The mechanism for the depressor response produced by the repeated administration of dextro‐methamphetamine was studied in rats and rabbits. In the urethane anaesthetized and atropinized rat, the methamphetamine‐induced depressor response was markedly inhibited by α‐adrenoreceptor antagonists or by chronic reserpinization in combination with α‐methyl‐p‐tyrosine, while it was not affected by propranolol. Yohimbine reversed the methamphetamine‐induced depressor response to a pressor one when it was administered during the course of the depressor phase whilst prazosin or phentolamine caused only a further depressor response. In the pithed rat with electrical stimulation of the spinal cord, the first administration of methamphetamine elicited a marked pressor response whereas, following treatment with cocaine, the first administration of methamphetamine produced only a depressor response which was abolished by yohimbine. In the rabbit isolated aorta prelabeled with 3H‐noradrenaline, methamphetamine enhanced the stimulationevoked 3H‐overflow and caused an enhanced contraction. However, in the presence of cocaine, methamphetamine reduced both stimulation‐evoked 3H‐overflow and neurogenic contractions. These findings suggest that the methamphetamine‐induced depressor response results from the inhibition of catecholamine release from noradrenergic nerve terminals probably mediated by the activation of peripheral presynaptic α2‐adrenoreceptors. Copyright © 1983, Wiley Blackwell. All rights reserved