Para-Halogenation Affects Monoamine Transporter Inhibition Properties and Hepatocellular Toxicity of Amphetamines and Methcathinones
Dino Luethi, Melanie Walter, Xun Zhou, Deborah Rudin, Stephan Krähenbühl, Matthias E. Liechti
Frontiers in Pharmacology April 24, 2019 DOI: 10.3389/fphar.2019.00438 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Transporter-transfected human embryonic kidney 293 cells and human hepatoma HepG2 cells |
| Interventions | Amphetamine 4-fluoroamphetamine 4-chloroamphetamine methcathinone 4-fluoromethcathinone 4-chloromethcathinone |
| Duration | 24 h exposure |
| Topics | Serotonin |
| Keywords | Pharmacology Amphetamine Toxicity Dopamine transporter Monoamine neurotransmitter Norepinephrine transporter Biochemistry Endocrinology |
| Citations | 33 |
| Key points | Para-halogenation of amphetamine-type stimulants increases serotonergic neurotoxicity risk and may heighten hepatic toxicity through mitochondrial impairment. |
Abstract
Halogenated derivatives of amphetamine-type stimulants are appearing on the drug market, often with altered pharmacological profile and sometimes different legal status compared to the non-halogenated substances. The aim of the present study was to investigate the pharmacological profile and hepatocellular toxicity of para-halogenated amphetamines and cathinones. The potential of amphetamine, 4-fluoroamphetamine, 4-chloroamphetamine, methcathinone, 4-fluoromethcathinone, and 4-chloromethcathinone to inhibit the monoamine transporters for norepinephrine, dopamine, and serotonin was determined in transporter-transfected human embryonic kidney 293 cells. Cell membrane integrity, ATP content, oxygen consumption rate, and superoxide levels were measured in human hepatoma HepG2 cells after exposure to the substances for 24 h. All compounds inhibited the norepinephrine transporter at submicromolar concentrations and the dopamine transporter at low micromolar concentrations. The selectivity of the compounds to inhibit the dopamine versus serotonin transporter decreased with increasing size of the para-substituent, resulting in potent serotonin uptake inhibition for the halogenated derivatives. All substances depleted the cellular ATP content at lower concentrations (0.25–2 mM) than cell membrane integrity loss occurred (≥0.5 mM), suggesting mitochondrial toxicity. The amphetamines and 4-chloromethcathinone additionally impaired the mitochondrial respiratory chain, confirming mitochondrial toxicity. The following toxicity rank order for the para-substituents was observed: chloride > fluoride > hydrogen. In conclusion, para-halogenation of stimulants increases the risk for serotonergic neurotoxicity. Furthermore, para-halogenation may increase hepatic toxicity mediated by mitochondrial impairment in susceptible users.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 9
- Designer drugs: mechanism of action and adverse effects Archives of Toxicology April 1, 2020
- Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics Experimental Neurology June 4, 2021
- Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy Journal of Psychopharmacology September 10, 2020
- Novel Psychoactive Phenethylamines: Impact on Genetic Material. International Journal of Molecular Sciences December 17, 2020
- Para-Halogenation of Amphetamine and Methcathinone Increases the Mitochondrial Toxicity in Undifferentiated and Differentiated SH-SY5Y Cells International Journal of Molecular Sciences April 18, 2020
and 4 more in the library
Cites 6
- 5‐HT loss in rat brain following 3, 4‐methylenedioxymethamphetamine (MDMA), p‐chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine British Journal of Pharmacology March 1, 1993
- The role of monoamines in the changes in body temperature induced by 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) and its derivatives British Journal of Pharmacology March 3, 2010
- The detection and prevention of unintentional consumption of DOx and 25x‐NBOMe at Portugal's Boom Festival Human Psychopharmacology: Clinical and Experimental May 1, 2017
- Fluorinated phenmetrazine “legal highs” act as substrates for high-affinity monoamine transporters of the SLC6 family Neuropharmacology October 12, 2017
- Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics The International Journal of Neuropsychopharmacology May 24, 2018
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