Hyperthermia Severely Affects the Vascular Effects of MDMA and Metabolites in the Human Internal Mammary Artery In Vitro

Abstract

3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a recreational drug used worldwide for its distinctive psychotropic effects. Although important cardiovascular effects, such as increased blood pressure and heart rate, have also been described, the vascular effects of MDMA and metabolites and their correlation with hyperthermia (major side effect of MDMA) are not yet fully understood and have not been previously reported. This study aimed at evaluating the effects of MDMA and its main catechol metabolites, alpha-methyldopamine (α-MeDA), N-methyl-alpha-methyldopamine (N-Me-α-MeDA), 5-(glutathion-S-yl)-alpha-methyldopamine [5-(GSH)-α-MeDA] and 5-(glutathion-S-yl)-N-methyl-alpha-methyldopamine [5-(GSH)-N-Me-α-MeDA], on the 5-HT-dependent vasoactivity in normothermia (37 °C) and hyperthermia (40 °C) of the human internal mammary artery (IMA) in vitro. The results showed the ability of MDMA, α-MeDA and N-Me-α-MeDA to exert vasoconstriction of the IMA which was considerably higher in hyperthermic conditions (about fourfold for MDMA and α-MeDA and twofold for N-Me-α-MeDA). The results also showed that all the compounds may influence the 5-HT-mediated concentration-dependent response of IMA, as MDMA, α-MeDA and N-Me-α-MeDA behaved as partial agonists and 5-(GSH)-α-MeDA and 5-(GSH)-N-Me-α-MeDA as antagonists. In conclusion, MDMA abuse may imply a higher cardiovascular risk associated both to MDMA and its metabolites that might be relevant in patients with underlying cardiovascular diseases, particularly in hyperthermia.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Green, A. R., Mechan, A. O., Elliott, J. M., O’Shea, E., & Colado, M. I. (2003). The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacological Reviews, 55(3), 463–508. doi:10.1124/pr.55.3.3.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Capela, J. P., Carmo, H., Remião, F., Bastos, M. L., Meisel, A., & Carvalho, F. (2009). Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: An overview. Molecular Neurobiology, 39(3), 210–271. doi:10.1007/s12035-009-8064-1.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Carvalho, M., Carmo, H., Costa, V. M., Capela, J. P., Pontes, H., Remião, F., et al. (2012). Toxicity of amphetamines: An update. Archives of Toxicology, 86(8), 1167–1231. doi:10.1007/s00204-012-0815-5.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Vollenweider, F. X., Gamma, A., Liechti, M., & Huber, T. (1998). Psychological and cardiovascular effects and short-term sequelae of MDMA (“ecstasy”) in MDMA-naïve healthy volunteers. Neuropsychopharmacology, 19(4), 241–251. doi:10.1016/S0893-133X(98)00013-X.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Mas, M., Farré, M., de la Torre, R., Roset, P. N., Ortuño, J., Segura, J., et al. (1999). Cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-methylenedioxymethamphetamine in humans. Journal of Pharmacology and Experimental Therapeutics, 290(1), 136–145.

    CAS  PubMed  Google Scholar 

  6. 6.

    Ducros, A., Boukobza, M., Porcher, R., Sarov, M., Valade, D., & Bousser, M.-G. (2007). The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain, 130(12), 3091–3101. doi:10.1093/brain/awm256.

    Article  PubMed  Google Scholar 

  7. 7.

    Milroy, C. M., & Parai, J. L. (2011). The histopathology of drugs of abuse. Histopathology, 59(4), 579–593. doi:10.1111/j.1365-2559.2010.03728.x.

    Article  PubMed  Google Scholar 

  8. 8.

    Cole, J. C., & Sumnall, H. R. (2003). Altered states: The clinical effects of ecstasy. Pharmacology and Therapeutics, 98(1), 35–58.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Silva, S., Carvalho, F., Fernandes, E., Antunes, M. J., & Cotrim, M. D. (2016). Contractile effects of 3,4-methylenedioxymethamphetamine on the human internal mammary artery. Toxicology in Vitro, 34, 187–193. doi:10.1016/j.tiv.2016.04.002.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Carvalho, M., Carvalho, F., Remião, F., de Lourdes Pereira, M., Pires-das-Neves, R., & de Lourdes Bastos, M. (2002). Effect of 3,4-methylenedioxymethamphetamine (“ecstasy”) on body temperature and liver antioxidant status in mice: Influence of ambient temperature. Archives of Toxicology, 76(3), 166–172. doi:10.1007/s00204-002-0324-z.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Green, A. R., O’Shea, E., Saadat, K. S., Elliott, J. M., & Colado, M. I. (2005). Studies on the effect of MDMA (“ecstasy”) on the body temperature of rats housed at different ambient room temperatures. British Journal of Pharmacology, 146(2), 306–312. doi:10.1038/sj.bjp.0706318.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Blessing, W. W., Seaman, B., Pedersen, N. P., & Ootsuka, Y. (2003). Clozapine reverses hyperthermia and sympathetically mediated cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (ecstasy) in rabbits and rats. Journal of Neuroscience, 23(15), 6385–6391.

