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MDMA (“ecstasy”), methamphetamine and their combination: long-term changes in social interaction and neurochemistry in the rat

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3,4-Methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) are illicit drugs that are increasingly used in combination. The acute and long-term effects of MDMA/METH combinations are largely uncharacterised.


The current study investigated the behavioural, thermal and neurotoxic effects of MDMA and METH when given alone or in combined low doses.


Male rats received four injections, one every 2 h, of vehicle, MDMA (2.5 or 5 mg/kg per injection), METH (2.5 or 5 mg/kg per injection) or combined MDMA/METH (1.25+1.25 mg/kg per injection or 2+2 mg/kg per injection). Drugs were given at an ambient temperature of 28°C to simulate hot nightclub conditions. Body temperature, locomotor activity and head-weaving were assessed during acute drug administration while social interaction, anxiety-related behavior on the emergence test and neurochemical parameters were assessed 4–7 weeks later.


All treatments acutely increased locomotor activity, while pronounced head-weaving was seen with both MDMA/METH treatments and the higher dose METH treatment. Acute hyperthermia was greatest with the higher dose MDMA/METH treatment and was also seen with MDMA but not METH treatment. Several weeks after drug administration, both MDMA/METH groups, both METH groups and the higher dose MDMA group showed decreased social interaction relative to controls, while both MDMA/METH groups and the lower dose MDMA group showed increased anxiety-like behaviour on the emergence test. MDMA treatment caused 5-HT and 5-HIAA depletion in several brain regions, while METH treatment reduced dopamine in the prefrontal cortex. Combined MDMA/METH treatment caused 5-HT and 5-HIAA depletion in several brain regions and a unique depletion of dopamine and DOPAC in the striatum.


These results suggest that MDMA and METH in combination may have greater adverse acute effects (head-weaving, body temperature) and long-term effects (decreased social interaction, increased emergence anxiety, dopamine depletion) than equivalent doses of either drug alone.

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  • Australian Bureau of Criminal Intelligence, (2002) Australian Illicit Drug Report 2001–2002. Canberra, Commonwealth of Australia

  • Bisagno V, Ferguson D, Luine VN (2002) Short toxic methamphetamine schedule impairs object recognition task in male rats. Brain Res 940:95–101

    Article  CAS  PubMed  Google Scholar 

  • Boys A, Lenton S, Norcross K (1997) Polydrug use at raves by a Western Australian sample. Drug Alcohol Rev 16:227–234

    Google Scholar 

  • Brecht ML, von Mayrhauser C (2002) Differences between ecstasy-using and nonusing methamphetamine users. J Psychoact Drugs 34:215–223

    Google Scholar 

  • Brown PL, Wise RA, Kiyatkin EA (2003) Brain hyperthermia is induced by methamphetamine and exacerbated by social interaction. J Neurosci 23:3924–3929

    CAS  PubMed  Google Scholar 

  • Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, Wilke F, Wartberg L, Zapletalova P, Clausen M (2003) Long-term effects of “ecstasy” use on serotonin transporters of the brain investigated by PET. J Nucl Med 44:375–384

    CAS  PubMed  Google Scholar 

  • Bull EJ, Hutson PH, Fone KCF (2003) Reduced social interaction following 3,4-methylenedioxymethamphetamine is not associated with enhanced 5-HT(2C) receptor responsivity. Neuropharmacology 44:439–448

    Article  CAS  PubMed  Google Scholar 

  • Cass WA, Manning MW (1999) Recovery of presynaptic dopaminergic functioning in rats treated with neurotoxic doses of methamphetamine. J Neurosci 19:7653–7660

    CAS  PubMed  Google Scholar 

  • Chapman DE, Hanson GR, Kesner RP, Keefe KA (2001) Long-term changes in basal ganglia function after a neurotoxic regimen of methamphetamine. J Pharmacol Exp Ther 296:520–527

    CAS  PubMed  Google Scholar 

  • Davidson C, Gow AJ, Lee TH, Ellinwood EH (2001) Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Rev 36:1–22

    Article  CAS  PubMed  Google Scholar 

  • Ernst T, Chang L, Leonido-Yee M, Speck O (2000) Evidence for long-term neurotoxicity associated with methamphetamine abuse: a 1H MRS study. Neurology 54:1344–1349

