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
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.
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.
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.
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.
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.
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.
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 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.
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.
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 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.
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.
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.
bioRxiv : the preprint server for biology
April 21, 2026
Jeanine Yacoub, Elena Bray, Jude Bayyat et al.
Halogenating the 2-position of DMT and psilacetin reduces their activity at 5-HT2A and 5-HT2B receptors, which are linked to psychedelic effects and heart valve toxicity, while preserving activity at other therapeutic targets like 5-HT6. The 2-Br-psilacetin analogue did not cause head-twitch behavior in mice and reduced head-twitch caused by another psychedelic, indicating lower potential for psychedelic effects. Intermediate doses improved stress-related mood measures and cued learning. These findings suggest that 2-halogenated tryptamines could be developed as safer, non-psychedelic therapeutics for psychiatric and neurodegenerative disorders.