Workshop on Clinical Consequences of Marijuana

United States

Introduction

This meeting was planned, organized, and conducted by Jag H. Khalsa, Ph.D., of the Center on AIDS and Other Medical Consequences of Drug Abuse (CAMCODA), and Rao Rapaka, Ph.D., of the Division of Neuroscience and Behavioral Research, both within the National Institute on Drug Abuse, NIH. A group of nationally and internationally recognized clinicians and scientists reviewed the available information and presented and discussed new data on the clinical consequences of marijuana. The topics covered included the general health consequences of marijuana as well as the cardiopulmonary-respiratory, endocrine-reproductive, immune, and treatment of consequences of marijuana. Speakers also touched upon the issue of translating/extrapolating findings from the in vitro and in vivo basic animal models to clinical situations. Finally, they made recommendations for future research. An executive summary of the proceedings for publication in a professional journal is in preparation. In addition, the proceedings will be published as a special supplement to a professional journal.

Abstracts

Marijuana and Immune Function in HIV/AIDS Patients

Donald I. Abrams, M.D.
University of California, San Francisco

Dr. Abrams is Professor of Clinical Medicine at the University of California, San Francisco, and Assistant Director of the Positive Health Program and Head of the Hematology-Oncology Section at San Francisco General Hospital. He has been conducting clinical investigations in HIV/AIDS since 1981.

Cannabinoids have been reported to have both immune-stimulating and immunosuppressive effects. Patients with HIV-1 infection may be especially vulnerable to such potential consequences. A randomized, prospective, controlled trial investigated the short-term effects of cannabinoids in patients on a stable antiretroviral regimen. Subjects received either a 3.95 percent THC marijuana cigarette (20), dronabinol 2.5 mg (22), or an oral placebo (20) three times daily during the 21-day inpatient experimental period. Immune system assays, including an immunophenotyping panel, natural killer-cell (NK) function, lymphoproliferation assay, and cytokine flow cytometry, were conducted at baseline and weekly thereafter. Median CD4+ and CD8+ lymphocyte counts rose in all three groups, with significantly greater increases in CD8+ T lymphocytes in the marijuana group relative to placebo recipients (p=0.007). There were no significant changes in naive/memory cells, activated lymphocytes, B cell, or NK numbers over the study period that could be directly attributed to the administration of cannabinoids. No untoward effects of cannabinoids on immune system function in HIV patients were found in this short trial.

Behavioral Consequences of Marijuana Dependence

Alan J. Budney, Ph.D.
University of Vermont

Dr. Budney is Associate Professor of Psychiatry and Psychology at the University of Vermont. He received his Ph.D. in clinical psychology from Rutgers University and completed his postdoctoral studies at the University of Vermont, where he assisted in the development of novel behavioral treatments for cocaine dependence. Dr. Budney's current research focuses on behavioral treatments for marijuana dependence and enhancing the understanding of marijuana withdrawal.

Treatment-seeking for marijuana dependence has increased almost twofold over the past 10 years. This presentation addressed the clinical significance of various behavioral aspects of marijuana dependence. Data from Dr. BudneyÕs clinical laboratory and other labs were used to characterize the adverse consequences, motivation to change, abstinence effects, and response to treatment associated with marijuana abuse and dependence. These data were compared with similar data from other types of substance dependence. Findings suggest that marijuana dependence is more similar than dissimilar to other forms of drug dependence.

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• Budney AJ, Higgins ST, Radonovich KJ, Novy PL. (2000) Adding voucher-based incentives to coping skills and motivational enhancement improves outcomes during treatment for marijuana dependence. Journal of Consulting and Clinical Psychology 68(6):1051-1061.
• Budney AJ, Hughes JR, Moore BA, Novy PL. (in press) Marijuana abstinence effects in marijuana smokers maintained in their home environment. Archives of General Psychiatry.
• Budney AJ, Novy P, Hughes JR. (1999) Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction 94(9):1311-1322.
• Budney AJ, Radonovich KJ, Higgins ST, Wong CJ. (1998) Adults seeking treatment for marijuana dependence: A comparison to cocaine-dependent treatment seekers. Experimental and Clinical Psychopharmacology 6(4):419-426.
• Higgins ST, Wong CJ, Badger GJ, Ogden DE, Dantona RL. (2000) Contingent reinforcement increases cocaine abstinence during treatment and 1 year of follow-up. Journal of Consulting and Clinical Psychology 68(1):64-72.
• Project Match Group (1997). Matching alcoholism treatments to client heterogeneity: Project MATCH posttreatment drinking outcomes. Journal of Studies on Alcohol 58(1):7-29.
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• Stephens RS, Roffman RA, Simpson EE. (1993) Adult marijuana users seeking treatment. Journal of Consulting and Clinical Psychology 61(6):1100-1104.
• Stephens RS, Roffman RA, Simpson EE. (1994). Treating adult marijuana dependence: A test of the relapse prevention model. Journal of Consulting and Clinical Psychology 62(1):92-99.
• Substance Abuse and Mental Health Services Administration. (1998) National Admissions to Substance Abuse Treatment Services: The Treatment Episode Data Set (TEDS) 1992-1996. Rockville, MD: U.S. Department of Health and Human Services.

Aberrant Ligand-Receptor Signaling With Cannabinoids Affects Preimplantation Embryo Development and Implantation

Sudhansu K. Dey, Ph.D.
B.C. Paria
University of Kansas Medical Center

Dr. Dey is University Distinguished Professor at the Department of Molecular and Integrative Physiology, University of Kansas Medical Center in Kansas City. He has authored more than 200 articles, primarily in the field of preimplantation embryo and implantation biology, with special reference to growth factors, cytokines, vasoactive agents, and cannabinoids. Dr. Dey is a National Institute of Child Health and Human Development/National Institutes of Health MERIT Awardee.

One of the concerns about exposure to cannabinoids is their adverse effects on reproductive functions, including retarded embryo development, fetal loss, and pregnancy failure. Preimplantation embryo development to the blastocyst stage and preparation of the uterus to the receptive stage are essential to successful implantation. Preimplantation mouse embryos express high-affinity cannabinoid receptorsÑCB(1)Ñand this receptor population is higher in the embryo than in the brain. Furthermore, the mouse uterus contains high levels of anandamide; the levels are lower at the implantation sites but higher at the interimplantation sites. The levels of anandamide are inversely related to those of anandamide hydrolase activity in the uterus. These findings suggest that preimplantation mouse embryos are possible targets for cannabinoids. Indeed, cannabinoids interfere with wild-type, but not with CB(1)/CB(2) mutant, mouse preimplantation embryos. Continuous infusion of (-)THC with P450 inhibitors alone via miniosmotic pumps during the preimplantation period prevents embryo implantation in wild-type, but not in CB(1)/CB(2) knock-out, mice. Furthermore, this inhibition is reversed by coadministration of SR141716A in wild-type mice, suggesting a role for CB(1)-R in this response. This implies that a protective mechanism exists for embryos against the adverse effects of cannabinoids during early pregnancy. In addition, aberrant expression of embryonic CB(1)-R and/or aberrant uterine anandamide synthesis and hydrolysis may contribute to unexplained infertility in women.

