Locomotor stimulant and methamphetamine-like interoceptive effects of putative impurity N-ethyl-methamphetamine in rodents: Role of Phase I metabolism.

Over the past 20 years, N-ethyl-methamphetamine (NEM) has been identified in seized methamphetamine (METH) samples. Often considered a byproduct or impurity of illicit METH synthesis, its structural similarity to METH suggests that it may have pharmacological actions of its own or be metabolically converted to METH or amphetamine (AMPH) in vivo. These studies assessed the potency and effectiveness of NEM as a locomotor stimulant compared to METH in NIH Swiss mice, and probed the role of cytochrome P450 (CYP) vs non-CYP metabolism in these locomotor effects using pretreatments with the broad spectrum CYP inhibitor 1-aminobenzotriazole (1-ABT) or the selective CYP2D6 inhibitor quinidine. Blood samples taken from mice treated with NEM, with and without pretreatments of 1-ABT or quinidine, were quantitively analyzed for NEM, METH, and AMPH using Quadrupole Time-of-Flight. Additionally, the discriminative stimulus effects of NEM were assayed in Sprague-Dawley rats trained to discriminate METH from saline. NEM produced dose-dependent locomotor stimulant and METH-like interoceptive effects, but with a slower onset and less potently than METH. Locomotor stimulant effects of NEM were abolished by pretreatment with 1-ABT or quinidine, and both pretreatments also decreased conversion of NEM to METH and AMPH in mouse blood. These data demonstrate METH-like biological effects of NEM and suggest that the likely mechanism for these effects is metabolic conversion of NEM to METH and AMPH via CYP2D6. NEM thus functions as a prodrug for METH and AMPH, and would be expected to have METH-like abuse liability in humans. SIGNIFICANCE STATEMENT: N-ethyl-methamphetamine (NEM) has been identified in seized methamphetamine (METH) samples, and is typically considered a byproduct or impurity of illicit METH synthesis. These studies demonstrate METH-like biological effects of NEM and suggest that the likely mechanism for these effects is metabolic conversion of NEM to METH and AMPH via CYP2D6. NEM thus functions as a prodrug for METH and AMPH, and would be expected to have METH-like abuse liability in humans.