Eur Neuropsychopharmacol
May 20, 2016
Anna Rickli, Olivier D. Moning, Marius C. Hoener et al.
374 citations
Novel psychoactive tryptamines (DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT) interact with serotonin 5-HT2A receptors as partial or full agonists, but with lower binding affinity than LSD. Their binding affinity correlates with reported psychoactive doses in humans. Several of these tryptamines, like psilocin and DMT, also interact with the serotonin transporter and partially with the norepinephrine transporter, similar to MDMA, whereas LSD does not. LSD, but not the tryptamines, interacts with adrenergic and dopaminergic receptors. The receptor interaction profiles suggest these tryptamines produce hallucinogenic effects similar to classic serotonergic hallucinogens along with MDMA-like psychoactive properties.
PLoS ONE
May 4, 2012
Cédric M. Hysek, Linda D. Simmler, V.g. Nicola et al.
158 citations
Taking the antidepressant duloxetine before MDMA (ecstasy) blocks many of the drug's effects. In a controlled experiment with 16 healthy volunteers, duloxetine prevented MDMA from raising blood pressure, heart rate, and norepinephrine levels, and also reduced the subjective drug experience. This happened even though duloxetine increased MDMA concentrations in the blood. Laboratory tests on human cells confirmed that duloxetine stops MDMA from releasing the neurotransmitters serotonin and norepinephrine. These findings indicate that MDMA's psychological effects depend on its ability to release both serotonin and norepinephrine, and suggest duloxetine could help treat dependence on stimulant drugs.
Clinical Pharmacology & Therapeutics
June 15, 2011
C.m. Hysek, Linda D. Simmler, M. Ineichen et al.
153 citations
Blocking the norepinephrine transporter with reboxetine reduces the cardiovascular and subjective stimulant effects of MDMA (ecstasy) in humans, even though MDMA and its active metabolite reach higher concentrations in the blood. In a double-blind, placebo-controlled crossover study with 16 healthy adults, reboxetine lowered MDMA-induced increases in plasma norepinephrine, blood pressure, heart rate, drug high, stimulation, and emotional excitement. The findings indicate that transporter-mediated norepinephrine release is essential for MDMA's cardiovascular and stimulant-like effects.
British Journal of Pharmacology
March 13, 2015
Anna Rickli, Simone Kopf, Marius C. Hoener et al.
115 citations
Benzofurans, a class of newly used psychoactive substances, inhibit norepinephrine and serotonin uptake more than dopamine uptake, similar to MDMA and unlike methamphetamine. They also release monoamines and interact with trace amine-associated receptor 1, like classic amphetamines. Most benzofurans are partial 5-HT2A receptor agonists, similar to MDMA, but also activate 5-HT2B receptors, which is associated with heart valve fibrosis, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY potently interacts with 5-HT2 receptors and binds to TA1 receptors, indicating predominant hallucinogenic properties and a risk for vasoconstriction.
Frontiers in Pharmacology
April 29, 2024
Jan Thomann, Oliver V Stoeckmann, Deborah Rudin et al.
52 citations
Psilocybin is rapidly converted to psilocin in the body, which causes psychedelic effects by binding to the 5-HT2A receptor. Psilocin is mainly broken down by glucuronidation or conversion to 4-hydroxyindole-3-acetic acid (4-HIAA). In laboratory experiments with human liver microsomes, about 29% of psilocin was metabolized, while specific enzymes CYP2D6 and CYP3A4 metabolized nearly 100% and 40%, respectively. Monoamine oxidase A produced small amounts of 4-HIAA and 4-hydroxytryptophol (4-HTP), but 4-HTP appeared only in lab tests and neither metabolite showed activity at serotonin receptors. Two new potential metabolites were found: norpsilocin in mice and an oxidized form in humans, though CYP2D6 genotype did not affect psilocin levels in people. These findings help understand drug interactions and psilocybin's therapeutic use.
