The study was limited by recall bias related to the marijuana use assessment; otherwise, it was well-designed. Although some cross-sectional studies in this review suggested that marijuana has metabolic benefits , those with more robust analytic designs found no evidence of benefit , and other prospective studies found potentially harmful effects . These findings are of particular interest. Many articles in the lay press have suggested to the public that marijuana use has cardiovascular benefits, reduces blood pressure, stabilizes blood sugar levels, or improves cholesterol profiles . Our review found insufficient evidence to support these claims. Given public opinion that marijuana is safe or even beneficial, the insufficiency of the literature is concerning . Finally, despite the popular belief that marijuana use causes “the munchies” , we found no evidence that it is associated with weight gain or obesity. An important consideration in our understanding of marijuana effects relates to the standards of evidence necessary to identify harms. Using experimental trials to study marijuana harms is unethical; only observational studies are feasible, despite their inherent biases. Further, the greatest clinical uncertainty concerns older patients at higher risk for cardiovascular disease who use marijuana regularly over long periods. Therefore, the best possible study to assess the effect of marijuana use on cardiovascular outcomes would be a prospective cohort study among higher-risk participants, with several exposure assessments during follow-up and a robust evaluation of baseline characteristics and outcomes. The best evidence currently available, in contrast, is from the MIOS and CARDIA cohorts, although both have serious flaws . Whereas MIOS assessed marijuana exposure only once and was limited by recall bias, CARDIA made several assessments of marijuana exposure, but the overall exposure in the cohort was minimal and the cohort was young and likely under powered to assess the outcomes of stroke and cardiovascular mortality. Our systematic review also highlights other important evidence gaps. First,hydroponic table most studies failed to capture current and lifetime marijuana use adequately.

More robust exposure assessment tools are necessary to allow evaluation of the acute and long-term health effects of marijuana . Second, almost a quarter of the studies failed to report the specific route of cannabis use and the chemical constitution of the cannabis examined. The number of marijuana users, as well as the variety of routes , is increasing; therefore, collection of data regarding use must be more standardized, because the various forms may differ in toxic effects. In particular, high quality safety data on the effects of edible marijuana on the cardiovascular system are lacking. The effects of THC persist in the body longer after oral administration than inhalation. Prospective studies examining the effects of edible marijuana on other cardiovascular events, such as acute myocardial infarction and stroke, are necessary, especially because use of edible forms is increasing among older adults, who are at higher risk for cardiovascular disease . Our study has several limitations that deserve comment. We excluded articles not published in English; thus, we may have overlooked relevant studies. The diverse representation of outcomes across studies, variation in study design, and frequent lack of effect size reporting precluded a meta-analysis. In addition, most studies inadequately assessed marijuana exposure. Finally, most studies in this review were rated as high ROB, so their results should be interpreted with caution. In summary, although several studies suggested a metabolic benefit from marijuana use, they were based on cross-sectional designs and not supported by prospective studies. Evidence examining the effect of marijuana on diabetes, hyperlipidemia, acute myocardial infarction, stroke, and cardiovascular mortality was insufficient. Adequately powered prospective studies are needed to determine the effect of chronic marijuana use on cardiovascular health. Head and neck squamous cell carcinomas, which include cancers of the oral cavity, oropharynx, and larynx, are the sixth most common cancers worldwide with an estimated annual burden of 355,000 deaths and 633,000 incident cases . In addition to traditional risk factors, such as tobacco and alcohol use, human papillomavirus infection has recently been established as a major etiologic factor for a subset of Head and Neck Squamous Cell Carcinomas—cancers arising from the oropharynx, including the base of tongue, tonsil, and other parts of the pharynx . The incidence of a majority of head and neck cancer subsets has declined significantly during the past 2 decades in the U.S. and other developed countries, largely due to declines in cigarette smoking .

In contrast to this overall pattern, the incidence of oropharyngeal and oral tongue cancers has significantly increased during the same period, especially among individuals <45 years of age . While increases in oropharyngeal cancer incidence are attributed to increased acquisition of oral HPV through changes in sexual behaviors among recent birth cohorts , the reasons underlying increasing oral tongue cancer incidence are largely unknown. Notably, HPV infection is not currently believed to play a major role in the etiology of oral tongue cancers . Marijuana use has significantly increased among individuals born after 1950 , raising the hypothesis of a role of marijuana use as a risk factor for oropharyngeal and oral tongue cancer development . A recent case-control study reported that marijuana use was strongly associated with increased risk of HPV-positive oropharyngeal cancer . Conversely, a case-control study of HNSCC demonstrated an inverse association of marijuana use on cancers of the oral cavity . However, epidemiologic studies that have examined the association of marijuana use with Head and Neck Squamous Cell Carcinomas have been inconsistent . We therefore investigated the association of marijuana use with risk of oropharyngeal and oral tongue cancers in a large pooled analysis consisting of 9 case-control studies that were part of the International Head and Neck Cancer Epidemiology consortium.All studies included in this analysis collected data on lifetime marijuana use from cases and controls, including duration of use and frequency of use. Four of the studies ) asked each subject to report the average frequency of marijuana use over their lifetime, while the remaining fivestudies [Schwartz], Latin America, Boston, Los Angeles, and North Carolina obtained information about marijuana use during different periods of the subject’s lifetime. For these later five studies the lifetime average frequency of marijuana use was calculated by weighting the frequency of each specific period by the duration of that period relative to the total years of marijuana use. For analysis, marijuana use was defined as ever/never,grow rack frequency of use per week and duration of use . Lastly, a “joint-year” variable was created as a measure of cumulative marijuana exposure, and defined as the number of joints per day multiplied by the duration of marijuana use in years and was categorized into a-priori categories . Four out of the nine studies defined marijuana use specifically as smoking marijuana whereas the remaining five studies defined marijuana use in any form.

