On the carcinogenicity of marijuana smoke. A hypothetical link between marijuana smoking and cancer has been established based on the following observations: 1. Marijuana smoke contains carcinogenic hydrocarbons; 2. Cannabinoid administration promotes cancer under certain laboratory conditions; 3. Lesions similar to those caused by tobacco smoke are found in the bronchial epithelium of marijuana smokers; 4. Marijuana tar produces tumors when painted on the skin of animals. The best evidence to date on the link between marijuana and cancer, however, derives from large case-control studies -- especially population-based studies. Such studies tend to suggest, if anything, an inverse association between marijuana use and cancers. I. Marijuana smoke contains higher levels of carcinogenic polycyclic aromatic hydrocarbons (PAH) than those found in tobacco smoke. As a rule, the level of carcinogenic PAHs within a chemical mixture is less important than the overarching influence of the mixture on carcinogenic PAH activation (Mahadevan et al. 2007). Indeed, marijuana smoke is presumed carcinogenic not only because it contains carcinogenic PAHs, but also because cannabinoids, in their own right, influence the cytochrome enzymes (CYP1) that determine carcinogenic PAH activation (Roth et al. 2001). Perhaps due to their phenolic hydrocarbon structure, cannabinoids share the anti-carcinogenic disposition of polyphenols to increase levels of CYP1A1 messenger RNA while competitively reducing CYP1A1 enzyme ativity through aryl hydrocarbon receptor ligation (Ciolino et al. 1998). Not surprisingly, spiking tobacco tar with delta-9 THC markedly reduced carcinogenic activity (Roth et al. 2001). II. Cannabinoid administration promotes cancer in mice. Intraperitoneal administration of immunosuppressive cannabinoids promotes cannabinoid-resistant lines of cancer in immune-competent strains of mice (Gardner et al. 2003, McKallip et al. 2005, Zhu et al. 2000); however, the preponderance of in vivo studies, have shown that cannabinoid administration -- either locally or systemically -- inhibits the growth of cancer (Aguado et al. 2007, Bifulco et al. 2001, Bifulco et al. 2004, Blazquez et al. 2003, Blazquez et al. 2004, Blazquez et al. 2006, Caffarel et al. 2006, Carracedo et al. 2006, Casanova et al. 2003, Chan et al. 1996, Duntsch et al. 2006, Grimaldi et al. 2006, Ligresti et al. 2006, Massi et al. 2004, McKallip et al. 2002, McKallip et al. 2006, Munson et al. 1975, Pisanti et al. 2007, Preet et al. 2008, Recht et al. 2001, Sanchez et al. 2001). The neoplastic effects of cannabinoids may vary according to the degree of malignancy, which, in turn, may depend on the presence of cannabinoid receptors (Ellert-Miklaszewska et al. 2007, Xu et al. 2006). Cannabinoids may control the growth of human cancers, in part, through the cannabinoid receptor 2 gene (CNR2), which emerged as the best-connected 'super hub' in an inferred large-scale association network for breast cancer data (Schäfer et al. 2005). The posological question remains as to whether smoking marijuana produces antineoplastic concentrations of cannabinoids in the exposed tissues of recreational or medicinal users. Perhaps the biggest obstacle to developing chemotherapy for lung cancer is the fact that optimal tissue concentrations cannot asily be reached in the bronchial epithelium, where anti-neoplastic cannabinoids from smoked marijuana naturally concentrate. Inhalation of marijuana smoke was shown to produce 800-1000% higher concentrations of THC in the lungs compared with those found in blood (75 +/- 38 ng/g wet wt tissue vs. 9.2 +/- 2.0 ng/ml: Sarafian et al. 2006). If the bronchial epithelium does, in fact, harbor malignant neovasculature prior to clinical detection, then smoking marijuana may treat lung cancer at its roots early on, while treatment still matters. III. Marijuana smokers develop 'precancerous' lesions similar to those caused by tobacco smoke. Marijuana smoking causes 'precancerous' epithelial lesions (PEL) such as squamous metaplasia (SM) and other changes associated with respiratory exposure to smoke in general (Barsky et al. 1998). On the one hand, SM not only follows exposure to potent carcinogens in laboratory strains of mice, but it also precedes the development of squamous cell carcinoma of lungs (SCCL) in humans. On the other hand, the multiplicity of SM was higher among SCCL-resistant mice (e. g., C57BL/6J = 5.0 - 6.0: Wang et al. 2004) than it was among SCCL-susceptible mice (e. g., NIH Swiss = 2.1 - 4.9: Wang et al. 2004); in humans, PEL such as SM are generally reversible and often regress spontaneously (Winterhalder et al. 2004). As it turns out, PEL may have little, if any, predictive value. In fact, according to recent findings, "Distribution and outcome of preneoplastic lesions have been found to be unrelated to various risk factors such as smoking. . . The 54% regression rate of all preneoplastic lesions, 26% to 39% progression rate to CIS/SCC of individuals with lower-grade dysplasia or severe dysplasia with no significant difference in progression rate and time to progression combined with nostepwise histologic changes unrelated to the initial