Molecular and cellular pharmacologyCannabinoid-induced alterations in brain disposition of drugs of abuse 1
Introduction
THC is the principal psychoactive constituent of marijuana [1] and possesses several pharmacological properties that may be therapeutically useful [2]. Marijuana is consumed by millions of Americans and very often is ingested with other drugs of abuse. Marijuana contains a complex mixture of dozens of different cannabinoids along with many other less characterized phytochemicals. CBD is another major cannabinoid constituent found in marijuana, and although it is not psychoactive [3], [4], it can inhibit the hepatic microsomal metabolism of THC as well as that of many other compounds in mice [5], [6], [7]. CBD has also been shown to alter the effects of THC in laboratory animals, as well as in human subjects [8], [9], [10], [11]. CBD treatment attenuates THC-induced psychological disturbances such as feelings of anxiety and panic after administration to human subjects [9], [10], [11]. Since CBD is not psychoactive and binds extremely weakly to cannabinoid receptors in the brain [4], CBD-mediated modulation of THC activity is probably not pharmacodynamic in nature but may be due to its effects on THC metabolism and/or disposition. In fact, we have shown previously [12] that CBD pretreatment increases brain levels of THC and, to an even greater extent, that of its primary oxidative metabolites. These increases in THC and its metabolites in the brain are much larger than would be predicted from their blood levels, which were only modestly affected by CBD pretreatment. Cannabinoid interactions that modulate brain levels of THC and its metabolites may contribute to the preference that individuals (using marijuana as a therapeutic agent) show for marijuana over THC alone. In addition, if cannabinoids are also found to increase brain levels of other abused drugs, it would provide a novel biochemical basis for the often found co-abuse of marijuana with such drugs. The co-abuse of marijuana with cocaine is well documented [13], and it was found to be used by 89% of patients identified as “problem” cocaine users [14], as well as in 35% of PCP abusers [15]. Furthermore, the combined use of cocaine and marijuana was identified in over 200 drug-abuse deaths [16]. More direct evidence that cannabinoids can alter cocaine effects has also been reported [17]. THC pretreatment increased cocaine plasma levels 2-fold in volunteers receiving intranasal cocaine. Furthermore, the duration and number of positive euphoric effects were found to be increased after THC pretreatment, whereas the duration of dysphoric effects was decreased. Although this study demonstrates an effect of THC on the pharmacokinetics of cocaine, very little is known of the effect of THC on other abused drugs or the mechanisms involved. Therefore, the present study was undertaken to further investigate the effects of CBD on brain levels of THC and to determine if this effect solely reflects a cannabinoid interaction or whether CBD may also affect the brain pharmacokinetics of other drugs of abuse as well.
Section snippets
Materials
CBD, THC, cocaine HCl, PCP HCl, dimethyl PCP HCl, morphine sulfate, methadone HCl, and MDMA were supplied by the National Institute on Drug Abuse. All cannabinoids were prepared for intraperitoneal or intravenous injection in a Tween 80 suspension as previously described [5]; other compounds were administered in saline.
Animal treatment
Male CF-1 mice (25–35 g, Charles River Laboratories), or Sprague-Dawley rats (250–300 g) were pretreated with cannabinoids (15–120 mg/kg, i.p.) or vehicle, 1 hr (or as noted)
Effect of cbd on thc brain levels
We have extended our previous studies [12] in order to characterize the dose- and time-course-effects of CBD-pretreatment on THC brain levels. We first compared the effect of the route of THC administration on CBD-mediated increases in its brain levels. Thus, although our previous study [12] employed the more technically demanding intravenous THC administration, we found in the present study that we achieved nearly identical THC brain levels when THC was administered intraperitoneally (Fig. 1,
Discussion
This extension of our previous study on the effect of CBD pretreatment on brain levels of THC [12] provides several important new findings. We have now shown that (i) CBD can exert its effect on brain levels of THC at much lower doses (Fig. 1) than the anticonvulsant dose (120 mg/kg) used previously, and (ii) manifestation of this effect requires CBD pretreatment as co-administration of the cannabinoids was not effective in altering their brain concentrations (Fig. 2). This requirement of
Acknowledgements
We wish to acknowledge the use of the Liver Center Core Facility on Spectrometry (KD-26743) and to thank Drs. M. A. Correia, Department of Cellular and Molecular Pharmacology, Leslie Z. Benet, Department of Biopharmaceutical Sciences, and Peter Bacchetti, Department of Epidemiology, Division of Biostatistics, University of California, San Francisco, for invaluable discussions. This work was supported by NIH Grant DA04265 (L.M.B.).
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Abbreviations: THC, tetrahydrocannabinol; CBD, cannabidiol; PCP, phencyclidine; MDMA, 3,4-methylenedioxyphenyl-methamphetamine HCl.