The forgotten psychedelic: Spatiotemporal mapping of brain organisation following the administration of 2C-B and psilocybin

As psychedelic-assisted psychotherapy gains momentum, clinical investigation of next-generation psychedelics may lead to novel compounds tailored for specific populations. 2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenethylamine reported to produce less dysphoria and subjective impairment than the psychedelic tryptamine psilocybin. Despite its popularity among recreational users and distinct pharmacodynamics, the neural correlates of 2C-B remain unexplored. Using 7T resting−state functional MRI in 22 healthy volunteers, we mapped out the acute effects of matched doses of 20 mg 2C-B, 15 mg psilocybin and placebo across spatiotemporal benchmarks of functional brain organisation. In a within-subjects, double-blind, placebo-controlled crossover design, we evaluated the neuropharmacological and neurobehavioural correlates of an array of connectivity measures – including static (sFC) and global connectivity (gFC), dynamic connectivity variability (dFC), and spontaneous brain complexity. Compared to placebo, 2C-B and psilocybin selectively reduced intra-network sFC, while broadly increasing between-network and subcortical-cortical connectivity. Compared to psilocybin, 2C-B exhibited less pronounced reductions in between-network FC but elicited elevations in transmodal sFC. Both compounds yielded spatially divergent increases in gFC yet produced similar increases in brain complexity. Using PET density modelling, the spatial distribution of neural effects aligned with documented differences in monoaminergic transporter and serotonergic receptor binding affinity beyond 5-HT2A, highlighting the role of pharmacology in shaping functional dynamics. Lastly, we show behavioural markers of psychedelic effects are non-linearly reflected by the desynchronisation of the transmodal axis of functional brain organisation. Together, our findings highlight 2C-B as a useful new addition to the study of psychedelic neuroscience and may motivate new pharmacotherapy strategies.