Endocrine Effects of Marijuana

Adrian S. Dobs, M.D., M.H.S.
Johns Hopkins University

Dr. Dobs is Professor of Medicine and Oncology, Vice-Chair of the Department of Medicine for Clinical Research, and Director of the School of Medicine Clinical Trials Unit, Johns Hopkins University. She received her undergraduate degree at Cornell University, medical school training at Albany Medical College, and clinical training in internal medicine at Montefiore Hospital, Albert Einstein College of Medicine in New York City. Dr. Dobs came to Johns Hopkins for a fellowship in endocrinology and metabolism where she also received a masterÕs in health sciences degree in clinical epidemiology from the Johns Hopkins School of Public Health. She is an investigator in the field of male gonadal function and is particularly interested in new forms of male hormone replacement therapy. As Director of the Clinical Trials Unit, she oversees a team of individuals dedicated to facilitating clinical research within an academic medical center environment. Dr. Dobs was recently awarded an $8 million National Institutes of Health grant to direct the Johns Hopkins Complementary and Alternative Cancer Center.

There are multiple metabolic and endocrine effects of marijuana use. Most of the studies are from the 1970s and early 1980s and suggest that marijuana works to inhibit the secretion of gonatrophins from the pituitary gland. Other studies suggest a direct effect of marijuana on the primary gonad, the ovary or testis. Marijuana likely acts to inhibit hypothalamic function. Remaining areas for investigation include the true incidences of hormonal and metabolic abnormalities with many uses and the mechanism of action. Although the effects are subtle, the metabolic consequences of marijuana use need to be further investigated since marijuana may become a more commonly used substance for recreational and medicinal purposes.

Marijuana Use is not Associated With Head, Neck or Lung Cancer in Adults Younger Than 55 Years: Results of a Case Cohort Study

Daniel E. Ford, M.D., M.P.H.
H.T. Vu, C. Hauer, K.L. Helzlsouer, J.C. Anthony
Johns Hopkins University School of Medicine

Dr. Ford is Associate Professor of Medicine, Epidemiology and Health Policy and Management at the Johns Hopkins University School of Medicine. He graduated from Cornell University and received his medical degree from the State University of New York, Buffalo, completed his residency in internal medicine at Johns Hopkins, and received a masterÕs of public health degree at the same institution. After 2 years of postgraduate training at the National Institute of Mental Health, Dr. Ford rejoined the faculty at Johns Hopkins. For more than a decade he has been a member of the team conducting research on the relationship between psychiatric disorders and physical health in the Baltimore Epidemiologic Catchment area study. Dr. Ford has completed several studies related to tobacco smoking cessation and currently is funded by the National Cancer Institute to develop an Internet-based smoking cessation program. He directs a fellowship program in primary care health services, has published more than 60 articles and book chapters, and is currently Associate Editor for the Journal of General Internal Medicine.

Marijuana smoke contains carcinogens. Several small case series and one potentially flawed small case-control study have provided evidence that marijuana is associated with head and neck cancer. We conducted a large case-control study to address this issue. We recruited 164 participants with consecutive incident cases of head, neck, or lung cancer (adults younger than 55 years) in the Baltimore region from four hospitals between 1994 and 1999. Also recruited as controls were 526 individuals (younger than 55 years) from the Baltimore Epidemiologic Catchment Area study based on a random household sample. Cases and controls completed identical assessments of exposures via self-report, direct computer entry. Lifetime and current uses of marijuana, tobacco, and alcohol were assessed with detailed questions of use by 5- to 10-year intervals of their lives, by weekend and weekday consumption, and by mode of administration of the substance. Control patients were younger (44 vs. 49 years, p<.001), more likely to be female (62 percent vs. 34 percent, p<.001), and less likely to be white (55 percent vs. 69 percent, p<.01). Substance use was commonly reported in both cases and controls (lifetime means, 125,000 tobacco cigarettes, 27,000 alcoholic drinks, and 8,700 marijuana joints). Consistent with other studies, use of tobacco and alcohol was associated with these cancers. Ever use of marijuana (66 percent controls vs. 60 percent cases, p=.17) and lifetime marijuana joints (8,135 vs. 8,946 joints, p=.64) were not associated with cancer. Marijuana use every day for 1 month or longer also was not associated with those cancers, with or without adjustment (19 percent controls, 12 percent cases, odds ratio=.74, 95 percent confidence interval .38, 1.43). Age of first use of marijuana, depth of inhalation of marijuana, and use of pipe versus joint for marijuana were not related to these cancers. Although power was limited, marijuana use was not associated with cancer for those who never used tobacco. Adjusting for all sociodemographic factors, family history of these cancers, lifetime tobacco use, and lifetime alcohol use did not change the relationship between marijuana and cancer. The balance of evidence from this study, the largest case-control study addressing marijuana use and cancer to date, does not favor the idea that marijuana as commonly used in the community is a major causal factor for head, neck, or lung cancer in young adults.

Developmental Effects of Prenatal Exposure to Marijuana

Peter Fried, Ph.D.
Carleton University, Ottawa, Canada

Dr. Fried is Professor of Psychology at Carleton University in Ottawa, Canada. For more than 20 years he has investigated whether prenatal exposure to marijuana, cigarettes, or both affects the development and behavior of children and adolescents. Dr. Fried's research has made significant contributions not only to documenting infancy and childhood consequences but also to exploring possible mechanisms for those consequences. Participants in this research have been followed longitudinally since birth and are now young adults. His present studies permit analyses of drug use by these young adults while continuing to examine developmental outcomes associated with prenatal marijuana and cigarette exposure.

In spite of marijuana being the most widely used illicit drug among women of reproductive age, there is a relative paucity of literature dealing with the neurobehavioral consequences in offspringÑparticularly long-term effects. This presentation described the consequences of prenatal exposure on aspects of cognitive functioning, attention, and visual analysis and hypothesis testing in an adolescent offspring sample that has been followed prospectively since birth. The consequences of fetal marijuana exposure are subtle and appear to affect not global intelligence but rather aspects of executive function (EF). EF is a nonunitary set of cognitive-behavioral abilities critical in effortful, nonroutine, goal-oriented situations primarily subserved by the prefrontal region of the brain. These findings, which can be differentiated from prenatal exposure to cigarettes in the same sample were discussed in terms of effects (or lack of effects) across different ages and the extant general marijuana and prefrontal literature.

