Expectancy in placebo-controlled trials of psychedelics: if so, so what?
Open accessAbstract
Modern psychedelic research remains in an early phase, and the eventual introduction of psychedelics into clinical practice remains in doubt. In this piece, we discuss the role of blinding and expectancy in psychedelic trials, and place this in a broader historical and contemporary context of blinding in trials across the rest of healthcare. We suggest that premature and uncritical promotion (‘hype’) of psychedelics as medicines is not only misleading, but also directly influences participant expectancy in ongoing psychedelic trials. We argue that although psychedelic trials are likely to significantly overestimate treatment effects by design due to unblinding and expectancy effects, this is not a unique situation. Placebo-controlled RCTs are not a perfect fit for all therapeutics, and problems in blinding should not automatically disqualify medications from licencing decisions. We suggest that simple practical measures may be (and indeed already are) taken in psychedelic trials to partially mitigate the effects of expectancy and unblinding, such as independent raters and active placebos. We briefly suggest other alternative trial methodologies which could be used to bolster RCT results, such as naturalistic studies. We conclude that the results of contemporary placebo-controlled RCTs of psychedelics should neither be dismissed due to imperfections in design, nor should early data be taken as firm evidence of effectiveness.
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Both fields of psychedelics and meditation are marked by strong bias effects, so reported beneficial effects can be overestimated.
“Both fields of psychedelics and meditation are marked by strong bias effects [119, 120], so reported in studies beneficial effects can be overestimated.”
From Mindfulness meditation and psychedelics: potential synergies and commonalities (2023) · cites this paper as [119]
The Introduction and “Blinding and expectancy” sections describe how difficulty blinding psychedelic trials and participants’ positive expectations can complicate estimates of benefit. The cited paper does not address meditation, so it supports the psychedelic portion of the jointly cited claim but not the statement about both fields. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe potential confounding effect of high positive expectancy has been seen in previous studies of PAT.
“The potential confounding effect of high positive expectancy has been seen in previous studies of PAT [58,59].”
From Psilocybin‐assisted psychotherapy for methamphetamine use disorder: A pilot open‐label safety and feasibility study. (2025) · cites this paper as [59]
In “Blinding and expectancy” (page unavailable), the paper says positive expectancy could affect outcomes and cites a microdosing trial in which expectation predicted well-being. But it also says this phenomenon has not been explored in detail in modern psychedelic clinical trials, so the claim overstates what previous psychedelic-assisted therapy studies have shown. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
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Background
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“also be approached by incorporating complementary evaluation methodologies, without compromising our epistemic standards (Butler et al., 2022).”
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“This is consistent with approaches taken in other fields of medicine, such as surgery, where experimental treatment is usually offered as an extension of existing care (Butler et al., 2022).”
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“…trials across fields, but are particularly pronounced in psychedelic research due to the prevailing ‘hype’ around these treatments, and the strong effect of expectations observed particularly in responses to psychedelics (Aday et al., 2022; Butler et al., 2022; Muthukumaraswamy et al., 2021).”
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“This expectancy effect not only represents a significant methodological challenge for clinical research 51,52 , it can also inflate patients’ expectations.”
BackgroundMechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics
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“An interesting approach is the administration of psychedelics in combination with an antagonist such as ketanserin or alternatively an anesthetic to examine whether the therapeutic effects are truly dependent on the subjective experience [263, 264, 269].”
Depression and anxiety in glioma patients
van der Meer, P. B., Dirven, L., Hertler, C., Boele, F. W., Batalla, A., Walbert, T., Rooney, A. G., & Koekkoek, J. A. F. (2023) · Neuro-Oncology Practice · doi:10.1093/nop/npad019 · Cited by 51 · see citing works
Borkel, L. F., Rojas‐Hernández, J., Henríquez‐Hernández, L. A., Santana, Á., & Hernández, D. J. Q. (2023) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2023.2295997 · Cited by 47 · see citing works
Mindfulness meditation and psychedelics: potential synergies and commonalities
Holas, P., & Kamińska, J. (2023) · Pharmacological Reports · doi:10.1007/s43440-023-00551-8 · Cited by 43 · see citing works
“For example, the uncritical promotion of psychedelics as a strong medicine directly affects participant expectancy in ongoing psychedelic trials [121].”
