MDMA, Methylone, and MDPV: Drug-Induced Brain Hyperthermia and Its Modulation by Activity State and Environment

  • Eugene A. KiyatkinEmail author
  • Suelynn E. Ren
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 32)


Psychomotor stimulants are frequently used by humans to intensify the subjective experience of different types of social interactions. Since psychomotor stimulants enhance metabolism and increase body temperatures, their use under conditions of physiological activation and in warm humid environments could result in pathological hyperthermia, a life-threatening symptom of acute drug intoxication. Here, we will describe the brain hyperthermic effects of MDMA, MDPV, and methylone, three structurally related recreational drugs commonly used by young adults during raves and other forms of social gatherings. After a short introduction on brain temperature and basic mechanisms underlying its physiological fluctuations, we will consider how MDMA, MDPV, and methylone affect brain and body temperatures in awake freely moving rats. Here, we will discuss the role of drug-induced heat production in the brain due to metabolic brain activation and diminished heat dissipation due to peripheral vasoconstriction as two primary contributors to the hyperthermic effects of these drugs. Then, we will consider how the hyperthermic effects of these drugs are modulated under conditions that model human drug use (social interaction and warm ambient temperature). Since social interaction results in brain and body heat production, coupled with skin vasoconstriction that impairs heat loss to the external environment, these physiological changes interact with drug-induced changes in heat production and loss, resulting in distinct changes in the hyperthermic effects of each tested drug. Finally, we present our recent data, in which we compared the efficacy of different pharmacological strategies for reversing MDMA-induced hyperthermia in both the brain and body. Specifically, we demonstrate increased efficacy of the centrally acting atypical neuroleptic compound clozapine over the peripherally acting vasodilator drug, carvedilol. These data could be important for understanding the potential dangers of MDMA in humans and the development of pharmacological tools to alleviate drug-induced hyperthermia – potentially saving the lives of highly intoxicated individuals.


Active ingredients of “bath salts” Brain metabolism Cerebral heat production Drug-induced intoxication Drugs of abuse MDMA (Ecstasy) Psychomotor stimulants Rave parties Vasoconstriction 







3,4-Methylenedioxymethamphetamine (Ecstasy)








Nucleus accumbens





This work was supported by the National Institute on Drug Abuse, Intramural Research Program (DA000445-14).

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest are disclosed.