    CAS  PubMed  Google Scholar 

  • Fleckenstein AE, Gibb JW, Hanson GR (2000) Differential effects of stimulants on monoaminergic transporters: pharmacological consequences and implications for neurotoxicity. Eur J Pharmacol 406:1–13

    Article  CAS  PubMed  Google Scholar 

  • Fone KCF, Beckett SRG, Topham IA, Swettenham J, Ball M, Maddocks L (2002) Long-term changes in social interaction and reward following repeated MDMA administration to adolescent rats without accompanying serotonergic neurotoxicity. Psychopharmacology 159:437–444

    CAS  PubMed  Google Scholar 

  • Fox HC, McLean A, Turner JJ, Parrott AC, Rogers R, Sahakian BJ (2002) Neuropsychological evidence of a relatively selective profile of temporal dysfunction in drug-free MDMA (“ecstasy”) polydrug users. Psychopharmacology 162:203–214

    Article  CAS  PubMed  Google Scholar 

  • Friedman SD, Castaneda E, Hodge GK (1998) Long-term monoamine depletion, differential recovery, and subtle behavioral impairment following methamphetamine-induced neurotoxicity. Pharmacol Biochem Behav 61:35–44

    CAS  PubMed  Google Scholar 

  • Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463–508

    Article  CAS  PubMed  Google Scholar 

  • Gurtman CG, Morley KC, Li KM, Hunt GE, McGregor IS (2002) Increased anxiety in rats after 3,4-methylenedioxymethamphetamine: association with serotonin depletion. Eur J Pharmacol 446:89–96

    Article  CAS  PubMed  Google Scholar 

  • Hansen JP, Riddle EL, Sandoval V, Brown JM, Gibb JW, Hanson GR, Fleckenstein AE (2002) Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity. J Pharmacol Exp Ther 300:1093–1100

    Google Scholar 

  • Hatzidimitriou G, McCann UD, Ricaurte GA (1999) Altered serotonin innervation patterns in the forebrain of monkeys treated with (±)3,4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery. J Neurosci 19:5096–5107

    CAS  PubMed  Google Scholar 

  • Haughey HM, Fleckenstein AE, Metzger RR, Hanson GR (2000) The effects of methamphetamine on serotonin transporter activity: role of dopamine and hyperthermia. J Neurochem 75:1608–1617

    Article  CAS  PubMed  Google Scholar 

  • Kita T, Wagner GC, Nakashima T (2003) Current research on methamphetamine-induced neurotoxicity: animal models of monoamine disruption. J Pharmacol Sci 92:178–195

    Article  CAS  PubMed  Google Scholar 

  • Malberg JE, Seiden LS (1998) Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J Neurosci 18:5086–5094

    CAS  PubMed  Google Scholar 

  • McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA (1998) Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci 18:8417–8422

    CAS  Google Scholar 

  • McCann UD, Mertl M, Eligulashvili V, Ricaurte GA (1999) Cognitive performance in (±) 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) users: a controlled study. Psychopharmacology 143:417–425

    CAS  PubMed  Google Scholar 

  • McGregor IS, Clemens KJ, Van Der Plasse G, Li KM, Hunt GE, Chen F, Lawrence AJ (2003a) Increased anxiety 3 months after brief exposure to MDMA (“ecstasy”) in rats: association with altered 5-HT transporter and receptor density. Neuropsychopharmacology 28:1472–1484

    Article  CAS  PubMed  Google Scholar 

  • McGregor IS, Gurtman CG, Morley KC, Clemens KJ, Blokland A, Li KM, Cornish JL, Hunt GE (2003b) Increased anxiety and “depressive” symptoms months after MDMA (“ecstasy”) in rats: drug-induced hyperthermia does not predict long-term outcomes. Psychopharmacology 168: 465–474

    Article  CAS  PubMed  Google Scholar 

  • Minium EW, King BM, Bear G (1993) Statistical reasoning in psychology and education, 3rd edn. Wiley, New York

  • Morley KC, McGregor IS (2000) (±)-3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) increases social interaction in rats. Eur J Pharmacol 408:41–49

