Selective 5-HT2AR agonism without 5-HT2BR activation is critical for safe psychedelic-inspired therapeutics. Here, we systematically probe the ligand-binding pockets of 5-HT2AR and 5-HT2BR and identify steric and conformational constraints at the side-extended pocket (SEP) and extended binding pocket (EBP) that dictate ligand orientation and receptor signaling. Guided by these insights, we...
Classical psychedelics exert hallucinogenic and therapeutic effects primarily through activation of serotonin 2 A receptor (5-HT2AR), offering promise as transformative treatments for neuropsychiatric disorders. However, their concurrent activation of 5-HT2BR—associated with cardiac valvulopathy—raises serious safety concerns, underscoring the need for subtype-selective psychedelics. To address...
Nature CommunicationsSeptember 3, 2026Eun-Kyung Hwang, Deborah Daphne, Charlie J Maddox et al.
The lateral habenula (LHb) integrates cortical and basal forebrain (BF) input and is implicated in negative affective states, but its involvement in negative affect associated with cannabis withdrawal is unknown. Here, effects of withdrawal from the psychoactive cannabis constituent, Δ9-tetrahydrocannabinol (Δ9-THC), on fear conditioning (FC) and LHb function were measured in rats using calcium...
The pathophysiology of depression involves multiple biological processes, including circuit dysfunction and impaired neuroplasticity, yet an integrative view linking these processes remains elusive. Here, we identify a convergent circuit for antidepressant response and plasticity modulation. We demonstrate that chemogenetic activation of the infralimbic cortex (IL) exerts rapid...
Psilocybin, a psychoactive compound contained in certain mushrooms, can provoke profound psychedelic experiences and also exerts established and controversial therapeutic efficacy in clinical depression and other neuropsychiatric conditions respectively. Here we report that a single systemic administration of the serotonergic psychedelic psilocybin can durably promote social behaviour in the...
Serotonergic psychedelics show therapeutic potential across neuropsychiatric disorders despite transient acute effects. These compounds share serotonin 2 A receptor agonism but differ in broader pharmacology, motivating a systematic comparison of their neurobiological effects. Here, we use [18 F]FDG-PET in rats to assess acute and one-week effects of psilocybin, LSD, and 2C-B on brain metabolic...
A prominent theory of psychedelics is that they increase brain entropy. Thirteen studies have evaluated psychedelic effects on fMRI brain entropy, each applying a distinct measure. Here we evaluated these metrics in an independent 28-participant healthy cohort with 121 pre- and post-psilocybin fMRI scans. We assessed relations between brain entropy and objective and subjective psychedelic drug...
Nature CommunicationsJune 5, 2026Maxwell B Wang, Max G'Sell, James F Castellano et al.
Critical real-world neurocognitive processes, such as settling into a conversation and neurophysiological fluctuations, vary over minutes-to-days in real-world environments. We harnessed simultaneous multi-electrode intracranial and video recordings in twenty people during a week of unconstrained, spontaneous behavior. Using dynamical deep learning algorithms, we found neurodynamics linked to...
The κ-opioid receptor (κOR) represents a promising non-addictive analgesic target due to its critical role in pain and reward pathways. Despite evidence of κOR dimerization, its molecular basis and pharmacological significance remain elusive. Here, we demonstrate stable κOR dimer formation in living cells and present cryo-electron microscopy structures of salvinorin A-bound κOR dimer complexed...
A central challenge in consciousness research is determining whether observers have a conscious experience of a stimulus. However, present/absent detection judgments are often biased by contextual factors, making it difficult to isolate conscious perception from non-perceptual influences. Traditional psychophysical methods struggle to disentangle these components. To address this, we conducted...
Psychedelics have robust effects on acute brain function and long-term behavior but whether they also cause enduring functional and anatomical brain changes is largely unknown. In an exploratory, placebo-controlled, within-subjects, electroencephalography (EEG), and magnetic resonance imaging (MRI) study in 28 healthy, entirely psychedelic-naive participants, anatomical and functional brain...
The psychedelic psilocybin has shown therapeutic potential, yet underlying neural mechanisms remain poorly understood. We investigated the impact of psilocin-the active metabolite of psilocybin-on basal activity and reactivity within the paraventricular nucleus of the thalamus (PVT) and PVT projections to central amygdala (CeA) in rats. Psilocin administration increased PVT c-Fos expression and...
