The mechanism of action of ACTH and corticosteroids is not known. Administration of ACTH can control spasms in patients with adrenal suppression, suggesting that the effect is independent of adrenal corticosteroid release. Corticotropin may have direct anticonvulsant effects, perhaps via suppression of corticotropin releasing hormone (CRH), an endogenous neuropeptide that may provoke convulsions in immature brain. This theory was suggested by a report in which administration of high-dose ACTH to rats resulted in a reduction of the expression of the CRH gene in amygdala. This reduction occurred in animals with and without adrenalectomy and thus was independent of endogenous cortisol production. The effect was reproduced by a peptide fragment of ACTH without corticotrophic activity and abolished by a melanocortin receptor antagonist. In preliminary investigations, ACTH fragments and CRH receptor antagonists have not been effective in patients with intractable IS. However, this result may occur in part because these peptides are not absorbed or do not cross the blood-brain barrier.