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.
Molecular Psychiatry
November 5, 2025
Dino Luethi, Grant C. Glatfelter, Eline Pottie et al.
1 citation
Psychedelic-like effects of ring-substituted amphetamines are primarily mediated by 5-HT 2A receptors. Small lipophilic substituents at the 4-position of 2,5-dimethoxyamphetamine enhance clinical potency. This study examined 4-alkylated 2,5-dimethoxyamphetamines (methyl, ethyl, propyl, butyl, amyl) for in vitro receptor activity and in vivo effects in mice using the head-twitch response (HTR) assay. Increasing 4-alkyl chain length raised affinity at 5-HT 2A receptors. The 4-propyl analog showed the highest potencies for 5-HT 2A receptor activation (1–9 nM) in vitro; other chain lengths ranged from 2–56 nM. In mice, maximal HTR counts varied from 23 to 119, with potencies from 0.42 to 2.76 mg/kg.
bioRxiv Preprint Server
April 28, 2025
Alexander D. Maitland, Nicholas R. Gonzalez, Donna Walther et al.
1 citation
preprint
A new automated method using open-source machine learning toolkits, DeepLabCut and SimBA, accurately quantifies the head twitch response (HTR) in mice from experimental videos. The approach, trained and validated on videos of C57BL/6J mice given various psychedelic drugs, performed best at 50% video resolution and 120 frames per second (precision 95.45%, recall 95.56%, F1 score 95.51%) and also worked well at lower frame rates. When applied to bufotenine, a tryptamine derivative, elevated HTRs occurred only after blocking serotonin 1A receptors (ED50 = 0.99 mg/kg, max counts = 24). HTR counts from the automated method strongly correlated with visual scoring and semi-automated software (r = 0.98–0.99). The method offers a modular, noninvasive, open-source alternative to existing techniques.
Figshare
June 23, 2026
Elena Bray, Grant C. Glatfelter, Alexander D. Maitland et al.
A new chemical synthesis of 4-bromo-N,N-dimethyltryptamine (4-Br-DMT) was developed, enabling the creation of novel tryptamine molecules with modifications at the C4 position via palladium cross-coupling reactions. This approach facilitates rapid development of a library of compounds for studying structure-activity relationships with serotonergic targets. Compared to psilocin and DMT, 4-Br-DMT exhibits a serotonergic profile but lacks psychedelic-like effects in mice, though it has a reduced safety profile.
ACS Omega
June 23, 2026
Elena Bray, Grant C. Glatfelter, Alexander D. Maitland et al.
4-Bromo-dimethyltryptamine (4-Br-DMT) shows serotonergic activity in mice without producing psychedelic-like effects, but its safety profile is reduced compared to psilocin and DMT.
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.
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.