Monoaminergic stimulants, such as amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), and cocaine, are among the most popular drugs of abuse. Other stimulants, such as methylphenidate and dextroamphetamine, are widely prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). MDMA is currently being investigated as a prescription drug for the treatment of posttraumatic stress disorder (Amoroso and Workman 2016; Mithoefer et al. 2011, 2016; Sharma and Couture 2014). Stimulants modulate monoaminergic neurotransmission mainly by interacting with norepinephrine, dopamine, and serotonin (5-hydroxytryptamine [5-HT]) transporters (NET, DAT, and SERT, respectively), in addition to interacting with monoaminergic receptors and other targets. At monoamine transporters, monoaminergic stimulants act as either transporter inhibitors or substrates that mediate non-exocytotic monoamine efflux (Fleckenstein et al. 2000; Rothman and Baumann 2003; Sitte and Freissmuth 2015). Different selectivity (Fig. 1) and potency (Fig. 2) at the different transporters result in different pharmacological effects, different clinical potencies (i.e., the dose that is necessary to induce a psychoactive effect), and different abuse liabilities (Aarde and Taffe 2017; Gannon et al. 2018; Javadi-Paydar et al. 2018; Kuhar et al. 1991; Luethi and Liechti 2018; Ritz et al. 1987; Vandewater et al. 2015; Wee et al. 2005; Wee and Woolverton 2006). In rats, substances that are selective for DAT vs. SERT facilitate dose-dependent and abuse-related intracranial self-stimulation, indicating high abuse potential. In contrast, substances that are selective for the SERT vs. DAT depress dose-dependent intracranial self-stimulation (Suyama et al. 2019), indicating a lower risk of abuse. Repeated exposure to substances with similar activity at the DAT and SERT may sustain the expression of DAT-mediated abuse-related effects while developing tolerance to SERT-mediated abuse-limiting effects, thus resulting in a higher abuse potential (Suyama et al. 2019). The number of available designer stimulants is constantly increasing, and their use can cause various physiological complications and mood disturbances, which are discussed in the subsequent sections for the different classes of designer stimulants.

Fig. 1 DAT vs. SERT selectivity of a variety of stimulants. Stimulants with low (< 0.1) DAT/SERT ratios are likely to induce entactogenic MDMA-like effects, while substances with a high (> 10) DAT/SERT ratio are associated with distinct psychostimulant effects and a high abuse potential. The DAT/SERT ratio is expressed as 1/DAT IC 50 : 1/SERT IC 50 . Full names of the substances and source of pharmacological data are provided in the supplementary information Full size image

Fig. 2 Correlation between reported clinical potencies and in vitro monoamine transporter inhibition of a variety of stimulants. Figure modified from (Luethi and Liechti 2018). Full names of the substances and source of pharmacological data are provided in the supplementary information Full size image

Amphetamines

In addition to traditional amphetamines that are used both medically and recreationally, several amphetamine designer drugs without approved medical uses have become available. MDMA is by far the most popular amphetamine designer drug. It was first synthesized by Merck in 1912 as a precursor in a new chemical pathway, but it was not further investigated until many years later (Freudenmann et al. 2006). In the 1980s, MDMA started to be used in psychotherapy and became popular as a recreational drug under the street name “ecstasy,” which led to a ban of MDMA in most countries soon afterward (Freudenmann et al. 2006; Green et al. 2003). MDMA has slowly found its way back into psychotherapy as a promising agent for the treatment of posttraumatic stress disorder (Amoroso and Workman 2016; Mithoefer et al. 2016, 2011). Recently, various other, often ring-substituted amphetamine derivatives (Fig. 3) have gained increasing popularity as designer drugs, many of which were initially legally obtainable.

Fig. 3 Examples of amphetamine, cathinone, and pyrovalerone derivatives. Full names of the substances are provided in the supplementary information Full size image

Mechanism of action of amphetamines

Most amphetamines are substrate-type monoamine releasers (Rothman and Baumann 2003; Simmler et al. 2013, 2014a; Sitte and Freissmuth 2015). In addition to potent effects at the NET, many amphetamines predominantly act at the DAT vs. SERT, resulting in greater reinforcing effects and higher abuse liability (Kuhar et al. 1991; Ritz et al. 1987; Wee et al. 2005; Wee and Woolverton 2006). In contrast, some amphetamines, including MDMA, have more pronounced effects at the SERT vs. DAT, resulting in an entactogenic effect profile and lower abuse liability (Baumann et al. 2000, 2012; Luethi et al. 2019a; Simmler et al. 2013). Para-substitution at the phenyl ring of amphetamines has been shown to shift their pharmacological profile toward more pronounced activity at the SERT vs. DAT (Luethi et al. 2018c, 2019b; Rickli et al. 2015a; Simmler et al. 2014a; Wee et al. 2005). In addition to their interactions with plasma membrane transporters, amphetamines are substrates at vesicular monoamine transporters (VMATs) and inhibit monoamine oxidases (Fleckenstein et al. 2007; Partilla et al. 2006; Sitte and Freissmuth 2015; Volz et al. 2007). Furthermore, amphetamine designer drugs have been reported to interact with various monoaminergic receptors, including serotonergic and adrenergic receptors, and trace amine-associated receptor 1 (TAAR1), which negatively modulates monoaminergic neurotransmission (Di Cara et al. 2011; Rickli et al. 2015a; Simmler et al. 2014a, 2016).

