Marijuana Smoking and Head and Neck Cancer

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                                                                            Marijuana Smoking and
                                                                            Head and Neck Cancer
                                                 Mia Hashibe, PhD, Daniel E. Ford, MD, MPH, and Zuo-Feng Zhang, MD, PhD

                                    A recent epidemiological study showed that marijuana                            marijuana. More molecular alterations have been observed
                                    smoking was associated with an increased risk of head and                       in bronchial mucosa specimens of marijuana smokers com-
                                    neck cancer. Among high school students and young adults,                       pared to nonsmokers. Field cancerization may be occurring
                                    the prevalence of marijuana use was on the rise in the 1990s,                   on the bronchial epithelium due to marijuana smoking expo-
                                    with a simultaneous decline in the perception that marijuana                    sure. Several case studies were suggestive of an association of
                                    use is harmful. It will be a major public health challenge to                   marijuana smoking with head and neck cancers and oral le-
                                    make people aware of the harmful effects of marijuana smok-                     sions. However, in a cohort study with 8 years of follow-up,
                                    ing, when some people view it as the illicit drug with the least                marijuana use was not associated with increased risks of all
                                    risk. The carcinogenicity of ∆9-tetrahydrocannabinol (THC) is                   cancers or smoking-related cancers. Further epidemiological
                                    not clear, but according to laboratory studies, it appears to                   studies are necessary to confirm the association of marijuana
                                    have antitumor properties such as apoptosis as well as tumor-                   smoking with head and neck cancers and to examine mari-
                                    promoting properties such as limiting immune function and                       juana smoking as a risk factor for lung cancer. It will also be of
                                    increasing reactive oxygen species. Marijuana tar contains                      interest to examine potential field cancerization of the upper
                                    similar carcinogens to tar from tobacco cigarettes, but each                    aerodigestive tract by marijuana and to explore marijuana as
                                    marijuana cigarette may be more harmful than a tobacco cig-                     a risk factor for oral premalignant lesions.
                                    arette since more tar is inhaled and retained when smoking                           Journal of Clinical Pharmacology, 2002;42:103S-107S

                                    T    he first epidemiological study showing that mari-
                                         juana smoking elevated the risk of head and neck
                                    cancers was recently published.1 The study was a case
                                                                                                                    exposure to tobacco smoke. Dose-response relation-
                                                                                                                    ships were observed for both the frequency (use per
                                                                                                                    day) and duration (years) of marijuana smoking.
                                    control design that included 173 cases with head and                                Marijuana is the second most commonly smoked
                                    neck cancers diagnosed at the Memorial Sloan                                    substance after tobacco and the most commonly used
                                    Kettering Cancer Center from 1992-1994 and 176 con-                             illegal drug in the United States.2 The prevalence of
                                    trols who were recruited while donating blood at the                            marijuana use declined from the late 1970s to the early
                                    hospital during the same period. The odds ratio for                             1990s but is on the rise in recent years. In the 1990s, the
                                    head and neck cancers among ever marijuana smokers                              annual use of marijuana almost tripled among 8th grad-
                                    was 2.6 (95% confidence interval = 1.1, 6.6) after ad-                          ers, doubled among 10th graders, increased by 80%
                                    justment for age, sex, race, education, alcohol use,                            among 12th graders, and increased somewhat more
                                    pack-years of cigarette tobacco smoking, and passive                            gradually among college students. The lifetime preva-
                                                                                                                    lence of marijuana use was 22.2% among 8th graders,
                                    From the Department of Epidemiology, UCLA School of Public Health and
                                                                                                                    39.6% among 10th graders, 49.1% among 12th graders,
                                    Jonsson Comprehensive Cancer Center, Los Angeles, California (Dr.               49.9% among full-time college students, and 54.5%
                                    Hashibe, Dr. Zhang), and the Department of Medicine, Epidemiology and           among young adults (ages 19-28) in 1998.
                                    Health Policy and Management, Johns Hopkins University School of Medi-              Young adults consider marijuana to be the illicit
                                    cine, Baltimore, Maryland (Dr. Ford). Dr. Hashibe is currently at the Unit of   drug with the least risk.3 From 1979 to 1991, the pro-
                                    Environmental Cancer Epidemiology, International Agency for Research            portion of seniors in high school perceiving marijuana
                                    on Cancer, Lyon, France. Address for reprints: Zuo-Feng Zhang, MD, PhD,
                                                                                                                    use as high risk increased simultaneously with the de-
                                    Professor of Epidemiology, Department of Epidemiology, UCLA School of
                                    Public Health, 71-225 CHS, Box 951772, Los Angeles, CA 90095-1772;              crease in marijuana use.2 However, since 1992, per-
                                    Email:                                                        ceived risk has been declining along with an increase
                                    DOI: 10.1177/0091270002238801                                                   in marijuana use among high school students. In 1991,

