dhanasekaran, toxicology lett, 2014, 229, 349-356
TRANSCRIPT
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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 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, 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
Article history:
Received 2 May 2014
Received in revised form 9 June 2014
Accepted 10 June 2014
Available online 25 June 2014
Keywords:
Bath salts
Synthetic cathinone
Designer drug
MDPV
Stimulant
Addiction
A B S T R A C T
The birth of the twenty rstcentury has provokeda substantial rise in the use of designer drugs, such as
syntheticcathinones,because of a decrease in theavailabilityandpurityof otherdrugsof abuse.Thekhat
plant or Catha edulis, contains cathinone, theparent compound. Synthetic cathinones are sold under the
name bathsalts asa ploy to circumvent legislation frombanning theiruse. Constantmodicationof 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.
1. Introduction
Synthetic cathinones, the active component in bath salts,
have surfaced asapopularalternative toother illicitdrugsofabuse,
such as cocaine, MDMA (ecstasy), and methamphetamine, due to
their potent psychostimulant and empathogenic effects. Mephe-
drone (4-methylmethcathinone), methylone (3,4-methylenediox-
ymethcathinone), MDPV (3,4-methylenedioxypyrovalerone),
3-FMC (3-uoromethcathinone), 4-FMC (4-uoromethcathinone),
buphedrone (a-methylamino-butyrophenone), butylone (beta-
keto-N-methyl-3,4-benzodioxyolybutanamine), methedrone
(4-methoxymethcathinone), and naphyrone (naphthylpyrovaler-
one) 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 SouthernAfrica to theArabian Peninsula (Krikorian,1984).As
khat ages, cathinone undergoes rapid enzymatic degradation to
cathineandnorephedrine, the inactivemetabolites (Al-Obaid et al.,
1998). Exposure to heat or sunlight accelerates this degradative* Corresponding author.
E-mail address: [email protected] (M. Dhanasekaran).
http://dx.doi.org/10.1016/j.toxlet.2014.06.020
0378-4274/ 2014 Elsevier Ireland Ltd. All rights reserved.
Toxicology Letters 229 (2014) 349356
Contents
lists
available
at
ScienceDirect
Toxicology Letters
journa l homepage: www.elsevier.com/locate/ toxlet
mailto:[email protected]://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://www.sciencedirect.com/science/journal/03784274http://www.elsevier.com/locate/toxlethttp://www.elsevier.com/locate/toxlethttp://www.sciencedirect.com/science/journal/03784274http://dx.doi.org/10.1016/j.toxlet.2014.06.020http://dx.doi.org/10.1016/j.toxlet.2014.06.020mailto:[email protected]://crossmark.dyndns.org/dialog/?doi=10.1016/j.toxlet.2014.06.020&domain=pdf -
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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).
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
unassesseduntilwell after thedrughasbeenexposed to thepublic.
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 Europeanclandestine 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
ofdrugs 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). Illicitdrugmanufacturershave
frugally resorted to cuttingMDMA 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 meph-
edrone 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,
Fig. 1. Chemical structures of Synthetic Cathinones derived from Methcathinone.
(Hanson, 2012), catching up with bath salts and spice. In: 08/01/2012.
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.
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 Euphoria Red dove
Bayou ivory ower Gold rush Route 69
Bloom Hurricane Charlie Scarface
Blue magic Ivory fresh Snow day
Blue silk Ivory wave Tranquility
Bolivian bath Lady bubbles Vanilla sky
Bonsai
winter
boost
Lunar
wave
White
doveCloud 10 Mr. Nice guy White lightening
Cloud 9 Mystic White rush
Cotton cloud Ocean snow Wicked X
Dynamite plus Pure white Zoom
350 D.P. Katz et al./ Toxicology Letters 229 (2014) 349356
http://www.suncoastrehabcenter.com/wp-content/uploads/2013/08/khat.jpghttp://www.suncoastrehabcenter.com/wp-content/uploads/2013/08/khat.jpghttp://www.doctoroz.com/videos/alternate-names-bath-salt-drughttp://www.doctoroz.com/videos/alternate-names-bath-salt-drughttp://www.doctoroz.com/videos/alternate-names-bath-salt-drughttp://www.doctoroz.com/videos/alternate-names-bath-salt-drughttp://www.suncoastrehabcenter.com/wp-content/uploads/2013/08/khat.jpghttp://www.suncoastrehabcenter.com/wp-content/uploads/2013/08/khat.jpg -
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derivatives, such as MDPV which has a 3,4-methylenedioxyar-
omatic ring, a pyrrolidine ring and propyl side chain are typically
prepared by reacting a suitably ring substituted bromophenylal-
kanone 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 benz-
aldehyde (i.e., piperonal) with butylmagnesium bromide followed
by
oxidation
with
chromium
reagents.
Theb-ketophenethylaminemoiety is theunique feature amongall synthetic cathinones, imparting the structural and pharmaco-
logical 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-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
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
metabo-
lites 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 alsoundergo 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).
