The vasoactive properties of the novel psychoactive substance methoxetamine

Background: Methoxetamine is an arylcyclohexylamine derivative of ketamine. Analytically confirmed reports of acute methoxetamine toxicity demonstrate that in addition to ketamine-like toxicity, methoxetamine is associated with cerebellar toxicity and acute stimulant effects including tachycardia and hypertension. The mechanisms of the hypertension seen in acute methoxetamine toxicity are not understood. The aim of this study was to investigate the vasoactive properties of methoxetamine at concentrations published in case reports of analytically confirmed acute methoxetamine toxicity (up to 0.2 mg/L).

Methods: Two pulmonary arteries of male Wistar rats were prepared and suspended in a standard tissue bath set-up containing Krebs buffer solution at pH 7.4 that was continuously oxygenated with 95% oxygen/5% carbon dioxide at 37°C. The arteries were pre-contracted with high potassium (45mM) to determine the maximal contractile response. Following washout, a prostaglandin PGH2 analogue U46619 or norepinephrine were added to induce partial contraction approximately 30–50% of maximum. Methoxetamine was then added to achieve concentrations of 0.1 mg/L, 0.2 mg/L and 0.3 mg/L in the organ bath. The contractile response after each dose was then observed.

Results: Contractions of the two arteries were achieved with 10 nanoM of U46619 and 100 microM of norepinephrine respectively. In the artery pre-contracted with U46619, contraction was achieved to 0.47 milli-Newtons (mN). Methoxetamine at concentrations of 0.1 mg/L, 0.2 mg/L and 0.3 mg/L in the tissue bath induced a relaxation response in a dose-dependent fashion of 0.411 mN (cumulative relaxation of 12.5%), 0.395 mN (15.9%) and 0.385 mN (18.1%) respectively. The artery pre-contracted with norepinephrine produced a contraction of 1.568mN. Methoxetamine at concentrations of 0.1 mg/L, 0.2 mg/L and 0.3 mg/L in the tissue bath induced a small contractile response of 1.570 mN (cumulative contraction of 0.14%), 1.596 mN (1.8%) and 1.667 mN (6.3%) respectively.

Discussion: This study suggests that methoxetamine possesses both vasodilating and vasoconstricting properties, depending on the drug used to pre-contract the artery suggesting that there may be more than one mechanism by which methoxetamine produces its vasoactive effects. Further experiments using this and other similar in vitro models may help identify the mechanism by which methoxetamine causes its cardiovascular effects.