Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca

Major depressive disorder (MDD) is heterogeneous and many patients do not achieve sustained remission with standard pharmacological treatments, leaving a subset with treatment-resistant depression. Earlier research has identified raised circulating inflammatory markers in some people with depression, notably interleukin 6 (IL-6) and C-reactive protein (CRP), and has linked chronic stress, reduced brain-derived neurotrophic factor (BDNF), and inflammation to depressive pathophysiology. Findings on whether conventional antidepressants reduce inflammatory markers are inconsistent, and baseline inflammation may influence treatment effects. Classical serotonergic psychedelics have attracted renewed interest as potentially fast-acting antidepressants, and some preclinical and mechanistic work has proposed direct anti-inflammatory actions mediated via 5-HT2A and sigma-1 (σ1R) receptors. Leite Galvão‑Coelho and colleagues set out to examine whether a single dose of ayahuasca alters blood inflammatory biomarkers and whether such changes relate to antidepressant effects. Using data from a randomised, double-blind, placebo-controlled trial in adults with treatment-resistant depression and healthy controls, the investigators measured plasma CRP and serum IL-6 before treatment and 48 hours after dosing, and tested correlations with serum cortisol and BDNF as well as associations with clinical change on the Montgomery-Åsberg Depression Rating Scale (MADRS). They hypothesised that changes in inflammatory markers would correlate with symptom improvement and might predict antidepressant response or remission at 48 hours.

The study was embedded in a randomised, double-blind, placebo-controlled, parallel-arm trial of ayahuasca versus placebo conducted at the Federal University of Rio Grande do Norte (University Hospital Onofre Lopes) in Brazil. Ethical approval and trial registration were in place and all volunteers gave written informed consent. In total 73 adult, psychedelic‑naïve volunteers were enrolled: 28 patients with treatment-resistant depression (patient group, PG) and 45 healthy controls (control group, CG). Treatment resistance was defined as failure to remit after at least two antidepressants from different classes. Patients were in a current moderate-to-severe depressive episode diagnosed using the Structured Clinical Interview for DSM-IV and had baseline MADRS scores >18; MADRS was the primary clinical outcome. All patients completed a washout period adjusted to prior medication half-lives and were not taking antidepressants during the study, although benzodiazepines or hypnotics were permitted if required. Participants were randomised 1:1 to receive a single oral liquid dose of ayahuasca (1 mL/kg) or an inert placebo. A single, characterised batch of ayahuasca was used (mean concentrations reported for N,N-dimethyltryptamine, harmine, harmaline and tetrahydroharmine). Placebo was formulated to mimic some gastrointestinal effects (water, yeast, citric acid, caramel colourant, zinc sulphate). Dosing sessions lasted about six hours in a comfortable hospital room; participants remained seated with eyes closed and listened to curated playlists. No formal psychotherapeutic protocol was provided beyond brief preparation and in-session support. Blood samples were collected at 07:00 following an 8-hour fast immediately before dosing (D0) and 48 hours after dosing (D2). Measured analytes were plasma CRP (immunoturbidimetry), serum IL-6, cortisol and BDNF (enzyme-linked immunosorbent assay), and liver enzymes GOT and GPT to screen for hepatic causes of altered CRP. Laboratory assays were performed blinded to treatment allocation. Statistical analyses treated group (CG, PG), treatment (ayahuasca, placebo) and phase (D0, D2) as categorical independent factors. MADRS and biomarker levels at D0 and change scores (Δ) to D2 were treated as quantitative outcomes. Body mass index (BMI) was included as a covariate. The authors used t-tests, Chi-square, Mann–Whitney tests, general linear models (GLM) with interaction terms, Spearman correlations, multiple regression and binary logistic regression to explore prediction of response (≥50% reduction in MADRS) and remission (MADRS ≤10) at D2. Analyses were performed in IBM SPSS Statistics 25 with bootstrap enabled and significance set at p < 0.05.

