A series of substituted phenylethylamines were examined for their relative potencies to 1) release and inhibit accumulation of labeled serotonin in brain synaptosomes, 2) compete with serotonin receptor binding and 3) induce the "serotonin syndrome" in mice. In general, the relative potencies of the phenylethylamine derivatives to produce the serotonin syndrome did not correlates well with their effects on synaptosomal uptake or release of serotonin or serotonin receptor binding. However, para chloro substitution was more effective than meta or ortho chlorophenylethylamine and para methoxy substitution more effective than ortho methoxyphenylethylamine for [3H]serotonin uptake inhibition and release and induction of the serotonin syndrome. Lineweaver Burk kinetic analysis indicated that para chlorophenylethylamine was a competitive inhibitor of [3H]serotonin uptake in vitro with a Ki of 4.3 x 10(-7) M. Fluoxetine, a specific serotonin uptake inhibitor, blocked p-chlorophenylethylamine and p-methoxyphenylethylamine-induced [3H]serotonin release. The ability of phenylethylamine derivatives to release preferentially [3H]serotonin in vitro without damaging serotonergic neurons and to consistently and rapidly produce the serotonin syndrome in vivo should make these compounds useful pharmacological tools for investigating brain serotonin metabolism.