Researchers from the Estonian Research Council have published a theoretical framework in Neuroscience & Biobehavioral Reviews that attempts to explain the effects of serotonergic psychedelics from a cellular level upward. The study, led by Karl Kristjan Kaup, focuses on the serotonin 2A (5-HT2A) receptor, which is widely accepted as the primary target for substances such as psilocybin, LSD, DMT, and mescaline.
The framework centers on layer V pyramidal neurons, which are abundant in the cortex and serve as major output cells projecting to the thalamus and other cortical areas. These neurons possess two distinct dendritic compartments: basal dendrites that receive local, feature-based sensory input, and apical dendrites that extend to the cortical surface to integrate distant, contextual signals from other brain regions.
The 5-HT2A receptor is densely expressed on the apical dendrites of these neurons. According to the model, psychedelic activation of these receptors shifts the neuron's computational balance away from local sensory drive and toward apical, context-driven integration. This mechanism, termed "apical hypercontextualization," suggests that psychedelics amplify the relational context surrounding a stimulus rather than the stimulus itself.
Because layer V pyramidal neurons are primary cortical output cells, this cellular shift is proposed to broadcast contextual signals widely across the brain via thalamic and cortical loops. The authors argue this bottom-up mechanism accounts for the global increases in network connectivity and entropy consistently observed in neuroimaging studies of psychedelic states.
The framework links this cellular action to phenomenological features of the psychedelic experience, including the loosening of boundaries between mental objects, enhanced remote associations, metaphorical thinking, and the pronounced influence of "set and setting" on the subjective experience. Visual effects such as context-dependent illusions and impaired processing of complex scenes are also explained by a relative strengthening of contextual over local feature processing.
The researchers emphasize that grounding psychedelic action in specific dendritic physiology connects receptor pharmacology directly to systems-level neuroscience and subjective experience. They suggest this mechanistic understanding is necessary to rationally develop therapeutic applications for conditions characterized by rigid cognitive patterns, such as depression and addiction.
The study is a theoretical review and synthesis of existing cellular, electrophysiological, and imaging data; it does not present new experimental findings. The authors note that direct empirical validation of the proposed apical hypercontextualization mechanism in humans remains a critical next step.
The paper, "Cellular mechanisms of serotonergic psychedelics - apical hypercontextualisation," was published in Neuroscience & Biobehavioral Reviews in 2026 (DOI: 10.1016/j.neubiorev.2026.106876).
Psychedelics amplify brain connectivity through serotonin receptors, study suggests
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