Baseline characteristics and pre-treatment biomarkers: The sample comprised 28 patients (seven men, 21 women) and 45 controls (20 men, 25 women). Patients were older than controls and had higher BMI; liver enzymes (GOT, GPT) were within reference ranges and did not differ significantly between groups. A large majority of patients had comorbid personality disorder (71%) and 43% had an anxiety disorder. Adjusting for BMI, patients had higher plasma CRP than controls (F = 30.60, df = 1, p = 0.001, Cohen's d = 0.74). IL-6 levels did not differ between patients and controls (F = 0.35, p = 0.550). In patients, baseline CRP showed a significant inverse correlation with serum cortisol (rho = -0.40, p = 0.033); no correlation was found between CRP and BDNF, and IL-6 was not correlated with the other measured variables. The number of prior unsuccessful antidepressant trials did not predict baseline CRP or IL-6. Effects of ayahuasca versus placebo at 48 hours (D2): Across both patients and controls, individuals who received ayahuasca (n = 37) showed a reduction in CRP at D2 compared with D0 after adjustment for BMI, whereas placebo recipients (n = 36) did not (GLM treatment*phase interaction: F = 8.20, df = 1, p = 0.005). Post hoc testing for the ayahuasca group indicated a significant D0–D2 decrease (p-adjusted Bonferroni = 0.040, Cohen's d = -1.37), while the placebo group showed no significant change. Quantitatively, patients treated with ayahuasca had a 26.6% reduction in CRP (controls reduced 32.39%); patients on placebo had a 20.4% increase (controls on placebo reduced 2.45%). During the dosing session, 90% of patients reported nausea and 57% vomited. Relation to clinical outcome: Among patients who received ayahuasca (n = 14), greater reductions in CRP (ΔCRP) correlated with lower MADRS scores at D2 (Spearman rho = 0.57, p ≤ 0.050). In this subgroup MADRS mean decreased from 28.28 (± SEM 3.01) at D0 to 14.23 (± SEM 3.05) at D2 (t = 3.26, df = 25, p = 0.003, Cohen's d = -1.25). No such correlation was observed in placebo-treated patients. Changes in CRP were not correlated with changes in cortisol or BDNF, and neither baseline CRP nor ΔCRP (alone or combined with other variables) predicted response or remission at D2. IL-6 showed no significant main effects or interactions by group, treatment or phase (GLM p = 0.43) and ΔIL-6 did not correlate with clinical change nor predict response/remission at D2.

Leite Galvão‑Coelho and colleagues interpret their findings as evidence that people with treatment-resistant depression exhibited a low-grade inflammatory profile at baseline, reflected by higher CRP, and that a single dose of ayahuasca reduced CRP levels 48 hours later in both patients and healthy controls. They emphasise the observed negative correlation between baseline CRP and cortisol in patients, consistent with the notion that hypocortisolaemia may contribute to elevated inflammation because cortisol is an anti-inflammatory hormone. The authors highlight that, in patients, larger reductions in CRP after ayahuasca correlated with greater improvements in depressive symptoms at D2, whereas IL-6 did not change and was not associated with clinical outcomes. The discussion situates these results within inconsistent prior literature on IL-6 and CRP in depression and on inflammatory responses to antidepressant treatment. The investigators note the biological complexity of IL-6, including its pro- and anti-inflammatory roles and timing differences that could decouple IL-6 and CRP measures. Possible mechanisms for an anti-inflammatory action of ayahuasca are referenced, including 5-HT2A and σ1R-mediated effects of classical psychedelics and harmine-mediated suppression of nuclear factor-κB signalling. The authors acknowledge that pro-inflammatory biomarkers did not predict response or remission at D2 and suggest this could reflect suboptimal timing of biomarker measurements because the largest clinical effects were observed at 7 days in the parent trial while biomarker sampling was limited to D2. Key limitations noted by the investigators include the modest sample size, the single time-point blood collections (one morning draw at each phase) which may miss circadian or delayed changes, the measurement of total rather than pro- and mature BDNF isoforms, and the presence of comorbid personality and anxiety disorders in the patient sample. They recommend larger trials with sequential sampling across the day and over multiple days, and studies assessing repeated ayahuasca sessions to evaluate whether more sustained anti-inflammatory effects occur. In their interpretation the findings support ayahuasca’s concurrent antidepressant and anti-inflammatory actions and underscore the potential value of biomarkers in depression research.