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Psychedelics have long resisted easy explanation. Their effects — the dissolution of boundaries between self and world, the flooding of unexpected associations, the sense that everything is somehow connected — are vivid and consistent across different substances and different people. But the biological mechanism behind these shared phenomenological qualities has remained contested. A new theoretical review, published in the journal Neuroscience & Biobehavioral Reviews, proposes an answer that begins not with brain-wide imaging data, but with a single type of neuron and its dendrites.
Starting Smaller Than Usual
Most neuroscience research on psychedelics — substances such as psilocybin, LSD, DMT, and mescaline — has relied on neuroimaging techniques that measure activity across large brain networks. These studies have revealed compelling patterns: psychedelics appear to increase connectivity between brain regions that are normally more segregated, and to disrupt the so-called default mode network associated with the sense of self. But they do not easily explain why those network-level changes occur. The new review, summarised by the Spanish cannabis science publication Revista THC, attempts to bridge that gap by working upward from cellular biology rather than downward from network observations.
The 5-HT2A Receptor and Where It Lives
Serotonergic psychedelics — the class that includes psilocybin and LSD — exert most of their effects through a single receptor: the 5-HT2A receptor, which responds to serotonin. What makes this receptor particularly interesting is not merely its existence, but its precise location within specific neurons. It is found in especially high concentrations in so-called Layer V pyramidal neurons: large, widely branching cells in the cortex that play a fundamental role in integrating information and transmitting it outward to other brain structures.
These neurons have two distinct types of projections — dendrites — that receive incoming signals. Basal dendrites, located near the base of the cell, gather local and direct information: the immediate properties of a sensory stimulus, what is happening right now in front of the organism. Apical dendrites extend toward the upper layers of the cortex and toward the thalamus, receiving signals from more distant brain regions. These signals carry contextual and associative information: memories, expectations, relationships between concepts, and broader mental states. The shorthand the review offers is elegant: one part of the neuron processes what is happening, while the other processes what it means within a wider context. Crucially, the 5-HT2A receptor is concentrated precisely in the apical dendrites.
Apical Hypercontextualisation
The central concept the review proposes is "apical hypercontextualisation" — the idea that psychedelics, by activating 5-HT2A receptors in the apical compartment of these neurons, shift the balance between the two sources of information. Under ordinary conditions, Layer V pyramidal neurons integrate both local sensory signals and contextual associative signals. The review's model suggests that psychedelics tilt that balance toward the apical component: the neuron becomes more influenced by context, association, and relationship, and relatively less anchored to the direct sensory input arriving at its base.
Because Layer V pyramidal neurons serve as major output pathways from the cortex, a change in what influences them has cascading consequences. If contextual signals gain disproportionate weight over these cells, that reconfigured information propagates across multiple brain regions — which would help explain the large-scale connectivity changes that neuroimaging studies have observed. A modification at the level of a receptor on one part of one type of neuron, the review argues, may be sufficient to account for effects that appear, at the network level, as dramatically increased cross-regional communication.
What This Means for Experience
The practical implications of this model map surprisingly well onto the phenomenology of psychedelic experience. If the boundaries between mental representations become more permeable — if a stimulus that normally remains relatively contained begins to interact with a wider field of memories, expectations, and associations — then the perceptual world would feel richer in connection and meaning. Objects would seem to relate to one another in unfamiliar ways. Metaphors and remote associations would arise more readily. The usual segmentation of experience into discrete, bounded categories would soften.
The model also offers a mechanistic account of one of the most practically important findings in psychedelic research: the significance of "set and setting" — the mental state and environment of the person consuming the substance. If psychedelics specifically amplify the influence of contextual information on neural processing, then the context a person brings to the experience — their expectations, emotional state, physical surroundings, and relational frame — would be expected to exert an unusually powerful shaping effect on what unfolds. This is not merely folk wisdom from decades of psychedelic culture; under the apical hypercontextualisation model, it has a plausible cellular basis.
Relevance for Therapeutic Research
Understanding the mechanism matters for therapeutic applications. Psilocybin-assisted therapy is currently in advanced clinical trials for treatment-resistant depression, end-of-life anxiety, and addiction, with research programmes running at institutions including Imperial College London and Johns Hopkins University. If the apical hypercontextualisation model holds up to further scrutiny, it could help explain not only why psychedelics produce the subjective experiences they do, but also why the therapeutic context — the relationship with the guide, the prepared set, the integration session — appears to be as important as the pharmacological agent itself.
It is worth noting that this is a theoretical review, not an experimental study. The model synthesises existing evidence from receptor pharmacology, cellular neuroscience, and phenomenological accounts, and proposes a coherent framework. But it will require targeted experimental testing — particularly direct measurement of apical versus basal dendritic activity in vivo during psychedelic states — before the hypothesis can be confirmed or refined. The authors are proposing a lens, not announcing a conclusion.
For the growing community of researchers, clinicians, and informed consumers following the science of psychoactive substances, the review represents an important shift in analytical resolution: moving the conversation about how these compounds work from the map of the whole brain toward the architecture of a single cell. That granularity, if experimentally validated, could inform more precise therapeutic protocols and a clearer scientific vocabulary for discussing some of the most complex subjective experiences humans report.
Sources:
Revista THC. "Por qué los psicodélicos hacen que todo conectado: una nueva explicación desde las neuronas." https://revistathc.com/por-que-los-psicodelicos-hacen-que-todo-conectado-una-nueva-explicacion-desde-las-neuronas/
Original theoretical review published in Neuroscience & Biobehavioral Reviews (full citation pending journal confirmation).
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