BackgroundThe need for establishing best practices and gold standards in psychedelic medicine
Feduccia, A. A., Agin-Liebes, G., Price, C. M., Grinsell, N., Paradise, S., & Rabin, D. M. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.03.083 · Cited by 43 · see citing works
Psychedelics for treatment resistant depression: are they game changers?
Kalfas, M., Taylor, R. H., Tsapekos, D., & Young, A. H. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2281582 · Cited by 37 · see citing works
“Failure of blinding could lead to expectancy bias [123,124].”
BackgroundPsilocybin and Other Classic Psychedelics in Depression
Nutt, D., Peill, J. M., Weiss, B., Godfrey, K., Carhart-Harris, R. L., & Erritzøe, D. (2023) · Current topics in behavioral neurosciences · doi:10.1007/7854_2023_451 · Cited by 37 · see citing works
Beyond the psychedelic hype: Exploring the persistence of the neoliberal paradigm
Davies, J., Pace, B. A., & Devenot, N. (2023) · Journal of Psychedelic Studies · doi:10.1556/2054.2023.00273 · Cited by 33 · see citing works
McIntyre, R. S., Kwan, A. T. H., Mansur, R. B., Oliveira-Maia, A. J., Teopiz, K. M., Maletic, V., Suppes, T. M., Stahl, S. M., & Rosenblat, J. D. (2025) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20230902 · Cited by 32 · see citing works
The crosstalk between 5-HT2AR and mGluR2 in schizophrenia
Saha, S., & González‐Maeso, J. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109489 · Cited by 30 · see citing works
(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders
Shafique, H. S., Demers, J. C., Biesiada, J., Golani, L. K., Cerne, R., Smith, J. L., Szostak, M., & Witkin, J. M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126804 · Cited by 31 · see citing works
“New data on this topic, including that on ( R )-ketamine, have recently been reported [101–104].”
BackgroundOptimizing outcomes in psilocybin therapy: Considerations in participant evaluation and preparation
Modlin, N. L., Miller, T. M., Rucker, J., Kirlić, N., Lennard-Jones, M., Schlosser, D. A., & Aaronson, S. T. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.01.077 · Cited by 28 · see citing works
Self-citationThe therapeutic potential of psychedelics: the European regulatory perspective
Butlen‐Ducuing, F., McCulloch, D. E.-W., Haberkamp, M., Mattila, T. K., Bałkowiec-Iskra, E., Aislaitner, G., Balabanov, P., Lundberg, J., Stenbæk, D. S., Elferink, A. J. A., et al. (2023) · The Lancet · doi:10.1016/s0140-6736(23)00264-7 · Cited by 29 · see citing works
Buot, A., Pallares, C., Oganesyan, A., Dauré, C., Bonnelle, V., Burguière, E., Dos Santos, J. F. A., N’Diaye, K., Ljuslin, M., Smith, P., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-39812-0 · Cited by 28 · see citing works
“Also placebo or expectation effects, which are important confounding factors in psychedelic assisted psychotherapy 14 , were not assessed.”
BackgroundRandomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed PatientsPreprint
Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., & Heifets, B. D. (2023) · medRxiv · doi:10.1101/2023.04.28.23289210 · Cited by 26 · see citing works
Wall, M. B., Demetriou, L., Giribaldi, B., Roseman, L., Ertl, N., Erritzøe, D., Nutt, D. J., & Carhart-Harris, R. L. (2025) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20230751 · Cited by 26 · see citing works
Psychedelics for the Treatment of Obsessive–Compulsive Disorder: Efficacy and Proposed Mechanisms
Collins, H. M. (2024) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyae057 · Cited by 26 · see citing works
Gattuso, J. J., Wilson, C., Hannan, A. J., & Renoir, T. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.16017 · Cited by 23 · see citing works
“…also applies to drug-naïve individuals, who know that psilocybin is capable of producing hallucinations and are thus more likely to identify if they have received placebo or psilocybin based on whether they are experiencing an alteration in consciousness (Aday et al., 2022; Butler et al., 2022).”