Adverse effects of amphetamines

Numerous studies have reported the adverse effects of amphetamine, lisdexamfetamine, and methamphetamine. Among amphetamine-derived designer drugs, MDMA is the best studied. For traditional amphetamines, mainly sympathomimetic adverse effects (e.g., anxiety, insomnia, headaches, mydriasis, bruxism, dry mouth, hyperthermia, hypertension, tachycardia, chest pain, palpitations, anorexia, nausea, vomiting, and abdominal pain) can be expected for newly emerged amphetamine-derived designer drugs (Carvalho et al. 2012; Derlet et al. 1989; Dolder et al. 2017; Heal et al. 2013; Vizeli and Liechti 2017; Wijers et al. 2017). Hyperthermia is a significant contributor to potentially severe adverse effects of amphetamines, including disseminated intravascular coagulation, renal failure, and rhabdomyolysis (Bingham et al. 1998; Carvalho et al. 2012; Cunningham 1997; Fahal et al. 1992; Ginsberg et al. 1970; Greene et al. 2003; Halachanova et al. 2001; Henry et al. 1992; Kendrick et al. 1977; Richards et al. 1999; Screaton et al. 1992; Vanden Eede et al. 2012). The uncoupling of oxidative phosphorylation in skeletal muscle through the activation of uncoupling protein 3 (UCP-3) and agonism at adrenergic receptors by norepinephrine release has previously been identified as an important contributor to MDMA-induced hyperthermia (Mills et al. 2003, 2004). Many adverse effects are similar for most amphetamines, but the prevalence of some events is higher for certain specific amphetamines. A comparison of the structures and pharmacological profiles of newly emerged amphetamine designer drugs with well-studied amphetamine derivatives helps to shed light on the likelihood of these specific adverse events. Hepatotoxicity is a potentially fatal adverse effect that has been associated with the use of amphetamines, and MDMA is the designer drug that has been most frequently linked to liver injury (Andreu et al. 1998; De Carlis et al. 2001; Ellis et al. 1996; Garbino et al. 2001; Jones et al. 1994; Kamijo et al. 2002). Different mechanisms may contribute to MDMA-induced hepatotoxicity, including monoamine release, hyperthermia, oxidative stress, impairments in the antioxidant response, mitochondrial dysfunction, and the formation of catechol metabolites by demethylenation (Carvalho et al. 2010, 2012). Cardiotoxicity is another potential complication of amphetamine use and largely attributable to sympathomimetic activation and additionally to secondary mechanisms, such as metabolic bioactivation and hyperthermia (Carvalho et al. 2012). The activation of 5-HT 2B receptors in cardiovascular tissues may potentially result in cardiac valvulopathy and is thus a concern for drugs that increase plasma 5-HT levels or directly activate 5-HT 2B receptors (Elangbam 2010; Elangbam et al. 2008; Huang et al. 2009; Roth 2007). Mild-to-moderate valvular heart disease has been observed in a population of heavy recreational MDMA users, and the 5-HT 2B receptor-mediated proliferation of cardiac valvular interstitial cells that was induced by MDMA was demonstrated in vitro (Droogmans et al. 2007; Setola et al. 2003). The MDMA metabolite 4-hydroxy-3-methoxymethamphetamine (HMMA) exhibits higher potency in stimulating vasopressin secretion; together with the excessive intake of hypotonic liquids and hyperthermia, it may cause potentially fatal hyponatremia, especially in female users likely because of effects of estrogen on vasopressin (Campbell and Rosner 2008; Fallon et al. 2002; Farah and Farah 2008; Forsling et al. 2001; Forsling et al. 2002; Ghatol and Kazory 2012; Hartung et al. 2002; Moritz et al. 2013; Rosenson et al. 2007; Simmler et al. 2011; Van Dijken et al. 2013). Monoamine depletion and reactive species contribute to the neurotoxicity of amphetamines (Carvalho et al. 2012). However, despite extensive research, the extent to which different amphetamines are neurotoxic remains largely unknown. Compared with amphetamine, an increase in serotonergic toxicity has been reported for the para-chlorinated derivative 4-chloroamphetamine, likely explained by highly potent serotonergic activity coupled with considerably potent dopaminergic activity (Colado et al. 1993; Fuller 1992; Johnson et al. 1990; Luethi et al. 2019b; Miller et al. 1986). However, unlike other halogenated stimulants, such as 4-fluoroamphetamine, 4-chloroamphetamine never achieved popularity as a designer drug, possibly because of its well-documented neurotoxicity. Nevertheless, the widely used 4-fluoroamphetamine has been associated with various mild-to-moderate adverse effects (e.g., agitation, severe headache, anxiety, confusion, tachypnea, hypertension, tachycardia, chest pain, electrocardiographic abnormalities, and nausea) and severe adverse effects (e.g., coma, convulsions, cerebral hemorrhage, inverted takotsubo cardiomyopathy, myocardial infarction, and fatalities following cardiac arrest) (Hondebrink et al. 2018). A detailed review of amphetamine toxicity, including toxicological pathways that involve the formation of reactive species, the depletion of antioxidants, and microglial activation, was previously published (Carvalho et al. 2012).

