Abuse‐Related Effects of “Bath Salts” Mixtures: Studies with MDPV, Methylone, and Caffeine in Rats.

Abstract

The recreational use of synthetic cathinones has become a serious public health problem worldwide. In the US, “bath salts” products often contain MDPV (a monoamine transporter inhibitor) or methylone (a monoamine transporter substrate); however, preparations often contain mixtures of multiple synthetic cathinones, or mixtures of a synthetic cathinone and caffeine. In order to determine if the reinforcing effects of mixtures of “bath salts” constituents differed from the reinforcing effects of the constituents alone, adult male Sprague Dawley rats were trained to self‐administer either 0.032 mg/kg/inf MDPV or 0.32 mg/kg/inf methylone under a progressive ratio (PR) schedule of reinforcement. Drug mixtures were based on the concept of dose equivalence, with each pair of drugs evaluated at three ratios (3:1, 1:1, and 1:3) relative to the mean ED50 for each drug. Dose addition analyses were used to calculate predicted effect levels for an additive interaction at each dose pair of each combination of drugs using the Emax, ED50, and slope parameters derived from dose‐response curves obtained in individual rats. Although high levels of responding were maintained by each of the “bath salts” mixtures, the nature of the interaction varied depending upon the constituent drugs. For combinations containing a cathinone and caffeine (MDPV+caffeine and methylone+caffeine), the interactions were generally additive, however, when mixed at a 3:1 ratio of their ED50s the reinforcing effects of both sets of mixtures were found to be supra‐additive. Interestingly, although combining caffeine with MDPV appeared to only increase the potency of the mixture, combining caffeine and methylone significantly increased the reinforcing effectiveness of the a “bath salts” mixture beyond that which would be predicted for an additive interaction. Unlike with combinations of cathinones and caffeine, when MDPV was combined with methylone departures from additivity tended to occur in the sub‐additive direction, with the onset of toxicity observed with larger dose pairs of the MDPV+methylone mixtures. Together, these studies suggest that the reinforcing effects of binary mixtures containing common bath salts constituents (i.e., MDPV, methylone, and caffeine) are generally additive in nature; however, both supra‐additive (MDPV+caffeine and methylone+caffeine) and sub‐additive interactions (MDPV+methylone) can be observed. Although such interactions could account for the high rates of bath salts abuse, further study will be needed to determine if similar interactions exist between these and other bath salts constituents with regard to other abuse‐related and toxic effects.Support or Funding InformationThis study was supported by a National Institutes of Health (NIH) research grant (R01 DA039146) from the National Institute on Drug Abuse (NIDA), as well as the NIH Intramural Research Programs of NIDA and National Institute on Alcohol Abuse and Alcoholism (NIAAA).