The observed marijuana-oropharyngeal cancer associationwas then divided by the bias factor to estimate an adjusted OR which accounted for confounding by HPV. The studies included in this analysis primarily collected information on marijuana use using interviewer or self-administered questionnaires. Therefore, differential misclassification of the reporting of marijuana use between cancer cases and controls is a possibility. To estimate the potential effect of reporting bias, simple probabilistic sensitivity analyses were conducted based on methods previously described . Sensitivity and specificity estimates used in this analysis were deriv.The rising incidence of oropharyngeal and oral tongue cancers over the last twenty years has paralleled trends of increasing use of marijuana among individuals born after 1950 . Therefore, we initially hypothesized that marijuana use could, in part, have contributed to the rising incidence of these cancers. Using pooled data from 9 case-control studies that contributed to the INHANCE consortium, we found evidence of a possible positive association of marijuana use with oropharyngeal cancer and a negative association with oral tongue cancer.. Our findings of a positive association of marijuana use and oropharyngeal cancer while in agreement with two prior studies contrasts with findings from five studies that showed no association . The possibility of a true association of marijuana use with oropharyngeal cancer risk was supported in the present study by the consistency of the observed associations with multiple measures of marijuana use including ever use, duration and frequency of use and was unaffected across strata of smoking and drinking. However,microgreens shelving the inconsistent association across studies in this pooled analysis combined with an attenuation in the association after adjustment for smoking and drinking make the effect of residual and unmeasured confounding highly plausible.
Differential exposure to HPV infection among marijuana smokers as compared to nonsmokers could be one source of potential confounding to explain the association of marijuana use with oropharyngeal cancer, as marijuana users engage more frequently in risky sexual behaviors leading to higher rates of sexually transmitted infections . We had serologic information on HPV 16 from four studies. Unfortunately, the association of marijuana use and oropharyngeal cancer among these four studies was not representative of all the studies included in the pooled analysis, although stratified analyses among these four studies by HPV 16 L1 serostatus revealed a modest positive association of ever and long duration marijuana use oropharyngeal cancer among seropositive individuals. Therefore, we attempted to estimate the potential confounding effect of HPV on this association using plausible estimates of the association of HPV infection on oropharyngeal cancer risk as well as differences in oral HPV prevalence by marijuana usage. This approach revealed a substantial and nearly complete attenuation of the association of marijuana use with oropharyngeal cancer risk. Lastly, the association of marijuana use appeared to be specific for those oropharyngeal cancers most likely to be HPV-associated: non-smoker/nondrinkers, and those with tonsil or base of tongue sites. These data suggest that the positive association of marijuana use and oropharyngeal cancer may be dependent on exposure to HPV. In lieu of more definitive information on tumor HPV infection status among cases and oral HPV infection status among cases and controls, the role of marijuana use as a potential risk factor in oropharyngeal cancer cannot be determined. We observed that marijuana use was strongly inversely associated with oral tongue cancer specifically, which is similar to what has been reported previously among oral cavity cancers in general . This association remained robust across all marijuana use metrics, was strengthened after adjustment for tobacco and alcohol use, and was consistent across the five studies that had sufficient numbers of cases. Given that a very small fraction of oral cavity cancers are attributed to HPV , it is not surprising that marijuana use remained strongly inversely associated with oral tongue cancer even after adjustment for HPV . Lastly, the inverse association appeared to be strongest amongst individuals <50 years of age, which are the same individuals that have the greatest observed per year increases in oral tongue cancer incidence . Therefore, this association may reflect a true inverse association of marijuana use on oral tongue cancer.
The major bio-active cannabinoid compound found in marijuana smoke, Δ – tetrahydrocannabinol -THC, has been shown to have both pro- and anti-carcinogenic capabilities. This cannabinoid functions primarily through engagement of specific cell surface receptors CB1, expressed on a range of cell types and CB2 present primarily on a variety of immune cells, particularly those found in the human tonsil . Engagement of these receptors on immune cells has been shown to suppress pro-inflammatory cytokine production and enhance anti-inflammatory cytokine production leading to reduced host immune responses to infectious agents as well as suppression of anti-tumor immunity . Conversely, Δ -THC has also been shown in epithelial cell lines to have distinct antitumor effects through arrest of uncontrolled cell growth, enhancement of apoptosis, and down regulation of angiogenesis and cellular migration . As a result, this cannabinoid has been investigated as a potential therapeutic agent in the treatment of glioma, breast and prostate cancers . Interestingly, the anti-tumor effect of this cannabinoid is mediated through the same CB1 and CB2 receptors. The effects of tetrahydrocannabinol -THC and other cannabinoids on modulating tumorigenesis may be cell and tissue specific based on receptor expression profiles. This may help explain the differing associations of marijuana smoke with oropharyngeal and oral tongue cancers. Lastly, the presence of other carcinogenic compounds present in marijuana smoke may also play a role in driving the association. Differences in the measurement of marijuana use, study sample recruitment, and measurement of demographic and other risk factors for Head and Neck Squamous Cell Carcinoma across the studies included in this analysis may have contributed to the heterogeneity observed across study sites. However, this heterogeneity was observed only for oropharyngeal cancer and not oral tongue cancer. Nevertheless, we included in our logistic regression models a random-effects term for each study to account for the heterogeneity of the association of marijuana use with oropharyngeal cancer outcomes. Furthermore, we acknowledge the possibility that misclassification in the measurement of marijuana use between cases and controls may explain some of these findings. Misclassification of marijuana exposure due to the use of self-administered or interviewer administered questionnaires has been suggested previously to be significant source of error in the observed association with head and neck cancers .
