1. Introduction

New psychoactive substances (NPSs) are a broad group of drugs of abuse that are not controlled by classic international drug laws [1]. The abuse of NPSs is a major problem worldwide, since NPSs can elicit serious toxic effects on users [2]. In recent years, several synthetic cathinones, designated as “legal highs”, have emerged and their use as recreational drugs has grown rapidly [3]. Structurally, synthetic cathinones are β-keto-amphetamine derivatives, with pharmacological and toxicological properties similar to amphetamines [3]. Synthetic cathinones, such as methcathinone (MC), 4-chloromethcathinone (4-CMC), and 4-methylmethcathinone (4-MMC, mephedrone), have recently been recognized by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) as emerging NPSs [4,5,6].

Despite clinical studies with and initial use of some synthetic cathinones for the treatment of depression, appetite suppression, or smoking-cessation, none of these compounds have been approved for one of these indications, mainly due to their adverse effect profile [7]. Relevant adverse effects reported for synthetic cathinones include anxiety, paranoia, depression, stroke, seizures, hyperthermia, heart failure, liver failure, and even death [7,8].

2. Specifics

Hyperthermia, also reported as “overheating”, is one of the prominent acute severe adverse effects of stimulant drug abuse, and one of the primary causes of death [9,10]. According to clinical case reports, drug-induced hyperthermia can result in many potentially fatal complications, such as hyponatremia, rhabdomyolysis, cerebral edema, disseminated intravascular coagulation, and coma [11]. Drug-induced hyperthermia can be caused by several factors. Most psychostimulant drugs can directly increase metabolic heat production by central and/or peripheral mechanisms as well as decrease heat dissipation [9,10]. Several clinical cases of hyperthermia induced by synthetic cathinones have been reported so far [12] and a large number of animal studies have been performed in mice and rats to investigate the effect of these compounds on the body temperature [13]. Polysubstance abuse may contribute to methcathinone-induced hyperthermia. Additionally, a drug that may accidentally or deliberately be used in combination with cathinones is 3,4-methylenedioxymethamphetamine (MDMA), an amphetamine derivative with well-known effects on thermoregulation [9,14]. In addition, environmental effects that users face in dancing clubs where these drugs are usually consumed may contribute as well as to hyperthermia associated with methcathinones and MDMA [15,16].

While the capacity of cathinones and many other recreational drugs to increase the body and brain temperature is well established, the effects of hyperthermia on neurotoxicity associated with these drugs is currently less well known [13]. Barbosa et al. investigated the effect of ecstasy and ecstasy metabolites on SH-SY5Y cells under normothermic (37 °C) and hyperthermic (40 °C) conditions [17]. They found that the metabolites were more toxic than the parent compound and that the toxicity increased with higher temperature. 

The aim of the current entry was to investigate in vitro the role of hyperthermia on methcathinone-induced neurotoxicity using the well-established SH-SY5Y neuronal cell model [18].