Although it is widely accepted that Δ9-tetrahydrocannabinol (Δ9-THC) is the primary psychoactive constituent of marijuana, questions persist as to whether other components contribute to marijuana's pharmacological activity. The present experiments assessed the cannabinoid activity of marijuana smoke exposure in mice and tested the hypothesis that Δ9-THC mediates these effects through a CB1 receptor mechanism of action. First, the effects of Δ9-THC on analgesia, hypothermia, and catalepsy were compared with those of a marijuana extract with equated Δ9-THC content after either i.v. administration or inhalation exposure. Second, mice were exposed to smoke of an ethanol-extracted placebo plant material or low-grade marijuana (with minimal Δ9-THC but similar levels of other cannabinoids) that were impregnated with varying quantities of Δ9-THC. To assess doses, Δ9-THC levels in the blood and brains of drug-exposed mice were determined following both i.v. and inhalation routes of administration. Both marijuana and Δ9-THC produced comparable levels of antinociception, hypothermia, and catalepsy regardless of the route of administration, and these effects were blocked by pretreatment with the CB1 antagonist SR141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl]. Importantly, the blood and brain levels of Δ9-THC were similar in mice exhibiting similar pharmacological effects, regardless of the presence of non-Δ9-THC marijuana constituents. The present experiments provide evidence that the acute cannabinoid effects of marijuana smoke exposure on analgesia, hypothermia, and catalepsy in mice result from Δ9-THC content acting at CB1 receptors and that the non-Δ9-THC constituents of marijuana (at concentrations relevant to those typically consumed) influence these effects only minimally, if at all.
Interest in investigating both the risks and potential benefits of marijuana as a therapeutic agent, as well as understanding the negative consequences of long-term recreational use, has been reinvigorated over the past several years. Δ9-THC, the primary psychoactive ingredient of marijuana, has been available for several years in an oral form (Marinol) for treatment of nausea and vomiting associated with cancer chemotherapy and for use in loss of appetite and weight loss related to AIDS. Additionally, cannabinoids may be useful in treating neurological/movement disorders, chronic pain, glaucoma, in neuroprotection, as well as other disease states (for recent review, see Baker et al., 2003; Croxford, 2003; Drysdale and Platt, 2003). There are also many unanswered questions about the negative consequences of long-term marijuana consumption or use of cannabinoid therapeutics, particularly when it comes to the issues of dependence liability and the possibility of long-term cognitive deficits. Although there is no controversy regarding whether Δ9-THC is the major psychoactive constituent in marijuana, questions have persisted regarding the degree to which other constituents of marijuana may contribute to its pharmacological effects, both beneficial and harmful.
Several hundred compounds have been isolated in various plant preparations, including 66 distinct phytocannabinoids (ElSohly, 2002). Of these, Δ9-THC, cannabidiol (CBD), cannnabichromene (CBC), cannabigerol, and cannabinol (CBN) are perhaps the most quantitatively important. It has been suggested that these other cannabinoids may act to modulate the effects of Δ9-THC, providing benefits that cannot be obtained with Δ9-THC alone. In fact, evidence in humans and animal models have shown that other constituents of marijuana can modify the effects of Δ9-THC. Particular interest has been given to CBD, which has been shown to antagonize some of the effects of Δ9-THC in mice such as catalepsy (Karniol and Carlini, 1973) and antinociception as assessed by suppression of an abdominal constriction response (Welburn et al., 1976), while potentiating other effects such as hot plate antinociception (Karniol and Carlini, 1973). It was recently reported that a CBD-rich marijuana extract produced no working memory deficits in rats trained to perform a delayed matching-to-place water maze task, even at doses that contained levels of Δ9-THC that by itself did produce deficits, suggesting an attenuation of Δ9-THC's memory-impairing effects (Fadda et al., 2004). In humans, CBD has been shown to attenuate most of the subjective effects of Δ9-THC, whereas it did not affect other effects such as tachycardia (Dalton et al., 1976; Zuardi et al., 1982). Also, CBD is known to alter the metabolism of Δ9-THC (Bornheim et al., 1995) and has been shown to have some antagonist activity at cannabinoid CB1 receptors at high doses (Petitet et al., 1998). However, these interactions are usually only seen at doses of CBD that are as high or higher than the dose of Δ9-THC, a combination that is not often the case with recreationally available marijuana (e.g., ElSohly et al., 2000). Also, several studies have reported opposite or no such interactions between Δ9-THC and CBD (e.g., Welburn et al., 1976; Jarbe et al., 1977; Zuardi et al., 1984; Fadda et al., 2004; Finn et al., 2004). Other constituents of marijuana have also been evaluated for their own activity and their ability to modulate the effects of Δ9-THC. For example, CBN has been shown to bind weakly to CB1 receptors and can produce effects similar to and additive with those of Δ9-THC, although again only at doses equal to or greater than the dose of Δ9-THC (Takahashi and Karniol, 1975; Petitet et al., 1998). The question of whether the relatively low concentrations of non-Δ9-THC constituents commonly found in marijuana may act together to modify Δ9-THC's effects remains unanswered.
The development of a variety of pharmacological tools, particularly selective CB1 antagonists such as SR141716 (Rinaldi-Carmona et al., 1994) and well-validated models of in vivo CB1 receptor activation allow a direct evaluation of the hypothesis that the effects of inhaled marijuana smoke are mediated via its Δ9-THC content acting at CB1 receptors. The present experiments were designed to address this question, as well as to examine whether or not other marijuana constituents may interact with Δ9-THC to modulate any of its effects, and whether any such interaction may differ following i.v. or inhalation exposures. The important issue of establishing the relationship between inhalation and i.v. administration on dose was addressed by measuring blood and brain levels of Δ9-THC. By quantifying blood and brain levels of drug at doses that elicited comparable pharmacological effects, we sought to determine the degree to which Δ9-THC contributes to the potency of several of marijuana's acute pharmacological effects.
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