European Journal of Pharmacology
December 8, 2017
Dino Luethi, Marius C. Hoener, Matthias E. Liechti
41 citations
Diclofensine, diphenidine, and methoxphenidine are new psychoactive substances that appeared on the illicit drug market. Diclofensine potently inhibited all three monoamine transporters (norepinephrine, dopamine, and serotonin) with similar inhibition potential in the range of 2.5-4.8 μM and also bound to adrenergic, dopamine, serotonin, and trace amine-associated receptors. Diphenidine inhibited norepinephrine and dopamine transporters in the low micromolar range but was a very weak serotonin transporter inhibitor, and it bound to adrenergic α1A and α2A receptors and serotonin 5-HT1A and 5-HT2A receptors. Methoxphenidine showed considerable inhibition only for the norepinephrine transporter and bound to adrenergic α2A and serotonin 5-HT2A and 5-HT2C receptors. None of the drugs mediated substrate-type efflux of monoamines. These interactions likely mediate the psychoactive effects of diclofensine and may contribute to those of diphenidine and methoxphenidine.
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.
International Journal of Molecular Sciences
July 31, 2021
Karolina E. Kolaczynska, Jan Thomann, Marius C. Hoener et al.
35 citations
Pyrovalerone cathinones, a class of potent psychoactive substances, were tested for their effects on monoamine transporters and receptors. All tested compounds strongly inhibited the dopamine and norepinephrine transporters, with IC50 values in the low micromolar range, but showed no activity at the serotonin transporter at concentrations below 10 µM. None of the substances triggered monoamine efflux. Two compounds, 4F-PBP and NEH, were particularly selective for the dopamine transporter, suggesting they likely produce strong psychostimulant effects and have high abuse potential. Extending the alkyl chain increased inhibition potency at dopamine and norepinephrine transporters, while a 3,4-methylenedioxy group enhanced serotonin transporter inhibition.
Frontiers in Pharmacology
November 28, 2019
Karolina E. Kolaczynska, Dino Luethi, Daniel Trachsel et al.
24 citations
A series of 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and their phenethylamine congeners (2C-O derivatives) were tested for binding and activation at serotonin, adrenergic, dopamine, and trace amine receptors, as well as monoamine transporters. Both amphetamine and phenethylamine derivatives bound with moderate to high affinity to the 5-HT2A receptor, with preference over 5-HT1A and 5-HT2C receptors. Extending the 4-alkoxy group generally increased binding affinities at 5-HT2A and 5-HT2C receptors but had mixed effects on activation. Phenethylamines bound more strongly to TAAR1 than their amphetamine analogs. The authors suggest that, based on high 5-HT2A binding, some compounds may produce psychedelic-like effects in humans.
Neuropharmacology
June 23, 2018
Julian Maier, Felix P. Mayer, Dino Luethi et al.
24 citations
4,4′-DMAR, a new psychoactive substance linked to 31 deaths in Europe between June 2013 and February 2014, acts as a potent non-selective monoamine releasing agent. It inhibits dopamine, norepinephrine, and serotonin transporters at low micromolar concentrations (IC50 values below 2 μM) and induces reverse transport via these transporters. It also inhibits the vesicular monoamine transporter 2 in both rat and human cells with potency similar to MDMA. Unlike aminorex and 4-methylaminorex, 4,4′-DMAR strongly affects the serotonin transporter, suggesting fatalities may involve monoaminergic toxicity including serotonin syndrome. Its activity at VMAT2 indicates potential long-term neurotoxicity with chronic abuse.
Frontiers in Pharmacology
February 9, 2022
Karolina E. Kolaczynska, Dino Luethi, Dino Luethi et al.
16 citations
Mescaline, a psychedelic found in peyote, belongs to a class of compounds called scalines and 3C-scalines, which may serve as novel therapeutics for psychedelic-assisted therapy. This in vitro study examined several previously uninvestigated scalines and 3C-scalines at key monoamine targets. These compounds bound to the 5-HT2A receptor with weak to moderately high affinity (Ki = 150–12,000 nM). 3C-scalines showed a marginal preference for 5-HT2A over 5-HT2C and 5-HT1A receptors, while scalines showed no preference. Extending the 4-alkoxy substituent increased binding affinities and activation potency at 5-HT2A but not 5-HT2B receptors.
Psychopharmacology
December 7, 2022
Adam L. Halberstadt, Dino Luethi, Marius C. Hoener et al.
