Synapse
January 1, 2000
Richard B. Rothman, Michael H. Baumann, Christina M. Dersch et al.
933 citations
Stimulants like amphetamine, MDMA, and methamphetamine are known to produce reinforcing effects in animals through the brain chemical dopamine. However, their subjective effects in humans—such as euphoria or alertness—may rely more on norepinephrine. Using lab tests, the authors measured how several stimulants affect the release of norepinephrine and dopamine. They found that all tested drugs were most potent at releasing norepinephrine. Crucially, the oral doses that produce amphetamine-like subjective effects in people correlated with the drugs' ability to release norepinephrine, not dopamine, and did not lower prolactin levels (a marker of dopamine release). These findings suggest norepinephrine may play a key role in the subjective experience of stimulants in humans.
Psychopharmacology
March 15, 2006
Michael H. Baumann, Xiaoying Wang, Richard B. Rothman
269 citations
High doses of MDMA (ecstasy) reduce serotonin levels in the brains of rats, but this reduction does not necessarily indicate that neurons have been damaged. The drug works by stimulating the release of serotonin, norepinephrine, and dopamine. At doses that cause long-term serotonin depletion (10-20 mg/kg), markers of actual neuronal damage such as cell death or gliosis are not reliably increased. Even moderate doses that do not deplete serotonin can produce lasting anxiety-like behaviors in rats, suggesting potential risks from the drug beyond neurotoxicity.
Synapse
July 14, 2004
Xiaoying Wang, Michael H. Baumann, Heng Xu et al.
101 citations
Two weeks after giving rats MDMA (7.5 mg/kg, three doses) or the toxin 5,7-DHT, the study measured serotonin levels and two protein markers in brain regions. MDMA reduced tissue serotonin by about 50% in cortex, hippocampus, and caudate but did not significantly change the amount of serotonin transporter or glial fibrillary acidic protein, a marker of nerve damage. In contrast, 5,7-DHT reduced serotonin by over 90%, lowered serotonin transporter protein by 20–35%, and increased glial fibrillary acidic protein by 30–39%. The authors conclude that this MDMA regimen does not cause degeneration of serotonin nerve terminals and that lasting serotonin depletion can occur without destroying the axons.
ACS Pharmacology & Translational Science
November 2, 2022
Eline Pottie, Marilyn Naeem, Vamshikrishna Reddy Sammeta et al.
91 citations
Psilocybin is a prodrug for psilocin, which produces psychedelic effects by activating serotonin 5-HT2A receptors. This study examined three naturally occurring compounds from psilocybin-containing mushrooms—psilocybin, baeocystin, and aeruginascin—along with their synthetic 4-acetoxy and 4-hydroxy analogues. In cell-based assays, secondary and tertiary tryptamines with 4-acetoxy or 4-hydroxy substitutions showed nanomolar affinity for several human serotonin receptor subtypes, including 5-HT2A and 5-HT1A. In mice, only the tertiary amines psilocin, psilocybin, and psilacetin induced head twitch responses (ED50 0.11–0.29 mg/kg), indicating psychedelic-like activity, which was blocked by a 5-HT2A antagonist.
Journal of Pharmacology and Experimental Therapeutics
May 1, 2001
Michael H. Baumann, Richard B. Rothman, John Pablo et al.
69 citations
Ibogaine, a compound with potential anti-addiction properties, is rapidly converted in the body to noribogaine. In rats, intravenous ibogaine caused dose-related tremors, while noribogaine did not. Both compounds raised stress hormones (corticosterone and prolactin), but ibogaine was more potent for corticosterone. Neither altered dopamine levels in the nucleus accumbens, but both increased extracellular serotonin, with noribogaine being about 10 times more potent as an indirect serotonin agonist. In vitro tests showed both inhibit serotonin uptake. Noribogaine appears biologically active and less likely to cause adverse effects, suggesting it may be a safer alternative for medication development.
Journal of Neuroscience
June 4, 2014
Eugene A. Kiyatkin, A. H. Kim, Ken T. Wakabayashi et al.
47 citations
MDMA (Ecstasy) can cause fatal brain hyperthermia when taken in hot, crowded environments, even at moderate doses that are harmless under cool, quiet conditions. In male rats, MDMA at 9 mg/kg (about one-fifth of the lethal dose) produced only weak brain temperature increases under standard lab conditions (quiet rest, 22–23°C). However, social interaction with another male rat and a warm environment (29°C) dramatically amplified brain hyperthermia. The key mechanism is peripheral vasoconstriction, which prevents heat dissipation through the skin. This shows that doses of MDMA that are nontoxic in cool, quiet settings become highly dangerous under conditions mimicking recreational use at rave parties or other hot, crowded venues.
Clinical Chemistry
June 30, 2017
Marilyn A. Huestis, Simon D. Brandt, Suman Rana et al.
42 citations
Novel psychoactive substances (NPS) have been present in clinical and forensic toxicology for over a century, with early examples including heroin, LSD, MDMA, and GHB. After synthetic cannabinoids emerged in the early 2000s, hundreds of synthetic cathinones, benzodiazepines, and opioids rapidly appeared. Toxicology laboratories, once focused on a narrow range of compounds, now face potent fentanyl derivatives mixed with or substituted for heroin, causing rising fatalities. Labs struggle to detect short-lived drug analogs, unknown urinary metabolites, and lack reference standards. Four international experts discuss what drove the global NPS market, how toxicology laboratories can address these challenges, and how public health and law enforcement can reduce NPS-related morbidity and mortality.
Journal of Psychopharmacology
April 30, 2019
Dino Luethi, Karolina E. Kolaczynska, Melanie Walter et al.