Cathinone and pyrovalerone derivatives

Cathinone designer drugs are derivatives of the β-keto-amphetamine cathinone, an alkaloid that is found in the leaves of the Catha edulis plant. The large-scale recreational use of synthetic cathinones is a relatively new phenomenon, although several compounds have been known for a long time. For example, the first synthesis of 4-methylmethcathinone (mephedrone) was published in 1929 (Sanchez 1929). Several other synthetic cathinones have been investigated for their medical potential, mostly as antidepressant or anorectic agents, but only a few were ever marketed because of concerns about abuse (Canning et al. 1979; Cunningham 1963; Dal Cason et al. 1997; Seaton et al. 1961; Soroko et al. 1977; Valente et al. 2014). Pyrovalerone derivatives represent a subgroup of synthetic cathinones based on the structure of pyrovalerone, which was developed in the 1960s as a treatment option for lethargy, fatigue, and obesity (Gardos and Cole 1971). As a result of their initial misleading marketing as “bath salts”, synthetic cathinones are still often referred to by that term (Baumann et al. 2013). Currently, synthetic cathinones (Fig. 3) represent the largest group of designer stimulants that are monitored by the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) (European Monitoring Centre for Drugs and Drug Addiction 2019).

Mechanism of action of cathinone and pyrovalerone derivatives

Similar to other monoaminergic stimulants, the psychoactive effects of synthetic cathinones are primarily mediated by interactions with monoamine transporters. Many cathinones are partially or fully effective substrate-type releasers at one or several monoamine transporters, but some compounds, such as pyrovalerone derivatives, are transporter inhibitors (Baumann et al. 2012; Eshleman et al. 2013, 2017; Luethi et al. 2018c; Mayer et al. 2016,2019a; Niello et al. 2019; Rickli et al. 2015a; Simmler et al. 2013). Mephedrone has additionally been shown to mediate monoamine release via organic cation transporter 3 (OCT3), indicating that cathinones target both high-affinity and low-affinity/high-capacity transporters (Mayer et al. 2019b). Similar to amphetamines, cathinone designer drugs also interact with several adrenergic and serotonergic receptors (Luethi et al. 2018c; Rickli et al. 2015a; Simmler et al. 2014a). Compared with amphetamines, however, cathinone designer drugs have been shown to interact less potently with TAAR1 and VMAT2 (Eshleman et al. 2013; Simmler et al. 2016). These less potent interactions at TAAR1 may result in a higher risk of cathinone dependence compared with amphetamines.

Adverse effects of cathinone and pyrovalerone derivatives

The use of synthetic cathinones has been associated with mainly sympathomimetic toxicity, which may manifest as agitation, tachycardia, hypertension and less frequently as lower levels of consciousness, hallucinations, hyponatremia, chest pain, palpitations, and nausea (Bäckberg et al. 2015c; Beck et al. 2015, 2016; Borek and Holstege 2012; Boulanger-Gobeil et al. 2012; Franzén et al. 2018; James et al. 2011; Ross et al. 2011, 2012; Umebachi et al. 2016; Wood et al. 2010). Rarely, severe adverse effects (e.g., seizures, significant peripheral organ damage, and rhabdomyolysis) have been reported (Bäckberg et al. 2015c; Beck et al. 2015, 2016; Borek and Holstege 2012; Boulanger-Gobeil et al. 2012; Franzén et al. 2018; Fröhlich et al. 2011; Penders et al. 2012; Ross et al. 2011, 2012). In vitro studies in neuronal, skeletal muscle, and hepatic cells indicated various cytotoxic mechanisms of synthetic cathinones, including mitochondrial dysfunction, glutathione depletion, oxidative stress, and apoptosis pathway activation, which are aggravated under hyperthermic conditions (Dias da Silva et al. 2019; Luethi et al. 2017, 2019b; Valente et al. 2016a, b, 2017a, b; Zhou et al. 2019). Unclear, however, is the extent to which these mechanisms contribute to clinical adverse effects of cathinones relative to sympathomimetic toxicity. Numerous cathinone-related fatalities have been reported (Adamowicz et al. 2014, 2016; Bäckberg et al. 2015c; Barrios et al. 2016; Beck et al. 2016; Busardò et al. 2015; Carbone et al. 2013; DeRoux and Dunn 2017; Eiden et al. 2013; Forrester 2012b; Kesha et al. 2013; Kudo et al. 2015; Lee et al. 2015; Liveri et al. 2016; Majchrzak et al. 2018; Marinetti and Antonides 2013; Maskell et al. 2011a; Nagai et al. 2014; Pearson et al. 2012; Pieprzyca et al. 2018; Potocka-Banas et al. 2017; Schifano et al. 2012; Sellors et al. 2014; Thirakul et al. 2017; Umebachi et al. 2016; Wood et al. 2010; Wright et al. 2013; Wyman et al. 2013; Zaami et al. 2018). Analytically confirmed cases of cathinone-related deaths were mainly attributed to hyperthermia, hypertension, cardiac arrest, and serotonin syndrome (Busardò et al. 2015; Zaami et al. 2018).

