Toxicology Letters 229 (2014) 349–356

Synthetic cathinones: “A khat and mouse game”

Daniel P. Katz, Dwipayan Bhattacharya, Subhrajit Bhattacharya, Jack Deruiter,C. Randall Clark, Vishnu Suppiramaniam, Muralikrishnan Dhanasekaran *Department of Drug Discovery and Development, Auburn University, Auburn, AL 36830, USA

H I G H L I G H T S

� Frequent chemical modifications of synthetic designer drugs enable clandestine manufacturers to avoid governmental bans and promote widespreaddistribution.

� Comparable mechanisms of action between the synthetic cathinones and amphetamines are mainly attributed to the similarities in their chemicalstructures.

� The stimulatory effects of synthetic cathinones are engendered by elevations in synaptic catecholamine concentrations.� The physical symptoms attributed to synthetic cathinones, observed in mammals, reflects increased sympathomimetic and dopaminergic surge.� If synthetic cathinones are designed carefully, they might definitely have a significant therapeutic value.

A R T I C L E I N F O

Article history:Received 2 May 2014Received in revised form 9 June 2014Accepted 10 June 2014Available online 25 June 2014

Keywords:Bath saltsSynthetic cathinoneDesigner drugMDPVStimulantAddiction

A B S T R A C T

The birth of the twenty first century has provoked a substantial rise in the use of designer drugs, such assynthetic cathinones, because of a decrease in the availability and purity of other drugs of abuse. The khatplant or Catha edulis, contains cathinone, the parent compound. Synthetic cathinones are sold under thename “bath salts” as a ploy to circumvent legislation from banning their use. Constant modification of thechemical structure by covert laboratories allows manufacturers to stay one step ahead of the legalprocess. Currently, the widespread distribution of “bath salts” has negative consequences for lawenforcement officials and public health resources. Comparable mechanisms of action, between thesynthetic cathinones and amphetamine, cocaine, and MDMA are attributed to the similarities in theirchemical structures. Synthetic cathinone’s potent stimulatory effects, coupled with their high abusepotential, and propensity for addiction demands additional pharmacological and toxicologicalevaluations for these existing and new designer drugs of abuse. If these drugs are designed carefully,they might also have a significant therapeutic value.

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1. Introduction

Synthetic cathinones, the active component in “bath salts”,have surfaced as a popular alternative to other illicit drugs of abuse,such as cocaine, MDMA (ecstasy), and methamphetamine, due totheir potent psychostimulant and empathogenic effects. Mephe-drone (4-methylmethcathinone), methylone (3,4-methylenediox-ymethcathinone), MDPV (3,4-methylenedioxypyrovalerone),3-FMC (3-fluoromethcathinone), 4-FMC (4-fluoromethcathinone),buphedrone (a-methylamino-butyrophenone), butylone (beta-

* Corresponding author.E-mail address: dhanamu@auburn.edu (M. Dhanasekaran).

http://dx.doi.org/10.1016/j.toxlet.2014.06.0200378-4274/ã 2014 Elsevier Ireland Ltd. All rights reserved.

keto-N-methyl-3,4-benzodioxyolybutanamine), methedrone(4-methoxymethcathinone), and naphyrone (naphthylpyrovaler-one) are a few synthetic cathinones, among others (Karila andReynaud, 2011). Fig. 1 illustrates the structural modifications ofmethcathinone that prouce several designer cathinones. Theparent compound, cathinone, is found in the leaves of Catha edulisForsk, the khat plant (Fig. 2). C. edulis was discovered in Yemen byPeter Forskal, an eighteenth century botanist (Feyissa and Kelly,2008). Cathinone’s stimulatory effects have been known forcenturies, mostly prevalent in Middle Eastern countries rangingfrom Southern Africa to the Arabian Peninsula (Krikorian, 1984). Askhat ages, cathinone undergoes rapid enzymatic degradation tocathine and norephedrine, the inactive metabolites (Al-Obaid et al.,1998). Exposure to heat or sunlight accelerates this degradative

Fig. 1. Chemical structures of Synthetic Cathinones derived from Methcathinone.(Hanson, 2012), catching up with bath salts and spice. In: 08/01/2012.

Table 1Alternative product names for “Bath Salts”.(Show, 2011), alternate names for the “bath salt” drug [online]. http://www.doctoroz.com/videos/alternate-names-bath-salt-drug.

