Pharmacological reviews
April 23, 2025
Benjamin R Cummins, Gerald B Billac, David E Nichols et al.
62 citations
Serotonin 5-HT2A receptors are found throughout the body and are most dense in brain cortical layer V. They are involved in normal physiology and neuropsychiatric diseases like schizophrenia. Atypical antipsychotics block these receptors, while psychedelic drugs such as psilocybin, dimethyltryptamine, and lysergic acid diethylamide activate them to produce lasting therapeutic effects in clinical trials for major depression and substance use disorders. The three main agonist scaffolds—tryptamines, ergolines, and phenylalkylamines—engage different amino acid residues in the receptor binding pocket, leading to functionally selective outcomes. Understanding these ligand-receptor interactions guides future drug discovery for optimized therapeutics.
ACS pharmacology & translational science
April 9, 2021
Thomas W Flanagan, Gerald B Billac, Alexus N Landry et al.
50 citations
Psychedelic drugs can reduce inflammation, but this effect does not depend on their mind-altering properties. By testing 21 different 5-HT2A receptor agonists in a rat model of allergic asthma, the drug 2,5-dimethoxyphenethylamine (2C-H) was identified as the key structure for anti-inflammatory activity. Specific chemical modifications either enabled or blocked this effect. No link was found between a drug's ability to trigger calcium signaling (a standard measure of receptor activation) and its ability to prevent asthma symptoms or produce behavioral effects. This suggests that anti-inflammatory benefits arise from distinct receptor pathways, not the canonical signaling pathway. These findings could guide development of non-psychoactive anti-inflammatory drugs targeting the 5-HT2A receptor.
Neuropharmacology
August 17, 2022
Jack E Henningfield, Marion A Coe, Roland R Griffiths et al.
34 citations
New medicines containing classic hallucinogenic and entactogenic psychedelics like psilocybin, LSD, and MDMA are being developed for psychiatric and neurological disorders. These substances are currently Schedule I under the US Controlled Substances Act (CSA) and similarly controlled globally. The CSA framework governs research, drug approval, and rescheduling; upon FDA approval, a drug containing a Schedule I substance must be rescheduled. Abuse potential research informs the eight CSA factors used for rescheduling, as well as product labeling and required risk evaluation and mitigation strategies (REMS). Standard human abuse potential studies are problematic for strong hallucinogens like psilocybin, so alternative strategies are discussed. Abuse-related research may also illuminate mechanisms of action, therapeutic effects, and effects on brain, behavior, mood, spirituality, and consciousness.
Psychedelic medicine (New Rochelle, N.Y.)
March 1, 2023
Meghan Hibicke, Hannah M Kramer, Charles D Nichols
25 citations
A single dose of psilocybin rescued cognitive function and reduced passive coping behavior in adult female rats that had experienced chronic stress during adolescence, effects that persisted for at least five weeks. Psilocybin did not alter these behaviors in non-stressed rats. The degree of immobility in the forced swim test correlated with impaired object pattern separation ability. No long-term changes in mRNA expression for synaptic plasticity-related genes were observed across several brain regions, though stress contributed to variability in the gene for glutamate metabotropic receptor 2 in the hippocampus. These findings suggest psilocybin produces enduring antidepressant-like effects without lasting alterations in synaptic density gene expression.
Psychopharmacology
December 11, 2023
Haley Maria Dourron, Charles D Nichols, Otto Simonsson et al.
23 citations
5-MeO-DMT, a tryptamine being developed as an antidepressant, may work through a mechanism distinct from typical psychedelics. This review compares the acute and post-acute effects of 5-MeO-DMT to epileptiform activity, particularly in temporal lobe epileptogenic zones. The authors note that 5-MeO-DMT has notable 5-HT1A receptor agonist properties and that aberrant 5-HT1A receptor functioning occurs in epilepsy. They suggest that 5-MeO-DMT's therapeutic mechanism might be partly mediated by evoking temporary epileptiform activity, similar to electroconvulsive therapy. The phenomenon of 'reactivations'—sudden re-experiencing of drug effects common after 5-MeO-DMT but not typical psychedelics—may indicate recurrent epileptiform activity. The review concludes that further evaluation of 5-MeO-DMT's unique mechanisms is warranted.
International review of neurobiology
January 1, 2025
David E Nichols, Charles D Nichols
3 citations
Classic psychedelics have been used for millennia for healing and religious purposes. Modern psychedelic science began in 1898 when Dr. Arthur Heffter identified mescaline as the active alkaloid in peyote. Western society's relationship with psychedelics has been contentious: initially valued as medicines and scientific tools, they were later criminalized during the 1960s counterculture, halting research for nearly 20 years. As the political climate shifted, clinical trials resumed, with high-profile studies demonstrating efficacy for psychiatric disorders. This review covers 125 years of psychedelic science, highlighting key events and findings that advanced understanding of their pharmacology, chemistry, and therapeutic potential.
Psychedelic medicine (New Rochelle, N.Y.)
March 1, 2024
Meghan Hibicke, Gerald Billac, Charles D Nichols
2 citations
In male Wistar-Kyoto rats, intravenous psilocin (the active form of psilocybin) produced persistent antidepressant-like effects, reducing immobility in the forced swim test at both 3 and 14 weeks after a single dose. When lorazepam was given 30 minutes before psilocin, the antidepressant-like effect was present at 3 weeks but absent by 14 weeks, and the effect at 14 weeks was weaker than in rats given psilocin alone. Lorazepam therefore reduced both the magnitude and longevity of psilocin's antidepressant-like effects in this animal model.