Psychological medicine
June 1, 2024
Balázs Szigeti, Brandon Weiss, Fernando E Rosas et al.
74 citations
In a double-blind trial comparing escitalopram and COMP360 psilocybin for major depressive disorder, patients held higher expectations for psilocybin than for escitalopram. Higher pre-trial expectancy for escitalopram predicted better outcomes with escitalopram, but expectancy for psilocybin did not predict response to psilocybin. Pre-treatment trait suggestibility was linked to therapeutic response in the psilocybin arm but not the escitalopram arm. These findings suggest that psychedelic therapy may be less influenced by expectancy biases than previously thought, and that highly suggestible individuals may be especially responsive to psilocybin treatment.
Biological psychiatry. Cognitive neuroscience and neuroimaging
May 1, 2024
Balázs Szigeti, Boris D Heifets
62 citations
Clinical trials of psychedelics such as psilocybin, LSD, and DMT have challenged how nondrug factors like participant expectations are measured and controlled in mental health research. Higher doses of these psychoactive substances make it harder to conceal treatment conditions in double-blind, placebo-controlled designs. Growing public enthusiasm for psychedelic therapy raises questions about whether trial results are biased by positive expectancy. This review covers key concepts of expectancy and its measurement, examines expectancy effects reported in modern microdose and macrodose trials, and considers expectancy as a physiological process that can be independent of or interact with drug effects. Expectancy can be harnessed to improve outcomes and managed to enhance trial rigor.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 9, 2025
Ellen R Bradley, Kimberly Sakai, Gisele Fernandes-Osterhold et al.
23 citations
In an open-label pilot trial, 12 people with mild to moderate Parkinson's disease plus depression or anxiety received psilocybin (10 mg then 25 mg) with psychotherapy. No serious adverse events occurred, and no worsening of Parkinson's symptoms was observed. Non-motor and motor symptoms improved, and gains in some cognitive domains were sustained one month later. Depression and anxiety scores improved to a clinically meaningful degree and remained improved three months after dosing. These first results in any neurodegenerative disease suggest psilocybin therapy for Parkinson's disease warrants further study.
British Journal of Clinical Pharmacology
July 17, 2023
Balázs Szigeti, Lawrence D. Phillips, David Nutt
13 citations
Randomized controlled trials (RCTs) are often considered the gold standard in medical research, but they have limitations including reliance on null hypothesis significance testing and poor generalizability. Bayesian analysis of real-world evidence (RWE) offers a complementary approach. In a case series of 20 children with epilepsy treated with medical cannabis, all experienced reduced seizures; Bayesian analysis with a flat prior gives a 95% probability that the next patient will improve (95% credible interval 87%–100%). For treatment-resistant depression treated with psilocybin, the probability of a favorable response ranges from 62% (QIDS-16) to 82% (MADRS). These analyses require fewer patients than traditional RCTs and provide directly actionable probabilities for clinicians and patients.
Alcohol and alcoholism (Oxford, Oxfordshire)
May 14, 2025
Hannah Thurgur, Ben Sessa, Laurie Higbed et al.
3 citations
In an open-label feasibility study, 14 adults with alcohol use disorder who had recently completed detoxification underwent an eight-week course of ten psychotherapy sessions, including two sessions with MDMA. Bayesian analysis estimated a 55%–63% probability of a two-level reduction in World Health Organization drinking risk three months after treatment. Preliminary findings also indicated reductions in alcohol craving and improvements in sleep and aspects of psychosocial functioning at the three-month follow-up compared to baseline. The results provide initial insights into MDMA-assisted psychotherapy's potential to improve quality of life and well-being beyond reducing drinking.
October 19, 2022
Stefan Baumann, Robin Carhart-Harris, David Nutt et al.
2 citations
preprint
In a placebo-controlled citizen science trial with 240 participants, microdosing tolerance was assessed by tracking whether correct guesses of receiving a microdose decreased with more doses taken. Correct guess probability declined overall, indicating tolerance developed. This tolerance was specific to LSD and LSD-analogue microdoses, not psilocybin microdoses. The findings suggest that microdosers may need to periodically suspend their routine to avoid tolerance and that psilocybin may be better suited for long-term protocols.
December 11, 2020
Balázs Szigeti, Laura Kärtner, Allan Blemings et al.
1 citation
A self-blinding citizen science study tested whether psychedelic microdosing improves well-being and cognition beyond placebo. 191 participants who already planned to microdose were randomly assigned to receive four weeks of microdoses, placebos, or a mix. All psychological outcomes—including well-being, mindfulness, and life satisfaction—improved from baseline in the microdose group, but the placebo group also improved, and no significant differences emerged between groups. Small acute differences in mood, energy, and creativity were observed, but these could be explained by participants correctly guessing whether they took a microdose. The findings suggest that the anecdotal benefits of microdosing are likely due to the placebo effect.
Balázs Szigeti
1 citation
preprint
The FDA rejected MDMA-assisted therapy for PTSD partly due to concerns about functional unblinding, where participants or clinicians guess treatment assignment because of the drug's noticeable effects, potentially biasing trial results. The authors define unmasking bias and calculate its magnitude for two other drugs, ketamine and escitalopram, using published data. They find that unmasking bias for these two drugs exceeds the treatment-versus-control effect size observed in MDMA trials. This indicates that the effect sizes for MDMA-assisted therapy are not too large to be explained by unmasking bias, though the findings do not prove that the therapy's effects are entirely or partially due to this bias.