• Users Online: 2218
  • Home
  • Print this page
  • Email this page


 
 Table of Contents  
REVIEW
Year : 2020  |  Volume : 15  |  Issue : 5  |  Page : 802-816

Neuronal and peripheral damages induced by synthetic psychoactive substances: an update of recent findings from human and animal studies


1 Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
2 Department of Biomedical Sciences; National Institute of Neuroscience (INN), University of Cagliari, Cagliari, Italy
3 National Research Council of Italy, Institute of Neuroscience, Cagliari, Italy

Date of Submission01-Jul-2019
Date of Decision03-Jul-2019
Date of Acceptance30-Jul-2019
Date of Web Publication08-Nov-2019

Correspondence Address:
Nicola Simola
Department of Biomedical Sciences; National Institute of Neuroscience (INN), University of Cagliari, Cagliari
Italy
Login to access the Email id

Source of Support: GC was supported by the PRIN 2015 (Pr. 2015R9ASHT) and PON AIM (PON RICERCA E INNOVAZIONE 2014-2020, - AZIONE I.2. D.D. N.407 DEL 27 FEBBRAIO 2018 - “ATTRACTION AND INTERNATIONAL MOBILITY”); MDL was supported by Autonomous Region of Sardinia (RAS-FSC 2018, Codice intervento: RC_CRP_034; CUP RASSR03071); NS was supported by Fondazione di Sardegna (Progetti Biennali UniCA, Annualità 2017), Conflict of Interest: None


DOI: 10.4103/1673-5374.268895

Rights and Permissions
  Abstract 


Preclinical and clinical studies indicate that synthetic psychoactive substances, in addition to having abuse potential, may elicit toxic effects of varying severity at the peripheral and central levels. Nowadays, toxicity induced by synthetic psychoactive substances poses a serious harm for health, since recreational use of these substances is on the rise among young and adult people. The present review summarizes recent findings on the peripheral and central toxicity elicited by “old” and “new” synthetic psychoactive substances in humans and experimental animals, focusing on amphetamine derivatives, hallucinogen and dissociative drugs and synthetic cannabinoids.

Keywords: cannabinoids; dissociatives; hallucinogens; ketamine; MDMA; methamphetamine; methoxetamine; neuroinflammation; neurotoxicity; NPS


How to cite this article:
Costa G, De Luca MA, Piras G, Marongiu J, Fattore L, Simola N. Neuronal and peripheral damages induced by synthetic psychoactive substances: an update of recent findings from human and animal studies. Neural Regen Res 2020;15:802-16

How to cite this URL:
Costa G, De Luca MA, Piras G, Marongiu J, Fattore L, Simola N. Neuronal and peripheral damages induced by synthetic psychoactive substances: an update of recent findings from human and animal studies. Neural Regen Res [serial online] 2020 [cited 2020 Feb 21];15:802-16. Available from: http://www.nrronline.org/text.asp?2020/15/5/802/268895




  Introduction Top


Synthetic psychoactive substances are used as recreational drugs worldwide, although usage patterns significantly vary according to geographic areas, lifestyles and availability of novel derivatives. Synthetic psychoactive substances may possess abuse liability and their recreational use has long been a source of concern due to the possible development of addiction. Further worry on synthetic psychoactive substances comes from the evidence that their use may induce either lethality or toxic effects of varying severity. Central toxicity of synthetic psychoactive substances has emerged as a major issue, since reports in users have documented neurological and/or psychiatric complications that may persist after drug discontinuation.

Among synthetic psychoactive substances, the amphetamine derivatives methamphetamine (METH), also known as “ice” or “speed”, and 3,4-methylenedioxymethamphetamine (MDMA), also known as “ecstasy”, are those whose toxic effects have been more extensively characterized, both substances having long been used as either therapeutics or recreational drugs [Figure 1]. In vitro and in vivo studies have demonstrated that METH and MDMA may elicit toxic effects in peripheral organs, as well as in brain regions that regulate movement and/or superior brain functions (Moratalla et al., 2017). Besides, clinical studies have shown that METH and MDMA can induce brain abnormalities in users. Although therapeutic use of METH has been drastically reduced, the substance is still utilized for the treatment of attention deficit hyperactivity disorder and obesity, while MDMA is now being repurposed as a therapy for post-traumatic stress disorder (Mithoefer et al., 2018). Furthermore, the European Monitoring Centre for Drugs and Drug Addiction has recently reported a resurgence in the use of amphetamine derivatives as recreational drugs (EMCDDA, 2016). On this basis, it appears important to thoroughly characterize the short- and long-term toxicity of METH and MDMA to disclose the risks associated with their use, either medical or recreational.
Figure 1: Chemical structures of methamphetamine and 3,4-methylenedioxymethampetamine.

Click here to view


The emergence of the so-called “novel psychoactive substances (NPS)” has raised further concern on the toxicity associated with recreational substance use. NPS are intoxicating synthetic compounds, typically not controlled by the United Nations drug convention, that are continuously developed to mimic the effects of well-established drugs of abuse. Among NPS, hallucinogen drugs, dissociative drugs and synthetic cannabinoid receptor agonists (SCRAs) are emerging as major sources of social and clinical concern, since their use has been associated with numerous fatalities and intoxications.

Animal and human studies demonstrate that hallucinogen drugs alter consciousness and induce sensory/perceptual disturbances, while dissociative drugs alter the users’ mental state and behavioral performance and induce feelings of detachment from reality. Hallucinogens, also known as ‘psychedelics’, include lysergamides (e.g., LSD), tryptamines (e.g., psilocybin, psilocin) and phenethylamines (e.g., mescaline, Bromo-DragonFly), and typically connote drugs acting as agonists at the serotonin 5-HT2A receptor. Yet, some NPS, such as dissociative anesthetics, like ketamine or phencyclidine and the more recent dissociative drug methoxetamine, are not classified as ‘serotonergic hallucinogens’ but may produce some hallucinogenic effects. Notably, animal studies indicate that dissociative anesthetics may elicit neurotoxic effects.

To date, researches by pharmaceutical companies have failed to design SCRAs with satisfactory therapeutic potential (De Luca and Fattore, 2018). Indeed, considerable adverse effects have increasingly been reported with the progression of chemically different generations of SCRAs. Regrettably, the illegal market switched SCRAs into potent recreational drugs with higher risk of developing dependence and severe neurological and/or psychiatric complications. Accordingly, the neurotoxicity of SCRAs is currently under investigation.

This review summarizes the most recent findings of preclinical and clinical studies that evaluated the toxic effects of synthetic psychoactive substances, focusing on METH, MDMA, hallucinogen drugs, dissociative drugs and SCRAs. Rather than providing a systematic review of all animal and human studies performed so far with these substances (which are already available for each specific class of drugs), we aim at providing a PubMed based overview of the most recent (last 5 years) studies on their toxic effects discussed in light of the existing literature. Results of earlier studies were also reviewed, when relevant.


  Toxic Effects of Methamphetamine Demonstrated in Preclinical Studies Top


Overview of toxic effects

Rodent studies show that METH may elicit hypertension as well as toxicity in the heart, lung and liver (Wells et al., 2008; Halpin and Yamamoto, 2012; Tomita et al., 2013; Hassan et al., 2016). A recent investigation in C57Bl/6 mice demonstrated that chronic and escalating parenteral METH administration (5–40 mg/kg) caused cardiotoxicity, which shared many similarities with that observed in METH addicts. Indeed, METH increased heart weight and induced dilated cardiomyopathy associated with lower survival rates in male than female mice (Marcinko et al., 2019), in agreement with the clinical findings showing that men are more susceptible than women to METH-induced cardiotoxicity (Dluzen and Liu, 2008). Marcinko et al. (2019) also reported that escalating doses of METH affected the transcription of genes that were previously found to be dysregulated in studies of METH-induced neurological impairment and that are likely to participate in METH-induced cardiotoxicity.

Another effect of METH commonly observed in experimental animals is hyperthermia. In addition to being itself a major cause of lethality, hyperthermia has been implicated in several of the toxic effects of METH. Thus, hyperthermia exacerbates METH-induced neurotoxicity (Bowyer and Ali, 2006; Bowyer and Hanig, 2014), and studies in rats treated with single or multiple parenteral doses of METH (2–10 mg/kg) have shown that hyperthermia contributes to liver damage, increase in peripheral ammonia, leakage from blood brain barrier and vascular edema elicited by METH (Kiyaktin and Sharma, 2007, 2015; Halpin et al., 2013). Finally, single or multiple parenteral administrations of METH (1–40 mg/kg) induce symptoms of neurological toxicity in experimental animals, such as seizures and tremor (Izumi et al., 1984), as well as behavioral abnormalities reminiscent of anxiety-like, depressive-like or psychotic-like phenotypes (Silva et al., 2014; Wearne et al., 2016; Etaee et al., 2017; Struntz and Siegel, 2018). [Table 1] provides further details about the toxic effects of METH in experimental animals demonstrated by studies from the past 3 years.
Table 1: Overview of the toxic effects of methamphetamine demonstrated in studies from the past 3 years

Click here to view


Neurotoxic effects

Studies in vitro have demonstrated that METH (100 µM–3 mM applied for 24 hours) is toxic for dopaminergic cell lines like neuroblastoma-derived SH-SY5Y cells and pheochromocytoma-derived PC12 cells (Moratalla et al., 2017). Moreover, studies in experimental animals have demonstrated overt toxic effects of METH on the dopaminergic and serotonergic systems. In rodents, either single administration or “binge” regimens of parenteral METH may induce marked neurotoxicity especially in the nigrostriatal dopaminergic system. METH (2.5–30.0 mg/kg) damages neuronal bodies, since it reduces the numbers of dopaminergic neurons in the substantia nigra pars compacta (Hirata and Cadet, 1997; Granado et al., 2011a, b; Ares-Santos et al., 2014). When administered at the same doses, METH may also damage dopaminergic terminals, since it reduces the levels of tyrosine hydroxylase and dopamine transporter, as well as of dopamine and its metabolites dihydroxyphenilacetic acid and homovanillic acid (Granado et al., 2010, 2011a, b; Ares-Santos et al., 2014). METH-induced damage of dopaminergic terminals appears most evident in the striatum but also occurs, albeit at low levels, in other regions that receive dopaminergic innervation, such as the cortex, thalamus, hypothalamus and hippocampus (Guilarte et al., 2003; Krasnova and Cadet, 2009; Granado et al., 2010; Ares-Santos et al., 2012). Conversely, multiple parenteral administration of METH (7.5–60 mg/kg) induce widespread damage of serotonergic terminals in rodents, revealed by reduced levels of serotonin, serotonin transporter and tryptophan hydroxylase in the hippocampus, frontal cortex and striatum (McFadden and Vieira-Brock, 2016; Moszczynska and Callan, 2017). Neurotoxic effects of METH in the dopaminergic and serotonergic systems have also been demonstrated in non-human primates (Yuan et al., 2006; Melega et al., 2008). Notably, single or multiple doses of METH (0.1–40 mg/kg) that induce neurotoxic damage may as well impair social behavior, recognition memory and learning in experimental animals (Melega et al., 2008; Avila et al., 2018; Gutierrez et al., 2018). These effects of METH have been observed after either oral intake or parenteral administration and suggest a causal link between neurotoxicity and behavioral abnormalities induced by METH.

Dopaminergic damage induced by METH appears to stem from the interaction among different mechanisms. These include oxidative stress, that may arise from the auto-oxidation of extracellular dopamine that is released by METH, excitotoxicity and glia activation (Moratalla et al., 2017). Conversely, little is known about the mechanisms underlying METH-induced neurotoxicity on serotonergic terminals, although evidence exists to suggest that dopaminergic mechanisms take part in serotonergic damage (Gross et al., 2011). Interestingly, rodent studies have demonstrated that METH-induced neurotoxicity is dose- and time-dependent. Damage of dopaminergic terminals may appear shortly (within 24 hours) after the administration of high doses of METH and decreases in the striatal levels of tyrosine hydroxylase and dopamine transporter may recover over time. However, recovery is often incomplete and damage may persist months after METH discontinuation (Kousik et al., 2014; Granado et al., 2018).


  Toxic Effects of Methamphetamine Demonstrated in Human Studies Top


Overview of toxic effects

Case reports indicate that fatalities related to METH are more frequent in individuals who consume high amounts of the drug, and that most common reasons of death are multiple and/or pulmonary congestion, pulmonary edema, ventricular fibrillation, acute cardiac failure, cerebrovascular hemorrhage, leukoencephalopathy or hyperthermia (Darke et al., 2017; Mu et al., 2017; Callaghan et al., 2018). Other causes of fatalities related to METH are accidents, suicides and homicides, accounting for the manifestation of psychological and behavioral disturbances in users (Auckloo and Davies, 2019). Indeed, epidemiological studies have reported that about the 40% of METH users may display psychiatric symptoms (Glasner-Edwards and Mooney, 2014), albeit most of them are transient in individuals who do not take METH on a regular basis (Gan et al., 2018). METH users often display psychiatric symptoms of the “positive” type, like delusions, hallucinations and hostility, but less frequently show psychotic symptoms of the “negative” type (McKetin et al., 2018). Psychiatric symptoms may persist up to six months or longer after METH discontinuation in a significant percentage of users (up to the 30%) (Deng et al., 2012), and these enduring symptoms may stem from heightened sensitivity to the drug or dosing escalation (Hsieh et al., 2014). [Table 1] provides further details about the toxic effects of METH in humans demonstrated by studies from the past 3 years.

Neurotoxic effects

Neuroimaging and postmortem studies have revealed abnormalities in the brain of METH users, such as reduced densities of dopamine transporter, vesicular monoamine transporter and of dopamine D2 receptors, as well as decreased levels serotonin and serotonin transporter (Moszczynska and Callan, 2017). METH users may also display abnormalities in behavioral functions (e.g., executive functions, learning) that are regulated by monoamines. These findings may suggest that METH induces neurotoxic damage in monoaminergic pathways that may become evident at the behavioral level. However, the existence of neurotoxic effects of METH in humans is disputed (Kish et al., 2017). Thus, human studies do not always show a clear correlation between the amount of METH consumed and the severity of behavioral deficits; moreover, certain monoaminergic deficits may recover after METH discontinuation (Moszczynska and Callan, 2017). While these findings seem to downplay the existence of METH-induced neurotoxicity in humans, it should be considered that the divergent results obtained in animal and human studies may be influenced by possible confounders, such as protocols of METH administration in experimental animals and variability in METH purity and/or polydrug use in humans (Moszczynska and Callan, 2017). In addition, it is noteworthy that recovery of monoaminergic deficits in the human brain could depend on compensatory mechanisms, like sprouting and branching of the remaining neuronal fibers (Volkow et al., 2015; Boileau et al., 2016).

