Drug acting on brain monoamines (5HT) were tested on EH sufferers. Fenfluramine, an anorectic agent, acts principally on brain 5HT. This drug, when given to EH sufferers, precipitates and aggravates pain. The headache provoked by fenfluramine is tachyphylactic, suggesting involvement of central transmitters. Therapeutic doses of fenfluramine do not affect blood vessel diameter. This further supports a biochemical mechanism for fenfluramine headache. A reversible systemic pain syndrome has been observed in two EH sufferers, treated chronically with fenfluramine. This syndrome appears indistinguishable from that previously observed in EH sufferers, given parachlorophenylalanine, an inhibitor of 5HT synthesis. The effect of fenfluramine supports the hypothesis that established and other experimental anti-migraine drugs act centrally by correcting abnormalities in the 5HT nociceptive system.