Changes in anxiety, quality of life, and functioning following psilocybin-assisted therapy in veterans with treatment-resistant depression

The primary analysis included 15 participants, and 10 entered long-term follow-up. Most were male (87%) and White, non-Hispanic (67%), with a mean age of 43.2 years. Comorbid PTSD was common (73%, n=11), and 20% reported prior psychedelic use. Baseline mean scores were 15.7 on the GAD-7, 40.4 on the Q-LES-Q-SF, 25.9 on the WSAS, and 42.0 on the PCL-5. Anxiety improved substantially. GAD-7 scores were lower than baseline at all follow-up points, with mean changes of -9.6 at Week 3, -8.0 at Week 12, -8.6 at Month 6, -11.0 at Month 9, and -8.0 at Month 12. The adjusted model showed a significant time effect, and all post-baseline differences from baseline were statistically significant. Effect sizes were large across follow-up, and the paper reports a 59% reduction at Week 3. Quality of life also improved, with Q-LES-Q-SF scores above baseline at all follow-up time points. Mean change was +10.5 at Week 3 and +11.1 at Week 12, then smaller improvements later. The overall time effect was significant, and baseline differences were significant at Week 3 and Week 12, but not at later time points. In the subset entering long-term follow-up, the overall time effect was no longer significant, although Week 3 and Week 12 remained significantly higher than baseline. Functional impairment on the WSAS decreased at all follow-up points, with mean changes of -12.2 at Week 3, -15.7 at Week 12, -11.1 at Month 6, -8.2 at Month 9, and -10.3 at Month 12. The time effect was significant, and baseline differences were significant at Week 3, Week 12, and Month 6, but not at Months 9 or 12. The authors report large effect sizes and a 46% reduction at Week 3. PTSD symptom scores on the PCL-5 were reported descriptively because of missing data and the smaller subset available. Scores fell from a baseline mean of 42.0 to 13.0 at Week 1 and 11.6 at Week 6, then to 19.6 at Week 12, 20.2 at Month 6, 24.2 at Month 9, and 33.2 at Month 12. The corresponding changes were described as 61% and 75% reductions at Weeks 1 and 6, 56% at Week 12, 55% at Month 6, 53% at Month 9, and 30% at Month 12. Effect sizes were large early on and declined over time. In robustness analyses that adjusted for concurrent change in MADRS, change in depression severity was independently associated with all three primary exploratory outcomes, and no post-baseline time point remained significant for any outcome after this adjustment. The authors describe this as indicating that a substantial part of the observed improvement overlapped with improvement in depression. Correlational analyses between acute subjective experience measures and change in MADRS were inconclusive: some emotional breakthrough correlations were moderately positive, but none were statistically significant after Bonferroni correction, and the CEQ and MEQ-30 correlations were generally small to moderate and non-significant.

Kelly and colleagues interpret the findings as preliminary evidence that a single psilocybin dose with psychological support may improve anxiety, quality of life, functioning, and PTSD symptoms in veterans with treatment-resistant depression. They emphasise that anxiety showed the most sustained improvement over 12 months, whereas quality of life and functioning improved earlier but were less durable. PTSD symptom reductions were also described as encouraging, though these were based on a smaller subset of participants. The authors compare these results with earlier psilocybin studies in depression and suggest that the anxiety findings are consistent with prior reports of improvement alongside reductions in depressive symptoms. They also note that quality-of-life gains echo earlier suggestions that psychedelic-assisted therapy may affect well-being and function, not just core mood symptoms. At the same time, they argue that the robustness analyses indicate much of the change in anxiety, quality of life, and functioning was tied to concurrent reductions in depression rather than clearly independent effects. They frame this as compatible with broader internalising symptom patterns, in which depression, anxiety, and impairment often move together. The paper also discusses acute psychedelic experience measures. Although some correlations, especially for emotional breakthrough, were moderate in size, none were statistically significant after correction, so the authors conclude that the role of acute subjective experience remains uncertain rather than absent. They suggest other mechanisms such as behavioural activation, cognitive flexibility, and integration-related processes may contribute, but these were not directly tested. The main limitations highlighted are the very small sample, the open-label design, the lack of a control group, possible expectancy effects, and the fact that the sample was recruited for treatment-resistant depression rather than PTSD or anxiety. The authors also note that integration sessions during the main study period may have contributed to early improvements, that long-term follow-up was optional and incomplete, and that PTSD data were missing for some participants because the measure was added later. They caution that the study is hypothesis-generating and call for adequately powered randomised controlled trials, with attention to implementation and feasibility in Veterans Affairs healthcare settings.

The authors conclude that psilocybin with psychological support provides preliminary evidence of benefit for anxiety, quality of life, and functioning in veterans with treatment-resistant depression, with the strongest and most sustained signal seen for anxiety. They also state that these effects appear to be largely associated with concurrent improvement in depression, and that the PTSD findings are promising but need replication in larger, better-powered studies.