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.
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.
Annals of the New York Academy of Sciences
June 1, 2002
B. Gough, Syed Z. Imam, Bruce E. Blough et al.
47 citations
Paramethoxyamphetamine (PMA), a drug sold illicitly as 'ecstasy' and linked to fatalities in Australia and the United States, produces neurotoxic effects on dopamine and serotonin systems in rats similar to MDMA and methamphetamine (METH). Extracellular levels of dopamine, its metabolites DOPAC and HVA, serotonin (5-HT), and its metabolite 5-HIAA were measured in the caudate of freely moving rats via microdialysis. METH (2.5 mg/kg) increased dopamine 700% and decreased DOPAC 30% and HVA 50%, with no serotonin changes. MDMA (10 and 20 mg/kg) increased dopamine up to 950% and serotonin up to 575%.
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.
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.
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
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.
Frontiers in Cellular Neuroscience
January 1, 2022
Charles Sutton, Erin Q Williams, Hoomam Homsi et al.
13 citations
Mutations in the dopamine transporter gene cause Dopamine Transporter Deficiency Syndrome (DTDS), a fatal infantile parkinsonism-dystonia with no current treatment. Pharmacological chaperones can rescue some disease-causing variants. This study examined structure-activity relationships for two known chaperones, bupropion and ibogaine. The isoquinuclidine substituent of ibogaine and its analogs is important for chaperone efficacy. For bupropion, the secondary amine group is essential. Additional analogs with varying chemical modifications showed variable chaperone efficacies, contributing to the design of improved dopamine transporter pharmacological chaperones.
ACS Pharmacology & Translational Science
March 13, 2026
Bo Jarrett Wood, M Frances Vest, Catharine Carfagno et al.
In male mice, chronic treatment with the SSRI fluoxetine (Prozac) reduced the head-twitch response—a behavioral sign of 5-HT2A receptor activation—caused by the psychedelic DOI, while acute fluoxetine had no effect on DOI. The reduced response reversed after a 14-day discontinuation of fluoxetine. Acute fluoxetine also weakened the efficacy (but not potency) of psilocybin, indicating that SSRI-psychedelic interactions may differ depending on the specific psychedelic compound. These results suggest that a history of SSRI use can alter sensitivity to psychedelics in a compound-specific manner, with implications for psychedelic-assisted therapy in people taking SSRIs.
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.