The Journal of neuroscience : the official journal of the Society for Neuroscience
November 8, 2023
Lindsay P. Cameron, Joseph Benetatos, Vern Lewis et al.
88 citations
Serotonergic psychedelics like psilocybin and LSD activate serotonin 5-HT2A receptors in cortical brain regions, altering perception, cognition, and emotions. Their ability to promote neuroplasticity—forming new neural connections and rewiring networks—is thought to underlie therapeutic potential for depression, anxiety, and substance use disorders. These compounds also interact with other serotonin receptor subtypes (5-HT1A, 5-HT2C) and neurotrophin receptors, adding complexity to their effects. Research is exploring nonhallucinogenic derivatives that retain therapeutic benefits without intense psychedelic experiences, potentially reducing adverse reactions. The review also discusses psychedelics as substrates for post-translational protein modification as part of their mechanism.
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.
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.
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.
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.
Neuropsychopharmacology
November 12, 2025
Hannah M. Kramer, Meghan Hibicke, Jason W. Middleton et al.
7 citations
A single dose of psilocybin or the selective 5-HT2A receptor agonist 25CN-NBOH reduces immobility in the forced swim test in rats for at least three months, with no decrease in effect size over that period. Both drugs produced similar behavioral effects, indicating that 5-HT2A receptor activation alone is sufficient for long-lasting changes. In the medial prefrontal cortex, layer 5 excitatory pyramidal neurons showed altered resting membrane potential, firing rates, and synaptic excitation months after treatment. However, no changes were found in synaptic density, spine classification, or expression of presynaptic and postsynaptic markers. The results suggest that enduring functional plasticity, rather than structural plasticity, underlies the long-term behavioral effects of psychedelics.
Molecular Pharmacology
January 1, 2026
Lindsay P. Cameron, Alaina M Jaster, Raul A Ramos et al.
3 citations
2,5-dimethoxy-4-iodoamphetamine (DOI) is a phenethylamine psychedelic that binds tightly to 5-HT2 receptors, especially 5-HT2A and 5-HT2C. The US Drug Enforcement Administration proposed placing DOI and a similar compound in Schedule I of the Controlled Substances Act, citing their psychoactivity and potential for abuse. This review describes DOI's history, its essential role as a pharmacological tool in over 1,200 publications across five decades, and how it advanced the study of serotonin receptors. It also suggests alternative compounds for studying 5-HT2 receptors if DOI becomes restricted for research.
Journal of Science Policy & Governance
July 2, 2026
Alaina M Jaster, Joseph J. Hennessey, Tanner L. Anderson et al.
Research on Schedule I substances in the United States is heavily restricted by the Controlled Substances Act, creating what is termed Research Harm—the restriction or deterrence of legitimate scientific inquiry due to governmental regulatory controls and criminal prohibitions. Barriers include lengthy DEA registration timelines, inconsistent guidance, and policy confusion, limiting access to substances with therapeutic potential like psilocybin, MDMA, cannabis, and DOI. The 2025 HALT Fentanyl Act introduces procedural improvements such as expedited registration and shared institutional access but leaves key regulatory issues unresolved. Recommended reforms include revising medical utility interpretations, conducting periodic evidence reviews, and establishing a scheduling framework for easier research access.
Psychedelics
December 17, 2024
Alaina M Jaster
The serotonin 2A receptor modulates the rewarding aspects of opioids and influences neuroplasticity differently across sexes. Endocannabinoids are involved in fear extinction, and biomarkers may indicate familial risk of depression. Psychedelic use among adolescent populations is also being investigated.
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.