Cardiovascular and Locomotor Effects of Binary Mixtures of Common Bath Salts Constituents: Studies with Methylone, MDPV, and Caffeine in Rats

Abstract

Background and PurposeThe use of "Bath Salts" drug preparations has been associated with high rates of toxicity and death. Preparations often contain mixtures of drugs including multiple synthetic cathinones or synthetic cathinones and caffeine; however, little is known about whether interactions among "Bath Salts" constituents contribute to the adverse effects often reported in users. Experimental ApproachThis study used adult male Sprague-Dawley rats to characterize the cardiovascular effects, locomotor effects, and pharmacokinetics of methylone, MDPV, and caffeine, administered alone and as binary mixtures. Dose-addition analyses were used to determine the effect levels predicted for a strictly additive interaction for each dose pair. Key ResultsMethylone, MDPV, and caffeine increased heart rate and locomotion, with methylone producing the largest increase in heart rate, MDPV producing the largest increase in locomotor activity, and caffeine being the least effective in stimulating heart rate and locomotor activity. MDPV and caffeine increased mean arterial pressure, with caffeine being more effective than MDPV. The nature of the interactions between methylone and MDPV tended toward sub-additivity for all endpoints, whereas interactions between MDPV or methylone and caffeine tended to be additive or sub-additive for cardiovascular endpoints, and additive or supra-additive for increases in locomotion. No pharmacokinetic interactions were observed between individual constituents, but methylone displayed non-linear pharmacokinetics at the largest dose evaluated. Conclusion and ImplicationsThese findings demonstrate that the composition of "Bath Salts" preparations can impact both cardiovascular and locomotor effects and suggest that such interactions among constituent drugs could contribute to the "Bath Salts" toxidrome reported by human users. What is already known"Bath Salts" preparations are associated with a sympathomimetic toxidrome in human users. What this study addsCharacterization of both pharmacokinetic and pharmacodynamic interactions between common "Bath Salts" constituents with regard to cardiovascular and locomotor effects. Clinical SignificanceThe vast majority of drug overdose deaths involve more than one substance. Though these studies focused on combinations of stimulant drugs, they provide direct evidence that the toxidrome resulting from multi-drug overdoses can be significantly different than would be expected for a single drug.