Simulated 5-HT2A receptor activation accounts for the high complexity of brain activity during psychedelic states

Serotonergic psychedelics, such as LSD, psilocybin, and DMT, have strong effects on human brain activity, yet their mechanisms of action at the whole-brain level are only partially understood. Here, we present a biophysically-based mean-field model that integrates cellular and network-level details to simulate the effects of these compounds at different spatial scales. By incorporating the brain-wide distribution of 5-HT _2A receptors, our model mechanistically links receptor activation to a reduction in leak membrane potassium conductance, consistent with electrophysiological data. Our simulations reveal that this microscopic perturbation leads to the emergence of a brain state characterized by asynchronous and irregular dynamics with increased firing rates, as well as significant alterations in spectral power. Specifically, we find a robust decrease in power within the delta, theta, and alpha frequency bands, a result consistent with empirical findings. This change in dynamics is accompanied by an increase in spontaneous complexity, as quantified by the Lempel-Ziv complexity index, as observed experimentally. Furthermore, our model accurately replicates experimental findings regarding the Perturbational Complexity Index (PCI), demonstrating that PCI does not increase significantly by psychedelic drug administration. This crucial dissociation, where spontaneous complexity and spectral power are increased while perturbational complexity is preserved, highlights the distinct neurophysiological substrates underlying different metrics in psychedelic states. Our multiscale model provides a robust, mechanistic framework for understanding how serotoninergic psychedelics modulate global brain activity, offering new insights consistent with empirical neuroimaging and electrophysiological data.