Toxicology Letters 229 (2014) 349356

Contents lists available at ScienceDirect

Toxicology Letters
journal homepage: www.elsevier.com/locate/toxlet

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 modications of synthetic designer drugs enable clandestine manufacturers to avoid governmental bans and promote widespread
distribution.

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

The stimulatory effects of synthetic cathinones are engendered by elevations in synaptic catecholamine concentrations.

The physical symptoms attributed to synthetic cathinones, observed in mammals, reects increased sympathomimetic and dopaminergic surge.

If synthetic cathinones are designed carefully, they might denitely have a signicant therapeutic value.

A R T I C L E I N F O

A B S T R A C T

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

The birth of the twenty rst century has provoked a substantial rise in the use of designer drugs, such as
synthetic cathinones, because of a decrease in the availability and purity of other drugs of abuse. The khat
plant or Catha edulis, contains cathinone, the parent compound. Synthetic cathinones are sold under the
name bath salts as a ploy to circumvent legislation from banning their use. Constant modication of the
chemical structure by covert laboratories allows manufacturers to stay one step ahead of the legal
process. Currently, the widespread distribution of bath salts has negative consequences for law
enforcement ofcials and public health resources. Comparable mechanisms of action, between the
synthetic cathinones and amphetamine, cocaine, and MDMA are attributed to the similarities in their
chemical structures. Synthetic cathinones potent stimulatory effects, coupled with their high abuse
potential, and propensity for addiction demands additional pharmacological and toxicological
evaluations for these existing and new designer drugs of abuse. If these drugs are designed carefully,
they might also have a signicant therapeutic value.
2014 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Bath salts
Synthetic cathinone
Designer drug
MDPV
Stimulant
Addiction

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 to
their potent psychostimulant and empathogenic effects. Mephedrone (4-methylmethcathinone), methylone (3,4-methylenedioxymethcathinone),
MDPV
(3,4-methylenedioxypyrovalerone),
3-FMC (3-uoromethcathinone), 4-FMC (4-uoromethcathinone),
buphedrone (a-methylamino-butyrophenone), butylone (beta-

* Corresponding author.
E-mail address: dhanamu@auburn.edu (M. Dhanasekaran).
http://dx.doi.org/10.1016/j.toxlet.2014.06.020
0378-4274/ 2014 Elsevier Ireland Ltd. All rights reserved.

keto-N-methyl-3,4-benzodioxyolybutanamine),
methedrone
(4-methoxymethcathinone), and naphyrone (naphthylpyrovalerone) are a few synthetic cathinones, among others (Karila and
Reynaud, 2011). Fig. 1 illustrates the structural modications of
methcathinone that prouce several designer cathinones. The
parent compound, cathinone, is found in the leaves of Catha edulis
Forsk, the khat plant (Fig. 2). C. edulis was discovered in Yemen by
Peter Forskal, an eighteenth century botanist (Feyissa and Kelly,
2008). Cathinones stimulatory effects have been known for
centuries, mostly prevalent in Middle Eastern countries ranging
from Southern Africa to the Arabian Peninsula (Krikorian, 1984). As
khat ages, cathinone undergoes rapid enzymatic degradation to
cathine and norephedrine, the inactive metabolites (Al-Obaid et al.,
1998). Exposure to heat or sunlight accelerates this degradative

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Table 1
Alternative 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
Bayou ivory ower
Bloom
Blue magic
Blue silk
Bolivian bath
Bonsai winter boost
Cloud 10
Cloud 9
Cotton cloud
Dynamite plus

Fig. 1. Chemical structures of Synthetic Cathinones derived from Methcathinone.

