Subacute effects of a single dose of psilocybin on biomarkers of inflammation in healthy humans: An open-label preliminary investigation

Psilocybin, a serotonergic psychedelic and prodrug of psilocin, has attracted interest as a potential treatment for several difficult-to-treat neuropsychiatric conditions, including Major Depressive Disorder, end-of-life anxiety and addiction. Previous preclinical work and a small number of human studies with other 5-HT2A receptor agonists (for example DMT, 5-MeO-DMT and DOI) suggest that agonism at the 5-HT2A receptor can reduce pro-inflammatory signalling, and that peripheral inflammatory markers (including CRP and TNF) are linked to neuropsychiatric disorders. Despite this, the effects of psilocybin itself on circulating inflammatory biomarkers in humans had not previously been evaluated, creating a gap in translational evidence linking psilocybin’s neurobiological and potential immunomodulatory actions. Rødbro Burmester and colleagues aimed to address that gap by testing whether a single oral dose of psilocybin alters peripheral markers of low-grade inflammation in healthy volunteers. The investigators pre-specified three biomarkers—high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor (TNF) and soluble urokinase plasminogen activator receptor (suPAR)—and hypothesised that psilocybin would reduce their blood concentrations when sampled approximately one day after administration. This preliminary, open-label study is presented as an initial human test of psilocybin’s putative anti-inflammatory effects.

Sixteen healthy adult participants were recruited via an online survey and underwent screening including a medical examination and blood panel. The extracted text reports exclusion criteria that included recent use of psychedelic drugs (within 6 months), recent use of other psychotropic medications (within 1 month) and present or prior primary psychiatric disorder, but the extraction does not provide the full list or further demographic details beyond noting that demographics appear in a table. Data from these participants overlapped with other neuroimaging projects: six participants were in a PET study and ten in a separate imaging study, but all were treated and assessed for the present biomarker analyses. The intervention was an open-label single oral dose of psilocybin administered in capsule form at about 10:00 a.m. Doses varied across participants (range 0.05–0.3 mg/kg) and the mean dose was approximately 0.22 mg/kg. Participants received preparatory consultations with assisting psychologists, had two psychologists present during the session, and were offered post-session integration; a physician was available for medical issues. Subjective drug intensity was measured repeatedly during the session using a Likert scale, and the MEQ30 was administered about 6 hours after dosing to quantify mystical-type experiences. Venous blood sampling for biomarker assays was performed approximately one hour before psilocybin administration (baseline) and at the same clock time the next day (about 24 hours after the first sample, roughly 23 hours after ingestion). Plasma and serum were prepared under standardised cold centrifugation and stored at −80°C until assay. hsCRP was measured in serum by a latex particle immunoassay with a lower detection limit of 0.30 mg/l; TNF was measured in plasma by sandwich ELISA with a lower detection limit of 2.3 ng/l; suPAR was quantified by ELISA (standards 0.7–14.3 µg/l). The extracted methods note assay performance characteristics (coefficients of variance, standard controls) for quality context. Statistical analyses were conducted in RStudio. For each biomarker a paired, two-sided Student’s t-test compared baseline to post-dose values; Cohen’s d for paired samples was reported as effect-size. The investigators also tested dose–response relationships using linear regression and performed bootstrap (1000 resamples) and permutation (1000 permutations) checks because of the small sample size; the authors report parametric and non-parametric results were similar and present the parametric tests. Significance was set at p < 0.05. A composite biomarker score was considered but not used because intercorrelation between markers was low.

Across the 16 participants, the study did not find statistically significant changes in serum hsCRP, plasma TNF, or serum suPAR when comparing the pre-dose sample to the sample obtained ~23 hours after psilocybin ingestion. Effect sizes were small; the authors report Cohen’s d values no larger than 0.31 and p-values ≥ 0.23 (parametric tests reported). The extracted text indicates an observed mean reduction in hsCRP of about 32% relative to baseline, but this change did not reach statistical significance and the 95% confidence interval for change in hsCRP was reported as −0.437 to 1.66 mg/l. TNF showed a numerical increase at the 24-hour time point; the increase was larger in female participants but this was largely driven by a single extreme outlier—omitting that case would bring female change in line with males. Dose–response analyses, including bootstrap and permutation checks, did not materially alter the conclusions reported from the parametric tests. The authors also note that baseline biomarker levels were generally within expected ranges for healthy individuals, but complete baseline distributions are presented in the paper’s tables rather than fully enumerated in the extracted text.

Rødbro Burmester and colleagues interpret the null findings as not supporting their hypothesis that a single dose of psilocybin reduces peripheral hsCRP, TNF or suPAR one day after administration in healthy volunteers. They nonetheless consider the observed 32% mean reduction in hsCRP—although non-significant—as broadly similar in magnitude to a previously reported reduction after ayahuasca, suggesting a possible convergent signal for 5-HT2A receptor agonists that warrants further testing. Conversely, the numerical increase in TNF is noted as inconsistent with some preclinical reports; the authors highlight that different serotonergic psychedelics have differing pharmacological profiles and that downstream signalling (functional selectivity) at the 5-HT2A receptor may yield distinct inflammatory effects across ligands. Key limitations acknowledged by the investigators include the small sample size (n = 16), which limits power to detect modest effects; the open-label design without a placebo arm; and the sparse sampling schedule (only baseline and ~23-hour post-dose samples), which may have missed transient or delayed changes given differing kinetics of the biomarkers (TNF can change within hours; CRP over days; suPAR over weeks). The authors also emphasise that peripheral markers might not capture central neuroinflammatory changes and recommend that future work consider CSF sampling, neuroinflammation PET targets, or metabolites of kynurenine and related pathways. Practical implications and recommendations made by the authors are cautious and focused on future research design: they estimate that detecting the observed hsCRP effect with conventional power would require roughly 80 participants, and they propose that subsequent studies should be randomised and blinded with placebo control, include multiple post-dose time points, assess more direct measures of neuroinflammation, and/or recruit clinical cohorts with elevated baseline inflammation. Finally, the authors note that psilocybin did not provoke an inflammatory response comparable to an endotoxin challenge, which they present as preliminary reassurance regarding acute pro-inflammatory risk in healthy people, while calling for confirmatory work in patient populations.