The ability of d-fenfluramine, a drug that releases brain serotonin and blocks its reuptake, to relieve premenstrual depression and excessive calorie and carbohydrate intakes was examined in 17 women with premenstrual syndrome. Subjects received d-fenfluramine (15 mg twice daily) or placebo, in random order, during the luteal phases of six menstrual cycles; ie, for three control and three treatment cycles each. Behavior was assessed with the Hamilton Rating Scale for Depression and its Addendum, and intakes of calories and nutrients were measured by allowing subjects unlimited access to isocaloric meal and snack foods rich in carbohydrates or protein. Pre-treatment follicular scores using the Hamilton Rating Scale for Depression and its Addendum were 2.0 +/- 0.5 and 0.5 +/- 0.5 (mean +/- SEM), respectively; corresponding luteal scores were 21.2 +/- 0.8 and 10.2 +/- 0.6 (P less than .0001). Luteal phase intakes of kilocalories, carbohydrates, and fats were also increased above follicular levels (P less than .01). d-Fenfluramine decreased premenstrual Hamilton Rating Scale for Depression and Addendum scores by 62% (P less than .001) and 60% (P less than .001), respectively; placebo reduced them by only 28% (P less than .02) and 30% (P less than .02). d-Fenfluramine also fully suppressed the premenstrual rise in kilocalorie, carbohydrate, and fat intakes (P less than .01).