histologic grading.... The initial WHO classification of any preneoplastic lesion cannot be reliably used for accurate risk assessment of field carciogenesis" (Breuer et al. 2005). IV. Marijuana tar produces tumors when painted on the skin of animals. Tar from marijuana smoke, like that from tobacco smoke, was shown to produce benign tumors (i.e., squamous-cell papilloma) when painted on the skin of animals (Hoffman et al. 1975); however, tar from tobacco smoke caused frank malignancies (i.e., squamous-cell carcinoma), whereas tar from marijuana smoke did not. In subsequent research on monkeys, prolonged exposure to marijuana smoke failed to produce any carcinogenic effects (Talaska et al. 1992). Interestingly enough, exposure to marijuana smoke was shown to retard the growth of sarcoma in rats (Watson 1989). This inhibition was unrelated to the cannabinoid content of the smoke. The appearance of papillomas on the skin indicates that tar from marijuana smoke, like that from tobacco smoke, is an effective initiator of benign tumors; however, the absence of squamous-cell carcinoma is consistent with the observation that cannabinoid administration induces the regression of squamous-cell carcinoma of skin by transforming the vascular hyperplasia of engorged tumors into pallid networks of small, differentiated capillaries (Casanova et al. 2003). Such transformation reflects the tendency of cannabinoids to thwart the neoplastic expression of angiogenic factors (Casanova et al. 2003, Portella et al. 2003). To date, no animal study has demonstrated the carcinogenicity of marijuana smoke. Future studies would, ideally, be conducted with animal models that reflect the stages of both initiation and progression observed in human cancer, but no such model currently exists (Khanna et al. 2005). In vivo studies on the neoplastic properties of cannabinoids have typically been conducted with BALB/c, B6C3F1, and C57BL/6 murine strains, which are not susceptible to chemically-induced SCCL. Even the most susceptible strains do not develop SCCL as the result of exposure to tobacco smoke (Wang et al. 2004), the definitive benchmark for human carcinogens. Murine SCCL results from exposure to a single carcinogen, whereas human SCCL typically results from exposure to complex mixtures of carcinogens such as those found in smoke. Unlike murine SCCL, adenocarcinoma of the lungs (ACL) in mice results from tobacco smoke exposure (Hutt et al. 2005). Lifetime inhalation of tobacco smoke was recently shown to induce ACL in B6C3F1 mice, which have a low baseline incidence of pulmonary neoplasia. The above study is recognized for being the first to adequately demonstrate the cancer-initiating effects of tobacco smoke exposure in the lungs of animals (Hecht 2005), yet it unexpectedly showed an increase in lifespan associated with lifetime tobacco smoke exposure, an observation attributed to reduced caloric intake or bodyweight (Hutt et al. 2005). Reduced caloric intake or bodyweight caused by tobacco smoke exposure may have increased survival in B6C3F1 mice despite the increased burden of tumors. In an earlier study on B6C3F1 mice, a decrease in bodyweight and tumors followed the administration of THC (Chan et al. 1996). Researchers from both of these studies acknowledge the importance of controlling for caloric intake/bodyweight the future studies (Huff et al. 2005, Hutt et al. 2005). In contrast to the mice that develop adenocarcinoma from carcinogen exposure, mice implanted with human adenocarcinoma exhibit the metastasis and reduced survival typically observed in humans with adenocacinoma (Meuwissen et al. 2005). While such xenograft models do not fully capture the natural behavior of human cancer (Gutmann et al. 2006), compared with chemically-induced models, they are more practical for evaluating malignant progression. In evaluating the carcinogenicity of any type of smoke, it might help to remember that it was epidemiology, rather than animal research, that first incriminated tobacco smoke as a carcinogen (Doll 1988, Proctor 2004). While there have been lurid case-reports of tobacco-related cancers among young and middle-aged marijuana smokers (Sridhar et al. 1994), a large cohort study found no evidence of precocious tobacco-related cancers among middle-aged marijuana smokers (Sidney et al. 1997). As tobacco-related cancers develop increasingly with age and exposure, the cohort study did not follow its participants for long enough to ascertain the relationship between marijuana smoking and tobacco-related cancers. Small case-control studies -- especially studies failing to control for the effects of tobacco smoking -- have inconsistently shown an association (Berthiller et al. 2008, Chacko et al. 2006, D'Souza et al. 2007, Hsairi et al. 1993, Llewellyn et al. 2004a, Llewellyn et al. 2004b, Sasco et al. 2002, Voirin et al. 2006, Zhang et al. 1999), whereas large case-control studies -- especially population-based studies -- have, if anything, shown an inverse association (Berthiller et al. 2009, Ford et al. 2001, Hashibe et al. 2006, Liang et al. 2009, Rosenblatt et al. 2004, Zhu et al. 2002). 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