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01/15/2013

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Biol. Chem., Vol. 392, pp. 103–115, January/February 2011
Copyright
by Walter de Gruyter
Berlin
New York. DOI 10.1515/BC.2011.016
2010/279
Article in press - uncorrected proof
Review
The ugly side of amphetamines: short- and long-term toxicityof 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’),methamphetamine and
D
-amphetamine
Thomas Steinkellner
1
, Michael Freissmuth
1
, HaraldH. Sitte
1,
* and Therese Montgomery
1,2
1
Centre for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna,Wa¨hringerstrasse 13a, A-1090 Vienna, Austria
2
Conway Institute of Biomolecular and BiomedicalResearch, University College Dublin, Dublin, Ireland
*Corresponding authore-mail: harald.sitte@meduniwien.ac.at
Abstract
Amphetamine (‘Speed’), methamphetamine (‘Ice’) and itscongener 3,4-methylenedioxymethamphetamine (MDMA;‘Ecstasy’) are illicit drugs abused worldwide for theireuphoric and stimulant effects. Despite compelling evidencefor chronic MDMA neurotoxicity in animal models, thephysiological consequences of such toxicity in humansremain unclear. In addition, distinct differences in the metab-olism and pharmacokinetics of MDMA between species anddifferent strains of animals prevent the rationalisation of real-istic human dose paradigms in animal studies. Here, weattempt to review amphetamine toxicity and in particularMDMA toxicity in the pathogenesis of exemplary humanpathologies, independently of confounding environmentalfactors such as poly-drug use and drug purity.
Keywords:
addiction; amphetamine; disease;3,4-methylenedioxymethamphetamine (MDMA).
Introduction
Methamphetamine (METH),
D
-amphetamine (
D
-AMPH) and3,4-methylenedioxymethamphetamine (MDMA; Figure 1)are illicit psychoactive drugs abused worldwide for theirstimulant, euphoric and in the case of MDMA, emphatho-genic/entactogenic effects. In contrast to MDMA,
D
-AMPHand METH are also available under medical prescription andare used in the treatment of attention deficit hyperactivitydisorder (ADHD), narcolepsy and weight control (Sulzer etal., 2005; Berman et al., 2009). Although never marketed,MDMA is reported to have been used by US psychothera-pists, prior to its classification as a schedule 1 drug in 1985(Capela et al., 2009).Amphetamines are a subclass of psychostimulants charac-terised by the presence of a
a
-methylphenethyl-amine corestructure. However, for the purposes of this review, the termamphetamines refers to METH,
D
-AMPH and the ring sub-stituted amphetamine derivative MDMA. The chronic toxi-cological and pharmacological effects of each of these drugshave been well documented and much has been discoveredwith regard to the mechanisms of action and structure-func-tion relationships of each compound. Amphetamines exerttheir acute effects both in the central nervous system (CNS)and in peripheral tissues. The acute clinical outcome isdependent upon the dose administered and typically includespositively prescribed subjective effects such as an increasedstate of arousal, euphoria, increased energy and talkativeness,but also negative emotions including anxiety, paranoia orauditory and visual hallucinations (Baylen and Rosenberg2006; Cruickshank and Dyer, 2009). The peripheral effectsof amphetamines are primarily mediated by its interactionwith the noradrenaline transporter (NAT) and are associatedwith an increase in extracellular noradrenaline (NA) concen-trations. These effects include increases in heart rate, bloodpressure, respiration rate, body temperature, psychomotoractivation and reduced appetite (Boenisch and Bruess, 2006;Cruickshank and Dyer, 2009). It is the sympathomimeticstimulating effect of amphetamines which renders themattractive as doping agents (Docherty, 2008).Herein we will attempt to delineate the relationship whichexists between amphetamines (in particular MDMA) and dis-ease, and highlight areas of ignorance that would benefitfrom concerted research efforts. It is only now as the firstgeneration of drug abusers begin to reach advanced age thatwe can truly begin to understand the long-term neuroadap-tive and physiological consequences of amphetamine abusein people.The peripheral and central effects of amphetamines on thehuman nervous system are mediated primarily through theirinteraction with the presynaptic monoamine transporters fordopamine (DAT), serotonin (SERT) and noradrenaline(NAT). Presynaptic monoamine transporters are responsiblefor the reuptake of released neurotransmitter from the syn-aptic cleft and thus exert key dynamic spatial and temporalcontrol over monoamine neurotransmission. As a conse-quence, the monoamine transporters act as important targetsfor multiple psychoactive agents in addition to ampheta-mines, such as cocaine and antidepressant drugs (Sitte andFreissmuth, 2010). All three transporters are members of thehigh affinity, neurotransmitter:sodium symporter (NSS) genefamily of facilitated transporters (Saier, 2000). Their hydro-phobic core is formed by 12 transmembrane helices. Their
 
