BY ALEXANDRE STIPANOVICH 10.16.25
When a psychedelic engages cortical 5-HT2A receptors, it sets off a chain reaction that transforms how the brain organizes and interprets its own activity.
The first receptors activated are those found on the somatodendritic compartments of layer V pyramidal neurons, particularly along the apical dendrites that integrate sensory and associative inputs. This is the most strategic location in the cortex for perturbing conscious processing. Activation of these receptors triggers a triad of electrophysiological changes: suppression of transient voltage-gated sodium channels (Zhou and Hablitz, 1999), modest depolarization of the resting membrane potential (Aghajanian and Marek, 1997; Celada et al., 2013), and reduction of AMPA-mediated excitatory postsynaptic currents (Araneda and Andrade, 1991). The neuron is brought closer to threshold but becomes less capable of sustaining fast, rhythmic firing. Its activity enters an unstable pattern of bursts and irregular spikes. This somatodendritic destabilization is the first stage of the psychedelic cascade, a microscopic perturbation that reshapes how cortical neurons integrate and relay information.
As these layer V pyramidal neurons shift into this irregular firing regime, the equilibrium between excitation and inhibition in local cortical microcircuits begins to wobble. Pyramidal neurons normally drive fast-spiking interneurons that maintain precise inhibitory control. When their firing becomes erratic, this delicate balance is disturbed. Rodent studies have reported increased extracellular glutamate and reduced rhythmic coherence following 5-HT2A stimulation (Marek and Aghajanian, 1996; Moghaddam et al., 1997; Muthukumaraswamy et al., 2013). These findings point to a relative tilt toward excitation, though the mechanism (true interneuron disinhibition or network-level desynchronization) remains unresolved. Direct recordings from interneurons in vivo are limited, and the notion of a uniform “loss of inhibitory tone” remains speculative. What can be said with more confidence is that cortical activity becomes less synchronized, more variable, and more globally interactive, consistent with a relaxation of the constraints that normally shape cortical hierarchy.
“[Under psychedelics] cortical activity becomes less synchronized, more variable, and more globally interactive, consistent with a relaxation of the constraints that normally shape cortical hierarchy.”
Once the network begins to favor excitation, the second 5-HT2A receptor population—presynaptic or axonal—comes into play. Activation of these receptors has been shown to block voltage-gated potassium channels of the Kv1.2 family (Avesar and Gulledge, 2012; Zhong and Yan, 2016). Because Kv1.2 channels normally repolarize axon terminals after an action potential, their inhibition prolongs depolarization, enhances calcium influx, and facilitates glutamate release (Marek and Aghajanian, 1996). This presynaptic mechanism likely amplifies the output of already destabilized pyramidal circuits, leading to a broader glutamatergic surge across cortico-cortical and thalamo-cortical pathways.
The thalamus, which typically filters and prioritizes sensory and cognitive traffic, is particularly sensitive to this glutamatergic drive. Under psychedelic conditions, cortical feedback floods thalamic relay nuclei, weakening their gating function and allowing information that is usually suppressed to reach the cortex unfiltered (Preller et al., 2018). Functional imaging studies show that as this feedback intensifies, canonical networks—such as the default-mode, visual, and salience networks—lose their distinct boundaries and become globally more integrated (Carhart-Harris et al., 2016). The brain’s functional topology thus transitions from a modular, energy-efficient configuration to a flatter, more metastable landscape. This shift corresponds to what has been described as an increase in neural entropy or a relaxation of high-level priors.
The overall sequence is therefore: binding to somatodendritic 5-HT2A receptors; altered intrinsic excitability and signal integration; perturbation of local excitation–inhibition balance; presynaptic Kv1.2 blockade and glutamate amplification; thalamocortical gating disruption; and finally, global desegregation of cortical networks. Each step is experimentally grounded, though the precise causal bridges between them remain incompletely understood. Rather than a settled chain of mechanisms, this cascade should be seen as a working model—one that connects receptor-level pharmacology to the large-scale dynamical signature of the psychedelic state.
References
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