Psychopharmacology
October 1, 2014
Bruce E Blough, Antonio Landavazo, Ann M Decker et al.
99 citations
Synthetic hallucinogenic tryptamines, including those originally described by Alexander Shulgin, are abused in the USA. While all psychoactive tryptamines act as agonists at serotonin 2A (5-HT₂A) receptors, their varied subjective effects suggest additional neurochemical mechanisms. This work evaluated 21 tryptamines for interactions with serotonin receptor subtypes and neurotransmitter transporters. Eight compounds released serotonin, thirteen inhibited serotonin uptake or were inactive. All were 5-HT₂A agonists with varying potencies; few activated 5-HT₁A receptors. Most recruited β-arrestin via 5-HT₂A. Serotonin transporter (SERT) activity may contribute significantly to some compounds' pharmacology. Releasers tended to be structurally smaller compounds. Two tertiary amines acted as selective SERT substrates, challenging the view that releasing activity requires primary or secondary amines.
The Journal of pharmacology and experimental therapeutics
February 1, 2007
Richard B Rothman, Daniel L Murphy, Heng Xu et al.
75 citations
Salvinorin A, a hallucinogenic compound that activates kappa-opioid receptors, also partially inhibits mu-opioid receptor binding through an allosteric mechanism. In cells expressing human mu-opioid receptors, salvinorin A reduced binding of two different radioligands (DAMGO and diprenorphine) in a dose-dependent, nonlinear way, altering both the number of binding sites and their affinity. It also slowed the dissociation of these ligands from the receptor and acted as an uncompetitive inhibitor of receptor signaling. Similar effects were observed in rat brain tissue. Together, these findings indicate that salvinorin A modulates the mu-opioid receptor allosterically, not by binding at the same site as typical opioids.
Neuropharmacology
November 1, 2018
Joshua S Elmore, Ann M Decker, Agnieszka Sulima et al.
59 citations
N-methoxybenzylated derivatives of 2C compounds, specifically 25C-NBOMe and 25I-NBOMe, show higher affinity for 5-HT2A receptors than their parent 2C compounds but are weaker in functional cellular assays. In rats, NBOMes were much more potent at inducing wet dog shakes and back muscle contractions compared to 2C-C and 2C-I. A selective 5-HT2A antagonist reversed these behaviors, confirming receptor involvement. Binding affinities correlated with potencies for back muscle contractions but not wet dog shakes. These findings indicate NBOMes are highly potent 5-HT2A agonists in rats, consistent with reported hallucinogenic effects in humans.
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.
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.