Psychostimulants and brain edema

  • Ricardo Alexandre Leitão IBILI & Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra
  • Ana Paula Silva IBILI & Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra


Psychostimulants consumption is a serious social and health problem worldwide. The increase in drug abuse has a huge socio-economic impact in society, and more precisely carries great costs in health treatments. In fact, it is well known that cocaine, 3,4-methylenedioxymethamphetamine (MDMA), amphetamine (AMPH) and methamphetamine (METH) have several neurotoxic effects, such as neurodegeneration, neuroinflammation and blood-brain barrier (BBB) disruption. Additionally, the increase of brain water content, a pathological condition also known as brain edema, has been associated with drugs use. Disturbances in the well-regulated water homeostasis may occur under several pathological conditions leading to severe alterations in brain function. Although several studies demonstrated a link between the abuse of psychostimulants and brain edema, very little is known about the underlying mechanisms that explain such brain alterations.

The water transport across cell membrane is regulated by bi-directional water channels called aquaporins (AQPs). Noteworthy, the AQP4 channel has an important role in water transport across BBB, being one of the most important at the Central Nervous System (CNS). In fact, alterations in AQP4 can originate cerebral edema due to abnormal increase in water content and consequent brain swelling. Furthermore, inflammatory mediators also seem to have a role in brain edema formation since the modulation of their action has a beneficial impact in brain edema outcome.

With the present review, we aim to summarize relevant information regarding the impact of psychostimulants on brain edema. Nevertheless, it is also evident that many questions remain unanswered. Thus, in order to improve the clinical outcome of human abusers, it is of crucial importance to understand what the role of AQP4 is. 