• Fried PA, Smith AM. (2001) A literature review of the consequences of prenatal marihuana exposure. An emerging theme of a deficiency in aspects of executive function. Neurotoxicology and Teratology 23(1):1-11.
• Fried PA, Watkinson B. (2000) Visuoperceptual functioning differs in 9- to 12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicology and Teratology 22(1)11-20.

Long-Term Neurocognitive Consequences of Marijuana: A Meta-Analytic Study

Igor Grant, M.D.
Raul Gonzalez, Catherine Carey, Loki Natarajan
Center for Medicinal Cannabis Research, University of California, San Diego (UCSD)

Dr. Grant is Professor and Executive Vice-Chair of the Department of Psychiatry at UCSD and Associate Chief of Psychiatry for Research at the San Diego Veterans Affairs Healthcare System. He is also Director of the University of California Center for Medicinal Cannabis Research. Dr. Grant also directs the National Institute of Mental Health-funded HIV Neurobehavioral Research Center and the NIDA-funded program project "NeuroAIDS: Effects of Methamphetamine".

The possibility that cannabinoids might be used medicinally for chronic diseases emphasizes the need to understand the potential long-term central nervous system (CNS) consequences of these compounds. Using a meta-analytic approach, the researchers reviewed the world literature on neuropsychological studies of chronic marijuana users. Using a "wide-net" approach, two raters initially identified 1,030 studies. These were winnowed to 117 studies that potentially addressed long-term effects; after application of predefined criteria for study adequacy and content, reviewers identified eight studies that met all criteria and five additional studies that met slightly liberalized criteria. Neuropsychological results were grouped into eight ability domains, and effect sizes were calculated by domain for each study and for the full set of studies. The effect sizes (99 percent confidence intervals [CIs]) ranged from -.004 (-.031, .023) for the perceptual motor domain to +.227 (.029, .425) for the domain of learning. For seven of the eight neuropsychological ability areas, the CI for effect sizes overlapped zero, indicating no significant effect. In the learning domain, a possibly small effect was noted in the direction of more difficulties in learning by regular cannabis users. The overall pooled effect size across domains was .141 (.003, .279), indicating essentially no global effect. Few studies on the chronic CNS effects of cannabis meet current research standards. The 13 studies that met the criteria yielded no basis for concluding that long-term cannabis use is associated with generalized neurocognitive decline, with the possible exception of slight decrements in the area of learning new information.

Consequences of Smoked Marijuana in Healthy and HIV-Infected Marijuana Smokers

Margaret Haney, Ph.D.
Columbia University

Dr. Haney is Assistant Professor of Clinical Behavioral Biology at Columbia University. Her research interests include characterizing marijuana dependence under controlled laboratory conditions, exploring potential pharmacotherapy for the treatment of marijuana dependence and cocaine dependence, and determining the role of cannabinoids in the treatment of HIV.

Data were presented from two avenues of marijuana research. First, they showed that daily marijuana smoking in healthy individuals produces dependence, as demonstrated by withdrawal symptoms such as increased irritability and anxiety and decreased food intake (Haney et al. 1999a,b). Maintenance on two antidepressant medications to treat marijuana withdrawal symptoms has been investigated: (1) sustained-release bupropion (BUP-SR: 0, 300 mg/day) and (2) nefazodone (0, 450 mg/day. Participants were regular marijuana smokers who lived in a residential laboratory in groups of two to four. While inpatients, participants smoked active marijuana (3.1 percent THC) repeatedly for 4 days, followed by 8 to 12 days of placebo marijuana (0.0 percent THC) smoking. Results show that during marijuana abstinence, (1) BUP-SR increased ratings of irritability, depression, and stomach pain and decreased food intake compared with placebo (Haney et al. 2001), and (2) nefazodone decreased anxiety during marijuana withdrawal but did not alter ratings of irritability and misery compared with placebo. The second avenue of research focused on the use of cannabinoids to treat HIV. Given that there are few scientific data contributing to the policy debates on medical marijuana, this study directly compared the effects of oral THC (0, 10, 20, 30 mg PO) to smoked marijuana (0.0, 1.8, 2.8, 3.9 percent THC) in marijuana smokers with HIV-related weight loss. All participants were maintained on HIV medications. Drugs were administered using a within-subject, staggered double-dummy design. Multiple dimensions of behavior, including food intake, mood, and cognitive performance, were measured. Preliminary data from four participants were presented.

• Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. (1999a) Abstinence symptoms following oral THC administration to humans. Psychopharmacology 141(4):385-394.
• Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. (1999b) Abstinence symptoms following smoked marijuana in humans. Psychopharmacology 141(4):395-404.
• Haney M, Ward AS, Comer SD, Hart CL, Foltin RW, Fischman MW. (2001) Bupropion SR worsens mood during marijuana withdrawal in humans. Psychopharmacology 155(2):171-179.

Cardiovascular Effects of Marijuana: A Review

Reese T. Jones, M.D.
University of California, San Francisco

Dr. Jones is Professor of Psychiatry at the University of California, San Francisco (UCSF). With his UCSF colleagues, he began National Institutes of Health-supported clinical psychopharmacology studies of marijuana in 1968. Dr. Jones' topics of interest include characterization of cannabinoid tolerance and dependence and cardiovascular, EEG, behavioral, and visual system effects.

Marijuana or THC typically elicits a variety of cardiovascular responses: increased heart rate and supine blood pressure or, after higher doses, orthostatic hypotension. Cardiac output increases, peripheral vascular resistance decreases, and maximum exercise performance is decreased. In animals a transient pressor response followed by bradycardia and hypotension is the usual pattern. The intensity and character of effects are a function of dose and recent marijuana exposure. Tolerance to initial effects appears rapidly. With prolonged exposure, supine blood pressure falls, orthostatic hypotension disappears, blood volume increases, heart rate slows, and circulatory responses to exercise and Valsalva are diminishedÑconsistent with centrally mediated, reduced sympathetic, and enhanced parasympathetic activity (evident in animal studies). MarijuanaÕs cardiovascular effects do not seem to cause serious health problems for young, healthy users. However, marijuana smoking by older people with cardiovascular disease poses greater risks because of the resulting increased cardiac work, catecholamines, carboxyhemoglobin, and hypotension.

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• Niederhoffer N, Szabo B. (2000) Cannabinoids cause central sympathoexcitation and bradycardia in rabbits. Journal of Pharmacology and Experimental Therapeutics 294(2):707-713.

Cardiovascular and Medical Complications of Marijuana: A Retrospective Cohort Study

Arthur L. Klatsky, M.D.
Kaiser Permanente, Oakland, California

Dr. Klatsky is Senior Consultant in Cardiology at the Kaiser Permanente (KP) Medical Center and Adjunct Investigator at KP's Division of Research in Oakland, California. Since 1976 he has been Principal Investigator of a series of studies on alcohol and health. He has written and lectured extensively. Dr. Klatsky received his M.D. degree from Harvard University.

