The International journal on drug policyJul 8, 2026

Why Addressing Negative Expectations Matters More Than Keeping Trials Blind in Psychedelic Studies

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 9, 2026

Abstract

Imperfect blinding in randomized trials is common and may influence outcomes in mental health research.

Treatment allocation in randomized trials is often correctly guessed, questioning the reliability of blinding integrity.
Patient-reported outcomes in mental disorders may be biased due to perceptions of unreliability, despite issues with clinician-rated scales.
The maintenance of reasonable doubt about treatment allocation is crucial for preserving the validity and ethics of placebo-controlled designs.
Expectancy bias in psychedelic trials can lead to differing outcomes based on perceived allocation, increasing the risk of a negative placebo effect known as lessebo.
Disappointment, rather than just pre-treatment expectations, may contribute to the lessebo effect, suggesting it is an underrecognized mechanism.
Mitigating disappointment through structured psychoeducation and realistic preparation could enhance the ethical rigor and interpretability of psychedelic trials.

Simplified

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.

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Competing interests

Declaration of competing interest A.L., J.L.F. and T.M. have no conflict of interest. L.V. co-founded the Isala Van Diest Fund, a non-profit organisation that previously ran training workshops on psychedelic-assisted therapy for mental health clinicians in Belgium. The organisation is not currently active.

PubMed

Why Addressing Negative Expectations Matters More Than Keeping Trials Blind in Psychedelic Studies

Abstract

Full Text

Funding

Competing interests

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