- The mechanism of action of carbon dioxide (CO2) angiogenesis is unknown; only recently have possible serotonergic (5-HT) influences begun to be studied. In separate double-blind challenges 1 week apart, 14 healthy volunteers received two vital capacity inhalations each of 35% CO2 and of air, once after a single capsule of placebo and once after a single capsule containing 4 mg of the 5-HT antagonist metergoline in a randomized crossover design. The inhalations were repeated 1 and 2 days after the ingestion of capsules, to investigate possible delayed effects of metergoline, and possible tolerance to repeated CO2 after placebo. We observed increased anxiety, and a trend for increased plasma noradrenaline (NA), after CO2. CO2 anxiogenesis was significantly enhanced by metergoline. Heart rate increased after both gas mixtures following metergoline administration. Plasma prolactin levels were lower after metergoline. Responses to CO2 did not differ between the day of placebo administration and the two subsequent days; on the days following metergoline administration there were almost no delayed effects. We hypothesize that 5-HT may function as an inhibitor of CO2 anxiogenesis, and that this is opposed by the 5-HT antagonist, metergoline. Absence of tolerance after repeated CO2 argues against psychological explanations of tolerance after other panicogens. Copyright © 2001 John Wiley & Sons, Ltd.