The relationship of marijuana use to health outcomes was examined in a study population of more than 65,000 KP Medical Care Program enrollees, ages 15 through 49 years, who completed questionnaires about smoking habits, including marijuana use, between 1979 and 1985. Marijuana use had little effect on non-AIDS mortality in men and on total mortality in women (Sidney et al. 1997a). Marijuana use and cancer were not associated in overall analyses, but association in nonsmokers of tobacco cigarettes suggested that marijuana use might affect certain site-specific cancer risks (Sidney et al. 1997b). Although overall marijuana use was not associated with outpatient visits for injury within 3 years of marijuana use ascertainment (Braun et al. 1998), it was associated with small increased risks of outpatient visits for injuries, respiratory illnesses, and other types of illnesses (Polen et al. 1993). Findings were also presented from unpublished data regarding hospitalizations for injuries and cardiovascular diseases.

• Braun BL, Tekawa IS, Gerberich SG, Sidney S. Marijuana use and medically attended injury events. (1998) Annals of Emergency Medicine 32(3 Pt 1):361-363.
• Polen MR, Sidney S, Tekawa IS, Sadler M, Friedman GD. (1993) Health care use by frequent marijuana smokers who do not smoke tobacco. Western Journal of Medicine 158(6):595-601.
• Sidney S, Beck JE, Tekawa IS, Quesenberry CP, Friedman GD. (1997a) Marijuana use and mortality. American Journal of Public Health 87(4):585-590.
• Sidney S, Quesenberry CP Jr, Friedman GD, Tekawa IS. (1997b) Marijuana use and cancer incidence (California, United States). Cancer Causes and Control 8(5):722-728.

Marijuana Withdrawal Syndrome in the Animal Model

Billy R. Martin, Ph.D.
Virginia Commonwealth University

Dr. Martin received his Ph.D. in pharmacology from the University of North Carolina, Chapel Hill, in 1974. Following postdoctoral training at the University of Uppsala (Sweden) and the University of Oxford (England), he became Professor of Pharmacology and Toxicology at Virginia Commonwealth University (VCU) in 1987. He is currently Louis and Ruth Harris Professor and Chair of the Department of Pharmacology and Toxicology at VCU. Dr. Martin served as the first President of the International Cannabis Research Society, Advisor to the World Health Organization, Member of the Institute of Medicine Advisory Panel, and President of the College on Problems of Drug Dependence. He received the VCU Distinguished Scholarship Award in 1996, Virginia Outstanding Scientist Award in 1998, and the ICRS Mechoulam Award this year. Dr. Martin's laboratory is funded by the National Institute on Drug Abuse. His research focuses on identifying the consequences of both acute and chronic exposure to drugs of abuse and understanding how these drugs affect the brain as well as elucidation of the mechanisms by which they produce tolerance and dependence.

Dr. Martin's laboratory as well as that of Tsou demonstrated that rats treated with THC, either by continuous infusion or repetitive injections, elicited a strong behavioral syndrome when challenged with SR 141716A. The most prominent signs were wet-dog shakes; less frequent signs included grooming, retropulsion, stretching, and so forth. The synthetic cannabinoid WIN 55,212 also produced a similar but milder syndrome in rats merely by terminating the infusion. SR 141716A challenge also can elicit a withdrawal syndrome in mice following five daily subcutaneous injections of low doses (10 mg/kg) of THC. The most prominent signs were headshakes and paw tremors. Mice exposed repetitively to marijuana smoke exhibited a dependence syndrome similar to that produced by THC. Finally, SR 141716A challenge precipitated a withdrawal syndrome in dogs that had been treated repetitively with THC for several days. Cannabinoids as well as marijuana readily produce a dependence syndrome in several animals. The development of cannabinoid dependence in laboratory animals is consistent with the dependence that occurs in humans. These studies have been supported by NIDA grants DA-03672, DA-02396, and P01-DA-09789.

Role of Cannabinoid Receptors in Health

Raphael Mechoulam, M.Sc., Ph.D.
Hebrew University, Medical Faculty, Jerusalem , Israel

Dr. Mechoulam received his M.Sc. degree in biochemistry from the Hebrew University in Jerusalem in 1953 and his Ph.D. degree in organic chemistry from the Weizmann Institute of Science in Rehovot, Israel, in 1958. After completing postdoctoral work at the Rockefeller Institute in New York (1959-1960), he returned to Rehovot where he initiated work on the chemistry of various natural products, including cannabinoids. In 1964 Dr. Mechoulam identified the active hashish constituent, tetrahydrocannabinol, and numerous other constituents, such as cannabigerol, cannabichromene, cannabinoid acids, and so forth. In 1966 he was appointed Head of the Laboratory of Natural Products at the Medical Faculty of Hebrew University. In 1975 Dr. Mechoulam became the Lyonel Jacobson Professor of Medicinal Chemistry, and from 1979 to 1982 he was Rector (equivalent to provost) of the University. Over the years Dr. Mechoulam has been a visiting professor at various universities, has presented invited and name lectures at meetings, and has received numerous prizes. He will receive an honorary Ph.D. degree from Ohio State University in August 2001. Dr. Mechoulam's research interests include the chemistry and biological activity of natural products and synthetic drugs.

Over the past decade, since the discovery of the cannabinoid receptors CB(1) and CB(2) and the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), the cannabinoid system has been examined in great detail. In most of their pharmacological activities, the effects of the endocannabinoids parallel those of THC, the active constituent of marijuana. A myriad of pharmacological effects of the endocannabinoids are noted in the central and peripheral nervous systems, as well as in the immune , cardiovascular, and reproductive systems; however, the physiological roles played by the endocannabinoids are not yet well defined. Solid evidence exists that the endocannabinoids are involved in the amelioration of pain, blocking of working memory, enhancement of appetite and suckling, cardiovascular modulationÑincluding blood pressure lowering during shockÑand embryo development. Work at the National Institutes of Health has demonstrated that 2-AG affects endothelin-1-induced Ca mobilization and other effects. It seems reasonable to assume that the endocannabinoid system is also of physiological importance in psychomotor control and in the regulation of some immune responses. Additional cannabinoid receptors have been postulated; cannabidiol may act through one of them. This major, nonpsychotropic plant cannabinoid has been shown to be antiepileptic, anti-inflammatory, and possibly anxiolytic; it is a potent antioxidant. The researchers have recently shown that although that it does not bind to the known CB(1) and CB(2) cannabinoid receptors, it inhibits anandamide hydrolysis by fatty acid amide hydrolase and is an inhibitor of its uptake. Palmitoylethanolamide, which does not bind to either CB(1) or CB(2), is also anti-inflammatory and possibly binds to one of the yet putative receptors.

