Redefining the real problem in psychedelic trials: Why fighting the Lessebo matters more than blinding integrity.

Imperfect blinding is a common issue in randomized trials, not just in psychedelic research, yet it is rarely assessed outside this field. In mental health, uncertainties from imperfect blinding combine with those from patient-reported outcomes, which are often viewed skeptically despite clinician-rated scales having their own limitations. Maintaining reasonable doubt about treatment allocation, not perfect blinding, supports placebo-controlled designs. Expectancy bias in psychedelic trials may lead to a 'lessebo' effect—a negative placebo effect from expecting to receive a placebo—driven by disappointment rather than pre-treatment expectation alone. The authors argue for shifting focus from preserving imperfect blinding to mitigating disappointment through structured psychoeducation, therapeutic alliance, and realistic preparation, which would improve ethical rigor and clinical usefulness.

Study at a glance

Abstract

Imperfect blinding is not specific to psychedelic trials. In randomized trials, treatment allocation is frequently correctly guessed, yet blinding integrity is rarely assessed outside of psychedelic research and is generally not considered a barrier in regulatory evaluation. The intense debate in psychedelics may reflect a broader double standard affecting mental health research, when uncertainties arising from imperfect blinding are confounded by those linked to patient-reported outcome measures. Indeed, people living with mental disorders are often viewed as unreliable reporters, despite well-documented limitations of clinician-rated scales and the absence of robust biological markers of symptomatic change. Importantly, it is the maintenance of reasonable doubt of treatment allocation that sustains internal validity and ethical feasibility of placebo-controlled designs, rather than perfect blinding. Concerns about expectancy bias in psychedelic trials are closely tied to blinding debates. When allocation is inferred, expectations may cluster in the arm perceived as active or in stereotyped experiences and influence outcomes differently in active and control arms, leading to a risk of lessebo, a negative placebo effect due to the negative expectation related to receiving a placebo. However, we argue that an underrecognized mechanism of lessebo is disappointment. This risk may reflect insufficient clinical management of disappointment rather than pre-treatment expectation alone. We therefore propose shifting the emphasis from preserving inevitably imperfect blinding towards mitigating disappointment in both arms. Establishing non-stereotyped expectations prior to treatment through structured psychoeducation, strengthened therapeutic alliance, and realistic preparation would help avoid lessebo effects. Such strategies would enhance ethical rigor, interpretability, and the clinical usefulness of psychedelic trials.