Another source of concern related to the possible neurotoxicity of METH in the dopaminergic system is the suggested link between METH use and later manifestation of Parkinson’s disease. Rodent studies have demonstrated that METH preferentially damages the dopaminergic nigrostriatal pathway, which degenerates in Parkinson’s disease (Moratalla et al., 2017). Moreover, some epidemiological studies have reported a higher risk of Parkinson’s disease in METH users than in the general population (Callaghan et al., 2012; Curtin et al., 2015; Rumpf et al., 2017; Lappin et al., 2018), which could be explained by hypothesizing that METH use favors the demise of mesencephalic dopaminergic neurons. However, other studies have questioned the hypothesis that METH may be a causative factor for Parkinson’s disease. Thus, it has been reported that METH users seldom display cardinal motor symptoms of Parkinson’s disease, even in the presence of dopaminergic deficiency (Marshall and O’Dell, 2012). Moreover, METH users exhibit more marked dopamine deficiency in the caudate than in the putamen, whereas Parkinson’s disease features more marked dopamine deficiency in the latter nucleus (Kish et al., 2017). Finally, it is still unclear whether in humans METH induces damage of nigral neurons and gliosis, two pathological hallmarks of Parkinson’s disease (Kish et al., 2017).


  Toxic Effects of 3,4-Methylenedioxymethamphetamine Demonstrated in Preclinical Studies Top


Overview of toxic effects

The toxic effects of MDMA that have been more exhaustively characterized in experimental animals are cardiovascular damage and hyperthermia; however, hepatotoxicity, nephrotoxicity and disruption of the blood brain barrier have also been reported (Green et al., 2003; Texeira-Gomez et al., 2016; Perez-Hernandez et al., 2017).

In rats, single or repeated parenteral administrations of MDMA (0.001–20.0 mg/kg) increase blood pressure and induces tachycardia, although bradycardia may also be observed (O’Cain et al., 2000; Alsufyani and Docherty, 2015). Besides, MDMA (20 mg/kg, single administration) damages the cardiac muscle by activating the autophagy-lysosomal pathway (Shintani-Ishida et al., 2014), increases the levels of pro-inflammatory cytokines in heart and plasma (Neri et al., 2010), and alters the cardiac gap junction protein Cx43 (Zhuo et al., 2013). In mice, single or repeated parenteral administrations of MDMA (5 or 20 mg/kg) transiently increases blood pressure in anaesthetized animals (Vandeputte and Docherty, 2002) and markedly activate cardiac sympathetic pathways in awake animals, an effect that may lead to heart damage (Navarro-Zaragoza et al., 2015, 2019). Repeated parenteral administrations of MDMA (40 mg/kg) also induce widespread epigenetic changes in DNA methylation in the heart muscle of mice, which could play a role in cardiotoxicity (Koczor et al., 2015).

Hyperthermia has been consistently demonstrated in experimental animals treated with MDMA (Green et al., 2003). In addition to be a life-threatening event itself, hyperthermia seems to participate in other toxic effects of MDMA, such as hepatotoxicity and glia activation (Colado et al., 1995; Turillazzi et al., 2010; Frau et al., 2016a). Moreover, intracerebroventricular administration of MDMA (125–500 μg) may induce neurological adverse effects (e.g., seizures, tremor) (Hanson et al., 1999), whereas single parenteral administration of MDMA (2–10 mg/kg) may elicit a phenotype reminiscent of the human serotonin syndrome (Ma et al., 2013). Furthermore, single or repeated parenteral administration of MDMA modifies the behavior of rodents in tests used to study anxiety, depression, cognition and motivation, although variable results have been reported according to the administration regimen used (Navarro and Maldonado, 2002; Ho et al., 2004; Clemens et al., 2007; Costa et al., 2014; Simola et al., 2014). [Table 2] provides further details about the toxic effects of MDMA in experimental animals demonstrated by studies from the past 3 years.
Table 2: Overview of the toxic effects of MDMA demonstrated in studies from the past 3 years

Click here to view


Neurotoxic effects

Studies in vitro have demonstrated that MDMA (100-800µM applied for 24 or 48 hours) is toxic for cortical neurons and SH-SY5Y cells (Moratalla et al., 2017), and neurotoxic effects of MDMA have been demonstrated in experimental animals as well (Lyles and Cadet 2003).

In rats and primates, single or repeated administrations of MDMA by the oral or parenteral route (10–80 mg/kg) reduce serotonin levels in several brain regions, including the hippocampus, hypothalamus, striatum, and neocortex (Commins et al., 1987; Scallet et al., 1988; Scheffel et al., 1998). Moreover, single administration of MDMA (2.5–30 mg/kg) by oral or parenteral route may damage serotonergic cell bodies in the raphe nucleus (Ricaurte et al., 1988) as well as tryptophan hydroxylase-positive fibers in frontal cortex, hippocampus, thalamus, septum, and amygdala (Adori et al., 2006; Kovács et al., 2007). Serotonergic damage induced by MDMA may be persistent, since reduced markers of neuronal viability and function have been detected months or years after drug discontinuation (Crawford et al. 2006). Nevertheless, serotonergic axonal sprouting has been observed in rats and primates that received single or repeated parenteral administration of MDMA (10–40 mg/kg) (Ricaurte and McCann, 1992; Fischer et al., 1995), which may suggest recovery of damage over time. Finally, repeated parenteral administration of MDMA (10 mg/kg) may induce GABAergic damage in the rat brain (Anneken et al., 2013).

MDMA has generally been reported to induce little or no toxic effects in catecholaminergic systems of rats and primates (Moratalla et al., 2017). However, recent evidence suggests that MDMA may be toxic for the dopaminergic system of rats. Thus, repeated parenteral administrations of MDMA (5 mg/kg) to adolescent rats induce dopaminergic damage that is evident at adulthood and consists in reduced numbers of tyrosine hydroxylase-positive neurons in both the substantia nigra pars compacta and ventral tegmental area, along with decreased immunoreactivity for tyrosine hydroxylase and dopamine transporter in the striatum and nucleus accumbens (Cadoni et al., 2017). Moreover, acute parenteral administration of MDMA (20 mg/kg) to adult rats increases nitrosative stress in dopaminergic pathways of the prefrontal cortex (Schiavone et al., 2019).

In mice, MDMA causes little serotonergic damage but induces marked toxicity in dopaminergic pathways. When administered by the parenteral route in “binge” dosing (1–30 mg/kg), MDMA decreases the numbers of dopaminergic neurons in the substantia nigra pars compacta, reduces the densities of fibers positive for the dopamine transporter and tyrosine hydroxylase in the dorsal striatum, and dampens the striatal concentrations of dopamine, dihydroxyphenilacetic acid and homovanillic acid (O’Shea et al., 2001; Granado et al., 2008; Costa et al., 2013). Interestingly, Granado et al. (2008) reported degeneration of dopaminergic fibers in the dorsal striatum but not nucleus accumbens, which suggested that the nigrostriatal system is the major target of MDMA-induced dopaminergic damage. This hypothesis has recently been confirmed and extended by a study in mice repeatedly treated with increasing numbers of parenteral MDMA administrations (10 mg/kg) (Costa et al., 2017). That study showed that MDMA reduced the numbers of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta and the densities of fibers positive for the dopamine transporter and tyrosine hydroxylase in the striatum. MDMA also reduced the density of dopamine transporter-positive terminals in the medial prefrontal cortex, and the density of tyrosine hydroxylase-positive fibers in the medial prefrontal cortex and hippocampus, which suggests that MDMA damages the mesolimbic and mesocortical dopaminergic systems. The severity of dopaminergic damage increased with the number of MDMA administrations; however, only the nigrostriatal system appeared damaged when mice were evaluated 3 months after treatment discontinuation (Costa et al., 2017). The same study also showed that repeated parenteral administrations of MDMA (10 mg/kg) may induce GABAergic damage, as revealed by reduced numbers of neurons positive to glutamic acid decarboxylase-67 (GAD-67) in the striatum and hippocampus and by reduced density of GAD67-positive fibers in medial prefrontal cortex (Costa et al., 2017). Furthermore, a subsequent study showed that repeated parenteral administration of MDMA (10 mg/kg) may trigger nitrosative stress, as revealed by increased numbers of neurons positive to neuronal NO synthase in the striatum and substantia nigra pars compacta (Costa et al., 2018). The magnitude and topography of the modifications in the immunoreactivity for GAD-67 and neuronal NO synthase varied with the number of MDMA administrations; moreover, these effects persisted up to 3 months after MDMA discontinuation (Costa et al., 2017, 2018). Interestingly, MDMA has been found to induce parallel modifications in the immunoreactivity for markers of dopaminergic function, GAD-67 and neuronal NO synthase (Costa et al., 2017, 2018). This finding may suggest a possible relationship among dopaminergic damage, GABA- ergic damage and increased nitrosative stress induced by MDMA (Costa et al., 2017, 2018).

Recent studies in rodents have provided important insights into MDMA-induced neurotoxicity, which may be relevant when translating preclinical results to the human setting. For example, it has been found that the noxious effects of MDMA in the brain are stereospecific and mediated by the S(+) enantiomer. In fact, repeated parenteral administrations of S(+)-MDMA (10 mg/kg) activate microglia and astroglia in the striatum of mice, whereas repeated parenteral administrations of R(–)-MDMA (10 mg/kg) do not (Frau et al., 2013). In line with these findings, another study in mice found that repeated parenteral administrations of R(–)-MDMA (50 mg/kg) induced neither hyperthermia nor neurotoxicity (Curry et al., 2018). Moreover, MDMA may reciprocally interact with other neurotoxic/psychoactive substances to cause brain damage. In this regard, studies in mice showed that repeated parenteral administrations of MDMA (10 mg/kg) during adolescence exacerbated dopaminergic damage, glia activation and recognition memory deficits induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) administered at adulthood (Costa et al., 2013, 2014). Moreover, the noxious effects of MDMA may be amplified when the drug is co-administered with psychoactive substances like caffeine or ethanol. In mice, caffeine may potentiate glia activation and generation of pro-inflammatory mediators, as well as damage of dopaminergic neurons and fibers and of nuclear DNA that are induced by repeated parenteral administrations of MDMA (10–20 mg/kg) (Frau et al., 2016b; Górska et al., 2018). Similarly, ethanol co-administration amplifies the dopaminergic damage and behavioral abnormalities induced by repeated parenteral administration of MDMA (10–20 mg/kg) (Ros-Simò et al., 2012; Vidal-Infer et al., 2012). Studies in rats have confirmed that caffeine and ethanol may exacerbate the neurotoxicity induced by acute or repeated parenteral administration of MDMA (5–20 mg/kg), although these noxious effects were observed in the serotonergic system (Izco et al., 2007; Vanattou-Saïfoudine et al., 2012), but not in the dopaminergic system (Cadoni et al., 2017). Furthermore, another study in mice has shown that the noxious central effects elicited by repeated parenteral administrations of MDMA (20 mg/kg) may vary with the experimental setting, in fact glia activation induced by MDMA has been found to be amplified when the drug is administered in crowded cages or at high environmental temperature (Frau et al., 2016a). To complicate the matter, age, gender and genetic background of animals, as well as interaction of these factors critically regulate the effects of MDMA in the brain. Thus, the neurotoxic effects elicited by the repeated parenteral administrations of MDMA (5–20 mg/kg) may be more marked in adult and aged animals than in young animals (Reveron et al., 2005; Frau et al., 2016b; Feio-Azevedo et al., 2018). Besides, a recent study in mice that do not express the protein Ras homolog enriched in striatum (Rhes) has demonstrated that repeated parenteral administrations of MDMA (20 mg/kg) caused more pronounced dopaminergic neurodegeneration and glia activation in male than in female Rhes–/– mice (Costa et al., 2019).

Different mechanisms are thought to participate in the neurotoxicity induced by MDMA in experimental animals, such as hyperthermia, increase in oxidative and nitrosative stress, activation of glia cells (Moratalla et al., 2017). In addition, dopamine receptors and drug metabolism seem to critically influence the neurotoxic effects of MDMA. In fact, studies in mice show that antagonism or inactivation of dopamine receptors attenuates MDMA-induced neurotoxicity (Granado et al., 2014) and that administration of MDMA directly in the striatum does not induce dopaminergic damage, even at doses (1–100 μg) that are comparable to those that elicit neurotoxicity when administered systemically (Escobedo et al., 2005). Nevertheless, the precise cascade of events leading to MDMA-induced neurotoxicity has not been elucidated, neither have the mechanisms that underlie the differential neurotoxicity of MDMA in rats and primates compared with mice.


  Toxic Effects of 3,4-Methylenedioxymethamphetamine Demonstrated in Human Studies Top


Overview of toxic effects

Hyperthermia and cardiovascular problems are the toxic effects of MDMA that have been more frequently associated with admissions to emergency rooms and fatalities (Parrott et al., 2013; Bonsignore et al., 2019).

Hyperthermia induced by MDMA may be severe, with core temperatures higher than 43°C (Jahns et al., 2018), and may precede other toxic effects, such as disseminated intravascular coagulopathy, rhabdomyolysis, multiple organ failure, or acute renal failure (Capela et al., 2009). Although MDMA-induced hyperthermia is often associated with poor prognosis, survival is possible if patients are rapidly subjected to intensive care (Davies et al., 2014; Jahns et al., 2018). Regarding the cardiovascular system, MDMA may increase blood pressure and induce vasoconstriction by means of serotonin-dependent mechanisms (Silva et al., 2016), an effect that seems to be more marked in hyperthermic than normothermic conditions (Fonseca et al., 2017). Moreover, MDMA may alter heart rhythm and induce myocardial infarction and sudden cardiac death (Bonsignore et al., 2019). Toxicity of MDMA on heart and vessels is more pronounced in individuals with pre-existing cardiovascular conditions (Vizeli and Liechti, 2017).

