Psychedelics exert their effects primarily through the serotonergic system. Like the endogenous neuromodulator, the drugs bind to many serotonin receptor subtypes. However, their receptor selectivity profiles and spatiotemporal patterns of action differ from those of serotonin and vary across compounds. In this review, we summarize studies that have established roles for serotonin in three...
SUMMARY How psychedelics act on cortical dendrites to produce long-lasting structural plasticity remains poorly understood. Here, we characterize the effects of psilocybin on dendritic calcium dynamics in pyramidal tract neurons of the mouse medial frontal cortex. Psilocybin transiently increases calcium event rates in apical dendritic tufts over a time course that parallels the drug’s...
Molecular PsychiatryJuly 7, 2026Axel F. Rosado, Abigail L. Yu, Jen-Hau Yang et al.
Classic serotonergic psychedelics such as psilocybin act as agonists at cortical serotonin (5-HT) 2A receptors (5-HT 2A R), inducing psychedelic effects in humans and head-twitch responses (HTRs) in rodents. Another class of psychedelic drugs called entactogens, exemplified by MDMA, function primarily as monoamine releasers and typically evoke minimal HTR despite causing serotonin release. The...
The classic psychedelic psilocybin elicits long-lasting neural plasticity and behavioral effects, but prior studies largely examined stress-naive animals. Using longitudinal imaging, we show that psilocybin increases dendritic spine density in frontal cortical neurons and facilitates fear extinction after chronic restraint stress, demonstrating psilocybin's effects in a translationally relevant...
Psychedelics show therapeutic potential for treating psychiatric disorders. While studies have emphasized the roles of cortical pyramidal cells, GABAergic neurons also express serotonin receptors and are therefore likely targets of psychedelics. In this study, we determine the effect of psilocybin on the activity dynamics of major GABAergic cell types in the mouse medial frontal cortex....
Psychedelics rose to prominence in the 1960s, around the same time when neurobiologists identified the midbrain raphe as the brain’s primary source of serotonin. It is therefore no surprise that early studies on classical psychedelics like d -lysergic acid diethylamide (LSD) focused on their effects within this brainstem nucleus. This review traces the arc of discovery: from the initial report...
Abstract New treatments for depression are needed that combine robust efficacy with improved scalability. Although psilocybin has demonstrated antidepressant effects in Phase 3 clinical trials, some of its psychedelic effects limit tolerability, necessitating administration in highly supervised clinical settings, and thus motivating development of serotonergic therapeutics that preserve...
Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal...
Studies of serotonergic or 'classic' psychedelics in nonhuman primates (NHPs) have provided valuable information about the drugs' effects on the brain and behavior in closely related species to humans. Psychedelics induce characteristic changes to both spontaneous and operant behaviors in NHPs, though variability exists in the different effects reported by different studies; this variability...
There is growing interest in developing psychedelic-inspired drugs for treating psychiatric disorders. However, identifying next-generation psychedelic analogs with ideal receptor selectivity and true therapeutic efficacy remains a major challenge. Recent progress has been driven by advances in determining agonist-induced biased signal transduction, high-content behavioral phenotyping via...
Abstract Psilocybin has profound therapeutic potential for various mental health disorders, but its mechanisms of action are unknown. Functional MRI studies have reported the effects of psilocybin on brain activity and connectivity; however, these measurements rely on neurovascular coupling to infer neural activity changes and assume that blood flow responses to neural activity are not altered...
Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses1-4. At the cellular level, psychedelics induce structural neural plasticity5,6, exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells7-9. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the...
Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in...
A feature in the pathophysiology of major depressive disorder (MDD), a mood disorder, is the impairment of excitatory synapses in the prefrontal cortex. Intriguingly, different types of treatment with fairly rapid antidepressant effects (within days or a few weeks), such as ketamine, electroconvulsive therapy and non-invasive neurostimulation, seem to converge on enhancement of neural...
ABSTRACT There is growing interest to investigate classic psychedelics as potential therapeutics for mental illnesses. Previous studies have demonstrated that one dose of psilocybin leads to persisting neural and behavioral changes. The durability of psilocybin’s effects suggests that there are likely alterations of gene expression at the transcriptional level. In this study, we performed...
There has been a recent renewal of interest in the therapeutic potential of serotonergic psychedelics. Here, we uncover the essential role of ventral hippocampus (vHpc) GABAergic interneurons in the anxiolytic effect evoked by the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT2A receptors in the...
Abstract Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses 1–4 . At the cellular level, psychedelics induce structural neural plasticity 5,6 , exemplified by the drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells 7–9 . A key question is how these cellular modifications map onto cell type-specific circuits to produce...
A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of...
Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early phase...
Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in...
To determine effects of psychedelics on neuronal architecture, we used two-photon microscopy to image dendritic spines in mouse frontal cortex after administering psilocybin (Neuron, 109, 2535, 2021) and compared with other psychoactive drugs.
Psychedelic drugs have reemerged as tools to treat several brain disorders. Cultural attitudes toward them are changing, and scientists are once again investigating the neural mechanisms through which these drugs impact brain function. The significance of this research direction is reflected by recent work, including work presented by these authors at the 2022 meeting of the Society for...
Psychedelics are serotonin 2A receptor agonists that can lead to profound changes in perception, cognition and mood. In this review, we focus on the basic neurobiology underlying the action of psychedelic drugs. We first discuss chemistry, highlighting the diversity of psychoactive molecules and the principles that govern their potency and pharmacokinetics. We describe the roles of serotonin...
Psychedelics are compounds that alter consciousness by acting on serotonin receptors in the brain. The term 'psychedelic', from the Greek for mind manifesting, refers to the drugs' subjective effects and was first proposed by Humphry Osmond in 1956. Other terms have been used to emphasize different aspects of the psychological experiences produced by various related compounds, including...
Summary Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and time scale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse...