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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

The paper argues that psychedelic psychiatry is entering a new era, characterized by a shift from prohibition to clinical investigation and therapeutic use. It describes how substances like psilocybin and MDMA are being studied for treating mental health conditions such as depression, PTSD, and anxiety, often in guided sessions with therapeutic support. The author contends that this emerging paradigm may transform mental healthcare by facilitating psychological breakthroughs and healing, though it also raises ethical and regulatory challenges. The work presents a historical and theoretical analysis of this transition, emphasizing the need for careful integration into clinical practice.

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 biosensor engineered from a serotonin 2A receptor can detect psychedelic-like activity in molecules, enabling high-throughput screening for new compounds. The approach identifies structural features that trigger receptor activation, which may accelerate the development of drugs with therapeutic potential and reduced hallucinogenic side effects.

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