  1. 1.
    Kiyatkin EA (2010) Brain temperature homeostasis: physiological fluctuations and pathological shifts. Front Biosci 15:73–92CrossRefPubMedGoogle Scholar
  2. 2.
    Abrams R, Hammel HT (1964) Hypothalamic temperature in unanesthetized albino rats during feeding and sleeping. Am J Physiol 206:641–646Google Scholar
  3. 3.
    Baker MA, Frye FM, Millet VE (1973) Origin of temperature changes evoked in the brain by sensory stimulation. Exp Neurol 38:502–519CrossRefGoogle Scholar
  4. 4.
    Delgado JMR, Hanai T (1966) Intracerebral temperatures in free-moving cats. Am J Physiol 211:755–769Google Scholar
  5. 5.
    McElligott JC, Melzack R (1967) Localized thermal changes evoked in the brain by visual and auditory stimulation. Exp Neurol 17:293–312CrossRefGoogle Scholar
  6. 6.
    Serota HM, Gerard RM (1938) Localized thermal changes in cat’s brain. J Neurophysiol 1:115–124CrossRefGoogle Scholar
  7. 7.
    Kovalson VM (1972) Brain temperature variations during natural sleep and arousal in white rats. Physiol Behav 10:667–670CrossRefGoogle Scholar
  8. 8.
    Smirnov MS, Kiyatkin EA (2008) Fluctuations in central and peripheral temperatures associated with feeding behavior in rats. Am J Physiol 295:R1414–R1424Google Scholar
  9. 9.
    Kiyatkin EA, Mitchum R (2003) Fluctuations in brain temperatures during sexual behavior in male rats: an approach for evaluating neural activity underlying motivated behavior. Neuroscience 119:1169–1183CrossRefGoogle Scholar
  10. 10.
    Mariak Z, Lyso T, Peikarski P, Lewko J, Jadeszko M, Szydlik P (2000) Brain temperature in patients with central nervous system lesions. Neurol Neurochir Pol 34:509–522Google Scholar
  11. 11.
    Rumana CS, Gopinath SP, Uzura M, Valadka AB, Robertson CS (1998) Brain temperatures exceed systemic temperatures in head-injured patients. Crit Care Med 26:562–567CrossRefGoogle Scholar
  12. 12.
    Rango M, Arighi A, Bonifati C, Bresolin N (2012) Increased brain temperature in Parkinson’s disease. Neuroreport 23:129–133CrossRefGoogle Scholar
  13. 13.
    Rango M, Arighi A, Bonifati C, Del Bo R, Comi G, Bresolin N (2014) The brain is hypothermic in patients with mitochondrial diseases. J Cereb Blood Flow Metab 34:915–920CrossRefPubMedGoogle Scholar
  14. 14.
    Sukstanskii AL, Yablonskiy DA (2006) Theoretical model of temperature regulation in the brain during changes in functional activity. Proc Natl Acad Sci U S A 103:12144–12149CrossRefPubMedGoogle Scholar
  15. 15.
    Fuller CA, Baker MA (1983) Selective regulation of brain and body temperatures in the squirrel monkey. Am J Physiol 245:R293–R297Google Scholar
  16. 16.
    Armenian P, Mamantov TM, Tsutaoka BT, Gerona RR, Silman EF, Wu AH, Olson KR (2013) Multiple MDMA (Ecstasy) overdoses at a rave event: a case series. J Intensive Care Med 28:252–258CrossRefGoogle Scholar
  17. 17.
    Dafters RI (1995) Hyperthermia following MDMA administration in rats: effects of ambient temperature, water consumption, and chronic dosing. Physiol Behav 58:877–882CrossRefGoogle Scholar
  18. 18.
    Kalant H (2001) The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ 165:917–928PubMedCentralPubMedGoogle Scholar
  19. 19.
    Nimmo SM, Kennedy BW, Tullett WM, Blyth AS, Dougall JR (1993) Drug-induced hyperthermia. Anesthesia 48:892–895CrossRefGoogle Scholar
  20. 20.
    Sei H, Furano N, Morita Y (1997) Diurnal changes in blood pressure, heart rate and body temperature during sleep in the rat. J Sleep Res 6:113–119CrossRefGoogle Scholar
  21. 21.
    Nybo L (2008) Hyperthermia and fatigue. J Appl Physiol 104:871–877CrossRefGoogle Scholar
  22. 22.
    Schmidt-Nielsen K (1997) Animal physiology. Adaptation and environment, 5th edn. Cambridge University Press, CambridgeGoogle Scholar
  23. 23.
    Siesjo B (1978) Brain energy metabolism. Wiley, New YorkGoogle Scholar
  24. 24.
    Feitelberg S, Lampl H (1935) Warmetonung der Grosshirnrinde bei Erregung und Ruhe. Functionshemmung. Arch Exp Path Pharmak 177:726–736 (in German)Google Scholar
  25. 25.