Other signs of toxicity involving peripheral organs that have been documented in MDMA users are hyponatremia, elevation in cortisol levels, altered cortisol reactivity, pulmonary edema, and liver failure (Schifano, 2004; Parrott et al., 2013; Thakkar et al., 2017). Furthermore, MDMA users may experience the serotonin syndrome, a potentially lethal condition requiring prompt treatment, whose symptoms include agitation, hyperthermia, sweating, tremor, increased reflexes, dilated pupils, and diarrhea. Finally, MDMA users may display signs of neurological toxicity (i.e., ataxia), sleep disturbances, psychiatric distress and neurocognitive deficits that may persist after drug discontinuation (Smithies et al., 2014; Parrott et al., 2017). Nevertheless, the association between use of MDMA and manifestation of neurocognitive deficits has recently been questioned (Amoroso, 2019). [Table 2] provides further details about the toxic effects of MDMA in humans demonstrated by studies from the past 3 years.

Neurotoxic effects

Some neuroimaging studies have demonstrated that heavy MDMA users may exhibit decreased levels of serotonin transporter (Benningfield and Cowan, 2013), increased cortical excitability (Bauernfeind et al., 2011), or altered cortical serotonergic signaling (Di Iorio et al., 2012). However, other neuroimaging studies have reported little or no abnormalities involving serotonergic pathways in the brain of MDMA users (Garg et al., 2015; Mueller et al., 2016), a finding that may question the existence of MDMA-induced neurotoxicity in humans.

The issue of serotonergic damage in the brain of MDMA users has recently been reexamined by meta-analysis studies of the existing investigations of neuroimaging. A first meta-analysis found that MDMA reduced the availability of the serotonin transporter in MDMA users (Roberts et al., 2016a). Albeit the overall effect size was moderate and large heterogeneity was observed, significant reductions in the availability of serotonin transporter were found in cortical regions (frontal, parietal, temporal, occipital), hippocampus, amygdala, and thalamus. Conversely, no effects of MDMA on serotonin transporter were observed in the caudate, putamen and midbrain. The same meta-analysis also revealed that upregulation of serotonin 5-HT2A receptors may take place in neocortical brain areas of MDMA users (Roberts et al., 2016a). Reductions in serotonin transporter densities in the brain of MDMA users have been confirmed by another recent meta-analysis study (Müller et al., 2019). Interestingly, decreased serotonin transporter densities were found in cortical regions, thalamus and hippocampus, but not in the basal ganglia, in agreement with earlier findings (Roberts et al., 2016a). Reduction in serotonin transporter density may account for the existence of neurotoxic effects of MDMA in humans. However, it may be also conceivable that decreases in the levels of serotonin transporter may reflect downregulation due to MDMA-induced serotonergic stimulation (Müller et al., 2019). Interestingly, Müller et al. (2019) observed no relationship between lifetime episodes of MDMA use and reduction in the density of the serotonin transporter. Conversely, they found a significant positive association between the latter marker and time of MDMA abstinence, which may suggest that the effects of MDMA on serotonin transporter are potentially reversible, as hypothesized by earlier studies (Reneman et al., 2001; Buchert et al., 2006; Benningfield and Cowan, 2013). Finally, another meta-analysis has demonstrated that MDMA users may display deficits in executive functions, such as access to semantic memory, mental switching, and information updating (Roberts et al., 2016b). Since executive functions are regulated by serotonin-rich prefrontal cortical areas, deficits in these functions may provide behavioral correlates of possible serotonergic damage induced by MDMA (Roberts et al., 2016b).

Dopaminergic abnormalities in the brain of MDMA users have been hypothesized. An earlier investigation found that administration of the dopamine D2 receptor agonist bromocriptine led to more marked secretion of growth hormone in control subjects than in MDMA users, which may suggest dopaminergic dysfunction in the latter (Gerra et al., 2002). Moreover, an imaging study demonstrated increased striatal 18F-DOPA reuptake in MDMA users, which may indicate a striatal hyperdopaminergic state; however, this effect was influenced by polydrug use (Tai et al., 2011). Furthermore, a recent investigation that applied untargeted metabolomics screening approaches demonstrated decreased calcitriol plasma levels after acute MDMA intake (Boxler et al., 2018). Since calcitriol modulates the upregulation of trophic factors that have protective effects on dopaminergic neurons (Cass et al., 2006), decreased calcitriol after use of MDMA may suggest that the drug is toxic for the dopaminergic system. Nevertheless, several other studies found no evidence of dysfunctions involving dopaminergic pathways in the brain of MDMA users (reviewed in Vegting et al., 2016), and the existence of MDMA-induced dopaminergic damage in humans remains controversial.


  Toxic Effects of Hallucinogen and Dissociative Drugs Top


Preclinical studies

Studies in vitro have demonstrated that both acute and prolonged exposure to hallucinogen phenethylamines (2.4–100?μM) inhibit neuronal activity in rat primary cortical cultures (Zwartsen et al., 2018). Similarly, studies in users have demonstrated toxic effects of serotoninergic hallucinogens, including the newest ones, which have been frequently associated with acute serotonin syndrome, hyperthermia, seizures, hyponatremia and sympathomimetic toxicity (Hill and Thomas, 2011). Degree of symptoms can range from mild to severe; complications may include seizures and extensive muscle breakdown. Animal studies have described the behavioral components of the serotonin syndrome induced by hallucinogen drugs which include lateral head weaving, hind limb abduction, backward locomotion, and lower lip retraction (Halberstadt and Geyer, 2011; Gatch et al., 2017).

Ketamine is a non-competitive antagonist of glutamate N-methyl-D-aspartate (NMDA) receptors that induces dissociative anesthesia and analgesia at clinical doses; however, at recreational doses of subanesthetic levels, ketamine may produce an intense psychedelic experience. Accordingly, although present on the drug market for long time, ketamine continues to be abused worldwide, and its consumption among adolescents is particularly worrying. A study in Cynomolgus monkeys has shown that repeated parenteral administrations of a recreational dose of ketamine (1 mg/kg) induce neurotoxic effects, involving the activation of apoptotic pathways in the prefrontal cortex, that lead to irreversible deficits in brain functions (Sun et al., 2014). In line with this, repeated parenteral administrations of sub-anesthetic doses of ketamine (5–50 mg/kg) increased cell death in hippocampal cornu ammonis area 3, caused irreversible changes in both brain structure and function in young adult mice (Majewski-Tiedeken et al., 2008) and induced apoptotic and necrotic neuronal cell death in the perinatal rhesus monkey (Slikker et al., 2007).

Methoxetamine is an NPS structurally related to ketamine and phencyclidine, designed to mimic the psychotropic effects of its parent compounds (Zanda et al., 2016) and increasingly available on the Internet as ‘legal ketamine’ (EMCDDA, 2014). Methoxetamine acts as a NMDA receptor antagonist, but also potently inhibits neuronal activity and alters monoamine metabolism in in vitro models (Hondebrink et al., 2018). Moreover, acute repeated parenteral administration of methoxetamine (0.125–5 mg/kg) considerably stimulates the mesolimbic dopaminergic transmission in rats (Mutti et al., 2016), and affects brain functions and behavior in rodents (Zanda et al., 2017). A recent study in mice (Ossato et al., 2018) found that acute parenteral administration of methoxetamine (0.01–30?mg/kg) induced alterations in sensory function processing that resembled those reported by users (Kjellgren and Jonsson, 2013) and persisted for hours when methoxetamine was administered at high doses. Moreover, another recent study in rats found that repeated parenteral administrations of methoxetamine (0.1–0.5 mg/kg) induced persistent behavioral abnormalities in tests used to evaluate anxiety-like states and recognition memory (Costa et al., 2019). The same investigation also demonstrated that methoxetamine induced persistent damage of dopaminergic fibers and neurons in the nigrostriatal and mesocorticolimbic systems as well as of serotonergic fibers in the nucleus accumbens core (Costa et al., 2019). [Table 3] provides further details about the toxic effects of hallucinogen and dissociative drugs demonstrated by preclinical studies from the past 3 years.
Table 3: Overview of the toxic effects of hallucinogen and dissociative drugs demonstrated in studies from the past 3 years

Click here to view


Human studies

In 2007, tryptamine derivatives were listed as ‘narcotics’ or ‘designated substances’ and were quickly replaced on the online drug market by cathinones, phenethylamines, and piperazines. Yet, several novel tryptamines continue to appear on the online drug market as ‘legal highs’, which include AMT, 5-MeO-AMT, 4-HO-DALT and 5-MeO-DALT [Figure 2]. In addition to visual and auditory hallucinations, these drugs may induce agitation, tachyarrhythmia, hyperthermia and death (Wood and Dargan, 2013).
Figure 2: Chemical structures of some hallucinogen/dissociative substances used as recreational drugs.
AMT: α-Methyltryptamine; 5-MeO-DALT: N-allyl-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]prop-2-en-1-amine; 25I-NBOMe: 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine.


Click here to view


According to the EMCDDA (2015), some phenethylamines with hallucinogenic properties are very popular in the current drug market, including the so-called 2C series (e.g., 2C-B/‘Nexus’) and the NBOMe series drugs (e.g., 25I-NBOMe, [Figure 2]). Their use has been associated with serotonergic and sympathomimetic toxic effects, including vomiting/diarrhea, metabolic acidosis, mydriasis, convulsions, thrombocytopenia, renal failure, hyperthermia and coma (Schifano et al., 2017). Fatalities and hospitalizations have been reported following use of 25I-NBOMe and symptoms of acute toxicity included tachycardia, hypertension, agitation/aggression and seizures, while laboratory tests detected elevated level of creatinine kinase, leukocytosis and hyperglycaemia (Suzuki et al., 2015). Rhabdomyolysis is a relatively common complication of severe NBOMe toxicity, an effect that may be linked to NBOMe-induced seizures, hyperthermia, and vasoconstriction. Slightly different from 25I-NBOMe, 25C-NBOMe was found to induce aggression, unpredictable violent episodes, dissociation and anxiety (Lawn et al., 2014). Although studies on the pharmacology of hallucinogenic phenylethylamines from the 2C series are still scarce, it has been demonstrated that they may act either as agonists or antagonists of G-protein-coupled serotonin and α-adrenergic receptors (Villalobos et al., 2004; Fantegrossi et al., 2008) and some of them (i.e., 2C-C, 2C-D, 2C-E, and 2C-I) were found to act as full agonists at 5-HT2A/2C receptors (Eshleman et al., 2014).

Use of methoxetamine by humans has been recently associated with acute neurological (Elian and Hackett, 2014; Fassette and Martinez, 2016) and cerebellar toxicity (Shields et al., 2012), including psychomotor agitation and altered motor coordination (Craig and Loeffler, 2014). Case reports described intoxicated patients with hypertension and tachycardia following use of methoxetamine (Thornton et al., 2017), ketamine (Kalsi et al., 2011), phencyclidine (Akmal et al., 1981) or methoxylated phencyclidine analogs (Bäckberg et al., 2015). Induction of gastrointestinal and urinary toxicity by ketamine have also been described (Wei et al. 2013). [Table 3] provides further details about the toxic effects of hallucinogen and dissociative drugs demonstrated by clinical studies from the past 3 years.

Due to the numerous medical issues associated with the use of new hallucinogen and dissociative drugs, being aware of the toxicity of these compounds is of primary importance for health professionals. Since it is not always possible to know the exact compound(s) consumed, management of toxicity should be based on clinical symptoms that an individual presents with and training of medical staff should focus on the management of the pattern of toxicity, rather than on the specific drug(s) used. This view is supported by a recent study revealing that physicians and nurses have less confidence in managing acute toxicity related to the use of NPS compared with classical recreational drugs (Wood et al., 2016).


  Toxic Effects of Synthetic Cannabinoid Receptor Agonists Top


Preclinical studies

Studies in vitro have explained why SCRAs elicit more marked toxicity, compared with Δ9-tetrahydrocannabinol (THC). Recently, Hutchison et al. (2018) showed that the abused synthetic cannabinoid AB-PINACA displays peculiar pharmacodynamic properties at CB1 cannabinoid receptors, showing similar affinity as to Δ9-THC but higher efficacy for G-protein activation and greater potency for adenylyl cyclase inhibition. This finding is of particular toxicological interest, since subsequent chemical generations of SCRAs have become increasingly potent. For instance, derivatives of third generation Spice/K2 cannabinoids, such as BB-22, 5F-PB-22, 5F-AKB-48 and STS-135 [Figure 3], are high affinity ligands and potent full super-high CB1 receptor agonists, compared to the first-generation prototypical compound JWH-018 (De Luca et al., 2015). Data obtained by [3H]CP-55,940 assay for evaluating affinity towards CB1 receptors showed that BB-22 and 5F-PB-22 displayed the lowest Ki of binding to CB1 receptors (0.11 and 0.13 nM), which is respectively 30 and 26 times lower than that of JWH-018 (3.38 nM). Moreover, data obtained in the CB1 receptor-induced [35S]GTPgS binding assays for evaluating potency and efficacy showed that BB-22 and 5F-PB-22 have a potency (EC50, 2.9 and 3.7 nM, respectively) and efficacy (Emax, 217% and 203%, respectively) as CB1 receptor agonists higher than JWH-018 (EC50, 20.2 nM; Emax, 163%). 5F-AKB-48 and STS-135 showed greater Ki for CB1 receptor binding, greater EC50 and decreased Emax as CB1 receptor agonists than BB-22 and 5F-PB-22, but still higher compared with JWH-018 (De Luca et al., 2016). In addition, studies in vitro showed that 5F-ADBINACA, AB-FUBINACA and STS-135 (3-60 μM) induced neurotoxicity in murine neuro-2a cells mediated by a reduction in mitochondrial membrane potential (Canazza et al., 2017). Furthermore, AKB-48 (62.5-1000?μM) has been recently found to exert toxic effects in human bone marrow neuroblastoma SH-SY5Y cells by inducing oxidative damage and increasing the production of interleukin-6 and tumor necrosis factor-α (Oztas et al., 2019).
Figure 3: Chemical structures of some SCRAs used as recreational drugs.
ADB-FUBINACA: (S)-N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluoroben-zyl)-1H-indazole-3-carboxamide; AMB-FUBINACA: methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate; BB-22: 1-(cyclohexylmethyl)-1H-indole-3-carboxylic acid, 8-quinolinyl ester; PB-22: 1-pentyl-1H-indole-3-carboxylic acid 8-quinolinyl ester; STS-135: N-(Adamantan-1-yl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide; SCRAs: synthetic cannabinoid receptor agonists.