                                    J Clin Pharmacol 2002;42:103S-107S                                                                                                         103S
                                                   HASHIBE ET AL

78.6% of high school seniors considered regular use of       cinoma cell lines.12 In a review of the antitumor activity
marijuana to be a great risk, but in 1998, this percentage   of the endocannabinoids (psychoactive cannabinoids),
dropped to 58.5%. Perceived risk appears to be corre-        endocannabinoids such as anandamide and 2-
lated directly with the level of marijuana use.              arachidonoyl-glycerol were suggested as templates for
   It may be confusing for the public that marijuana is      therapeutic agents.13 The authors discuss that the
used for medicinal purposes and being investigated for       endocannabinoids themselves may not be useful as
potential beneficial uses yet may also have harmful ef-      therapeutic agents since they are degraded by cells. In
fects on physical health. It is a public health challenge    another study, marijuana smoke suppressed the growth
to make people aware of the harmful effects of mari-         of primary and secondary tumors in Fisher rats im-
juana smoking. More epidemiological studies are nec-         planted with murine sarcoma tumor cells, but adminis-
essary to confirm the association of marijuana smoking       tration of THC did not suppress tumors.14
with head and neck cancers and to examine the associ-           Although some studies report antitumor effects of
ation with lung cancer. It seems biologically plausible      THC, other characteristics of THC are suggestive of
that marijuana smoking may cause cancer. In this pa-         marijuana constituents playing a role in the biological
per, we will review the potential carcinogens in mari-       mechanism for the association between marijuana and
juana, molecular alterations associated with mari-           cancer. THC impaired the immune response and in-
juana, and case reports of oral lesions and marijuana.       creased the growth of tumors in weakly immunogenic
   Inferring any causal role for marijuana and cancer        murine lung cancer models.15 Application of THC to
will require an evaluation of observational data. There      human cell lines also showed a disadvantageous effect
can be no randomized clinical trials assessing expo-         on the immune system.16 Exposing a human endothe-
sure. Therefore, it is important to consider potential       lial cell line to marijuana smoke containing 4% THC
confounders. The most important confounder to con-           led to 80% higher reactive oxygen species formation
sider is exposure to tobacco. Marijuana smokers are          than the controls and decreased glutathione levels
also more likely to use tobacco.4 In addition, tobacco       (19% of control values),17 though the reactive oxygen
smokers who also currently smoke marijuana are less          species formation was about the same for the cells ex-
likely to be able to quit using tobacco.5 We will review a   posed to marijuana smoke without THC. THC also acti-
cohort study on marijuana use and all cancers, as well       vates the transcription of P4501A1 (CYP1A1), an en-
as the first case-control study on marijuana use and         zyme that converts polycyclic aromatic hydrocarbons
head and neck cancers.                                       into carcinogens.18 According to laboratory studies, it
                                                             seems that THC may have a dual effect, with character-
LAB AND                                                      istics that promote tumorigenesis such as limiting im-
CARCINOGENICITY DATA                                         mune function and increasing reactive oxygen species,
                                                             in addition to a protective effect against tumors with its
Potential Carcinogens                                        antiproliferative properties.19 Examining the effects of
in Marijuana                                                 THC in humans will be crucial, possibly with epidemi-
                                                             ological studies that examine different modes of mari-
∆9-tetrahydrocannabinol (THC) is the major psychoac-         juana use.
tive ingredient in marijuana. The amount of THC varies          Marijuana smoke contains similar carcinogens as to-
by how the marijuana is taken: marijuana or the flower       bacco, including phenols and polycyclic aromatic hy-
tops of the plant is smoked (1%-5% THC), hashish or          drocarbons such as benzo[α]pyrene. Benzo[α]pyrene is
dried resin of the plant is smoked in a pipe (6%-10%         present at a higher concentration in marijuana tar than
THC), or hash oil is taken (30%-60% THC).6 It has been       in tar from tobacco.20 Other substances, such as carbon
reported that there is little evidence that THC is           monoxide, hydrogen cyanide, and nitrosamines, are
mutagenic or carcinogenic.7 One study in which rats          present in marijuana smoke at similar levels to tobacco
and mice received THC in corn oil reported that there        smoke. Marijuana smoking involves the inhalation of
was no evidence for the carcinogenicity of THC.8 In          approximately three times the amount of tar and reten-
fact, some research groups examined THC and other            tion of one-third more the amount of tar in the respira-
marijuana constituents as antitumor agents. THC was          tory tract relative to tobacco smoking.21 Subjects inhale
shown to cause apoptosis in human prostate cancer            marijuana with one-third greater volume and hold
cells PC-39 and in C6.9 glioma cells,10 as well as the re-   their breath with marijuana four times longer than for
gression of malignant gliomas in Wistar rats. 11             tobacco. These patterns of smoking a marijuana ciga-
Cannabigerol, a nonpsychoactive cannabinoid, was             rette may expose the head and neck area, especially
shown to inhibit growth of human oral epitheloid car-        the oral cavity, to more smoke particulates than a to-