    CAS  PubMed  Google Scholar 

  13. 13.

    Saadat, K. S., Elliott, J. M., Colado, M. I., & Green, A. R. (2004). Hyperthermic and neurotoxic effect of 3,4-methylenedioxymethamphetamine (MDMA) in guinea pigs. Psychopharmacology (Berl), 173(3–4), 452–453. doi:10.1007/s00213-003-1653-1.

    CAS  Google Scholar 

  14. 14.

    Fiege, M., Wappler, F., Weisshorn, R., Gerbershagen, M. U., Menge, M., & Schulte Am Esch, J. (2003). Induction of malignant hyperthermia in susceptible swine by 3,4-methylenedioxymethamphetamine (“ecstasy”). Anesthesiology, 99(5), 1132–1136.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Taffe, M. A., Lay, C. C., Von Huben, S. N., Davis, S. A., Crean, R. D., & Katner, S. N. (2006). Hyperthermia induced by 3,4-methylenedioxymethamphetamine in unrestrained rhesus monkeys. Drug and Alcohol Dependence, 82(3), 276–281. doi:10.1016/j.drugalcdep.2005.09.013.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    He, G.-W. (2013). Arterial grafts: Clinical classification and pharmacological management. Annals of Cardiothoracic Surgery, 2(4), 507–518. doi:10.3978/j.issn.2225-319X.2013.07.12.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Otsuka, F., Yahagi, K., Sakakura, K., & Virmani, R. (2013). Why is the mammary artery so special and what protects it from atherosclerosis? Annals of Cardiothoracic Surgery, 2(4), 519–526. doi:10.3978/j.issn.2225-319x.2013.07.06.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Conti, A., Monopoli, A., Forlani, A., Ongini, E., Antona, C., & Biglioli, P. (1990). Role of 5-HT2 receptors in serotonin-induced contraction in the human mammary artery. European Journal of Pharmacology, 176(2), 207–212.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Tanaka, N., Nakamura, E., Ohkura, M., Kuwabara, M., Yamashita, A., Onitsuka, T., et al. (2008). Both 5-hydroxytryptamine 5-HT2A and 5-HT1B receptors are involved in the vasoconstrictor response to 5-HT in the human isolated internal thoracic artery. Clinical and Experimental Pharmacology and Physiology, 35(7), 836–840. doi:10.1111/j.1440-1681.2008.04933.x.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Capela, J. P., Macedo, C., Branco, P. S., Ferreira, L. M., Lobo, A. M., Fernandes, E., et al. (2007). Neurotoxicity mechanisms of thioether ecstasy metabolites. Neuroscience, 146(4), 1743–1757. doi:10.1016/j.neuroscience.2007.03.028.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Capela, J. P., Meisel, A., Abreu, A. R., Branco, P. S., Ferreira, L. M., Lobo, A. M., et al. (2006). Neurotoxicity of ecstasy metabolites in rat cortical neurons, and influence of hyperthermia. Journal of Pharmacology and Experimental Therapeutics, 316(1), 53–61. doi:10.1124/jpet.105.092577.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Macedo, C., Branco, P. S., Ferreira, L. M., Lobo, A. M., Capela, J. P., Fernandes, E., et al. (2007). Synthesis and cyclic voltammetry studies of 3,4-methylenedioxymethamphetamine (MDMA) human metabolites. Journal of Health Science, 53(1), 31–42.

    CAS  Article  Google Scholar 

  23. 23.

    Liechti, M. E., & Vollenweider, F. X. (2000). The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine (“Ecstasy”) in healthy volunteers. Journal of Psychopharmacology, 14(3), 269–274.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Yildiz, O., Ciçek, S., Ay, I., Tatar, H., & Tuncer, M. (1996). 5-HT1-like receptor-mediated contraction in the human internal mammary artery. Journal of Cardiovascular Pharmacology, 28(1), 6–10.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Bexis, S., & Docherty, J. R. (2006). Effects of MDMA, MDA and MDEA on blood pressure, heart rate, locomotor activity and body temperature in the rat involve alpha-adrenoceptors. British Journal of Pharmacology, 147(8), 926–934. doi:10.1038/sj.bjp.0706688.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Liechti, M. E., Saur, M. R., Gamma, A., Hell, D., & Vollenweider, F. X. (2000). Psychological and physiological effects of MDMA (“Ecstasy”) after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans. Neuropsychopharmacology, 23(4), 396–404. doi:10.1016/S0893-133X(00)00126-3.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Parrott, A. C. (2012). MDMA and temperature: A review of the thermal effects of “Ecstasy” in humans. Drug and Alcohol Dependence, 121(1–2), 1–9. doi:10.1016/j.drugalcdep.2011.08.012.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Mallick, A., & Bodenham, A. R. (1997). MDMA induced hyperthermia: A survivor with an initial body temperature of 42.9 degrees C. Journal of Accident and Emergency Medicine, 14(5), 336–338.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Connolly, E., & O’Callaghan, G. (1999). MDMA toxicity presenting with severe hyperpyrexia: A case report. Critical Care and Resuscitation, 1(4), 368–370.

