Nicotinamide co-administration with methamphetamine: Effects on the P450 and dopaminergic systems

Abstract

Scope and Method of Study: The adulteration of illicit methamphetamine (MA) with nicotinamide (NIC) has become so prevalent in the United States that researchers must now consider the possibility that NIC may possess some ability to enhance the psychostimulant effects of MA. The purpose of this project was to evaluate the metabolic and dopaminergic sequelae of MA, NIC, and their co- administration (COMBO). The effects of MA, NIC, and their COMBO on human CYP3A4 and CYP2D6 Supersomes and isolated rat liver microsomes (RLM) at 1hr and 7 days post last treatment (1hrPT, 7dayPT, respectfully) was investigated with commercially available kits. The dopaminergic changes were evaluated by measuring [3 H] dopamine uptake, [3 H] dopamine release, dopamine receptor binding ([3 H] raclopride), and dopamine transporter binding ([3 H] GBR12935) at 1hrPT and 7dayPT in two different brain regions, the striatum (STR) and nucleus accumbens (ACC).

Findings and Conclusions: We observed MA and COMBO treated group induced alterations in DA uptake, DA release, and CYP2D-mediated metabolism. Our RLM studies demonstrated significant inhibition with a more rapid return to normal with COMBO treatment. The dopaminergic studies revealed characteristic changes within both brain regions with the COMBO treated group producing a sustained reduction in DA uptake over the MA group in STR. The COMBO also resulted in a significant decrease in the amount of KCL evoked DA released in the STR while both MA and COMBO treatment resulted in an increased amount of basal DA release in both brain regions. Under our experimental conditions, the co-administration of NIC with MA does not produce overwhelming evidence to synergistic metabolic or dopaminergic changes. However, the studies provide an introduction as to the understanding of changes associated with MA and NIC co-administration.