Soliman, P., Curley, D. E., Capone, C., Eaton, E. M., & Haass‐Koffler, C. L. (2024) · Psychopharmacology · doi:10.1007/s00213-024-06598-6 · Cited by 24 · see citing works
“Specifically, positive expectancy confounds may work synergistically with the psychedelic agent to produce clinical outcomes (Butler et al. 2022).”
Williams, Z. J., Barnett, H., & Szigeti, B. (2026) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2025.4809 · Cited by 22 · see citing works
Yong, A. S. J., Bratuskins, S., Sultani, M. S., Blakeley, B., Davey, C. G., & Bell, J. S. (2025) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/00048674251315642 · Cited by 21 · see citing works
“The challenge in blinding is not unique to MDMA and is commonly raised in other drugs with psychoactive properties, such as ketamine, benzodiazepines, gabapentinoids, opiates and stimulants (Butler et al., 2022).”
Psychedelic medicines for end-of-life care: Pipeline clinical trial review 2022
Jing, X., Hoeh, N. R., & Menkes, D. B. (2023) · Palliative & Supportive Care · doi:10.1017/s147895152300069x · Cited by 17 · see citing works
“Concerns have thus been raised about the possible overestimation of treatment effects in psychedelic studies (Butler et al. 2022;Muthukumaraswamy et al. 2021).”
BackgroundModlin, N. L., Creed, M., Sarang, M., Maggio, C., Rucker, J., & Williamson, V. (2024) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s432537 · Cited by 19 · see citing works
“In this context, some have advocated for CBT to be considered the “default” model in PT, 131 while others have highlighted the utility of the common factors theory of psychotherapy, 74 psychoanalytic psychology 132 and non-specific psychological support.”
BackgroundInfluentialSelf-citationThe development of psilocybin therapy for treatment-resistant depression: an update
Borissova, A., & Rucker, J. (2023) · BJPsych Bulletin · doi:10.1192/bjb.2023.25 · Cited by 18 · see citing works
Self-citationSex-specific role of the 5-HT2A receptor in psilocybin-induced extinction of opioid reward
Jaster, A. M., Hadlock, T. M., Buzzi, B., Maltman, J. L., Silva, G. M., Saha, S., Köşeli, E., Pondelick, A. M., Thakur, N., Zhang, X., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64887-w · Cited by 19 · see citing works
Berkovitch, L., Fauvel, B., Preller, K. H., & Gaillard, R. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106239 · Cited by 14 · see citing works
Examining the Psychoactive Differences between Kratom Strains
Huisman, G., Menke, M., Grundmann, O., Schreiber, R., & Mason, N. L. (2023) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph20146425 · Cited by 15 · see citing works
Muthukumaraswamy, S. D. (2023) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2023.2279736 · Cited by 15 · see citing works
“’ Butler et al. [45] argue that ‘Placebo-controlled RCTs are not a perfect fit for all therapeutics, and problems in blinding should not automatically disqualify medications from licensing decisions.’”
BackgroundPsilocybin for Depression: From Credibility to Feasibility, What’s Missing?
Munafò, A., Arillotta, D., Mannaioni, G., Schifano, F., Bernardini, R., & Cantarella, G. (2022) · Pharmaceuticals · doi:10.3390/ph16010068 · Cited by 15 · see citing works
Butlen‐Ducuing, F., Haberkamp, M., Aislaitner, G., Bałkowiec-Iskra, E., Mattila, T. K., Doucet, M. V., Kollb-Sielecka, M., Balabanov, P., Leuchs, A., & Elferink, A. J. A. (2023) · European Psychiatry · doi:10.1192/j.eurpsy.2023.2479 · Cited by 14 · see citing works
“It is acknowledged that the clinical development of psychedelic agents presents several challenges, such as use of placebo, and risk of unblinding, choice of comparator, expectancy bias, dosing, safety, maintenance of effect, and role of associated psychotherapy or psychological support [10, 11].”
