Chloroephedrine: contaminant of methamphetamine synthesis with cardiovascular activity.

Chloroephedrine is an intermediate and possible contaminant formed when methamphetamine is manufactured using ephedrine or pseudoephedrine as precursors. The purpose of this study was to determine whether this contaminant has biological activity and might contribute to methamphetamine-induced cardiovascular toxicity. In conscious rats, the (-) and (+) isomers of chloroephedrine (0.1 and 1.0 mg/kg, i.v.) dose-dependently increased mean arterial pressure (MAP) and heart rate (HR). The potency of the pressor effects of (-) and (+)-chloroephedrine was between that of ephedrine and pseudoephedrine. The increases in HR elicited by the four stimulants were similar except that the tachycardia elicited by all doses of ephedrine and pseudoephedrine were preceded by a brief decrease in HR. The i.v. administration of 10 mg/kg of (+) or (-)-chloroephedrine produced biphasic (decrease followed by increase) the MAP and HR responses. Ephedrine and pseudoephedrine did not decrease MAP at any dose tested. The initial decrease in HR elicited by (-)-chloroephedrine was significantly reduced and the hypotensive response abolished by atropine, indicating that these components of the MAP and HR responses resulted from vagal activation. The secondary pressor response elicited by (-)-chloroephedrine was significantly reduced and the tachycardia significantly increased by pretreatment with phentolamine (3 mg/kg, i.v.). The increase in HR was reversed by propranolol. These results indicate that (-) and (+)-chloroephedrine have sympathomimetic properties similar to other known sympathomimetic stimulants. In addition, larger doses of chloroephedrine can activate the vagus nerve. The combination of (+)-methamphetamine and (-)-chloroephedrine did not markedly alter the magnitude of the MAP and HR responses of (+)-methamphetamine alone except at high doses of (-)-chloroephedrine (10 mg/kg). Contamination of illicit methamphetamine with chloroephedrine may have toxic consequences.

Cardiovascular and sympathetic responses and reflex changes elicited by MDMA.

The recreational use of 3,4-methylenedioxymethamphetamine (MDMA) has increased as have the number of clinical reports linking MDMA use with cardiovascular toxicity. Nonetheless, the cardiovascular and sympathetic nerve responses elicited by MDMA have not been well characterized. The purpose of this study was to characterize the mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve responses elicited by the acute administration of MDMA and to determine whether neurotoxic doses of MDMA change cardiovascular and/or cardiovascular reflex function. In conscious rats, MDMA or d-amphetamine elicited similar dose-dependent increases in MAP. MDMA elicited significant bradycardia at doses above 1.0 mg/kg. Pretreatment with phentolamine significantly reduced the duration but not the magnitude of the pressor response elicited by MDMA. In pentobarbital-anesthetized rats, MDMA (0.1 mg/kg) increased renal sympathetic nerve activity (RSNA; 33 +/- 10%), while larger doses significantly decreased RSNA (-91 +/- 3%, max). Neurotoxic doses of MDMA (20 mg/kg, s.c., b.i.d. for 4 days) significantly enhanced the bradycardic component of the Bezold-Jarisch reflex elicited by i.v. serotonin when tested either 2 days or 2 weeks after the last neurotoxic treatment. However, neurotoxic treatment did not significantly affect baroreceptor reflex function. These results indicate that the acute administration of MDMA and d-amphetamine produce similar cardiovascular and sympathetic responses. Neurotoxic doses of MDMA can also significantly alter cardiovascular reflex function. These findings raise the possibility that MDMA may have the potential to produce cardiovascular and/or cardiac toxicity similar to that elicited by other amphetamine analogs.