Nat Commun
December 15, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
153 citations
Serotonergic psychedelics show therapeutic potential, but the specific roles of 5-HT2A receptor signaling pathways are unclear. Researchers developed selective ligands with varying Gq efficacies, including β-arrestin-biased ones. In male mice, 5-HT2A-Gq recruitment efficacy, not β-arrestin2 recruitment, predicted psychedelic potential measured by head-twitch response magnitude. Disrupting Gq-PLC signaling reduced this response, and a threshold Gq activation level was needed for psychedelic-like effects, explaining why partial agonists like lisuride are non-psychedelic. β-arrestin-biased agonists blocked psychedelic effects and caused receptor downregulation and tachyphylaxis. Fine-tuning 5-HT2A Gq-signaling enables development of non-psychedelic 5-HT2A agonists.
ACS Pharmacology & Translational Science
December 14, 2020
Adam K. Klein, Muhammad Chatha, Lauren J. Laskowski et al.
103 citations
The 5-HT2A receptor is the primary target for psilocybin and other serotonergic hallucinogens. Seventeen tryptamines with 4-hydroxy or 4-acetoxy groups and various N,N-dialkyl substituents were tested. All acted as full or partial agonists at 5-HT2 subtypes, with similar potencies at 5-HT2A and 5-HT2B receptors, though bulkier N-alkyl groups reduced potency at 5-HT2C receptors and increased 5-HT2B efficacy. O-acetylation reduced in vitro 5-HT2A potency by 10- to 20-fold without altering efficacy. All compounds induced head twitches in mice, consistent with LSD-like effects. Acetylation had little effect on head-twitch potency, suggesting O-acetylated tryptamines may act as prodrugs deacetylated in vivo. These derivatives have psilocybin-like properties, supporting their classification as psychedelic drugs.
Journal of Natural Products
February 20, 2020
Alexander M. Sherwood, Adam L. Halberstadt, Adam K. Klein et al.
79 citations
A new synthetic method allows access to tryptamine natural products found in psilocybin-producing mushrooms. Laboratory and animal experiments tested whether these compounds are psychoactive. In mice, the natural product baeocystin did not produce a head twitch response, a behavioral marker of psychedelic activity, even though its predicted breakdown product, norpsilocin, strongly activates the 5-HT2A receptor, which is associated with psychedelic effects. This suggests that baeocystin itself may not be psychedelic, despite its metabolite's activity.
Drug Testing and Analysis
May 13, 2019
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
72 citations
1-Butanoyl-LSD (1B-LSD), a new analog of lysergic acid diethylamide (LSD), was fully characterized using multiple analytical techniques including NMR, mass spectrometry, and infrared spectroscopy, allowing clear differentiation from a similar compound, 1P-ETH-LAD. In behavioral tests with C57BL/6J mice, 1B-LSD produced a dose-dependent increase in head-twitch response, a marker of serotonergic hallucinogen activity, though with only about 14% of LSD's potency (ED50 = 976.7 nmol/kg vs. 132.8 nmol/kg for LSD). This suggests 1B-LSD has LSD-like behavioral effects and may act as a pro-drug for LSD, but further research is needed to confirm psychoactive effects in humans.
Drug Testing and Analysis
March 16, 2020
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
38 citations
1-Cylopropanoyl-LSD (1CP-LSD), a new lysergamide-based designer drug, was analyzed using multiple chemical and spectroscopic methods. Incubation with human serum converted 1CP-LSD into LSD, suggesting it may act as a prodrug for LSD in the body. In mice, 1CP-LSD induced a head-twitch response (HTR) with an ED50 of 430.0 nmol/kg, comparable to 1P-LSD (ED50 = 349.6 nmol/kg), indicating an LSD-like behavioral profile. The study includes analysis of blotters and pellets, and detected artificially induced degradation products during GC-MS analysis. Clinical studies are needed to determine its potency and effects in humans.
Neuropharmacology
November 19, 2019
Adam L. Halberstadt, Muhammad Chatha, Adam K. Klein et al.
37 citations
The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52) and other 1-acyl-substituted LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs assumed to act as prodrugs for LSD. Competitive binding studies and calcium mobilization assays showed 1-acyl-substitution reduced affinity for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude, and these derivatives had weak efficacy or acted as antagonists in Ca2+-mobilization assays. Despite this, they induced head twitches in mice with relatively high potency. High levels of LSD were detected in rat plasma after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating rapid and efficient deacylation in vivo, consistent with the prediction that these compounds serve as prodrugs for LSD.
Journal of Psychopharmacology
January 6, 2026
Connor J. Maltby, Adam K. Klein, Enya Paschen et al.
3 citations
Psilocybin produces rapid and sustained antidepressant effects in major depressive disorder, but the underlying neurobiological mechanisms are unclear. In mice, psilocybin caused dose-dependent occupancy of the 5-HT₂A receptor in the prefrontal cortex, with an inverted-U dose-response for head twitch behavior peaking between 44% and 62% receptor occupancy. A 1.5 mg/kg dose increased time spent in open areas of the elevated zero maze, indicating reduced anxiety, while 3 mg/kg reduced immobility in the forced swim test, suggesting antidepressant-like effects. Both doses shifted α-tubulin post-translational modifications toward more dynamic microtubules and selectively increased synaptic protein expression in the prefrontal cortex, but not the amygdala. These findings indicate that psilocybin's therapeutic effects may involve dose- and region-specific enhancement of neuronal plasticity, with distinct signatures for anxiolytic-like and antidepressant-like properties.
Journal of Psychopharmacology
October 16, 2025
Gerard J. Marek, Soma Makai‐bölöni, Daniel Umbricht et al.
2 citations
A single intravenous dose of GM-2505, a novel 5-HT2A receptor agonist, was safe and well tolerated in 48 healthy volunteers at doses up to 20 mg. The drug produced mild, transient increases in blood pressure and pulse, no significant electrocardiograph changes, and a half-life of 40–50 minutes. Dose-dependent effects appeared on neuroendocrine hormones, neuropsychological and neurophysiological measures, subjective drug effects, and resting-state electroencephalography, with decreased theta and alpha power and increased slow and fast gamma power. These pharmacodynamic effects resembled those of other 5-HT2A agonists, but GM-2505's shorter duration of cardiovascular and subjective effects than psilocybin and longer than DMT suggests a more practical temporal profile for supervised clinical use, with an optimal dose range of 10–15 mg IV.