Current Topics in Behavioral Neurosciences
January 1, 2017
Juan F López-Giménez, Javier González-Maeso
302 citations
Hallucinogens such as mescaline, psilocybin, and LSD profoundly alter consciousness, emotion, and cognition. Their discovery, particularly LSD's similarity to serotonin, suggested that biogenic amines like serotonin are involved in mental disorders such as schizophrenia. Although hallucinogens bind to multiple G protein-coupled receptor subtypes, their key effects involve agonist activity at the serotonin 5-HT2A receptor. This chapter reviews recent advances in understanding hallucinogen action by characterizing the structure, neuroanatomical location, and function of the 5-HT2A receptor.
Journal of Neuroscience
October 1, 2003
Javier González-Maeso, Tony Yuen, Barbara J. Ebersole et al.
295 citations
Different drugs that activate the same serotonin receptor (5-HT2AR) can produce distinct patterns of gene expression in the brain, which correspond to different behavioral effects. The hallucinogens DOI and LSD triggered a head-twitch response in mice and produced similar changes in the somatosensory cortex transcriptome, while the nonhallucinogenic drug lisuride did not cause this behavior and generated a different transcriptome fingerprint. These effects were absent in mice lacking the 5-HT2AR, confirming the receptor's role. The findings suggest that drugs acting at the same receptor can induce unique cellular response patterns in the living brain, detectable through transcriptome analysis.
ACS Chemical Neuroscience
September 24, 2012
James B. Hanks, Javier González-Maeso
152 citations
The serotonin 5-HT(2A) receptor is the primary target of psychedelic drugs like LSD, mescaline, and psilocybin. These substances produce profound changes in cognition, emotion, and sensory processing that seem uniquely human, raising questions about the validity of animal models. However, recent research indicates that behavioral abnormalities induced by psychedelics in rodents can predict effects in humans. This review examines the behavioral effects of psychedelic drugs in rodent models, evaluates the translational potential of these findings, and identifies areas needing further research to clarify the molecular mechanisms and neural circuits underlying their neuropsychological effects.
Journal of Neuroscience
January 16, 2013
Terrell Holloway, José L. Moreno, Adrienne Umali et al.
122 citations
Severe stress during pregnancy in mice alters the expression of two brain receptors linked to schizophrenia: serotonin 5-HT2A increases and metabotropic glutamate mGlu2 decreases in the frontal cortex. These changes correspond to behavioral differences in adult offspring, such as a heightened response to a hallucinogenic drug and reduced antipsychotic-like effects of a mGlu2/3 agonist. Cross-fostering ruled out maternal care as a cause, and similar effects appeared after prenatal immune activation. The findings support the idea that early neurodevelopmental disruptions contribute to schizophrenia risk.
Journal of Neuroscience
February 2, 2011
José L. Moreno, Mitsumasa Kurita, Terrell Holloway et al.
122 citations
Maternal infection with influenza virus in mice alters the expression of serotonin and glutamate receptors in the frontal cortex of adult offspring, leading to behavioral changes relevant to schizophrenia. The 5-HT 2A receptor is upregulated and the mGlu 2 receptor is downregulated. Offspring show increased head-twitch responses to hallucinogens and reduced antipsychotic-like effects of a glutamate agonist, along with altered signaling pathways. These findings suggest a biochemical link between prenatal viral infection and schizophrenia-related behaviors, potentially guiding new treatments.
Current Medicinal Chemistry
March 1, 2009
Javier González-Maeso, Stuart C. Sealfon
74 citations
G protein-coupled receptors (GPCRs) are the most common target for therapeutic drugs. The traditional ternary complex model, where receptors shift between active and inactive states, has been revised because different agonists can activate distinct signaling pathways from the same receptor. This agonist-trafficking model proposes that agonists stabilize unique receptor conformations that preferentially trigger specific pathways. Hallucinogenic drugs like LSD, psilocybin, and mescaline, which act on serotonin 5-HT2A receptors, offer a useful system to study this phenomenon. Non-hallucinogenic chemicals like lisuride show similar in vitro activity at the same receptor but do not induce hallucinogenic effects, highlighting unresolved questions about how agonist-trafficking determines behavioral outcomes.
Scientific Reports
October 3, 2019
Mario de la Fuente Revenga, Jong M. Shin, Hiba Vohra et al.