Arctic blast Euphoria Red doveBayou ivory flower Gold rush Route 69Bloom Hurricane Charlie ScarfaceBlue magic Ivory fresh Snow dayBlue silk Ivory wave TranquilityBolivian bath Lady bubbles Vanilla skyBonsai winter boost Lunar wave White doveCloud 10 Mr. Nice guy White lighteningCloud 9 Mystic White rushCotton cloud Ocean snow Wicked XDynamite plus Pure white Zoom

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process, therefore cultivators commonly wrap the leaves andshoots in banana peels to preserve freshness and moisture (Yousefet al., 1995). Users amass a large bolus of leaves and shoots tomacerate against the lining of the cheek, for buccal absorption(Sawair et al., 2007). Absorption also occurs from the stomach andsmall intestine following the deglutition of discharged juices. In2006, an estimated 10 million people abuse khat worldwide(Rosenbaum et al., 2012).

“Aura”, “Bliss”, “Energy 1”, “Hurricane Charlie”, and “Whiterush” are common “bath salt” product names (Table 1) intended toentice consumers, even though packages are clearly labeled “notfor human consumption” (Shanks et al., 2012; Spiller et al., 2011;Ross et al., 2012). “Bath salts” are manufactured by surreptitiouslabs then sold on the internet and in legal retail outlets as incense,air fresheners, and plant food to evade the law, preventinglegislation from outlawing these drugs (Vardakou et al., 2011).

Fig. 2. Fresh leaves and shoots of the khat plant, Catha edulis Forsk.(Scottdouglas, 2013), Yemen-country of khat. http://www.suncoastrehabcenter.com/wp-content/uploads/2013/08/khat.jpg.

Frequent chemical modifications of synthetic designer drugsenable manufacturers to avoid governmental bans and promotewidespread distribution (Brandt et al., 2010; Shanks et al., 2012).Synthetic cathinone development paradoxically contradicts theethical development of drugs. Drug development follows a distinctset of guidelines and steps: development of a lead compound,animal testing, pharmacokinetic studies, safety and efficacystudies, and human trials. A reversed development phenomenonoccurs, in which bath salts are synthesized, packaged, distributed,and sold directly to the consumer (without FDA approval).Meanwhile, critical safety evaluations and other testing remainunassessed until well after the drug has been exposed to the public.Additional modifications to new and existing synthetic cathinoneswill necessitate pharmacological and toxicological evaluations;therefore, this longstanding tortuous battle between syntheticchemists and the drug enforcement administration will remain anobstacle to conquering our “war on drugs”.

2. Prevalence

Cathinone derivatives began to appear first in the Europeanrecreational drug market in the mid- 2000s. At that time to 2010,the most commonly encountered cathinones on the Europeanclandestine market were mephedrone, methylone, and MDPV.Since this time there have been more than 5500 drug seizures ofMDPV in Europe, either in bulk form or solid dosage forms (tablets,capsules, powders), and 107 non-fatal intoxications and 99 deathsassociated with this drug alone. Also since 2010 there have beenincreasing reports of more designer cathinone analogues inEurope, as well as their appearance in the US clandestine drugmarket.

According to the American Association of Poison ControlCenters, the number of closed human exposures regardingsynthetic cathinones substantially increased from 306 to 6137,in 2010 and 2011; respectively (aapcc, 2013). The drug abusewarning network (DAWN) reported that of the 2.5 millionemergency department visits related to the misuse or abuse ofdrugs in 2011; 22,904 of these visits were due to “bath salt”exposure (DAWN, 2013). The 2011 rise in the abuse of bath saltsbecame known as “America’s new drug problem” (Bath Salts Drug,2011). This surge in “bath salt” consumption is attributed to adecrease in the availability and purity of the more common drugsof abuse (caffeine, MDMA, cocaine). Illicit drug manufacturers havefrugally resorted to “cutting” MDMA with synthetic cathinones todilute their purity (Brunt et al., 2011). The Netherlands observed adrop of MDMA potency in ecstasy tablets, from greater than 90% oftablets containing MDMA before 2009, to just below half beingcompletely devoid of MDMA. Piperazine derivatives and meph-edrone were substituted for MDMA in these “pseudo”-ecstasytablets (Brunt et al., 2011). Similarly, law enforcement officials inthe UK reported a considerable decrease in the purity of cocaine,