Ongoing Case-Control Study of Marijuana Use and Cancer

Hal Morgenstern, Ph.D.
D.P. Tashkin, S. Greenland, Z-F Zhang, W. Cozen, T.M. Mack
University of California, Los Angeles

Dr. Morgenstern, Professor of Epidemiology at the University of California, Los Angeles (UCLA) School of Public Health, is a well-known epidemiologist with extensive research experience in a wide range of public health areas, including musculoskeletal conditions, cancers, neuropsychiatric disorders, nonintentional injuries, cardiovascular disease, psychosocial aspects of disease, occupational and environmental health, research methods, and access to and quality of health care. He is Principal Investigator of three federally funded projects on medical versus chiropractic care in the treatment of low back pain, the use of cervical manipulation versus mobilization in the treatment of neck pain, and the effects of marijuana use on the risks of lung and upper aerodigestive tract (UAT) cancers. Among Dr. Morgenstern's recent projects are studies of the effects of occupational exposures to low-level ionizing radiation and chemicals on cancer mortality in aerospace workers, the effects of pool-fencing ordinances and other factors on childhood drowning in Los Angeles County, the impact of a physician-directed intervention on inappropriate prescribing of medications to nursing home patients, the occurrence of tardive dyskinesia among psychiatric patients treated with antipsychotics, and methods of ecologic analysis in epidemiology. He has authored numerous publications in the biomedical literature, including the textbook Epidemiologic Research: Principles and Quantitative Methods, and has received four teaching awards in the Schools of Public Health at Yale University (1985) and UCLA (1989, 1997, and 1999).

Stress experiences in adulthood appear to have a strong influence on susceptibility to drug-taking in various animal models and have also been observed in clinical populations suffering from substance abuse. From the animal data, it is evident that repeated stress not only increases the propensity to drug-taking, but also augments the psychomotor effects of psychostimulants, a phenomenon that is termed behavioral sensitization. For the most part, stress-induced behavioral sensitization is dependent on glucocorticoid hormone action (Piazza and Le Moal, 1996). Central limbic-hypothalamic-pituitary-adrenal (LHPA) axis mechanisms (possibly corticotropin-releasing hormone [CRH]) also appear to be critical. It is apparent that an increased secretion of glucocorticoids or higher sensitivity to the effects of this hormone, either naturally present in certain individuals or induced by stress in others, increases the vulnerability to develop drug intake, possibly through an enhancement of the activity of mesencephalic dopaminergic neurons. In addition, impulsivity and risk-taking behavior, vulnerability traits for drug abuse, have been linked to serotonergic mechanisms. A number of clinical and epidemiological studies have found a strong association between psychosocial stressors early in life (e.g., parental loss, child abuse) and an increased risk for depression, anxiety, impulsive behavior, and substance abuse in adulthood (Kendler et al., 1992). Thus, intrinsic vulnerability to drug intake may be influenced by the exposure to adverse early life experience that may lead to a permanent alteration of the normal physiology of the LHPA and other neurotransmitter systems that mediate drug abuse. Studies using rodents also suggest that early experience may induce long-lasting modifications on individual predisposition to self-administration of psychostimulants. Specifically, prenatal stress is associated with prolonged CORT secretion in response to stress and increases both locomotor reactivity to amphetamine and amphetamine self-administration in adult offspring.

Despite public opinion that the potential medicinal benefits of marijuana outweigh its risks, several lines of evidence from biochemical, cellular, tissue, and animal studies provide a biologically plausible basis for the hypothesis that marijuana is a risk factor for respiratory tract cancers. Thus far, however, there is no epidemiologic evidence for this association, primarily because of the long induction/latency of human carcinomas and the infrequent use of marijuana in the general U.S. population before the late 1960s. The major objective of this 5-year project is to estimate the effects of marijuana use on the risks of lung cancer and upper aerodigestive tract (UAT) cancers among Los Angeles County residents who are younger than 60 years of age. Secondary objectives are to assess the interaction effects of marijuana and tobacco use, estimate the effects of other factors for which the epidemiologic evidence is inconsistent or sparse, and initiate a molecular study by obtaining tumor specimens for cases and buccal cells from cases and controls. The design is a population-based, case-control study involving 600 lung cancer cases, 600 UAT cancer cases, and 1,200 controls. Histologically confirmed cases are being identified by the rapid ascertainment system of the University of Southern California Cancer Surveillance Program. One control is being matched to each case on age, gender, and neighborhood. The major source of data is personal interviews conducted with all subjects in their homes.

Neuropsychological Performance in Long-Term Cannabis Users

Harrison G. Pope, Jr., M.D.
Harvard Medical School and McLean Hospital

Dr. Pope is Professor of Psychiatry at Harvard Medical School and Chief of the Biological Psychiatry Laboratory at the McLean Hospital Alcohol and Drug Abuse Research Center in Belmont, Massachusetts. He has authored more than 300 published papers on a range of topics in psychiatry, including substance abuse, eating disorders, mood disorders, and psychopharmacology.

The cognitive effects of long-term cannabis use are insufficiently understood. Most studies concur that cognitive deficits persist at least several days after stopping heavy cannabis use (Pope et al. 1995, Pope and Yurgelun-Todd 1996, Fletcher et al. 1996, Struve et al. 1999, Patrick and Struve 2000). However, it is less clear whether such deficits persist long term, although a few findings suggest this possibility (Schwartz et al. 1989, Solowij 1998, Struve et al. 1998). The researchers administered neuropsychological tests to individuals who had smoked cannabis at least 5,000 times in their lives and to control subjects who had smoked no more than 50 times in their lives. The heavy smokers showed deficits on memory of word lists on days zero, 1, and 7 of a supervised abstinence period. By day 28, however, no significant differences were found between users and controls on any test, nor were there any significant associations between total lifetime cannabis consumption and test performance. These findings suggest that cannabis-associated cognitive deficits are reversible and related to recent cannabis exposure rather than irreversible and related to cumulative lifetime use.

• Fletcher JM, Page JB, Francis DJ, Copeland K, Naus MJ, Davis CM, Morris R, Krauskopf D, Satz P. (1996) Cognitive correlates of long-term cannabis use in Costa Rican men. Archives of General Psychiatry 53(11):1051-1057.
• Patrick G, Struve FA, (2000) Reduction of auditory P50 gating response in marihuana users: Further supporting data. Clinical Electroencephalography 31(2):88-93.
• Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd, D. (in press) Neuropsychological performance in long-term cannabis users. Archives of General Psychiatry.
• Pope HG Jr, Gruber AJ, Yurgelun-Todd D. (1995) The residual neuropsychological effects of cannabis: the current status of research. Drug and Alcohol Dependence 38:25-34.
• Pope HG Jr, Yurgelun-Todd D. (1996) The residual cognitive effects of heavy marijuana use in college students. Journal of American Medical Association 275(7):521-527.
• Schwartz RH, Gruenewald PJ, Klitzner M, Fedio P. (1989) Short-term memory impairment in cannabis-dependent adolescents. American Journal of Diseases of Children 143(10):1214-1219.
• Solowij N. (1998) Cannabis and Cognitive Functioning. Cambridge, UK: Cambridge University Press.
• Struve FA, Patrick G, Straumanis JJ, Fitz-Gerald MJ, Manno J. (1998) Possible EEG sequelae of very long duration marihuana use: Pilot findings from topographic quantitative EEG analyses of subjects with 15 to 24 years of cumulative daily exposure to THC. Clinical Electroencephalography 29(1):31-36.
• Struve FA, Straumanis JJ, Patrick G, Leavitt J, Manno JF, Manno BR. (1999) Topographic quantitative EEG sequelae of chronic marihuana use: A replication using medically and psychiatrically screened normal subjects. Drug and Alcohol Dependence 56(3):167-179.

