Marijuana Smoking and
Head and Neck Cancer
Mia Hashibe, PhD, Daniel E. Ford, MD, MPH, and Zuo-Feng Zhang, MD, PhD
T
he first epidemiological study showing that mari-juana smoking elevated the risk of head and neck cancers was recently published.1The study was a case control design that included 173 cases with head and neck cancers diagnosed at the Memorial Sloan Kettering Cancer Center from 1992-1994 and 176 con-trols who were recruited while donating blood at the hospital during the same period. The odds ratio for head and neck cancers among ever marijuana smokers was 2.6 (95% confidence interval = 1.1, 6.6) after ad-justment for age, sex, race, education, alcohol use, pack-years of cigarette tobacco smoking, and passiveexposure to tobacco smoke. Dose-response relation-ships were observed for both the frequency (use per day) and duration (years) of marijuana smoking.
Marijuana is the second most commonly smoked substance after tobacco and the most commonly used illegal drug in the United States.2 The prevalence of marijuana use declined from the late 1970s to the early 1990s but is on the rise in recent years. In the 1990s, the annual use of marijuana almost tripled among 8th grad-ers, doubled among 10th gradgrad-ers, increased by 80% among 12th graders, and increased somewhat more gradually among college students. The lifetime preva-lence of marijuana use was 22.2% among 8th graders, 39.6% among 10th graders, 49.1% among 12th graders, 49.9% among full-time college students, and 54.5% among young adults (ages 19-28) in 1998.
Young adults consider marijuana to be the illicit drug with the least risk.3From 1979 to 1991, the pro-portion of seniors in high school perceiving marijuana use as high risk increased simultaneously with the de-crease in marijuana use.2 However, since 1992, per-ceived risk has been declining along with an increase in marijuana use among high school students. In 1991, From the Department of Epidemiology, UCLA School of Public Health and
Jonsson Comprehensive Cancer Center, Los Angeles, California (Dr. Hashibe, Dr. Zhang), and the Department of Medicine, Epidemiology and Health Policy and Management, Johns Hopkins University School of Medi-cine, Baltimore, Maryland (Dr. Ford). Dr. Hashibe is currently at the Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, Lyon, France. Address for reprints: Zuo-Feng Zhang, MD, PhD, Professor of Epidemiology, Department of Epidemiology, UCLA School of Public Health, 71-225 CHS, Box 951772, Los Angeles, CA 90095-1772; Email: [email protected].
DOI: 10.1177/0091270002238801
A recent epidemiological study showed that marijuana smoking was associated with an increased risk of head and neck cancer. Among high school students and young adults, the prevalence of marijuana use was on the rise in the 1990s, with a simultaneous decline in the perception that marijuana use is harmful. It will be a major public health challenge to make people aware of the harmful effects of marijuana smok-ing, when some people view it as the illicit drug with the least
risk. The carcinogenicity of∆9-tetrahydrocannabinol (THC) is
not clear, but according to laboratory studies, it appears to have antitumor properties such as apoptosis as well as tumor-promoting properties such as limiting immune function and increasing reactive oxygen species. Marijuana tar contains similar carcinogens to tar from tobacco cigarettes, but each marijuana cigarette may be more harmful than a tobacco cig-arette since more tar is inhaled and retained when smoking
marijuana. More molecular alterations have been observed in bronchial mucosa specimens of marijuana smokers com-pared to nonsmokers. Field cancerization may be occurring on the bronchial epithelium due to marijuana smoking expo-sure. Several case studies were suggestive of an association of marijuana smoking with head and neck cancers and oral le-sions. However, in a cohort study with 8 years of follow-up, marijuana use was not associated with increased risks of all cancers or smoking-related cancers. Further epidemiological studies are necessary to confirm the association of marijuana smoking with head and neck cancers and to examine mari-juana smoking as a risk factor for lung cancer. It will also be of interest to examine potential field cancerization of the upper aerodigestive tract by marijuana and to explore marijuana as a risk factor for oral premalignant lesions.
