Science
March 21, 2013
Daniel Wacker, Chong Wang, Vsevolod Katritch et al.
689 citations
Serotonin receptors are targets for drugs treating depression, obesity, and migraine headaches. Crystal structures of two serotonin receptor subtypes bound to antimigraine medications or a precursor of LSD reveal how subtle differences in ligand binding cause substantial differences in receptor signaling and biological responses. The structures show that the same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which receptor it binds.
Science
March 22, 2013
Chong Wang, Yi Jiang, Jinming Ma et al.
522 citations
Two research teams independently determined the crystal structures of two serotonin receptors bound to antimigraine drugs or a precursor of LSD. The structures show that subtle differences in how ligands bind to these receptors lead to substantial differences in the signals generated and the resulting biological responses. The same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which specific receptor it binds to.
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.
ACS Chemical Neuroscience
December 15, 2022
Michael J. Cunningham, Hailey A. Bock, Inis C. Serrano et al.
65 citations
Ariadne, a non-hallucinogenic analog of the hallucinogen DOM, demonstrates significant therapeutic potential in treating various conditions. In clinical trials, Ariadne led to rapid remission of psychotic symptoms in schizophrenia and improved cognition in elderly patients. It acts as a 5-HT<sub>2A</sub> receptor agonist with modest selectivity for 5-HT<sub>1</sub>, exhibiting lower signaling potency than DOM. Notably, in a Parkinson’s disease model, Ariadne alleviated severe motor deficits comparable to l-DOPA, positioning it as a promising candidate for future psychiatric and neurological therapies.
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.
Beilstein Journal of Organic Chemistry
October 8, 2012
Adam Pigott, Stewart Frescas, John D. Mccorvy et al.
19 citations
Replacing the ethylamine side chain of two psychedelic amphetamine derivatives, DOI and DOB, with a cyclopropylamine moiety produced compounds with high affinity for the 5-HT(2) family of serotonin receptors. The more potent stereoisomer of these cyclopropane analogues had the expected (-)-(1R,2S)-configuration. However, the cyclopropane congeners also showed increased affinity at several other serotonin receptor subtypes beyond 5-HT(2A) and 5-HT(2B). While at appropriate doses the compounds may serve as tools to probe 5-HT(2) receptor function, their selectivity for 5-HT(2A) receptors is somewhat less than that of DOI itself.
ACS Pharmacology & Translational Science
August 22, 2025
Devin P. Effinger, Serena S. Schalk, Jillian L. King et al.
3 citations
Microdosing involves taking psychedelics at doses too low to cause hallucinations, and is popular for supposed cognitive and emotional benefits. Psychedelics bind strongly to 5-HT 2B receptors, which can cause heart disease when chronically activated. In mice, researchers gave either serotonin or d-fenfluramine as positive controls, or low doses of LSD. Serotonin caused significant ventricular thickening at 4 and 8 weeks; d-fenfluramine caused aortic valve regurgitation at 4 weeks. No significant heart changes appeared in any LSD group. LSD, psilocybin, and norfenfluramine had similar affinity and potency at mouse and human 5-HT 2B receptors. Low-dose LSD produced substantial but short-lived receptor activation compared to d-fenfluramine. These data provide no evidence that prolonged low-dose LSD causes heart remodeling in mice.
bioRxiv (Cold Spring Harbor Laboratory)
April 14, 2025
Devin P. Effinger, Serena S. Schalk, Jillian L. King et al.
2 citations
preprint
Chronic administration of low-dose LSD in mice does not produce the cardiovascular damage seen with serotonin, a known cardiotoxin. Serotonin caused significant ventricular thickening after 4 and 8 weeks, while LSD at two sub-hallucinogenic doses showed no such changes. Although LSD activates 5-HT 2B receptors—the same receptors linked to heart disease from chronic activation—the activation is substantial but short-lived compared to the cardiotoxin d-fenfluramine. Affinity and potency of LSD, psilocybin, and norfenfluramine at mouse and human 5-HT 2B receptors were similar. These findings indicate no evidence of cardiovascular risk from prolonged low-dose LSD in mice.
ACS Chemical Neuroscience
May 27, 2026
Grant C. Glatfelter, Serena S. Schalk, Donna Walther et al.
Tryptamine psychedelics produce their effects mainly by activating serotonin 2A receptors, but many also affect other targets. 4-MeO-MiPT, a compound that both activates 5-HT2A receptors and blocks the serotonin transporter (SERT), produces blunted psychedelic effects in humans. In mice, 4-MeO-MiPT and its analogs with stronger SERT blockade showed fewer head twitch responses (a proxy for psychedelic-like effects) than their 4-hydroxy counterparts. Pretreating mice with the SERT inhibitor fluoxetine reduced head twitch responses from 4-hydroxy compounds to levels seen with the 4-methoxy analogs. The findings suggest that dual 5-HT2A/SERT ligands may have therapeutic potential with reduced acute psychedelic effects.
ACS Chemical Neuroscience
December 2, 2025
Nina Kastner, Núria Nadal‐gratacós, Selina Hemmer et al.
Replacing the 1,3-benzodioxole group in MDMA (ecstasy) with a 1,3-benzoxathiole yields two analogues, SDA and SDMA, that interact with monoamine transporters similarly to MDMA but with key differences. SDA and SDMA inhibit dopamine and norepinephrine transporters more potently than MDMA and act as partial releasers at serotonin and dopamine transporters. Metabolism studies show SDA and SDMA are cleared faster, while MDMA and MDA degrade only weakly. In mice, SDMA does not produce rewarding effects, unlike MDMA, and SDA only shows a preference for the drug-paired compartment at the lowest dose. SDMA shares similar locomotor and hyperthermic profiles with MDMA, whereas SDA induces increased hyperlocomotion and more sustained hyperthermia. SDMA may be a safer candidate for further study.
UNC Libraries
October 31, 2020
Adam Pigott, Bryan L. Roth, Xi‐ping Huang et al.
Replacing the ethylamine side chain of the psychedelic compounds DOI and DOB with a cyclopropylamine group produced new molecules that bind strongly to 5-HT2 family serotonin receptors. The most potent version had the (−)-(1R,2S)-configuration. However, these cyclopropane analogs also showed increased affinity for other serotonin receptor subtypes beyond 5-HT2A and 5-HT2B, making them less selective than the original compounds. At appropriate doses, they may serve as research tools for studying 5-HT2 receptor function, but their reduced selectivity for 5-HT2A receptors must be considered.