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.
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.
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
Psilocybin has shown remarkable potential in enhancing neuroplasticity, with studies indicating a 30% reduction in depressive symptoms among participants. In trials involving over 200 individuals, this hallucinogen significantly influenced serotonin receptors, leading to increased synaptic plasticity in the prefrontal cortex. Notably, psilocybin acts as a glutamate receptor agonist, promoting excitatory postsynaptic potential and dendritic spine growth. These findings highlight the promising role of psychedelics in addressing mental health challenges through their impact on neurotransmitter systems and behavior, paving the way for innovative therapeutic approaches.
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.