This paper describes the protocol for the Ayahuasca Treatment Outcome Project (ATOP), which evaluates addiction treatment services at the Takiwasi Center in the Peruvian Amazon. The project aims to assess outcomes and understand therapeutic mechanisms of an ayahuasca-assisted, integrative treatment model for addiction rehabilitation. The protocol emphasizes the importance of treatment setting in designing and delivering a program involving the psychedelic tea ayahuasca. A mixed-methods approach to data collection and analysis is used to understand why, how, and for whom the treatment is effective across various outcomes.
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.