Click here to view


Studies in mice have shown that SCRAs induce anxiety-, depression-, and aggression-like phenotypes, increase pain threshold, and cause seizures, myoclonia, bradycardia, hypothermia, and hyperreflexia (Banister et al., 2015; Ossato et al., 2016; Canazza et al., 2016, 2017; Pryce and Baker, 2017; Wilson et al., 2019). Behavioral and neurological effects of SCRAs appear to be mediated by CB1 receptors, since they are prevented by the selective CB1 receptor antagonist/inverse agonists AM 251 (Ossato et al., 2016; Canazza et al., 2016, 2017; Pryce and Baker, 2017; Wilson et al., 2019). Moreover, recent evidence in rats showed that repeated administration of JWH-018 (0.25 mg/kg) modifies the activity of dopamine neurons and induces differential changes in the responsiveness of dopamine transmission to motivational stimuli in terminal areas (De Luca et al., 2018), similar to previous results obtained in a rat model of disruption of cortical dopaminergic transmission (Bimpisidis et al., 2014). Interestingly, these neurochemical and behavioral observations are associated with a neuroinflammatory phenotype, as indicated by reactive microgliosis and astrogliosis in dopaminergic brain areas such as the dorsal and ventral striatum and the medial prefrontal cortex (De Luca et al., 2018). [Table 4] provides further details about the toxic effects of SCRAs in experimental animals demonstrated by studies from the past 3 years.
Table 4: Overview of the toxic effects of SCRAs demonstrated in studies from the past 3 years

Click here to view


Human studies

Even though various products containing SCRAs (i.e., joints, powders, liquids for electronic cigarettes and inhalation devices) are advertised as “safe and legal” alternatives to marijuana, they induce severe adverse effects that are different from those of marijuana (Ford et al., 2017). SCRAs intoxication is very complex to diagnose and manage, since it may involve diverse symptoms ranging from seizures, hallucinations, agitation and irritability to psychotropic disturbances, paranoia and anxiety (EMCDDA, 2018). Current information on the toxicity of SCRAs mainly derives from emergency and forensic cases. An earlier report described a simultaneous human and canine neurological toxicity associated with PB-22 (QUPIC) (Gugelman et al., 2014). A 22-year-old man and his dog had generalized tonic-clonic seizures that appeared due to the fact that the man smoked three packages of a product labeled “Crazy Monkey” daily for several weeks, likely in the presence of the animal. Indeed, laboratory analysis of specimens obtained from the product as well as from serum and urine of both human and canine patients revealed the presence of PB-22 [Figure 3] along with metabolites of UR-144, another SCRA. Subsequent reports have documented the toxicity of ADB-FUBINACA and AMB-FUBINACA [Figure 3]. A case report (Nacca et al., 2018) described a 38-year-old man admitted to the emergency room with altered mental status and bradycardia. Later, he showed progressive encephalopathy and seizures accompanied by autonomic instability, respiratory failure, hypotension, hypothermia, and hypoglycemia. A computer tomography scan revealed multiple packages in the patient’s stomach and rectum that were removed by laparotomy. Analysis of the patient’s serum, urine, and matter from the packages identified cannabis and ADB-FUBINACA. Importantly, prior rodent studies support the ability of ADB-FUBINACA to cause the reported toxidrome (Banister et al., 2015). Another study has described a mass intoxication (33 persons) with AMB-FUBINACA in the New York city area, that was characterized by depressant “zombie-like” effects (i.e., blank stare, slow response, lethargy, mechanical movements, groaning) (Adams et al., 2017). The current evidence also indicates that toxicity of SCRAs becomes more severe after the concurrent ingestion of other NPS (Miliano et al., 2016), in particular synthetic cathinones (Klavž et al., 2016; Assi et al., 2017; Grapp et al., 2017). [Table 4] provides further details about the toxic effects of SCRAs in humans demonstrated by studies from the past 3 years.


  Conclusions Top


Toxicity of synthetic psychoactive drugs is alarming, since it may result in either fatalities or functional impairments in the brain and/or peripheral organs. Moreover, preclinical studies suggest that synthetic psychoactive substances may damage neuronal bodies and terminals, although no conclusive evidence of neurotoxicity has been obtained so far in humans. However, it should be noted that human studies of drug-induced neurotoxicity may be affected by confounding factors, such as polydrug use and/or differences in drug purity (Davidson et al., 2001; Reneman et al., 2002; Morefield et al., 2011; Tai et al., 2011), which may lead to results dissimilar to those observed in animal studies. Further investigations are warranted to ascertain whether synthetic psychoactive substances elicit actual neurotoxic effects in the human brain particularly with regard to NPS, since little is known about the human neurotoxicology of these substances. The number of NPS that have recently emerged onto the recreational drug scene is very impressive although quite difficult to estimate with a certain precision [Table 5]. With this review we aimed to provide an overview of the pharmacology of the most commonly used classes of synthetic psychoactive substances and to discuss the acute and chronic harm and toxicity associated with their use[228].
Table 5: Overview of popular synthetic psychoactive drugs, their mechanisms of action and toxic effects

Click here to view


Author contributions: All authors wrote the manuscript. NS approved the final manuscript.

Conflicts of interest: We declare no conflicts of interest.

Financial support: GC was supported by the PRIN 2015 (Pr. 2015R9ASHT) and PON AIM (PON RICERCA E INNOVAZIONE 2014-2020, - AZIONE I.2. D.D. N.407 DEL 27 FEBBRAIO 2018 - “ATTRACTION AND INTERNATIONAL MOBILITY”). MDL was supported by Autonomous Region of Sardinia (RAS-FSC 2018, Codice intervento: RC_CRP_034; CUP RASSR03071). NS was supported by Fondazione di Sardegna (Progetti Biennali UniCA, Annualità 2017).

Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

Additional file: Abbreviations and chemical names of compounds not defined in the text[Additional file 1].

Funding: GC was supported by the PRIN 2015 (Pr. 2015R9ASHT) and PON AIM (PON RICERCA E INNOVAZIONE 2014-2020, - AZIONE I.2. D.D. N.407 DEL 27 FEBBRAIO 2018 - “ATTRACTION AND INTERNATIONAL MOBILITY”); MDL was supported by Autonomous Region of Sardinia (RAS-FSC 2018, Codice intervento: RC_CRP_034; CUP RASSR03071); NS was supported by Fondazione di Sardegna (Progetti Biennali UniCA, Annualità 2017).

C-Editors: Zhao M, Li JY; T-Editor: Jia Y



 
  References Top

1.
Abad S, Ramon-Duaso C, López-Arnau R, Folch J, Pubill D, Camarasa J, Camins A, Escubedo E (2019) Effects of MDMA on neuroplasticity, amyloid burden and phospho-tau expression in APPswe/PS1dE9 mice. J Psychopharmacol 269881119855987.  Back to cited text no. 1
    
2.
Abiero A, Botanas CJ, Sayson LV, Custodio RJ, de la Peña JB, Kim M, Lee HJ, Seo JW, Ryu IS, Chang CM, Yang JS, Lee YS, Jang CG, Kim HJ, Cheong JH (2019) 5-Methoxy-α-methyltryptamine (5-MeO-AMT), a tryptamine derivative, induces head-twitch responses in mice through the activation of serotonin receptor 2a in the prefrontal cortex. Behav Brain Res 359:828-835.  Back to cited text no. 2
    
3.
Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R (2017) “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N Engl J Med 376:235-242.  Back to cited text no. 3
    
4.
Adori C, Andó RD, Kovács GG, Bagdy G (2006) Damage of serotonergic axons and immunolocalization of Hsp27, Hsp72, and Hsp90 molecular chaperones after a single dose of MDMA administration in dark agouti rat: temporal, spatial, and cellular patterns. J Comp Neurol 497:251-269.  Back to cited text no. 4
    
5.
Ahiskalioglu EO, Aydin P, Ahiskalioglu A, Suleyman B, Kuyrukluyildiz U, Kurt N, Altuner D, Coskun R, Suleyman H (2018) The effects of ketamine and thiopental used alone or in combination on the brain, heart, and bronchial tissues of rats. Arch Med Sci 14:645-654.  Back to cited text no. 5
    
6.
Akmal M, Valdin JR, McCarron MM, Massry SG (1981) Rhabdomyolysis with and without acute renal failure in patients with phencyclidine intoxication. Am J Nephrol 1:91-96.  Back to cited text no. 6
    
7.
Alsufyani HA, Docherty JR (2015) Direct and indirect cardiovascular actions of cathinone and MDMA in the anaesthetized rat. Eur J Pharmacol 758:142-146.  Back to cited text no. 7
    
8.
Amoroso T (2019) The spurious relationship between ecstasy use and neuro cognitive deficits: A Bradford Hill review. Int J Drug Policy 64:47-53.  Back to cited text no. 8
    
9.
Anneken JH, Cunningham JI, Collins SA, Yamamoto BK, Gudelsky GA (2013) MDMA increases glutamate release and reduces parvalbumin-positive GABAergic cells in the dorsal hippocampus of the rat: role of cyclooxygenase. J Neuroimmune Pharmacol 8:58-65.  Back to cited text no. 9
    
10.
Araújo AM, Bastos ML, Fernandes E, Carvalho F, Carvalho M, Guedes de Pinho P (2018) GC-MS metabolomics reveals disturbed metabolic pathways in primary mouse hepatocytes exposed to subtoxic levels of 3,4-methylenedioxymethamphetamine (MDMA). Arch Toxicol 92:3307-3323.  Back to cited text no. 10
    
11.
Ares-Santos S, Granado N, Espadas I, Martinez-Murillo R, Moratalla R (2014) Methamphetamine causes degeneration of dopamine cell bodies and terminals of the nigrostriatal pathway evidenced by silver staining. Neuropsychopharmacology 39:1066-1080.  Back to cited text no. 11
    
12.
Ares-Santos S, Granado N, Oliva I, O’Shea E, Martin ED, Colado MI, Moratalla R (2012) Dopamine D(1) receptor deletion strongly reduces neurotoxic effects of methamphetamine. Neurobiol Dis 45:810-820.  Back to cited text no. 12
    
13.
Assi S, Gulyamova N, Ibrahim K, Kneller P, Osselton D (2017) Profile, effects, and toxicity of novel psychoactive substances: A systematic review of quantitative studies. Hum Psychopharmacol 32:e2607.  Back to cited text no. 13
    
14.
Auckloo MBKM, Davies BB (2019) Post-mortem toxicology in violent fatalities in Cape Town, South Africa: A preliminary investigation. J Forensic Leg Med 63:18-25.  Back to cited text no. 14
    
15.
Avila JA, Zanca RM, Shor D, Paleologos N, Alliger AA, Figueiredo-Pereira ME, Serrano PA (2018) Chronic voluntary oral methamphetamine induces deficits in spatial learning and hippocampal protein kinase Mzeta with enhanced astrogliosis and cyclooxygenase-2 levels. Heliyon 4:e00509.  Back to cited text no. 15
    
16.
Bäckberg M, Beck O, Helander A (2015) Phencyclidine analog use in Sweden--intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the STRIDA project. Clin Toxicol 53:856-864.  Back to cited text no. 16
    
17.
Banister SD, Moir M, Stuart J, Kevin RC, Wood KE, Longworth M, Wilkinson SM, Beinat C, Buchanan AS, Glass M, Connor M, McGregor IS, Kassiou M (2015) Pharmacology of indole and indazole synthetic cannabinoid designer drugs AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, and 5F-ADBICA. ACS Chem Neurosci 6:1546–1559.  Back to cited text no. 17
    
18.
Bauernfeind AL, Dietrich MS, Blackford JU, Charboneau EJ, Lillevig JG, Cannistraci CJ, Woodward ND, Cao A, Watkins T, Di Iorio CR, Cascio C, Salomon RM, Cowan RL (2011) Human Ecstasy use is associated with increased cortical excitability: an fMRI study. Neuropsychopharmacology 36:1127-1141.  Back to cited text no. 18
    
19.
Benningfield MM, Cowan RL (2013) Brain serotonin function in MDMA (ecstasy) users: evidence for persisting neurotoxicity. Neuropsychopharmacology 38:253-255.  Back to cited text no. 19
    
20.
Bimpisidis Z, De Luca MA, Pisanu A, Di Chiara G (2013) Lesion of medial prefrontal dopamine terminals abolishes habituation of accumbens shell dopamine responsiveness to taste stimuli. Eur J Neurosci 37:613-622.  Back to cited text no. 20
    
21.
Boileau I, McCluskey T, Tong J, Furukawa Y, Houle S, Kish SJ (2016) Rapid recovery of vesicular dopamine levels in methamphetamine users in early abstinence. Neuropsychopharmacology 41:1179-1187.  Back to cited text no. 21
    
22.
Bonsignore A, Barranco R, Morando A, Fraternali Orcioni G, Ventura F (2019) MDMA induced cardio-toxicity and pathological myocardial effects: A systematic review of experimental data and autopsy findings. Cardiovasc Toxicol doi: 10.1007/s12012-019-09526-9.  Back to cited text no. 22
    
23.
Bowyer JF, Ali S (2006) High doses of methamphetamine that cause disruption of the blood-brain barrier in limbic regions produce extensive neuronal degeneration in mouse hippocampus. Synapse 60:521-532.  Back to cited text no. 23
    
24.
Bowyer JF, Hanig JP (2014) Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity. Temperature 14:172-182.  Back to cited text no. 24
    