57 citations
A fully automated system detects head-twitch behavior (HTR) in mice, a behavioral marker of psychedelic drug action at the serotonin 5-HT2A receptor. The system was validated using the psychedelic DOI in mice lacking the 5-HT2A receptor and by evaluating false-positive and false-negative events. Automation enabled efficient time-course studies. Pharmacological interactions between the 5-HT2A receptor and metabotropic glutamate receptor 2 (mGluR2) were explored: the mGluR2/3 antagonist LY341495 potentiated DOI-induced HTR, while the mGluR2/3 agonist LY404039 blocked it. This system can accelerate understanding of 5-HT2A receptor pharmacology and its behavioral outputs in rodents.
Neuroscience Letters
September 25, 2022
Alaina M Jaster, Jason Younkin, Travis Cuddy et al.
53 citations
The psychedelic compound DOI triggers more head-twitch behavior—a mouse proxy for human psychedelic effects—in female C57BL/6J mice than in males, a sex difference not seen in 129S6/SvEv mice. The 5-HT2A receptor antagonist volinanserin fully blocked this behavior in both sexes. Despite greater behavioral sensitivity in females, brain and plasma levels of DOI were lower in females 30 and 60 minutes after injection, and no sex difference appeared in frontal-cortex IP1 accumulation. These findings indicate strain-dependent and sex-related differences in the behavioral and pharmacokinetic responses to DOI, underscoring the need to include sex as a biological variable in preclinical psychedelic research.
Molecular Psychiatry
September 1, 2023
Alaina M Jaster, Javier González-Maeso
50 citations
Clinical trials show psychedelics can alleviate depression and anxiety and reduce nicotine and alcohol use, but the molecular mechanisms behind these lasting therapeutic effects remain poorly understood. Preclinical research is split between pathways dependent on the serotonin 5-HT2A receptor and those that are independent. Combining molecular, behavioral, and genetic techniques in neuropharmacology is beginning to clarify these mechanisms. The subjective experience during psychedelic-assisted therapy appears important, but without cross-validation between clinical and preclinical studies, the reasons for the experience and its translational validity may be lost.
Neuroscience Letters
January 16, 2013
José L. Moreno, Terrell Holloway, Vinayak Rayannavar et al.
44 citations
Hallucinogenic drugs like LSD, mescaline, and psilocybin all bind strongly to the serotonin 5-HT(2A) receptor. Drugs that affect metabotropic glutamate 2/3 (mGlu2/3) receptors can alter the cellular and behavioral effects of hallucinogens. In mice, chronic treatment (21 days) with the mGlu2/3 receptor antagonist LY341495 (1.5 mg/kg) reduced the hallucinogenic-like effects of LSD (0.24 mg/kg). This treatment decreased binding of a radiolabeled tracer to 5-HT(2A) receptors in the somatosensory cortex of normal mice, but not in mice lacking the mGlu2 receptor. It also reduced head-twitch behavior and the expression of certain genes (c-fos, egr-1, egr-2) that are normally triggered by hallucinogenic drugs. These results suggest that repeatedly blocking mGlu2 receptors dampens the 5-HT(2A) receptor-mediated effects of LSD.
Psychopharmacology
June 1, 2022
Alaina M Jaster, Harrison Elder, Samuel A Marsh et al.
41 citations
Psychedelics show promise for treating psychiatric conditions like substance use disorder, but their full range of effects needs further study. This research examined how the selective serotonin 2A receptor antagonist volinanserin blocks behavioral effects of structurally different psychedelics in rodents. Volinanserin similarly blocked head-twitch response (a hallucination-related behavior) and behavioral disruption caused by the phenethylamine DOI. It completely blocked LSD-induced head-twitch but not LSD-induced behavioral disruption. Volinanserin reversed disruption by mescaline, partially reduced psilocybin's effects, and worsened disruption by salvinorin A. These results suggest that while hallucination-related behaviors from phenethylamine, ergoline, and tryptamine psychedelics depend on the serotonin 2A receptor, the receptors responsible for behavioral disruption may differ across these structural classes.
Naunyn-Schmiedeberg's archives of pharmacology
May 1, 2024
Rika Takaba, Daisuke Ibi, Keisuke Yoshida et al.
31 citations
Serotonergic psychedelics like psilocin (the active metabolite of psilocybin), DOI, and TCB-2 produce antidepressant-like effects in mice by activating the 5-HT2A receptor. Twenty-four hours after a single injection, treated mice showed significantly less immobility in the forced swimming test and tail-suspension test—indicating reduced behavioral despair—compared to control mice. Blocking the 5-HT2A receptor with volinanserin eliminated these antidepressant-like effects. Psilocin's effect in the forced swimming test lasted at least three weeks. In the novelty-suppressed feeding test, psilocin reduced feeding latency (an anxiolytic-like effect), but volinanserin did not block this, and DOI and TCB-2 had no effect. None of the drugs altered spontaneous movement or head-twitch response. The findings suggest 5-HT2A activation mediates antidepressant but not anxiolytic effects of these psychedelics.