Cannabinoids, such as Δ9-tetrahydrocannabinol (THC), produce anxiety at high doses, yet the underlying neural mechanisms remain poorly understood. The anterior cingulate cortex (ACC) sends dense monosynaptic projections to the dorsomedial striatum (DMS). Optogenetic excitation of the ACC → DMS pathway promotes anxiolytic-like behavior, suggesting that its suppression could induce anxiogenic...
The synthesis of salvinorin A by Salvia divinorum is of considerable interest for developing pain relief, anti-opioid addiction and antidepressant medications, but progress has been compromised by limited access to plant material and the complexity of the biosynthetic pathway. Initially using S. splendens, a closely related species, the first steps in the biosynthetic pathway have been...
The psychedelic psilocybin may have lasting therapeutic effects for patients with chronic pain syndromes. Some preclinical data suggest these putative benefits derive from direct analgesic effects; however, this possibility has not been comprehensively tested in preclinical models. Here, we evaluated the analgesic properties of a single exposure to psilocybin at acute and chronic time points in...
Nature CommunicationsDecember 9, 2025Cristina Martín-Monteagudo, Javier Sánchez Romero, Julia Adams et al.
Cannabis is the most widely used illicit drug, particularly during adolescence. Its consumption disrupts glutamate homeostasis and synaptic plasticity in the nucleus accumbens (NAc). Here, we identify a functionally distinct accumbal astrocytic ensemble, associated with the ventral hippocampus-NAc (vHip→NAc) circuit, that is critical for tetrahydrocannabinol (THC)-induced synaptic and...
Conscious perception, a critical aspect of human cognition, is assumed to emerge from a complex network of interacting brain regions that transmit information via feedforward and recurrent pathways. This study presents single- and multiunit recordings from the human lateral occipital complex (LO), a key region for shape and object recognition, during three distinct perceptual paradigms:...
Ketamine is the first glutamatergic agent in clinical use for major depression, but its primary target remains unclear. Further research is needed to develop more specific interventions with fewer side effects. Ketamine is a noncompetitive antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor. Here, we show that ketamine preferentially targets GluN2D-containing NMDA receptors on...
Psilocybin alters perception and brain dynamics. Here, we investigate the effects of psilocybin using psychophysics, ultra-high field functional MRI, and computational modeling. We find that psilocybin alters contextual perception in the Ebbinghaus illusion, as well as contextual modulation in cortical responses to visual stimuli. We propose a computational model capable of capturing and...
Emerging evidence suggests that classical psychedelics may offer therapeutic potential for opioid use disorder (OUD) by alleviating key hallmarks such as altered reward processing and dependence. However, the mechanisms behind these effects remain unclear. Our data demonstrate that a single administration of the psychedelic psilocybin (PSI) reduces conditioned behavior and withdrawal induced by...
Abstract Psilocybin increases social connectedness and has strong clinical transdiagnostic efficacy for mental illness, making it a candidate treatment to reduce maternal disconnect, anxiety, and blunted affect seen in peripartum mood disorders. However, the efficacy and safety of psilocybin in peripartum mood disorders has not been investigated. We used a social stress model to examine the...
Through its widespread reciprocal connections with the cerebral cortex, the claustrum is implicated in sleep and waking cortical network states. Yet, basic knowledge of neuromodulation in this structure is lacking. The claustrum is richly innervated by serotonergic fibers, expresses serotonin receptors, and is suggested to play a role in the ability of psilocybin, which is metabolized to the...
Magneto/electroencephalography (M/EEG) studies of dreaming are an essential paradigm in the investigation of neurocognitive processes of human consciousness during sleep, but they are limited by the number of observations that can be collected per study. Dream research also involves substantial methodological and conceptual variability, which poses problems for the integration of results. To...
Nitrous oxide (N2O) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N2O induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions. N2O-induced L5 activation rescues a stress-associated...
Psilocybin shows significant therapeutic potential for psilocybin-assisted psychotherapy in addressing various psychiatric conditions. The biosynthetic approach promises rapid and efficient production of psilocybin. Understanding the enzymes that contribute to the biosynthesis of psilocybin can enhance its production process. In this study, we elucidate the crystal structures of...