(Hanson, 2012), catching up with bath salts and spice. In: 08/01/2012.

process, therefore cultivators commonly wrap the leaves and

shoots in banana peels to preserve freshness and moisture (Yousef
et al., 1995). Users amass a large bolus of leaves and shoots to
macerate against the lining of the cheek, for buccal absorption
(Sawair et al., 2007). Absorption also occurs from the stomach and
small intestine following the deglutition of discharged juices. In
2006, an estimated 10 million people abuse khat worldwide
(Rosenbaum et al., 2012).
Aura, Bliss, Energy 1, Hurricane Charlie, and White
rush are common bath salt product names (Table 1) intended to
entice consumers, even though packages are clearly labeled not
for human consumption (Shanks et al., 2012; Spiller et al., 2011;
Ross et al., 2012). Bath salts are manufactured by surreptitious
labs then sold on the internet and in legal retail outlets as incense,
air fresheners, and plant food to evade the law, preventing
legislation 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.

Euphoria
Gold rush
Hurricane Charlie
Ivory fresh
Ivory wave
Lady bubbles
Lunar wave
Mr. Nice guy
Mystic
Ocean snow
Pure white

Red dove
Route 69
Scarface
Snow day
Tranquility
Vanilla sky
White dove
White lightening
White rush
Wicked X
Zoom

Frequent chemical modications of synthetic designer drugs

enable manufacturers to avoid governmental bans and promote
widespread distribution (Brandt et al., 2010; Shanks et al., 2012).
Synthetic cathinone development paradoxically contradicts the
ethical development of drugs. Drug development follows a distinct
set of guidelines and steps: development of a lead compound,
animal testing, pharmacokinetic studies, safety and efcacy
studies, and human trials. A reversed development phenomenon
occurs, in which bath salts are synthesized, packaged, distributed,
and sold directly to the consumer (without FDA approval).
Meanwhile, critical safety evaluations and other testing remain
unassessed until well after the drug has been exposed to the public.
Additional modications to new and existing synthetic cathinones
will necessitate pharmacological and toxicological evaluations;
therefore, this longstanding tortuous battle between synthetic
chemists and the drug enforcement administration will remain an
obstacle to conquering our war on drugs.
2. Prevalence
Cathinone derivatives began to appear rst in the European
recreational drug market in the mid- 2000s. At that time to 2010,
the most commonly encountered cathinones on the European
clandestine market were mephedrone, methylone, and MDPV.
Since this time there have been more than 5500 drug seizures of
MDPV in Europe, either in bulk form or solid dosage forms (tablets,
capsules, powders), and 107 non-fatal intoxications and 99 deaths
associated with this drug alone. Also since 2010 there have been
increasing reports of more designer cathinone analogues in
Europe, as well as their appearance in the US clandestine drug
market.
According to the American Association of Poison Control
Centers, the number of closed human exposures regarding
synthetic cathinones substantially increased from 306 to 6137,
in 2010 and 2011; respectively (aapcc, 2013). The drug abuse
warning network (DAWN) reported that of the 2.5 million
emergency department visits related to the misuse or abuse of
drugs in 2011; 22,904 of these visits were due to bath salt
exposure (DAWN, 2013). The 2011 rise in the abuse of bath salts
became known as Americas new drug problem (Bath Salts Drug,
2011). This surge in bath salt consumption is attributed to a
decrease in the availability and purity of the more common drugs
of abuse (caffeine, MDMA, cocaine). Illicit drug manufacturers have
frugally resorted to cutting MDMA with synthetic cathinones to
dilute their purity (Brunt et al., 2011). The Netherlands observed a
drop of MDMA potency in ecstasy tablets, from greater than 90% of
tablets containing MDMA before 2009, to just below half being
completely devoid of MDMA. Piperazine derivatives and mephedrone were substituted for MDMA in these pseudo-ecstasy
tablets (Brunt et al., 2011). Similarly, law enforcement ofcials in
the UK reported a considerable decrease in the purity of cocaine,