Immune Function in Marijuana Smokers

Michael D. Roth, M.D.
Gayle C. Baldwin, Steven M. Dubinett, Sylvia M. Kiertscher, Ruth Choi, Li Zhu, Michael Yuan, Donald P. Tashkin
Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles

Dr. Roth is Professor of Pulmonary and Critical Care Medicine at the University of California, Los Angeles, School of Medicine. His research background is in the fields of immunology and lung biology, with special emphasis on tumor immunology and the interaction of inhaled drugs of abuse on the lung, immunity, and host defenses.

Nahas and collegues (Science 1974) first reported that the ability to activate T cells was suppressed in chronic marijuana smokers. This concept remained controversial until the discovery of cannabinoid receptors (CBr) on immune cells, providing a pathway by which _9-tetrahydrocannibinal (THC) might mediate immunologic effects. Using human cells, the researchers demonstrated that THC (5-5,000 ng/mL) produces a concentration-dependent reduction in T-cell proliferation and IFN-_ production via a CB2r-dependent pathway. At the level of gene expression, THC increased expression of Th1 cytokines (IFN-_/IL-2) and reduced expression of Th2 cytokines (IL-4/IL-5). Similar skewing of Th1/Th2 cytokine balance was observed in mice treated with THC in vivo and associated with accelerated tumor growth (Zhu et al., Journal of Immunology 2000) and ineffective responses to opportunistic infection (Klein et al., Journal of Immunology 2000). These effects are consistent with the defects in cell-mediated immunity and cytokine production previously observed in cells recovered from the lungs of chronic marijuana smokers (Baldwin et al., American Journal of Respiratory and Critical Care Medicine 1997). Suppression of cell-mediated immunity by _9-THC may place marijuana smokers at risk for infection or cancer.

Reproductive Effects of Marijuana: Sperm Fertility

Herbert Schuel, Ph.D.
L.J. Burkman, J. Lippes, A. Makriyannis, A. Giuffrida, D. Piomelli
State University of New York, Buffalo

Dr. Schuel is Professor of Anatomy and Cell Biology at the State University of New York (SUNY), Buffalo. He obtained his Ph.D. degree with L.V. Heilbrunn at the University of Pennsylvania. Subsequently, Dr. Schuel did postdoctoral work with C.B. Metz in the Oceanographic Institute, Florida State University; with N.G. Anderson in the Biology Division, Oak Ridge National Laboratory (as a National Institutes of Health [NIH] Postdoctoral Fellow); and with Lazlo Lorand in the Chemistry Department, Northwestern University. Before moving to Buffalo, he held academic positions in the Department of Biology, Oakland University; Department of Anatomy, Mount Sinai School of Medicine (where he received an NIH Research Career Development Award); and Department of Biochemistry, SUNY, Downstate Medical Center. Most of Dr. Schuel's research has been devoted to the study of fertilization in sea urchins. Using this model system, he discovered that sea urchin sperm contain functional cannabinoid receptors, which directly modulate sperm functions required for fertilization. On the basis of these findings, Dr. Schuel and his collaborators discovered that endocannabinoid signaling regulates sperm capacitation and fertilizing capacity in humans. He will present data showing that anandamide and related acyl-ethanolamides are constituents of human reproductive fluids.

Cannabinoids affect multiple reproductive functions, from hormone secretion to birth of offspring (Schuel et al. 1999). CB(1) is expressed in human testis and prostate, and arachidonylethanolamide (anandamide) (AEA) is produced in rodent testis, oviduct, and uterus (Galiegue et al. 1995, Sugiura et al. 1996, Paria et al. 1999). Cannabinoids and AEA act on sperm cannabinoid receptors to reduce sperm fertility by blocking the acrosome reaction in sea urchins (Schuel et al. 1999). The researchers report that specific binding of [3H]CP-55,940 to human sperm is saturable, suggesting that they express cannabinoid receptors. Ejaculated human sperm require several hours' exposure to secretions of the female reproductive tract before they acquire the capacity to fertilize eggs in vivo or incubation in appropriate culture media in vitro (Yanagimachi 1994). HPLC/MS analysis (Giuffrida et al. 2000) showed that AEA is present in human seminal plasma, midcycle oviductal fluid, and follicular fluid. Sperm are exposed sequentially to these fluids in vivo as they move from the vagina to the site of fertilization in the oviduct (Yanagimachi 1994). R-methanandamide (AM-356), a potent and metabolically stable AEA analog (Abadji et al. 1994), and (-)D9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana (Mechoulam and Hanus 2000), modulated sperm capacitation in vitro by producing biphasic effects on hyperactivated motility and inhibiting morphological alterations over the acrosomal cap. AM-356 (1 nm) reduced tight binding of sperm in the hemizona assay by 50 percent, which predicts reduced sperm fertilizing capacity (Burkman et al. 1988). These findings suggest that AEA signaling regulates sperm functions required for fertilization in the human reproductive tract and that abuse of marijuana could affect these processes. This research is supported in part by a Multidisciplinary Research Pilot Project grant from SUNY, Buffalo, to HS and LJB; a Moir P. Tanner Foundation grant to LJB; the Departments of Anatomy and Cell Biology, GYN/OB, and the School of Medicine; and NIDA grants DA-03801, DA-09158, DA-12447, and DA-12431 to DP.

