Bath salts use is associated with high rates of abuse, toxicity, and death. Bath salt preparations often contain mixtures of drugs including multiple synthetic cathinones (eg, 3,4-methylenedioxypyrovalerone (MDPV) or 3,4-methylenedioxymethcathinone (methylone)) or synthetic cathinones and caffeine; however, little is known about whether interactions among bath salt constituents contribute to the abuse-related effects of bath salts preparations. This study used male Sprague-Dawley rats responding under a progressive ratio schedule to quantify the reinforcing effectiveness of MDPV, methylone, and caffeine, administered alone and as binary mixtures (n=12 per mixture). Each mixture was evaluated at four ratios (10 : 1, 3 : 1, 1 : 1, and 1 : 3) relative to the mean ED for each drug alone. Dose-addition analyses were used to determine the predicted, additive effect for each dose pair within each drug mixture. MDPV, methylone, and caffeine maintained responding in a dose-dependent manner, with MDPV being the most potent and effective, and caffeine being the least potent and effective of the three bath salts constituents. High levels of responding were also maintained by each of the bath salts mixtures. Although the nature of the interactions tended toward additivity for most bath salts mixtures, supra-additive (3 : 1 MDPV : caffeine, and 3 : 1 and 1 : 1 methylone : caffeine) and sub-additive (3 : 1, 1 : 1, and 1 : 3 MDPV : methylone) interactions were also observed. Together, these findings demonstrate that the composition of bath salts preparations can have an impact on both their reinforcing potency and effectiveness, and suggest that such interactions among constituent drugs could contribute to the patterns of use and effects reported by human bath salts users.

"Bath salts" preparations contain synthetic cathinones which interact with monoamine transporters and function as either monoamine uptake inhibitors or releasers. 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone) were three of the most common cathinones (i.e., "first-generation" cathinones); however, after the US Drug Enforcement Administration placed them under Schedule I regulations, they were replaced with structurally related cathinones that were not subject to regulations (i.e., "second-generation" cathinones). Although the reinforcing effects of some second-generation cathinones have been described (e.g., α-pyrrolidinopentiophenone [α-PVP]), little is known about how structural modifications, particularly those involving the methylenedioxy moiety and α-alkyl side chain, impact the abuse liability of other second-generation cathinones (e.g., α-pyrrolidinopropiophenone [α-PPP], 3,4-methylenedioxy-α-pyrrolidinobutiophenone [MDPBP], and 3,4-methylenedioxy-α-pyrrolidinopropiophenone [MDPPP]). The present study used male Sprague-Dawley rats (n = 12 per drug) to directly compare: (1) the acquisition of responding for α-PVP (0.032 mg/kg/inf), α-PPP (0.32 mg/kg/inf), MDPBP (0.1 mg/kg/inf), and MDPPP (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement; and (2) full dose-response curves for each drug to maintain responding under an FR5 schedule of reinforcement. The average number of days (∼4 days) and percentage (100%) of rats that acquired self-administration was similar for each drug. The observed rank order potency to maintain responding under an FR5 schedule of reinforcement (α-PVP ≈ MDPBP>α-PPP > MDPPP) is consistent with their potencies to inhibit dopamine uptake. These are the first studies to report on the reinforcing effects of the unregulated second-generation cathinones MDPBP, MDPPP, and α-PPP and indicate all three compounds are readily self-administered, suggesting each possesses high potential for abuse. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Rationale: "Bath salts" preparations often contain combinations of synthetic cathinones (e.g., 3,4methylenedioxymethcathinone [methylone], 3,4-methylenedioxypyrovalerone [MDPV]) and caffeine, and evidence suggests that mixtures of synthetic cathinones and caffeine (e.g., MDPV +caffeine or methylone+caffeine) can be more potent and/or effective reinforcers than predicted for an additive interaction. Objective: To use demand curve analyses to compare the reinforcing effectiveness of MDPV and methylone to mixtures of MDPV+caffeine and methylone+caffeine. Methods: Male Sprague-Dawley rats acquired methylone self-administration (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement, and generated full dose-response curves for methylone (0.01-1 mg/kg/inf) under an FR5 schedule of reinforcement. Demand curves were then obtained for methylone, MDPV, caffeine, and methylone+caffeine and MDPV+caffeine mixtures by increasing the FR across sessions according to the following series: 3,

Polysubstance use makes up a majority of drug use, yet relatively few studies investigate the abuse‐related effects of drug mixtures. Dose‐addition analyses provide a rigorous and quantitative method to determine the nature of the interaction (i.e., supraadditive, additive, or subadditive) between two or more drugs. As briefly reviewed here, studies in rhesus monkeys have applied dose‐addition analyses to group level data to characterize the nature of the interaction between the reinforcing effects of stimulants and opioids (e.g., mixtures of cocaine + heroin). Building upon these foundational studies, more recent work has applied dose‐addition analyses to better understand the nature of the interaction between caffeine and illicit stimulants such as MDPV and methamphetamine in rats. In addition to utilizing a variety of operant procedures, including drug discrimination, drug self‐administration, and drug‐primed reinstatement, these studies have incorporated potency and effectiveness ratios as a method for both statistical analysis and visualization of departures from additivity at both the group and individual subject level. As such, dose‐addition analyses represent a powerful and underutilized approach to quantify the nature of drug–drug interactions that can be applied to a variety of abuse‐related endpoints in order to better understand the behavioral pharmacology of polysubstance use.