Pharmacokinetics and Receptor Mechanism Are Associated with Distinct Thalamic Dynamical Signatures Across Five Drug Classes: A Resting-State fMRI Investigation
Ryan Malone
Zenodo (CERN European Organization for Nuclear Research) April 27, 2026 preprint DOI: 10.5281/zenodo.19816803 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Secondary analysis of resting-state fMRI datasets Qualitative |
|---|---|
| Sample size | 71 |
| Population | Participants from five resting-state fMRI datasets: LSD (N = 20, within-subject crossover), psilocybin (N = 7, precision mapping), DMT (N = 20, IV bolus), ketamine (N = 20), and propofol (N = 4, preliminary) |
| Interventions | LSD Psilocybin DMT Ketamine Propofol |
| Measures | mean seed-based connectivity, sliding-window dynamic connectivity variance, BOLD signal variance and AR1, lateralisation indices |
| Key points | LSD increased thalamic broadcast connectivity (Δ = +0.057) and psilocybin reduced dynamic connectivity variance (dz = −1.02), while DMT showed an exploratory lateralisation asymmetry and ketamine showed no significant changes on any metric. The authors argue these findings are consistent with pharmacokinetics shaping thalamic dynamical signatures within a shared 5-HT2A integration pattern, and that the ketamine null suggests receptor-specific rather than generic altered-state effects. |
Abstract
Background: LSD, psilocybin, and DMT all act primarily at 5-HT2A receptors yet producequalitatively distinct phenomenological profiles. A recent large-scale cross-psychedelicneuroimaging study (Bzdok, Girn et al., 2026, Nature Medicine; N = 267, 11 datasets) identifieda common signature of increased network integration across 5-HT2A agonists. Whetherpharmacokinetic variation — not just receptor mechanism — shapes differences in thalamicdynamics within this shared signature remains poorly characterised.Methods: Five independent resting-state fMRI datasets were analysed: LSD (OpenNeurods003059; N = 20, within-subject crossover), psilocybin (OpenNeuro ds006072; N = 7, precisionmapping), DMT (Timmermann et al., 2023; N = 20, IV bolus), ketamine (N = 20), and propofol(N = 4, preliminary). Harvard-Oxford Subcortical Atlas ROI extraction via Nilearn. Four metricfamilies were computed for all conditions: mean seed-based connectivity, sliding-windowdynamic connectivity variance, BOLD signal variance and AR1, and lateralisation indices.Primary metrics were pre-specified per condition based on prior literature; the full cross-metricmatrix is reported in Supplementary Table S1.Results: Two confirmed
Findings: LSD showed significant thalamic broadcast connectivityincrease (Δ = +0.057, p = 0.004; N = 20) and psilocybin showed significant reduction in dynamicconnectivity variance (dz = −1.02, p = 0.036; N = 7). One exploratory finding: DMT showedthalamic lateralisation asymmetry (p = 0.028, exploratory; N = 20). One informative null:ketamine showed no significant changes across any metric (all p > 0.30; N = 20). Onepreliminary directional observation: propofol showed dynamical collapse signatures (n = 4,excluded from conclusions). Cross-drug comparisons are qualitative given heterogeneousacquisition parameters.Conclusions: These findings are consistent with pharmacokinetics shaping thalamic dynamicalsignatures within the shared 5-HT2A integration pattern identified by Bzdok et al. (2026). Theketamine null is consistent with thalamic responses to 5-HT2A agonists being receptor-specificrather than generic altered-state effects.