BackgroundUsing Cannabis and CBD to Sleep: An Updated Review
Lavender, I., Garden, G., Grunstein, R. R., Yee, B. J., & Hoyos, C. M. (2024) · Current Psychiatry Reports · doi:10.1007/s11920-024-01564-7 · Cited by 16 · see citing works
“…factors (i.e., pre-existing medical conditions, treatment or drugs which may impact sleep quality and outcomes) and addressed expectancy and blinding issues when examining psychoactive cannabinoids such as THC and CBN (long acknowledged as an issue in psychoactive and hypnotic drug trials [68–70]).”
Unblinding and demand characteristics in the treatment of depression
Goodwin, G. M., Croal, M., Marwood, L., & Malievskaia, E. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.02.030 · Cited by 13 · see citing works
Rucker, J., Butler, M., Hambleton, S., Bird, C., Seynaeve, M., Cheema, S., Campbell‐Coker, K., Maggio, C., Dunbar, F., Lambru, G., et al. (2024) · Headache The Journal of Head and Face Pain · doi:10.1111/head.14837 · Cited by 13 · see citing works
Self-citationPsychedelic Therapy: A Primer for Primary Care Clinicians—Historical Perspective and Overview
Tabaac, B. J., Shinozuka, K., Arenas, A., Beutler, B. D., Cherian, K. N., Evans, V. D., Fasano, C., & Muir, O. S. (2024) · American Journal of Therapeutics · doi:10.1097/mjt.0000000000001727 · Cited by 12 · see citing works
“69 The mechanisms underlying psychedelic therapies also remain poorly understood, raising concerns about possible unforeseen long-term adverse effects.”
BackgroundEthical Aspects of Psychedelic-Assisted Treatments: An Overview
Poppe, C. J., & Repantis, D. (2024) · Current topics in behavioral neurosciences · doi:10.1007/7854_2024_533 · Cited by 11 · see citing works
Petridis, P. D., Grinband, J., Agin-Liebes, G., Kinslow, C. J., Zeifman, R. J., Bogenschutz, M. P., Griffiths, R. R., & Ross, S. (2024) · Nature Mental Health · doi:10.1038/s44220-024-00331-0 · Cited by 10 · see citing works
Modern pharmacotherapy guidance for treating alcohol use disorders
Soyka, M., & Rösner, S. (2024) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2024.2445734 · Cited by 10 · see citing works
“Apart from apparent risks associated with the use of psychedelics in RCTs from a methodological point, challenges related to blinding and expectancy effects of patients persist [93].”
Yaden, D. B., Graziosi, M., Owen, A. M., Agin-Liebes, G., Aaronson, S. T., Allen, K. E., Barrett, F. S., Bogenschutz, M. P., Carhart-Harris, R. L., Ching, T. H. W., et al. (2025) · Psychedelic Medicine · doi:10.1089/psymed.2024.0019 · Cited by 11 · see citing works
“91 The contribution of expectancy effects may work synergistically with genuine psychedelic-induced subjective effects and therapeutic mechanisms to potentiate greater change.”
Colosimo, F. A., Borsellino, P., Krider, R. I., Márquez, R., & Vida, T. A. (2024) · Psychoactives · doi:10.3390/psychoactives3010007 · Cited by 9 · see citing works
“Newer trials have used independent raters and active placebos to partially account for participant expectancy and de-blinding [182].”