78.6% of high school seniors considered regular use of marijuana to be a great risk, but in 1998, this percentage dropped to 58.5%. Perceived risk appears to be corre-lated directly with the level of marijuana use.
It may be confusing for the public that marijuana is used for medicinal purposes and being investigated for potential beneficial uses yet may also have harmful ef-fects on physical health. It is a public health challenge to make people aware of the harmful effects of mari-juana smoking. More epidemiological studies are nec-essary to confirm the association of marijuana smoking with head and neck cancers and to examine the associ-ation with lung cancer. It seems biologically plausible that marijuana smoking may cause cancer. In this pa-per, we will review the potential carcinogens in juana, molecular alterations associated with mari-juana, and case reports of oral lesions and marijuana.
Inferring any causal role for marijuana and cancer will require an evaluation of observational data. There can be no randomized clinical trials assessing expo-sure. Therefore, it is important to consider potential confounders. The most important confounder to con-sider is exposure to tobacco. Marijuana smokers are also more likely to use tobacco.4In addition, tobacco smokers who also currently smoke marijuana are less likely to be able to quit using tobacco.5We will review a cohort study on marijuana use and all cancers, as well as the first case-control study on marijuana use and head and neck cancers.
LAB AND
CARCINOGENICITY DATA Potential Carcinogens in Marijuana
∆9-tetrahydrocannabinol (THC) is the major psychoac-tive ingredient in marijuana. The amount of THC varies by how the marijuana is taken: marijuana or the flower tops of the plant is smoked (1%-5% THC), hashish or dried resin of the plant is smoked in a pipe (6%-10% THC), or hash oil is taken (30%-60% THC).6It has been reported that there is little evidence that THC is mutagenic or carcinogenic.7One study in which rats and mice received THC in corn oil reported that there was no evidence for the carcinogenicity of THC.8 In fact, some research groups examined THC and other marijuana constituents as antitumor agents. THC was shown to cause apoptosis in human prostate cancer cells PC-39and in C6.9 glioma cells,10as well as the re-gression of malignant gliomas in Wistar rats.11 Cannabigerol, a nonpsychoactive cannabinoid, was shown to inhibit growth of human oral epitheloid
car-cinoma cell lines.12In a review of the antitumor activity of the endocannabinoids (psychoactive cannabinoids), endocannabinoids such as anandamide and 2-arachidonoyl-glycerol were suggested as templates for therapeutic agents.13 The authors discuss that the endocannabinoids themselves may not be useful as therapeutic agents since they are degraded by cells. In another study, marijuana smoke suppressed the growth of primary and secondary tumors in Fisher rats im-planted with murine sarcoma tumor cells, but adminis-tration of THC did not suppress tumors.14
Although some studies report antitumor effects of THC, other characteristics of THC are suggestive of marijuana constituents playing a role in the biological mechanism for the association between marijuana and cancer. THC impaired the immune response and in-creased the growth of tumors in weakly immunogenic murine lung cancer models.15Application of THC to human cell lines also showed a disadvantageous effect on the immune system.16Exposing a human endothe-lial cell line to marijuana smoke containing 4% THC led to 80% higher reactive oxygen species formation than the controls and decreased glutathione levels (19% of control values),17though the reactive oxygen species formation was about the same for the cells ex-posed to marijuana smoke without THC. THC also acti-vates the transcription of P4501A1 (CYP1A1), an en-zyme that converts polycyclic aromatic hydrocarbons into carcinogens.18According to laboratory studies, it seems that THC may have a dual effect, with character-istics that promote tumorigenesis such as limiting im-mune function and increasing reactive oxygen species, in addition to a protective effect against tumors with its antiproliferative properties.19Examining the effects of THC in humans will be crucial, possibly with epidemi-ological studies that examine different modes of mari-juana use.
