Psilocybin can produce rapid and sustained antidepressant-like and anxiolytic effects, yet the receptor and circuit mechanisms underlying these behavioral changes remain unclear. While the serotonin 2A receptor mediates psilocybin's acute psychedelic effects, psilocin (the active metabolite of psilocybin) binds many serotonin receptor subtypes. Our prior work has identified the serotonin 1B...
More than fifty million individuals worldwide are experiencing neurodegenerative disorders, which include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and frontotemporal dementia. These disorders have a significant role in the gradual degradation of cognition and motor skills. Most current treatment approaches have little...
Psilocybin has emerged as a promising therapeutic agent, with clinical benefits attributed to enhanced neuroplasticity rather than acute pharmacological effects. However, the fundamental mechanisms underlying these effects remain poorly understood. Using planarians as a model system, we investigated whether psilocybin enhances associative learning using a conditioned place preference paradigm....
Abstract Background The head-twitch response (HTR) is a serotonin 2A receptor (5-HT 2A R) dependent behavioral correlate of serotonergic psychedelic action in rodent models. Although cortical 5-HT 2A Rs have been implicated in HTRs, the contribution of specific cortical circuits to this behavior remains poorly defined, with a few reports implicating the medial prefrontal cortex (mPFC) in the...
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...
Rats emit 50-kHz ultrasonic vocalizations (USVs), a widely used measure of drug-induced motivational and affective effects and dopaminergic activity. Although psychedelic drugs are promising for addiction treatment, the effects of ayahuasca (AYA) on 50-kHz ultrasonic vocalizations (USVs) remain unclear. We investigated whether acute AYA treatment attenuates lisdexamfetamine (LDX)-induced USVs,...
PsychopharmacologySeptember 29, 2026Praneet Suresh, Josie Kins, Lex Levkovskyy et al.
Psychedelics exhibit rapid, durable therapeutic effects across diverse psychiatric conditions, yet their broad-spectrum psychoactivity poses challenges for clinical translation. As a proof-of-concept, we aimed to quantify associations between 19 neurotransmitter receptors and the subjective effects of 21 psychedelic drugs with broadly assayed binding profiles. We used a custom Global Vectors...
Serotonergic psychedelics are promising treatments for neuropsychiatric disorders, and their immunomodulatory effects may contribute to their clinical efficacy. However, we lack a systematic review and meta-analysis of these effects across in vitro, in vivo non-human, and human studies. We systematically searched PubMed, EMBASE, Web of Science, PsycINFO, LILACS and ClinicalTrials.gov for all...
This hypothesis and perspective article proposes that dosing schedule should be treated as an independent pharmacological variable in psilocybin microdosing research. Existing controlled studies relevant to depression and mood have predominantly used intermittent schedules. The first dedicated randomized trial in major depressive disorder used 2 mg psilocybin once weekly and did not demonstrate...
Abstract Background The 5-HT 2 receptor subfamily (5-HT 2A , 5-HT 2B , and 5-HT 2C ) is a cornerstone of neuropsychiatric drug design, yet the precise molecular determinants of their activation and biased signaling remain only partially elucidated. This study aimed to investigate the conformational transitions and energetic landscapes across diverse functional states to provide a refined...
The serotonin 2A receptor is the most abundant excitatory serotonin receptor in the brain and the target for serotonergic psychedelics. Despite its importance, the mechanisms of action and structure−activity relationship of receptor agonists are not fully understood. Experimental 5-HT2AR structures have identified a hydrophobic tunnel lateral to the orthosteric site. Here, we have examined this...
INTRODUCTION: Depressive and anxiety disorders impose a substantial public health burden, yet current serotonergic therapies are limited by delayed onset, modest remission rates, and adverse side effects. Here we put forward the serotonin 1B receptor (5-HT1BR) as an important therapeutic target for mood related pathology. AREAS COVERED: We synthesize converging evidence from human and...
Pharmacotherapy for depression is commonly prescribed, yet fewer than half of patients achieve remission with a single treatment. Many also experience intolerable side effects, highlighting the need for new treatment approaches. Classic psychedelics interact with the serotonin (5-HT) receptor class and are therefore strongly involved in the treatment of psychiatric illnesses such as depression,...
Psychedelics and psychostimulants produce subjective and often positive affective effects in humans. In rats, positive affective states are often associated with frequency-modulated ultrasonic vocalizations (USVs). We examined whether the hallucinogenic 2,5-dimethoxy-4-iodoamphetamine (DOI; 1.25-2.5 mg/kg) and LSD (0.04-0.08 mg/kg), the non-hallucinogenic lisuride (0.03 or 0.3 mg/kg) and the...
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...
Psilocybin facilitates fear extinction in rodents, but its clinical utility is hampered by 5-hydroxytryptamine (5-HT) 2A-receptor-mediated hallucinogenic effects. This study aimed to explore whether 5-HT2A receptor is obligatory for psilocybin's fear extinction and neuroplasticity effect. Male C57BL/6J mice underwent auditory-cue fear conditioning. Ketanserin (5-HT2A/2C antagonist) or MDL100907...
Translational PsychiatrySeptember 14, 2026Muhammad Asim, Julia A. Galiza Soares, Jason M Tucciarone
Serotonin (5-hydroxytryptamine; 5-HT) modulates a vast array of brain functions via its diverse receptor subtypes. Among these, the serotonin 5-HT2A receptor (5-HT2AR) has garnered intense recent interest for its pivotal role in mediating the effects of psychedelic compounds. Substantial evidence indicates that psychedelics act as agonists at the 5-HT2AR, triggering profound alterations in...
Abstract Precise control over the thermodynamics and kinetics of receptor–ligand interactions is pivotal for manipulating physiological processes and developing targeted therapies. However, conventional pharmacological approaches often lack the spatiotemporal precision required for noninvasive in vivo modulation. Terahertz (THz) technology offers a promising alternative by using nonionizing...
Abstract Background Recent clinical trials show that 5-MeO-DMT produces rapid antidepressant effects, yet the receptor mechanisms underlying these outcomes remain incompletely defined. Although 5-MeO-DMT is a high-affinity agonist at multiple serotonergic receptors, the relative contribution of 5-HT1A and 5-HT2A receptor signaling to its antidepressant-like actions has not been causally...
Psilocybin, a tryptamine alkaloid found naturally in numerous Psilocybe mushroom species, is currently being investigated for its therapeutic potential in treating several neurobehavioral and psychiatric diseases. Our previous data showed that the 5-HT2B receptor (5-HT2BR) immobility and increases in climbing behavior in the forced swim test (FST), revealing that psilocybin's predictive...