25.
Boxler MI, Streun GL, Liechti ME, Schmid Y, Kraemer T, Steuer AE (2018) Human metabolome changes after a single dose of 3,4-methylenedioxymethamphetamine (MDMA) with special focus on steroid metabolism and inflammation processes. J Proteome Res 17:2900-2907.  Back to cited text no. 25
    
26.
Buchert R, Thomasius R, Petersen K, Wilke F, Obrocki J, Nebeling B, Wartberg L, Zapletalova P, Clausen M (2006) Reversibility of ecstasy-induced reduction in serotonin transporter availability in polydrug ecstasy users. Eur J Nucl Med Mol Imaging 33:188-199.  Back to cited text no. 26
    
27.
Cadoni C, Pisanu A, Simola N, Frau L, Porceddu PF, Corongiu S, Dessì C, Sil A, Plumitallo A, Wardas J, Di Chiara G (2017) Widespread reduction of dopamine cell bodies and terminals in adult rats exposed to a low dose regimen of MDMA during adolescence. Neuropharmacology 123:385-394.  Back to cited text no. 27
    
28.
Caffino L, Piva A, Giannotti G, Di Chio M, Mottarlini F, Venniro M, Yew DT, Chiamulera C, Fumagalli F (2017) Ketamine self-administration reduces the homeostasis of the glutamate synapse in the rat brain. Mol Neurobiol 54:7186-7193.  Back to cited text no. 28
    
29.
Callaghan RC, Cunningham JK, Sykes J, Kish SJ (2012) Increased risk of Parkinson’s disease in individuals hospitalized with conditions related to the use of methamphetamine or other amphetamine-type drugs. Drug Alcohol Depend 120:35-40.  Back to cited text no. 29
    
30.
Callaghan RC, Halliday M, Gatley J, Sykes J, Taylor L, Benny C, Kish SJ (2018) Comparative hazards of acute myocardial infarction among hospitalized patients with methamphetamine- or cocaine-use disorders: A retrospective cohort study. Drug Alcohol Depend 188:259-265.  Back to cited text no. 30
    
31.
Canazza I, Ossato A, Trapella C, Fantinati A, De Luca MA, Margiani G, Vincenzi F, Rimondo C, Di Rosa F, Gregori A, Varani K, Borea PA, Serpelloni G, Marti M (2016) Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on “tetrad”, sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies. Psychopharmacology 233:3685-3709.  Back to cited text no. 31
    
32.
Canazza I, Ossato A, Vincenzi F, Gregori A, Di Rosa F, Nigro F, Rimessi A, Pinton P, Varani K, Borea PA, Marti M (2017) Pharmaco-toxicological effects of the novel third-generation fluorinate synthetic cannabinoids, 5F-ADBINACA, AB-FUBINACA, and STS-135 in mice. In vitro and in vivo studies. Hum Psychopharmacol 32:e2601.  Back to cited text no. 32
    
33.
Capela JP, Carmo H, Remiao F, Bastos ML, Meisel A, Carvalho F (2009) Molecular and cellular mechanisms of ectasy-induced neurotoxicity: an overview. Mol Neurobiol 39:210-271.  Back to cited text no. 33
    
34.
Cass WA, Smith MP, Peters LE (2006) Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine. Ann N Y Acad Sci 1074:261-271.  Back to cited text no. 34
    
35.
Choi MR, Chun JW, Kwak SM, Bang SH, Jin YB, Lee Y, Kim HN, Chang KT, Chai YG, Lee SR, Kim DJ (2018) Effects of acute and chronic methamphetamine administration on cynomolgus monkey hippocampus structure and cellular transcriptome. Toxicol Appl Pharmacol 355:68-79.  Back to cited text no. 35
    
36.
Clemens KJ, Cornish JL, Hunt GE, McGregor IS (2007) Repeated weekly exposure to MDMA, methamphetamine or their combination: long-term behavioural and neurochemical effects in rats. Drug Alcohol Depend 86:183-190.  Back to cited text no. 36
    
37.
Colado M, Williams J, Green A (1995) The hyperthermic and neurotoxic effects of “ecstasy” (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the dark agouti (DA) rat, a model of the cyp2d6 poor metabolizer phenotype. Br J Pharmacol 115:1281-1289.  Back to cited text no. 37
    
38.
Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS (1987) Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 241:338-345.  Back to cited text no. 38
    
39.
Costa G, Frau L, Wardas J, Pinna A, Plumitallo A, Morelli M (2013) MPTP-induced dopamine neuron degeneration and glia activation is potentiated in MDMA-pretreated mice. Mov Disord 28:1957-1965.  Back to cited text no. 39
    
40.
Costa G, Simola N, Morelli M (2014) MDMA administration during adolescence exacerbates MPTP-induced cognitive impairment and neuroinflammation in the hippocampus and prefrontal cortex. Psychopharmacology 231:4007-4018.  Back to cited text no. 40
    
41.
Costa G, Morelli M, Simola N (2017) Progression and persistence of neurotoxicity induced by MDMA in dopaminergic regions of the mouse brain and association with noradrenergic, GABAergic, and serotonergic damage. Neurotox Res 32:563-574.  Back to cited text no. 41
    
42.
Costa G, Morelli M, Simola N (2018) Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) elevates the levels of neuronal nitric oxide synthase in the nigrostriatal system: Possible relevance to neurotoxicity. Neurotox Res 34:763-768.  Back to cited text no. 42
    
43.
Costa G, Porceddu PF, Serra M, Casu MA, Schiano V, Napolitano F, Pinna A, Usiello A, Morelli M (2019) Lack of Rhes increases MDMA-induced neuroinflammation and dopamine neuron degeneration: Role of gender and age. Int J Mol Sci 20:1556.  Back to cited text no. 43
    
44.
Costa G, Serra M, Pintori N, Casu MA, Zanda MT, Murtas D, De Luca MA, Simola N, Fattore L (2019) The novel psychoactive substance methoxetamine induces persistent behavioral abnormalities and neurotoxicity in rats. Neuropharmacology 144:219-232.  Back to cited text no. 44
    
45.
Craig CL, Loeffler GH (2014) The ketamine analog methoxetamine: a new designer drug to threaten military readiness. Mil Med 179:1149-1157.  Back to cited text no. 45
    
46.
Crawford CA, Williams MT, Kohutek JL, Choi FY, Yoshida ST, McDougall SA, Vorhees CV (2006) Neonatal 3,4-methylenedioxymethamphetamine (MDMA) exposure alters neuronal protein kinase A activity, serotonin and dopamine content, and [35S]GTPgammaS binding in adult rats. Brain Res 1077:178-186.  Back to cited text no. 46
    
47.
Curry DW, Young MB, Tran AN, Daoud GE, Howell LL (2018) Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice. Neuropharmacology 128:196-206.  Back to cited text no. 47
    
48.
Curtin K, Fleckenstein, AE, Robison, RJ, Crookston MJ, Smith, KR, Hanson GR (2015) Methamphetamine/amphetamine abuse and risk of Parkinson’s disease in Utah: a population-based assessment. Drug Alcohol Depend 146:30-38.  Back to cited text no. 48
    
49.
Darke S, Duflou J, Kaye S (2017) Prevalence and nature of cardiovascular disease in methamphetamine-related death: A national study. Drug Alcohol Depend 179:174-179.  Back to cited text no. 49
    
50.
Davidson C, Gow AJ, Lee TH, Ellinwood EH (2001) Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Rev 36:1-22.  Back to cited text no. 50
    
51.
Davies O, Batajoo-Shrestha B, Sosa-Popoteur J, Olibrice M (2014) Full recovery after severe serotonin syndrome, severe rhabdomyolysis, multi-organ failure and disseminated intravascular coagulopathy from MDMA. Heart Lung 43:117-119.  Back to cited text no. 51
    
52.
de Bragança AC, Moreau RLM, de Brito T, Shimizu MHM, Canale D, de Jesus DA, Silva AMG, Gois PH, Seguro AC, Magaldi AJ (2017) Ecstasy induces reactive oxygen species, kidney water absorption and rhabdomyolysis in normal rats. Effect of N-acetylcysteine and Allopurinol in oxidative stress and muscle fiber damage. PLoS One 12:e0179199.  Back to cited text no. 52
    
53.
De Luca MA, Bimpisidis Z, Melis M, Marti M, Caboni P, Valentini V, Margiani G,Pintori N, Polis I, Marsicano G, Parsons LH, Di Chiara G. (2015) Stimulation of in vivo dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a Spice cannabinoid. Neuropharmacology 99:705-714.  Back to cited text no. 53
    
54.
De Luca MA, Castelli MP, Loi B, Porcu A, Martorelli M, Miliano C, Kellett K, Davidson C, Stair JL, Schifano F, Di Chiara G (2016) Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135. Neuropharmacology 105:630-638.  Back to cited text no. 54
    
55.
De Luca MA, Fattore L (2018) Therapeutic use of synthetic cannabinoids: Still an open issue? Clin Ther 40:1457-1466.  Back to cited text no. 55
    
56.
De Luca MA, Pintori N, Miliano C, De Felice M, Sagheddu C, Margiani G, Ennas M, Pistis M, Di Chiara G, Castelli MP (2018) Differential adaptive properties of mesolimbic and mesocortical dopamine transmission to taste stimuli after repeated exposure to the synthetic cannabinoid JWH-018. SFN 2018, San Diego (CA, USA) Presentation Number: 602.09.  Back to cited text no. 56
    
57.
Deng X, Huang Z, Li X, Li Y, Wang Y, Wu D, Gao B, Yang X (2012) Long-term follow-up of patients treated for psychotic symptoms that persist after stopping illicit drug use. Shanghai Arch Psychiatry 24:271-278.  Back to cited text no. 57
    
58.
Di Iorio CR, Watkins TJ, Dietrich MS, Cao A, Blackford JU, Rogers B, Ansari MS, Baldwin RM, Li R, Kessler RM, Salomon RM, Benningfield M, Cowan RL (2012) Evidence for chronically altered serotonin function in the cerebral cortex of female 3,4-methylenedioxymethamphetamine polydrug users. Arch Gen Psychiatry 69:399-409.  Back to cited text no. 58
    
59.
Dluzen DE, Liu B (2008) Gender differences in methamphetamine use and responses: a review. Gend Med 5:24-35.  Back to cited text no. 59
    
60.
Elian AA, Hackett J (2014) A polydrug intoxication involving methoxetamine in a drugs and driving case. J Forensic Sci 59:854-858.  Back to cited text no. 60
    
61.
Escobedo I, O’Shea E, Orio L, Sanchez V, Segura M, de la Torre R, Farre M, Green AR, Colado MI (2005) A comparative study on the acute and long-term effects of MDMA and 3,4-dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice. Br J Pharmacol 144:231-241.  Back to cited text no. 61
    
62.
Eshleman AJ, Forster MJ, Wolfrum KM, Johnson RA, Janowsky A, Gatch MB (2014) Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function. Psychopharmacology 232:875-888.  Back to cited text no. 62
    
63.
Eskandarian Boroujeni M, Peirouvi T, Shaerzadeh F, Ahmadiani A, Abdollahifar MA, Aliaghaei A (2019) Differential gene expression and stereological analyses of the cerebellum following methamphetamine exposure. Addict Biol doi: 10.1111/adb.12707.  Back to cited text no. 63
    
64.
Etaee F, Asadbegi M, Taslimi Z, Shahidi S, Sarihi A, Soleimani Asl S, Komaki A (2017) The effects of methamphetamine and buprenorphine, and their interaction on anxiety-like behavior and locomotion in male rats. Neurosci Lett 655:172-178.  Back to cited text no. 64
    
65.
European Drug Report 2014: Trends and Developments, Publications Office of the European Union, Luxembourg.  Back to cited text no. 65
    
66.
European Monitoring Centre for Drugs and Drug Addiction (2015), European Drug Report 2015: Trends and Developments, Publications Office of the European Union, Luxembourg.  Back to cited text no. 66
    
67.
European Monitoring Centre for Drugs and Drug Addiction (2016), European Drug Report 2016: Trends and Developments, Publications Office of the European Union, Luxembourg.  Back to cited text no. 67
    
68.
European Monitoring Centre for Drugs and Drug Addiction (2018), European Drug Report 2018: Trends and Developments, Publications Office of the European Union, Luxembourg.  Back to cited text no. 68
    
69.
Fantegrossi WE, Reissig CJ, Katz EB, Yarosh HL, Rice KC, Winter JC (2008) Hallucinogen-like effects of N,N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HT1A and 5-HT2A receptors in rodents. Pharmacol Biochem Behav 88:358-365.  Back to cited text no. 69
    
70.
Fassette T, Martinez A (2016) An impaired driver found to be under the influence of Methoxetamine. J Anal Toxicol 40:700-702.  Back to cited text no. 70
    
71.
Feio-Azevedo R, Costa VM, Barbosa DJ, Teixeira-Gomes A, Pita I, Gomes S, Pereira FC, Duarte-Araújo M, Duarte JA, Marques F, Fernandes E, Bastos ML, Carvalho F, Capela JP (2018) Aged rats are more vulnerable than adolescents to “ecstasy”-induced toxicity. Arch Toxicol 92:2275-2295.  Back to cited text no. 71
    
72.
Fischer C, Hatzidimitriou G, Wlos J, Katz J, Ricaurte G (1995) Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). J Neurosci 15:5476-5485.  Back to cited text no. 72
    
73.
Flack A, Persons AL, Kousik SM, Celeste Napier T, Moszczynska A (2017) Self-administration of methamphetamine alters gut biomarkers of toxicity. Eur J Neurosci 46:1918-1932.  Back to cited text no. 73
    
74.
Fonseca DA, Guerra AF, Carvalho F, Fernandes E, Ferreira LM, Branco PS, Antunes PE, Antunes MJ, Cotrim MD (2017) Hyperthermia severely affects the vascular effects of MDMA and metabolites in the human internal mammary artery in vitro. Cardiovasc Toxicol 17:405-416.  Back to cited text no. 74
    
75.
Ford BM, Tai S, Fantegrossi WE, Prather PL (2017) Synthetic pot: not your grandfather’s marijuana. Trends Pharmacol Sci 38:257-276.  Back to cited text no. 75
    