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. ELISA-
based
screening
of
synthetic
cathinones
is
ineffective
because
the
immunoassay
may
produce
false
positive
screens
for
metham-
phetamine (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
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 syn-thetic 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
neurotransmit-
ter
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
proton-
monoamine
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 trans-
port (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). Theb-ketoamphetaminesdisplay roughly a 10 fold reducedafnity for TAAR1 when compared to the non-b-ketoamphet-amines
(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
Fig. 4. Structural similarities of amphetamine and methamphetamine with their
b-Keto
equivalent.(Brock,
2013),
cathinones-illicit
drugs.
352 D.P. Katz et al./ Toxicology Letters 229 (2014) 349356
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display nonselective monoamine uptake inhibition as well as
MDMA-like5-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 theirnon-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
methamphet-
amine and cocaine ratio, >10 and 3.1, respectively (Simmler et al.,
2013), revealing ahigh abuse potential (Baueret al.,2013). A recent
study
from
Aarde
et
al.
revealed
that
the
amount
of
MDPV
self-
administered
intravenously
by
lever
presses
in
rats
was
far
greater
than that of methamphetamine (Aarde et al., 2013). Ratsunderwent lever press training in which 45mg pellets were
delivered
under
a
xed-ratio,
that
is,
a
one-press-per-reinforcer
schedule
(FR1).
Additional
testing
to
quantify
the
rats desire
to
redosewasmeasured by increasing the numberof leverpresses for
a single infusion. Interestingly, the average numberof leverpresses
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
dopaminewill be favored. Increased dopaminergic transmission inlimbic 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
andBozarth,
1987). Species
specic hyperlocomotion
is
more
favorable
in
Sprague-Dawley
rats
when
compared
to
Wistar
rats,
during
mephedrone exposure. Additionally, mephedrones rapid clear-
ance 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 thatMDMA and its structural analogs
exhibited
stimulatory
activity
as
compared
to
amphetamines
and
their
parent
compound.
MDMA
and
MDMA-analogs
exhibited
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 (Karup-
pagounder
et
al.,
2014).
Rat studies indicate that the activities of the monoamine
biosynthetic enzymes, tyrosine hydroxylase, and tryptophan
hydroxylase are greatly reduced following multiple methcathi-
none
administrations
and
consequentially
the
levels
of
dopamine,
serotonin,and theirmetabolitesaredecreased 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
environ-
ment, 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, hinderingmemory 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
D.P. Katz et al./ Toxicology Letters 229 (2014) 349356 353
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8/10/2019 Dhanasekaran, Toxicology Lett, 2014, 229, 349-356
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tachycardia, hyperthermia, and premature ventricular contrac-
tions (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
superuousmonoaminergicneurotransmission (Mash et al., 2009;
Ruttenber
et
al.,
1997).
This
40-year-old
man
had
ceased
his
cocaineuse and switched to bath salts. Afterexposurehe showedaggression, 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 hasbeen 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% ofmephedrone
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 48h. Furthermore,
over 30% reported having more than three of the diagnostic and
statistical
manual
IV
criteria
for
dependence
including
increased
tolerance, continuing to takedespitehavingproblemswithuse 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 effectsobserved 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 neurotoxicmechanisms
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,
be-
tween
the
medicinal
chemist,
pharmacologist,
and
toxicologist
is
crucial for determining potential drug candidates operating by
similar or distinct mechanisms of action to those of well-
established
drugs.
Predicting
efcacious
synthetic
cathinones
and
performing
pharmacological
testing,
before
their
release
intosociety, will obviate the strung out legal process drug manufac-
turers 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.
Table 2
Effects of bath salts/MDPV-analogues.
Organ system Actions of cathinones
Central nervous system Euphoria, hallucination, delirium, anxiety, anoxic brain injury
Opthalmic system Mydriasis, blurred vision, nystagmus
Cardiovascular system Tachycardia, cardiac arrest, coagulopathy
Pulmonary system Respiratory arrest, acidosis
Gastroirtestinal system Loss of appetite, nausea, emisis
Renal system Renal failure, CPK elevation, hypovolemia
Hepatic
system
HepatotoxicityReproductive system Increase sexual drive
Skeletal muscle Rhabdomylosis, muscle pain
Others Hyperthermia, bone pain, Necrotizing fascitis, Serotonin syndrome
Table 3
Therapeutic potential/contraindications of disease states with synthetic cath-
inones.
Therapeutic potential Contraindicated
ADHD Anxiety
Appetite suppressant Arrythmia
Analeptic Epilepsy
Bradycardia glaucoma
Benign prostatic Hiccups
Hyperplasia Hypertension
Bulimia Induce cardiac arrest
Cardiac stimulant Insomnia
Chronic fatigue syndrome Migraine
Depression Pheochromocytoma
Horners syndrome PTSD
Hyperkalemia Tachycardia
Induce childbirth Tremors
Nervosa
Narcolepsy
Miosis
Orthostatic hypotension
Sexual dysfunction
Shock
Syncope
354 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-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).
356 D.P. Katz et al./ Toxicology Letters 229 (2014) 349356
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