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from 60% in 1999 to 22% in 2009, resulting in a rise of drug seizures(Hand, 2009). In October of 2011, the United States governmentresponded by classifying mephedrone, MDPV, and methylone asschedule I drug’s. As defined by the United States ControlledSubstances Act schedule I drugs, substances, or chemicals must beclassified as having no current therapeutic use, a high susceptibili-ty for abuse, and a lack of safety that may lead to psychological orphysical dependence. Heroin, lysergic acid diethylamide (LSD),marijuana (cannabis), 3,4-methylenedioxymethamphetamine (ec-stasy), methaqualone, and peyote are also currently classified asschedule I drugs (DEA, 2014). The United States government’sintervention on bath salts resulted in an abatement of reportedhuman exposures, from 2676 reports in 2012 to 690 reportsthrough August 31 of 2013 (aapcc, 2013).

3. Patterns of use, pharmacokinetic aspects, and drugcombinations

The preferred routes of exposure for synthetic cathinones arenasal insufflation (snorting) and ingestion. Users frequentlypractice “keying” and “bombing” (Newcombe, 2009), the formerinvolves snorting powder via a key, and the latter entails ingestingpowder rolled up in cigarette paper. The rapid onset of action frominsufflation combined with the prolonged effects of ingestionresult in an immediate and sustained intoxication (Deluca et al.,2009). Less common modalities include rectal administration,gingival delivery, inhalation, intramuscular injection, and intrave-nous injection (Newcombe, 2009). Users insufflating mephedronenote a 10–20 min delay, before the onset of effects, followed by a 1–2 h duration, while oral dosing was delayed 15–45 min and lasted2–4 h in duration (EMCDDA, 2010; Newcombe, 2009). MDPV’slipophilic nature enables extensive central nervous systemstimulation by translocation across the blood brain barrier; evenminute doses of 3–5 mg have produced psychoactive effectsaltering mood, consciousness, and behavior. Typical MDPV dosesrange from 5 to 20 mg (Ross et al., 2012), associated with an onsetof action in 15–30 min, and a duration of 3–4 h (Erowid, 2011).Shockingly, some “bath salt” products containing MDPV have beenlabeled, “for ultimate relaxation use 50 g in your bath and go upfrom their” (Ross et al., 2012). MDPV’s short duration of actionleads users to “fiending”, consuming numerous doses in succession(Ross et al., 2012; Schifano et al., 2011), to avert the harsh come-down effects, while in turn building tolerance, and potentiallyresulting in an overdose.

Fig. 3. Synthes

Synthetic cathinones consumed in combination with otherdrugs are intended to intensify desired effects or curtail noxiouseffects. Routine drug combinations with beta-ketones include:cocaine, amphetamines, methamphetamines, cannabis, kratom,GHB, other synthetic cathinones, alcohol, beta blockers, GBL,zopiclone, caffeine, pregabalin, famotidine, omeprazole, domper-idone, opiates, and benzodiazepines (drugs-forum, 2014). MDPV,in combination with antipsychotics for the treatment of schizo-phrenia, depression, or anxiety, must be recognized and avoideddue to the antipsychotic medication lowering the thresholdpotential for seizures, already manifested as a physical symptomof MDPV exposure (Marks and Luchins, 1991).

4. Chemistry

Like the amphetamine-type drugs of abuse, cathinone deriv-atives have a chiral center and can exist in two stereoisomeric(enantiomeric) forms (R and S), which may differ in potency.Cathinone from a natural source, in khat, is the S-enantiomer.However, it is likely that most ring-substituted derivatives on theclandestine market (Fig. 1) are racemic mixtures (equal amounts ofR and S). It is also believed that racemization of all cathinonederivatives can occur through keto–enol tautomerism. Cathinoneis unstable and can readily degrade into dimers and other inactivedecomposition products. All known cathinone derivatives areeither N-alkylated or the nitrogen atom is part of a pyrrolidine ring(Fig. 1), and most are produced as hydrochloride salts for enhancedstability. Many illicit cathinone products are N-methylated, i.e.,ephedrone derivatives, whereby mephedrone can be described as4-methylephedrone. The pyrrolidine derivatives (PPP, MDPV) canbe regarded as a sub-set of ‘designer drugs’ sharing the sameskeleton as pyrovalerone.