BackgroundButler, M., Bird, C., Maggio, C., Durden, A., Modlin, N. L., Campbell‐Coker, K., Edwards, M. J., Pick, S., Millman, L. S. M., Lowery, E., et al. (2024) · Wellcome Open Research · doi:10.12688/wellcomeopenres.22543.1 · Cited by 8 · see citing works
Self-citationEvidence versus expectancy: the development of psilocybin therapy
Rucker, J. (2023) · BJPsych Bulletin · doi:10.1192/bjb.2023.28 · Cited by 9 · see citing works
Self-citationKnock, E., Siefried, K. J., Bedi, G., Albert, S., Day, R. O., Ezard, N., Ross, M., Liknaitzky, P., & Brett, J. (2025) · Addiction · doi:10.1111/add.70187 · Cited by 9 · see citing works
Psychedelika und Dissoziativa in der Psychiatrie: Herausforderungen in der Behandlung
Jungwirth, J., Bavato, F., & Quednow, B. B. (2024) · Der Nervenarzt · doi:10.1007/s00115-024-01727-0 · Cited by 7 · see citing works
Wahba, M., Hayes, C., Kletter, M., & McAllister-Williams, H. (2024) · BJPsych Open · doi:10.1192/bjo.2024.768 · Cited by 7 · see citing works
Calnan, M., Blest‐Hopley, G., Busch, C., Adams, M., Ruffell, S., Piper, T., Roseman, L., Kettner, H., & Carhart-Harris, R. L. (2025) · Brain and Behavior · doi:10.1002/brb3.70660 · Cited by 8 · see citing works
Singleton, S. P., Sevchik, B. L., Lahey, A., Cuijpers, P. J., Harrer, M., Jones, M. T., Nayak, S. M., Strain, E. C., Vandekar, S., Dworkin, R. H., et al. (2026) · Nature Mental Health · doi:10.1038/s44220-026-00630-8 · Cited by 6 · see citing works
“…expectancy in arms receiving psilocybin treatment, there may be a substantial underperformance in the placebo arm, as evidenced by an underperformance of placebo arms in psychedelic trials compared with placebo arms in trials of escitalopram (a selective serotonin-reuptake inhibitor) 44–47 .”
Taylor, J. J., Szigeti, B., Silverberg, N. D., Ahmadzad-Asl, M., Kare, M. R., Webler, R. D., Orsini, D. K., Rosenblat, J. D., Bschor, T., Baethge, C., et al. (2026) · The Lancet Psychiatry · doi:10.1016/s2215-0366(26)00018-0 · Cited by 6 · see citing works
Bozzatello, P., Novelli, R., Schisano, R., Brasso, C., Rocca, P., & Bellino, S. (2025) · Pharmaceuticals · doi:10.3390/ph18050665 · Cited by 7 · see citing works
“Furthermore, it is difficult to perform blind studies on psychedelic substances due to their psychoactive and hallucinogenic properties, even at very low doses [173].”
Considering the nocebo effect in the psychedelic discourse
Bălăeţ, M. (2024) · Journal of Psychedelic Studies · doi:10.1556/2054.2024.00365 · Cited by 5 · see citing works
Donegan, C. J., Daldegan‐Bueno, D., Noorani, T. N., Sumner, R. L., Forsyth, A., Evans, W., Smith, T., Hoeh, N. R., Sundram, F., Menkes, D. B., et al. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110670 · Cited by 4 · see citing works
Rucker, J., Mantingh, T., Kerr‐Gaffney, J., Bird, C., Chu, P., Modlin, N. L., Campbell‐Coker, K., Hambleton, S., Seath, P., Hignett, R., et al. (2026) · Nature Medicine · doi:10.1038/s41591-026-04541-0 · Cited by 4 · see citing works
“…model of psilocybin-assisted therapy relies on https://doi.org/10.1038/s41591-026-04541-0 the subjective drug effects and their integration; therefore, expectancies, subjective effects and pharmacological effects likely work synergistically and thus may be intrinsic to the treatment 21 .”
InfluentialSelf-citationPsychedelics and mental health: reimagining care through science, insight, and compassion
Mikellides, G., & Kyriazis, M. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1649929 · Cited by 4 · see citing works
Silva, F., Butlen‐Ducuing, F., Guizzaro, L., & Balabanov, P. (2025) · Neuroscience Applied · doi:10.1016/j.nsa.2025.105516 · Cited by 4 · see citing works
LSD microdosing attenuates the impact of temporal priors in time perceptionPreprint
Sadibolova, R., Murray-Lawson, C., Family, N., Williams, L. T. J., Luke, D. P., & Terhune, D. (2023) · bioRxiv · doi:10.1101/2023.04.14.536983 · Cited by 3 · see citing works
“…and putative therapeutic effects (e.g., antidepressant effects), which are plausibly shaped in part by participants’ expectancies (Burke & Blumberger, 2021; Butler et al., 2022; Olson et al., 2020), it is unlikely that participants expect to exhibit reduced temporal under-reproduction under LSD.”