Benzofuran and indole derivatives

Various analogs of MDMA and its metabolite 3,4-methylenedioxyamphetamine (MDA) have become available as designer drugs, in which a dihydrobenzofuran, benzofuran, or indole group replaces the benzodioxole group (Fig. 4). Some benzofuran designer drugs were originally investigated as part of a study that examined the role of ring oxygen atoms in interactions between MDA and monoamine transporters (Monte et al. 1993). The indole designer drugs 5-(2-aminopropyl)indole (5-IT, 5-API) and 6-(2-aminopropyl)indole (6-IT, 6-API) emerged from industrial research and are positional isomers of the psychedelic tryptamine α-methyltryptamine (αMT) (Hofmann and Troxler 1962).

Fig. 4 Examples of stimulant designer drugs and reference substances. Full names of the substances are provided in the supplementary information Full size image

Mechanism of action of benzofuran and indole derivatives

In addition to norepinephrine uptake inhibition, stimulant benzofuran and dihydrobenzofuran designer drugs have moderate-to-high selectivity in inhibiting 5-HT vs. dopamine uptake, often with substrate activity at the transporters (Monte et al. 1993; Rickli et al. 2015b). Furthermore, affinity at adrenergic, serotonergic, and histaminergic receptors, partial agonism at 5-HT 2A receptors, and partial to full agonism at 5-HT 2B receptors have been reported for these designer drugs (Dawson et al. 2014; Iversen et al. 2013; Rickli et al. 2015b). The indoles 5-IT and 6-IT are potent substrates at the NET, DAT, and SERT in rat synaptosomes (Marusich et al. 2016). The position of the alkylamine side chain is determining of DAT vs. SERT selectivity, with 5-IT having significantly (eightfold) more potent monoamine-releasing actions at the DAT vs. SERT in rat synaptosomes, whereas 6-IT is eightfold more selective for the SERT (Marusich et al. 2016). In human transporter-transfected cells, 5-IT has been shown to be a very potent inhibiter of norepinephrine uptake, but it did not significantly induce norepinephrine efflux at a single high concentration. However, it had substrate activity at the DAT and SERT (Luethi et al. 2018c). Additionally, 5-IT has affinity for adrenergic and serotonergic receptors and partially activates 5-HT 2A and 5-HT 2B receptors, which may result in additional perceptual psychedelic-like effects at high doses (Luethi et al. 2018c). Furthermore, 5-IT is an inhibitor of human monoamine oxidase (MAO)-A (Herraiz and Brandt 2014).

