Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances

Abstract

New psychoactive substances (NPS) with amphetamine-, aminoindan-, and benzofuran basic chemical structures have recently emerged for recreational drug use. Detailed information about their psychotropic effects and health risks is often limited. At the same time, it emerged that the pharmacological profiles of these NPS resemble those of amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Amphetamine-like NPS induce psychostimulation and euphoria mediated predominantly by norepinephrine (NE) and dopamine (DA) transporter (NET and DAT) inhibition and transporter-mediated release of NE and DA, thus showing a more catecholamine-selective profile. MDMA-like NPS frequently induce well-being, empathy, and prosocial effects and have only moderate psychostimulant properties. These MDMA-like substances primarily act by inhibiting the serotonin (5-HT) transporter (SERT) and NET, also inducing 5-HT and NE release. Monoamine receptor interactions vary considerably among amphetamine- and MDMA-like NPS. Clinically, amphetamine- and MDMA-like NPS can induce sympathomimetic toxicity. The aim of this chapter is to review the state of knowledge regarding these substances with a focus on the description of the in vitro pharmacology of selected amphetamine- and MDMA-like NPS. In addition, it is aimed to provide links between pharmacological profiles and in vivo effects and toxicity, which leads to the conclusion that abuse liability for amphetamine-like NPS may be higher than for MDMA-like NPS, but that the risk for developing the life-threatening serotonin syndrome may be increased for MDMA-like NPS.

The SLC6A3 gene polymorphism is related to the development of attentional functions but not to ADHD

“…Both DAT and NET are established targets of therapeutics. Atomoxetine is a selective NET blocker, whereas psychostimulants exert their action via interference with both transporters function, resulting in an increase of extracellular DA and norepinephrine levels [18][19][20][21] .…”

No Influence of Dopamine System Gene Variations on Acute Effects of MDMA

“…Nevertheless, this missing link between DA genetic variations and MDMA-related phenotypes might not solely be caused by a lack of genetic influence on the MDMA effects but rather the potentially minor role of DA in MDMA effects. Although MDMA is an amphetamine, it acts mainly on the 5-HT system and therefore leads to its classification as an entactogen (7, 62).…”

“…Additionally, recent investigations are looking into MDMA as a medication to assist psychotherapy in patients with posttraumatic stress disorder (PTSD) (1–3). MDMA acts mainly as a releaser and reuptake inhibitor of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) via an interaction with the respective transporter (4–7). The subjective effects of MDMA have been shown to mainly depend on transporter-mediated release of 5-HT and NE (8).…”

Modulation of Social Cognition via Hallucinogens and “Entactogens”

“…It releases 5-HT, NE, and, to a lower extent, DA from nerve terminals via action on monoamine transporters, and increases plasma levels of oxytocin, prolactin, and cortisol (10). MDMA is also a low-potency partial agonist of 5-HT receptors (95–97). GHB has direct agonist effects on GHB- and GABA B -receptors and neuromodulatory properties on glutamate, dopamine, serotonin, norepinephrine, and cholinergic transmission (22).…”