    Hayward JN, Baker MA (1968) Role of cerebral blood flow in the regulation of brain temperature in the monkey. Am J Physiol 215:389–403Google Scholar
  26. 26.
    Kiyatkin EA, Brown PL, Wise RA (2002) Brain temperature fluctuation: a reflection of functional neural activation. Eur J Neurosci 16:164–168CrossRefGoogle Scholar
  27. 27.
    Bola RA, Kiyatkin EA (2016) Robust brain hyperglycemia during general anesthesia: relationships with metabolic brain inhibition and vasodilation. Front Physiol 7:39. doi: 10.3389/fphys.2016.00039CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Kiyatkin EA, Brown PL (2005) Brain and body temperature homeostasis during sodium pentobarbital anesthesia with and without body warming in rats. Physiol Behav 84:563–570CrossRefGoogle Scholar
  29. 29.
    Di Chiara G (2002) Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 137:75–114CrossRefGoogle Scholar
  30. 30.
    Mogenson GJ, Jones DL, Yim CY (1980) From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol 14:69–97CrossRefGoogle Scholar
  31. 31.
    Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492CrossRefGoogle Scholar
  32. 32.
    Alberts DS, Sonsalla PK (1995) Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: pharmacological profile of protective and nonprotective agents. J Pharmacol Exp Ther 275:1104–1114Google Scholar
  33. 33.
    Freedman RR, Johanson C-E, Tancer ME (2005) Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 183:248–256CrossRefGoogle Scholar
  34. 34.
    Gordon CJ, Watkinson WP, O’Callaghan PP, Miller DB (1991) Effects of 3,4-methylenedioxymetamphetamine on autonomic thermoregulatory responses of the rat. Pharmacol Biochem Behav 38:339–344CrossRefGoogle Scholar
  35. 35.
    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 55:463–508CrossRefGoogle Scholar
  36. 36.
    Mechan AO, Esteban B, O’Shea E, Elliott JM, Colado MI, Green AR (2002) The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenediomethamphetamine (MDMA, “ecstasy”) to rats. Br J Pharmacol 135:170–180CrossRefPubMedGoogle Scholar
  37. 37.
    Pederson NP, Blessing WW (2001) Cutaneous vasoconstriction contributes to hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy) on conscious rabbits. J Neurosci 21:8648–8654CrossRefGoogle Scholar
  38. 38.
    Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M et al (2013) Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive ‘bath salts’ products. Neuropsychopharmacology 38:552–562CrossRefPubMedGoogle Scholar
  39. 39.
    German CL, Fleckenstein AE, Hanson GR (2014) Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci 97:2–8CrossRefPubMedGoogle Scholar
  40. 40.
    Spiller HA, Ryan ML, Weston RG, Jansen J (2011) Clinical experience with and analytical confirmation of “bath salts” and “legal highs” (synthetic cathinones) in the United States. Clin Toxicol 49:499–505CrossRefGoogle Scholar
  41. 41.
    Prosser JM, Nelson LS (2012) The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol 8:33–42CrossRefPubMedGoogle Scholar
  42. 42.
    Ross EA, Reisfield GM, Watson MC, Chronister CW, Goldberger BA (2012) Psychoactive “bath salts” intoxication with methylenedioxypyrovalerone. Am J Med 125:854–858CrossRefGoogle Scholar
  43. 43.
    Baumann MH, Partilla JS, Lehner KR (2013) Psychoactive “bath salts”: not so soothing. Eur J Pharmacol 698:1–5CrossRefPubMedGoogle Scholar
  44. 44.
    Baumann MH, Ayestas MA Jr, Partilla JS, Sink JR, Shulgin AT, Daley PF et al (2012) The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology 37:1192–1203CrossRefPubMedGoogle Scholar
  45. 45.
    Eshleman AJ, Wolfrum KM, Hatfield MG, Johnson RA, Murphy KV, Janowsky A (2013) Substituted methcathinones differ in transporter and receptor interactions. Biochem Pharmacol 85:1803–1815CrossRefPubMedGoogle Scholar
  46. 46.
    Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J et al (2013) Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 168:458–470CrossRefPubMedGoogle Scholar
  47. 47.
    Cameron KN, Kolanos R, Solis E Jr, Glennon RA, De Felice LJ (2013) Bath salts components mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human dopamine transporter. Br J Pharmacol 168:1750–1757CrossRefPubMedGoogle Scholar