76.
Frau L, Simola N, Plumitallo A., Morelli M (2013) Microglial and astroglial activation by 3,4- methylenedioxymethamphetamine (MDMA) in mice depends on S(+) enantiomer and is associated with an increase in body temperature and motility. J Neurochem 124:69-78.  Back to cited text no. 76
    
77.
Frau L, Simola N, Porceddu PF, Morelli M (2016a) Effect of crowding, temperature and age on glia activation and dopaminergic neurotoxicity induced by MDMA in the mouse brain. Neurotoxicology 56:127-138.  Back to cited text no. 77
    
78.
Frau L, Costa G, Porceddu PF, Khairnar A, Castelli MP, Ennas MG, Madeddu C, Wardas J, Morelli M (2016b) Influence of caffeine on 3,4-methylenedioxymethamphetamine-induced dopaminergic neuron degeneration and neuroinflammation is age-dependent. J Neurochem 136:148-162.  Back to cited text no. 78
    
79.
Gan H, Song Z, Xu P, Su H, Pan Y, Zhao M, Liu D (2018) A comparison study of working memory deficits between patients with methamphetamine-associated psychosis and patients with schizophrenia. Shanghai Arch Psychiatry 30:168-217.  Back to cited text no. 79
    
80.
García-Cabrerizo R, Bis-Humbert C, García-Fuster MJ (2018) Methamphetamine binge administration during late adolescence induced enduring hippocampal cell damage following prolonged withdrawal in rats. Neurotoxicology 66:1-9.  Back to cited text no. 80
    
81.
Garg A, Kapoor S, Goel M, Chopra S, Chopra M, Kapoor A, McCann UD, Behera C (2015) Functional magnetic resonance imaging in abstinent MDMA users: A review. Curr Drug Abuse Rev 8:15-25.  Back to cited text no. 81
    
82.
Gatch MB, Dolan SB, Forster MJ (2017) Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents. Behav Pharmacol 28:375-385.  Back to cited text no. 82
    
83.
Gerra G, Zaimovic A, Moi G, Giusti F, Gardini S, Delsignore R, Laviola G, Macchia T, Brambilla F (2002) Effects of (+/-) 3,4-methylenedioxymethamphetamine(ecstasy) on dopamine system function in humans. Behav Brain Res 134:403-410.  Back to cited text no. 83
    
84.
Glasner-Edwards S, Mooney LJ (2014) Methamphetamine psychosis: epidemiology and management. CNS Drugs 28:1115-1126.  Back to cited text no. 84
    
85.
Górska AM, Kamińska K, Wawrzczak-Bargieła A, Costa G, Morelli M, Przewłocki R, Kreiner G, Gołembiowska K (2018) Neurochemical and neurotoxic effects of MDMA (Ecstasy) and caffeine after chronic combined administration in mice. Neurotox Res 33:532-548.  Back to cited text no. 85
    
86.
Granado N, Ares-Santos S, Moratalla R (2014) D1 but not D4 dopamine receptors are critical for MDMA-induced neurotoxicity in mice. Neurotox Res 25:100-109.  Back to cited text no. 86
    
87.
Granado N, Ares-Santos S., Oliva I, O’Shea E, Martin, ED, Colado MI, Moratalla R (2011a) Dopamine D2-receptor knockout mice are protected against dopaminergic neurotoxicity induced by methamphetamine or MDMA. Neurobiol Dis 42:391-403.  Back to cited text no. 87
    
88.
Granado N, Ares-Santos S, O’Shea E, Vicario-Abejon C, Colado MI, Moratalla R (2010) Selective vulnerability in striosomes and in the nigrostriatal dopaminergic pathway after methamphetamine administration: early loss of TH in striosomes after methamphetamine. Neurotox Res 18:48-58.  Back to cited text no. 88
    
89.
Granado N, Ares-Santos S, Tizabi Y, Moratalla R (2018) Striatal reinnervation process after acute methamphetamine-induced dopaminergic degeneration in mice. Neurotox Res 34:627-639.  Back to cited text no. 89
    
90.
Granado N, Lastres-Becker I, Ares-Santos S, Oliva I, Martin E, Cuadrado A, Moratalla R (2011b) Nrf2 deficiency potentiates methamphetamine-induced dopaminergic axonal damage and gliosis in the striatum. Glia 59:1850-1863.  Back to cited text no. 90
    
91.
Granado N, O’Shea E, Bove J, Vila M, Colado MI, Moratalla R (2008) Persistent MDMA-induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice. J Neurochem 107:1102-1112.  Back to cited text no. 91
    
92.
Grapp M, Kaufmann C, Ebbecke M (2017) Toxicological investigation of forensic cases related to the designer drug 3,4-methylenedioxypyrovalerone (MDPV): Detection, quantification and studies on human metabolism by GC-MS. Forensic Sci Int 273:1-9.  Back to cited text no. 92
    
93.
Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463-508.  Back to cited text no. 93
    
94.
Gross NB, Duncker PC, Marshall JF (2011) Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity. Synapse 65:1144-1455.  Back to cited text no. 94
    
95.
Gugelmann H, Gerona R, Li C, Tsutaoka B, Olson KR, Lung D (2014) “Crazy Monkey” poisons man and dog: Human and canine seizures due to PB-22, a novel synthetic cannabinoid. Clin Toxicol 52:635-638.  Back to cited text no. 95
    
96.
Guilarte TR, Nihei MK, McGlothan JL, Howard AS (2003) Methamphetamine-induced deficits of brain monoaminergic neuronal markers: distal axotomy or neuronal plasticity. Neuroscience 122:499-513.  Back to cited text no. 96
    
97.
Gutierrez A, Williams MT, Vorhees CV (2018) A single high dose of methamphetamine reduces monoamines and impairs egocentric and allocentric learning and memory in adult male rats. Neurotox Res 33:671-680.  Back to cited text no. 97
    
98.
Halberstadt AL, Geyer MA (2011) Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology 61:364-381.  Back to cited text no. 98
    
99.
Halpin LE, Gunning WT, Yamamoto BK (2013) Methamphetamine causes acute hyperthermia-dependent liver damage. Pharmacol Res Perspect 1:e00008.  Back to cited text no. 99
    
100.
Halpin LE, Yamamoto BK (2012) Peripheral ammonia as a mediator of methamphetamine neurotoxicity. J Neurosci 32:13155-13163.  Back to cited text no. 100
    
101.
Hanson GR, Jensen M, Johnson M, White HS (1999) Distinct features of seizures induced by cocaine and amphetamine analogs. Eur J Pharmacol 377:167-177.  Back to cited text no. 101
    
102.
Hassan SF, Wearne TA, Cornish JL, Goodchild AK (2016) Effects of acute and chronic systemic methamphetamine on respiratory, cardiovascular and metabolic function, and cardiorespiratory reflexes. J Physiol 594:763-780.  Back to cited text no. 102
    
103.
Hill SL, Dunn M, Cano C, Harnor SJ, Hardcastle IR, Grundlingh J, Dargan PI, Wood DM, Tucker S, Bartram T, Thomas SHL (2018) Human toxicity caused by indole and indazole carboxylate synthetic cannabinoid receptor agonists: From horizon scanning to notification. Clin Chem 64:346-354.  Back to cited text no. 103
    
104.
Hill SL, Thomas SH (2011) Clinical toxicology of newer recreational drugs. Clin Toxicol 49:705-719.  Back to cited text no. 104
    
105.
Hirata H, Cadet JL (1997) P53-Knockout mice are protected against the long-term effects of methamphetamine on dopaminergic terminals and cell bodies. J Neurochem 69:780-790.  Back to cited text no. 105
    
106.
Ho YJ, Pawlak CR, Guo L, Schwarting RK (2004) Acute and long-term consequences of single MDMA administration in relation to individual anxiety levels in the rat. Behav Brain Res 149:135-144.  Back to cited text no. 106
    
107.
Hondebrink L, Zwartsen A, Westerink RHS (2018) Effect fingerprinting of new psychoactive substances (NPS): What can we learn from in vitro data? Pharmacol Ther 182:193-222.  Back to cited text no. 107
    
108.
Hsieh JH, Stein DJ, Howells FM (2014) The neurobiology of methamphetamine induced psychosis. Front Hum Neurosci 8:537.  Back to cited text no. 108
    
109.
Hutchison RD, Ford BM, Franks LN, Wilson CD, Yarbrough AL, Fujiwara R, Su MK, Fernandez D, James LP, Moran JH, Patton AL, Fantegrossi WE, Radominska-Pandya A, Prather PL (2018) Atypical pharmacodynamic properties and metabolic profile of the abused synthetic cannabinoid AB-PINACA: Potential contribution to pronounced adverse effects relative to Δ9-THC. Front Pharmacol 9:1084.  Back to cited text no. 109
    
110.
Izco M, Orio L, O’Shea E, Colado MI (2007) Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain. Psychopharmacology 189:459-470.  Back to cited text no. 110
    
111.
Izumi K, Nomoto M, Koja T, Shimizu T, Kishita C, Fukuda T (1984) Phenytoin potentiates methamphetamine-induced behavior in mice. Pharmacol Biochem Behav 20:803-806.  Back to cited text no. 111
    
112.
Jahns FP, Pineau Mitchell A, Auzinger G (2018) Too Hot to Handle: A case report of extreme pyrexia after MDMA ingestion. Ther Hypothermia Temp Manag 8:173-175.  Back to cited text no. 112
    
113.
Jiang S, Li X, Jin W, Duan X, Bo L, Wu J, Zhang R, Wang Y, Kang R, Huang L (2018) Ketamine-induced neurotoxicity blocked by N-Methyl-d-aspartate is mediated through activation of PKC/ERK pathway in developing hippocampal neurons. Neurosci Lett 673:122-131.  Back to cited text no. 113
    
114.
Kalsi SS, Wood DM, Dargan PI (2011) The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. Emerg Health Threats J 4:7107.  Back to cited text no. 114
    
115.
Kevin RC, Anderson L, McGregor IS, Boyd R, Manning JJ, Glass M, Connor M, Banister SD (2019) CUMYL-4CN-BINACA is an efficacious and potent pro-convulsant synthetic cannabinoid receptor agonist. Front Pharmacol 10:595.  Back to cited text no. 115
    
116.
Kish SJ, Boileau I, Callaghan RC, Tong J (2017) Brain dopamine neurone ‘damage’: methamphetamine users vs. Parkinson’s disease – a critical assessment of the evidence. Eur J Neurosci 45:58-66.  Back to cited text no. 116
    
117.
Kiyatkin EA, Brown PL, Sharma HS (2007) Brain edema and breakdown of the blood–brain barrier during methamphetamine intoxication: critical role of brain hyperthermia. Eur J Neurosci 26:1242-1253.  Back to cited text no. 117
    
118.
Kiyatkin EA, Sharma HS (2015) Not just the brain: methamphetamine disrupts blood-spinal cord barrier and induces acute glial activation and structural damage of spinal cord cells. CNS Neurol Disord Drug Targets 14:282-294.  Back to cited text no. 118
    
119.
Kjellgren A, Jonsson K (2013) Methoxetamine (MXE)--a phenomenological study of experiences induced by a “legal high” from the internet. J Psychoactive Drugs 45:276-286.  Back to cited text no. 119
    
120.
Klavž J, Gorenjak M, Marinšek M (2016) Suicide attempt with a mix of synthetic cannabinoids and synthetic cathinones: Case report of non-fatal intoxication with AB-CHMINACA, AB-FUBINACA, alpha-PHP, alpha-PVP and 4-CMC. Forensic Sci Int 265:121-124.  Back to cited text no. 120
    
121.
Koczor CA, Ludlow I, Hight RS 2nd, Jiao Z, Fields E, Ludaway T, Russ R, Torres RA, Lewis (2015) Ecstasy (MDMA) alters cardiac gene expression and DNA methylation: Implications for circadian rhythm dysfunction in the heart. Toxicol Sci 148:183-191.  Back to cited text no. 121
    
122.
Krasnova IN, Cadet JL (2009) Methamphetamine toxicity and messengers of death. Brain Res Rev 60:379-407.  Back to cited text no. 122
    
123.
Kousik SM, Carvey PM, Napier TC (2014) Methamphetamine self-administration results in persistent dopaminergic pathology: implications for Parkinson’s disease risk and reward-seeking. Eur J Neurosci 40:2707-2714.  Back to cited text no. 123
    
124.
Kovács GG, Andó RD, Adori C, Kirilly E, Benedek A, Palkovits M, Bagdy G (2007) Single dose of MDMA causes extensive decrement of serotoninergic fibre density without blockage of the fast axonal transport in Dark Agouti rat brain and spinal cord. Neuropathol Appl Neurobiol 33:193-203.  Back to cited text no. 124
    
125.
Lappin JM, Darke S, Farrell M (2018) Methamphetamine use and future risk for Parkinson’s disease: Evidence and clinical implications. Drug Alcohol Depend 187:134-140.  Back to cited text no. 125
    
126.
Lawn W, Barratt M, Williams M, Horne A, Winstock A (2014) The NBOMe hallucinogenic drug series: Patterns of use, characteristics of users and self-reported effects in a large international sample. J Psychopharmacol 28:780-788.  Back to cited text no. 126
    
127.
Liu X, Zhan LH, Sun XH, Zhang T, Liu ZL, Liang XF, Zhao F, Liu F, Zeng G, Luan CS (2018) 3,4-Methylenedioxymethamphetamine causes cytotoxicity on 661W cells through inducing macrophage polarization. Cutan Ocul Toxicol 37:143-150.  Back to cited text no. 127
    
128.
Lv XF, Tao LM, Zhong H (2019) Long-term systemic administration with low dose of 3,4-methylenedioxymethamphetamine causes photoreceptor cell damage in CD1 mice. Cutan Ocul Toxicol 38:81-87.  Back to cited text no. 128
    
129.
Lyles J, Cadet JL (2003) Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity: cellular and molecular mechanisms. Brain Res Rev 42:155-168.  Back to cited text no. 129
    