104S    J Clin Pharmacol 2002;42:103S-107S

bacco cigarette. It seems that regardless of the THC          multiple countries indicate that marijuana use is more
content, marijuana smoking involves greater depo-             common than expected in young adults with head and
sition of tar compared to tobacco smoking. This may           neck cancer.25,26 One case series scanned surgical pa-
explain the observation that smoking a few mari-              thology records in one hospital for all cases of upper
juana cigarettes and smoking more than 20 tobacco             and lower respiratory tract squamous cell cancers in
cigarettes had similar effects on the histopathology of       patients younger than 40 years of age. Taylor27 found
the tracheobronchial epithelium.22 It is of interest to ex-   that 7 of the 10 cases had regular or heavy marijuana
amine whether the effect of one marijuana cigarette is        use documented in their hospital records.
also more harmful to the head and neck region than               In addition to case studies for head and neck cancers
smoking one tobacco cigarette.                                and respiratory tract cancers, there have been a few
                                                              case studies on oral lesions and marijuana use. In a ret-
Molecular Alterations                                         rospective study including 105 oral papilloma cases,
                                                              all of the subjects had smoked marijuana for at least
Bronchial mucosa biopsy specimens of marijuana                once a day for 2 years.28 Oral papillomas are benign ep-
smokers without any disease showed more molecular             ithelial tumors of the oral cavity that are not consid-
abnormalities than nonsmokers.23 This study included          ered to be premalignant lesions. A total of 152
28 nonsmokers and 76 subjects who smoked tobacco,             leukoedema, 4 oral leukoplakia, and 6 erythroplakia
marijuana, and/or cocaine. Among the smokers, 12              lesions were identified among 266 subjects who
subjects smoked marijuana only. The molecular mark-           smoked marijuana, methaqualone, and tobacco.29
ers examined included Ki-67 (a proliferation marker),         Methaqualone is a combination of marijuana, tobacco,
EGFR (epidermal growth factor receptor), p53 (tumor           and crushed methaqualone tablets, unique to the South
suppressor), and DNA ploidy (marker of genetic insta-         African region. Leukoedema is a benign gray-white le-
bility). Abnormalities in Ki-67, EGFR, and p53 were           sion that is not considered to be an oral premalignant
more common in subjects who smoked any of these               lesion. Oral leukoplakia is the most common oral
three substances compared to nonsmokers. Subjects             premalignant lesion while erythroplakia is a rare but
who only smoked marijuana had a higher percentage of          severe oral premalignant lesion. Of the 6 erythroplakia
abnormalities in Ki-67 (92%) than nonsmokers (29%)            cases, 3 marijuana smokers did not smoke tobacco and
(p < 0.001). A higher percentage of abnormalities in          4 marijuana smokers did not drink alcohol. This case
EGFR was also shown for marijuana-only smokers                report suggests an association of marijuana with oral
(58%) than nonsmokers (7%) (p < 0.001). The preva-            premalignant lesions, but epidemiological studies us-
lence of abnormal DNA ploidy was higher among mari-           ing well-conceived control groups are necessary to in-
juana smokers (13%) compared to nonsmokers (5%),              fer any association with confidence.
though the difference was not statistically significant.
The observation of multiple molecular alterations sup-        Cohort Study
ports an association between marijuana and cancer