  48. 48.
    Pearson JM, Hargraves TL, Hair LS, Massucci CJ, Frazee CC 3rd, Garg U et al (2001) Three fatal intoxications due to methylone. J Anal Toxicol 36:444–451CrossRefGoogle Scholar
  49. 49.
    Borek HA, Holstege CP (2012) Hyperthermia and multiorgan failure after abuse of “bath salts” containing 3,4-methylenedioxypyrovalerone. Ann Emerg Med 60:103–105CrossRefGoogle Scholar
  50. 50.
    Kesha K, Boggs CL, Ripple MG, Allan CH, Levine B, Jufer-Phipps R et al (2013) Methylenedioxypyrovalerone (“bath salts”)-related death: case report and review of the literature. J Forensic Sci 58:1654–1659CrossRefPubMedGoogle Scholar
  51. 51.
    Murray BL, Murphy CM, Beuhler MC (2012) Death following recreational use of designer drug “bath salts” containing 3,4-methylenedioxypyrovalerone (MDPV). J Med Toxicol 8:69–75CrossRefPubMedGoogle Scholar
  52. 52.
    Aarde SM, Huang PK, Creehan KM, Dickerson TJ, Taffe MA (2013) The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats. Neuropharmacology 71:130–140CrossRefPubMedGoogle Scholar
  53. 53.
    Fantegrossi WE, Gannon BM, Zimmerman SM, Rice KC (2013) In vivo effects of abused ‘bath salt’ constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice: drug discrimination, thermoregulation, and locomotor activity. Neuropsychopharmacology 38:563–573CrossRefGoogle Scholar
  54. 54.
    Kiyatkin EA, Kim AH, Wakabayashi KT, Baumann MH, Shaham Y (2014) Critical role of peripheral vasoconstriction in fatal brain hyperthermia induced by MDMA (Ecstasy) under conditions that mimic human drug use. J Neurosci 34:7754–7762CrossRefPubMedGoogle Scholar
  55. 55.
    Kiyatkin EA, Kim AH, Wakabayashi KT, Baumann MH, Shaham Y (2015) Effects of social interaction and warm ambient temperature on brain hyperthermia induced by the designer drugs methylone and MDPV. Neuropsychopharmacology 40:436–445CrossRefGoogle Scholar
  56. 56.
    Romanovsky AA, Ivanov AI, Shimansky YP (2002) Ambient temperature for experiments in rats: a new method for determining the zone of thermal neutrality. J Appl Physiol 92:2667–2679CrossRefGoogle Scholar
  57. 57.
    Davis WM, Hatoum HT, Waters IW (1987) Toxicity of MDA (3,4-methylenedioxyamphetamine) considered for relevance to hazards of MDMA (Ecstasy) abuse. Alcohol Drug Res 7:123–134Google Scholar
  58. 58.
    Gordon CJ (1990) Thermal biology of the laboratory rat. Physiol Behav 47:963–991CrossRefGoogle Scholar
  59. 59.
    Rowell LB (1983) Cardiovascular aspects of human thermoregulation. Circ Res 52:367–379CrossRefGoogle Scholar
  60. 60.
    Banks ML, Sprague JE, Kisor DF, Czoty PW, Nichols DE, Nader MA (2007) Ambient temperature effects on 3,4-methylenedioxymethamphetamine-induced theremodysregulation and pharmacokinetics in male monkeys. Drug Metab Dispos 35:1840–1845CrossRefGoogle Scholar
  61. 61.
    Taffe MA, Lay CC, Von Huben SN, Davis SA, Crean RD, Katner SN (2006) Hyperthermia induced by 3,4-methylenedioxymethamphetamine in unrestrained rhesus monkeys. Drug Alcohol Depend 20:276–281CrossRefGoogle Scholar
  62. 62.
    Von Huben RD, Lay CC, Crean RD, Davis SA, Katner SN, Taffe MA (2007) Impact of ambient temperature on hyperthermia induced by (+/-)3,4- methylenediomethamphetamine in rhesus macaques. Neuropsychopharmacology 32:673–681CrossRefGoogle Scholar
  63. 63.
    Parrott AC (2014) The potential dangers of using MDMA for psychotherapy. J Psychoactive Drugs 46:37–43CrossRefPubMedGoogle Scholar
  64. 64.
    Nybo L, Secher NH, Nielson B (2002) Inadequate heat release from the human brain during prolonged exercise with hyperthermia. J Physiol 545:697–704CrossRefPubMedGoogle Scholar
  65. 65.
    Proulx CI, Ducharme MB, Kenny GP (2003) Effect of water temperature on cooling efficiency during hyperthermia in humans. J Appl Physiol 94:1317–1323CrossRefGoogle Scholar
  66. 66.
    Blessing W, Seaman B, Pedersen N, Ootsuka Y (2003) Clozapine reverses hyperthermia and sympathetically mediated cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (ecstasy) in rabbits and rats. J Neurosci 15:6385–6391CrossRefGoogle Scholar
