Ayahuasca Improves Self-perception of Speech Performance in Subjects With Social Anxiety Disorder: A Pilot, Proof-of-Concept, Randomized, Placebo-Controlled Trial

Social anxiety disorder (SAD) is a common and disabling condition characterised by avoidance, fear in social situations and autonomic symptoms; performance-only SAD (for example, public speaking) is frequent. Existing treatments—cognitive behavioural therapy and first-line antidepressant medications—have limitations: delayed onset, incomplete response for many patients, adverse effects, and a substantial relapse rate after discontinuation. Neurobiological studies implicate prefrontal, limbic and paralimbic circuitry and altered self-referential processing in SAD, and a negative self-focused cognitive bias is central to the disorder. Ayahuasca is a traditional Amazonian hallucinogen containing DMT plus β-carbolines that inhibit MAO-A and permit oral DMT activity. Prior preclinical, observational and small clinical studies indicate anxiolytic and antidepressant effects of ayahuasca and other classic serotonergic hallucinogens; the authors’ group has reported rapid antidepressant effects in treatment-resistant depression after a single ayahuasca dose. Anecdotal reports also suggest enhanced performance (speech, singing, music) after ayahuasca. Dos Santos and colleagues therefore designed a randomised, double-blind, placebo-controlled, single-dose pilot trial in volunteers with SAD to test whether ayahuasca would improve self-perception of public-speaking performance (primary outcome) and reduce subjective anxiety during a simulated public-speaking test, with additional assessments of subjective effects, facial emotion recognition, tolerability and plasma brain-derived neurotrophic factor (BDNF).

The trial used a randomised, double-blind, placebo-controlled, parallel-group design conducted from September 2015 to July 2019. Undergraduate students at the University of São Paulo were screened with the Social Phobia Inventory (SPIN) and those meeting cutoff (≥19) or reporting excessive social fear were interviewed with the SCID-5-CV for diagnostic confirmation. Inclusion criteria required an SAD diagnosis, age 18–65 years, no prior ayahuasca use and ≤2 lifetime uses of other hallucinogens; key exclusions included current treatment for SAD, major medical or other psychiatric disorders (except comorbid anxiety disorders), use of psychoactive medications, recurrent illicit drug use and pregnancy/lactation. From 894 screened, 17 volunteers (15 women) met criteria and were randomised: 9 to ayahuasca and 8 to placebo. All 17 completed the experimental session and three follow-ups (7, 14, 21 days), but equipment problems meant some outcome analyses used 14 participants (7 per group). Interventions consisted of a single oral dose of either ayahuasca or placebo, both at 2 mL/kg. The ayahuasca batch (prepared by a Santo Daime church) was administered from refrigerated storage; alkaloid concentrations were periodically measured by ultraperformance liquid chromatography–mass spectrometry and showed reductions over the 46-month trial. Placebo was formulated to mimic organoleptic properties (mineral water, glycerin, propylene glycol, methylparaben) and both liquids were administered in opaque bottles with procedures to limit olfactory identification. The experimental session included 11 assessment time points from baseline to 355 minutes: the psychoactive phase covered baseline to 240 minutes, then at 300–355 minutes participants performed a simulated public-speaking test (SPST) comprising anticipatory, preparation and speech phases. Follow-up visits occurred at days 7, 14 and 21. Primary and secondary measures included the State version of the Self-statements During Public Speaking Scale (SSPS) applied during the SPST (primary), the Visual Analog Mood Scale (VAMS) collected across all 11 time points (grouped into anxiety, sedation, cognitive impairment, discomfort factors), the Bodily Symptoms Scale (BSS), Beck Anxiety Inventory (BAI; baseline, 240 minutes and follow-ups), a computerized Recognition of Emotions in Facial Expressions (REFE) task (baseline, 90, 240 minutes and follow-ups), and cardiovascular measures (heart rate, blood pressure). Subjective spontaneous reports and observer impressions were also recorded. Blinding efficacy was assessed by asking participants and the three session researchers which substance they believed had been administered. Statistical analysis used two-way repeated-measures ANOVA with time (within-subject) and group (between-subject) factors, Bonferroni correction for pairwise comparisons, significance at P < 0.05 and effect size reported as η2. No formal sample size calculation was performed because this was a pilot feasibility study.

