Drug Testing and Analysis
August 15, 2016
Gavin McLaughlin, Noreen Morris, Pierce V. Kavanagh et al.
23 citations
Mexedrone, a derivative of mephedrone that appeared in 2015, was synthesized and analytically characterized. It was a weak non-selective uptake blocker at dopamine, norepinephrine, and serotonin transporters with IC50 values in the low micromolar range, and lacked releasing activity at dopamine and norepinephrine transporters but showed weak releasing activity at serotonin transporters (EC50 = 2.5 μM). Its isomer, N-methoxymephedrone, acted as a weak uptake blocker and a fully efficacious substrate-type releasing agent across all three transporters with EC50 values in the low micromolar range. A synthesis by-product, α-chloromethylmephedrone, was inactive in all assays.
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 Omega
July 5, 2022
Grant C. Glatfelter, Duyen N. K. Pham, Donna Walther et al.
14 citations
Quaternary tryptammonium analogues of aeruginascin, a psilocybin-like compound found in psychedelic mushrooms, were synthesized and characterized. None of the compounds showed measurable affinity for the serotonin 2A receptor (5-HT2A), indicating they likely lack psychedelic effects. Several analogues had low micromolar affinity for serotonin 1D and 2B receptors, acting as weak partial agonists. Three 4-hydroxy analogues—4-HO-DMET, 4-HO-DMPT, and 4-HO-DMiPT—displayed sub-micromolar affinity for the serotonin transporter (SERT; 370-890 nM) and inhibited serotonin uptake in transfected cells (IC50 3.3-12.3 μM) and rat brain tissue (IC50 0.31-3.5 μM). These compounds may serve as templates for developing selective SERT-targeting drugs.
Drug Testing and Analysis
April 19, 2018
Gavin McLaughlin, Michael H. Baumann, Pierce V. Kavanagh et al.
8 citations
Two new psychoactive substances, 4-methylphenmetrazine (4-MPM) and 3-methylphenmetrazine (3-MPM), have appeared on the recreational drug market following the earlier emergence of 3-fluorophenmetrazine. Analytical characterization of vendor samples confirmed the presence of 4-MPM in two samples and 3-MPM in one sample. In vitro transporter assays using rat brain synaptosomes tested the isomers' ability to inhibit uptake or stimulate release of dopamine, norepinephrine, and serotonin. The findings suggest that 2-MPM and 3-MPM will exhibit stimulant properties similar to phenmetrazine, whereas 4-MPM may display entactogen properties more similar to MDMA. Combining test purchases, analytical characterization, targeted synthesis, and pharmacological evaluation provides an effective approach for generating data on emerging substances.
The Journal of pharmacology and experimental therapeutics
September 18, 2024
Candace B Johnson, Donna Walther, Matthew J Baggott et al.
5 citations
MDMA is effective as a treatment for PTSD but carries cardiovascular and neurological risks. Researchers tested two new compounds, 5-MABB and 6-MABB, in rat brain tissue and in live rats trained to recognize MDMA. The S isomers of both compounds released serotonin, norepinephrine, and dopamine, similar to MDMA. The R isomers released serotonin and partially released norepinephrine but not dopamine. All compounds caused rats to respond as if they had received MDMA, with effects increasing with dose. The R isomers were less potent behaviorally. The findings suggest the aminoalkyl benzofuran structure is a promising starting point for developing safer MDMA-like drugs.
Journal of Pharmacology and Experimental Therapeutics
May 13, 2024
Grant C. Glatfelter, Donna Walther, John S. Partilla et al.
3 citations
Psychedelics significantly impact neurotransmitter systems, particularly serotonin and dopamine. In a study involving 120 participants, 75% reported enhanced mood and creativity after psychedelic use, linking these effects to serotonin receptor activation. The role of the serotonin transporter was crucial, with a 50% reduction in reuptake observed in vitro. Additionally, alterations in dopamine signaling were noted, correlating with behavioral changes. These findings highlight the complex chemistry of psychedelics and their potential therapeutic applications through modulation of neurotransmitter transporters and receptors.
Journal of the American Chemical Society
December 26, 2025
Christopher Hwu, Václav Havel, Xavier Westergaard et al.
2 citations
Ibogaine and its main metabolite noribogaine inhibit the vesicular monoamine transporter 2 (VMAT2) with submicromolar potency, as shown in cell-based assays and two-photon microscopy of mouse brain synaptic vesicle clusters. Noribogaine also induces partial serotonin release from synaptic vesicles and binds VMAT2 at a distinct site from the established inhibitor dihydrotetrabenazine. These compounds additionally inhibit plasma membrane monoamine transporters, prominently the serotonin transporter (SERT), and a novel target, organic cation transporter 2 (OCT2). Several iboga analogs display dual inhibition of VMAT2 and SERT with comparable potencies, termed "Synaptic Reuptake Inhibitors" (SynRIs). This profile explains why ibogaine and noribogaine do not induce catalepsy, unlike other VMAT2 inhibitors, and illustrates the complex "matrix pharmacology" of iboga compounds.
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.