2026 ECNP Congress

PS03-3166

Effects of 5-HT2AR modulation on regional homogeneity and interactions with 5-HT2AR binding, a human pharmaco-fMRI and PET study

Martin Korsbak Madsen — A.S. Olsen, D.E.W. McCulloch, G.M. Knudsen, P. Fisher · Copenhagen University Hospital Rigshospitalet, Neurobiology Research Unit, Copenhagen East, Denmark

2026 ECNP Congress

Introduction

The serotonin 2A receptor (5-HT2AR) is a highly expressed cortical 5-HT receptor and a key target for serotonergic psychedelics (agonists) and atypical antipsychotics (antagonists). 5-HT2AR agonists vs antagonists may have opposing effects on local neuronal activity but this is poorly characterized in humans. Here, we contrasted the effect of psilocybin (active agonist metabolite: psilocin) and ketanserin (antagonist) on regional homogeneity (ReHo), an fMRI measure of local BOLD signal correlation. Further, we evaluated whether baseline 5-HT2AR binding, assessed with [11C]Cimbi-36 PET, moderated these associations.

Methods

The study was a randomized single-blind within-subject crossover design, with a minimum 3-week washout period between drug sessions (peroral, psilocybin dose mean(SD): 19.8(3.7) mg; ketanserin dose: 20 mg, fixed dose). Data from 27 healthy participants was available (9 female, age mean(SD): 32.8(7.6). Resting-state BOLD fMRI data was acquired pre-drug and approx. 80 min after drug (T80) on ketanserin and psilocybin days on two different 3T Siemens MRI scanners. Each participant completed scans on a single scanner. Additional BOLD fMRI data was collected on psilocybin days (at 40, 130 and 300 mins after drug administration). Plasma drug level was measured in proximity to all scans. [11C]Cimbi-36 PET data was collected at baseline. Average binding potential (BPnd) in neocortex was computed using the simplified reference tissue model (reference region: cerebellum). BOLD fMRI data was preprocessed using fMRIprep (v.25.1.3) (denoising: motion parameters, aCompCor and with and without global signal regression (GSR)). ReHo (Kendall’s coefficient of concordance) was calculated in MNI space for each gray matter voxel in relation to its 27 nearest neighbour voxels, and a cortical average was calculated for each scan. Linear mixed effects models were fit to assess statistical significance, adjusting for age, sex, scanner, and head motion. Predictors in separate models were: 1) interaction between drug (psilocybin vs ketanserin), timepoint (pre-drug vs T80), 2) plasma psilocin level (PPL) and 3) plasma ketanserin level (PKL). Subsequently, BPnd was included as an interaction term. Post hoc, we evaluated if effects were present when modeled separately for each scanner and for GSR.

Results

The ReHo change from pre- to post-drug for psilocybin was significantly different compared to ketanserin ����[95%CI]: -0.04[-0.06;-0.03] (Puncorrected < 0.001). ReHo was negatively correlated with PPL (����[95%CI]: -0.002[ -0.003; -0.001] ΔReHo/(μg/L) (Puncorrected < 0.001), but not PKL (P=0.6)). 5-HT2AR BPnd did not significantly moderate any associations. Effects were virtually identical for each scanner when modelled separately and were unaffected by GSR.

Conclusions

Psilocin dose-dependently reduced ReHo, whereas ketanserin effects were negligible. The absence of BPnd moderation suggests that receptor occupancy, rather than individual differences in receptor density, is the primary determinant of psilocybin’s effects on local neural dynamics. Importantly, these results were consistent in two different scanners and insensitive to GSR. Our results suggest that whole-brain ReHo is a robust and reproducible pharmacodynamic marker of psychedelic 5-HT2AR agonism, with potential utility in drug development of psychedelic medicines.

References

No references