Endogenous peptides with opioid-like activity and some of their metabolites modulate the central effects of various neurotransmitters. This has raised the possibility that alterations in leucine-enkephalin (LEU) metabolism, resulting in significant changes in its bioavailability, may influence the course of some conditions characterized by abnormal synaptic transmission. We have tested this hypothesis by determining kinetic parameters, as well as by identifying the products, from the in vitro plasma LEU degradation by samples obtained from various patient populations. The effect of various psychotropic drugs upon this reaction was also studied. Subjects included male chronic schizophrenics (n = 15), chronic users of various drugs of addiction, including (n = 9) or excluding (n = 8) alcohol, chronic alcoholics (n = 12) and female migraineurs (n = 10) during or outside of an acute migraine episode; for comparison we used a group of sex-matched (20 males and 10 females), age-comparable, drug-free, healthy volunteers. LEU was rapidly and completely metabolized in each and every one of the samples studied. Neither gender (64 males and 20 females sample tested individually), age (males and females range of 23 to 70 and 25 to 65 years, respectively), nor subjects medical condition appeared to make a significant difference in either the t12 of LEU elimination, the Iv of this reaction (x ± SD, median, minimum and maximum of 12.0 min ± 0.9, 12.0 min and 10.6 to 13.7 min, and 1.2 pg/min ± 0.3, 1.1 pg/min, and 0.6 to 2.0 pg/min, respectively), or in the Km and Vmax values for aminopeptidase LEU degradation (x ± SD; 0.81 mM ± 0.01 and 14.30 umol/L/min ± 1.17, respectively). LEU degradation was strongly inhibited by aminopeptidase inhibitors, by some selected neuroleptics and specific serotonin reuptake inhibitors, and to a lesser extent by various L-tyrosine-containing LEU fragments. The kinetics of this reaction was not significantly affected by either thiorphan, N-carboxyphenylmethyl leucine or any other of a number of monoamine neurotransmitters, substances of abuse, nonsteroidal antiinflammatory agents, triptan-type antimigraine agents and miscellaneous compounds tested. The possible relevance of these results in explaining some of the differences in the pharmacological profile of the drugs studied will be discussed.