Safety, tolerability and subjective effects of vaporized N,N-Dimethyltryptamine: A randomized double-blind clinical trial

Major Depressive Disorder (MDD) is a leading contributor to global disease burden and is frequently accompanied by maladaptive cognitive schemas—pessimistic beliefs about the self and future—that are thought to sustain depressive symptoms. Cognitive behavioural therapy combined with selective serotonin reuptake inhibitors (SSRIs) is a common first-line approach, and previous studies have shown that psychedelic-assisted interventions, when delivered with psychological support, can produce rapid and sustained reductions in depressive symptoms. A mechanistic hypothesis addressed in the literature is that classic psychedelics acting at the serotonin 2A receptor (5-HT2A R) may temporarily increase neural and psychological plasticity, creating a window for adaptive revision of entrenched negative cognitive biases.

Henry and colleagues conducted a two-arm, randomized controlled trial comparing psilocybin therapy with escitalopram in patients with MDD. Fifty-nine participants were randomised and matched for age, gender and education, with 30 allocated to the psilocybin arm and 29 to the escitalopram arm. Trial registration and ethics approvals were obtained and all participants provided written informed consent.

The main cognitive-bias outcomes showed divergent patterns across treatments. On the self-report Life Orientation Test–Revised (LOT-R), a time × condition interaction was reported (F(1,57)=15.89, p=0.0002); post-hoc tests indicated a large and significant increase in optimism scores in the psilocybin group at six weeks (effect size reported as d=1.1), with no change following escitalopram. The Prediction of Future Life Events (POFLE) behavioural task produced a significant main effect of time (F(1,99)=20.86, p<0.0001) but no overall condition effect. Further analyses found a time × condition interaction for forecasting of desirable events (F(1,44)=7.93, p=0.007), although there was a baseline between-group difference in forecasting of desirable events (psilocybin group more pessimistic at baseline). After adjusting for baseline scores via ANCOVA, no significant between-group difference in change was observed; nevertheless, within-condition tests showed a significant increase in optimism for desirable events after psilocybin. Conversely, escitalopram produced a within-condition improvement in pessimism for undesirable events (M diff ≈0.07, SE≈0.03, p=0.018, d≈0.5).

Henry and colleagues interpret the findings as indicating that two high-dose psilocybin sessions, delivered with psychological support, produced broader and larger reductions in negative cognitive bias than six weeks of escitalopram. Specifically, psilocybin was associated with increased self-reported optimism (LOT-R), improved forecasting for desirable future events (POFLE, within-condition), and reductions across all subscales of dysfunctional attitudes (DAS-24). Escitalopram produced improvements in depressive symptoms and in the achievement subscale of the DAS-24 and reduced pessimism for undesirable events, which the authors discuss in relation to possible SSRI-associated affective blunting. The investigators link their results to serotonergic mechanisms—particularly 5-HT2A R-mediated plasticity—and to predictive-processing frameworks that posit psychedelics reduce the precision-weighting of entrenched predictive models, thereby enabling revision of maladaptive beliefs. The discussion emphasises the role of psychological support (set and setting, therapeutic alliance, music, preparatory and integration sessions) in shaping outcomes and notes that different models of psychotherapy delivery exist in the field.

The authors conclude that psilocybin therapy produced more robust and comprehensive improvements in measures of negative cognitive bias in patients with MDD than a six-week course of escitalopram, supporting further investigation of safety and efficacy at larger scale.