The International Journal of Neuropsychopharmacology
June 10, 2013
José L. Moreno, Javier González-Maeso
30 citations
Psychedelic drugs like LSD and dissociative drugs like PCP produce psychotic and cognitive symptoms in healthy people that resemble aspects of schizophrenia. Serotonin 5-HT2A and metabotropic glutamate 2 receptors are involved in how these drugs work. This review examines recent studies using LSD-like and PCP-like drugs in rodents that link these receptors to the biology of schizophrenia and its treatment.
Journal of Neurochemistry
November 6, 2021
Alaina M Jaster, Mario de la Fuente Revenga, Javier González-Maeso
28 citations
Psychedelic research is accelerating across disciplines and biological levels. Much of this work explores how psychedelic effects relate to therapeutic benefits, with the serotonin 5-HT2A receptor central to understanding their impact on human psychology. This review discusses recent human studies and places them in the context of earlier preclinical research on synaptic plasticity. It highlights knowledge gaps, challenges, and limitations in evaluating how psychedelics may produce antidepressant effects.
Pharmacological Research
May 1, 2025
Eda Koseli, Belle Buzzi, Torin Honaker et al.
11 citations
Psilocybin and a similar psychedelic, DOI, reduced pain-related behaviors in mice with chronic pain. In a mouse model of chemotherapy-induced nerve damage, both drugs reversed sensitivity to cold and touch in a dose-dependent manner, with different timing of effects. In a model of persistent inflammatory pain, they also reversed sensitivity to heat. These pain-relieving effects depended on activation of the 5-HT2A serotonin receptor. The findings suggest that classical psychedelics may be effective for treating chronic pain through this receptor pathway.
bioRxiv (Cold Spring Harbor Laboratory)
February 25, 2021
Mario de la Fuente Revenga, Bohan Zhu, Christopher A. Guevara et al.
11 citations
preprint
A single dose of the psychedelic DOI produces rapid and sustained antidepressant-like effects by altering chromatin organization at enhancer regions of genes involved in synaptic assembly in the frontal cortex, an effect mediated by the 5-HT2A receptor. These epigenetic changes drive lasting synaptic plasticity and accelerate fear extinction. The findings suggest that epigenetic-driven synaptic plasticity underlies psychedelics' long-lasting antidepressant action, but also indicate potential risks for individuals with underlying vulnerability to psychosis, as the altered neuronal epigenome overlapped with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder.
Nature Communications
November 20, 2025
Alaina M Jaster, Thomas M Hadlock, Belle Buzzi et al.
9 citations
A single dose of the psychedelic psilocybin reduces conditioned behavior and withdrawal caused by the opioid oxycodone in male mice but not in females. This sex-specific effect is mediated by the 5-HT2A receptor in frontal cortex pyramidal neurons that project to the nucleus accumbens. Psilocybin also alters epigenomic regulation after repeated oxycodone exposure and induces sex-specific structural plasticity in the nucleus accumbens independently of the 5-HT2A receptor. Female frontal cortex and nucleus accumbens show fewer changes at gene enhancer regions in response to psilocybin, repeated oxycodone, or their combination compared to males, with the frontal cortex displaying more pronounced sex differences at the epigenomic level.
Research Square (Research Square)
July 7, 2023
Rika Takaba, Daisuke Ibi, Keisuke Yoshida et al.
4 citations
Serotonergic psychedelics like psilocin, DOI, and TCB-2 produce antidepressant-like effects in mice by activating the serotonin 5-HT2A receptor. Mice given a single injection of these drugs showed less immobility in the forced swimming and tail-suspension tests 24 hours later, effects blocked by a 5-HT2A antagonist. The antidepressant-like effect of psilocin lasted at least three weeks. However, only psilocin reduced anxiety-like behavior in the novelty-suppressed feeding test, and this effect was not blocked by the 5-HT2A antagonist. The drugs did not alter spontaneous movement or head-twitch responses. The findings indicate 5-HT2A mediates antidepressant but not anxiolytic effects of these psychedelics.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
February 2, 2026
Maya C Gaines-Smith, Justin M Silverman, Michael Fiorillo et al.