39 citations
Metabolites of the popular illicit drugs MDMA, methylone, and MDPV can interact with human monoamine transporters and receptors at concentrations relevant to their pharmacological effects. MDMA and methylone inhibited norepinephrine uptake more potently than dopamine or serotonin uptake. N-demethylation of MDMA did not change its uptake inhibition profile, but N-demethylation of methylone reduced overall potency. Opening the methylenedioxy ring produced catechol metabolites that maintained norepinephrine and dopamine uptake inhibition but had much weaker effects on serotonin uptake. Further O-methylation of these catechols reduced norepinephrine uptake inhibition, yielding metabolites without significant stimulant properties. N-demethylated metabolites of MDMA and methylone circulate unconjugated and may contribute to the drugs' effects in human users.
Drug Testing and Analysis
May 19, 2014
Simon D. Brandt, Michael H. Baumann, John S. Partilla et al.
37 citations
A new designer drug, para-methyl-4-methylaminorex (4,4'-DMAR), was linked to 26 deaths in Europe in 2013. Laboratory analysis of samples from online vendors identified the (±)-cis isomer in at least 18 cases. The drug acts as a potent releaser at dopamine, norepinephrine, and serotonin transporters, with EC50 values of 8.6 nM, 26.9 nM, and 18.5 nM respectively. Its potency at dopamine and norepinephrine transporters rivaled that of d-amphetamine and aminorex, but it was far more potent at the serotonin transporter. This broad activity predicts serious side effects including psychosis, agitation, hyperthermia, and cardiovascular stimulation, especially at high doses or with other stimulants.
British Journal of Pharmacology
October 12, 2013
Charles W. Schindler, Eric B. Thorndike, Bruce E. Blough et al.
35 citations
The cardiovascular effects of MDMA (Ecstasy) are partly caused by its metabolite HHMA. In rats, MDMA increased blood pressure, heart rate, and activity in a dose-dependent way. The metabolite MDA mimicked MDMA's effects, while HHMA increased heart rate more potently and to a greater extent than MDMA itself. The dihydroxy metabolites did not alter motor activity, and two other metabolites, HMMA and HMA, had no effects. The heart rate increases from MDMA and HHMA were blocked by the beta-blocker propranolol, suggesting a beta-adrenoceptor mechanism. HHMA may significantly contribute to MDMA's cardiovascular toxicity.
Drug Metabolism and Disposition
October 19, 2013
Marta Concheiro, Michael H. Baumann, Karl B. Scheidweiler et al.
32 citations
MDMA, an illicit drug with potential clinical use for PTSD and anxiety, shows nonlinear accumulation in male rats due to metabolic autoinhibition. After doses of 2.5, 5, and 10 mg/kg, MDMA and its metabolite MDA increased more than proportionally with dose, while other metabolites remained constant. Serotonin syndrome severity correlated with MDMA concentrations, and core temperature correlated with MDA concentrations, suggesting distinct mechanisms for behavioral and hyperthermic effects. At 2.5 mg/kg, MDMA Cmax was 164 ± 47.1 ng/ml, with HHMA and HMMA as major metabolites and less than 20% converted to MDA. These findings, given similarities to human pharmacokinetics, support using rat data at clinically relevant doses.
Neuropharmacology
October 12, 2017
Felix P. Mayer, Nadine V. Burchardt, Ann M. Decker et al.
30 citations
Three isomers of the new psychoactive substance 3-fluorophenmetrazine (2-FPM, 3-FPM, and 4-FPM) inhibit dopamine and norepinephrine transporters with potencies comparable to cocaine (IC50 values below 2.5 μM) but show much weaker effects at the serotonin transporter (IC50 values above 80 μM). They also induce efflux of monoamines via all three transporters, an effect enhanced by the ionophore monensin. These compounds act as monoamine releasers with marked potency at catecholamine transporters implicated in abuse and addiction.
ACS Pharmacology & Translational Science
March 10, 2023
Marilyn Naeem, Grant C. Glatfelter, Duyen N. K. Pham et al.
25 citations
Tryptamine psychedelics structurally related to psilocybin, including those with variations at the 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl substitutions, primarily target multiple serotonin receptors, especially 5-HT2A and 5-HT1A. 4-Acetoxy and 4-propionoxy analogues show somewhat weaker binding affinities but similar target profiles across serotonin receptors. Variations in N,N-dialkyl groups produce differential binding at non-serotonin targets such as alpha and dopamine receptors, histamine receptors, and serotonin transporters. In mice, 4-PrO-DMT produces dose-related psilocybin-like effects: 5-HT2A-mediated head twitch response at 0.3-3 mg/kg and 5-HT1A-mediated hypothermia and reduced locomotion at 3-30 mg/kg. Data indicate that 5-HT2A-mediated head twitch response is attenuated by 5-HT1A agonist activity at high doses.
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.
ACS Chemical Neuroscience
January 8, 2024
Alexander M. Sherwood, Elise K. Burkhartzmeyer, Samuel E. Williamson et al.
18 citations
Psilocin, a metabolite of psilocybin, produces psychedelic effects in vivo, while norpsilocin, which differs by a single N-methyl group, does not. To explore this, eight norpsilocin derivatives with varied secondary amine groups were synthesized to increase lipophilicity and brain permeability. In mouse head-twitch response (HTR) studies, extending norpsilocin's N-methyl group to an N-ethyl group (4-HO-NET) produced psilocin-like activity (ED50 = 1.4 mg/kg). N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced HTRs (ED50 = 1.1–3.2 mg/kg), with variable maximum effects (26–77 total HTR events). Bulky tert-butyl or cyclohexyl groups did not elicit psilocin-like HTRs. In vitro, these tryptamines interacted with multiple serotonin receptor subtypes and other CNS proteins.
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.
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.
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 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.