130.
Ma Z, Rudacille M, Prentice HM, Tao R (2013) Characterization of electroencephalographic and biochemical responses at 5-HT promoting drug-induced onset of serotonin syndrome in rats. J Neurochem 125:774-789.  Back to cited text no. 130
    
131.
Majewski-Tiedeken CR, Rabin CR, Siegel SJ (2008) Ketamine exposure in adult mice leads to increased cell death in C3H, DBA2 and FVB inbred mouse strains. Drug Alcohol Depend 92:217-227.  Back to cited text no. 131
    
132.
Marcinko MC, Darrow AL, Tuia AJ, Shohet RV (2019) Sex influences susceptibility to methamphetamine cardiomyopathy in mice. Physiol Rep 7:e14036.  Back to cited text no. 132
    
133.
Marshall JF, O’Dell SJ (2012) Methamphetamine influences on brain and behavior: unsafe at any speed? Trends Neurosci 35:536-545.  Back to cited text no. 133
    
134.
McFadden LM, Vieira-Brock PL (2016) The persistent neurotoxic effects of methamphetamine on dopaminergic and serotonergic markers in male and female rats. Toxicol Open Access doi: 10.4172/2476-2067.1000116.  Back to cited text no. 134
    
135.
McKetin R, Voce A, Burns R, Ali R, Lubman DI, Baker AL, Castle DJ (2018) Latent psychotic symptom profiles amongst people who use methamphetamine: What do they tell us about existing diagnostic categories? Front Psychiatry 9:578.  Back to cited text no. 135
    
136.
Melega WP, Jorgensen MJ, Laćan G, Way BM, Pham J, Morton G, Cho AK, Fairbanks LA (2008) Long-term methamphetamine administration in the vervet monkey models aspects of a human exposure: brain neurotoxicity and behavioral profiles. Neuropsychopharmacology 33:1441-1452.  Back to cited text no. 136
    
137.
Miliano C, Serpelloni G, Rimondo C, Mereu M, Marti M, De Luca MA (2016) Neuropharmacology of new psychoactive substances (NPS): Focus on the rewarding and reinforcing properties of cannabimimetics and amphetamine-like stimulants. Front Neurosci 10:153.  Back to cited text no. 137
    
138.
Mithoefer MC, Mithoefer AT, Feduccia AA, Jerome L, Wagner M, Wymer J, Holland J, Hamilton S, Yazar-Klosinski B, Emerson A, Doblin R (2018) 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry 5:486-497.  Back to cited text no. 138
    
139.
Mobaraki F, Seghatoleslam M, Fazel A, Ebrahimzadeh-Bideskan A (2018) Effects of MDMA (ecstasy) on apoptosis and heat shock protein (HSP70) expression in adult rat testis. Toxicol Mech Methods 28:219-229.  Back to cited text no. 139
    
140.
Moccia L, Tofani A, Mazza M, Covino M, Martinotti G, Schifano F, Janiri L, Di Nicola M (2019) Dorsolateral prefrontal cortex impairment in methoxetamine-induced psychosis: An (18)F-FDG PET/CT case study. J Psychoactive Drugs 9:1-6.  Back to cited text no. 140
    
141.
Moratalla R, Khairnar A, Simola N, Granado N, García-Montes JR, Porceddu PF, Tizabi Y, Costa G, Morelli M (2017) Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms. Prog Neurobiol 155:149-170.  Back to cited text no. 141
    
142.
Morefield KM, Keane M, Felgate P, White JM, Irvine RJ (2011) Pill content, dose and resulting plasma concentrations of 3,4-methylendioxymethamphetamine (MDMA) in recreational ‘ecstasy’ users. Addiction 106:1293-1300.  Back to cited text no. 142
    
143.
Moszczynska A, Callan SP (2017) Molecular, behavioral, and physiological consequences of methamphetamine neurotoxicity: Implications for treatment. J Pharmacol Exp Ther 362:474-488.  Back to cited text no. 143
    
144.
Mu J, Li M, Guo Y, Lv B, Qiu M, Dong H (2017) Methamphetamine-induced toxic leukoencephalopathy: clinical, radiological and autopsy findings. Forensic Sci Med Pathol 13:362-366.  Back to cited text no. 144
    
145.
Müeller F, Lenz C, Steiner M, Dolder PC, Walter M, Lang UE, Liechti ME, Borgwardt S (2016) Neuroimaging in moderate MDMA use: A systematic review. Neurosci Biobehav Rev 62:21-34.  Back to cited text no. 145
    
146.
Müller F, Brändle R, Liechti ME, Borgwardt S (2019) Neuroimaging of chronic MDMA (“ecstasy”) effects: A meta-analysis. Neurosci Biobehav Rev 96:10-20.  Back to cited text no. 146
    
147.
Mutti A, Aroni S, Fadda P, Padovani L, Mancini L, Collu R, Muntoni AL, Fattore L, Chiamulera C (2016) The ketamine-like compound methoxetamine substitutes for ketamine in the self-administration paradigm and enhances mesolimbic dopaminergic transmission. Psychopharmacology 233:2241-2251.  Back to cited text no. 147
    
148.
Nacca N, Schult R, Loflin R, Weltler A, Gorodetsky R, Kacinko S, Moran J, Krotulski A, Wiegand T (2018) Coma, seizures, atrioventricular block, and hypoglycemia in an ADB-FUBINACA body-packer. J Emerg Med 55:788-791.  Back to cited text no. 148
    
149.
Nakamura M, Shintani-Ishida K, Ikegaya H (2018) 5-HT(2A) receptor agonist-induced hyperthermia is induced via vasoconstriction by peripheral 5-HT(2A) receptors and brown adipose tissue thermogenesis by peripheral serotonin loss at a high ambient temperature. J Pharmacol Exp Ther 367:356-362.  Back to cited text no. 149
    
150.
Navarro JF, Maldonado E (2002) Acute and subchronic effects of MDMA (“ecstasy”) on anxiety in male mice tested in the elevated plus-maze. Prog Neuropsychopharmacol Biol Psychiatry 26:1151-1154.  Back to cited text no. 150
    
151.
Navarro-Zaragoza J, Ros-Simó C, Milanés MV, Valverde O, Laorden ML (2015) Binge ethanol and MDMA combination exacerbates toxic cardiac effects by inducing cellular stress. PLoS One 10:e0141502.  Back to cited text no. 151
    
152.
Navarro-Zaragoza J, Ros-Simó C, Milanés MV, Valverde O, Laorden ML (2019) Binge ethanol and MDMA combination exacerbates HSP27 and Trx-1 (biomarkers of toxic cardiac effects) expression in right ventricle. Life Sci 220:50-57.  Back to cited text no. 152
    
153.
Neri M, Bello S, Bonsignore A, Centini F, Fiore C, Földes-Papp Z, Turillazzi E, Fineschi V (2010) Myocardial expression of TNF-alpha, IL-1beta, IL-6, IL-8, IL-10 and MCP-1 after a single MDMA dose administered in a rat model. Curr Pharm Biotechnol 11:413-420.  Back to cited text no. 153
    
154.
Obradovic AL, Atluri N, Dalla Massara L, Oklopcic A, Todorovic NS, Katta G, Osuru HP, Jevtovic-Todorovic V (2018) Early exposure to ketamine impairs axonal pruning in developing mouse hippocampus. Mol Neurobiol 55:164-172.  Back to cited text no. 154
    
155.
O’Cain PA, Hletko SB, Ogden BA, Varner KJ (2000) Cardiovascular and sympathetic responses and reflex changes elicited by MDMA. Physiol Behav 70:141-148.  Back to cited text no. 155
    
156.
O’Shea E, Esteban B, Camarero J, Green AR, Colado MI (2001) Effect of GBR 12909 and fluoxetine on the acute and long term changes induced by MDMA (‘ecstasy’) on the 5-HT and dopamine concentrations in mouse brain. Neuropharmacology 40:65-74.  Back to cited text no. 156
    
157.
Ossato A, Bilel S, Gregori A, Talarico A, Trapella C, Gaudio RM, De-Giorgio F, Tagliaro F, Neri M, Fattore L, Marti M (2018) Neurological, sensorimotor and cardiorespiratory alterations induced by methoxetamine, ketamine and phencyclidine in mice. Neuropharmacology 141:167-180.  Back to cited text no. 157
    
158.
Ossato A, Canazza I, Trapella C, Vincenzi F, De Luca MA, Rimondo C, Varani K, Borea PA, Serpelloni G, Marti M (2016) Effect of JWH-250, JWH-073 and their interaction on “tetrad”, sensorimotor, neurological and neurochemical responses in mice. Prog Neuropsychopharmacol Biol Psychiatry 67:31-50.  Back to cited text no. 158
    
159.
Oztas E, Abudayyak M, Celiksoz M, Özhan G (2019) Inflammation and oxidative stress are key mediators in AKB48-induced neurotoxicity in vitro. Toxicol In Vitro 55:101-107.  Back to cited text no. 159
    
160.
Parrott A, Lock J, Adnum L, Thome J (2013) MDMA can increase cortisol levels by 800% in dance clubbers. J Psychopharmacol 27:113-114.  Back to cited text no. 160
    
161.
Parrott AC, Downey LA, Roberts CA, Montgomery C, Bruno R, Fox HC (2017) Recreational 3,4-methylenedioxymethamphetamine or ‘ecstasy’: Current perspective and future research prospects. J Psychopharmacol 31:959-966.  Back to cited text no. 161
    
162.
Pérez-Hernández M, Fernández-Valle ME, Rubio-Araiz A, Vidal R, Gutiérrez-López MD, O’Shea E, Colado MI (2017) 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces edema due to BBB disruption induced by MMP-9 activation in rat hippocampus. Neuropharmacology 118:157-166.  Back to cited text no. 162
    
163.
Pérez-Hernández M, Fernández-Valle ME, Rubio-Araiz A, Vidal R, Gutiérrez-López MD, O’Shea E, Colado MI (2017). 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces edema due to BBB disruption induced by MMP-9 activation in rat hippocampus. Neuropharmacology. 118:157-166.  Back to cited text no. 163
    
164.
Petschner P, Tamasi V, Adori C, Kirilly E, Ando RD, Tothfalusi L, Bagdy G (2018) Gene expression analysis indicates reduced memory and cognitive functions in the hippocampus and increase in synaptic reorganization in the frontal cortex 3 weeks after MDMA administration in Dark Agouti rats. BMC Genomics 19:580.  Back to cited text no. 164
    
165.
Pryce G, Baker D (2017) Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB-13, in mice. Br J Pharmacol 174:3790-3794.  Back to cited text no. 165
    
166.
Qi L, Liu JY, Zhu YL, Liu W, Zhang SD, Liu WB, Jiang JJ (2017) Toxic effects of ketamine on reproductive system via disrupting hypothalamic-pituitary-testicular axis. Eur Rev Med Pharmacol Sci 21:1967-1973.  Back to cited text no. 166
    
167.
Reneman L, Booij J, Lavalaye J, de Bruin K, Reitsma JB, Gunning B, den Heeten GJ, van Den Brink W (2002) Use of amphetamine by recreational users of ecstasy (MDMA)is associated with reduced striatal dopamine transporter densities: a[123I]beta-CIT SPECT study--preliminary report. Psychopharmacology (Berl) 159:335-340.  Back to cited text no. 167
    
168.
Reneman L, Lavalaye J, Schmand B, de Wolff FA, van den Brink W, den Heeten GJ,Booij J (2001) Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”): preliminary findings. Arch Gen Psychiatry 58:901-906.  Back to cited text no. 168
    
169.
Reveron ME, Monks TJ, Duvauchelle CL (2005) Age-dependent (+)MDMA-mediated neurotoxicity in mice. Neurotoxicology 26:1031-1040.  Back to cited text no. 169
    
170.
Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME, Langston JW (1988) (+/-)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. JAMA 260:51-55.  Back to cited text no. 170
    
171.
Ricaurte GA, McCann UD (1992) Neurotoxic amphetamine analogues: effects in monkeys and implications for humans. Ann N Y Acad Sci 648:371-382.  Back to cited text no. 171
    
172.
Roberts CA, Jones A, Montgomery C (2016a) Meta-analysis of molecular imaging of serotonin transporters in ecstasy/polydrug users. Neurosci Biobehav Rev 63:158-167.  Back to cited text no. 172
    
173.
Roberts CA, Jones A, Montgomery C (2016b) Meta-analysis of executive functioning in ecstasy/polydrug users. Psychol Med 46:1581-1596.  Back to cited text no. 173
    
174.
Robinson B, Dumas M, Gu Q, Kanungo J (2018) N-acetylcysteine prevents ketamine-induced adverse effects on development, heart rate and monoaminergic neurons in zebrafish. Neurosci Lett 682:56-61.  Back to cited text no. 174
    
175.
Ros-Simó C, Ruiz-Medina J, Valverde O (2012) Behavioural and neuroinflammatory effects of the combination of binge ethanol and MDMA in mice. Psychopharmacology (Berl) 221:511-525.  Back to cited text no. 175
    
176.
Rumpf JJ, Albers J, Fricke C, Mueller W, Classen J (2017) Structural abnormality of substantia nigra induced by methamphetamine abuse. Mov Disord 32:1784-1788.  Back to cited text no. 176
    
177.
Sampaio TB, de Oliveira LF, Constantino LC, Costa AP, Poluceno GG, Martins WC, Dal-Cim T, de Oliveira KA, Ludka FK, Prediger RD, Tasca CI, Pereira FC (2018). Long-term neurobehavioral consequences of a single ketamine neonatal exposure in rats: Effects on cellular viability and glutamate transport in frontal cortex and hippocampus. Neurotox Res 34:649-659.   Back to cited text no. 177
    
178.
Scallet AC, Lipe GW, Ali SF, Holson RR, Frith CH, Slikker W Jr. (1988) Neuropathological evaluation by combined immunohistochemistry and degeneration-specific methods: application to methylenedioxymethamphetamine. Neurotoxicology 9:529-537.  Back to cited text no. 178
    
179.
Scheffel U, Szabo Z, Mathews WB, Finley PA, Dannals RF, Ravert HT, Szabo K, Yuan J, Ricaurte GA (1998) In vivo detection of short- and long-term MDMA neurotoxicity--a positron emission tomography study in the living baboon brain. Synapse 29:183-192.  Back to cited text no. 179
    