As mentioned previously, cathinone or khat can be isolatedfrom its natural source, the C. edulis plant. Cathinone and othersimple N-alkyl- and ring substituted derivatives (methcathinone,mephedrone, methadrone, etc., Fig. 1) can also be synthesizedclandestinely by oxidation of an appropriately substituted phenyl-ethanolamine precursor using potassium permanganate in sulfuricacid or other oxidizing agents as illustrated in Fig. 3A. An advantageof such an approach is that the precursor chemicals can beobtained as specific enantiomers, thereby ensuring that thesynthesis of the cathinone derivative is stereoselective. One ofthe hazards of using these methods is that the product can becontaminated with the oxidizing metal (i.e., manganese) which istoxic to the end user. The structurally more complex cathinone

is of MDPV.

Fig. 4. Structural similarities of amphetamine and methamphetamine with theirb-Keto equivalent.(Brock, 2013), cathinones-illicit drugs.

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derivatives, such as MDPV which has a 3,4-methylenedioxyar-omatic ring, a pyrrolidine ring and propyl side chain are typicallyprepared by reacting a suitably ring substituted bromophenylal-kanone with pyrrolidine, giving rise to racemic products (Fig. 3B).The required substituted bromophenylalkanone intermediate isobtained by reaction of the appropriate phenylalkanone withbromine (Fig. 3B). The phenylalkanones can be prepared bysequential treatment of commercially available substituted benz-aldehyde (i.e., piperonal) with butylmagnesium bromide followedby oxidation with chromium reagents.

The b-ketophenethylamine moiety is the unique feature amongall synthetic cathinones, imparting the structural and pharmaco-logical differences of methcathinone from methamphetamine andmethylone from MDMA (Gibbons and Zloh, 2010). The ketoneattached to the beta carbon augments the polarity of the molecule,rendering the synthetic cathinones hydrophilic; hence, they areless able to cross the blood brain barrier (BBB) to producepsychostimulant effects (Gibbons and Zloh, 2010). In fact,molecular modeling studies have shown cathinone log P valuesare one unit lower than their methyl-amphetamine complements(Gibbons and Zloh, 2010). Higher doses are required to produceequivalent effects accompanied by ineluctable side effects (Hill andThomas, 2011). On the other hand, the pyrrolidine derivatives3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylene-dioxy-alpha-pyrrolidinopropriophenone (MDPPP) display supe-rior lipophilicity with concomitant potency (Gibbons and Zloh,2010). The tertiary amino group in MDPV enables the molecule tobe easily dissolved in organic solvents (caymanchem, 2014).

The metabolism of methylone, ethylone, and butylone isinitiated by phase I demethylation of the methylenedioxy ring,converting the parent drug to a catechol metabolite. Thismetabolite is then methylated by catechol O-methyltransferase(COMT) to produce the 40-hydroxy-30-methoxy or 30-hydroxy-40-methoxymethcathinone metabolites. The O-methylation metabo-lites undergo phase II partial conjugation, by glucuronides andsulfates, increasing the molecular weight and water solubility ofthe drug while yielding inactive metabolites for renal excretion(Zaitsu et al., 2009). Methylone, ethylone, and butylone may alsoundergo some N-demethylation and ketone reduction, but theseappear to be minor pathways of metabolism for these drugs.Mephedrone undergoes metabolism by N-demethylation to aprimary amine, ketone reduction to the corresponding alcohol, andtoluyl methyl group oxidation to the alcohol. The alcohols formedfrom mephedrone oxidation are conjugated as glucuronides andsulfates and excreted (Meyer et al., 2010b). MDPV metabolism, inhepatocytes, begins with the opening of the methylenedioxy ring,the conversion to a catechol ring by demethylation, a methylationby COMT, and finally glucuronidation and sulfation, similar to thatobserved with other 3,4-methylenedioxyphenyl cathinoes(i.e., methylone) (Strano-Rossi et al., 2010). MDPV may also bemetabolized by other oxidative pathways including hydroxylation.The cytochrome P450 (CYP450) liver isoenzymes CYP2C19,CYP2D6, CYP2B6, and CYP1A2 are enzymes implicated in themetabolism of synthetic cathinones (Meyer et al., 2010a).