through the mechanism of field cancerization effects          One prospective cohort study from Kaiser Permanente
on the bronchial epithelium. The field cancerization          in California found that marijuana use, measured from
theory proposes that carcinogenic exposures can cause         a voluntary self-administered research questionnaire
simultaneous genetic defects on the epithelium of the         as part of a multiphasic health checkup, was not asso-
upper aerodigestive tract, putting the epithelium at          ciated with increased risk of all cancers or smoking-
high risk for the development of multiple lesions.24          related cancers after 8 years of follow-up. Nontobacco
Since marijuana smoking may cause field                       smokers who used marijuana were more likely to de-
cancerization of the bronchial epithelium, studies need       velop prostate cancer, and there was nearly an in-
to be conducted to examine whether it can cause field         creased risk for cervical cancer, but multiple compari-
cancerization of the upper aerodigestive tract.               sons were completed.30 Even though the sample was
                                                              64,855 individuals, the relatively young age of the sam-
CASE STUDIES                                                  ple and few cases of cancer limited the power of this
The available evidence on the possible carcinogenicity
of marijuana and the similarities between marijuana           Case Control Study
and tobacco makes it plausible to determine if mari-
juana use is a risk factor for the development of head        A hospital-based case control study was conducted at
and neck cancer in humans. Several case studies from          Memorial Sloan-Kettering Cancer Center between 1992

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                                                    HASHIBE ET AL

and 1994.1 The relationship between marijuana use             smoking such as greater inhalation of tar, longer reten-
and head and neck cancer was investigated using a case        tion of marijuana smoke, and greater volume of
control study of 173 previously untreated cases with          marijuana smoke inhaled. Furthermore, marijuana
pathologically confirmed diagnoses of squamous cell           smokers appear to have more molecular alterations on
carcinoma of the head and neck and 176 cancer-free            the bronchial mucosa than nonsmokers. Field
controls. Exposure data were collected using a struc-         cancerization may be occurring due to marijuana expo-
tured questionnaire, which included history of tobacco        sure on the bronchial epithelium. Case studies sug-
smoking, alcohol use, and marijuana use. The associa-         gested an association of marijuana smoking with head
tions between marijuana use and head and neck cancer          and neck cancers, respiratory cancer, and oral
were analyzed by Mantel-Haenszel methods and logis-           premalignant lesions. A case control study reported an
tic regression models. Controlling for age, sex, race, ed-    association between head and neck cancers and mari-
ucation, alcohol consumption, pack-years of cigarette         juana use, but a cohort study did not show an increased
smoking, and passive smoking, the risk of squamous            risk of cancers with respect to marijuana use. Further
cell carcinoma of the head and neck was increased with        epidemiological studies are necessary to determine
marijuana use (odds ratio [OR] comparing ever with            whether marijuana smoking can cause oral
never users = 2.6, 95% confidence interval [CI] = 1.1,        premalignant lesions and cancer, possibly due to field
6.6). Dose-response relationships were observed for           cancerization of the upper aerodigestive tract.
frequency of marijuana use per day (p for trend < 0.05)
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