BackgroundHow to set up a psychedelic study: Unique considerations for research involving human participants
Glennon, M. J., Bird, C., Yadav, P., Kleine, P., Suseelan, S., Boman-Markaki, C., Kotoula, V., Butler, M., Leech, R., Roseman, L., et al. (2026) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2026.106657 · Cited by 5 · see citing works
Self-citationPsilocybin effects on brain functional connectivity: a systematic review of fMRI studies
Farré‐Colomés, À., Rublinetska, O., & Soto-Angona, Ó. (2026) · Discover Mental Health · doi:10.1007/s44192-026-00384-w · Cited by 2 · see citing works
“Active placebos, such as low doses of psy-chedelics or other psychoactive compounds that produce perceptible but comparable psychoactive effects, are considered more effective in reducing expectancy-related bias than inert placebos [49].”
Kršák, M., Sparrow, D., ROSNER, B. A., DeMolles, D. A., & Shannon, S. (2026) · Therapeutic Advances in Psychopharmacology · doi:10.1177/20451253261470523 · Cited by 2 · see citing works
Li, J.-R., Chiang, K.-T., Kao, Y., Yu, C., Yang, F., Liang, C., & Hsu, T. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.10.016 · Cited by 2 · see citing works
Enhanced independence: De-biasing processes in psychedelic research and beyond
Cheung, K., Ehrenkranz, R. C., & Yaden, D. B. (2025) · Research Ethics · doi:10.1177/17470161251326588 · Cited by 2 · see citing works
“Additionally, symptoms could be assessed by independent raters who would be ideally unaware of the treatment’s nature (Butler et al., 2022; Wen et al., 2024).”
Singleton, S. P., Sevchik, B. L., Lahey, A., Cuijpers, P. J., Harrer, M., Jones, M. T., Nayak, S. M., Strain, E. C., Vandekar, S., Dworkin, R. H., et al. (2025) · medRxiv · doi:10.1101/2025.08.13.25333530 · Cited by 2 · see citing works
“Double-blinding in psychedelic-assisted psychotherapy has been the topic of extensive discourse in the field 48–51 .”
Jylkkä, J., & Hupli, A. (2024) · Springer eBooks · doi:10.1007/978-3-031-65790-0_9 · Cited by 1 · see citing works
Psychedelic studies in nonhuman primates: Past and future
Masthay, J. C., Kwan, A. C., & Chang, S. W. C. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03240-5 · Cited by 2 · see citing works
“…not require double blinding, a feature that is notoriously dif fi cult to achieve in clinical trials due to psychedelics ’ dramatic subjective effects; even with ‘ active ’ placebo control substances, individuals can often quickly deduce whether or not they have received the psychedelic [105, 106].”
Villiger, D. (2025) · Philosophy Compass · doi:10.1111/phc3.70059 · Cited by 1 · see citing works
Pierre, M. S., Argento, E., Cates, J., Kryskow, P., Harvey, K., Stamets, P. E., Santos-Brault, E., Paschall, S. A., Kuypers, K. P. C., Rootman, J. M., et al. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06913-9 · Cited by 1 · see citing works
“…in the present study, appear to be attributable to psilocybin The distinction – and potential interactions - between pharmacological effects and expectancies remains a conten - tious issue in research on microdosing (Butler et al. 2022; Polito and Liknaitzky 2022; Szigeti and Heifets 2024).”
