How psychedelics work
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Psychedelics amplify the relations between representations. They enhance the impression that information makes and the strength of its connection to everything else. In the brain, increased firing in a subset of layer V pyramidal neurons projecting to the thalamus (in the middle) leads to a broad distribution of the signal into apical dendrites of many cortical regions.
view moreCredit: Borjan Milinkovic, Karl-Kristjan Kaup
Psychedelics like psilocybin (from magic mushrooms), LSD, DMT and mescaline profoundly alter how we perceive, feel and think. After decades of neglect, they are again the subject of serious scientific inquiry, largely because of their promise for treating depression, anxiety, addiction and other conditions. But this therapeutic promise has run ahead of a more basic understanding: while a great deal of attention has gone to whether psychedelics help treat mental disorders, far less has gone to what they actually do in a general sense — the fundamental way they change perception, thought and consciousness. Only by understanding these basic mechanisms can we ever make sense of the therapeutic effects.
There is also a gap in how that basic question has been approached. Most attempts to explain the mechanisms of psychedelics have been pitched at the level of whole-brain neuroimaging — describing how activity across large networks reorganises during a trip. But neuroimaging only ever captures aggregate activity: the summed behaviour of millions of cells at once, not what the individual neurons, receptors and dendrites underneath are actually doing.
The aim of the new framework published in Neuroscience & Biobehavioral Reviews is to build the explanation from the bottom up, starting with cellular neurobiology and electrophysiology. Thus, the framework starts with the individual neurons, receptors and dendrites that psychedelics actually act on. This matters because a picture grounded in cells can connect the pharmacology of the drug to the lived experience in a way that network maps alone cannot. From this cellular foundation, the authors argue that psychedelics have a single unifying effect, which is called apical hypercontextualisation.
Almost everything about the effects of psychedelics starts at one receptor: the serotonin 2A receptor, or 5-HT2A. There is near consensus in the field that the bulk of psychedelic effects depend on this receptor. Block it, and the psychedelic effects are blocked; the intensity of the trip even tracks how many of these receptors the drug occupies. Researchers agree on that, but the new framework tries to understand how exactly the effect on receptors is linked to global effects seen at the level of brain imaging or cognition.
Crucially, the 5-HT2A receptor is not scattered randomly in the brain. It is most abundant in the cortex, and especially on one type of cell: the layer V pyramidal neuron. These are large, elaborately branched cells that act as the brain's key integrators and as the main output stream from the cortex to deeper structures. Because of these properties, they have long been considered central to consciousness itself.
Here is the part worth slowing down on. A layer V pyramidal neuron has, in effect, two very different sets of branches, and they do different jobs. The basal dendrites, near the cell body, mostly receive local input — the direct, feature-by-feature "what is right in front of me" signal. The apical dendrites are different. They form a long trunk that reaches up and branches into a tuft in the topmost layer of the cortex, and they gather input from far away: distant cortical regions and the thalamus. That input is not object-based or feature-based — it is contextual and associative.
A useful way to picture the difference is this. The basal branches carry the more direct, local signal of the stimulus as it arrives. But that signal, on its own, means very little. The apical branches supply everything the stimulus is bound up with: the wider setting, memories, expectations, and its links to other things active in the mind. And this is the key idea behind contextualisation — a mental object is not first defined by itself and then related to other things. What it is comes from how it relates. The apical compartment is where those relations live, and it has even been suggested to set the boundaries between one mental object and the next.
And this is exactly where the 5-HT2A receptor sits most densely. The main target of psychedelics is the very part of the neuron responsible for context and relation.
Now we can much better understand what psychedelics do. They tip these neurons toward their apical, context-gathering side. Normally, a layer V neuron fires based on a balance between its direct, local input and its wider contextual input. Psychedelics, acting through the 5-HT2A receptor, weaken the local side and strengthen the contextual side so the cell is driven more by relations and associations than by the raw stimulus in front of it. Because these neurons are among the brain's main output cells, feeding into the thalamus and back out across the cortex, tilting them this way has a large downstream consequence: the contextual signal gets broadcast widely, spreading across many regions instead of staying local. This is exactly what whole-brain neuroimaging has been showing all along — psychedelics make brain activity more global, with normally separate networks talking to each other far more. The contribution of the present framework is to show where that global shift comes from at the level of the cell.
The bigger picture is that psychedelics do not alter the direct neural representation of a stimulus so much as they amplify the relations between representations. They do not enhance the raw sensory information itself; they enhance the impression that information makes and how strongly it connects to everything else. A signal that would normally stay in its lane instead spreads, mingles and gets contextualised by whatever else is active. The boundaries between mental objects loosen.
This one idea ties together the classic features of the psychedelic experience. Visually, it explains why psychedelics can leave a lone stimulus intact but disrupt how stimuli relate — strengthening context-dependent illusions, warping the edges between objects, and impairing moving or complex scenes more than simple static ones. In cognition, it explains the flood of remote associations, metaphorical and dream-like thinking, and unexpected insight — the mind making connections it usually cannot reach. It even accounts for why "set and setting" matter so much: if subtle internal representations are amplified and broadcast, then a person's mindset and surroundings can steer the whole experience.
Grounding psychedelic action in this cellular machinery is an attempt to explain psychedelics in properly neurobiological terms: from the physical, biological material the drugs act on. It links receptor pharmacology, dendritic physiology and lived experience in one framework, and it explains, rather than merely restates, what the neuroimaging has been showing — with direct implications for how these drugs might reset rigid patterns of thought in mental illness. Ultimately, psychedelics do not change what we represent, but how our representations relate to one another.
Journal
Neuroscience & Biobehavioral Reviews
Method of Research
Literature review
Subject of Research
Not applicable
Article Title
Cellular mechanisms of serotonergic psychedelics - apical hypercontextualisation
