Psilocybin microdosing does not affect emotion-related symptoms and processing: A preregistered field and lab-based study

Microdosing — the regular ingestion of sub-hallucinogenic doses of psychedelics, typically around 5–10% of a standard dose — has been promoted anecdotally and in observational studies as improving mood and reducing anxiety. Earlier experimental work on microdosing is inconsistent: most controlled human trials found no reliable antidepressant or anxiolytic effects, some observational longitudinal studies have reported improvements without placebo controls, and animal studies have produced mixed findings. Research with standard (full) doses of psilocybin suggests possible mechanisms relevant to mood change, including altered emotion processing and changes in interoceptive awareness, but it is unclear whether these mechanisms operate at microdose levels or after repeated low-dose administration. Marschall and colleagues designed a preregistered, double-blind, placebo-controlled, within-subject crossover study to test whether repeated psilocybin microdosing over two 3-week blocks would: (1) reduce symptoms of depression and anxiety as measured by the DASS-21, (2) alter emotion processing (slower reaction times for negative facial expressions) on an emotional go/no-go task, and (3) increase interoceptive awareness on selected MAIA subscales. The study combined field-based dosing (participants prepared capsules at a microdosing workshop) with lab-based behavioural testing timed 1.5 h after dosing to capture acute effects; confirmatory hypotheses and analysis plans for the DASS-21 and emotional go/no-go task were preregistered, while MAIA and other analyses were exploratory.

The study used a double-blind, placebo-controlled, within-subject crossover design with two 3-week dosing blocks separated by a 2-week break. Participants attended a microdosing workshop where they prepared seven capsules of either dried psilocybin-containing truffle (0.7 g per capsule) or matched placebo capsules; a member of the Psychedelic Society of the Netherlands randomized which bag (labelled ‘1’ or ‘2’) each participant received for a given block. Participants were instructed to self-administer doses according to behavioural guidelines (5–7 doses per block, at least one day between doses, ingest dose 30–150 minutes before a lab session) and to abstain from other psychoactive substances during the study. Recruitment screened out people with a history of psychotic disorders, mania, borderline personality disorder, substance abuse, current medication use, and other serious physical or mental health issues. Of 75 screened and enrolled, attrition and non-compliance reduced the analyzable samples: 52 participants contributed S1 and S3 data (MAIA sessions) and 44 contributed S2 and S4 data (DASS-21 and emotional go/no-go sessions); several participants were excluded for guideline non-adherence. Sessions were scheduled 1.5 h after dosing, with S1 and S3 occurring after the second dose in each bag and S2 and S4 after the seventh dose. Primary instruments were the shortened Depression Anxiety Stress Scale (DASS-21), an emotional go/no-go task using validated facial expressions (sad, fearful, angry, happy, neutral), and four MAIA subscales (noticing, emotional awareness, self-regulation, body listening). The DASS-21 was administered at baseline and at S2 and S4 (after the seventh dose in a block). The emotional go/no-go assessed reaction times (RTs) to go stimuli across emotion blocks; two fearful/neutral blocks were omitted due to task instruction errors. The MAIA was administered at S1 and S3 (after the second dose) with items rated for current state. Dose potency was measured on a truffle sample and reported as approximately 2129.2 µg/g of alkaloids, equating to roughly 1.5 mg psilocybin per 0.7 g dried-truffle dose. Statistical analysis followed the preregistration: both frequentist and Bayesian repeated-measures ANOVAs (rmANOVAs) were used, with condition (psilocybin vs placebo), emotion block (for RTs), and block-order (psilocybin-first vs placebo-first) included as factors where appropriate. The team pre-specified that Bayesian evidence with BF10 > 7 would indicate substantial support for the alternative hypothesis; intention-to-treat or other imputation strategies are not reported in the extracted text.