Bloy, C., Sarma, A., Marsh, B., Hardy, L., Grabski, M., Mollaahmetoğlu, Ö. M., Shotton, J., Bhaskaran, S., Lingford-Hughes, A. R., Curran, H. V., et al. (2026) · Addiction · doi:10.1111/add.70320 · Cited by 1 · see citing works
Erne, L., Mueller, L., Straumann, I., Ademaj, B., Eckert, A., Vukalović, I., Valenta, J., Luethi, D., Liechti, M. E., & Vogt, S. B. (2026) · Translational Psychiatry · doi:10.1038/s41398-026-03987-7 · Cited by 1 · see citing works
Systems-based psychiatry: insights from psychedelic research on mechanisms of healing
Shannon, S., & Weil, A. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1789902 · Cited by 1 · see citing works
Dronabinol for nightmares in post-traumatic stress disorder: a randomized controlled trial
Roepke, S., Schoofs, N., Priebe, K., Wülfing, F., Meyer, K., Gieselmann, A., Stieglbauer, K., Gómez, M. G., Biedermann, S. V., Gallinat, J., et al. (2026) · Nature Medicine · doi:10.1038/s41591-026-04546-9 · Cited by 1 · see citing works
“However, these findings underscore the challenges of maintaining blinding in trials of psychoactive compounds and warrant cautious interpretation of patient-reported outcomes 47 .”
Experience, plasticity, and context: Beyond single-level models of antidepressant action
Eckert, D. (2026) · Journal of Psychopharmacology · doi:10.1177/02698811261473402 · Cited by 1 · see citing works
Applying the EU Regulatory Framework to Determine the Benefit–Risk Profile of Psychedelics
Browne, K., Bałkowiec-Iskra, E., Elferink, A. J. A., Haberkamp, M., Straus, S. M. J. M., Sepodes, B. M. N., Silva, F., Butlen‐Ducuing, F., Jansen, J., Silva, I., et al. (2025) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.5c00456 · Cited by 1 · see citing works
Canale, L., Raval, D., Chatha, P., Penn, K., Weber, C. G., Stout, C., & Weleff, J. (2023) · American Journal of Psychiatry Residents Journal · doi:10.1176/appi.ajp-rj.2023.190103
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Breeksema, J. J. (2024) · doi:10.33612/diss.912040905
Patel, P. C., & Wolfe, M. T. (2025) · Journal of Business Venturing Insights · doi:10.1016/j.jbvi.2025.e00549
The Potential of Psychedelics in the Treatment of Eating Disorders
Gukasyan, N., Hilbert, S. N., & Guarda, Á. S. (2025) · doi:10.1093/9780197675212.003.0027
Efficacy and Safety of Psychoactive Tryptamines in Addiction: A Systematic Review
van der Meer, P. B., Schukking, N., Dik, M., van Reemst, A., Fuentes, J. J., Kaptein, A. A., Schoones, J. W., Verboeket, S. O., de Waal, M. M., Goudriaan, A. E., et al. (2025) · Psychedelic Medicine · doi:10.1177/28314425251364182
“57 Maintaining successful masking in psychedelic trials remains a hurdle, for which no solution is currently available.”
Ritual to Relief: Ethical Frontiers in Repurposing Psychoactive Substances
O’Leary, E., Dodd, S., & Stahl, S. M. (2025) · Cambridge University Press eBooks · doi:10.1017/9781009585330.003
Causal Inference in Studies with Functional Unmasking: Psychedelics and BeyondPreprint
Loewinger, G. C., Stensrud, M. J., Nayak, S. M., Yaden, D. B., & Levis, A. W. (2025) · medRxiv · doi:10.64898/2025.12.05.25341713
“The belief/expectancy distinction is close to those proposed in (Butler et al., 2022; Szigeti and Heifets, 2024) 2013) that propose targeting controlled direct effects using flexible mediation analysis techniques, and mediation analyses in randomized trials (Lynch et al., 2008).”
Lewis, B. R., Reid, M. C., Novick, A. M., Byrne, K., Niciu, M. J., Fonzo, G. A., Meyer, T. D., Feifel, D., El‐Mallakh, R. S., Soares, J., et al. (2026) · Journal of Psychopharmacology · doi:10.1177/02698811251413490 · Cited by 1 · see citing works
“…been largely ineffective in reducing functional unblinding, with a majority of participants correctly identifying the study arm they were randomly assigned to following dosing (Aday et al., 2025; Bogenschutz et al., 2022; Butler et al., 2022; Muthukumaraswamy, 2023; Muthukumaraswamy et al., 2021).”