D.P. Katz et al. / Toxicology Letters 229 (2014) 349356

from 60% in 1999 to 22% in 2009, resulting in a rise of drug seizures

(Hand, 2009). In October of 2011, the United States government
responded by classifying mephedrone, MDPV, and methylone as
schedule I drugs. As dened by the United States Controlled
Substances Act schedule I drugs, substances, or chemicals must be
classied as having no current therapeutic use, a high susceptibility for abuse, and a lack of safety that may lead to psychological or
physical dependence. Heroin, lysergic acid diethylamide (LSD),
marijuana (cannabis), 3,4-methylenedioxymethamphetamine (ecstasy), methaqualone, and peyote are also currently classied as
schedule I drugs (DEA, 2014). The United States governments
intervention on bath salts resulted in an abatement of reported
human exposures, from 2676 reports in 2012 to 690 reports
through August 31 of 2013 (aapcc, 2013).

3. Patterns of use, pharmacokinetic aspects, and drug

combinations
The preferred routes of exposure for synthetic cathinones are
nasal insufation (snorting) and ingestion. Users frequently
practice keying and bombing (Newcombe, 2009), the former
involves snorting powder via a key, and the latter entails ingesting
powder rolled up in cigarette paper. The rapid onset of action from
insufation combined with the prolonged effects of ingestion
result in an immediate and sustained intoxication (Deluca et al.,
2009). Less common modalities include rectal administration,
gingival delivery, inhalation, intramuscular injection, and intravenous injection (Newcombe, 2009). Users insufating mephedrone
note a 1020 min delay, before the onset of effects, followed by a 1
2 h duration, while oral dosing was delayed 1545 min and lasted
24 h in duration (EMCDDA, 2010; Newcombe, 2009). MDPVs
lipophilic nature enables extensive central nervous system
stimulation by translocation across the blood brain barrier; even
minute doses of 35 mg have produced psychoactive effects
altering mood, consciousness, and behavior. Typical MDPV doses
range from 5 to 20 mg (Ross et al., 2012), associated with an onset
of action in 1530 min, and a duration of 34 h (Erowid, 2011).
Shockingly, some bath salt products containing MDPV have been
labeled, for ultimate relaxation use 50 g in your bath and go up
from their (Ross et al., 2012). MDPVs short duration of action
leads users to ending, consuming numerous doses in succession
(Ross et al., 2012; Schifano et al., 2011), to avert the harsh comedown effects, while in turn building tolerance, and potentially
resulting in an overdose.

Fig.

351

Synthetic cathinones consumed in combination with other

drugs are intended to intensify desired effects or curtail noxious
effects. 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, domperidone, opiates, and benzodiazepines (drugs-forum, 2014). MDPV,
in combination with antipsychotics for the treatment of schizophrenia, depression, or anxiety, must be recognized and avoided
due to the antipsychotic medication lowering the threshold
potential for seizures, already manifested as a physical symptom
of MDPV exposure (Marks and Luchins, 1991).
4. Chemistry
Like the amphetamine-type drugs of abuse, cathinone derivatives 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 the
clandestine market (Fig. 1) are racemic mixtures (equal amounts of
R and S). It is also believed that racemization of all cathinone
derivatives can occur through ketoenol tautomerism. Cathinone
is unstable and can readily degrade into dimers and other inactive
decomposition products. All known cathinone derivatives are
either N-alkylated or the nitrogen atom is part of a pyrrolidine ring
(Fig. 1), and most are produced as hydrochloride salts for enhanced
stability. Many illicit cathinone products are N-methylated, i.e.,
ephedrone derivatives, whereby mephedrone can be described as
4-methylephedrone. The pyrrolidine derivatives (PPP, MDPV) can
be regarded as a sub-set of designer drugs sharing the same
skeleton as pyrovalerone.
As mentioned previously, cathinone or khat can be isolated
from its natural source, the C. edulis plant. Cathinone and other
simple N-alkyl- and ring substituted derivatives (methcathinone,
mephedrone, methadrone, etc., Fig. 1) can also be synthesized
clandestinely by oxidation of an appropriately substituted phenylethanolamine precursor using potassium permanganate in sulfuric
acid or other oxidizing agents as illustrated in Fig. 3A. An advantage
of such an approach is that the precursor chemicals can be
obtained as specic enantiomers, thereby ensuring that the
synthesis of the cathinone derivative is stereoselective. One of
the hazards of using these methods is that the product can be
contaminated with the oxidizing metal (i.e., manganese) which is
toxic to the end user. The structurally more complex cathinone