All studies collected information on tobacco use including ever vs. never use of cigarettes and cigars/pipes. In six out of nine studies [Schwartz], Seattle-LEO [Vaughan], North Carolina , Los Angeles, Houston, and Boston) ever smoking cigarettes was defined as anyone smoking at least 100 cigarettes in their lifetime. Three studies defined ever smoking cigarettes as smoking one or more cigarettes per day for greater than or equal to one year. Lastly, “pack-years” of cigarette smoking was created as a cumulative measure of cigarette smoking duration and intensity and treated as a continuous variable in the analysis. For each study, pack-years was directly calculated by multiplying the number of cigarettes smoked by the age of initiation and cessation of smoking . Cigar and Pipe use was defined as ever vs. never. Four studies [Schwartz], North Carolina , Los Angeles, and Seattle-LEO [Vaughan] defined ever cigar/pipe use as use for six months or greater at anytime in the past. Two studies defined ever cigar/pipe use as smoking once per day for at least one year or more. One study defined ever pipe use as ever smoking 12 ounces of tobacco and cigar use as smoking one cigar per week for at least one year. Lastly, two studies collected “ever vs. never” information from questionnaire data without defining a frequency or duration of use cut-off. Alcohol consumption was defined as ever vs. never for all studies. Ever use of alcohol was defined as either greater than four or more drinks in a year [Schwartz] and Baltimore [HOTSPOT], greater than or equal to one drink per week for greater than or equal to one year , greater than either one or four drinks per month, or ever consumed in a lifetime . Total alcohol consumption was calculated as the total volume of pure ethanol consumed from beer, wine, and liquor multiplied by the age of initiation and cessation . Total alcohol consumption was treated as a continuous variable in all analyses. Odds ratio and 95% confidence intervals were estimated using logistic regression to assess the association between marijuana use and oropharyngeal and oral tongue cancer diagnosis. Given that all the case-control studies included in this analysis utilize incident cases derived from open and dynamic populations, the odds ratio estimated in this study approximates the relative risk. To control for heterogeneity in effects across study, study indicator was included as a random effects intercept term in all regression models. We tested for heterogeneity across study using a log likelihood ratio test for the goodnesss of fit of the model with and without a product term for marijuana use and study. Furthermore, we quantified the among-study variability of the association of ever marijuana use with both cancer outcomes by estimating the population effects interval which is derived from the point estimate of the association and the τ 2 estimated from meta-regression analysis . Regression models were adjusted for age , sex, education , race/ethnicity , pack-years of cigarette smoking , ever pipe/cigar smoking , and intensity of alcohol drinking . The Tampa study was excluded from analyses on duration and frequency of marijuana use because there were insufficient cases and controls in each category of marijuana use. For subjects with missing data on education level , multiple imputation analysis was performed. Logistic regression was used to predict education level using age, sex, race/ethnicity, study, and case-control status. Five imputations were created and a summary estimate for the association of marijuana use and cancer outcomes was calculated using logistic regression using the MI ESTIMATE command in STATA. Analysis excluding individuals with missing educational status demonstrated similar associations of marijuana use with cancer . Tobacco and alcohol use is a recognized risk factor for both oropharyngeal and oral tongue cancers and is strongly correlated with marijuana use . Therefore, sub-group analyses were performed to further assess the presence of residual confounding by smoking status by restricting the study sample to never tobacco users/never drinkers. Given the relatively small number of oral tongue cancer cases who were NSND, light smokers and light drinkers were categorized as never tobacco users/never drinkers for this analysis. The potential multiplicative interaction of tobacco and alcohol use on the association of marijuana use and cancer outcomes were compared by the inclusion of a product term of marijuana use and tobacco/alcohol use in the logistic regression model to estimate the ratio of odds ratios . In addition, the additive interaction of tobacco and alcohol use on the association of marijuana use with cancer outcomes was also tested through estimation of the Relative Excess Risk due to Interaction using a generalized linear model . Because sexual behaviors and marijuana use could be highly correlated, we conducted two separate analyses to evaluate the potential confounding effects of HPV on the observed associations of marijuana use with risk of oropharyngeal cancer. First, analyses were stratified by HPV 16 L1 serologic status. Data on HPV L1 antibodies were available in four studies: Boston, Latin America, Houston, and Seattle [Schwartz]. Second, given the absence of either detailed information on oral sexual behaviors or oral HPV status in a majority of studies, we utilized external information to indirectly adjust the marijuana-oropharyngeal cancer association for confounding by HPV using the methods described by Steenland and Greenland . These analyses utilized external information on the association of marijuana use with oral HPV prevalence , the association of current marijuana use and oral HPV infection , and the association of oral HPV infection with oropharyngeal cancer risk to calculate a bias factor .