Physiological Effects of Binary Mixtures of Common Bath Salt Constituents: Studies with MDPV, Methylone, and Caffeine in Rats.

It is becoming increasingly clear among treatment providers, policy makers, and basic scientists alike, that polysubstance abuse is the norm rather than the exception. This is supported by the increased incidence of drug mixtures in drug overdoses, both fatal and nonfatal. In particular, toxicity produced via use of multiple substances has been highlighted by "bath salts" mixtures, often comprising at least one synthetic cathinone (e.g. 3,4-methylenedioxypyrovalerone [MDPV] or 3,4-methylenedioxy-N-methylcathinone [methylone]), in addition to other stimulants such as caffeine. Use of these drug mixtures has garnered much attention in the popular press due to frequent reports of bizarre behaviors, and adverse psychiatric (paranoia, hallucinations, aggression) and physiological (tachycardia, hypertension, hyperthermia) events leading to large numbers of emergency room visits and/or death. Although synergistic interactions between the reinforcing effects of common "bath salts" constituents have been observed (e.g., greater than predicted breakpoints under a progressive ratio schedule of reinforcement and greater economic demand), much less is known regarding interactions between the physiological effects of these drugs. The goal of the current study was to characterize the behavioral, cardiovascular, and thermoregulatory effects of MDPV, methylone, and caffeine, and subsequently, to determine the nature of the interactions between binary mixtures of these drugs. Male Sprague Dawley rats were implanted with an intravenous catheter and a radio-telemetric probe capable of recording core body temperature, heart rate, blood pressure, and locomotor activity. Rats were habituated to the test chamber for one hour before receiving an intravenous infusion of either MDPV (0.032-3.2 mg/kg), methylone (0.1-10 mg/kg), caffeine (0.32-32 mg/kg), or a binary mixture (3:1, 1:1, or 1:3) of methylone+MDPV, methylone+caffeine, or MDPV+caffeine. Recordings continued for six hours following drug administration. MDPV, methylone, and caffeine produced dose-dependent increases in core body temperature (caffeine > MDPV > methylone), blood pressure (MDPV > caffeine > methylone), heart rate (methylone > MDPV > caffeine), and locomotor activity (MDPV > caffeine = methylone) relative to baseline measurements. MDPV was more potent than methylone, which was more potent than caffeine. Binary mixtures of methylone+MDPV, methylone+caffeine, and MDPV+caffeine resulted in largely additive interactions across all endpoints, with possible departures from additivity observed at the largest dose-pairs evaluated. These data demonstrate that intravenous administration of either MDPV, methylone, or caffeine alters temperature, heart rate, blood pressure, and locomotor activity in a dose-dependent manner, consistent with what has been reported in "bath salts" users in emergency room settings. To more deeply characterize the interactions between these constituents, future studies will determine the degree to which the reinforcing and physiological effects of these drug mixtures could be mediated by pharmacokinetic interactions between individual constituents.