3. Synthesis of MDPV.

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D.P. Katz et al. / Toxicology Letters 229 (2014) 349356

derivatives, such as MDPV which has a 3,4-methylenedioxyaromatic ring, a pyrrolidine ring and propyl side chain are typically
prepared by reacting a suitably ring substituted bromophenylalkanone with pyrrolidine, giving rise to racemic products (Fig. 3B).
The required substituted bromophenylalkanone intermediate is
obtained by reaction of the appropriate phenylalkanone with
bromine (Fig. 3B). The phenylalkanones can be prepared by
sequential treatment of commercially available substituted benzaldehyde (i.e., piperonal) with butylmagnesium bromide followed
by oxidation with chromium reagents.
The b-ketophenethylamine moiety is the unique feature among
all synthetic cathinones, imparting the structural and pharmacological differences of methcathinone from methamphetamine and
methylone from MDMA (Gibbons and Zloh, 2010). The ketone
attached to the beta carbon augments the polarity of the molecule,
rendering the synthetic cathinones hydrophilic; hence, they are
less able to cross the blood brain barrier (BBB) to produce
psychostimulant effects (Gibbons and Zloh, 2010). In fact,
molecular modeling studies have shown cathinone log P values
are one unit lower than their methyl-amphetamine complements
(Gibbons and Zloh, 2010). Higher doses are required to produce
equivalent effects accompanied by ineluctable side effects (Hill and
Thomas, 2011). On the other hand, the pyrrolidine derivatives
3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-alpha-pyrrolidinopropriophenone (MDPPP) display superior lipophilicity with concomitant potency (Gibbons and Zloh,
2010). The tertiary amino group in MDPV enables the molecule to
be easily dissolved in organic solvents (caymanchem, 2014).
The metabolism of methylone, ethylone, and butylone is
initiated by phase I demethylation of the methylenedioxy ring,
converting the parent drug to a catechol metabolite. This
metabolite is then methylated by catechol O-methyltransferase
(COMT) to produce the 40 -hydroxy-30 -methoxy or 30 -hydroxy-40 methoxymethcathinone metabolites. The O-methylation metabolites undergo phase II partial conjugation, by glucuronides and
sulfates, increasing the molecular weight and water solubility of
the drug while yielding inactive metabolites for renal excretion
(Zaitsu et al., 2009). Methylone, ethylone, and butylone may also
undergo some N-demethylation and ketone reduction, but these
appear to be minor pathways of metabolism for these drugs.
Mephedrone undergoes metabolism by N-demethylation to a
primary amine, ketone reduction to the corresponding alcohol, and
toluyl methyl group oxidation to the alcohol. The alcohols formed
from mephedrone oxidation are conjugated as glucuronides and
sulfates and excreted (Meyer et al., 2010b). MDPV metabolism, in
hepatocytes, begins with the opening of the methylenedioxy ring,
the conversion to a catechol ring by demethylation, a methylation
by COMT, and nally glucuronidation and sulfation, similar to that
observed with other 3,4-methylenedioxyphenyl cathinoes
(i.e., methylone) (Strano-Rossi et al., 2010). MDPV may also be
metabolized by other oxidative pathways including hydroxylation.
The cytochrome P450 (CYP450) liver isoenzymes CYP2C19,
CYP2D6, CYP2B6, and CYP1A2 are enzymes implicated in the
metabolism of synthetic cathinones (Meyer et al., 2010a).

