Expectancy effects in psychedelic trials

Psychedelic clinical trials face a particular challenge with blinding because the strong psychoactive effects of compounds such as psilocybin, LSD and DMT make it difficult for participants to remain unaware of treatment allocation. Szigeti and colleagues note that when participants can infer their treatment condition, positive expectancy linked to media coverage and cultural enthusiasm may inflate apparent treatment benefits; they cite instances where the vast majority of participants correctly guessed allocation despite formal blinding procedures. This paper sets out to clarify how expectancy-related processes operate in psychedelic research. Rather than presenting new trial data, the authors review key conceptual distinctions (placebo response versus placebo effect; expectancy versus unblinding), summarise empirical findings from both macrodose and microdose studies, and consider neurophysiological pathways that might mediate expectancy. The stated aim is to identify measurement gaps and propose ways expectancy can be measured, manipulated, or accounted for in future trials to improve rigor and interpretability.

The paper is a narrative review synthesising conceptual work and empirical findings from modern-era psychedelic trials. The authors organise the material around core topics: definitions and measurement of placebo/expectancy, assessment of blinding integrity, empirical reports from macrodose and microdose trials, experimental and design strategies to separate expectancy from pharmacological effects, and neurophysiological evidence relevant to expectancy mechanisms. They draw on heterogeneous sources including RCTs, observational studies, experimental expectancy manipulations, and neuroimaging work. The extracted text does not report a formal search strategy, eligibility criteria, databases searched, date ranges, or a risk-of-bias assessment for included studies. Consequently, this review should be read as a targeted synthesis and conceptual analysis rather than a systematic review or meta-analysis with reproducible literature-search methods. Where trial-level details are described, the authors rely on individual published examples and selected re-analyses to illustrate broader points about blinding, expectancy measurement, and potential interactions between drug and placebo processes.

The authors first distinguish placebo constructs: the placebo response (all health changes after an inactive treatment, including non-specific care effects) versus the placebo effect (the component attributable to placebo mechanisms, ideally measured against a no-treatment control). Expectancy — most often operationalised as the expectation of improvement from active treatment — is identified as a central mechanism within placebo effects, but standardised measurement is uncommon. Common validated instruments exist (Credibility and Expectancy Scale, Stanford Expectations of Treatment Scale, Patient Prognostic Expectancy Inventory, Expectancies of Change Inventory, Treatment Expectation Questionnaire), yet many psychedelic trials have used ad hoc measures. Blinding integrity is infrequently assessed in psychiatric trials more broadly, and where it is assessed it is often ineffective. The review summarises striking data from psychedelic macrodose RCTs showing very high correct-guess rates: Holze reported only 1 of 20 participants misidentified LSD as placebo (≈95% correct), and Bogenschutz reported 90/95 treated patients correctly guessed allocation (94% correct). Expectancy itself was explicitly measured in only a few macrodose studies; in one double-blind head-to-head trial of escitalopram versus psilocybin, pretreatment expectancy predicted outcome in the SSRI arm but not in the psilocybin arm, although equivalence testing could not confirm a true null. Observational work on ayahuasca reported that participants who expected favourable personality change showed greater measured changes on some personality domains, consistent with expectancy effects in non-randomised settings. Microdosing trials have generally paid more attention to expectancy and unblinding because subjective effects are subtler. Correct-guess rates are lower than in macrodose trials but still exceed chance: roughly 65–70% correct overall versus the ~50% expected under successful blinding. Several microdose RCTs found associations between correct guessing and positive outcomes, suggesting unblinding inflates effect estimates. An LSD microdose RCT (10 µg) showed treatment-placebo differences on seven visual analogue scales in the full sample, but when analysis was restricted to participants who answered "I do not know" for allocation (a truly blind subgroup), only two scales remained significant (energy and feeling well). A large citizen-science RCT re-analysis using computational correction for weak blinding reported that nearly all originally significant microdose–placebo differences disappeared except for self-rated energy. Across microdosing trials reported effect sizes cluster around 0.3 standardised mean difference (SMD), which the authors note is smaller than the commonly used minimally important difference (MID) of 0.5 SMD; this raises the possibility that many reported microdose effects are too small to generate benign unblinding via noticeable clinical improvements and instead may reflect expectancy or side-effect cues (malicious unblinding). Trial attempts to improve blinding with active placebos (e.g. niacin) have been used, but the authors report that blinding was still likely weak and that psychedelic effects are often distinct enough to be recognisable even by naive participants. On experimental approaches to separate expectancy and drug effects, designs such as the balanced placebo (2×2: actual drug vs placebo crossed with told drug vs told placebo) and open/hidden paradigms are discussed. These designs can isolate expectancy effects but rely on deception, which raises ethical concerns in psychologically sensitive psychedelic trials. An extreme blinding method—general anaesthesia—was used in a ketamine study where both ketamine and placebo produced large effects comparable to awake ketamine trials; expectations were not measured there, but the result suggests expectancy may account for a substantial part of observed benefit in some contexts. The review summarises neurophysiological evidence linking expectancy and placebo responses to endogenous opioid and other neuromodulatory systems. PET studies using the mu-opioid ligand 11C-carfentanil have shown opioid system engagement (sgACC, PAG, rostral ventromedial medulla, amygdala, nucleus accumbens, medial thalamus) during experimentally induced placebo analgesia. Parallel work using similar PET paradigms in antidepressant-placebo experiments identified overlapping regions. The opioid system has also been implicated in ketamine's antidepressant action: naltrexone pretreatment blocked ketamine's benefit in one trial, raising possibilities that ketamine engages opioid-dependent pathways, placebo mechanisms require a functional opioid system, or both. Imaging data in psilocybin antidepressant studies are limited but report sgACC activation and increased coupling among networks that include salience and reward-related regions, which the authors note are consistent with placebo-related circuitry. Finally, the review emphasises that placebo-related processes are heterogeneous: expectancy-mediated effects may rely on opioidergic signalling, conditioned/procedural placebo responses may recruit different circuits, and other neurotransmitters (dopamine, endocannabinoids) have been linked to placebo phenomena in other disorders.