Marijuana smoke contains similar carcinogens as to-bacco, including phenols and polycyclic aromatic hy-drocarbons such as benzo[α]pyrene. Benzo[α]pyrene is present at a higher concentration in marijuana tar than in tar from tobacco.20Other substances, such as carbon monoxide, hydrogen cyanide, and nitrosamines, are present in marijuana smoke at similar levels to tobacco smoke. Marijuana smoking involves the inhalation of approximately three times the amount of tar and reten-tion of one-third more the amount of tar in the respira-tory tract relative to tobacco smoking.21Subjects inhale marijuana with one-third greater volume and hold their breath with marijuana four times longer than for tobacco. These patterns of smoking a marijuana ciga-rette may expose the head and neck area, especially the oral cavity, to more smoke particulates than a
to-bacco cigarette. It seems that regardless of the THC content, marijuana smoking involves greater depo-sition of tar compared to tobacco smoking. This may explain the observation that smoking a few mari-juana cigarettes and smoking more than 20 tobacco cigarettes had similar effects on the histopathology of the tracheobronchial epithelium.22It is of interest to ex-amine whether the effect of one marijuana cigarette is also more harmful to the head and neck region than smoking one tobacco cigarette.
Molecular Alterations
Bronchial mucosa biopsy specimens of marijuana smokers without any disease showed more molecular abnormalities than nonsmokers.23This study included 28 nonsmokers and 76 subjects who smoked tobacco, marijuana, and/or cocaine. Among the smokers, 12 subjects smoked marijuana only. The molecular mark-ers examined included Ki-67 (a proliferation marker), EGFR (epidermal growth factor receptor), p53 (tumor suppressor), and DNA ploidy (marker of genetic insta-bility). Abnormalities in Ki-67, EGFR, and p53 were more common in subjects who smoked any of these three substances compared to nonsmokers. Subjects who only smoked marijuana had a higher percentage of abnormalities in Ki-67 (92%) than nonsmokers (29%) (p < 0.001). A higher percentage of abnormalities in EGFR was also shown for marijuana-only smokers (58%) than nonsmokers (7%) (p < 0.001). The preva-lence of abnormal DNA ploidy was higher among mari-juana smokers (13%) compared to nonsmokers (5%), though the difference was not statistically significant. The observation of multiple molecular alterations sup-ports an association between marijuana and cancer through the mechanism of field cancerization effects on the bronchial epithelium. The field cancerization theory proposes that carcinogenic exposures can cause simultaneous genetic defects on the epithelium of the upper aerodigestive tract, putting the epithelium at high risk for the development of multiple lesions.24 Since marijuana smoking may cause field cancerization of the bronchial epithelium, studies need to be conducted to examine whether it can cause field cancerization of the upper aerodigestive tract.
CASE STUDIES
The available evidence on the possible carcinogenicity of marijuana and the similarities between marijuana and tobacco makes it plausible to determine if mari-juana use is a risk factor for the development of head and neck cancer in humans. Several case studies from
multiple countries indicate that marijuana use is more common than expected in young adults with head and neck cancer.25,26One case series scanned surgical pa-thology records in one hospital for all cases of upper and lower respiratory tract squamous cell cancers in patients younger than 40 years of age. Taylor27found that 7 of the 10 cases had regular or heavy marijuana use documented in their hospital records.
In addition to case studies for head and neck cancers and respiratory tract cancers, there have been a few case studies on oral lesions and marijuana use. In a ret-rospective study including 105 oral papilloma cases, all of the subjects had smoked marijuana for at least once a day for 2 years.28Oral papillomas are benign ep-ithelial tumors of the oral cavity that are not consid-ered to be premalignant lesions. A total of 152 leukoedema, 4 oral leukoplakia, and 6 erythroplakia lesions were identified among 266 subjects who smoked marijuana, methaqualone, and tobacco.29 Methaqualone is a combination of marijuana, tobacco, and crushed methaqualone tablets, unique to the South African region. Leukoedema is a benign gray-white le-sion that is not considered to be an oral premalignant lesion. Oral leukoplakia is the most common oral premalignant lesion while erythroplakia is a rare but severe oral premalignant lesion. Of the 6 erythroplakia cases, 3 marijuana smokers did not smoke tobacco and 4 marijuana smokers did not drink alcohol. This case report suggests an association of marijuana with oral premalignant lesions, but epidemiological studies us-ing well-conceived control groups are necessary to in-fer any association with confidence.