Sensitivity analyses that modeled the effects of differential and non-differential misclassification of marijuana exposure demonstrated that correction for misclassification did alter the strength of the association with each cancer outcome . Therefore,greenhouse tables it cannot be ruled out that either differential or non-differential misreporting of marijuana exposure may explain the observed associations of marijuana use with oropharynx and oral tongue cancers. This pooled analysis of nine case-control studies conducted in the US and Latin America is the largest to date to investigate the relationship of marijuana use specifically with cancers of the oropharynx and oral tongue. The differing associations of marijuana use on oropharyngeal and oral tongue cancers observed in this study provides some epidemiologic support for the biological effect of cannabinoids as both a pro- and anti-carcinogenic agent. However, given the strong association of HPV on orpoharyngeal cancer not measured in this study, the modest attenuated effect of marijuana on these caners may well be explained by confounding by HPV. Additional studies focusing on cannabinoid receptor expression profiles and downstream effector functions across cell types involved in tumorigenesis of these cancers may yield important etiologic information as to the role of marijuana on head and neck cancer risk. Depressive disorders have been associated with morphological brain abnormalities, although the majority of studies have been conducted in adults. Reduced hippo campal volumes have been found among depressed adults , although this may be associated with age of onset and one found no hippo campal differences . White matter abnormalities have also been associated with increased depressive symptoms and suicidality in adult populations . Due to adolescent neuromaturation, which includes pruning of gray matter and proliferation of white matter, these adult results cannot be generalized to depressed adolescents . Three studies including depressed children and adolescents found no significant differences in hippocampal volumes , although one did report larger amygdala-hippocampus ratios and another reported reduced amygdale volumes .Further, one study found that depressed adolescents had smaller overall and frontal white matter volumes compared to healthy controls . To make matters more complicated, marijuana use is highly prevalent among adolescents; nearly half of high school seniors have tried it during their lifetime . Further, marijuana use appears moderately associated with an increased risk of depressive symptoms in both adults and adolescents . While some longitudinal studies found no or weak links between marijuana use and depression , recent studies have shown that heavy marijuana use during adolescence is associated with later risk for depressive symptoms . There are several possible explanations for the link between major depressive disorders and chronic marijuana use. The endogenous cannabinoid system is widely distributed throughout the central nervous system, including the prefrontal and hippocampal regions , as well as white matter areas . Although animal studies have suggested cellular effects, especially in hippocampal regions , and despite developmental changes to the endogenous cannabinoid system during adolescence , no studies to date have examined structural brain changes associated with marijuana use among human adolescents. Adult animal models suggest that damage to the cannabinoid system, specifically to the CB1 receptors, results in depressive-like symptoms in mice .
Adult human studies utilizing magnetic resonance imaging have yielded conflicting results, with two studies finding gray and white matter abnormalities among young adult marijuana polydrug users and one study found no differences . Wilson and colleagues , found that adult participants who had used marijuana before age 17 had smaller gray matter and larger white matter volumes compared to later-onset users. In sum, because marijuana may disrupt adolescent neurodevelopment , including the developing endogenous cannibinoid system , previous findings among depressed adolescents without comorbid substance use cannot necessarily be generalized to the rather sizeable population of marijuana users . Therefore, the goals of the present study were to examine: 1) the relationship between white matter and hippocampal volumes and depressive symptoms and 2) whether marijuana use moderates the relationship between brain structure and depressive symptoms in a sample of thirty-two adolescents. Adolescents were recruited from high schools, universities, and through ads. All youth were between 16 to 18 years old, fluent in English, and had a parent/guardian available to consent and provide history. Other comprehensive exclusionary criteria included: psychotropic medication use; history of DSM-IV Axis I disorder ; LOC >2 minutes; serious medical illness; learning disability/mental retardation; significant maternal drinking or drug use during pregnancy; complicated birth ; parental history of bipolar I or psychotic disorders; left handedness; vision or hearing problem; and MRI contraindications. Finally, any youth with data suggestive of substance use in the 28 days prior to the session were excluded from analyses. All participants and, if under age 18, their parent/guardian, underwent written informed consent and, for minors, assent in accordance with the UCSD IRB. Of those eligible, data were collected from sixteen marijuana using and sixteen drug-free adolescents . MJ-users took marijuana at least 60 times in their lifetime, did not meet criteria for Heavy Drinker status , and did not use substances other than marijuana, alcohol, or nicotine > 25 times in their lifetime. Controls never met criteria for Heavy Drinker, had < 5 experiences with marijuana, and never used any other drug besides nicotine. Trained laboratory assistants administered the youth screening interviews to assess the aforementioned inclusion and exclusion criteria. Parents or guardians of youth were then contacted. Parents and youth were informed that they would not receive information regarding each other’s responses or test results. If still eligible, potential youth and parent/guardians were administered a detailed interview assessing demographic and psychosocial functioning, Axis I psychiatric disorders, and drug use history. To improve open disclosure, different lab assistants interviewed the parent and youth. If eligible, they were scheduled to begin the monitored abstinence protocol.