The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine

Steinkellner, Thomas; Freissmuth, Michael; Sitte, Harald H.; Montgomery, Therese

doi:10.1515/bc.2011.016

Cited by 94 publications

(66 citation statements)

References 166 publications

(222 reference statements)

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“…The direct mechanisms that underlie the toxic actions are difficult to elucidate because ecstasy is not the only drug involved and pills may be adulterated with other compounds. However, likely effects are due to a combination of a serotonin syndrome as well as the drug's sympathomimetic effects and ability to lead to the release of arginine vasopressin (AVP) (50). In recent years, ecstasy has been associated with a spectrum of nephrotoxic effects, including AKI and hyponatremia (51).…”

Section: Methamphetamines (Ecstasy) Backgroundmentioning

confidence: 99%

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Pendergraft

Herlitz

Thornley‐Brown

et al. 2014

Clinical Journal of the American Society of Nephrology

112

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The kidneys can be injured in diverse ways by many drugs, both legal and illegal. Novel associations and descriptions of nephrotoxic effects of common and emerging drugs of abuse have appeared over the past several years. Anabolic androgenic steroids, illicitly used by athletes and others for decades to increase muscle mass and decrease body fat, are emerging as podocyte toxins given recent descriptions of severe forms of FSGS in long-term abusers. Synthetic cannabinoids, a new group of compounds with marijuana-like effects, recently became popular as recreational drugs and have been associated with an atypical form of AKI. 3,4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a widely used synthetic recreational drug with mood-enhancing properties and a constellation of toxicities that can result in death. These toxic effects include hyperthermia, hypotonic hyponatremia due to its arginine vasopressin secretagogue-like effects, rhabdomyolysis, and cardiovascular collapse. Cocaine, a serotonin-norepinephrine-dopamine reuptake inhibitor that serves as an illegal stimulant, appetite suppressant, and anesthetic, also causes vasoconstriction and rhabdomyolysis. Recent adulteration of much of the world's supply of cocaine with levamisole, an antihelminthic agent with attributes similar to but distinct from those of cocaine, appears to have spawned a new type of ANCAassociated systemic vasculitis. This review discusses the nephrotoxic effects of these common and emerging drugs of abuse, of which both community and health care providers should become aware given their widespread abuse. Future investigation into pathogenetic mechanisms associated with these drugs is critical and may provide a window into ways to lessen and even prevent the nephrotoxic effects of these drugs of abuse and perhaps allow a deeper understanding of the nephrotoxicities themselves.

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Section: Methamphetamines (Ecstasy) Backgroundmentioning

confidence: 99%

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Pendergraft

Herlitz

Thornley‐Brown

et al. 2014

Clinical Journal of the American Society of Nephrology

112

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“…Specifically, 3,4-methylenedioxyamphetamine (MDA; "Sally") and 3,4-methylenedioxy-N-methylamphetamine (MDMA; "Ecstasy" or "Molly") are synthetic drugs that are consumed for recreational purposes because they exert psychostimulatory and entactogenic effects (Steinkellner et al, 2011). It is well established that MDA and MDMA are transporter substrates that induce transporter-mediated release of serotonin (5-HT), dopamine, and norepinephrine from neurons (Baumann et al, 2007;Rickli et al, 2015b).…”

Section: Introductionmentioning

confidence: 99%

Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters

et al. 2015

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Determining the structural elements that define substrates and inhibitors at the monoamine transporters is critical to elucidating the mechanisms underlying these disparate functions. In this study, we addressed this question directly by generating a series of N-substituted 3,4-methylenedioxyamphetamine analogs that differ only in the number of methyl substituents on the terminal amine group. Starting with 3,4-methylenedioxy-N-methylamphetamine, 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA) were prepared. We evaluated the functional activities of the compounds at all three monoamine transporters in native brain tissue and cells expressing the transporters. In addition, we used ligand docking to generate models of the respective proteinligand complexes, which allowed us to relate the experimental findings to available structural information. Our results suggest that the 3,4-methylenedioxyamphetamine analogs bind at the monoamine transporter orthosteric binding site by adopting one of two mutually exclusive binding modes. 3,4-methylenedioxyamphetamine and 3,4-methylenedioxy-N-methylamphetamine adopt a high-affinity binding mode consistent with a transportable substrate, whereas MDDMA and MDTMA adopt a lowaffinity binding mode consistent with an inhibitor, in which the ligand orientation is inverted. Importantly, MDDMA can alternate between both binding modes, whereas MDTMA exclusively binds to the low-affinity mode. Our experimental results are consistent with the idea that the initial orientation of bound ligands is critical for subsequent interactions that lead to transporter conformational changes and substrate translocation.

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“…Because release-inducing substances enter nerve terminals via transporters, they are more likely to exert intracellular effects and toxicity compared with pure uptake inhibitors (Sulzer et al, 2005). Typically, releasers act on vesicular monoamine transporters and deplete vesicles, which can have short-or long-term toxic consequences (Steinkellner et al, 2011).…”

Section: Effects Of Cathinones On Transporter-mediated Effluxmentioning

confidence: 99%

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

Simmler

Liechti

2016

Current Topics in Behavioral Neurosciences

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Pharmacological assays carried out in transfected cells have been very useful for describing the mechanism of action of cathinone new psychoactive substances (NPS). These in vitro characterizations provide fast and reliable information on psychoactive substances soon after they emerge for recreational use. Well-investigated comparator compounds, such as methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, and lysergic acid diethylamide, should always be included in the characterization to enhance the translation of the in vitro data into clinically useful information. We classified cathinone NPS according to their pharmacology at monoamine transporters and receptors. Cathinone NPS are monoamine uptake inhibitors and most induce transportermediated monoamine efflux with weak to no activity at pre-or postsynaptic receptors. Cathinones with a nitrogen-containing pyrrolidine ring emerged as NPS that are extremely potent transporter inhibitors but not monoamine releasers. Cathinones exhibit clinically relevant differences in relative potencies at serotonin vs. dopamine transporters. Additionally, cathinone NPS have more dopaminergic vs. serotonergic properties compared with their non-β-keto amphetamine analogs, suggesting more stimulant and reinforcing properties. In conclusion, in vitro pharmacological assays in heterologous expression systems help to predict the psychoactive and toxicological effects of NPS.

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The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine

Cited by 94 publications

References 166 publications

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

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