Adverse effects of benzofuran and indole derivatives

Benzofuran designer drugs may cause agitation, insomnia, headache, drowsiness, dry mouth, dry eyes, bruxism, hyperthermia, tachycardia, palpitations, nausea, diarrhea, hot flashes, clonus of the hands and feet, and psychological symptoms, including visual and auditory hallucinations, depression, anxiety, panic attacks, paranoia, and psychosis (Jebadurai et al. 2013; Nugteren-van Lonkhuyzen et al. 2015). A case of drug-induced psychosis with symptoms of self-harm, paranoia, and suicidal thoughts but unremarkable physical examination was reported with the analytically confirmed presence of 6-(2-aminopropyl)benzofuran (6-APB) in combination with metabolites of a synthetic cannabinoid and tetrahydrocannabinol (Chan et al. 2013). In addition to fatal intoxications that involve benzofurans combined with other designer drugs (Adamowicz et al. 2014; Elliott and Evans 2014), benzofuran toxicity was implicated as the cause of death in an accidental intoxication, in which 5-APB and presumptively a smaller amount of 5-(2-Aminopropyl)-2,3-dihydrobenzofuran (5-APDB) were detected as sole compounds in addition to alcohol (McIntyre et al. 2015a). Autopsy revealed white foam in the trachea, marked congestion and edema of the lungs, and congestive splenomegaly (McIntyre et al. 2015a). Benzofurans induce oxidative stress, disrupt mitochondrial function, and activate apoptosis cascades in vitro, but the in vivo relevance of these sequelae remain unclear (Roque Bravo et al. 2019). 5-IT has been linked to various sympathomimetic adverse effects, including extreme agitation, anxiety, confusion, insomnia, restlessness, hallucinations, seizures, tremors, dilated pupils without light reaction, hyperthermia, sweating, hypertension, tachycardia, arrhythmias, renal failure, myoclonus, muscle rigidity, rhabdomyolysis, and in some cases, serotonergic toxicity (Bäckberg et al. 2014; Coppola and Mondola 2013b; Katselou et al. 2015). Furthermore, 5-IT was involved in several intoxication cases with a fatal outcome within a time span of only a few months (Katselou et al. 2015; Kronstrand et al. 2013; Seetohul and Pounder 2013). Many of 5-IT-associated deaths have been attributed to cardiac arrest, to which 5-HT 2B receptor activation by 5-IT may have contributed (Katselou et al. 2015; Luethi et al. 2018c; Seetohul and Pounder 2013). In most of the fatal and non-fatal intoxication cases, additional substances have been detected. In some cases, the users reported to be unaware that they took 5-IT, because the products were mislabeled as 6-APB (Bäckberg et al. 2014; Kronstrand et al. 2013; Seetohul and Pounder 2013). Although the reported doses of 5-IT and 6-APB are similar, they differ in their selectivity for the dopaminergic vs. serotonergic system (Luethi et al. 2018c; Luethi and Liechti 2018; Rickli et al. 2015b). The extent to which mislabeling played a role in 5-IT intoxication remains unclear.

Aminoindanes

Aminoindane designer drugs (Fig. 4) have become widely available when first-generation designer stimulants, including mephedrone, were finally placed under legal control (Pinterova et al. 2017; Sainsbury et al. 2011). Aminoindanes are conformationally restricted analogs of amphetamine that were originally investigated as bronchodilatory, analgesic, and anti-Parkinson agents, and subsequently as drugs with psychotherapeutic value (Pinterova et al. 2017; Solomons and Sam 1973). Some aminoindane designer drugs have been reported to be entactogens with lower serotonergic neurotoxicity relative to non-aminoindane entactogens (Johnson et al. 1990; Nichols et al. 1991). The desired psychoactive effects of aminoindane designer drugs include euphoria, the mild distortion of vision, time, and space, a greater intensity of perceptions and colors, empathy, and arousal (Coppola and Mondola 2013a; Corkery et al. 2013).

Mechanism of action of aminoindanes

Similar to amphetamines, aminoindane designer drugs are monoamine transporter substrates, with relevant affinity for adrenergic, dopaminergic, and serotonergic receptors (Iversen et al. 2013; Luethi et al. 2018c; Simmler et al. 2014b). Ring-substituted aminoindanes, such as 5,6-methylenedioxy-2-aminoindane (MDAI), 5-iodoaminoindane (5-IAI), and 5-methoxy-6-methyl-2-aminoindane (MMAI), are selective for the SERT vs. DAT (Luethi et al. 2018c; Simmler et al. 2014b). Potent actions of MDAI and 5-IAI on the NET result in an in vitro pharmacological profile that is similar to MDMA, suggesting similar entactogenic effects (Simmler et al. 2014b). MMAI acts as a selective 5-HT releaser with less pronounced effects on the NET, indicating that its effects are different from typical entactogens, such as MDMA (Luethi et al. 2018c). According to in vitro studies, the non-ring-substituted aminoindanes 2-aminoindane (2-AI) and N-methyl-2-AI are selective norepinephrine releasers and devoid of pharmacologically relevant DAT or SERT interactions (Luethi et al. 2018c; Simmler et al. 2014b).

Adverse effects of aminoindanes

Self-reported undesirable effects of aminoindane designer drugs include agitation, anxiety, panic attacks, headache, insomnia, hallucinations, and tachycardia (Coppola and Mondola 2013a). Three fatal cases were reported with confirmed MDAI intake, and serotonin syndrome could have been a factor that contributed to death (Corkery et al. 2013). The likelihood of the serotonergic toxicity of aminoindanes in humans has not been investigated, but signs of serotonin syndrome were reported for a high dose of MDAI in rats (Palenicek et al. 2016).