cathinone and methcathinone are inadequately incorporated

(Kikura-Hanajiri et al., 2007). Drug testing laboratories must
constantly create new methods for novel designer cathinones that
can accurately quantify the levels of synthetic cathinones in urine,
blood, and hair. Method development requires research, time, and
man power that may hinder drug testing laboratories from keeping
up to date testing.
6. Pharmacology
Analogous mechanisms of action between the synthetic
cathinones and amphetamines are attributed to the similarities
in their chemical structures (Prosser and Nelson, 2012). Fig. 4
compares the structures of amphetamine and methamphetamine
with the b-ketoamphetamines. The stimulatory effects of synthetic cathinones are engendered by elevations in synaptic
catecholamine concentrations (Coppola and Mondola, 2012),
primarily via two mechanisms. First, these molecules bind to
and inhibit the monoamine uptake transporters for dopamine
(DAT), norepinephrine (NET), and serotonin (SERT), diminishing
their clearance from the synaptic cleft (Cozzi et al., 1999). Second,
as substrate releasers, they exhibit non-exocytotic neurotransmitter release from intracellular stores by reversal of transporter ux
and inhibiting the vesicular monoamine transport receptor
(VMAT2) (Prosser and Nelson, 2012). MDMA has been suggested
to compete for substrate binding sites on VMAT2, a protonmonoamine antiporter, as well as scattering intravesicular pH
gradients mandatory for vesicular monoamine accumulation and
transport (Rudnick and Wall, 1993; Sulzer and Rayport, 1990).
Amphetamine binds to the trace amine associated receptor
1 (TAAR1), a G protein-coupled receptor, in the presynaptic
neuron, diminishing dopamine receptor ring rate and activating
protein kinase A and protein kinase C, then phosphorylating DAT.
Phosphorylated DAT will reverse transporter ux or deposit
neurotransmitter into the presynaptic neuron terminating transport (Miller, 2011). A PKC-modulated DAT internalization event
reduces the number of dopamine transporters on the presynaptic
membrane preventing the reuptake of dopamine (Xie and Miller,
2009). The b-ketoamphetamines display roughly a 10 fold reduced
afnity for TAAR1 when compared to the non-b-ketoamphetamines (Simmler et al., 2013).
The relative selectivity of synthetic cathinones to inhibit
monoamine transporters (DAT, NET, and SERT) and promote
substrate release differentiates their effects on neurotransmission.
Simmler et al. classies the synthetic cathinones into three groups
depending on their potencies at the transporters and as substrate
releasers. The cocaine-MDMA-mixed cathinones containing
mephedrone, methylone, ethylone, butylone, and naphyrone all

5. Detection
Gas chromatography/mass spectrometry (GC/MS) or liquid
chromatography/mass spectrometry (LC/MS) is essential for the
identication and conrmation of synthetic cathinones. ELISAbased screening of synthetic cathinones is ineffective because the
immunoassay may produce false positive screens for methamphetamine (Torrance and Cooper, 2010). MDPV has also been
shown to cross react with immunoassays creating false positives
for phencyclidine (PCP) (Macher and Penders, 2013). Rat studies
show that methylone is thoroughly incorporated in hair while

Fig. 4. Structural similarities of amphetamine and methamphetamine with their

b-Keto equivalent.(Brock, 2013), cathinones-illicit drugs.

