel evidence that systemic inflammation and early-life infection increase the risk of later depression and that anti-inflammatory interventions (the review uses ketamine and minocycline as illustrative examples) can reduce depressive- and anxiety-like behaviours in animal models. Therapeutic applicability in animals and humans: Animal studies are presented showing biphasic, dose-dependent behavioural effects: acute anxiogenic responses in some tests but longer-term reductions in anxiety and facilitation of extinction of aversive memory in rodents; similar anxiolytic signals at low doses in zebrafish but locomotor suppression and increased anxiety measures at higher doses. β-carbolines (harmane, norharmane, harmine) reduced immobility time in the forced swim test in mice. In humans, observational studies among members of religious groups using ayahuasca reported reductions in anxiety and depression over the short term (7–14 days), with the authors noting possible confounding by the religious context. Clinical research in Brazil is described: a single dose of ayahuasca produced a significant reduction in depressive symptom severity measured by HAM-D and MADRS within hours; SPECT imaging at 8 hours post-administration showed increased cerebral blood perfusion in subgenual regions, nucleus accumbens and insula, regions relevant to depression. Non-human primate data showed reversal of depressive-like behaviour and normalisation of fecal cortisol following a single dose after eight weeks of social isolation. In a human trial of patients with treatment-resistant depression, salivary cortisol increased after ayahuasca to levels similar to healthy controls within 48 hours whereas plasma cortisol did not change; a separate randomised, double-blind, placebo-controlled clinical trial was reported to be the first to assess BDNF modulation, finding effects after ayahuasca in this population. A reported association between reduction in depressive symptoms and serum C-reactive protein (CRP) is noted, while IL-6 did not differ between depressive and control patients at baseline and did not change after ayahuasca in the cited study. Toxicity: Chronic dosing studies in animals simulating ritual exposure were summarised: dosing up to four times the usual ritual volume over 70 days produced no adverse clinical signs, while eight times the ritual volume caused stress-related behaviours and two deaths among treated animals. A separate rodent study estimated a lethal DMT dose greater than 15.1 mg/kg, equivalent to more than 50 times the usual dose; in vitro assays reportedly found no cytotoxicity of DMT. The authors interpret these findings as indicating a wide margin between typical ceremonial doses and doses producing toxicity, while noting that very high or chronic exposure can be harmful.

Goulart Da Silva and colleagues interpret the assembled evidence as indicating that ayahuasca's therapeutic effects in neuropsychiatric and neurological conditions may be mediated, at least in part, by anti-inflammatory and neuroprotective actions of its constituents, notably DMT and 5-MeO-DMT acting via serotonergic receptors and the sigma-1 receptor. They highlight concordant findings from cellular models, organoids, animal behavioural experiments and early human studies that together suggest modulation of inflammatory signalling pathways (for example NFAT and NF-κB), promotion of synaptic proteins and increases in neurotrophic support such as BDNF. The authors situate their synthesis alongside previous literature linking chronic neuroinflammation to depression, anxiety and neurodegeneration, arguing that drugs with anti-inflammatory properties may therefore have therapeutic utility across these domains. They present ayahuasca as a distinctive psychedelic that has demonstrable anti-inflammatory activity in preclinical models and some clinical signals in mood disorders. Nonetheless, the review emphasises key uncertainties acknowledged by the authors: many human studies are small, observational or subject to contextual confounding (for example ritual use), some biomarkers show inconsistent changes (IL-6 did not change in one cited study despite CRP associations), and mechanistic pathways require further elucidation. The authors call for additional controlled clinical trials and mechanistic research to confirm efficacy, clarify dose–response relationships and fully characterise the pharmacological mechanisms underlying anti-inflammatory and neuroplastic effects.

The authors conclude that available evidence supports the notion that ayahuasca may offer therapeutic benefits for disorders associated with neuroinflammatory processes, particularly anxiety and depression, and possibly cognitive disorders. They characterise the plant decoction as a promising strategy with a favourable safety margin because very high doses are required to reach toxicity, but they emphasise that further studies are needed to confirm therapeutic effects and to fully elucidate the mechanisms involved.