5. Detection

Gas chromatography/mass spectrometry (GC/MS) or liquidchromatography/mass spectrometry (LC/MS) is essential for theidentification and confirmation of synthetic cathinones. ELISA-based screening of synthetic cathinones is ineffective because theimmunoassay may produce false positive screens for metham-phetamine (Torrance and Cooper, 2010). MDPV has also beenshown to cross react with immunoassays creating false positivesfor phencyclidine (PCP) (Macher and Penders, 2013). Rat studiesshow that methylone is thoroughly incorporated in hair while

cathinone and methcathinone are inadequately incorporated(Kikura-Hanajiri et al., 2007). Drug testing laboratories mustconstantly create new methods for novel designer cathinones thatcan accurately quantify the levels of synthetic cathinones in urine,blood, and hair. Method development requires research, time, andman power that may hinder drug testing laboratories from keepingup to date testing.

6. Pharmacology

Analogous mechanisms of action between the syntheticcathinones and amphetamines are attributed to the similaritiesin their chemical structures (Prosser and Nelson, 2012). Fig. 4compares the structures of amphetamine and methamphetaminewith the b-ketoamphetamines. The stimulatory effects of syn-thetic cathinones are engendered by elevations in synapticcatecholamine concentrations (Coppola and Mondola, 2012),primarily via two mechanisms. First, these molecules bind toand inhibit the monoamine uptake transporters for dopamine(DAT), norepinephrine (NET), and serotonin (SERT), diminishingtheir clearance from the synaptic cleft (Cozzi et al., 1999). Second,as substrate releasers, they exhibit non-exocytotic neurotransmit-ter release from intracellular stores by reversal of transporter fluxand inhibiting the vesicular monoamine transport receptor(VMAT2) (Prosser and Nelson, 2012). MDMA has been suggestedto compete for substrate binding sites on VMAT2, a proton-monoamine antiporter, as well as scattering intravesicular pHgradients mandatory for vesicular monoamine accumulation andtransport (Rudnick and Wall, 1993; Sulzer and Rayport, 1990).Amphetamine binds to the trace amine associated receptor1 (TAAR1), a G protein-coupled receptor, in the presynapticneuron, diminishing dopamine receptor firing rate and activatingprotein kinase A and protein kinase C, then phosphorylating DAT.Phosphorylated DAT will reverse transporter flux or depositneurotransmitter into the presynaptic neuron terminating trans-port (Miller, 2011). A PKC-modulated DAT internalization eventreduces the number of dopamine transporters on the presynapticmembrane preventing the reuptake of dopamine (Xie and Miller,2009). The b-ketoamphetamines display roughly a 10 fold reducedaffinity for TAAR1 when compared to the non-b-ketoamphet-amines (Simmler et al., 2013).

The relative selectivity of synthetic cathinones to inhibitmonoamine transporters (DAT, NET, and SERT) and promotesubstrate release differentiates their effects on neurotransmission.Simmler et al. classifies the synthetic cathinones into three groupsdepending on their potencies at the transporters and as substratereleasers. The cocaine-MDMA-mixed cathinones containingmephedrone, methylone, ethylone, butylone, and naphyrone all

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display nonselective monoamine uptake inhibition as well asMDMA-like 5-HT release, barring naphyrone (Simmler et al., 2013).Their data illustrates that cocaine-MDMA-mixed cathinonesdisplay greater dopaminergic monoamine transport inhibitionwhen compared to their non-b-ketone amphetamine counterparts(Simmler et al., 2013). The methamphetamine-like cathinones,including cathinone, methcathinone, and flephedrone, exert theireffects as preferential catecholamine inhibitors and dopaminereleasers (Simmler et al., 2013). Cozzi et al. states methcathinoneand methylone are potent inhibitors of plasma membranecatecholamine transporters but have very limited effect oninhibiting VMAT2 (Cozzi et al., 1999). Pyrovalerone and MDPV,the pyrovalerone–cathinones, are both potent and selectivemonoamine uptake inhibitors with no action as substrate releasers(Simmler et al., 2013).

