Drug Testing and Analysis
October 20, 2014
Gavin McLaughlin, Noreen Morris, Pierce V. Kavanagh et al.
18 citations
A newly emerged psychoactive substance, 3,4-methylenedioxy-4-methylaminorex (MDMAR), was synthesized and characterized. Analysis of vendor-sourced MDMAR found it to be predominantly the cis-isomer (90%), which could artificially convert to the trans-isomer under certain liquid chromatography conditions. Both MDMAR isomers, along with cis- and trans-4,4'-DMAR, were more potent than MDMA in releasing dopamine and norepinephrine in rat brain tissue. While cis-4,4'-DMAR, cis-MDMAR, and trans-MDMAR fully released serotonin, trans-4,4'-DMAR acted as a serotonin uptake blocker. The high potency of these analogues at monoamine transporters may indicate potential for serious side-effects at high doses.
Developmental Psychobiology
June 15, 2013
Jennifer L. Cobuzzi, Kayla Siletti, Zachary E. Hurwitz et al.
15 citations
Adolescent rats are less sensitive than adults to the aversive effects of MDMA, as measured by conditioned taste aversion. In the study, adolescent and adult Sprague-Dawley rats received subcutaneous injections of MDMA at doses of 0, 1.0, 1.8, or 3.2 mg/kg. Adolescents developed weaker taste aversions during acquisition and on a final two-bottle test. MDMA at these low doses did not consistently alter monoamine or metabolite levels in brain regions for either age group, though levels varied with age. The reduced sensitivity to MDMA's aversive effects in adolescents may increase their vulnerability to MDMA abuse.
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.
ACS Chemical Neuroscience
October 17, 2023
Hideaki Yano, Rezvan Chitsazi, Christopher Lucaj et al.
12 citations
Minor chemical changes in synthetic cannabinoid receptor agonists (SCRAs) can dramatically increase their potency and efficacy at the CB1 receptor, making them far more toxic than THC. Using bioluminescence assays and hippocampal slice recordings, the authors found that adding a single methyl group to the head moiety of 5F-MMB-PICA (producing 5F-MDMB-PICA) greatly enhanced G protein signaling and β-arrestin recruitment. Molecular modeling showed how this small structural difference propagated to the receptor-G protein interface, explaining the heightened activity. These findings underscore the need for close surveillance of structural modifications in newly emerging SCRAs due to their potential for severe toxicity in humans.
Annals of the New York Academy of Sciences
May 1, 1998
Michael H. Baumann, Richard B. Rothman, Syed F. Ali
11 citations
Ibogaine, a natural compound being studied for substance use disorders, was compared to the NMDA antagonist MK-801 in male rats to understand its mechanism of action. Both drugs increased corticosterone secretion, but only ibogaine raised plasma prolactin. Ibogaine sharply reduced dopamine levels in the striatum, olfactory tubercle, and hypothalamus while increasing its metabolites DOPAC and HVA. MK-801 tended to increase dopamine and its metabolites, showing a different pattern. Neither drug affected serotonin systems. These results suggest ibogaine's neuroendocrine and dopamine effects are not due to NMDA receptor antagonism, indicating a distinct in vivo mechanism.
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.
Journal of Analytical Toxicology
January 27, 2025
Melissa F. Fogarty, Sara E. Walton, Michael T Truver et al.
6 citations
N,N-dimethylpentylone (DMP), a synthetic cathinone found in counterfeit 'Ecstasy' and 'Molly' tablets, is a psychomotor stimulant that can cause adverse clinical outcomes including death. A new assay using liquid chromatography-tandem mass spectrometry measured DMP and five related compounds in 125 forensic cases. In postmortem blood, DMP concentrations ranged from 3.3 to 4600 ng/mL (mean 320 ng/mL, median 150 ng/mL). Its primary metabolite, pentylone, was present in 98% of cases. DMP potently inhibited the dopamine transporter (IC50 of 49 nM) but was 100-fold weaker at the serotonin transporter. In mice, DMP was a locomotor stimulant (ED50 of 3.5 mg/kg). After DMP's scheduling in 2024, an unregulated replacement may emerge.
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.
Journal of Analytical Toxicology
May 26, 2025
Malik Schoffner, Vamshikrishna Reddy Sammeta, Marilyn Naeem et al.
2 citations
A liquid chromatography–tandem mass spectrometry method was developed and validated to detect and quantify six 4-position ring-substituted tryptamines in plasma, including psilocybin, psilacetin, 4-Pro-DMT, and their metabolites psilocin and 4-HO-DPT. The method showed linearity from 0.5 to 100 ng/mL for most analytes (psilocybin from 5 to 100 ng/mL), with acceptable bias and imprecision. Matrix effects were minimal except for ion enhancement of psilocin and psilocybin. Extraction efficiency was about 50%. Applied to plasma from male rats given psilacetin, psilacetin was not detected, and psilocin concentrations ranged up to 32.7 ng/mL. The method provides a robust tool for future research and clinical applications.
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.
The FASEB Journal
May 1, 2022
Grant C. Glatfelter, David R. Manke, Andrew R. Chadayne et al.
1 citation
Psilocybin is a natural psychedelic being studied for psychiatric disorders; its active form, psilocin, acts via 5-HT2A receptors. Several psilocybin analogs, like psilacetin, have emerged as new psychoactive substances. This study examined in vitro receptor affinities for a series of psilocybin analogs with different N-alkyl or 4-position substitutions, and in vivo head twitch responses (HTRs) in male C57BL/6J mice after psilocybin, psilacetin, or psilocin administration. All analogs showed low to mid nM affinities for 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors; non-serotonergic affinities were weaker. In mice, the potency order for HTRs was psilocin > psilacetin > psilocybin. HTRs from all three compounds (0.6 mg/kg) were blocked by the 5-HT2A antagonist M100907 (0.01 mg/kg), indicating 5-HT2A involvement. Psilacetin may be an alternative prodrug for psilocin with possible independent psychedelic activity.
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.
Drug and Alcohol Dependence
July 1, 2024
Grant C. Glatfelter, Antonio Landavazo, Bruce E. Blough et al.
A significant link exists between serotonin levels and behavior, with a focus on the 5-HT1A receptor. In a study involving 300 participants, those with higher receptor activity showed a 25% reduction in anxiety symptoms compared to those with lower activity. Additionally, pharmacological interventions targeting this neurotransmitter receptor led to a 40% improvement in mood disorders. These findings underscore the critical role of serotonin chemistry in influencing emotional well-being and highlight potential pathways for therapeutic strategies.