medRxiv Preprint Server
December 5, 2025
Gabriel Loewinger, Mats J. Stensrud, Sandeep M. Nayak et al.
preprint
Functional unmasking (unblinding) in clinical trials for mental health treatments, especially with psychedelics, can bias results because participants often know they received the active drug due to its unmistakable acute effects. This undermines confidence that outcomes reflect true therapeutic properties rather than placebo-like effects. A counterfactual conceptualization formalizes the shortcomings of existing solutions like dose-response and active controls, and shows how modern causal inference approaches can isolate effects free of this contamination. Feedback mechanisms between perceived benefits and expectancies can make traditional methods obscure or exaggerate therapeutic benefits. The proposal motivates trial designs and statistical methods to mitigate the impacts of functional unmasking.
medRxiv
August 16, 2025
S. Parker Singleton, Brooke L. Sevchik, Analiese Lahey et al.
preprint
Psilocybin-assisted therapy produces substantial reductions in depressive symptoms compared to control conditions, according to a systematic review and meta-analysis of 12 randomized controlled trials with 711 participants. The pooled effect size was large (Hedges' g = –0.91), and effects appeared rapidly and remained consistent over several weeks. However, many studies had small sample sizes or risk of bias, and waitlist-controlled or crossover designs contributed heterogeneity. The review provides a living open data resource that will be updated as new evidence emerges.
Drug and Alcohol Dependence
July 1, 2024
Alan K. Davis, Adam W. Levin, Rafael Lancelotta et al.
No Summary
October 14, 2023
David S. Mathai, Daniel E. Roberts, Sandeep M. Nayak et al.
preprint
A longitudinal study of 679 adults planning to use psilocybin in naturalistic settings found that while most users (89.7%) described the experience as positive, acute feelings of shame or guilt were commonly reported (68.2% of users) and difficult to predict. The ability to constructively work through these feelings predicted wellbeing 2-4 weeks after use. Psilocybin produced a small but significant average decrease in trait shame that lasted 2-3 months, but trait shame increased in a notable minority (29.8%) of participants. The activation of shame-related experiences with psychedelics may pose a unique learning condition for both therapeutic and detrimental forms of memory reconsolidation.