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Cell

ISSN 1097-4172

8 papers in the library · 1,160 citations · publishing 2016-2026

Papers

Crystal structure of an LSD-bound human serotonin receptor

Cell January 26, 2017 Daniel Wacker, Sheng Wang, J. Mccorvy et al. 466 citations

The hallucinogen LSD binds to the human serotonin receptor 5-HT2B, and its crystal structure reveals conformational rearrangements that accommodate LSD, explaining the selectivity of its diethylamide group. LSD dissociates very slowly from both 5-HT2BR and 5-HT2AR, a key receptor for its psychoactive effects. Molecular dynamics simulations suggest that a 'lid' formed by extracellular loop 2 (EL2) at the binding pocket entrance may cause LSD's slow binding kinetics. A mutation that increases this lid's mobility greatly speeds up LSD's binding and selectively reduces LSD-mediated β-arrestin2 recruitment, providing a molecular explanation for LSD's actions at human serotonin receptors.

DOI: 10.1016/j.cell.2016.12.033 Full text Biology Medicine Chemistry

Psychedelic Psychiatry's Brave New World.

Cell April 1, 2020 David Nutt, David Erritzøe, Robin Carhart-Harris 330 citations

Following a decades-long global halt in psychedelic research, new investigations into drugs like psilocybin that act on the 5-HT2A receptor are showing promise for treating serious psychiatric disorders, including depression and addiction. Neuroscience and clinical studies are yielding exciting results in this area.

DOI: 10.1016/j.cell.2020.03.020 Psychedelic therapy Depression PTSD Anxiety +15

Psychedelic-inspired drug discovery using an engineered biosensor.

Cell April 28, 2021 Chunyang Dong, Calvin Ly, Lee E. Dunlap et al. 207 citations

A genetically encoded fluorescent sensor called psychLight, based on the 5-HT2A receptor structure, detects behaviorally relevant serotonin release and correctly predicts whether structurally similar 5-HT2AR ligands will cause hallucinogenic behavioral effects. Using psychLight, a non-hallucinogenic psychedelic analog was identified that produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The sensor enables in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and development of non-hallucinogenic therapeutics targeting the 5-HT2AR.

DOI: 10.1016/j.cell.2021.03.043 Full text

Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.

Cell May 11, 2023 Isha Singh, Anubha Seth, Christian B Billesbølle et al. 97 citations

Docking over 200 million small molecules against the inward-open state of the serotonin transporter (SERT) identified two potent, low-nanomolar inhibitors that stabilize an outward-closed conformation. These compounds showed little activity against common off-targets, and a cryo-EM structure confirmed the predicted binding geometry. In mouse behavioral assays, both compounds exhibited anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold greater than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects. The work suggests a promising path toward new treatments for depression, anxiety, and addiction with improved safety.

DOI: 10.1016/j.cell.2023.04.010 Full text Depression Addiction Docking Functional selectivity +10

Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks

Cell December 5, 2025 Quan Jiang, Ling-Xiao Shao, Shenqin Yao et al. 15 citations

A single dose of psilocybin causes structural remodeling of dendritic spines in the medial frontal cortex of mice. Using monosynaptic rabies tracing, the researchers mapped brain-wide inputs to frontal cortical pyramidal neurons and found that psilocybin's effect on connectivity is network specific: it strengthens routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on drug-evoked spiking activity, as silencing a presynaptic region during psilocybin administration disrupts the rewiring. These results reveal how psilocybin impacts large-scale cortical network connectivity and show that neural activity modulation can sculpt psychedelic-evoked plasticity.

DOI: 10.1016/j.cell.2025.11.009 Psilocybin Neuroplasticity Default mode network Dendritic spine +11

Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets.

Cell April 30, 2026 Hermany Munguba, Anisul Arefin, Ryota Hasegawa et al. 4 citations

Ketamine's rapid antidepressant effects depend on mu-opioid receptors (MORs) located on somatostatin-expressing interneurons in the medial prefrontal cortex. Chronic stress causes these interneurons to become hypertrophic, leading to excessive inhibition of pyramidal neurons, a disruption that ketamine reverses. By identifying GPCRs enriched in these interneurons through RNA sequencing, the authors validate several antidepressant targets and show that activating multiple GPCRs synergistically produces potent antidepressant-like effects with fewer side effects. This approach offers a general strategy for discovering GPCR-based treatments for brain disorders.

DOI: 10.1016/j.cell.2026.04.006 Full text Ketamine Synaptic plasticity Gpcr Antidepressant +6