Abdul-Muneer, P. M., Chandra, N., & Haorah, J. (2015). Interactions of Oxidative Stress and Neurovascular Inflammation in the Pathogenesis of Traumatic Brain Injury. Molecular Neurobiology, 51(3), 966-979.
Adeva, M. M., Souto, G., Donapetry, C., Portals, M., Rodriguez, A., & Lamas, D. (2012). Brain edema in diseases of different etiology. Neurochemistry International, 61(2), 166-174.
Ago, M., Ago, K., Hara, K., Kashimura, S., & Ogata, M. (2006). Toxicological and histopathological analysis of a patient who died nine days after a single intravenous dose of methamphetamine: a case report. Legal Medicine (Tokyo), 8(4), 235-239.
Asai, H., Kakita, H., Aoyama, M., Nagaya, Y., Saitoh, S., & Asai, K. (2013). Diclofenac enhances proinflammatory cytokine-induced aquaporin-4 expression in cultured astrocyte. Cellular and Molecular Neurobiology, 33(3), 393-400.
Bailey, D. M., Bartsch, P., Knauth, M., & Baumgartner, R. W. (2009). Emerging concepts in acute mountain sickness and high-altitude cerebral edema: from the molecular to the morphological. Cellular and Molecular Life Sciences, 66(22), 3583-3594.
Barroso-Moguel, R., Mendez-Armenta, M., Villeda-Hernandez, J., Nava-Ruiz, C., & Santamaria, A. (2002). Brain lesions induced by chronic cocaine administration to rats. Progress in Neuro-psychopharmacology & Biological Psychiatry, 26(1), 59-63.
Barroso-Moguel, R., Villeda-Hernandez, J., Mendez-Armenta, M., & Rios, C. (1997). Brain capillary lesions produced by cocaine in rats. Toxicology Letters, 92(1), 9-14.
Berankova, K., Habrdova, V., Balikova, M., & Strejc, P. (2005). Methamphetamine in hair and interpretation of forensic findings in a fatal case. Forensic Science International, 153(1), 93-97.
Candelario-Jalil, E., Taheri, S., Yang, Y., Sood, R., Grossetete, M., Estrada, E. Y., Fiebich, B. L., & Rosenberg, G. A. (2007). Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. Journal of Pharmacology and Experimental Therapeutics, 323(2), 488-498.
Chen, F., Ohashi, N., Li, W., Eckman, C., & Nguyen, J. H. (2009). Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure. Hepatology, 50(6), 1914-1923.
Claffey, C. (2011). A 26-year-old woman with sudden onset cerebral edema. Journal of Emergency Nursing, 37(1), 55-56.
Ding, R., Chen, Y., Yang, S., Deng, X., Fu, Z., Feng, L., Cai, Y., Du, M., Zhou, Y., & Tang, Y. (2014). Blood-brain barrier disruption induced by hemoglobin in vivo: Involvement of up-regulation of nitric oxide synthase and peroxynitrite formation. Brain Research, 1571, 25-38.
Fraser, J. A., Peacher, D. F., Freiberger, J. J., Natoli, M. J., Schinazi, E. A., Beck, I. V., Walker, J. R., Doar, P. O., Boso, A. E., Walker, A. J., Kernagis, D. N., & Moon, R. E. (2011). Risk factors for immersion pulmonary edema: hyperoxia does not attenuate pulmonary hypertension associated with cold water-immersed prone exercise at 4.7 ATA. Journal of Applied Physiology (1985), 110(3), 610-618.
Ghatol, A., & Kazory, A. (2012). Ecstasy-associated acute severe hyponatremia and cerebral edema: a role for osmotic diuresis? The Journal of Emergency Medicine, 42(6), e137-140.
Gonçalves, J., Baptista, S., & Silva, A. P. (2014). Psychostimulants and brain dysfunction: A review of the relevant neurotoxic effects. Neuropharmacology, 87C, 135-149.
Gyori, E., & Lew, E. O. (2007). Unsuspected central nervous system gummas in a case of "cerebral infarct" associated with cocaine use. The American Journal of Forensic Medicine and Pathology, 28(3), 208-211.
Hackett, P. H. (1999). High altitude cerebral edema and acute mountain sickness. A pathophysiology update. Advances in Experimental Medicine and Biology, 474, 23-45.
Harring, T. R., Deal, N. S., & Kuo, D. C. (2014). Disorders of sodium and water balance. Emergency Medicine Clinics of North America, 32(2), 379-401.
Heiss, J. D., Papavassiliou, E., Merrill, M. J., Nieman, L., Knightly, J. J., Walbridge, S., Edwards, N. A., & Oldfield, E. H. (1996). Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. The Journal of Clinical Investigation, 98(6), 1400-1408.
Horowitz, M., & Robinson, S. D. (2007). Heat shock proteins and the heat shock response during hyperthermia and its modulation by altered physiological conditions. Progress in Brain Research, 162, 433-446.
Igarashi, H., Huber, V. J., Tsujita, M., & Nakada, T. (2011). Pretreatment with a novel aquaporin 4 inhibitor, TGN-020, significantly reduces ischemic cerebral edema. Neurological Sciences, 32(1), 113-116.
Kalantar-Zadeh, K., Nguyen, M. K., Chang, R., & Kurtz, I. (2006). Fatal hyponatremia in a young woman after ecstasy ingestion. Nature Clinical Practice Nephrology, 2(5), 283-288, quiz 289.
Khanna, A., Kahle, K. T., Walcott, B. P., Gerzanich, V., & Simard, J. M. (2014). Disruption of ion homeostasis in the neurogliovascular unit underlies the pathogenesis of ischemic cerebral edema. Translation Stroke Research, 5(1), 3-16.
Kim, J. E., Ryu, H. J., & Kang, T. C. (2013). Status epilepticus induces vasogenic edema via tumor necrosis factor-alpha/ endothelin-1-mediated two different pathways. PLoS One, 8(9), e74458.
Kitamura, O. (2009). Detection of methamphetamine neurotoxicity in forensic autopsy cases. Legal Medicine (Tokyo), 11 Suppl 1, S63-65.
