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

As clinical interest in psychedelic-assisted psychotherapy grows, there is increasing motivation to characterise next-generation compounds that may offer improved tolerability profiles for specific patient populations. 2C-B (2,5-dimethoxy-4-bromophenethylamine) is a phenethylamine psychedelic reported by recreational users to produce less dysphoria and cognitive impairment than classical tryptamine psychedelics such as psilocybin, despite broadly comparable subjective effects at matched doses. Its neural correlates had not previously been characterised in humans. This study mapped the acute effects of 2C-B and psilocybin on functional brain organisation using 7T resting-state fMRI in healthy volunteers, benchmarking findings against established neuroimaging signatures of psychedelic action and examining the relationship between brain changes, pharmacological receptor maps, and subjective experience.

Twenty-two healthy volunteers participated in a within-subject crossover design receiving 20 mg 2C-B, 15 mg psilocybin, and placebo in separate sessions. Doses were selected to produce psychotropic equivalence verified by visual analogue scales administered immediately before and after resting-state fMRI acquisition at 7T. Spatiotemporal benchmarks of functional brain organisation were assessed using three primary outcome measures: static functional connectivity (sFC), dynamic functional connectivity variance (dFC), and sample entropy (sampEn). Drug effects were analysed using network-based statistics and linear mixed effects models. The pharmacological specificity of brain changes was assessed through dominance analysis relating regional drug effects to 5-HT2A receptor density and monoamine transporter maps from publicly available receptor atlases.

Both 2C-B and psilocybin produced comparable subjective effects during fMRI acquisition, confirming psychotropic equivalence. Widespread alterations in spatiotemporal brain organisation were observed under both compounds, broadly consistent with prior reports of diminished unimodal-transmodal network segregation under classical psychedelics. Psilocybin selectively reduced within-network connectivity in visual networks A and B and default mode network C, whilst 2C-B showed a distinct spatial profile with differences in the degree and distribution of network changes. Dominance analysis revealed that changes in dFC under both compounds were best explained by an inverse relationship with 5-HT2A receptor density — regions of higher 5-HT2A expression showed greater reductions in dynamic FC variance. However, 2C-B's effects were somewhat less spatially constrained to 5-HT2A expression than psilocybin's, consistent with 2C-B's additional agonism at other receptor subtypes beyond 5-HT2A.

The finding that 2C-B and psilocybin produce partially overlapping but spatially distinct patterns of functional reorganisation — despite subjective equivalence — supports the hypothesis that pharmacological differences beyond 5-HT2A agonism shape the neural signature of psychedelic action. The tight coupling between regional 5-HT2A receptor density and dynamic FC changes for both compounds confirms 5-HT2A as the primary mediator of broad-network psychedelic effects, whilst compound-specific residuals implicate contributions from other binding targets. These results provide the first characterisation of 2C-B's neural correlates in humans, addressing a notable gap given the compound's recreational prevalence. Psychotropic equivalence does not imply neuroimaging equivalence — a distinction with practical implications for the use of novel compounds in clinical and research contexts where specific neural signatures may carry therapeutic relevance.

7T resting-state fMRI demonstrates that 2C-B and psilocybin produce widespread yet spatially distinct alterations of functional brain organisation despite comparable subjective effects at matched doses. Both compounds' effects are primarily governed by 5-HT2A receptor density, consistent with this receptor's role as the principal mediator of classical psychedelic brain changes. The distinct spatial profile of 2C-B relative to psilocybin — attributable in part to its additional receptor interactions — warrants further investigation in both basic and clinical psychedelic research settings.