This landmark meta-analysis proposes a convergent account of psychedelic effects that synthesizes pharmacological, neuroimaging, and phenomenological findings. Examining DMT, LSD, and psilocybin, the authors identify both shared mechanisms and meaningful differences in their effects on brain function. LSD appears especially prominent in what they describe as “visionary restructuralisation,” a finding that correlates with enhanced connectivity between the visual network and the rest of the brain. DMT, by contrast, shows particularly strong effects on transmodal networks, which integrate higher-order brain regions involved in complex information processing. Psilocybin appears broadly similar in mechanism but differs somewhat in the relative weighting of its effects across brain networks.

Across psychedelics, the altered state is associated with increased crosstalk among brain subsystems that ordinarily operate in a more segregated fashion. This desegregation may help explain ego dissolution, as the default mode network, which helps sustain the ordinary sense of a bounded and cohesive self, becomes less dominant and less internally coherent. Importantly, these effects appear nonlinear: relatively small changes at the receptor level can produce large and difficult-to-predict changes in whole-brain connectivity.

For clinical psychiatry, this framework offers one possible way to understand the recent interest in the rapid antidepressant effects of psychedelics. These effects may partly relate to increased connectivity involving the frontoparietal network, which supports cognitive flexibility and is often functionally constrained in severe depression. By transiently disrupting rigid, overlearned patterns of brain organization, psychedelics may create conditions in which new modes of communication and adaptation become possible. In a patient with treatment-resistant depression, this can be thought of, cautiously, as a kind of forced reboot of the brain’s operating system. (via Nature Medicine)