Several lines of evidence suggest that marijuana smoking may be a risk factor for the development of respiratory cancer (Table 3). First, the tar phase of marijuana smoke contains more of some pro-carcinogenic polycyclic aromatic hydrocarbons, including benz[a]pyrene, than the tar collected from tobacco cigarettes (3,4,7). Second, because of the manner in which marijuana cigarettes are smoked, approximately fourfold more of the particulate phase of the smoke (tar) is deposited in the human respiratory tract than occurs during tobacco smoking (6). This enhanced lung deposition during marijuana smoking, combined with the high concentration of known carcinogens in marijuana smoke, significantly magnifies the level of exposure to carcinogens from each marijuana cigarette. Third, THC can interact with the aryl hydrocarbon receptor and, independent of other components in the smoke, activate transcription of cytochrome P4501A1 (7). Cytochrome P4501A1 is involved in the biotransformation of polycyclic aromatic hydrocarbons into active carcinogens and plays a central role in the development of lung cancer. Fourth, hamster lung explants exposed to marijuana smoke for up to 2 years exhibited abnormalities in cell growth and accelerated malignant transformation (43). Fifth, bronchial biopsies from habitual marijuana smokers overexpressed surrogate endpoint markers of pretumor progression, as already described (36). Sixth, non-small-cell lung cancer cell lines implanted into immunocompetent mice displayed accelerated growth when the animals were given intraperitoneal injections of THC (44). Tumors and splenic tissue from these THC-treated mice overproduced immunosuppressive cytokines (interleukin [IL]-10 and transforming growth factor [TGF]-P) and underproduced immunostimulatory cytokines (IL-2 and interferon [IFN]-y) compared with vehicle-treated mice. When the tumor growth experiments were repeated in the presence of a selective CB2 antagonist, SR144528, the augmentation of tumor cell growth by THC was blocked. These findings suggest that THC accelerates tumor growth by a cytokine-dependent and CB2 receptor-mediated mechanism that impairs the development of antitumor immunity.
Although strongly suggesting that marijuana smoking is carcinogenic, these findings are not definitive proof that it is a clinically significant cancer risk factor. Additional support for this conclusion is provided by several small case series, each reporting an unusually high proportion of marijuana smokers among young individuals (<4045 years) in whom respiratory tract cancers have been diagnosed (45-49). The few controlled epidemiological studies that have addressed this issue, however, have revealed conflicting results. A large cohort study of participants in a health maintenance organization (n = 65,000) failed to show an association between marijuana smoking and the development of tobacco-related cancers (50). Interpretation of this study was limited by the fact that the participants were relatively young at the end of follow-up and relatively few cancers had therefore developed (50). A case-control study (n = 173 head and neck cancer cases, 176 controls) found that a history of daily or near-daily marijuana smoking was associated with a 2.6-fold greater risk (95% confidence interval [CI] 1.1-6.6) for developing head and neck cancer after controlling for other known risk factors, such as tobacco smoking and alcohol use (51). Moreover, a dose-response relationship was noted, and the risk of marijuana smoking for the development of cancer was even higher among younger individuals (<55 years). In contrast, however, another case-control study of 407 cases of oral squamous cell cancer and 615 controls failed to find an association with marijuana use (odds ratio [OR] = 0.9, CI 0.6-1.3), even among younger, heavier, and longer-term marijuana smokers (52). A case-control study conducted in Morocco, including 118 lung cancer cases and 235 controls, found that the combined use of hashish and snuff was associated with a 6.67-fold greater risk (95% CI 1.65-26.90) for developing lung cancer, while the risk was much lower for the use of hashish without snuff (1.93-fold [95% CI 0.57-6.58]), suggesting possible synergism between the effects of cannabis and tobacco on respiratory carcinogenesis (53). A recently published case-control study of risk factors for oral cancer in young people (<45 years) from the United Kingdom, which included 116 cases of squamous cell cancer of the oral cavity and 207 matched controls, failed to implicate cannabis use as a risk factor (54). On the other hand, a recently reported population-based case-control study of incident cases of cancers of the lung (n = 611) and upper aerodigestive tract (oral cavity, pharynx, and esophagus) (n = 601), along with 1040 cancer-free population controls, from Los Angeles County did not find any positive association between marijuana use (including heavy lifetime use, i.e., a cumulative total of > 10,950 joints) and the risk of lung or upper aerodigestive tract cancers after controlling for potential confounders (including tobacco use) (54a). Moreover, no interactions were observed between the effects of marijuana and tobacco. These results suggest that any possible association between marijuana use and respiratory cancer may be below practically detectable limits for typical levels of marijuana use.
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