• Abadji, V, Lin S, Taha G, Griffin G, Stevenson LA, Pertwee RG, Makriyannis A. (1994) (R)-methanandamide: A chiral novel anandamide possessing high potency and metabolic stability. Journal of Medicinal Chemistry 37(12):1889-1893.
• Burkman LJ, Coddington CC, Franken DR, Kruger TF, Rosenwaks Z, Hodgen GD. (1988) The hemizona assay (HZA): Development of a diagnostic test for the binding of human spermatozoa to human hemizona pellucida to predict fertilization potential. Fertility and Sterility 49(4):688-697.
• Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte populations. European Journal of Biochemistry 232(1):54-61.
• Giuffrida A, Rodriguez De Fonseca F, Piomelli D. (2000) Quantification of bioactive acylethanolamides in rat plasma by electrospray mass spectrometry. Analytical Biochemistry 280(1): 87-93.
• Mechoulam R, Hanus L. (2000) A historical overview of chemical research on cannabinoids. Chemistry and Physics of Lipids 108(1-2):1-13.
• Paria BC, Das SK, Dey SK. (1999) Cannabinoid ligand-receptor signaling during early pregnancy in the mouse. In: Nahas, G., Sutin, K.M., and Agurell S. Marihuana and Medicine. Totowa NJ: Humana Press Inc., pp. 393-409.
• Schuel H, Chang MC, Burkman LJ, Picone RP, Makriyannis A, Zimmerman AM, Zimmerman S. (1999) Cannabinoid receptors in sperm. In: Nahas G, Sutin KM, Agurell S. Marihuana and Medicine. Totowa, NJ: Humana Press Inc., pp. 335-345.
• Sugiura T, Kondo S, Sukagawa A, Tonegawa T, Nakane S, Yamashita A, Waku K. (1996) Enzymatic synthesis of anandamide, an endogenous cannabinoid receptor ligand, through N-acylphosphatidylethanolamine pathway in testis: involvement of Ca(2+)-dependent transacylase and phosphodiesterase activities. Biochemical and Biophysical Research Communications 218(1):113-117.
• Yanagimachi R. (1994) Mammalian fertilization. In: Knobil E, Neil JD. The Physiology of Reproduction, (2d ed.) New York: Raven Press, 1:189-317.

Pulmonary/Respiratory Consequences of Marijuana

Donald P. Tashkin, M.D.
University of California, Los Angeles

Dr. Tashkin is Professor of Medicine in the Pulmonary and Critical Care Division, Department of Medicine, University of California, Los Angeles, School of Medicine. One of his major research interests over the past 25 years has been the impact of habitual use of marijuana on the lung and its immune defenses. Dr. Tashkin's contributions to knowledge in this area are extensive and include more than 65 peer-reviewed original scientific publications and numerous presentations at national and international scientific meetings. His work in this area has been funded by grants from NIDA. Dr. Tashkin has also served as an advisor to NIDA on issues pertaining to the pulmonary consequences of smoked drug abuse and experimental administration of smoked marijuana and crack cocaine. He recently organized a FASEB summer research conference on the pulmonary pathophysiologic and immune consequences of smoked substance abuse. Dr. Tashkin has also contributed to several educational documentaries on the subject of drug abuse and the lung.

Controlled and uncontrolled community-based observational studies point to the following long-term clinical consequences of the habitual use of marijuana: (1) an increased prevalence of chronic cough, sputum production, and wheeze (Tashkin et al. 1987); (2) an increased frequency of acute bronchitic episodes (Tashkin et al. 1987); (3) mild, chronic airflow obstruction (Taylor et al. 2000, Tashkin et al. 1997); (4) pneumothorax and/or pneumomediastinum (isolated case reports); (5) large upper long zone bullae (small case series); (6) increased frequency of outpatient visits for respiratory illness (Polen et al. 1993); (7) possible predisposition to invasive Aspergillus pneumonia in immunocompromised patients; (8) possible increased risk for the development of opportunistic infection in HIV-positive patients ; and (9) possible increased risk for upper and lower respiratory tract cancer. The effects of habitual use of marijuana on airway pathology were assessed by bronchoscopic examination of 168 smokers of healthy habitual smokers of marijuana and/or tobacco and nonsmoking control subjects (Roth et al. 1998, Fligiel et al. 1997, Barsky et al. 1998). The following findings have been observed in smokers of marijuana alone compared with nonsmokers: (1) endoscopic evidence of increased frequency of bronchial mucosal erythema, edema, and mucus hypersecretion; (2) correlative histopathologic evidence of airway injury, including increased size and number of submucosal blood vessels, submucosal edema, and hyperplasia of mucus-secreting goblet cells; (3) increased frequency and severity of squamous metaplasia, basal (reserve) cell hyperplasia, goblet cell hyperplasia, loss of ciliated surface epithelium, epithelial inflammation, cellular disorganization, increased nuclear-to-cytoplasmic ratio, and basement membrane thickening; and (4) overexpression of immunohistopathologic surrogate markers linked to an increased risk of bronchogenic carcinoma, including epidermal growth factor receptor, Ki-67 (marker of cell proliferation), globular actin, and DNA ploidy. These findings have the following clinical implications. First, habitual marijuana smoking can cause potentially serious airway pathology at a relatively early age despite the absence of any clinical or physiologic evidence of disease. Second, regular marijuana use appears to be at least as damaging to the epithelium of the central airways as the smoking of tobacco, despite the far smaller daily number of marijuana joints smoked by marijuana smokers (three to four joints) than the daily number of tobacco cigarettes smoked (>20), suggesting a more damaging effect of marijuana than tobacco per cigarette smoked. Possible reasons for this disparity include differences in the physical characteristics of marijuana and tobacco cigarettes and in the technique of smoking each substance (Wu et al. 1988). Third, the frequent replacement of the ciliated bronchial epithelium of marijuana smokersÑby nonciliated cells, including hyperplastic mucus-secreting (goblet) cells or reserve cells, or by metaplastic squamous epitheliumÑhelps explain the high frequency of symptoms of chronic bronchitis in smokers of marijuana alone. Finally, some of the changes that were noted in the bronchial mucosa of smokers of marijuana with or without tobaccoÑparticularly squamous metaplasia, cellular disorganization, nuclear variation, mitotic figures, and increased nuclear-to-cytoplasmic ratioÑmay be considered to be potential precursors of subsequent bronchogenic carcinoma. The latter changes, taken together with the immunohistologic findings suggesting dysregulated growth of bronchial epithelial cells, support the concept that habitual smoking of marijuana may be an important risk factor for the later development of respiratory tract malignancy. Alveolar macrophages comprise more than 90 percent of the cells residing in the alveolar spaces and are critically important to the lung's immune defenses. Regular use of marijuana has been shown to have the following effects on the number, structure, and function of alveolar macrophages harvested by bronchoalveolar lavage from habitual smokers of marijuana alone (without tobacco) compared with nonsmoking control subjects: (1) a twofold increase in alveolar macrophage number (Barbers et al. 1987); (2) increased size and complexity of intracytoplasmic inclusions; (3) impairment in fungicidal activity against C. albicans (Sherman et al. 1991) and C. pseudotropicalis (Baldwin et al. 1997); impairment in phagocytosis and killing of S. aureus; reduced superoxide ion (O2-) release under both basal and stimulated conditions; inhibition of production of inducible nitric oxide synthase (Baldwin et al. 1997); and inhibition of lipopolysaccharide-stimulated production of proinflammatory cytokines (TNF-a, IL-6, and GM-CSF) (Baldwin et al. 1997). The clinical implications of these findings are that marijuana smoking may impair the lung's second line of defense against infection due to impairment in the critical antimicrobial function of alveolar macrophages. In view of the marijuana-related impairment in mucociliary function (the lung's first line of defense), this additional impairment in alveolar macrophage function implies that marijuana smoking may predispose to pulmonary infection, especially in patients whose immune defenses are already compromised by HIV infection and/or cancer and related chemotherapy.