  67. 67.
    Sprague JE, Moze P, Caden D, Rusyniak DE, Holmes C, Goldstein DS et al (2005) Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model. Crit Care Med 33:1311–1316CrossRefGoogle Scholar
  68. 68.
    Baldessarini RJ, Frankenburg FR (1991) Clozapine. N Engl J Med 11:746–754Google Scholar
  69. 69.
    Breier A, Buchanan RW, Waltrip Ii RW, Listwak S, Holmes C, Goldstein DS (1994) The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy. Neuropsychopharmacology 10:1–7CrossRefGoogle Scholar
  70. 70.
    Bakris G (2009) An in-depth analysis of vasodilation in the management of hypertension: focus on adrenergic blockade. J Cardiovasc Pharmacol 53:379–387CrossRefGoogle Scholar
  71. 71.
    Sponer G, Strein K, Bartsch W, Muller-Beckmann B (1992) Vasodilatory action of carvedilol. J Cardiovasc Pharmacol 19(Suppl 1):S5–S11CrossRefGoogle Scholar
  72. 72.
    Hardman HF, Haavik CO, Seevers MH (1973) Relationship of the structure of mescaline and seven analogs to toxicity and behavior in five species of laboratory animals. Toxicol Appl Pharmacol 25:299–309CrossRefGoogle Scholar
  73. 73.
    Brown PL, Kiyatkin EA (2004) Brain hyperthermia induced by MDMA (“ecstasy”): modulation by environmental conditions. Eur J Neurosci 20:51–58CrossRefGoogle Scholar
  74. 74.
    Hysek C, Schmid Y, Rickli A, Simmler L, Donzelli M, Grouzmann E et al (2012) Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans. Br J Pharmacol 166:2277–2288CrossRefPubMedGoogle Scholar
  75. 75.
    Shioda K, Nisijima K, Yoshino T, Kuboshima K, Iwamura T, Yui K et al (2008) Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats. Neurotoxicology 29:1030–1036CrossRefGoogle Scholar
  76. 76.
    Taffe MA (2012) Delta9-Tetrahydrocannabinol attenuates MDMA-induced hyperthermia in rhesus monkeys. Neuroscience 201:125–133CrossRefGoogle Scholar
  77. 77.
    Yeh SY (1997) Effects of salicylate on 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity in rats. Pharmacol Biochem Behav 58:701–708CrossRefGoogle Scholar
  78. 78.
    Kiyatkin EA, Kim AH, Wakabayashi KT, Baumann MH, Shaham Y (2016) Clinically relevant pharmacological strategies that reverse MDMA-induced brain hyperthermia potentiated by social interaction. Neuropsychopharmacology 41:549–559CrossRefGoogle Scholar
  79. 79.
    Dao CK, Nowinski SM, Mills EM (2014) The heat is on: molecular mechanisms of drug-induced hyperthermia. Temperature 1:183–191CrossRefGoogle Scholar
  80. 80.
    Lindt S, Lauener H, Eichenberger E (1971) The toxicology of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b, e)(1,4)diazepine (clozapine). Farmaco Prat 26:585–602Google Scholar
  81. 81.
    Charkoudian N (2010) Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. J Appl Physiol 109:1221–1228CrossRefPubMedGoogle Scholar
  82. 82.
    Kellogg DL Jr (2006) In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges. J Appl Physiol 100(5):1709–1718CrossRefGoogle Scholar
  83. 83.
    Carvedilol (2012) HSDB [Internet] Bethesda (MD): National Library of Medicine (US). Hazardous Substances Databank Number: 7044. Available from:
  84. 84.
    Liechti ME (2014) Effects of MDMA on body temperature in humans. Temperature 1:192–200CrossRefGoogle Scholar
  85. 85.
    Ruffolo RR Jr, Gellai M, Hieble JP, Willette RN, Nichols AJ (1990) The pharmacology of carvedilol. Eur J Clin Pharmacol 38:S82–S88CrossRefGoogle Scholar
  86. 86.
    Tomlinson B, Cronin CJ, Graham BR, Prichard BN (1987) Haemodynamics of carvedilol in normal subjects compared with propranolol, pindolol, and labetalol. J Cardiovasc Pharmacol 10(Suppl 11):S69–S75CrossRefGoogle Scholar
  87. 87.
    Baumann MH, Zolkowska D, Kim I, Scheidweiler KB, Rothman RB, Huestis MA (2009) Effects of dose and route of administration on pharmacokinetics of (+/-)3.4-methylenedioxymethamphetamine in the rat. Drug Metab Dispos 37:2163–2170CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Behavioral Neuroscience Branch, National Institute on Drug Abuse – Intramural Research Program, NIHBaltimoreUSA

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