Piperazines

Piperazine designer drugs (Fig. 4) have been widely sold as legal party pills or powders and appeared as pure substances or adulterants in pills that are sold as “ecstasy” because of their somewhat MDMA-like pharmacological profile, alone or combined (Baumann et al. 2005; Bossong et al. 2010; Lin et al. 2011; Sheridan et al. 2007; Wood et al. 2008). Various therapeutic drugs have a piperazine moiety, and some piperazine designer drugs have a history of medical use. For example, 1-benzylpiperazine (BZP) has been investigated as an antihelmintic agent and antidepressant, and meta-chlorophenylpiperazine (m-CPP) is an active metabolite of different antidepressants (Arbo et al. 2012; Schep et al. 2011). Other frequently used piperazine designer drugs include trifluoromethylphenylpiperazine (TFMPP), 1-(3,4-methylenedioxybenzyl)piperazine (MDBZP), and 4-methoxyphenylpiperazine (MeOPP).

Mechanism of action of piperazines

Piperazine designer drugs exert mixed effects at monoamine transporters. TFMPP and m-CPP are selective 5-HT vs. dopamine reuptake inhibitors (DAT/SERT ratio < 0.05), and m-CPP also inhibits norepinephrine uptake with potency that is similar to the inhibition of 5-HT uptake (Simmler et al. 2014b). Both substances bind to several serotonergic, adrenergic, dopaminergic, and histaminergic receptors with submicromolar or low micromolar affinity (Simmler et al. 2014b). In contrast, BZP is a selective NET inhibitor with relatively weak inhibition of dopamine and 5-HT uptake, without any potent affinity at monoamine receptors (Simmler et al. 2014b). BZP was also shown to be a DAT substrate in rat synaptosomes and human DAT-transfected cells, and m-CPP was reported to elicit 5-HT efflux in human SERT-transfected cells (Baumann et al. 2005; Simmler et al. 2014b). TFMPP mediated 5-HT efflux in rat synaptosomes but not in transfected cells at a single high concentration of 100 μM (Baumann et al. 2005; Simmler et al. 2014b). A combination of TFMPP and BZP was reported to closely mimic the effects of MDMA in rats (Baumann et al. 2005).

Adverse effects of piperazines

Adverse effects of piperazine designer drugs are mostly sympathomimetic, including agitation, insomnia, headaches, dizziness, dilated pupils, hyperthermia, tachycardia, nausea, urine retention, and inducible clonus (Arbo et al. 2012; Gee et al. 2005, 2008, 2010; Katz et al. 2016a; Kovaleva et al. 2008; Schep et al. 2011; Wilkins et al. 2008; Wood et al. 2008). In addition to sympathomimetic toxicity, dissociative symptoms, visual and auditory hallucinations, and psychological symptoms (e.g., short temper, confusion, anxiety, depression, and paranoia) have been associated with the use of piperazine designer drugs (Gee et al. 2008; Kovaleva et al. 2008; Schep et al. 2011; Wilkins et al. 2008; Wood et al. 2008). Furthermore, toxic seizures were frequently observed in patients who were admitted to the emergency department after the use of BZP-containing party pills. Although there seems to be a trend toward higher concentrations being more frequently associated with seizures, they may also occur at low doses (Gee et al. 2005, 2008). Other severe adverse effects of BZP include hyponatremia, severe combined metabolic and respiratory acidosis, hepatic injury, renal failure, disseminated intravascular coagulation, and rhabdomyolysis (Gee et al. 2010; Katz et al. 2016a). A case of severe hyperthermia with resultant multi-organ failure and a case of hyponatremia that led to fatal brain edema were reported for the concomitant use of piperazine designer drugs and MDMA (Balmelli et al. 2001; Gee et al. 2010). The contribution of these individual compounds to the observed clinical manifestations remains unclear, but piperazines and MDMA may elicit additive or synergistic toxicity. In vitro, piperazine designer drugs have been reported to upregulate key enzymes of cholesterol biosynthesis, induce oxidative stress, disrupt mitochondrial function, and activate apoptosis pathways, all of which may potentially contribute to clinical toxicity (Arbo et al. 2016a, b; Dias da Silva et al. 2017; Dias-da-Silva et al. 2015; Majrashi et al. 2018).

Phenidate derivatives

Derivatives of the piperidine prescription drug methylphenidate have appeared as designer drugs (Fig. 4), with substitutions at the phenyl ring and different lengths of the carbon side chain (Luethi et al. 2018b). Similar to methylphenidate, phenidate derivatives may be used to induce euphoria or as cognitive enhancers (Ho et al. 2015; Lüthi and Liechti 2019). Various methylphenidate-based designer drugs originated from drug development efforts and later appeared on the recreational drug market as pure compounds or in the form of branded products (Bailey et al. 2015; Deutsch et al. 1996; Ho et al. 2015; Markowitz et al. 2013; Misra et al. 2010). When insufflated, the pharmacological and subjective-effect profile of methylphenidate is similar to cocaine, and phenidate derivatives may, therefore, be used as substitutes for cocaine (Vogel et al. 2016).