Kiyatkin, E. A., Brown, P. L., & Sharma, H. S. (2007). Brain edema and breakdown of the blood-brain barrier during methamphetamine intoxication: critical role of brain hyperthermia. European Journal Neuroscience, 26(5), 1242-1253.
Kiyatkin, E. A., & Sharma, H. S. (2011). Expression of heat shock protein (HSP 72 kDa) during acute methamphetamine intoxication depends on brain hyperthermia: neurotoxicity or neuroprotection? Journal of Neural Transmission, 118(1), 47-60.
Kramer, L., Bauer, E., Schenk, P., Steininger, R., Vigl, M., & Mallek, R. (2003). Successful treatment of refractory cerebral oedema in ecstasy/cocaine-induced fulminant hepatic failure using a new high-efficacy liver detoxification device (FPSA-Prometheus). Wiener Klinische Wochenschrift, 115(15-16), 599-603.
Krasnova, I. N., & Cadet, J. L. (2009). Methamphetamine toxicity and messengers of death. Brain Research Reviews, 60(2), 379-407.
Liu, L., Lu, Y., Kong, H., Li, L., Marshall, C., Xiao, M., Ding, J., Gao, J., & Hu, G. (2012). Aquaporin-4 deficiency exacerbates brain oxidative damage and memory deficits induced by long-term ovarian hormone deprivation and D-galactose injection. International Journal of Neuropsychopharmacology, 15(1), 55-68.
Liu, S., Zhu, S., Zou, Y., Wang, T., & Fu, X. (2014a). Knockdown of IL-1beta Improves Hypoxia-ischemia Brain Associated with IL-6 Up-regulation in Cell and Animal Models. Molecular Neurobiology.
Liu, Y., Tang, G., Li, Y., Wang, Y., Chen, X., Gu, X., Zhang, Z., Wang, Y., & Yang, G. Y. (2014b). Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion. Journal of Neuroinflammation, 11, 177.
Manley, G. T., Fujimura, M., Ma, T., Noshita, N., Filiz, F., Bollen, A. W., Chan, P., & Verkman, A. S. (2000). Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nature Medicine, 6(2), 159-163.
Matthai, S. M., Davidson, D. C., Sills, J. A., & Alexandrou, D. (1996). Cerebral oedema after ingestion of MDMA ("ecstasy") and unrestricted intake of water. British Medical Journal, 312(7042), 1359.
Nag, S., Manias, J. L., & Stewart, D. J. (2009). Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol, 118(2), 197-217.
Northrop, N. A., & Yamamoto, B. K. (2012). Persistent neuroinflammatory effects of serial exposure to stress and methamphetamine on the blood-brain barrier. Journal of NeuroImmune Pharmacology, 7(4), 951-968.
Panahpour, H., Dehghani, G. A., & Bohlooli, S. (2014). Enalapril attenuates ischaemic brain oedema and protects the blood-brain barrier in rats via an anti-oxidant action. Clinical and Experimental Pharmacology and Physiology, 41(3), 220-226.
Papadopoulos, M. C., Manley, G. T., Krishna, S., & Verkman, A. S. (2004). Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. The Journal of the Federation of American Societies for Experimental Biology, 18(11), 1291-1293.
Papadopoulos, M. C., & Verkman, A. S. (2013). Aquaporin water channels in the nervous system. Nature Reviews Neuroscience, 14(4), 265-277.
Rajkowska, G., Hughes, J., Stockmeier, C. A., Javier Miguel-Hidalgo, J., & Maciag, D. (2013). Coverage of blood vessels by astrocytic endfeet is reduced in major depressive disorder. Biological Psychiatry, 73(7), 613-621.
Ratilal, B. O., Arroja, M. M., Rocha, J. P., Fernandes, A. M., Barateiro, A. P., Brites, D. M., Pinto, R. M., Sepodes, B. M., & Mota-Filipe, H. D. (2014). Neuroprotective effects of erythropoietin pretreatment in a rodent model of transient middle cerebral artery occlusion. Journal of Neurosurgery, 121(1), 55-62.
Sauvageau, A. (2008). Death from a possible anaphylactic reaction to ecstasy. Clinical Toxicology (Philadelphia), 46(2), 156.
Sharma, H. S., & Ali, S. F. (2008). Acute administration of 3,4-methylenedioxymethamphetamine induces profound hyperthermia, blood-brain barrier disruption, brain edema formation, and cell injury. Annals of the New York Academy of Science, 1139, 242-258.
Sharma, H. S., & Kiyatkin, E. A. (2009). Rapid morphological brain abnormalities during acute methamphetamine intoxication in the rat: an experimental study using light and electron microscopy. Journal of Chemical Neuroanatomy, 37(1), 18-32.
Silva, A. P., Martins, T., Baptista, S., Gonçalves, J., Agasse, F., & Malva, J. O. (2010). Brain injury associated with widely abused amphetamines: neuroinflammation, neurogenesis and blood-brain barrier. Current Drug Abuse Reviews, 3(4), 239-254.
Tait, M. J., Saadoun, S., Bell, B. A., & Papadopoulos, M. C. (2008). Water movements in the brain: role of aquaporins. Trends in Neuroscience, 31(1), 37-43.
Trevisan, E., Bertero, L., Bosa, C., Magistrello, M., Pellerino, A., Ruda, R., & Soffietti, R. (2014). Antiangiogenic therapy of brain tumors: the role of bevacizumab. Neurological Sciences, 35(4), 507-514.
UNODC. (2014). World Drug Report 2014.
Walcott, B. P., Kahle, K. T., & Simard, J. M. (2012). Novel treatment targets for cerebral edema. Neurotherapeutics, 9(1), 65-72.
Westman, J., Drieu, K., & Sharma, H. S. (2000). Antioxidant compounds EGB-761 and BN-520 21 attenuate heat shock protein (HSP 72 kD) response, edema and cell changes following hyperthermic brain injury. An experimental study using immunohistochemistry in the rat. Amino Acids, 19(1), 339-350.
Zelenina, M. (2010). Regulation of brain aquaporins. Neurochemistry International, 57(4), 468-488.
Avaliação e Intervenção em Saúde