Catalysts for change: the cellular neurobiology of psychedelics

Human use of psychedelic compounds spans millennia, from traditional ceremonial and medicinal contexts to modern clinical research. Bement and colleagues note that naturally occurring agents such as ayahuasca (containing DMT), 5-MeO-DMT, and psilocybin have long cultural histories, whereas synthetic compounds such as LSD were introduced in the 20th century. After decades of restricted research following regulatory scheduling, human research has resumed and small clinical trials over the past 20 years have reported promising, sometimes durable, therapeutic effects for conditions including depression, anxiety, substance use disorders, and obsessive–compulsive disorder. The authors emphasise that the intensity of the acute subjective psychedelic experience often correlates with subsequent therapeutic benefit, and that single or a few doses of psilocybin can produce symptomatic relief lasting months in some participants. This Perspective sets out to examine the cellular and subcellular mechanisms that could link the acute pharmacology and phenomenology of psychedelics to the longer-term structural and behavioural changes seen in humans. The investigators focus particularly on neural plasticity as a putative central mechanism, and outline current understanding of receptor signalling, interactions with glutamatergic systems, electrophysiological and network effects, gene expression and structural plasticity, and the roles of stress and inflammation in acute and lasting drug actions. The aim is to synthesise mechanistic insights that might explain how transient drug exposures produce protracted changes in mood and behaviour and to identify key unanswered questions for future research.

Psychedelics share structural similarity with serotonin and are generally characterised as agonists at the serotonin 5-HT2A receptor, but they differ in receptor selectivity and broader pharmacology. Bement and colleagues describe two chemical classes: indolealkylamines (for example, LSD, psilocybin, DMT, 5-MeO-DMT) that show activity at 5-HT1A and other monoaminergic receptors, and phenylalkylamines (for example, mescaline, DOI) that are more selective for 5-HT2A and 5-HT2C receptors. Despite varied off-target binding, the acute subjective and neurophysiological effects in humans correlate strongly with central 5-HT2A receptor occupancy and are largely blocked by 5-HT2A antagonists. The authors also note that depression and related mood disorders are associated with increased 5-HT2A receptor density in regions such as the prefrontal cortex, and that both antidepressant treatment and psychedelic administration can reduce that density. A central mechanistic concept reviewed is biased agonism at the 5-HT2A receptor: different ligands stabilise different receptor conformations that preferentially engage distinct downstream pathways. Psychedelic ligands tend to produce larger Gq-mediated responses (phospholipase C, protein kinase C, ERK, CREB) than some non-psychedelic agonists, but signalling through Gi/o pathways and β-arrestin-dependent cascades also contribute in ligand- and context-dependent ways. The extracted text highlights that genetic or pharmacological loss of Gq signalling blunts but does not eliminate psychedelic responses in animals, and that some psychedelic-associated phosphoproteomic and transcriptomic changes are sensitive to pertussis toxin, implicating Gi/o family involvement. The role of β-arrestin signalling remains unclear and may vary by ligand. Interactions between serotonergic and glutamatergic systems are presented as a key mechanism linking receptor activation to plasticity. Psychedelics increase extracellular glutamate in the prefrontal cortex, which promotes release of neurotrophic factors and activates ionotropic and metabotropic glutamate receptors. Metabotropic receptors mGluR2 and mGluR3 can suppress psychedelic responses, and evidence suggests physical and functional coupling between 5-HT2A receptors and mGluR2 that can alter downstream G-protein coupling. The authors report findings consistent with heterodimeric or heterocomplex formation between 5-HT2A and mGluR2, which may integrate serotonergic and glutamatergic signalling and influence rapid antidepressant-like effects in regions implicated in mood and fear learning. At the level of neural activity and networks, psychedelics acutely increase cortical excitability and alter functional connectivity. Experiments in humans indicate shifts from externally driven to internally driven activity in sensory cortices, increases in signal complexity (an indirect measure of informational richness), and engagement of pathways not typically active under baseline conditions. Psychedelics reduce connectivity within the default mode network and alter amygdala–prefrontal connectivity during emotional processing, changes that plausibly relate to reductions in rumination and altered emotional responses seen in mood disorders. The authors stress that the persistence and causal relationship of these acute connectivity changes to long-term clinical benefits remain open questions. Converging cellular and structural data from animal and in vitro models indicate that psychedelics promote multiple forms of neural plasticity. Rodent and neuronal culture studies show increased dendritic spine size, neurite outgrowth, enhanced spine formation, and hippocampal neurogenesis following psychedelic administration. These structural changes appear to involve signalling pathways including TrkB, mTOR, and 5-HT2A receptor activation, and are accompanied by changes in plasticity-related gene expression—examples include increased BDNF and Arc expression in cortex and hippocampus after single doses. Human studies report acute increases in plasma BDNF after psychedelic administration. The authors propose that these molecular and structural effects amount to a transient ‘‘window’’ of enhanced, nonspecific plasticity that could be harnessed therapeutically in conjunction with psychotherapeutic support, but they note that the duration and regional specificity of such a window have not been established experimentally. Finally, the review addresses stress and inflammation as modulatory factors. Psychedelics elicit an acute physiological stress response—elevated catecholamines and glucocorticoids—and the investigators discuss two possible routes for this effect: direct 5-HT2A receptor action in hypothalamic circuitry governing the hypothalamic–pituitary–adrenal axis, and stress secondary to the challenging components of the altered state of consciousness. Because acute stress can itself be pro-neuroplastic, the authors consider whether stress responses contribute to therapeutic plasticity, but acknowledge debate about whether the challenging aspects of the experience are necessary for benefit. On inflammation, psychedelics appear to have anti-inflammatory actions: 5-MeO-DMT lowers proinflammatory cytokines in humans, and DOI reduces peripheral cytokine cascades via 5-HT2A receptors. Microglia express 5-HT receptor subtypes and respond to psychedelic compounds in preclinical studies, raising the possibility of direct modulation of brain immune cells. The review notes early translational activity, including a Phase I trial exploring LSD in healthy older adults as a potential intervention for neurodegenerative disease, but emphasises that therapeutic implications of anti-inflammatory effects are at an early stage.

Bement and colleagues conclude that psychedelics act as multifaceted ‘‘catalysts’’ that produce acute changes in gene expression, neurotransmitter and neuroendocrine release, neural activity and connectivity, and subjective experience, which can culminate in long-term alterations in mood and behaviour. The authors argue that elucidating the mechanistic links between these acute effects and durable structural brain changes is essential but complicated by the complex signalling engaged by psychedelics and by incomplete mechanistic understanding of the psychiatric disorders they can ameliorate. They highlight priorities for future research, including identification of the loci and time course of pro‑neuroplastic effects; determination of which signalling pathways are necessary for therapeutic plasticity; clarification of whether psychedelics open a temporally limited, nonspecific window of plasticity or induce regionally selective changes relevant to psychiatric phenotypes; and exploration of alternative strategies to promote beneficial plasticity. The review closes by noting that many questions remain, and predicts substantial expansion of mechanistic and clinical understanding of the therapeutic potential of psychedelics over the coming decade.