The distinction at the heart of this new study concerns a question that has shadowed the modern psychedelic renaissance almost since its inception: are the therapeutic benefits of psilocybin inseparable from its hallucinatory effects, or can the two be mechanistically uncoupled? For clinicians, the answer carries enormous practical weight. A psychedelic-assisted therapy session requires hours of supervised administration, specially trained practitioners, and carefully controlled settings, all of which drive up cost and limit patient access. If the synaptic remodeling that presumably underlies lasting symptom relief could be achieved without the subjective journey, treatment could theoretically become faster, cheaper, and available to patients who cannot tolerate or consent to a full psychoactive experience. The new findings from the University of California, Santa Cruz provide the strongest cell-type-resolved evidence to date that such a separation is biologically plausible, while simultaneously complicating the picture in unexpected ways.

The experimental logic of the study rests on a long tradition in behavioral pharmacology. In rodents, the head-twitch response, a rapid rotational movement of the head, has been validated over decades as a behavioral proxy for the perceptual effects of classical psychedelics in humans. It is triggered selectively by agonists of the serotonin 2A receptor, the same molecular target that is widely believed to mediate the subjective effects of psilocybin, LSD, and related compounds in people. Although no animal behavior can fully capture a human hallucination, the head-twitch response has become the standard screen for identifying candidate non-hallucinogenic psychedelic analogues, and it anchors the interpretation of the dissociation reported here. When the researchers manipulated 5-HT2A receptors in layer 5 pyramidal neurons and found that head twitching survived intact while synaptic changes vanished, they were exploiting this well-established translational bridge.

Layer 5 pyramidal neurons are a compelling place to look for psychedelic action. These are among the largest neurons in the cortex, with cell bodies in the fifth cortical layer and apical dendrites that extend all the way to the brain surface, where they receive a dense plexus of inputs from the thalamus and other cortical areas. They serve as the principal output neurons of the neocortex, projecting to subcortical structures and to other cortical regions, and they are thought to integrate information across cortical layers before broadcasting it. 5-HT2A receptors are expressed at high density on the apical dendrites of these cells, particularly in layer 1, which has long suggested that serotonin and serotonergic psychedelics exert an especially powerful influence on this population. Previous work had shown that activating receptors on these neurons can alter cortical network dynamics, but whether this specific cell type was responsible for the structural plasticity that psychedelics induce had not been directly tested.

The imaging methodology underlying the synaptic observations deserves attention because it represents years of technical refinement. The researchers used two-photon microscopy through chronic cranial windows, a preparation that allows the same dendritic branches in the living mouse cortex to be revisited repeatedly over days or weeks. This longitudinal design is essential for distinguishing between different forms of plasticity. A single snapshot of dendritic spines, the tiny protrusions that harbor most excitatory synapses, cannot reveal whether a synapse is newly formed, long-lived, or in the process of being eliminated. By tracking individual spines across time points before and after psilocybin administration, the team could decompose the drug’s effects into formation of new spines, stabilization of those new spines, and elimination of pre-existing spines, each of which carries different implications for how cortical circuits are rewired.

The results paint a more dynamic picture than the simple ‘psychedelics grow new synapses’ narrative that has dominated popular coverage of the field. Psilocybin did indeed promote the formation of new spines and their maturation into more stable structures, consistent with earlier reports from the same laboratory and others showing rapid and persistent dendritic growth after a single dose. But the drug also accelerated the elimination of synapses that existed before treatment. This combination of construction and pruning suggests that psilocybin does not simply add connectivity in a blanket fashion; rather, it appears to open a window of heightened structural turnover during which the cortical circuitry is remodeled. Similar patterns of rapid formation followed by selective stabilization have been described during motor learning, leading to the provocative idea that psychedelics may recapitulate, in a compressed timeframe, the structural processes that normally accompany experience-dependent learning.

The functional significance of spine turnover connects to one of the most influential ideas in contemporary depression research. Chronic stress and depression are associated with the loss of dendritic spines and synapses in the prefrontal cortex, and work from several laboratories has shown that antidepressant interventions that rescue behavior also rescue spine density, and that this structural rescue is required for the sustained behavioral benefit. Ketamine, the rapid-acting antidepressant, promotes spine regrowth in prefrontal cortex within a day, and preventing that regrowth prevents the antidepressant effect from persisting. Against this backdrop, the ability of psilocybin to drive both spine formation and spine elimination in cortex takes on clinical relevance: it may allow maladaptive connections to be dismantled while new, potentially healthier patterns of connectivity are established, a kind of structural reset that could explain why a single exposure can produce benefits lasting months.