Feasibility and adherence were high: all 17 randomised volunteers completed the session and the three follow-ups, and no serious adverse events or dropouts occurred. Due to equipment issues, primary and most secondary analyses were conducted on 14 participants (7 per group). Primary outcome (SSPS): Analyses showed a significant between-group effect favouring ayahuasca: F1,12 = 7.740, P = 0.017, η2 = 0.392. The ayahuasca group exhibited progressive increases in positive self-statements across the SPST phases, with significant differences at anticipatory speech (P = 0.049), speech performance (P = 0.013), end of speech (P = 0.016) and postspeech (P = 0.008). Subjective mood and anxiety (VAMS and BAI): The VAMS anxiety factor showed a significant effect of time (F5.243, 62.916 = 3.848, P = 0.004, η2 = 0.243), with anxiety increasing during the early SPST phases, but no significant time×group interaction or between-group differences. A significant time×group interaction was observed for the cognitive deterioration VAMS factor (F3.152, 37.823 = 4.422, P = 0.008, η2 = 0.269), although pairwise group differences were not significant. Sedation showed a time effect (F3.650, 43.806 = 6.776, P < 0.001, η2 = 0.361); discomfort did not change. The BAI (the only measure with data for all 17 participants) showed no significant effects of time, group or interaction. Bodily Symptoms Scale (BSS): Significant effects of time (F3.551, 42.611 = 3.293, P = 0.023, η2 = 0.215), group (F1.12, 42.611 = 7.507, P = 0.018, η2 = 0.385) and time×group interaction (F3.551, 42.611 = 2.938, P = 0.036, η2 = 0.197) were reported. Compared with placebo, ayahuasca increased somatic symptoms at 90 minutes (P = 0.036) and 120 minutes (P = 0.041), with near-significant increases at 40 minutes (P = 0.05) and 180 minutes (P = 0.052). Recognition of emotions in facial expressions (REFE): There were significant effects of time for overall accuracy (F5, 60 = 4.650, P = 0.001, η2 = 0.279) and reaction time (F2.858, 34.293 = 7.843, P = 0.003, η2 = 0.327), and emotion-specific time effects (for sadness accuracy and reaction-time changes for fear, disgust and anger). However, no significant time×group interactions or between-group differences were found; the authors note that all significant time effects were observed within the ayahuasca group. BDNF and other measures: Plasma BDNF showed no significant changes, but only a few valid samples were available and results were presented descriptively. Observer impressions and spontaneous reports indicated mainly mild-to-moderate psychedelic effects in the ayahuasca group; some volunteers reported calmness or reduced anxiety in the week after the session. Tolerability and cardiovascular effects: Ayahuasca-associated adverse effects included gastrointestinal discomfort and nausea (n = 4), vomiting (n = 3), drowsiness (n = 2), transient confusion (n = 2), headache (n = 2), diarrhea, fear/distress and one transient dissociative/depersonalisation episode that resolved with researcher support. Heart rate showed a significant effect of time during the session (F10, 12 = 15.49, P < 0.01, η2 = 0.563) but no group differences; systolic and diastolic blood pressures showed significant time×group interactions but no between-group differences. Transient moderate hypertension and episodes of tachycardia occurred in both groups. No serious cardiovascular events were reported. Blinding efficacy: Blinding failed in this trial—participants and the session researchers correctly guessed the administered substance in 100% of sessions.

Dos Santos and colleagues report that a single ayahuasca dose was feasibly administered in this pilot randomised trial and that the primary hypothesis was supported: compared with placebo, ayahuasca significantly improved self-perception of speech performance on the SSPS across most SPST phases. The authors emphasise that this procognitive effect on self-perception occurred independently of measurable reductions in task-related anxiety on standard scales, although some participants reported subjective calmness and reduced anxiety in follow-up. The authors note that baseline anxiety in the sample was generally mild (mean BAI ~9.8), which may have limited detection of anxiolytic effects on the scales. Regarding social cognition, ayahuasca did not produce significant between-group changes in the REFE task despite time-related improvements in accuracy and reaction time that were observed only in the ayahuasca group; the authors suggest these could reflect learning effects or increased sensitivity to emotional faces, but the small sample size, task ceiling/learning effects and the predominantly female, highly educated sample may have influenced results. No significant BDNF effects were observed, but data were sparse. Safety findings replicated earlier work: the most common adverse effects were transient gastrointestinal and mild cognitive/perceptual symptoms, and one brief challenging episode was managed without pharmacological intervention. The authors regard the tolerability as acceptable for a single dose in this controlled setting. The discussion highlights several limitations acknowledged by the investigators: significant degradation of ayahuasca alkaloids over the prolonged storage period (with DMT declining from 1.53 mg/mL to 0.23 mg/mL over 46 months), use of comparatively low DMT concentrations, failure of blinding (participants and staff guessed drug assignment perfectly), small sample size, reliance on self-report measures for speech performance and an unrepresentative sample (mostly female undergraduate students). These constraints reduce generalisability and may have attenuated some effects. The authors recommend systematic dose–response studies, better storage and periodic chemical verification of ayahuasca, improved blinding strategies (including consideration of active psychoactive placebos), more objective and ecological outcome measures, and trials in clinical SAD populations with varied severity and with repeated dosing and neuroimaging to clarify mechanisms. Overall, they interpret the findings as preliminary evidence that ayahuasca can specifically improve cognitive self-perception of performance in people with SAD and propose further research to explore therapeutic applications and mechanisms.

Compared with placebo, a single ayahuasca dose significantly improved self-perception of speech performance in volunteers with SAD, indicating a potential procognitive effect relevant to a core feature of the disorder—a negative self-perception. The authors conclude that ayahuasca merits further exploration as an adjunct or novel intervention to enhance self-confidence in performance contexts (for example, art therapy or as an exposure-like technique within CBT), while emphasising the need for larger, better-controlled trials to confirm efficacy, clarify mechanisms and address methodological limitations.