Long-term amphetamine administration (5 mg/kg, ip, twice a day for 14 days) profoundly decreased the TRH level in the rat adrenal medulla at 2 h (by ca. 76%), 24 h (by ca. 51%) and 72 h (by ca. 48%) after the last drug injection. Single amphetamine (5 mg/kg ip) had no significant effect on the TRH level in that tissue, as measured at 2 h after the drug injection. Since TRH in the adrenal medulla is thought to exert a paracrine, inhibitory influence on the adrenal cortex, depletion of the peptide content may contribute to a persistent elevation of the plasma corticosterone level following repeated treatment with amphetamine.