Minor tranquilizers have been shown to be specific inhibitors of the elevation of plasma corticosteroid levels in rats subjected to mild stress. The inability of several anxiolytic compounds to show activity at high doses prompted an investigation of the effect on corticosteroid levels of these drugs over a wider dosage range. It was found that at high doses, the drugs themselves cause an elevation of corticosteroid levels masking the blocking of the stress-induced elevations. It was discovered that upon sub-chronic administration, the drug-induced elevation diminishes while the ability to inhibit stress-induced elevation persists. Finally, an extensive dose response curve for phenobarbital demonstrated a variety of responses, depending upon the dose; an antistress effect at low dose, a relatively ineffective dose range from 50-100 mg/kg, and a corticosteroid lowering effect at anesthetic doses. The lack of effect of moderately high doses has been explained through their depressant side effects, which in themselves are stressful to the animal.