D.P. Katz et al. / Toxicology Letters 229 (2014) 349356

display nonselective monoamine uptake inhibition as well as

MDMA-like 5-HT release, barring naphyrone (Simmler et al., 2013).
Their data illustrates that cocaine-MDMA-mixed cathinones
display greater dopaminergic monoamine transport inhibition
when compared to their non-b-ketone amphetamine counterparts
(Simmler et al., 2013). The methamphetamine-like cathinones,
including cathinone, methcathinone, and ephedrone, exert their
effects as preferential catecholamine inhibitors and dopamine
releasers (Simmler et al., 2013). Cozzi et al. states methcathinone
and methylone are potent inhibitors of plasma membrane
catecholamine transporters but have very limited effect on
inhibiting VMAT2 (Cozzi et al., 1999). Pyrovalerone and MDPV,
the pyrovaleronecathinones, are both potent and selective
monoamine uptake inhibitors with no action as substrate releasers
(Simmler et al., 2013).
MDPV is a potent monoamine transporter inhibitor with
relative potencies for DAT > NET >> SERT (Baumann et al., 2013b;
Simmler et al., 2013), but is a feeble substrate releaser. The >100
DAT/SERT inhibition ratio for MDPV trumps the methamphetamine and cocaine ratio, >10 and 3.1, respectively (Simmler et al.,
2013), revealing a high abuse potential (Bauer et al., 2013). A recent
study from Aarde et al. revealed that the amount of MDPV selfadministered intravenously by lever presses in rats was far greater
than that of methamphetamine (Aarde et al., 2013). Rats
underwent lever press training in which 45 mg pellets were
delivered under a xed-ratio, that is, a one-press-per-reinforcer
schedule (FR1). Additional testing to quantify the rats desire to
redose was measured by increasing the number of lever presses for
a single infusion. Interestingly, the average number of lever presses
for an infusion of methamphetamine was 60, while MDPV showed
a remarkable 600 lever presses, 10 times the amount of
methamphetamine (Aarde et al., 2013). Some rats desire for
redosing was so intense, a single infusion of MDPV was delivered
after 3000 lever presses (Aarde et al., 2013). Excessive release of
dopamine in the synapse plays a major role in feelings of pleasure,
motivation, and satisfaction. Feelings of satisfaction become
desired; therefore, repeated behaviors that cause the release of
dopamine will be favored. Increased dopaminergic transmission in
limbic nuclei, particularly from the ventral tegmental area to the
nucleus accumbens (reward center), underlies the reinforcing
effects of drugs of abuse. Previously, Watterson et al. proposed a
dose-dependent decline in reward thresholds when MDPV was
administered by intra-cranial self-stimulation (Watterson et al.,
2012). Also, MDPV induced a greater extent of overall behavior
when compared to methamphetamine, indicating a positive place
preference and greater reward value (Aarde et al., 2013). The
synthetic cathinones served as a reliable replacement for
amphetamine and MDMA when administered to rats trained to
distinguish between the two (Dal Cason et al., 1997).
The prototypical change in behavior, in rats and mice, observed
after psychomotor stimulant exposure, is a rise in locomotor
activity, often linked to addiction (Calabrese, 2008; Wise and
Bozarth, 1987). Species specic hyperlocomotion is more favorable
in Sprague-Dawley rats when compared to Wistar rats, during
mephedrone exposure. Additionally, mephedrones rapid clearance strengthens the users tendency to redose, in a binge
paradigm, when compared to MDMA (Kehr et al., 2011). MDPV
is superior to mephedrone and methylone at inducing locomotor
activity (Fantegrossi et al., 2013). The MDPV-treated rat wheel
activity is two-phased, generating greater total rotations at
reduced doses and fewer rotations at elevated doses, while
mephedrone displays monophasic rises in wheel activity, as seen
in MDMA (Huang et al., 2012). From our previous studies with
MDMA-analogs, we reported that MDMA and its structural analogs
exhibited stimulatory activity as compared to amphetamines and
their parent compound. MDMA and MDMA-analogs exhibited