    CAS  PubMed  Google Scholar 

  30. 30.

    Freedman, R. R., Johanson, C.-E., & Tancer, M. E. (2005). Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl), 183(2), 248–256. doi:10.1007/s00213-005-0149-6.

    CAS  Article  Google Scholar 

  31. 31.

    Zhang, G., & Tao, R. (2011). Enhanced responsivity of 5-HT2A receptors at warm ambient temperatures is responsible for the augmentation of the 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced hyperthermia. Neuroscience Letters, 490(1), 68–71. doi:10.1016/j.neulet.2010.12.028.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Vanhoutte, P. M., Shimokawa, H., Tang, E. H. C., & Feletou, M. (2009). Endothelial dysfunction and vascular disease. Acta Physiologica, 196(2), 193–222. doi:10.1111/j.1748-1716.2009.01964.x.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Battaglia, G., Brooks, B. P., Kulsakdinun, C., & De Souza, E. B. (1988). Pharmacologic profile of MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. European Journal of Pharmacology, 149(1–2), 159–163.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Carvalho, M., Remião, F., Milhazes, N., Borges, F., Fernandes, E., Carvalho, F., et al. (2004). The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine. Toxicology, 200(2–3), 193–203. doi:10.1016/j.tox.2004.03.016.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Capela, J. P., Ruscher, K., Lautenschlager, M., Freyer, D., Dirnagl, U., Gaio, A. R., et al. (2006). Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia. Neuroscience, 139(3), 1069–1081. doi:10.1016/j.neuroscience.2006.01.007.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Parrott, A. C. (2005). Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy. Journal of Psychopharmacology, 19(1), 71–83. doi:10.1177/0269881105048900.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    García-Repetto, R., Moreno, E., Soriano, T., Jurado, C., Giménez, M. P., & Menéndez, M. (2003). Tissue concentrations of MDMA and its metabolite MDA in three fatal cases of overdose. Forensic Science International, 135(2), 110–114.

    Article  PubMed  Google Scholar 

  38. 38.

    Segura, M., Ortuño, J., Farré, M., McLure, J. A., Pujadas, M., Pizarro, N., et al. (2001). 3,4-Dihydroxymethamphetamine (HHMA). A major in vivo 3,4-methylenedioxymethamphetamine (MDMA) metabolite in humans. Chemical Research in Toxicology, 14(9), 1203–1208.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Chu, T., Kumagai, Y., DiStefano, E. W., & Cho, A. K. (1996). Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion. Biochemical Pharmacology, 51(6), 789–796.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Jones, D. C., Duvauchelle, C., Ikegami, A., Olsen, C. M., Lau, S. S., de la Torre, R., et al. (2005). Serotonergic neurotoxic metabolites of ecstasy identified in rat brain. Journal of Pharmacology and Experimental Therapeutics, 313(1), 422–431. doi:10.1124/jpet.104.077628.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Hysek, C., Schmid, Y., Rickli, A., Simmler, L. D., Donzelli, M., Grouzmann, E., et al. (2012). Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans. British Journal of Pharmacology, 166(8), 2277–2288. doi:10.1111/j.1476-5381.2012.01936.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Hysek, C. M., Brugger, R., Simmler, L. D., Bruggisser, M., Donzelli, M., Grouzmann, E., et al. (2012). Effects of the α2-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers. Journal of Pharmacology and Experimental Therapeutics, 340(2), 286–294. doi:10.1124/jpet.111.188425.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge all the support and help in the collection of samples from the nurses of Cardiothoracic Surgery, University Hospital of Coimbra.

Author information

Affiliations

Authors

Corresponding author

Correspondence to D. A. Fonseca.

Ethics declarations

Conflicts of interest

The authors report no conflicts of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fonseca, D.A., Guerra, A.F., Carvalho, F. et al. Hyperthermia Severely Affects the Vascular Effects of MDMA and Metabolites in the Human Internal Mammary Artery In Vitro. Cardiovasc Toxicol 17, 405–416 (2017). https://doi.org/10.1007/s12012-017-9398-y

Download citation

Keywords

  • 3,4-Methylenedioxymethamphetamine
  • MDMA
  • Catecholic metabolites of MDMA
  • 5-Hydroxytryptamine
  • Vascular effects
  • Hyperthermia
  • Human internal mammary artery