104
T. Steinkellner et al.
Article in press - uncorrected proof
Figure 1
Amphetamine and congeners.The chemical structures of amphetamines and the congeners areshown as indicated (the chemical names in parentheses representthe IUPAC names): amphetamine
w
street name: ‘Speed’;
D
-form:(2
S
)-1-phenylpropan-2-amine
x
, methamphetamine
w
street name:‘crank’ or ‘Crystal meth’;
D
-form: (2
S
)-
 N 
-methyl-1-phenylpropan-2-amine
x
, 3,4-methylenedioxymethamphetamine or MDMA
w
streetname: ‘Ecstasy’; 1-(1,3-benzodioxol-5-yl)-
 N 
-methylpropan-2-amine
x
.
amino and carboxy termini are located within the cell andcontain multiple consensus sites for protein kinase C (PKC),protein kinase A and Ca
2
q
 /calmodulin-dependent proteinkinase (Vaughan, 2004). A crystal structure of a bacterialtransporter LeuT
 Aa
has been available for several years(Yamashita et al., 2005). LeuT
 Aa
was originally thought tobe a leucine transporter (hence its name), but it transportsother substrates such as alanine more efficiently. LeuT
 Aa
isa bacterial homolog of the NSS and its structure has provideda template for educated guesses on the structure-functionrelationship in SLC6 family members (Forrest et al., 2008;Shi et al., 2008; Zhao et al., 2010).Amphetamines act as competitive substrates at NAT, DATand SERT. Therefore, the reuptake of endogenous neuro-transmitters is reduced in their presence. Concomitantly and– more importantly – they also induce reverse transport of endogenous neurotransmitter and hence non-exocytotic neuro-transmitter release (Sitte and Freissmuth, 2010). Such actionslead to a significant increase in the levels of extracellularserotonin (5-HT), NA and dopamine (DA) and are thoughtto account for the majority of acute amphetamine-inducedbehavioural and psychological effects (Green et al., 2003).Amphetamines also inhibit the action of vesicular mono-amine transporters (VMATs) and monoamine oxidases(MAOs), although at significantly lower concentrations thanthat required for non-exocytotic neurotransmitter release. Forexample, MDMA inhibits MAO-A 10 times more potentlythan MAO-B, yet possesses an IC
50
value of only 44
m
M
atMAO-A (Leonardi and Azmitia, 1994) and approximately30
m
M
at VMAT
2
(Partilla et al., 2006) when analysed in rattissue
in vitro
, both of which are approximately 500-foldhigher than its EC
50
(0.074
m
M
) for 5-HT release in ratsynaptosomes (Baumann et al., 2007). Furthermore, phar-macological doses (0.3–1 mg/kg) of MDMA, METH and
D
-AMPH do not block MAO activity when administered tomale Sprague-Dawley rats
in vivo
(Zolkowska et al., 2006),whereas the MAO-A inhibitor clorgyline has been shown tosynergistically enhance the effects of higher doses of MDMA(10–40 mg/kg) on serotonin mediated behaviour, body tem-perature and 5-HT release in rats (Hewton et al., 2007; Alveset al., 2009b). In contrast to MAO-A, both the gene silencingand inhibition of MAO-B protected against MDMA-induced5-HT neurotoxicity and oxidative mitochondrial damage inrats (Sprague and Nichols, 1995; Falk et al., 2002; Hrometzet al., 2004; Alves et al., 2007), whereas 5-HT (but not DAdepletions) are reduced in MAO-B deficient mice followingchronic MDMA administration (Fornai et al., 2001). Thus,although MAOs clearly play a role in the mediation of chron-ic MDMA-induced neurotoxicity in rodents, the overall sig-nificance of MDMA-induced VMAT and MAO inhibition inacute central drug effects at pharmacological doses
in vivo
is as yet unclear.The affinity for DAT, NAT and SERT differs amongamphetamines: for instance, the addition of the 3,4-methy-lenedioxy group to the phenyl ring of MDMA significantlyincreases its affinity for SERT and NAT over DAT (Capelaet al., 2009). The selectivity of METH, MDMA and
D
-AMPH for different monoamine transporters has also beenassociated with the specificity of their neurotoxic actions tothe underlying monoaminergic neuronal systems. For exam-ple, METH has been reported to exert selective neurotoxicityin the dopaminergic nigrostriatal system, comparable to thatof the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine (MPTP). Subsequently, both MPTP and METH are usedto produce animal models of Parkinson’s disease (PD) (Son-salla et al., 1996; Harvey et al., 2000; Granado et al., 2010),even though an increased risk of PD in chronic humanMETH abusers has yet to be confirmed by epidemiologicaldata (Guilarte, 2001; Chang et al., 2007).