Cohort Study
One prospective cohort study from Kaiser Permanente in California found that marijuana use, measured from a voluntary self-administered research questionnaire as part of a multiphasic health checkup, was not asso-ciated with increased risk of all cancers or smoking-related cancers after 8 years of follow-up. Nontobacco smokers who used marijuana were more likely to de-velop prostate cancer, and there was nearly an in-creased risk for cervical cancer, but multiple compari-sons were completed.30Even though the sample was 64,855 individuals, the relatively young age of the sam-ple and few cases of cancer limited the power of this study.
Case Control Study
A hospital-based case control study was conducted at Memorial Sloan-Kettering Cancer Center between 1992
and 1994.1 The relationship between marijuana use and head and neck cancer was investigated using a case control study of 173 previously untreated cases with pathologically confirmed diagnoses of squamous cell carcinoma of the head and neck and 176 cancer-free controls. Exposure data were collected using a struc-tured questionnaire, which included history of tobacco smoking, alcohol use, and marijuana use. The associa-tions between marijuana use and head and neck cancer were analyzed by Mantel-Haenszel methods and logis-tic regression models. Controlling for age, sex, race, ed-ucation, alcohol consumption, pack-years of cigarette smoking, and passive smoking, the risk of squamous cell carcinoma of the head and neck was increased with marijuana use (odds ratio [OR] comparing ever with never users = 2.6, 95% confidence interval [CI] = 1.1, 6.6). Dose-response relationships were observed for frequency of marijuana use per day (p for trend < 0.05) and years of marijuana use (p for trend < 0.05). These associations were stronger for subjects who were 55 years of age and younger (OR = 3.1, 95% CI = 1.0, 9.7). Possible interaction effects of marijuana use were ob-served with cigarette smoking, mutagen sensitivity, and, to a lesser extent, alcohol use. The results suggest that marijuana use may increase the risk of head and neck cancer with a strong dose-response pattern. The analysis indicated that marijuana use might interact with mutagen sensitivity and other risk factors to in-crease the risk of head and neck cancer. The results need to be interpreted with some caution in drawing causal inferences because of certain methodological limitations, especially with regard to interactions.
Two case control studies are currently under way to replicate these findings. As is true of most case control studies, a major issue is the selection of controls. The ongoing studies will be using community-based con-trols and identifying cases from more than one hospital.
CONCLUSION
The carcinogenicity of THC is not yet clear, but labora-tory studies have found that THC exhibits antitumor properties such as apoptosis as well as tumor-promoting properties such as limiting immune function and in-creasing reactive oxygen species. It will be of interest to examine the association of THC levels and cancer in epidemiological studies, perhaps by examining differ-ent modes of marijuana use. The tar compondiffer-ent of mar-ijuana contains similar carcinogens to tobacco, but each marijuana cigarette may be more harmful than a tobacco cigarette due to the characteristics of marijuana
smoking such as greater inhalation of tar, longer reten-tion of marijuana smoke, and greater volume of marijuana smoke inhaled. Furthermore, marijuana smokers appear to have more molecular alterations on the bronchial mucosa than nonsmokers. Field cancerization may be occurring due to marijuana expo-sure on the bronchial epithelium. Case studies sug-gested an association of marijuana smoking with head and neck cancers, respiratory cancer, and oral premalignant lesions. A case control study reported an association between head and neck cancers and mari-juana use, but a cohort study did not show an increased risk of cancers with respect to marijuana use. Further epidemiological studies are necessary to determine whether marijuana smoking can cause oral premalignant lesions and cancer, possibly due to field cancerization of the upper aerodigestive tract.
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