The cell-type-specific manipulations in the new study relied on genetic tools that allow 5-HT2A receptors to be either restored or deleted exclusively in layer 5 pyramidal neurons. In mice lacking the receptor globally, psilocybin failed to induce spine formation, demonstrating that the receptor is necessary for the plasticity effect. Remarkably, re-expressing the receptor only in layer 5 pyramidal neurons was sufficient to restore psilocybin-induced spine formation and stabilization, even though the drug still engaged 5-HT2A receptors elsewhere in the brain and body. This sufficiency result is the more striking of the two, because it implies that signaling within this single cortical population can orchestrate a remodeling program that visibly alters dendritic structure, potentially through intracellular signaling cascades, local protein synthesis, or interactions with neighboring astrocytes and inhibitory interneurons that remain to be worked out.

Equally important is what did not change. When the receptor was removed from layer 5 pyramidal neurons, or restored only to those neurons, the head-twitch response was unaffected, rising and falling with psilocybin dose just as it did in control animals. This means the receptors driving the hallucination proxy must reside on other cell types, perhaps on other cortical neurons, on thalamic afferent targets, or on interneurons that shape cortical rhythm and sensory processing. The finding aligns with a growing appreciation that 5-HT2A receptors are expressed across many neuronal and non-neuronal populations, and that different subsets of these receptors may couple to different downstream signaling pathways, a concept known as functional selectivity or biased agonism. It also dovetails with recent work identifying specific psychedelic-responsive neuronal ensembles whose activation appears necessary for the anxiolytic effects of psilocybin, suggesting that distinct behavioral outcomes may be mapped onto distinct cellular substrates.

The dissociation reported here resonates with, and helps to interpret, a parallel line of research on non-hallucinogenic psychedelic analogues. Several groups have engineered compounds, including analogues of ibogaine, LSD, and amphetamine-based psychedelics, that retain or enhance the neuroplastic properties of their parent molecules while showing greatly reduced head-twitch responses in mice. Others have used engineered biosensors to screen for 5-HT2A ligands biased away from the signaling pathway correlated with hallucination. Critics have cautioned that the absence of head twitching in a mouse does not guarantee the absence of subjective effects in a human, and that question remains genuinely open. But the new data add a crucial mechanistic anchor: they show that the circuit elements required for plasticity and for the hallucination proxy are not merely pharmacologically separable with different drugs, but anatomically separable within the same brain, responding to the same drug at the same time.

There are also intriguing connections to work suggesting that some of psilocybin’s plasticity-promoting activity may not require cell-surface receptors at all. A 2023 study reported that psychedelics can promote neuroplasticity through activation of intracellular 5-HT2A receptors, and separate work found that psychedelic compounds can directly bind the TrkB receptor, the receptor for brain-derived neurotrophic factor. These findings raise the possibility that the full plasticity program engaged by psilocybin involves converging signals from multiple molecular entry points, with the layer 5 pyramidal neuron population serving as a critical integrator or executor. A related recent study found that psilocybin’s lasting behavioral effects require both pyramidal cell types and 5-HT2A receptors, reinforcing the view that these excitatory cortical neurons are central to the drug’s long-term actions even if other mechanisms contribute.

Several caveats temper the clinical enthusiasm that these results naturally invite. The head-twitch response, while standard, is an imperfect surrogate for human subjective experience, and hallucinations in people involve distributed networks spanning sensory cortex, thalamus, and association areas that a simple rotational reflex cannot capture. The experiments were conducted in healthy mice rather than in animal models of depression or anxiety, leaving open whether the same layer 5-dependent plasticity operates in a diseased brain. And spine formation, however suggestive, is a structural correlate whose causal role in therapeutic improvement must still be demonstrated behaviorally. Nonetheless, by pinpointing where in the cortical cellular landscape psilocybin’s plasticity is generated, and by showing that this locus is distinct from the one generating the hallucination proxy, the study converts a broad pharmacological question into a tractable set of circuit-level hypotheses. Future work can now ask which cell types carry the head-twitch signal, how layer 5 pyramidal neurons communicate the remodeling instruction to their synaptic partners, and whether drugs can be designed to engage the first program while sparing the second, a goal that would transform the logistics and reach of psychedelic medicine.

Subject of Research: 5-HT2A receptors in layer 5 pyramidal neurons mediate the neuroplastic but not the hallucinogenic effects of psilocybin

Article Title: 5-HT2A receptors in layer 5 pyramidal neurons mediate the neuroplastic but not the hallucinogenic effects of psilocybin

Article References: Baker, J. J., Kogan, E., Ma, S., Lu, J., & Zuo, Y. (2026). 5-HT2A receptors in layer 5 pyramidal neurons mediate the neuroplastic but not the hallucinogenic effects of psilocybin. Nature Neuroscience. https://doi.org/10.1038/s41593-026-02490-y

Image Credits: AI Generated

DOI: 10.1038/s41593-026-02490-y

Keywords: HT2A, receptors, layer, pyramidal, neurons, mediate, neuroplastic, hallucinogenic, effects, psilocybin, scientific research