D
-AMPH has alsobeen reported to induce dopaminergic neurotoxicity in non-human primates when administered at doses equivalent tothose used in the treatment of ADHD (Ricaurte et al., 2005).In contrast, MDMA is regarded as a selective serotonergicneurotoxin and has been associated with cognitive dysfunc-tion in humans (Karlsen et al., 2008). All three drugs haveaddictive potential and can lead to varying degrees of drugdependence.
Acute MDMA toxicity and death in humans
MDMA abuse can lead to death. However, in comparison tothe widespread use of MDMA, fatal intoxications are rareevents (EMCDDA, 2009), the majority of which are accom-panied by acute hyperthermia, hyponatramia, cardiovascularcollapse and rhabdomyolysis (Lyles and Cadet, 2003; Halland Henry, 2006). The direct mechanisms that underlie thetoxic actions are difficult to elucidate because, in the major-ity of cases, MDMA is not the only drug involved. AcuteMDMA toxicity in humans appears to be mainly due to the
 
Toxic properties of amphetamines
105
Article in press - uncorrected proof
combined action of a serotonin syndrome and sympathomi-metic effects (de la Torre et al., 2000). However, epilepticseizures have also been reported (Baylen and Rosenberg,2006; Giorgi et al., 2006; Karlsen et al., 2008). A serotoninsyndrome is the hallmark of acute MDMA toxicity in ani-mals (Green et al., 2003).
Chronic MDMA neurotoxicity in animals
Few direct correlations exist between MDMA abuse andhuman disease states other than addiction. However, thereare over 200 studies which demonstrate the acute biphasiceffect of MDMA on serotonergic neurotransmission in ratsand monkeys (Capela et al., 2009). Following the initialMDMA-induced release of 5-HT, the intracellular levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) are significantly reduced within 3–6 h. Recovery canoccur within 24 h but the administration of multiple dosesof MDMA, at
G
20 mg/kg in rats, can induce further decreas-es in serotonergic biomarkers and SERT surface levels thatare still present 1 week later (Schmidt et al., 1986; Stone etal., 1986; Battaglia et al., 1987; Schmidt, 1987; Xie et al.,2006). Similar findings have been reported in monkeys butat lower doses, i.e., 2.5–5 mg/kg. This comparison indicatesthat monkeys are more susceptible to MDMA toxicity thanrats (Capela et al., 2009, Green et al., 2009). Furthermore,in contrast to other rat strains such as the Sprague-Dawleyor Wistar rats described above, significant decreases in sero-tonergic biomarkers have been reported in Dark Agouti ratsfollowing only single doses of 10–15 mg/kg MDMA (Capelaet al., 2009).MDMA also inhibits tryptophan hydroxylase activity, therate limiting enzyme in 5-HT biosynthesis, in rats and reduc-es the expression of VMAT2 in baboons (Green et al., 2003).Numerous neuroanatomical and immunohistological studieshave highlighted the axonal degeneration of 5-HT neuronsfollowing high doses of MDMA in rats and monkeys(Ricaurte et al., 1988; Green et al., 2003). Furthermore,abnormal reorganisation of 5-HT-projections and increasedaxonal ‘sproutinghas also been reported in monkeys(Fischer et al., 1995; Hatzidimitriou et al., 1999). However,the selective nature of MDMA neurotoxicity in rats hasrecently been questioned (Schmued, 2003). Furthermore, incontrast to rats, MDMA primarily targets dopaminergicneurotransmission in mice (Itzhak et al., 2003; Granado et al.,2008) and has been shown to deplete both DA and its metab-olites in numerous mouse studies (Capela et al., 2009). It isnot clear why observations in rats and monkeys differ fromthose in mice, but