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Here, we determined the extent of hypothalamic-pituitary-thyroid (HPT) axis and uncoupling protein-3 (UCP3) involvement in methamphetamine (METH)-induced hyperthermia. Sprague–Dawley rats treated with METH (40 mg/kg, s.c.) responded with a hyperthermic response that peaked 1 h post-treatment and was sustained through 2 h. After METH treatment, thyroparathyroidectomized (TX) animals developed hypothermia that was sustained for the 3 h monitoring period. In TX animals supplemented for 5 days with levothyroxine (100 μg/kg, s.c.), METH-induced hypothermia was eliminated and the hyperthermic response was restored. Thyroid hormone levels (T3 and T4), measured in euthyroid animals 1 h after METH, remained unchanged. As seen in rats, 1 h post-METH (20 mg/kg, i.p.) treatment, wild-type (WT) mice developed profound hyperthermia that was sustained for 2 h. In marked contrast, UCP3−/− animals developed a markedly blunted hyperthermic response at 1 h compared to WT animals. Furthermore, UCP3−/− mice could not sustain this slight elevation in temperature. Two hours post-METH treatment, UCP3−/− animal temperature returned to baseline temperatures. UCP3−/− mice were also completely protected against the lethal effects of METH, whereas 40% of WT mice succumbed to the hyperthermia. These findings suggest that thyroid hormone plays a permissive role in the thermogenic effects induced by METH. Furthermore, the findings indicate that UCP3 plays a major role in the development and maintenance of the hyperthermia induced by METH. The relationship of these results to the hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is also discussed.