Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?
Ole Jensen, Muhammad Rafehi, Lukas Gebauer, Jürgen Brockmöller
Frontiers in Pharmacology January 20, 2021 DOI: 10.3389/fphar.2020.609811 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Topics | MDMA Mescaline Serotonin |
| Keywords | Pharmacology Fenfluramine Methamphetamine Hallucinogen Monoamine neurotransmitter Reuptake Serotonin transporter Dopamine transporter Biochemistry |
| Citations | 24 |
| Key points | Mescaline is strongly transported by OCT1, and several other psychostimulants are substrates of OCT2, with transport activity varying by genetic variant. |
Abstract
Psychostimulants are used therapeutically and for illegal recreational purposes. Many of these are inhibitors of the presynaptic noradrenaline, dopamine, and serotonin transporters (NET, DAT, and SERT). According to their physicochemical properties, some might also be substrates of polyspecific organic cation transporters (OCTs) that mediate uptake in liver and kidneys for metabolism and excretion. OCT1 is genetically highly polymorphic, with strong effects on transporter activity and expression. To study potential interindividual differences in their pharmacokinetics, 18 psychostimulants and hallucinogens were assessed in vitro for transport by different OCTs as well as by the high-affinity monoamine transporters NET, DAT, and SERT. The hallucinogenic natural compound mescaline was found to be strongly transported by wild-type OCT1 with a K m of 24.3 µM and a v max of 642 pmol × mg protein −1 × min −1 . Transport was modestly reduced in variants *2 and *7, more strongly reduced in *3 and *4, and lowest in *5 and *6, while *8 showed a moderately increased transport capacity. The other phenylethylamine derivatives methamphetamine, para -methoxymethamphetamine, (-)-ephedrine, and cathine ((+)-norpseudoephedrine), as well as dimethyltryptamine, were substrates of OCT2 with K m values in the range of 7.9–46.0 µM and v max values between 70.7 and 570 pmol × mg protein −1 × min −1 . Affinities were similar or modestly reduced and the transport capacities were reduced down to half in the naturally occurring variant A270S. Cathine was found to be a substrate for NET and DAT, with the K m being 21-fold and the v max 10-fold higher for DAT but still significantly lower compared to OCT2. This study has shown that several psychostimulants and hallucinogens are substrates for OCTs. Given the extensive cellular uptake of mescaline by the genetically highly polymorphic OCT1, strong interindividual variation in the pharmacokinetics of mescaline might be possible, which could be a reason for highly variable adverse reactions. The involvement of the polymorphic OCT2 in the renal excretion of several psychostimulants could be one reason for individual differences in toxicity.
Comparable studies
Other preclinical and animal studies on mescaline, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Brain mechanisms of hallucinogens and entactogens Humans and rats | 2001 | Review | |
| Effects of hallucinogenic agents mescaline and phencyclidine on zebrafish behavior and physiology Zebrafish (Danio rerio) | 2012 | Experimental study | |
| Lysergic Acid Diethylamide- and Mescaline-Induced Attenuation of the Effect of Punishment in the Rat Rats | 1976 | Experimental study | |
| Dihydrobenzofuran Analogues of Hallucinogens. 3. Models of 4-Substituted (2,5-Dimethoxyphenyl)alkylamine Derivatives with Rigidified Methoxy Groups Rats (trained to discriminate saline from LSD tartrate) and rat cortical and... | 1996 | In vivo drug discrimination assay and in vitro radioligand binding assay |
Citations in the library
Cited by 9
- Mescaline: The forgotten psychedelic Neuropharmacology October 14, 2022
- Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1-3 and Human Plasma Membrane Monoamine Transporter. International Journal of Molecular Sciences November 30, 2021
- Harnessing Pharmacogenomics in Clinical Research on Psychedelic‐Assisted Therapy Clinical Pharmacology & Therapeutics September 30, 2024
- How do psychostimulants enter the human brain? Analysis of the role of the proton-organic cation antiporter. Biochemical Pharmacology October 1, 2021
- MDMA pharmacokinetics: A population and physiologically based pharmacokinetics model-informed analysis. CPT: Pharmacometrics & Systems Pharmacology February 1, 2025
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