Several drugs that inhibit the effects of serotonin may reduce or prevent experimental CNS ischemic damage, but these drugs are not approved for human use in the United States. Administration of cyproheptadine (which is available for clinical use) 15 minutes before or 5 minutes after the onset increased the duration of experimental rabbit spinal cord ischemia required to produce irreversible paraplegia. Drugs thought to be serotonin agonists did not aggravate the damage, but bufotenin reversed protective effect of cyproheptadine. The results suggest that serotonin antagonists reduce ischemic CNS damage; cyproheptadine may be a potential treatment for ischemic stroke.