Descriptive checks showed baseline DASS-21 Anxiety and Depression means in the normal range and Stress in the moderate range; Cronbach's alpha values varied by subscale and block (e.g. Depression α ≈ 0.79 across blocks; Anxiety α = 0.69 in block 1 and 0.49 in block 2). Dose analysis indicated approximately 1.5 mg psilocybin per administered 0.7 g truffle capsule. Confirmatory analyses: For the preregistered outcomes, psilocybin microdosing did not differ from placebo. Repeated-measures comparisons of DASS-21 Depression and Anxiety scores found no main effect of condition, F(1, 43) = 0.59, p = 0.45, η2 = 0.006, and Bayesian analysis indicated moderate to strong evidence for the null (BF10 = 0.24). Subscale t tests were non-significant and Bayesian statistics supported the null for depression (t(43) = 0.04, p = 1.00, d = 0.01, BF10 = 0.16) and anxiety (t(43) = 1.36, p = 0.36, d = 0.21, BF10 = 0.39). Including block-order produced no interaction with condition (F(1, 42) = 0.64, p = 0.43; BF10 = 0.034). The emotional go/no-go task revealed a strong main effect of emotion on RTs (F(5, 195) = 40.14, p < 0.001, η2 = 0.20), but no main effect of condition (F(1, 39) = 0.88, p = 0.35, η2 = 0.009) and no Condition × Emotion interaction (F(5, 195) = 0.37, p = 0.87, η2 = 0.002). Bayesian evidence favoured the null for the interaction (BF10 = 0.15). A post hoc power assessment indicated the observed design had low power for the hypothesised interaction (estimated power ~0.12 given observed effect sizes), though a simulated scenario suggested 40 participants might be sufficient for a small hypothesised interaction effect. Exploratory MAIA analyses found no condition effects across the four subscales (all p > 0.3; BF10 values ≈ 0.26–0.38), but a consistent main effect of block-order emerged for several subscales (e.g. emotional awareness F(1, 50) = 21.49, p < 0.001, η2 = 0.12, BF10 = 24.31). Independent-samples tests showed higher emotional awareness and self-regulation scores in the placebo condition during block 1 (psilocybin-first vs placebo-first differences; t-tests significant after correction), but these differences were not present in block 2. The authors note they did not have baseline MAIA scores, so pre-existing group differences cannot be ruled out. Additional DASS-21 analyses incorporating baseline indicated significant differences across measurement timepoints (baseline, block 1, block 2), F(2, 78) = 14.03, p < 0.001, η2 = 0.109, BF10 = 1.44e+6. Paired comparisons showed reductions from baseline to block 1 in depression and stress scores irrespective of condition, but no consistent placebo vs psilocybin differences. Sex did not interact with condition on primary outcomes. Condition identification analyses revealed participants could not reliably guess their condition in block 1 (χ2(2) = 4.89, p = 0.09; Bayesian support for null) but did correctly identify their condition in block 2 (χ2(2) = 13.71, p = 0.001; BF10 = 268.84), indicating breaking of blind in the second block. Analyses of expectation and perceived drug strength produced few effects and none that survived correction; overall, explicit expectations did not explain outcome differences. Reported subjective effects and qualitative guesses were collected and tabulated but are reported in supplementary material according to the extracted text.

Marschall and colleagues interpret their findings as providing no evidence that repeated psilocybin microdosing alters interoceptive awareness, emotion processing, or symptoms of depression and anxiety compared with placebo. They emphasise that the null confirmatory results were supported by Bayesian statistics, and that some changes observed across time (reductions from baseline to block 1 in depression and stress) occurred irrespective of condition, consistent with placebo or non-specific study effects. The authors situate their null findings relative to prior work in four ways. First, their sample was screened to be physically and mentally healthy, with baseline DASS-21 scores generally in the normal range; this may have limited scope for improvement compared with studies that included participants with higher initial symptomatology. Second, this study focused specifically on psilocybin microdoses whereas some previous observational findings combined different psychedelics; variability in active compounds and dose potency could account for divergent results. Third, duration and dosing regimen may matter: three weeks of dosing may be insufficient to evoke structural neural plasticity that has been observed after single larger psychedelic doses in preclinical models. Fourth, use of a placebo-controlled design enables disentangling expectation effects from pharmacological effects, and the authors note that positive expectancy and conditioning can produce strong symptom reductions, potentially explaining observational reports. Several methodological limitations acknowledged by the authors could have influenced the results. These include selection bias (participants self-selected from microdosing workshops, with most having prior psychedelic experience), variability in actual psilocybin content because participants prepared doses from truffles, substantial attrition and guideline non-compliance that reduced sample size, and limited power to detect small interaction effects in the emotional go/no-go task. They also note that testing was performed 1.5 h after dosing and therefore reflects acute rather than inter-dose persistent effects, and that the combined field-and-lab approach may limit generalisability to clinical settings. Finally, breaking of blind in block 2 represents a potential confound for cumulative or expectation-driven effects, though explicit expectation measures did not statistically account for the primary null findings. The authors conclude that either microdosing and placebo were equally ineffective on the measures used, or that non-explicit expectancy and conditioning effects masked pharmacological effects. They recommend future research in substance-naïve samples and in participants with clinical-range anxiety or depression, better control and quantification of psilocybin dose, strategies to preserve blinding, larger sample sizes planned a priori for expected effect sizes, and assessment of both acute and persistent (between-dose) effects to clarify whether microdosing has reproducible psychological or mechanistic impacts beyond expectation.

In sum, this preregistered double-blind, placebo-controlled crossover study found no evidence that repeated psilocybin microdosing (approximately 1.5 mg psilocybin per 0.7 g truffle dose, administered across two 3-week blocks) affects interoceptive awareness, emotion processing on an emotional go/no-go task, or symptoms of anxiety and depression compared with placebo. The authors highlight that participants tended to break blind by the second block, that baseline mental health was generally within the normal range, and that dose variability and sample selection limit generalisability. They recommend future controlled trials in substance-naïve and clinically symptomatic populations, with stricter dosing control and procedures to preserve blinding, to determine whether microdosing has reliable therapeutic or mechanistic effects.