Abstract: Mutations have been discovered in mammalian G protein-coupled serotonin 5-HT2A and 5-HT2C receptors which render the mutated receptors constitutively active. An alignment methodology based on the highly conserved sixth transmembrane domain has been discovered for the monoamine receptors which accurately predicts the amino acid position in the third intracellular loop which, when mutated, produces constitutive activation of the receptor. Constitutive activation of the G protein-coupled serotonin receptors has been shown by the demonstration of an enhanced affinity and potency for serotonin, by increased basal activity of the second messenger system in the absence of agonist, and by reduction of the basal second messenger activity by inverse agonists.