Mechanism of action of phenidate derivatives

Similar to methylphenidate, methylphenidate-based designer drugs act as potent NET and DAT inhibitors that are devoid of substrate activity (Luethi et al. 2018b; Simmler et al. 2014b). Some less potent interactions with the SERT and adrenergic and serotonergic receptors have been reported but are not likely to play a relevant role in the psychoactive actions of most phenidate derivatives (Luethi et al. 2018b).

Adverse effects of phenidate derivatives

Adverse effects of phenidate derivatives are similar to amphetamines and include agitation, anxiety, hypertension, tachycardia, and palpitations (Bailey et al. 2015). Because of their relatively slow onset of action when taken orally, the nasal insufflation or injection of phenidate derivatives is common, especially in heavy users. Nasal pain and septum perforations after insufflation and infections after intravenous injection may occur (Ho et al. 2015; Lafferty et al. 2016; Parks et al. 2015). The rapid onset of action after nasal or intravenous use, combined with the marked DAT vs. SERT selectivity of phenidate derivatives, has been linked to a higher risk of addiction (Luethi et al. 2018b). In several cases, phenidate derivatives have been analytically confirmed post-mortem, in which ethylphenidate is the most frequently detected compound (Krueger et al. 2014; Maskell et al. 2016; Parks et al. 2015; Shoff et al. 2019). Many decedents had a history of heroin use, and intravenous injection was a common route of administration. In addition to phenidate derivatives, other drugs, including benzodiazepines and opioids, have been detected in most fatal cases (Krueger et al. 2014; Maskell et al. 2016; Parks et al. 2015).

Aminorex analogs

Various analogs of the anorectic agent aminorex have become available as designer drugs (Fig. 4). Aminorex was first marketed as an over-the-counter appetite suppressant in parts of Europe in the 1960s, but it was withdrawn a few years later because of an epidemic of chronic pulmonary hypertension that was associated with many fatalities (Maier et al. 2018a). Aminorex analogs that have found their way onto the designer drug market include 4-methylaminorex (4-MAR) and 4,4′-dimethylaminorex (4,4′-DMAR), the reported effects of which include euphoria, mental and physical stimulation, sociability, empathy, arousal, and changes in visual perception (European Monitoring Centre for Drugs and Drug Addiction 2015; Glanville et al. 2015; Loi et al. 2017). A comprehensive review of the history of aminorex use and the emergence of its designer drug analogs was recently published (Maier et al. 2018a).

Mechanism of action of aminorex analogs

In human transporter-transfected cells, 4,4′-DMAR is a potent inhibitor of norepinephrine, dopamine, and 5-HT reuptake. 4-MAR has similarly potent dopamine and norepinephrine reuptake properties as 4,4′-DMAR, but 5-HT uptake inhibition is less pronounced compared with its para-methylated counterpart (Maier et al. 2018b; Rickli et al. 2019). Aminorex and its derivative 4-MAR mediate norepinephrine and dopamine efflux in rat synaptosomes, with weak substrate activity at the SERT (Brandt et al. 2014; Rothman et al. 2001). 4,4′-DMAR and 3′,4′-methylenedioxy-4-methylaminorex (MDMAR) induce norepinephrine, dopamine, and 5-HT efflux in rat synaptosomes (Brandt et al. 2014; McLaughlin et al. 2015). Dynamic superfusion experiments revealed the substrate activity of 4,4′-DMAR at human monoamine transporters (Maier et al. 2018b). In human transporter-transfected cells that were preloaded with monoamines and exposed to drugs at a single high concentration (100 μM), only dopamine efflux was observed for 4,4′-DMAR, and dopamine and 5-HT efflux was observed for 4-MAR (Rickli et al. 2019). In addition to interactions with plasmalemmal transporters, 4,4′-DMAR has been shown to inhibit human VMAT2-mediated dopamine uptake (Maier et al. 2018b). In addition to their primary effects on transporters, minor interactions with serotonergic 5-HT 2C and adrenergic α 2A receptors have been described for 4-MAR, and low affinity at 5-HT 2A and 5-HT 2C receptors has been described for 4,4′-DMAR (Maier et al. 2018b; Rickli et al. 2019).

Adverse effects of aminorex analogs

Adverse effects of aminorex designer drugs that have been reported by users on various Internet discussion platforms include agitation, dysphoria, insomnia, amnesia, panic attacks, psychosis, hallucinations, facial spasms, dilated pupils, foaming at the mouth, dry mouth, jaw clenching, elevations of body temperature, sweating, elevations of heart rate, nausea, and restless legs (Glanville et al. 2015; Loi et al. 2017; Maier et al. 2018a). Pulmonary hypertension (i.e., the adverse effect that led to the removal of aminorex from the market) has been associated with the recreational use of 4-MAR (Gaine et al. 2000). Designer drug analogs of aminorex have been analytically confirmed in several drug-related deaths (Cosbey et al. 2014; Davis and Brewster 1988; European Monitoring Centre for Drugs and Drug Addiction 2015). Although other substances were present in most fatal cases, 4,4′-DMAR was mentioned to be the cause of death or to have played a contributory role in several of these fatalities (European Monitoring Centre for Drugs and Drug Addiction 2015). Brain edema, seizures, hyperthermia, respiratory and cardiac arrest, and internal bleeding were all listed as adverse events or autopsy findings that were associated with the use of 4,4′-DMAR (European Monitoring Centre for Drugs and Drug Addiction 2015).