7 citations
A series of 4-thio-substituted phenylalkylamines, including the psychedelic drugs 2C-T-2 and 2C-T-7, were tested in mice using the head twitch response (HTR), a behavioral proxy for human psychedelic effects. Adding an α-methyl group to the parent compound 2C-T increased potency fivefold, and extending the 4-methylthio group by one to three methylene units also increased potency. Fluorination of the 4-position alkylthio chain or a 4-allylthio substituent reduced activity, and bulky 4-benzylthio groups showed little or no effect. Binding studies confirmed nanomolar affinity for 5-HT2 receptor subtypes and partial agonism at 5-HT2A, supporting classification of these compounds as psychedelic drugs.
European Neuropsychopharmacology
April 1, 2022
Karolina E. Kolaczynska, Paula Ducret, Daniel Trachsel et al.
7 citations
MDA and related amphetamine-based compounds found in street drugs and sport supplements vary in their effects on monoamine transporters and receptors. Most compounds inhibited norepinephrine uptake most potently and preferentially blocked serotonin over dopamine uptake, except 3C-BOH and N,α-DEPEA, which favored dopamine uptake. Several compounds triggered monoamine release, and most bound to serotonin 5-HT2A and 5-HT2C receptors with micromolar affinity, acting as partial or full agonists at 5-HT2A and 5-HT2B. Some also interacted with adrenergic receptors and TAAR1. Fluorinated MDA analogs resembled MDMA's profile, while 3C-BOH and N,α-DEPEA showed amphetamine-like dopaminergic activity. Further pharmacokinetic and pharmacodynamic studies are needed to assess risks and therapeutic potential.
Frontiers in Pharmacology
November 20, 2025
Karolina E. Kolaczynska, Daniel Trachsel, Marius C. Hoener et al.
1 citation
A class of psychedelic compounds called 4-substituted 2,6-dimethoxyphenethylamines and their amphetamine counterparts (Ψ derivatives) were tested for their interactions with monoamine receptors and transporters. These derivatives showed moderate to high affinity and activity at the human 5-HT2A receptor, the primary target for psychedelics, with binding affinities ranging from 8 to 1,600 nM and activation potencies from 32 to 3,400 nM. They acted as partial agonists at this receptor. The phenethylamine derivatives also bound to 5-HT1A and 5-HT2C receptors with moderate affinity, while amphetamine derivatives had weaker affinities. Some Ψ derivatives interacted with TAAR1 and adrenergic receptors. Compared to 2,4,5-trisubstituted derivatives, the 2,4,6-trisubstituted Ψ derivatives were generally less potent at the 5-HT2A receptor but more potent than 3,4,5-trisubstituted derivatives.
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.
The FASEB Journal
May 1, 2022
Deborah Rudin, Dino Luethi, Marius C. Hoener et al.
4-Halogenated derivatives of 2,5-dimethoxyamphetamine (DOX) show increasing selectivity for the 5-HT2A receptor as the halogen size increases, with DOI exhibiting nearly 1000-fold higher selectivity than DOF. All tested derivatives acted as partial to full agonists at the 5-HT2A receptor. Their 5-HT2 receptor interaction potency resembled that of their 2C analogues, but with greater 5-HT2A versus 5-HT1A selectivity. None showed nanomolar affinity for TAAR1, adrenergic, dopaminergic, or monoamine transporters. This enhanced selectivity may explain the higher clinical potency of DOX derivatives but could also increase seizure risk, suggesting 2C derivatives may be safer for clinical applications.
The FASEB Journal
May 1, 2022
Dino Luethi, Deborah Rudin, Marius C. Hoener et al.
The pharmacological properties of 4-alkylated 2,5-dimethoxyamphetamines were examined in vitro, focusing on how the length of the 4-alkyl chain affects interactions with monoaminergic targets. The 4-alkylated derivatives (DOM, DOET, DOBU, DOAM) showed potent nanomolar affinity at serotonin 5-HT2A and 5-HT2C receptors, unlike the parent compound 2,5-DMA. Increasing alkyl chain length enhanced selectivity for 5-HT2A over 5-HT1A and 5-HT2C receptors. DOM and DOET activated the 5-HT2B receptor as partial agonists (EC50: 68–128 nM, Emax: 73–85%), while DOBU and DOAM did not (EC50 > 10,000 nM). The derivatives showed weak or no interaction with other monoaminergic targets. The findings suggest that 5-HT2A and 5-HT2C receptor affinity alone does not sufficiently predict clinical or psychedelic potency.