353

similar pharmacological activities such as enhanced reactive

oxygen species generation and inhibition of mitochondrial
complex-I activity. Thus, MDPV and its structural analogs also
can induce similar pharmacological/toxicological activities due to
their pharmacophore and structural resemblance (Karuppagounder et al., 2014).
Rat studies indicate that the activities of the monoamine
biosynthetic enzymes, tyrosine hydroxylase, and tryptophan
hydroxylase are greatly reduced following multiple methcathinone 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). Gygi
et al. revealed that dopamine and serotonin tissue concentrations
are depleted for 30 days after administration. The selective D1
antagonist and selective D2 antagonist, SCH23390, and eticlopride,
respectively, prevented a decrease in tyrosine hydroxylase activity
but had no effect on tryptophan hydroxylase (Gygi et al., 1997).
Den Hollander et al. reported a signicant reduction in the rate
of spontaneous alternations with mephedrone-treated mice when
compared to saline-treated mice in the T-maze, a test for
measuring the willingness of rodents to explore a new environment, suggesting detrimental effects on spatial working memory,
whereas methylone-treated mice exhibited no changes when
compared to the saline control (Den Hollander et al., 2013). The
reduction in spontaneous alternations refers to the rat showing
less of a tendency to explore a previously visited arm. Additionally,
Morris water maze tests revealed no correlation between drug
treatment and the capacity for mice to escape opaque water by
learning 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 in
rats, ensued by 5 weeks of abstinence, spawned deterioration in
novel object recognition, hindering memory performance (Motbey
et al., 2012). The regulation of body temperature is dependent on
the recurrence of exposure. Hypothermia is observed in rats during
acute 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 acute
exposure to MDPV, while ambient temperatures provide no change
in body temperature (Fantegrossi et al., 2013). Administration of
high doses of mephedrone to group-housed rats depleted brain
serotonin levels (Hadlock et al., 2011), while binge dosing to single
housed rats produced no long term effects on neurotransmitter
levels (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 in
humans, reects increased sympathomimetic surge, including:
tachycardia, hypertension, hyperthermia, diaphoresis, seizures,
tremors, mydriasis, rhabdomyolysis, and emesis. Users also report
panic attacks, insomnia, nausea, headache, dizziness, confusion,
anhedonia, suicidal thoughts, paranoia, panic attacks, psychosis,
anorexia, kidney damage, hyponatremia, chest pain, S-T segment
alterations, trismus, bruxism, abdominal pain, tolerance, and
dependence(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 on
different organ systems are listed in Table 2.
An outstanding toxidrome, resulting in severe intoxication
delirium, due to bath salt ingestion, occurred after an admitted
patient to the ER, was found at his home suffering from severe
hallucinations (Kasick et al., 2012). Outside the ER, the patient
showed typical physical signs of bath salt consumption including

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D.P. Katz et al. / Toxicology Letters 229 (2014) 349356

Table 2
Effects of bath salts/MDPV-analogues.
Organ system

Actions of cathinones

Central nervous system

Opthalmic system
Cardiovascular system
Pulmonary system
Gastroirtestinal system
Renal system
Hepatic system
Reproductive system
Skeletal muscle
Others

Euphoria, hallucination, delirium, anxiety, anoxic brain injury

Mydriasis, blurred vision, nystagmus
Tachycardia, cardiac arrest, coagulopathy
Respiratory arrest, acidosis
Loss of appetite, nausea, emisis
Renal failure, CPK elevation, hypovolemia
Hepatotoxicity
Increase sexual drive
Rhabdomylosis, muscle pain
Hyperthermia, bone pain, Necrotizing fascitis, Serotonin syndrome

