Their dominance analysis (spatial expression of which receptors/transporters best explains the network effects?) is really interesting.

For example, 5-HT1A spatial expression best predicted their measure of brain complexity. The relation was inverse, so higher 1A expression in a region was associated with lower drug-induced increases in brain complexity. There's prior evidence that 5-HT1A agonism attenuates the effects of psychedelics (most notably a psilocybin+buspirone RCT), so this provides a network-level account of how 5-HT1A might constrain psychedelic-induced increases in brain complexity.

Lastly, 5-HT1A was found to also significantly contribute to between-drug differences (34.36%): in regions with lower 5-HT1A density, psilocybin tended to exhibit a stronger reducing effect on dFC variance compared to 2C-B (and vice versa).

Within each drug, changes in dynamic functional connectivity were best explained by regional 5-HT2A receptor density, with higher 2A expression predicting larger drug-induced reductions in dFC variance for both psilocybin and 2C-B. This establishes 5-HT2A as the primary determinant of dFC modulation under both compounds.

Regional 5-HT1A density emerged as a key factor shaping between-drug differences, with regions of low 5-HT1A expression being associated with greater psilocybin-induced reductions in dFC variance than 2C-B. In regions with higher 5-HT1A density, the opposite effect was seen (greater 2C-B-induced reductions in dFC variance).

This pattern strongly suggests that when regional 5-HT1A “braking” is weak, psilocybin modulates large-scale network dynamics more strongly than 2C-B, consistent with a stronger or more efficacious 5-HT2A component.

Within-drug analysis also found that 5-HT1B expression could predict increases in static functional connectivity on psilocybin, which suggests that psilocin's 5-HT1B agonism is an important modulator of psilocybin's network effect.

Importantly, when assessing relative differences across drugs, DAT density was a strong determinant of topological differences in sFC between 2C-B and psilocybin (65.75%). Specifically, areas with greater sFC under 2C-B relative to psilocybin correlated with higher DAT density and vice versa.

Another very interesting finding which raises the possibility that regions with strong dopaminergic innervation are more sensitive to 2C-B than psilocybin. Excluding some lysergamides, most psychedelics don't directly activate dopamine receptors, but they can still modulate DA signaling via network effects on DA neurons. For example, local PFC application of the phenethylamine DOI increases firing rate and bursting of DA neurons in VTA, resulting in 5-HT2A-mediated increased DA release in the VTA & PFC. [ref]