MDPV is a potent monoamine transporter inhibitor withrelative potencies for DAT > NET >> SERT (Baumann et al., 2013b;Simmler et al., 2013), but is a feeble substrate releaser. The >100DAT/SERT inhibition ratio for MDPV trumps the methamphet-amine and cocaine ratio, >10 and 3.1, respectively (Simmler et al.,2013), revealing a high abuse potential (Bauer et al., 2013). A recentstudy from Aarde et al. revealed that the amount of MDPV self-administered intravenously by lever presses in rats was far greaterthan that of methamphetamine (Aarde et al., 2013). Ratsunderwent lever press training in which 45 mg pellets weredelivered under a fixed-ratio, that is, a one-press-per-reinforcerschedule (FR1). Additional testing to quantify the rats’ desire toredose was measured by increasing the number of lever presses fora single infusion. Interestingly, the average number of lever pressesfor an infusion of methamphetamine was 60, while MDPV showeda remarkable 600 lever presses, 10 times the amount ofmethamphetamine (Aarde et al., 2013). Some rats desire forredosing was so intense, a single infusion of MDPV was deliveredafter 3000 lever presses (Aarde et al., 2013). Excessive release ofdopamine in the synapse plays a major role in feelings of pleasure,motivation, and satisfaction. Feelings of satisfaction becomedesired; therefore, repeated behaviors that cause the release ofdopamine will be favored. Increased dopaminergic transmission inlimbic nuclei, particularly from the ventral tegmental area to thenucleus accumbens (reward center), underlies the reinforcingeffects of drugs of abuse. Previously, Watterson et al. proposed adose-dependent decline in reward thresholds when MDPV wasadministered by intra-cranial self-stimulation (Watterson et al.,2012). Also, MDPV induced a greater extent of overall behaviorwhen compared to methamphetamine, indicating a positive placepreference and greater reward value (Aarde et al., 2013). Thesynthetic cathinones served as a reliable replacement foramphetamine and MDMA when administered to rats trained todistinguish between the two (Dal Cason et al., 1997).

The prototypical change in behavior, in rats and mice, observedafter psychomotor stimulant exposure, is a rise in locomotoractivity, often linked to addiction (Calabrese, 2008; Wise andBozarth, 1987). Species specific hyperlocomotion is more favorablein Sprague-Dawley rats when compared to Wistar rats, duringmephedrone exposure. Additionally, mephedrone’s rapid clear-ance strengthens the user’s tendency to redose, in a bingeparadigm, when compared to MDMA (Kehr et al., 2011). MDPVis superior to mephedrone and methylone at inducing locomotoractivity (Fantegrossi et al., 2013). The MDPV-treated rat wheelactivity is two-phased, generating greater total rotations atreduced doses and fewer rotations at elevated doses, whilemephedrone displays monophasic rises in wheel activity, as seenin MDMA (Huang et al., 2012). From our previous studies withMDMA-analogs, we reported that MDMA and its structural analogsexhibited stimulatory activity as compared to amphetamines andtheir parent compound. MDMA and MDMA-analogs exhibited

similar pharmacological activities such as enhanced reactiveoxygen species generation and inhibition of mitochondrialcomplex-I activity. Thus, MDPV and its structural analogs alsocan induce similar pharmacological/toxicological activities due totheir pharmacophore and structural resemblance (Karup-pagounder et al., 2014).

Rat studies indicate that the activities of the monoaminebiosynthetic enzymes, tyrosine hydroxylase, and tryptophanhydroxylase are greatly reduced following multiple methcathi-none administrations and consequentially the levels of dopamine,serotonin, and their metabolites are decreased in the frontal cortex,hippocampus, and neostriatum (Gygi et al., 1996; Sparago et al.,1996). As expected, striatal [3H] dopamine and hippocampal [3H]5-HT synaptosomal uptake are also reduced (Gygi et al., 1997). Gygiet al. revealed that dopamine and serotonin tissue concentrationsare depleted for 30 days after administration. The selective D1antagonist and selective D2 antagonist, SCH23390, and eticlopride,respectively, prevented a decrease in tyrosine hydroxylase activitybut had no effect on tryptophan hydroxylase (Gygi et al., 1997).