species-dependent divergent oxidativemetabolism is thought to be a contributing factor. Collec-tively, these findings indicate that MDMA has the potentialto produce a distal axotomy of 5-HT neurons in rats andprimates. Nonetheless, significant controversy exists regard-ing the ability of MDMA to induce ‘reactive gliosis’ in rats,or more specifically to increase glial fibrillary acidic proteinexpression (Pubill et al., 2003; Li et al., 2006, Chipana etal., 2008). Until a consensus can be reached regarding theability of MDMA to induce the expression of this crucialneurotoxic CNS marker, the possibility that MDMA induced5-HT depletions in rats are due to persistent adaptive changesin gene expression and/or protein function rather then neuro-toxic damage must also be considered (Baumann et al.,2007). Furthermore, the majority of these studies wereconducted using chronic drug administration paradigms(multiple i.p. or s.c. injections of 10 mg/kg or higher), asdetermined by ‘interspecies scaling’; an equation which esti-mates the equivalent dose rates between rodents and humans(Ricaurte and McCann, 2001). The relevance of the ‘allo-metric equation’ when extrapolating the results of MDMAanimal studies to humans has recently been called into ques-tion (de la Torre and Farre, 2004; Baumann et al., 2007;Green et al., 2009) and is further complicated by both inter-species metabolic variations and the non-linear pharmaco-kinetics of MDMA metabolism in both humans and monkeys(de la Torre et al., 2000; Farre et al., 2004; Kolbrich et al.,2008; Green et al., 2009). The hepatic metabolism of MDMA is a crucial factor in the manifestation of MDMAneurotoxicity in rodents (de la Torre and Farre, 2004; Monkset al., 2004; Escobedo et al., 2005; Jones et al., 2005). Thisis also emphasised by the fact that the direct injection of MDMA into rat brain fails to reproduce the acute or long-term neurotoxic effects evident following peripheral admin-istration (Esteban et al., 2001). Thus, neuroanatomicalmarkers, dose, drug bioavailability and species-specific met-abolic pathways must all be carefully assessed when inter-preting the results of chronic toxicological animal data andmore in-depth studies are required to further elucidate theseareas. In spite of the obvious differences which exist in bothspecies and even strain sensitivities to MDMA toxicity, themajority of animal data still suggests that MDMA is a sero-tonergic neurotoxin. However, the direct functional conse-quences of such neurotoxicity in humans have yet to beelucidated.
Chronic MDMA toxicity in humans: clinicalstudies
There are well-known limitations in extrapolating the resultsof animal studies to humans (de la Torre and Farre, 2004).Consequently, the actual neurotoxic potential of MDMA inhumans remains a subject of much debate (Curran, 2000;Gouzoulis-Mayfrank and Daumann, 2006b; Baumann et al.,2007). Nonetheless, MDMA induces similar neurochemical,endocrine and behavioural effects in rats and humans atequivalent doses (Baumann et al., 2007). In addition,decreased levels of cerebrospinal fluid 5-HIAA and SERTbinding sites have been reported in human MDMA userswhen compared to non-MDMA users (McCann et al., 1994,1999; Semple et al., 1999; Reneman et al., 2001). Moreover,the magnitude of this decline was found to correlate with theextent of MDMA abuse (McCann et al., 1998). Findingsfrom these early brain imaging studies have recently beencorroborated by the employment of more stringent and sen-sitive parameters, thus confirming the interpretation that

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