Phenmetrazine derivatives

Phenmetrazine is a reinforcing stimulant, which was previously used as an appetite suppressant before it was eventually withdrawn from the market (Chait et al. 1987). Phenmetrazine-derived designer drugs (Fig. 4) represent a relatively understudied class of drugs, among which 3-fluorophenmetrazine (3-FPM) use appears to be the most widespread.

Mechanism of action of phenmetrazine derivatives

Like the parent compound, ring-fluorinated derivatives of phenmetrazine are substrates at the NET and DAT, with minor substrate activity at the SERT (Mayer et al. 2018; Rothman et al. 2002). Ring-methylated phenmetrazine derivatives were reported to have greater potency at the SERT, in addition to activity at the NET and DAT (McLaughlin et al. 2018). Para-substituted compounds were shown to have the greatest serotonergic effects among the phenmetrazine derivatives, similar to ring-substituted amphetamine and cathinone designer drugs (Luethi et al. 2019b; Rickli et al. 2015a).

Adverse effects of phenmetrazine derivatives

Based on their mechanism of action, phenmetrazine designer drugs are expected to elicit stimulatory toxicity that is similar to amphetamines. A series of non-fatal intoxications that involved 3-FPM were reported within the Swedish STRIDA project, mostly with sympathomimetic adverse effects (Bäckberg et al. 2016). However, polydrug intoxication prevented attribution of the observed effects to 3-FPM, underscored by the fact that the clinical features included some oppositional effects (e.g., both miotic and dilated pupils and both hypertension and hypotension) (Bäckberg et al. 2016). Nevertheless, the authors of this case series suggested that 3-FPM is a harmful compound, as one-third of patients presented severe adverse events (Bäckberg et al. 2016). In addition to other polydrug intoxications that involve 3-FPM (Benesch and Iqbal 2018; Ellefsen et al. 2017), a case of severe kidney injury and limb ischemia that were associated with intravenous 3-FPM use was reported (Fawzy et al. 2017). The authors of the latter case report hypothesized that the intravenous use of 3-FPM resulted in severe vasoconstriction, possibly with concomitant infection, and caused widespread ischemia (Fawzy et al. 2017).

Thiophene designer drugs

Various analogs of amphetamines and cathinones with a thiophene group that replaces the phenyl ring have appeared as designer drugs (Fig. 4). Some of the thiophene designer drugs were first described in the 1940s and elicited effects that were reported to be comparable to their phenyl ring analogs (Alles and Feigen 1941; Blicke and Burckhalter 1942). To date, most pharmacological studies and toxicological reports involve methiopropamine (MPA), the thiophene analog of methamphetamine.

Mechanism of action of thiophene designer drugs

MPA is a quasi-equipotent inhibitor of norepinephrine and dopamine uptake and was reported to interact with various serotonergic, adrenergic, dopaminergic, N-methyl-d-aspartate (NMDA), and sigma-1 receptors (Iversen et al. 2013).

Adverse effects of thiophene designer drugs

MPA use has been associated with significant acute toxicity and psychotic, cardiovascular, and gastrointestinal symptoms, including agitation, anxiety, confusion, a lower level of consciousness, insomnia, visual hallucinations, elevations of creatine kinase, tachycardia, palpitations, chest tightness, nausea, and vomiting (Daveluy et al. 2016; Lee et al. 2014; White et al. 2019). However, for most intoxication cases, the use of multiple substances was reported, and the extent to which MPA contributed to the reported adverse effects remains unclear. A death from isolated MPA use was described, in which cardiac arrhythmia that induced cardiovascular collapse was named as the probable cause of death (Anne et al. 2015). Dopaminergic neurodegeneration and myocardial, renal, and gastrointestinal damage were observed in mice that were exposed to MPA (Foti et al. 2019; Nguyen et al. 2019).

Miscellaneous stimulants

Several designer drugs have appeared that do not belong to any classes that are discussed in the previous sections. Any substance that interacts with monoamine transporters may potentially be sold as a stimulant designer drug, even if it is not or only remotely chemically related to the widely used stimulant classes. One example of such a substance is the potent NET, DAT, and SERT blocker diclofensine, a tetrahydroisoquinoline derivative that was originally developed as an antidepressant (Luethi et al. 2018a).