    Article  CAS  PubMed  Google Scholar 

  • Morley KC, Gallate JE, Hunt GE, Mallet PE, McGregor IS (2001) Increased anxiety and impaired memory in rats 3 months after administration of 3,4-methylenedioxymethamphetamine (“ecstasy”). Eur J Pharmacol 433:91–99

    CAS  PubMed  Google Scholar 

  • Pubill D, Canudas AM, Pallas M, Camins A, Camarasa J, Escubedo E (2003) Different glial response to methamphetamine- and methylenedioxymethamphetamine-induced neurotoxicity. Naunyn-Schmiedeberg’s Arch Pharmacol 367:490–499

    Google Scholar 

  • Rawson RA, Gonzales R, Brethen P (2002) Treatment of methamphetamine use disorders: an update. J Subst Abuse Treat 23:145–150

    Article  PubMed  Google Scholar 

  • Reneman L, Endert E, de Bruin K, Lavalaye J, Feenstra MG, de Wolff FA, Booij J (2002) The acute and chronic effects of MDMA (“ecstasy”) on cortical 5-HT2A receptors in rat and human brain. Neuropsychopharmacology 26:387–396

    Article  CAS  PubMed  Google Scholar 

  • Sabol KE, Lew R, Richards JB, Vosmer GL, Seiden LS (1996) Methylenedioxymethamphetamine-induced serotonin deficits are followed by partial recovery over a 52-week period. Part I: synaptosomal uptake and tissue concentrations. J Pharmacol Exp Ther 276:846–854

    CAS  PubMed  Google Scholar 

  • Schmidt CJ, Black CK, Taylor VL (1990) Antagonism of the neurotoxicity due to a single administration of methylenedioxymethamphetamine. Eur J Pharmacol 181:59–70

    Article  CAS  PubMed  Google Scholar 

  • Shankaran M, Yamamoto BK, Gudelsky GA (1999) Mazindol attenuates the 3,4-methylenedioxymethamphetamine-induced formation of hydroxyl radicals and long-term depletion of serotonin in the striatum. J Neurochem 72:2516–2522

    CAS  PubMed  Google Scholar 

  • Shinba T, Yamamoto K, Cao GM, Mugishima G, Andow Y, Hoshino T (1996) Effects of acute methamphetamine administration on spacing in paired rats: investigation with an automated video-analysis method. Prog Neuropsychopharmacol Biol Psychiatry 20:1037–1049

    Article  CAS  PubMed  Google Scholar 

  • Stone DM, Johnson M, Hanson GR, Gibb JW (1988) Role of endogenous dopamine in the central serotonergic deficits induced by 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 247:79–87

    CAS  PubMed  Google Scholar 

  • Stuerenburg HJ, Petersen K, Baumer T, Rosenkranz M, Buhmann C, Thomasius R (2002) Plasma concentrations of 5-HT, 5-HIAA, norepinephrine, epinephrine and dopamine in ecstasy users. Neuroendocrinol Lett 23:259–261

    CAS  PubMed  Google Scholar 

  • Thomasius R, Petersen K, Buchert R, Andresen B, Zapletalova P, Wartberg L, Nebeling B, Schmoldt A (2003) Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users. Psychopharmacology 167:85–96

    CAS  PubMed  Google Scholar 

  • Topp L, Hando J, Dillon P, Roche A, Solowij N (1999) ecstasy use in Australia: patterns of use and associated harm. Drug Alcohol Depend 55:105–115

    CAS  PubMed  Google Scholar 

  • Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler M, Gatley SJ, Miller E, Hitzemann R, Ding YS, Logan J (2001) Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci 21:9414–9418

    CAS  PubMed  Google Scholar 

  • Wallace TL, Gudelsky GA, Vorhees CV (1999) Methamphetamine-induced neurotoxicity alters locomotor activity, stereotypic behavior, and stimulated dopamine release in the rat. J Neurosci 19:9141–9148

    CAS  PubMed  Google Scholar 

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This work was supported by an NH&MRC grant to Iain S. McGregor and Glenn E. Hunt.

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Correspondence to Iain S. McGregor.

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Clemens, K.J., van Nieuwenhuyzen, P.S., Li, K.M. et al. MDMA (“ecstasy”), methamphetamine and their combination: long-term changes in social interaction and neurochemistry in the rat. Psychopharmacology 173, 318–325 (2004).

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