ACS pharmacology & translational science
March 8, 2024
Grant C Glatfelter, Eline Pottie, John S Partilla et al.
28 citations
Lisuride, a non-psychedelic analogue of LSD, lacks psychedelic effects because it acts as a partial agonist at the 5-HT2A receptor and a potent agonist at the 5-HT1A receptor, which counteracts psychedelic activity. In vitro, LSD strongly activated 5-HT2A signaling, while lisuride showed only partial efficacy (6-52% of maximum) and blocked LSD's effects. In male mice, LSD caused head twitch responses (a behavioral marker of psychedelic action), whereas lisuride suppressed these responses and induced hypothermia and reduced movement. Blocking the 5-HT1A receptor restored baseline head twitches but did not increase them above normal, indicating that lisuride's lack of psychedelic effects stems from its partial agonist-antagonist activity at 5-HT2A, not solely from 5-HT1A activation.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 1, 2022
Deborah Rudin, John D McCorvy, Grant C Glatfelter et al.
18 citations
Derivatives of (2-aminopropyl)indole and (2-aminopropyl)benzofuran are new psychoactive substances with stimulant effects. This study characterized six isomers of the sulfur-based analog (2-aminopropyl)benzo[β]thiophene (APBT) in vitro and three isomers in vivo. APBTs inhibited monoamine reuptake and induced transporter-mediated substrate release, similar to MDMA, but did not stimulate locomotion in mice. Instead, they acted as full agonists at 5-HT2 receptor subtypes and induced head-twitch responses, indicating psychedelic-like activity. Replacing oxygen with sulfur enhanced serotonin transporter release potency and 5-HT2 receptor activity, shifting the profile toward psychedelic and entactogenic effects with minimal psychomotor stimulation, suggesting potential for drug-assisted psychotherapy.
ACS chemical neuroscience
December 18, 2024
Grant C Glatfelter, Allison A Clark, Natalie G Cavalco et al.
14 citations
5-MeO-DMT and its analogs bind to multiple serotonin and adrenergic receptors, with potent activity at 5-HT2A and 5-HT1A receptors. In mice, these compounds induce head twitch responses (a proxy for psychedelic-like effects) with varying potencies (ED50 0.2–1.8 mg/kg) and maximal effects (20–60 head twitches per 30 minutes), while higher doses cause hypothermia and reduced movement (ED50 3.2–20.6 mg/kg). Blocking 5-HT1A receptors enhances head twitch responses, unmasking activity in some analogs and increasing maximal responses to 40–90 head twitches per 30 minutes, indicating that 5-HT1A activation dampens 5-HT2A-mediated psychedelic-like effects. Suppression of head twitch responses by 5-HT1A only occurred at high 5-MeO-DMT doses, suggesting other receptors also modulate these effects.
Psychopharmacology
May 17, 2025
Shelby A McGriff, Jacquelin C Hecker, Alexander D Maitland et al.
12 citations
The head twitch response (HTR) in mice is a behavior increased by serotonergic psychedelics and used as a proxy for psychedelic-like effects. This study compared HTRs induced by DOI, LSD, and psilocybin in male and female C57BL/6J mice. Drug potencies for inducing HTRs were similar between sexes for all drugs, with LSD showing increased maximal counts in females. The maximum number of HTRs was higher in females for all drugs, with significant sex differences for DOI and LSD. Dose-by-sex interactions were significant for psilocybin and LSD, with females displaying more HTRs at the highest doses. Locomotor and temperature effects were similar between sexes. Overall, no substantial sex differences in potency were found, but females uniformly showed more HTRs at high doses.
Psychopharmacology
November 15, 2025
Michael H Baumann, Grant C Glatfelter, Sara E Walton et al.
1 citation
Intranasal delivery of the psychedelic compound N,N-dimethyltryptamine (DMT) is feasible and produces rapid drug uptake in rats. DMT given intranasally or subcutaneously caused similar effects, including increased flat body posture and decreased body temperature. Intranasal administration led to faster pharmacokinetics, with a half-life range of 11.9–14.3 minutes compared to 45.5–122.7 minutes for subcutaneous delivery, and higher peak drug concentrations. Importantly, maximal DMT concentrations in rats receiving low intranasal doses (30.2–55.6 ng/mL) overlap with psychoactive levels reported in humans, suggesting this non-invasive route may be viable for therapeutic use.
bioRxiv : the preprint server for biology
April 21, 2026
Jeanine Yacoub, Elena Bray, Jude Bayyat et al.
Halogenating the 2-position of DMT and psilacetin reduces their activity at 5-HT2A and 5-HT2B receptors, which are linked to psychedelic effects and heart valve toxicity, while preserving activity at other therapeutic targets like 5-HT6. The 2-Br-psilacetin analogue did not cause head-twitch behavior in mice and reduced head-twitch caused by another psychedelic, indicating lower potential for psychedelic effects. Intermediate doses improved stress-related mood measures and cued learning. These findings suggest that 2-halogenated tryptamines could be developed as safer, non-psychedelic therapeutics for psychiatric and neurodegenerative disorders.