bioRxiv : the preprint server for biology
October 12, 2024
Mario de la Fuente Revenga, Javier González-Maeso
preprint
Psychedelics like LSD, psilocybin, and DOI produce their distinct effects by activating the serotonin 2A receptor (5-HT2AR). A new ex vivo method measures drug-induced activation of this receptor in mouse brain tissue by tracking changes in inositol monophosphate (IP1), a downstream signaling molecule. The method was specific to 5-HT2AR, as IP1 increases were absent in knockout mice. Head-twitch response counts, a behavioral correlate of psychedelic effects, correlated with IP1 levels in the frontal cortex. LSD increased IP1, while lisuride, a non-psychedelic 5-HT2AR agonist, did not. MDMA also raised IP1, likely by releasing serotonin, unlike 5-HTP or fluoxetine. This approach offers mechanistic insights into psychedelic and serotonergic drug action.
Molecular Psychiatry
July 16, 2026
Marco Taddei-Tardón, Lidia Medina-Rodríguez, Jessica L Maltman et al.
Serotonergic psychedelics recruit an integrated 5-HT2A-TrkB signaling network that drives neuroplastic changes. Using a neural stem cell-derived in vitro model, a panel of tryptamines, phenethylamines, and ergolines was tested alongside ketamine and TrkB agonists. TrkB silencing abolished dendritogenic responses to all tested compounds, while 5-HT2A receptor silencing selectively impaired psychedelic-induced plasticity. Most compounds increased synaptogenesis and induced c-Fos and Egr-2 expression, with ligand-specific differences for psilocin, DOI, and Ariadne. Gq/11 or Gi/o protein coupling differentially modified neuroplastic and transcriptional responses. Psychedelics also induced a 5-HT2A receptor-dependent lactate response sensitive to disruption of either Gq/11 or Gi/o coupling.
bioRxiv : the preprint server for biology
November 26, 2025
Sandra M. Martin-Guerrero, Marco Taddei-Tardón, Jessica L Maltman et al.
preprint
Chemically diverse psychedelics trigger a coordinated reorganization of phosphorylation patterns across many proteins in neural cells. This global signaling response contains a distinct signature that separates hallucinogenic compounds from non-hallucinogenic counterparts of similar structure. Using a glycolysis-regulating transcription factor as an example, hallucinogenic psychedelics, but not their non-hallucinogenic analogues, enhance markers of glycolytic metabolism. These findings reveal that hallucinogenic and non-hallucinogenic psychedelics engage separable intracellular architectures, establishing a framework for understanding how different psychoactive compounds couple receptor activation to specific cellular states.
The Biochemist
January 19, 2024
Javier González-Maeso
Psychedelics like psilocybin, mescaline, and LSD alter cognition and perception through the serotonin 5-HT2A receptor. Recent evidence shows they can produce lasting changes in neuroplasticity in preclinical models and are being tested for treating depression and anxiety. Key questions remain, including whether the hallucinogenic experience is necessary for therapeutic effects and how to design valid placebo controls. The authors conclude that the therapeutic potential is supported but more mechanistic preclinical studies are needed to establish causality.
Schizophrenia
January 1, 2023
Alaina M Jaster, Javier González-Maeso
The head-twitch response (HTR) in rodents is a behavioral marker of serotonin 2A receptor activation caused by psychedelics. This work describes a method using a magnetic ear tag reporter with automated quantification and biphasic detection to measure HTR in mice given the psychedelic DOI. The approach can help study molecular mechanisms of psychosis and identify signaling processes relevant to antipsychotic and psychedelic compounds.
Trends in Neurosciences
April 1, 2009
Javier González-Maeso, Stuart C. Sealfon
Research on psychedelics like LSD and dissociative drugs such as PCP has converged with studies of schizophrenia, as their effects mimic core symptoms of the disorder. Some atypical antipsychotics were identified by their high affinity for serotonin 5-HT(2A) receptors, the same target as LSD-like drugs. Effects of PCP-like drugs are strongly influenced by modulation of both 5-HT(2A) and metabotropic glutamate 2/3 receptors. A serotonin-glutamate receptor complex in cortical pyramidal neurons may be the target of both psychedelics and certain antipsychotics. Recent findings on receptor, signaling, and circuit mechanisms could unify the serotonin and glutamate neurochemical hypotheses of schizophrenia.