Unblinding and demand characteristics in the treatment of depression.
Guy M. Goodwin, Megan Croal, Lindsey Marwood, Ekaterina Malievskaia
Journal of Affective Disorders May 1, 2023 DOI: 10.1016/j.jad.2023.02.030 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Randomized Peer reviewed |
|---|---|
| Topics | Depression Psilocybin |
| Keywords | Demand characteristics Unblinding Clinical-trials blinding Masking Placebo-control Antidepressants ssris Depression-medication Mood-medicine Psychedelics psilocybin Magic-mushrooms Hallu |
| Citations | 13 |
| Key points | Argues that unblinding is not the principal mechanism driving outcomes in antidepressant RCTs, and that for psychedelic therapy unblinding is inherent to the treatment's mechanism of action and does not necessarily invalidate efficacy. |
Abstract
Blinding of treatment allocation in clinical trials in psychiatry is regarded as an ideal. The potential impact of unblinding chimes with a general concern for psychological research: so-called demand characteristics can undermine confidence in findings from experimental and clinical studies. Scepticism can result in nihilism. The reliance on subjective report of symptoms in clinical trials of drug efficacy in depression provides an important example. It is regularly implied that if subjective effects, including specific adverse reactions, unblind participants to an active treatment then evidence for its efficacy is suspect. In fact, the strong association between dose and subjective effects does not translate into a strong relationship with efficacy in randomised controlled trials (RCTs) of conventional antidepressant drugs; this observation falsifies the proposition that unblinding is the principal mechanism driving RCT outcomes in studies of depression. Instead, changes in brain function, that occur soon after treatment starts, do predict treatment outcomes and align with our understanding of neurotransmitter effects from neuroscience. Psychedelic experience for the treatment of depression must be unblinding, but the effect results directly from serotonergic receptor activation and changes in brain connectivity. Where such effects are part of a novel mechanism of action, a strong dose response relationship would be expected, irrespective of unblinding. We highlight the importance of exploring blinding as a mechanism, confirming dose-related outcomes, and dissociating unblinding effects from efficacy. Unblinding does not necessarily invalidate the subjective experience of sustained recovery from depression.
Comparable studies
Other theoretical and historical papers on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin-assisted therapy of major depressive disorder using Acceptance and Commitment Therapy as a therapeutic frame | 2020 | Theoretical or philosophical paper | |
| The Yale Manual for Psilocybin-Assisted Therapy of Depression (using Acceptance and Commitment Therapy as a Therapeutic Frame) | 2020 | Theoretical or philosophical paper | |
| Psilocybin-Assisted Compassion Focused Therapy for Depression | 2022 | Theoretical or philosophical paper | |
| Psychedelic-assisted psychotherapy for the treatment of major depression: a synthesis of phenomenological explanations. | 2022 | Theoretical or philosophical paper | |
| Psilocybin as a Novel Pharmacotherapy for Treatment-Refractory Anorexia Nervosa | 2021 | Theoretical or philosophical paper |
Citations in the library
Cited by 8
- Reduced Brain Responsiveness to Emotional Stimuli With Escitalopram But Not Psilocybin Therapy for Depression American Journal of Psychiatry May 7, 2025
- Is the psychedelic experience an essential aspect of the therapeutic effect of serotonergic psychedelics? Conceptual, discovery, development and implementation implications for psilocybin and related agents Expert Opinion on Drug Safety August 28, 2023
- Psychedelics and connectedness to natural and social worlds: An examination of the evidence and a proposed conceptual framework. Current Opinion in Psychology April 1, 2025
- Psychedelics, entactogens and psychoplastogens for depression and related disorders British Journal of Pharmacology June 15, 2025
- MDMA for PTSD and beyond: a new paradigm brings hope. Frontiers in Human Neuroscience December 11, 2024
and 3 more in the library
Cites 16
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 11 more in the library