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Abstract

The transition towards the brain state induced by psychedelic drugs is frequently neglected in favor of a static description of their acute effects. We used a time-dependent whole-brain model to reproduce large-scale brain dynamics measured with fMRI from 15 volunteers under 20 mg of bolus intravenous N,N-Dimethyltryptamine (DMT), a short-lasting psychedelic. To capture the transient effects of DMT, we parametrized the proximity to a global bifurcation using a pharmacokinetic equation and adopted the empirical functional connectivity dynamics (FCD) as optimization target. Post-administration, DMT rapidly destabilized brain dynamics, peaking after ≈5 minutes, followed by a recovery to baseline. Simulated perturbations revealed a transient of heightened reactivity, where stimulation maximally impacted the FCD. Local reactivity concentrated in fronto-parietal regions and visual cortices, and correlated with serotonin 5HT2a receptor density, the primary target of psychedelics. These advances suggest a mechanism to explain key features of the psychedelic state, such as increased brain complexity, diversity, and flexibility. Our model also predicts that the temporal evolution of these features aligns with pharmacokinetics. These results contribute to understanding how psychedelics introduce a transient where minimal perturbations can achieve a maximal effect, shedding light on how short psychedelic episodes may extend an overarching influence over time.