Discriminative Stimulus Effects of Binary Drug Mixtures: Studies with Cocaine, MDPV, and Caffeine

Abstract

Illicit drug preparations often include more than one pharmacologically active compound. For example, cocaine and synthetic cathinones [e.g., 3,4-methylenedioxypyrovalerone (MDPV)] are often mixed with caffeine before sale. Caffeine is likely added to these preparations because it is inexpensive and legal; however, caffeine might also mimic or enhance some of the effects of cocaine or MDPV. In these studies, male Sprague-Dawley rats were trained to discriminate 10 mg/kg cocaine from saline, and the discriminative stimulus effects of cocaine, caffeine, and MDPV were evaluated alone and as binary mixtures (cocaine and caffeine, MDPV and caffeine, and cocaine and MDPV) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the dose of each drug that produced 50% cocaine-appropriate responding. Dose-addition analyses were used to determine the nature of the drug-drug interactions for each mixture (e.g., additive, supra-additive, or subadditive). Although additive interactions were observed for most mixtures, supra-additive interactions were observed at the 50% effect level for the 1:1 mixture of cocaine and caffeine and at the 80% effect level for all three mixtures of cocaine and caffeine, as well as for the 3:1 and 1:3 mixtures of cocaine and MDPV. These results demonstrate that with respect to cocaine-like discriminative stimulus effects, caffeine can function as a substitute in drug preparations containing either cocaine or MDPV, with enhancements of cocaine-like effects possible under certain conditions. Further research is needed to determine whether similar interactions exist for other abuse-related or toxic effects of drug preparations, including cocaine, synthetic cathinones, and caffeine.

Fig. 1.

Dose-response curves for the percent of responding that occurred on the cocaine-appropriate lever (top panel) during test sessions in which cumulative doses of cocaine, caffeine, MDPV, methamphetamine, or midazolam were administered, as well as when saline (S) was administered before each of six cycles. Data represent the mean (± 1 S.E.M.) for seven rats, with each dose-response curve determined in triplicate for MDPV, methamphetamine, midazolam, and saline, or doubly determined in triplicate for cocaine and caffeine. Bottom panel shows the mean (± 1 S.E.M.) rate of responding observed during test sessions. Response-rate data reflect data from all cycles of each test session; however, data for the percent cocaine-appropriate responding were included only for doses/cycles in which a rat earned at least one reinforcer.

Fig. 2.

Dose-response curves for the percent of responding that occurred on the cocaine-appropriate lever during test sessions in which cumulative doses of binary mixtures of cocaine and caffeine (top row), MDPV and caffeine (middle row), or cocaine and MDPV (bottom row) were administered. Each mixture was tested at three fixed-dose ratios [3:1 (left column), 1:1 (center column), and 1:3 (right column)] relative to the ED₅₀ for each constituent drug. Experimentally determined dose-response curves (black lines, open symbols) represent the mean (± 1 S.E.M.) for seven rats, with all dose-response curves determined in triplicate for each rat. Predicted, additive dose-response curves represent the mean (± 1 S.E.M.) for seven rats and are depicted as gray lines (no symbols). Because total cocaine equivalents were calculated for individual rats, cumulative total cocaine equivalents (mg/kg) represent the mean (± 1 S.E.M.) for seven rats.

Fig. 3.

Potency ratios (observed/predicted additive) for binary mixtures of cocaine and caffeine (top row), MDPV and caffeine (middle row), and cocaine and MDPV (bottom row) at three different effect levels: 20% (left column), 50% (center column), and 80% (right column). Potency ratios for individual subjects are depicted by their ID no. The group mean and 95% CI are depicted by the vertical gray line and error bars, respectively.