The effects of removal of thyroid or hypophyseal tissue on MDMA-induced hyperthermia were examined in rats given a single dose of 40 mg/kg MDMA. Thyroparathyroidectomized (TX), hypophysectomized (HYPO) and sham operated rats were compared after MDMA or saline, with rats in an environment maintained at 23 deg C. The researchers measured core (body) temperature rectally and skeletal temperature via probe in biceps. They assessed striatal and hippocampal serotonin via high performance liquid chromatography (HPLC) in brains removed from rats killed 4 days (in TX rats) to 7 days post-drug (in all other conditions). The researchers assayed blood levels of T4 (a thyroid hormone) in a separate group of anesthetized rats given 40 mg/kg MDMA or saline. As expected, MDMA induced hyperthermia (as measured both in core and skeletal temperature), but a statistically significant decrease in core and skeletal temperature was seen after MDMA in hypophysectomized animals, and thyroparathyroidectomized animals also showed hypothermia after MDMA. Removal of hypophyseal or thyroid tissue also greatly reduced or eliminated MDMA-associated reduction in striatal and hippocampal serotonin. Giving TX rats levothyroxine (100 mcg/kg for 5 days) reinstated hyperthermia, though still not to the degree as seen in sham-treated rats given MDMA alone. Treatment with prazosin (an alpha1-adrenergic antagonist) attenuated MDMA-induced hyperthermia without producing temperature changes on its own, and it potentiated hypothermia in MDMA-treated thyroparathoidectomized rats. Prazosin also attenuated skeletal temperature 3 h after MDMA (but not 1 or 2 h afterwards). The Beta3-adrenergic antagonist cyanopindolol reduced skeletal temperature, but not core temperature, after MDMA. T4 levels were elevated after MDMA. The authors hypothesize that the HPA axis activity, particularly in the thyroid, may be involved in producing MDMA-induced hyperthermia. Because both alpha1 and beta3 adrenergic receptor antagonists attenuated hyperthermia, the researchers also hypothesize that sympathetic system activity is involved in MDMA-induced hyperthermia as well. The authors noted that alpha1 and Beta3 adrenergic antagonists differentially influenced body temperature, and that administering the two drugs together completely abolished MDMA-induced hyperthermia. Study findings suggest that non-shivering heat production (metabolic) heat production may be involved in MDMA-induced hyperthermia as well as shivering heat producing. (The authors discuss data (presented but unpublished) indicating that MDMA can regulate mRNA levels for uncoupling proteins, involved in body heat production (thermogenesis). These findings lead them to conclude that Ecstasy users with hyperthermia should be treated with a combination of sympatholytic drugs (those that reduce sympathetic system activity). Study findings also support a relationship between hyperthermia and MDMA neurotoxicity. It is important to note that the dose used in this study is far above the dose commonly consumed by humans. Hence it is unclear as to whether similar mechanisms underlie or are partly involved in hyperthermia seen in ecstasy users. Since hyperthermia in humans may also be related to behaviors such as dancing for extended periods of time without fluid replacement or to "serotonin syndrome," the significance of these findings in understanding the causes of ecstasy-related hyperthermia in humans remains uncertain.