Examination of patients with various forms of anxiety and phobic disorders (according to DSM-4 criteria) demonstrated a considerable shortening of enkephalin half-life and reduced total enkephalinase activity in the blood during generalized anxiety, but not during panic disorders and agoraphobia. This was probably related to low blood concentration of endogenous inhibitors of enkephalin-degrading enzymes in patients with generalized anxiety disorders. Heptapeptide Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), which attenuates behavioral anxiety reactions and does not cause side effects typical of most anxiolytics, dose-dependently inhibited enzymatic hydrolysis of plasma enkephalin (IC50 15 microM). Selank was more potent than peptidase inhibitors bacitracin and puromycin in inhibiting enkephalinases. These results suggest that high efficiency of Selank in the therapy of anxiety and phobic disorders, including generalized anxiety, is due to its ability to inhibit enkephalin hydrolysis.