3 citations
The drug MDMA, also known as ecstasy, is being studied as a possible aid in psychotherapy for hard-to-treat mental health conditions, but how it works in the brain is not fully understood. In experiments with mice, the S(+) form of MDMA, but not the R(-) form, activated a specific serotonin receptor (5-HT2AR) and caused changes in brain cell connections in the frontal cortex of males. The R(-) form had little effect except for a head-twitch response in females. Blocking the serotonin transporter with fluoxetine prevented these effects, showing that MDMA works indirectly by increasing serotonin levels. These results reveal that MDMA's effects on brain plasticity depend on both the drug's chemical form and the sex of the animal.
Journal of Pain
April 1, 2024
M. Imad Damaj, Eda Koseli, Belle Buzzi et al.
2 citations
No Summary
ACS Chemical Neuroscience
January 2, 2026
Mario de la Fuente Revenga, Javier González-Maeso
1 citation
The subjective effects that define psychedelics like LSD, psilocybin, and DOI are linked to activation of the serotonin 2A receptor (5-HT2AR), but what differentiates psychedelic from nonpsychedelic 5-HT2AR agonists is unclear. A new ex vivo platform was developed to measure drug-mediated activation of the Gq/11 pathway in mouse brain tissue by tracking inositol monophosphate (IP1) levels. In the frontal cortex of mice, DOI produced time-bound, dose-dependent IP1 increases that correlated with head twitch responses. LSD elevated IP1, while lisuride did not, consistent with their respective psychedelic and nonpsychedelic natures. MDMA also increased IP1, attributed to serotonin release, unlike the serotonin precursor 5-HTP or fluoxetine. This method provides mechanistic insights into psychedelic action and Gq/11-coupled receptors.
ACS Chemical Neuroscience
December 17, 2025
Justin M Silverman, Michael Fiorillo, Jason Younkin et al.
1 citation
α-Ethyltryptamine (AET), a synthetic tryptamine once used as an antidepressant, acts through a dual mechanism involving both direct activation of the 5-HT2A receptor and indirect serotonin release via the serotonin transporter (SERT). In vitro, AET and its isomers displaced ketanserin from the 5-HT2A receptor with micromolar affinity, but only the S(+)-AET isomer showed weak partial agonist activity. In mice, all forms of AET produced a head-twitch response that was blocked by a 5-HT2A antagonist and also by fluoxetine, indicating that SERT-mediated serotonin release contributes to its behavioral effects. This dual pharmacology distinguishes AET from classical psychedelics and aligns it with MDMA-like compounds, suggesting potential for modulating mood and cognition.
Elife
March 31, 2026
Jessica L Maltman, Javier González-Maeso
Exposure to psilocin, the active metabolite of the psychedelic psilocybin, increases structural complexity and strengthens synaptic connections in human neurons derived from stem cells. These changes suggest enhanced neuroplasticity at the cellular level.
BMC Neuroscience
March 24, 2026
Michael Fiorillo, Javier González-Maeso
Pretreating male mice with the psychedelic compound DOI, which activates serotonin 5-HT2A receptors, reduced brain inflammation and sickness behaviors caused by a later immune challenge with lipopolysaccharide (LPS). DOI lowered hippocampal levels of the inflammatory cytokines IL-6 and TNF-α, restored normal movement, decreased immobility in a forced swim test, and sped up body-weight recovery. These protective effects were partly preserved in mice lacking the 5-HT2A receptor, suggesting both receptor-dependent and receptor-independent mechanisms. Mice missing the receptor showed exaggerated inflammatory responses to LPS. Higher IL-6 levels in the hippocampus correlated with more depressive-like behavior, while higher IL-13 and IL-2 levels correlated with less immobility.
bioRxiv (Cold Spring Harbor Laboratory)
March 23, 2026
Marco Taddei-Tardón, Lidia Medina-Rodríguez, Jessica L Maltman et al.
Serotonergic psychedelics, including tryptamines, phenethylamines, and ergolines, promote structural and transcriptional changes in neurons through an integrated signaling network involving the 5-HT2A receptor and TrkB. Using a neural stem cell-derived model, the study shows that TrkB silencing blocks dendritogenesis induced by psychedelics, ketamine, and TrkB agonists, while 5-HT2A silencing selectively impairs psychedelic-induced plasticity. Most compounds increase synaptogenesis and immediate-early gene expression, though psilocin and the phenethylamines DOI and Ariadne show ligand-specific differences. Lactate production, dependent on 5-HT2A and both Gq/11 and Gi/o protein signaling, also occurs. These results establish a platform for dissecting psychedelic action.