tachycardia, hyperthermia, and premature ventricular contractions (Kasick et al., 2012). Overdosing on bath salts will lead to
violence, homicidal combative behavior, self-mutilation, coma,
and death. Cases have resulted in users lacerating themselves with
knives and assaulting relatives (Ross et al., 2012). Thus, synthetic
cathinones have been linked to several deaths. One occurrence
brought about excited delirium syndrome (ExDS), from MDPV
consumption (Murray et al., 2012), which spurred an overdose and
superuous monoaminergic neurotransmission (Mash et al., 2009;
Ruttenber et al., 1997). This 40-year-old man had ceased his
cocaine use and switched to bath salts. After exposure he showed
aggression, acted uncontrollably, became delusional, removed his
raiment, 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, and
cardiac arrest (Takeuchi et al., 2011). This case has been reported as
the rst death due to MDPV consumption (Murray et al., 2012).
More deaths can be expected to follow, so expanding our
knowledge on the symptoms associated with bath salt induced
deaths will assist emergency physicians and toxicologists on the
diagnosis and treatment of poisoned individuals.
At present there are no published studies detailing the addictive
potential or withdrawal syndromes associated with synthetic
cathinone use. However, in one British survey over 50% of
mephedrone users reported that they considered the drug to be
addictive, and in another survey nearly half of the mephedrone
uses reported continuous use for more than 48 h. Furthermore,
over 30% reported having more than three of the diagnostic and
statistical manual IV criteria for dependence including increased

Table 3
Therapeutic potential/contraindications of disease states with synthetic cathinones.
Therapeutic potential

Contraindicated

ADHD
Appetite suppressant
Analeptic
Bradycardia
Benign prostatic
Hyperplasia
Bulimia
Cardiac stimulant
Chronic fatigue syndrome
Depression
Horners syndrome
Hyperkalemia
Induce childbirth
Nervosa
Narcolepsy
Miosis
Orthostatic hypotension
Sexual dysfunction
Shock
Syncope

Anxiety
Arrythmia
Epilepsy
glaucoma
Hiccups
Hypertension
Induce cardiac arrest
Insomnia
Migraine
Pheochromocytoma
PTSD
Tachycardia
Tremors

tolerance, continuing to take despite having problems with use and

impaired control of use.
Therapeutic uses of synthetic cathinones are scant, but a few
have been documented. Bupropion, a ring substituted cathinone, is
prescribed as an antidepressant and as a smoking-cessation aid
(EMCDDA, 2010). Amfepramone and pyrovalerone are antiquated,
but were once used as anorectics (EMCDDA, 2010). MDPVs
notorious amphetamine and cocaine-like effects observed at larger
doses 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 may
display therapeutic potential by increasing stimulant activity via
sympathetic neurotransmission, reducing the abuse potential, and
minimizing any adverse effects. Structural congeners must also be
avoided because they exacerbate disease states, very much a ip
of 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 the
downward spiral of populations worldwide. The abuse of drugs
remains of great concern due to its detrimental effects on law
enforcement ofcials and public health resources. The neurotoxic
mechanisms of bath salts are not very clearly established
compared to other drugs of abuse. Therefore, understanding the
molecular mechanisms mediating the insults of bath salts is of
immense importance for international public health. Clandestine
bath salt manufacturers will continue to synthesize new
analogues, while relying on downtime, before legislation can
schedule and ban the new designer drugs of abuse. Manufacturers
will participate in this circuitous cat and mouse game for the
foreseeable future. A coordinated multi-pronged approach, between the medicinal chemist, pharmacologist, and toxicologist is
crucial for determining potential drug candidates operating by
similar or distinct mechanisms of action to those of wellestablished drugs. Predicting efcacious synthetic cathinones
and performing pharmacological testing, before their release into
society, will obviate the strung out legal process drug manufacturers depend on. Hence, additional research is essential for
understanding and elucidating the pharmacological/toxicological
proles of bath salts needed to raise public awareness on the
dangers and potential therapies of synthetic cathinones.
Conict of interest
The authors declare that there are no conicts of interest.
Transparency document
The Transparency document associated with this article can be
found in the online version.

D.P. Katz et al. / Toxicology Letters 229 (2014) 349356

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Further reading
http://www.aapcc.s3.amazonaws.com/les/library/Bath_Salts_Web_Data_through_12.2013_3 pdf (visited January 17, 2014).
http://www.bathsaltsdrug.blogspot.com/2011/04/americas-new-drug-problemsnorting-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).