Szigeti and colleagues interpret the assembled evidence to mean that expectancy effects are widely anticipated in psychedelic trials but rarely and inconsistently measured. They stress a conceptual separation between expectancy (an internal anticipatory state) and unblinding (participants' correct inference of allocation), arguing both are related yet distinct and should be tracked separately. The authors recommend routine, standardised measurement of expectancy and blinding integrity at multiple timepoints across a trial rather than a single baseline or end-of-trial assessment, because expectations and perceived treatment can change dynamically with experience. The paper highlights methodological and ethical constraints that complicate causal inference in psychedelic research. Randomised, blinded trials are difficult to implement with full integrity for psychedelics, and designs that could isolate expectancy (balanced placebo, deception paradigms, general anaesthesia) are ethically fraught or impractical at scale. Consequently, the investigators suggest alternative avenues to untangle causal mechanisms: incorporation of imaging and biomarker endpoints in prospective studies, and causal analysis of rich time-series observational data. They also note that placebo and drug effects may interact rather than sum linearly, and that some psychopharmacological effects may require a functional placebo-response substrate (for example, opioid signalling) to manifest fully. Limitations acknowledged by the authors include the small number of trials that formally assess expectancy or blinding integrity, heterogeneity in measurement approaches, and sparse neuroimaging data specifically linking psychedelic therapeutic mechanisms to established placebo circuits. They urge coordinated adoption of validated expectancy and blinding questionnaires, systematic assessment across trials, and further experimental work to clarify when and how expectancy contributes to observed therapeutic outcomes. Finally, the authors caution that laboratory-generated expectancies in blinded trials may differ from expectations encountered in real-world clinical roll-out, which has implications for generalisability and the implementation of psychedelic therapies.

The authors conclude that expectancy effects are expected in psychedelic research but remain under-measured. They call for consistent use of standardised measures of expectancy and blinding integrity throughout trials. Szigeti and colleagues further propose two non-exclusive roles for expectancy: as an independent driver of outcome and as a physiological substrate required for the full therapeutic effect of psychedelics, where drug-induced experiential changes alter expectations and thereby enable psychotherapeutic change. They emphasise the importance of considering how trial-generated expectancies differ from those in routine clinical settings as psychedelic therapies are translated into health systems.