Den Hollander et al. reported a significant reduction in the rateof spontaneous alternations with mephedrone-treated mice whencompared to saline-treated mice in the T-maze, a test formeasuring the willingness of rodents to explore a new environ-ment, suggesting detrimental effects on spatial working memory,whereas methylone-treated mice exhibited no changes whencompared to the saline control (Den Hollander et al., 2013). Thereduction in spontaneous alternations refers to the rat showingless of a tendency to explore a previously visited arm. Additionally,Morris water maze tests revealed no correlation between drugtreatment and the capacity for mice to escape opaque water bylearning the location of the hidden platform in a large circular pool,indicating no effect on long term spacial learning and memory(Den Hollander et al., 2013). Binge mephedrone administration inrats, ensued by 5 weeks of abstinence, spawned deterioration innovel object recognition, hindering memory performance (Motbeyet al., 2012). The regulation of body temperature is dependent onthe recurrence of exposure. Hypothermia is observed in rats duringacute exposure of mephedrone (Miller et al., 2013; Shortall et al.,2013) while repeated binge administration, in rats and mice,results in hyperthermia (Angoa-Perez et al., 2012; Baumann et al.,2012). Elevated temperatures lead to hyperthermia during acuteexposure to MDPV, while ambient temperatures provide no changein body temperature (Fantegrossi et al., 2013). Administration ofhigh doses of mephedrone to group-housed rats depleted brainserotonin levels (Hadlock et al., 2011), while binge dosing to singlehoused rats produced no long term effects on neurotransmitterlevels (Baumann et al., 2012), indicating a populated environment,such as night clubs, may worsen adverse effects (Baumann et al.,2013a).

The physical symptoms of synthetic cathinones, observed inhumans, reflects increased sympathomimetic surge, including:tachycardia, hypertension, hyperthermia, diaphoresis, seizures,tremors, mydriasis, rhabdomyolysis, and emesis. Users also reportpanic attacks, insomnia, nausea, headache, dizziness, confusion,anhedonia, suicidal thoughts, paranoia, panic attacks, psychosis,anorexia, kidney damage, hyponatremia, chest pain, S-T segmentalterations, trismus, bruxism, abdominal pain, tolerance, anddependence(Winstock et al., 2010; Borek and Holstege, 2012;Durham, 2011; Penders and Gestring, 2011; Regan et al., 2011;Drugs-forum, 2014). The effects of synthetic cathinones ondifferent organ systems are listed in Table 2.

An outstanding toxidrome, resulting in severe intoxicationdelirium, due to “bath salt” ingestion, occurred after an admittedpatient to the ER, was found at his home suffering from severehallucinations (Kasick et al., 2012). Outside the ER, the patientshowed typical physical signs of “bath salt” consumption including

Table 2Effects of bath salts/MDPV-analogues.

Organ system Actions of cathinones

Central nervous system Euphoria, hallucination, delirium, anxiety, anoxic brain injuryOpthalmic system Mydriasis, blurred vision, nystagmusCardiovascular system Tachycardia, cardiac arrest, coagulopathyPulmonary system Respiratory arrest, acidosisGastroirtestinal system Loss of appetite, nausea, emisisRenal system Renal failure, CPK elevation, hypovolemiaHepatic system HepatotoxicityReproductive system Increase sexual driveSkeletal muscle Rhabdomylosis, muscle painOthers Hyperthermia, bone pain, Necrotizing fascitis, Serotonin syndrome

354 D.P. Katz et al. / Toxicology Letters 229 (2014) 349–356

tachycardia, hyperthermia, and premature ventricular contrac-tions (Kasick et al., 2012). Overdosing on “bath salts” will lead toviolence, homicidal combative behavior, self-mutilation, coma,and death. Cases have resulted in users lacerating themselves withknives and assaulting relatives (Ross et al., 2012). Thus, syntheticcathinones have been linked to several deaths. One occurrencebrought about excited delirium syndrome (ExDS), from MDPVconsumption (Murray et al., 2012), which spurred an overdose andsuperfluous monoaminergic neurotransmission (Mash et al., 2009;Ruttenber et al., 1997). This 40-year-old man had ceased hiscocaine use and switched to “bath salts”. After exposure he showedaggression, acted uncontrollably, became delusional, removed hisraiment, and ran out in public. The man resisted arrest, displaying“superhuman” strength and violent behavior (Murray et al., 2012).Excited delirium syndrome symptoms include delirium, agitation,hyperthermia, tachycardia, a period of conceding defeat, andcardiac arrest (Takeuchi et al., 2011). This case has been reported asthe first death due to MDPV consumption (Murray et al., 2012).More deaths can be expected to follow, so expanding ourknowledge on the symptoms associated with “bath salt” induceddeaths will assist emergency physicians and toxicologists on thediagnosis and treatment of poisoned individuals.