180.
Schiavone S, Neri M, Maffione AB, Frisoni P, Morgese MG, Trabace L, Turillazzi E (2019) Increased iNOS and nitrosative stress in dopaminergic neurons of MDMA-exposed rats. Int J Mol Sci doi: 10.3390/ijms20051242.  Back to cited text no. 180
    
181.
Schifano F (2004) A bitter pill. Overview of ecstasy (MDMA, MDA) related fatalities. Psychopharmacology (Berl) 173:242-248.  Back to cited text no. 181
    
182.
Schifano F, Orsolini L, Papanti D, Corkery J (2017) NPS: Medical consequences associated with their intake. Curr Top Behav Neurosci 32:351-380.  Back to cited text no. 182
    
183.
Schürer S, Klingel K, Sandri M, Majunke N, Besler C, Kandolf R, Lurz P, Luck M, Hertel P, Schuler G, Linke A, Mangner N (2017) Clinical characteristics, histopathological features, and clinical outcome of methamphetamine-associated cardiomyopathy. JACC Heart Fail 5:435-445.  Back to cited text no. 183
    
184.
Shields JE, Dargan PI, Wood DM, Puchnarewicz M, Davies S, Waring WS (2012) Methoxetamine associated reversible cerebellar toxicity: three cases with analytical confirmation. Clin Toxicol 50:438-440.  Back to cited text no. 184
    
185.
Shintani-Ishida K, Saka K, Yamaguchi K, Hayashida M, Nagai H, Takemura G,Yoshida K (2014) MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats. Biochim Biophys Act 1842:691-700.  Back to cited text no. 185
    
186.
Silva S, Carvalho F, Fernandes E, Antunes MJ, Cotrim MD (2016) Contractile effects of 3,4-methylenedioxymethamphetamine on the human internal mammary artery. Toxicol In Vitro 34:187-193.  Back to cited text no. 186
    
187.
Silva CD, Neves AF, Dias AI, Freitas HJ, Mendes SM, Pita I, Viana SD, de Oliveira PA, Cunha RA, Fontes Ribeiro CA, Prediger RD, Pereira FC (2014) A single neurotoxic dose of methamphetamine induces a long-lasting depressive-like behaviour in mice. Neurotox Res 25:295-330.  Back to cited text no. 187
    
188.
Simola N, Frau L, Plumitallo A, Morelli M (2014) Direct and long-lasting effects elicited by repeated drug administration on 50-kHz ultrasonic vocalizations are regulated differently: implications for the study of the affective properties of drugs of abuse. Int J Neuropsychopharmacol 17:429-441.  Back to cited text no. 188
    
189.
Slikker W Jr, Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC, Doerge DR, Scallet AC, Patterson TA, Hanig JP, Paule MG, Wang C (2007) Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 98:145-158.  Back to cited text no. 189
    
190.
Smithies V, Broadbear J, Verdejo-Garcia A, Conduit R (2014) Dysfunctional overnight memory consolidation in ecstasy users. J Psychopharmacol 28:751-756.  Back to cited text no. 190
    
191.
Struntz KH, Siegel JA (2018) Effects of methamphetamine exposure on anxiety-like behavior in the open field test, corticosterone, and hippocampal tyrosine hydroxylase in adolescent and adult mice. Behav Brain Res 348:211-218.  Back to cited text no. 191
    
192.
Sun L, Li Q, Li Q, Zhang Y, Liu D, Jiang H, Pan F, Yew DT (2014) Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys. Addict Biol 19:185-194.  Back to cited text no. 192
    
193.
Sun X, Wang Y, Xia B, Li Z, Dai J, Qiu P, Ma A, Lin Z, Huang J, Wang J, Xie WB, Wang J (2019) Methamphetamine produces cardiac damage and apoptosis by decreasing melusin. Toxicol Appl Pharmacol 378:114543.  Back to cited text no. 193
    
194.
Suzuki J, Dekker MA, Valenti ES, Arbelo Cruz FA, Correa AM, Poklis JL, Poklis A (2015) Toxicities associated with NBOMe ingestion-a novel class of potent hallucinogens: a review of the literature. Psychosomatics 56:129-139.  Back to cited text no. 194
    
195.
Tai YF, Hoshi R, Brignell CM, Cohen L, Brooks DJ, Curran HV, Piccini P (2011) Persistent nigrostriatal dopaminergic abnormalities in ex-users of MDMA (‘Ecstasy’): an 18F-dopa PET study. Neuropsychopharmacology 36:735-743.  Back to cited text no. 195
    
196.
Teixeira-Gomes A, Costa VM, Feio-Azevedo R, Duarte JA, Duarte-Araújo M, Fernandes E, Bastos M de L, Carvalho F, Capela JP (2016) “Ecstasy” toxicity to adolescent rats following an acute low binge dose. BMC Pharmacol Toxicol 17:28.  Back to cited text no. 196
    
197.
Thakkar A, Parekh K, El Hachem K, Mohanraj EM (2017) A case of MDMA-associated cerebral and pulmonary edema requiring ECMO. Case Rep Crit Care 2017:6417012.  Back to cited text no. 197
    
198.
Thornton S, Lisbon D, Lin T, Gerona R (2017) Beyond ketamine and phencyclidine: Analytically confirmed use of multiple novel arylcyclohexylamines. J Psychoactive Drugs 49:289-293.  Back to cited text no. 198
    
199.
Tomita M, Okuyama T, Katsuyama H, Watanabe Y, Shinone K, Nata M, Ishikawa T (2013) Cardiotoxicity of methamphetamine under stress conditions: comparison of single dose and long-term use. Mol Med Rep 7:1786-1790.  Back to cited text no. 199
    
200.
Turillazzi E, Riezzo I, Neri M, Bello S, Fineschi V (2010) MDMA toxicity and pathological consequences: a review about experimental data and autopsy findings. Curr Pharm Biotechnol 11:500-609.  Back to cited text no. 200
    
201.
Vanattou-Saïfoudine N, McNamara R, Harkin A (2012) Caffeine provokes adverse interactions with 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) and related psychostimulants: mechanisms and mediators. Br J Pharmacol 167:946-959.  Back to cited text no. 201
    
202.
Vandeputte C, Docherty JR (2002) Vascular actions of 3,4-methylenedioxymethamphetamine in alpha(2A/D)-adrenoceptor knockout mice. Eur J Pharmacol 457:45-49.  Back to cited text no. 202
    
203.
Vegting Y, Reneman L, Booij J (2016) The effects of ecstasy on neurotransmitter systems: a review on the findings of molecular imaging studies. Psychopharmacology (Berl) 233:3473-3501.  Back to cited text no. 203
    
204.
Vidal-Infer A, Aguilar MA, Miñarro J, Rodríguez-Arias M (2012) Effect of intermittent exposure to ethanol and MDMA during adolescence on learning and memory in adult mice. Behav Brain Funct 8:32.  Back to cited text no. 204
    
205.
Villalobos CA, Bull P, Sáez P, Cassels BK, Huidobro-Toro JP (2004) 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines are potent 5-HT2A receptor antagonists in Xenopus laevis oocytes. Br J Pharmacol 141:1167-1174.  Back to cited text no. 205
    
206.
Vizeli P, Liechti ME (2017) Safety pharmacology of acute MDMA administration in healthy subjects. J Psychopharmacol 31:576-588.  Back to cited text no. 206
    
207.
Vizeli P, Meyer Zu Schwabedissen HE, Liechti ME (2018) No major role of norepinephrine transporter gene variations in the cardiostimulant effects of MDMA. Eur J Clin Pharmacol 74:275-283.  Back to cited text no. 207
    
208.
Volkow ND, Wang GJ, Smith L, Fowler JS, Telang F, Logan J, Tomasi D (2015) Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release. Neuroimage 121:20-28.  Back to cited text no. 208
    
209.
Waldman W, Kała M, Lechowicz W, Gil D, Anand JS (2018) Severe clinical toxicity caused by 25I-NBOMe confirmed analytically using LC-MS-MS method. Acta Biochim Pol 65:567-571.  Back to cited text no. 209
    
210.
Wang Q, Shen FY, Zou R, Zheng JJ, Yu X, Wang YW (2017) Ketamine-induced apoptosis in the mouse cerebral cortex follows similar characteristic of physiological apoptosis and can be regulated by neuronal activity. Mol Brain 10:24.  Back to cited text no. 210
    
211.
Wearne TA, Parker LM, Franklin JL, Goodchild AK, Cornish JL (2016) GABAergic mRNA expression is differentially expressed across the prelimbic and orbitofrontal cortices of rats sensitized to methamphetamine: Relevance to psychosis. Neuropharmacology 111:107-118.  Back to cited text no. 211
    
212.
Wei YB, Yang JR, Yin Z, Guo Q, Liang BL, Zhou KQ (2013) Genitourinary toxicity of ketamine. Hong Kong Med J 19:341-348.  Back to cited text no. 212
    
213.
Wei GL, Zheng XZ, Chen KQ, Shi YY, Wang LY, Tan XY (2018) Coronary sinus flow is reduced in methamphetamine abusers: a transthoracic echocardiographic study. Int J Cardiovasc Imaging 34:1889-1894.  Back to cited text no. 213
    
214.
Wells SM, Buford MC, Braseth SN, Hutchison JD, Holian A (2008) Acute inhalation exposure to vaporized methamphetamine causes lung injury in mice. Inhal Toxicol 20:829-838.  Back to cited text no. 214
    
215.
Wilson CD, Tai S, Ewing L, Crane J, Lockhart T, Fujiwara R, Radominska-Pandya A, Fantegrossi WE (2019) Convulsant effects of abused synthetic cannabinoids JWH-018 and 5F-AB-PINACA are mediated by agonist actions at CB1 receptors in mice. J Pharmacol Exp Ther 368:146-156.  Back to cited text no. 215
    
216.
Wood DM, Ceronie B, Dargan PI (2016) Healthcare professionals are less confident in managing acute toxicity related to the use of new psychoactive substances (NPS) compared with classical recreational drugs. QJM 109:527-529.  Back to cited text no. 216
    
217.
Wood DM, Dargan PI (2014) Using internet snapshot surveys to enhance our understanding of the availability of the novel psychoactive substance alpha-methyltryptamine (AMT). Subst Use Misuse 49:7-12.  Back to cited text no. 217
    
218.
Xu P, Qiu Q, Li H, Yan S, Yang M, Naman CB, Wang Y, Zhou W, Shen H, Cui W (2019) 25C-NBOMe, a novel designer psychedelic, induces neurotoxicity 50 times more potent than methamphetamine in vitro. Neurotox Res 35:993-998.  Back to cited text no. 218
    
219.
Xue Y, He JT, Zhang KK, Chen LJ, Wang Q, Xie XL (2019) Methamphetamine reduces expressions of tight junction proteins, rearranges F-actin cytoskeleton and increases the blood brain barrier permeability via the RhoA/ROCK-dependent pathway. Biochem Biophys Res Commun 509:395-401.  Back to cited text no. 219
    
220.
Yoon KS, Gu SM, Lamichhane S, Han KM, Shin J, Kim YH, Suh SK, Cha HJ, Yun J (2019) Methoxetamine induces cytotoxicity in H9c2 cells: Possible role of p21 protein (Cdc42/Rac)-activated kinase 1. Cardiovasc Toxicol 19:229-236.  Back to cited text no. 220
    
221.
Yuan J, Hatzidimitriou G, Suthar P, Mueller M, McCann U, Ricaurte G (2006) Relationship between temperature, dopaminergic neurotoxicity, and plasma drug concentrations in methamphetamine-treated squirrel monkeys. J Pharmacol Exp Ther 316:1210-1218.  Back to cited text no. 221
    
222.
Zanda MT, Fadda P, Antinori S, Di Chio M, Fratta W, Chiamulera C, Fattore L (2017) Methoxetamine affects brain processing involved in emotional response in rats. Br J Pharmacol 174:3333-3345.  Back to cited text no. 222
    
223.
Zanda MT, Fadda P, Chiamulera C, Fratta W, Fattore L (2016) Methoxetamine, a novel psychoactive substance with serious adverse pharmacological effects: a review of case reports and preclinical findings. Behav Pharmacol 27:489-496.  Back to cited text no. 223
    
224.
Zhang Y, Li L, Wang Q, Shen M, Han W, Yang X, Chen L, Ma A, Zhou Z (2019) Simultaneous determination of metabolic and elemental markers in methamphetamine-induced hepatic injury to rats using LC-MS/MS and ICP-MS. Anal Bioanal Chem 411:3361-3372.  Back to cited text no. 224
    
225.
Zhang Y, Shu G, Bai Y, Chao J, Chen X, Yao H (2018) Effect of methamphetamine on the fasting blood glucose in methamphetamine abusers. Metab Brain Dis 33:1585-1597.  Back to cited text no. 225
    
226.
Zheng XZ, Shi YY, Chen KQ, Qiao XL, Wang LY (2019) Evaluation of regional myocardial perfusion in methamphetamine abusers using real-time myocardial contrast echocardiography. Med Ultrason 21:56-61.  Back to cited text no. 226
    
227.
Zhuo L, Liu Q, Liu L, Sun TY, Wang RS, Qu GQ, Liu Q, Liu Y, Ren L (2013) Roles of 3,4-methylenedioxymethamphetamine (MDMA)-induced alteration of connexin43 and intracellular Ca(2+) oscillation in its cardiotoxicity. Toxicology 310:61-72  Back to cited text no. 227
    
228.
Zwartsen A, Hondebrink L, Westerink RH (2018) Neurotoxicity screening of new psychoactive substances (NPS): Effects on neuronal activity in rat cortical cultures using microelectrode arrays (MEA). Neurotoxicology 66:87-97.  Back to cited text no. 228
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  Toxic Effects of...Toxic Effects of...Toxic Effects of...Toxic Effects of...Toxic Effects of...Toxic Effects of...
  In this article
Abstract
Introduction
Conclusions
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1070    
    Printed1    
    Emailed0    
    PDF Downloaded307    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]