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.
Journal of Neuroscience
November 12, 2014
Michael H. Baumann, Ernesto Solis, Lucas R. Watterson et al.
157 citations
The abuse of synthetic psychoactive substances known as "designer drugs" or "new psychoactive substances" (NPS) is increasing rapidly. These drugs are manufactured as legal alternatives to traditional illicit drugs. Synthetic cathinones ("bath salts") and synthetic cannabinoids ("spice") have received substantial media attention. Low recreational doses can produce desirable effects, but high doses or chronic exposure often lead to dangerous medical consequences including psychosis, violent behaviors, tachycardia, hyperthermia, and death. Despite their popularity, there is a paucity of scientific data about these drugs. This review describes the mechanisms of action and neurobiological effects of synthetic cathinones and cannabinoids.
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.
British Journal of Pharmacology
September 26, 2014
Ryan A. Gregg, Michael H. Baumann, John S. Partilla et al.
79 citations
The synthetic cathinone mephedrone (MEPH) has two mirror-image forms (enantiomers), R-MEPH and S-MEPH, which produce different effects in rats. Both enantiomers similarly release dopamine, but R-MEPH is much weaker than S-MEPH at releasing serotonin. R-MEPH caused more repetitive movements, produced sensitization to those movements after repeated doses, and was rewarding in a conditioned place preference test, whereas S-MEPH was not. In a brain-stimulation reward test, both enantiomers showed biphasic effects, but R-MEPH produced greater facilitation. These findings indicate that R-MEPH's stronger dopamine actions and weaker serotonin actions make it more stimulant-like than S-MEPH.
Annals of the New York Academy of Sciences
October 1, 2004
Michael H. Baumann, Robert D. Clark, Allison G. Budzynski et al.
71 citations
The combination of the piperazine analogs BZP and TFMPP mimics the neurochemical effects of MDMA in rat brain. MDMA stimulates transporter-mediated release of serotonin (5-HT) and dopamine (DA), with greater effect on serotonin. BZP selectively releases DA, while TFMPP selectively releases serotonin. Coadministration of BZP and TFMPP produces elevations in extracellular serotonin and dopamine that mirror MDMA's effects, and at high doses, the rise in dopamine exceeds the sum of each drug alone, suggesting drug-drug synergism. These findings provide a basis for recreational use of the combination to mimic MDMA.
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.
Addiction
July 1, 2014
Michael H. Baumann
49 citations
Synthetic cathinones, the active ingredients in 'bath salts' products, pose a global public health threat due to their abuse potential and life-threatening effects at high doses. These amphetamine-like stimulants disrupt monoamine transporter function, increasing dopamine, norepinephrine, and serotonin levels. Mephedrone and methylone act as releasing agents, while MDPV is a potent blocker. Animal studies show high abuse liability. Since U.S. scheduling in 2011, poison control reports dropped from 6,137 to 995 in 2013, but bans hinder research and spur new replacement cathinones with unknown pharmacology. Overdose symptoms include psychosis, hyperthermia, and excited delirium; treatment is supportive.
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.
Addiction Biology
January 5, 2016
Alexander F. Hoffman, Matthew D. Lycas, Jakub Kaczmarzyk et al.
39 citations
Synthetic cannabinoids found in 'Spice' products are potent activators of CB1 receptors in the mouse hippocampus, disrupting synaptic transmission and long-term potentiation (LTP). JWH-018 was the most potent inhibitor of hippocampal synaptic transmission (EC50 ~15 nM), followed by AM2201 (EC50 ~60 nM), while XLR-11 (EC50 ~900 nM) and Δ9-THC (EC50 ~700 nM) were much less potent. All effects were reversed by CB1 receptor antagonists, and AM2201 had no effect in mice lacking CB1 receptors. Exposure to any of these cannabinoids significantly impaired LTP, suggesting that synthetic cannabinoids can cause profound cognitive and behavioral deficits.
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.
Addiction Biology
February 3, 2021
Bree A. Humburg, Chloe J. Jordan, Hai‐Ying Zhang et al.
30 citations
Most cannabinoids reduce rather than enhance reward-seeking behavior in mice, according to an optogenetic self-stimulation procedure. Cocaine dose-dependently increased responding, shifting stimulation–response curves upward. In contrast, Δ9-tetrahydrocannabinol (THC), WIN55,212-2, and ACEA dose-dependently decreased responding and shifted curves downward; cannabidiol had no effect. Among newer synthetic cannabinoids, XLR-11 produced a cocaine-like increase, AM-2201 produced a THC-like reduction, and 5F-AMB had no effect. CB1 receptors were expressed mainly in VTA GABA and glutamate neurons, while CB2 receptors were expressed mainly in VTA dopamine neurons. These findings suggest most cannabinoids are reward attenuating or aversive in mice.
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 Chemical Neuroscience
March 9, 2021
Grant C. Glatfelter, Donna Walther, Michael Evans‐brown et al.
29 citations
Eutylone, a new synthetic cathinone appearing in recreational drug markets, acts as a hybrid monoamine transporter compound. In rat brain tissue, eutylone inhibited dopamine and norepinephrine uptake (most potently at dopamine transporters, IC50 = 120 nM) and showed weak partial serotonin-releasing activity. It stimulated locomotion in mice (ED50 = 2 mg/kg), indicating psychostimulant effects similar to pentylone, suggesting abuse liability and risk of adverse effects in humans.
ACS Chemical Neuroscience
April 23, 2020
Hideaki Yano, Pramisha Adhikari, Sett Naing et al.
26 citations
Synthetic cannabinoids (SCs) like AM2201 and JWH-018, but not the phytocannabinoid Δ9-tetrahydrocannabinol, act as positive allosteric modulators (PAMs) at the 5-HT1A receptor, a noncannabinoid site. In vitro, AM2201 potentiated 5-HT1A agonist-activated G protein-coupled inwardly rectifying potassium channel currents in neurons. In mice lacking cannabinoid receptor 1, AM2201 also potentiated the hypothermic response to 5-HT1A receptor stimulation. These findings suggest that PAM activity at 5-HT1A receptors may be a novel noncannabinoid mechanism contributing to the adverse effects of certain synthetic cannabinoids.
Frontiers in Psychiatry
February 27, 2018
Joshua S. Elmore, Michael H. Baumann
26 citations
Repeated exposure to the synthetic cannabinoid JWH-018, found in psychoactive 'spice' products, produces tolerance to its own hypothermic and cataleptic effects in male rats, and transiently enhances sensitivity of 5-HT1A receptors, as shown by augmented behavioral and hypothermic responses to the 5-HT1A agonist 8-OH-DPAT one day after treatment cessation. However, it does not affect behaviors induced by the 5-HT2A/2C receptor agonist DOI.
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.
ACS Pharmacology & Translational Science
April 8, 2022
Grant C. Glatfelter, Michael R. Chojnacki, Shelby A. McGriff et al.
18 citations
A simple, noninvasive method using computer analysis of video recordings accurately measures the head twitch response (HTR) in mice, a behavioral proxy for psychedelic drug effects in humans. Male mice injected with the 5-HT2 receptor agonist DOI showed dose-related increases in HTRs (0.03–3 mg/kg), which were blocked by the 5-HT2A antagonist M100907. Computer scoring closely matched visual scoring by trained observers, captured nearly all HTRs, and produced few false positives from behaviors like grooming. Optimizing lighting improved results. This method offers a reliable, surgery-free alternative for studying psychedelic-like activity.