• Baldwin GC, Tashkin DP, Buckley DM, Park AN, Dubinett SM, Roth MD. (1997) Marijuana and cocaine impair alveolar macrophage function and cytokine production. American Journal of Respiratory and Critical Care Medicine 156(5):1606-1613.
• Barbers RG, Gong H Jr, Tashkin DP, Oishi J, Wallace JM. (1987) Differential examination of bronchoalveolar lavage cells in tobacco cigarette and marijuana smokers. American Review of Respiratory Disease 135(6):1271-1275.
• Barsky SH, Roth MD, Kleerup EC, Simmons M, Tashkin DP. (1998) Histopathologic and molecular alterations in bronchial epithelium in habitual smokers of marijuana, cocaine, and/or tobacco. Journal of the National Cancer Institute90(16):1198-1205.
• Fligiel SE, Roth MD, Kleerup EC, Barsky SH, Simmons MS, Tashkin DP. (1997) Tracheobronchial histopathology in habitual smokers of cocaine, marijuana, and/or tobacco. Chest 112(2):319-326.
• Polen MR, Sidney S, Tekawa IS, Sadler M, Friedman GD. (1993) Health care use by frequent marijuana smokers who do not smoke tobacco. Western Journal of Medicine 158(6):596-601.
• Roth MD, Arora A, Barsky SH, Kleerup EC, Simmons M, Tashkin DP. (1998) Visual and pathologic evidence Airway inflammation in young marijuana and tobacco smokers. American Journal of Respiratory and Critical Care Medicine157(3 pt 1):928-937.
• Sherman MP, Campbell LA, Gong H Jr, Roth MD, Tashkin DP. (1991) Antimicrobicidal and respiratory burst characteristics of pulmonary alveolar macrophages recovered from smokers of marijuana alone, smokers of tobacco alone, smokers of marijuana and tobacco, and nonsmokers. American Review of Respiratory Disease 144(6):1351-1356.
• Tashkin DP, Coulson AH, Clark VA, Simmons M, Bourque LB, Duann S, Spivey GH, Gong H. (1987) Respiratory symptoms and lung function in habitual heavy smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco alone, and nonsmokers. American Review of Respiratory Disease 135(1):209-216.
• Tashkin DP, Simmons MS, Sherrill DL, Coulson AH. (1997) Heavy habitual marijuana smoking does not cause an accelerated decline in FEV1 with age. American Journal of Respiratory and Critical Care Medicine 155(1):141-148.
• Taylor DR, Poulton R, Moffitt TE, Ramankutty P, Sears MR. (2000) The respiratory effects of cannabis dependence in young adults. Addiction 95(11):1669-1677.
• Wu TC, Tashkin DP, Djahed B, Rose JE. (1988) Pulmonary hazards of smoking marijuana as compared with tobacco. New England Journal of Medicine 318(6):347-351.

Marijuana Use and Increased Risk of Squamous Cell Carcinoma of the Head and Neck

Zuo-Feng Zhang, M.D., Ph.D.
Hal Morgenstern, Margaret R. Spitz, Donald P. Tashkin, Guo-Pei Yu, James R. Marshall, T.C. Hsu, Stimson P. Schantz
University of California, Los Angeles (UCLA)

Dr. Zhang obtained his M.D. degree in 1983 from Shanghai Medical University and his Ph.D. degree from the State University of New York, Buffalo. In 1987 he did postdoctoral training at the International Agency for Research on Cancer. Dr. Zhang is Professor of Epidemiology and Director of the UCLA Cancer Epidemiology Training Program. His research interests include cancer molecular genetic epidemiology. Dr. Zhang is the author of 110 published articles.

Marijuana is the most commonly used illicit drug in the United States. In some subcultures, it is widely perceived to be harmless. Although the carcinogenic properties of marijuana smoke are similar to those of tobacco, no epidemiologic studies of the relationship between marijuana use and head and neck cancer have been published. The relationship between marijuana use and head and neck cancer was investigated in 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 at Memorial Sloan-Kettering Cancer Center between 1992 and 1994. Epidemiologic data were collected using a structured questionnaire, which included history of tobacco smoking, alcohol use, and marijuana use. The associations between marijuana use and head and neck cancer were analyzed by Mantel-Haenszel methods and logistic regression models. Controlling for age, sex, race, education, 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 percent confidence interval [CI]: 1.1, 6.6). Dose-response relationships were observed for frequency of marijuana use per day (p <0.05) and years of marijuana use (p <0.05). These associations were stronger for subjects who were 55 years of age and younger (OR=3.1, 95 percent CI: 1.0, 9.7). Possible interaction effects of marijuana use were observed with cigarette smoking, mutagen sensitivity, and to a lesser extent, alcohol use. Results suggest that marijuana use may increase the risk of head and neck cancer with a strong dose-response pattern. Analysis indicated that marijuana use may interact with mutagen sensitivity and other risk factors to increase 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.

Recommendations for Future Research

1. In the area of the general health consequences of marijuana use, future research should address the neurocognitive effects of chronic marijuana use by adolescents and young adults; animal models for studying marijuana dependence in humans; marijuana effects in various human diseases (cardiovascular, endocrine, pulmonary/respiratory diseases; immune dysfunction-related infections); chronic effects of marijuana on sleep disorders; drug-drug interactions between marijuana and those used in the treatment of mental disorders or other diseases; and functional assays to study neuropsychiatric/behavioral deficits.
2. In the cardiovascular area, future research should study the effects of chronic marijuana use on atherosclerotic events (effects on clotting mechanisms; lipid metabolism) and endothelial function; arrhythmic effects of chronic marijuana use; effects on body weight resulting from plasma fluid changes (renal effects via renin-angiotensin-aldosterone system); and long-term effects on coronary output using noninvasive techniques.
3. Future pulmonary and cancer studies should address lung immunity among chronic marijuana smokers; incidence, prevalence, and underlying pathophysiology (molecular/genetic basis) of head and neck cancer and other cancers (cervix, prostate) associated with chronic marijuana use; population-based epidemiologic studies; and tumor registries to determine whether chronic marijuana smoking is associated with cancers.
4. Study the long-term effects of marijuana on the immune, endocrine and reproductive systems.
5. Participants also recommended that NIDA train young investigators from other disciplines to conduct research on the clinical consequences of marijuana.