Predictors of the Effectiveness of Psychedelics in Treating Depression—A Scoping Review
Chmiel, J., & Rybakowski, F. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052202 · Cited by 1 · see citing works
“Reviews of masking integrity in psychedelic trials, together with theoretical accounts, recommend measuring expectancy but caution against over-attributing outcomes to it when the pharmacology so powerfully determines the state content [95,135–137].”
Ziv, G., Levin, O., & Masiulis, N. (2026) · Kinesiology Review · doi:10.1123/kr.2025-0076
Laursen, D. R. T., Salazar, J., Jűrgens, G., & Hróbjartsson, A. (2026) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2026.112345
Market approval and the right to health: a human rights perspective on MDMA-assisted therapy
Bublitz, C. (2026) · JME Practical Bioethics · doi:10.1136/jmepb-2025-000039
Ten practical suggestions for setting up a psychedelic study
Caulfield, A., Butler, M., & Mehta, M. A. (2026) · Journal of Psychopharmacology · doi:10.1177/02698811261458350
“This functional unblinding may lead to inflation of effects in the active group, particularly in ‘high expectancy’ conditions (Butler et al., 2022; Hudson and Pope, 2026).”
Self-citationKetamine-induced analgesia and dissociation show distinct behavioral and neural correlates
Goldway, N., Jalon, I., Agbaria, Y., Pasternak, Y., Sar-El, R., Mirelman, D., Sarna, N., Green, N., Hendler, T., & Sharon, H. (2026) · Neuropsychopharmacology · doi:10.1038/s41386-026-02496-x
Cognitive neuroscience of hypnosis
Lanfranco, R. C., & Terhune, D. B. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-29258-3.00030-6
Barrett, F. S., Wolinsky, D., Daily, Z., Ciancio, J., Arthur, K., & Vandrey, R. G. (2026) · Psychopharmacology · doi:10.1007/s00213-026-07138-0
Hewitt, T., Seth, A. K., & Schwartzman, D. J. (2026) · Royal Society Open Science · doi:10.1098/rsos.260647
Sevchik, B. L., Singleton, S. P., Lahey, A., Cuijpers, P. J., Harrer, M., Jones, M. T., Nayak, S. M., Strain, E. C., Vandekar, S., Yaden, D. B., et al. (2026) · Neuropsychopharmacology · doi:10.1038/s41386-026-02575-z
Seynaeve, M., Schneider, L., Roullier, I., Lazenby, K., Lilley, C., Lobo, S., Ermakova, A. O., Wells, H., Cleare, A. J., & Rucker, J. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1682810
“…effects, expectations, investigator enthusiasm, and cultural narratives can in fl uence experience and reporting through demand characteristics, functional unblinding and placebo responses (96, 103 – 106 The burden of research is a major reason patients decline or withdraw from trials (107).”
Self-citationde Paula, C. C., Vicentini, A. B., Guerra, L. T. L., Maekawa, R. M., Reis, J. A. S., Villanova, B., Gomes, C. C., Bellucci, T., Rossi, G. N., Bouso, J. C., et al. (2026) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000002267
- Authors
- Butler, M., Jelen, L., & Rucker, J.
- Affiliations
- King's College London (GB)
- Venue
- Psychopharmacology
- Published
- 2022-09-05
- Volume
- 239
- Issue
- 10
- Pages
- 3047-3055
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC9481484
- OpenAlex
- W4294667223
- Cited by
- 100
- References
- 62
- Citations by year
- 2026: 26 · 2025: 23 · 2024: 20 · 2023: 30 · 2022: 1
- FWCI
- 16.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Psychopharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- National Institute for Health and Care Research (NIHR-INF-1861)
- Medical Research Council (MR/T028084/1)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- psychedelics, expectancy effects, blinding, unblinding, active placebo, naturalistic study, overestimation of treatment effects, trial design limitations
- MeSH terms
- Emotions, Hallucinogens, Humans, Psilocybin, Randomized Controlled Trials as Topic
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