At present there are no published studies detailing the addictivepotential or withdrawal syndromes associated with syntheticcathinone use. However, in one British survey over 50% ofmephedrone users reported that they considered the drug to beaddictive, and in another survey nearly half of the mephedroneuses reported continuous use for more than 48 h. Furthermore,over 30% reported having more than three of the diagnostic andstatistical manual IV criteria for dependence including increased

Table 3Therapeutic potential/contraindications of disease states with synthetic cath-inones.

Therapeutic potential Contraindicated

ADHD AnxietyAppetite suppressant ArrythmiaAnaleptic EpilepsyBradycardia glaucomaBenign prostatic HiccupsHyperplasia HypertensionBulimia Induce cardiac arrestCardiac stimulant InsomniaChronic fatigue syndrome MigraineDepression PheochromocytomaHorners syndrome PTSDHyperkalemia TachycardiaInduce childbirth TremorsNervosaNarcolepsyMiosisOrthostatic hypotensionSexual dysfunctionShockSyncope

tolerance, continuing to take despite having problems with use andimpaired control of use.

Therapeutic uses of synthetic cathinones are scant, but a fewhave been documented. Bupropion, a ring substituted cathinone, isprescribed as an antidepressant and as a smoking-cessation aid(EMCDDA, 2010). Amfepramone and pyrovalerone are antiquated,but were once used as anorectics (EMCDDA, 2010). MDPV’snotorious amphetamine and cocaine-like effects observed at largerdoses are correlated with mild stimulatory effects at small doses,similar to methylphenidate (Ritalin), which boosts concentration,alertness, socialization and sexual performance (Erowid, 2011).Future probable structural congeners of synthetic cathinones maydisplay therapeutic potential by increasing stimulant activity viasympathetic neurotransmission, reducing the abuse potential, andminimizing any adverse effects. Structural congeners must also beavoided because they exacerbate disease states, very much a “flipof a coin”. Table 3 lists several disease states in which “bath salts”may provide therapeutic potential or may be harmful to the user.

7. Conclusion

Drug abuse is a severe complication contributing to thedownward spiral of populations worldwide. The abuse of drugsremains of great concern due to its detrimental effects on lawenforcement officials and public health resources. The neurotoxicmechanisms of “bath salts” are not very clearly establishedcompared to other drugs of abuse. Therefore, understanding themolecular mechanisms mediating the insults of “bath salts” is ofimmense importance for international public health. Clandestine“bath salt” manufacturers will continue to synthesize newanalogues, while relying on downtime, before legislation canschedule and ban the new designer drugs of abuse. Manufacturerswill participate in this circuitous “cat and mouse game” for theforeseeable future. A coordinated multi-pronged approach, be-tween the medicinal chemist, pharmacologist, and toxicologist iscrucial for determining potential drug candidates operating bysimilar or distinct mechanisms of action to those of well-established drugs. Predicting efficacious synthetic cathinonesand performing pharmacological testing, before their release intosociety, will obviate the strung out legal process drug manufac-turers depend on. Hence, additional research is essential forunderstanding and elucidating the pharmacological/toxicologicalprofiles of “bath salts” needed to raise public awareness on thedangers and potential therapies of synthetic cathinones.

Conflict of interest

The authors declare that there are no conflicts of interest.

Transparency document

The Transparency document associated with this article can befound in the online version.

D.P. Katz et al. / Toxicology Letters 229 (2014) 349–356 355

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Further reading

http://www.aapcc.s3.amazonaws.com/files/library/Bath_Salts_Web_Data_-through_12.2013_3 pdf (visited January 17, 2014).

http://www.bathsaltsdrug.blogspot.com/2011/04/americas-new-drug-problem-snorting-bath.html (visited April 25, 2014).

http://www.caymanchem.com/pdfs/10624 pdf (visited February 16, 2014).http://www.drugs-forum.com (visited January 28, 2014).http://www.emcdda.europa.eu/online/annual-report/2010/boxes/p92 (April 25,

2014).http://www.erowid.org/experiences/subs/exp_MDPV.shtml (January 28, 2014).http://www.justice.gov/dea/druginfo/ds.shtml (visited April 25, 2014).http://www.samhsa.gov/data/spotlight/spot117-bath-salts-2013 pdf (visited April

25, 2014).