Chapter 3 - Continued

Amotivational Syndrome

One of the more controversial of the effects claimed for marijuana is the production of an "amotivational syndrome." This syndrome is not a medical diagnosis, but it has been used to describe young people who drop out of social activities and show little interest in school, work, or other goal-directed activity. When heavy marijuana use accompanies these symptoms, the drug is often cited as the cause, but there are no convincing data to demonstrate a causal relationship between marijuana smoking and these behavioral characteristics.23 It is not enough to observe that a chronic marijuana user lacks motivation. Instead, relevant personality traits and behavior of subjects must be assessed before, as well as, after the subject becomes a heavy marijuana user. Because such research can only be done on subjects who become heavy marijuana users on their own, a large population study such as the Epidemiological Catchment Area study described earlier in this chapter - would be needed to shed light on the relationship between motivation and marijuana use. Even then, while a causal relationship between the two could, in theory, be dismissed by an epidemiological study, causality not be proven.

Summary on Psychological Effects

Measures of mood, cognition, and psychomotor performance should be incorporated into clinical trials evaluating the efficacy of marijuana or cannabinoid drugs for a given medical condition. Ideally, participants would complete mood assessment questionnaires at various intervals throughout the day for a period prior to and at weekly intervals during treatment, and, where appropriate, after the cessation of marijuana therapy. A full psychological screening of research participants should be conducted to determine whether there is an interaction between the mood altering effects of chronic marijuana use and the psychological characteristics of the individual. Similarly, the cognitive and psychomotor functioning of individuals should be assessed prior to and at regular intervals during the course of a chronic regimen of marijuana or cannabinoid treatment to determine to what extent tolerance develops to the impairing effects of marijuana and to monitor whether new problems develop.

3.31

When compared to changes produced by either placebo or an active control medication, the magnitude of desirable therapeutic effects produced by marijuana could be determined, as well as the frequency and magnitude of adverse psychological side effects. This would allow a more thorough assessment of the risk:benefit ratio associated with the use of marijuana for a given indication.

CONCLUSION: The psychological effects of cannabinoids, such as anxiety reduction, sedation, and euphoria can influence their potential therapeutic value. Those effects are potentially undesirable for certain patients and situations, and beneficial for others. In addition, psychological effects can complicate the interpretation of other aspects of the drug effect.

RECOMMENDATION: Psychological effects of cannabinoids such as anxiety reduction and sedation, which can influence medical benefits, should be evaluated in clinical trials.

Physiological Harms: Tissue and Organ Damage

Many people who spoke to the IOM study team in favor of the medical use of marijuana cited the absence of marijuana overdoses as evidence that it is safe. Indeed, epidemiological data indicate that - for the general population - marijuana use is not associated with increased mortality.(Sidney 1997a ) However, there are other serious health outcomes to consider, and they are discussed below.

It is important to keep in mind that most of the studies that report physiological harms resulting from marijuana use are based on the effects of marijuana smoking. Thus we emphasize that the effects reported cannot be presumed to be caused by THC alone or even in combination with other cannabinoids found in marijuana. It is likely that smoke is a major cause of the reported effects. In most studies, the methods used make it impossible to weigh the relative contributions of smoke versus cannabinoids.

Immune System

The relationship between marijuana and the immune system presents many facets, including potential benefits and suspected harms. This section reviews the evidence on suspected harms to the immune system caused by marijuana use.

Despite the many claims that marijuana suppresses the human immune system, the health impact of marijuana-induced immunomodulation is still unclear. Few studies have been done with animals or humans to assess the effects of marijuana exposure on host resistance to bacteria, viruses or tumors.

3.32

Human studies

Several approaches have been used to determine the effects of marijuana on the human immune system, but each of these has serious limitations which will be discussed below.

Leukocyte assays from marijuana smokers

One of the more common approaches has been to isolate peripheral blood leukocytes from individuals who have smoked marijuana in order to evaluate the immune response of those cells in vitro - most often by measuring mitogen-induced cell proliferation, a normal immune response. Almost without exception, this approach has failed to demonstrate any reduction in leukocyte function. The major problem with this approach is that after drawing blood samples from the study subjects, the leukocytes need to be isolated from whole blood before they are tested. This is done by high-speed centrifugation followed by extensive washing of the cells, thus resulting in removal of the cannabinoid; perhaps for that reason no adverse effects have been demonstrated in peripheral blood leukocytes from marijuana Smokers. 74, 90, 122, 159

Leukocyte responses to THC

Another approach is to isolate peripheral blood leukocytes from healthy control individuals who do not smoke marijuana and then to measure the effect of THC on the ability of these cells to proliferate in response to mitogenic stimulation in vitro. However, it is notable that one significant difference between leukocytes isolated from a marijuana smoker, as described above, and the in vitro studies in which THC has been added directly to leukocyte cell cultures is in the cannabinoid composition. Marijuana smoke contains many distinct cannabinoid compounds of which THC is just one. Moreover, since the immunomodulatory activity of many of the other cannabinoid compounds present in marijuana smoke has never been tested, and because it is now known that at least one of those - cannabinol (CBN) - has greater activity on the immune system than the central nervous system, 63

it is unclear whether the profile of activity observed with THC accurately represents the effects of marijuana smoke on immune competence. Likewise, it is unclear to what extent different cannabinoids in combination exhibit additive, synergistic or antagonistic effects with respect to their immunomodulatory activity. This issue is further complicated by the fact that leukocytes express both types of cannabinoid receptors, CB1 and CB2

One additional factor which may affect the immunomodulatory activity of cannabinoids in leukocytes is metabolism. Since leukocytes have very low levels of

3.33

the cytochrome P-450 drug metabolizing enzymes 20, the metabolism of cannabinoids is probably different between in vivo and in vitro exposure. This last point is primarily pertinent to investigations of chronic and not acute cannabinoid exposure.

Human-derived cell lines

A third approach for investigating the effects of cannabinoids on human leukocytes has been to study human-derived cell lines. b As described above, the cell lines are treated in vitro with cannabinoids to test their responses to different stimuli. Although cell lines are a convenient source of human cells, the same problems described above apply. Additionally, the cell lines might not be the same as the original cells. For example, cell lines do not necessarily have the same number of cannabinoid receptors as the original human cells.

Rodent studies

The most widely used approach is to evaluate the effects of cannabinoids in rodents, using rodent-derived cells in vitro. The rationale for this approach is based on the fact that the human and rodent immune systems are remarkably similar, and it is assumed that the effects produced by cannabinoids on the rodent immune system will be similar to those produced in humans. Although no significant species differences in immune system sensitivity to cannabinoids have been reported, it is important to consider the possibility.

Summary

The complete effect of marijuana smoking on immune function remains unknown. More importantly, it is not known whether smoking leads to increased rates of infections, tumors, allergies, or autoimmune responses. The problem is how to duplicate the "normal" marijuana smoking pattern while at the same time removing other potential immune modulating life-style factors such as alcohol and tobacco use. Epidemiological studies are needed to determine whether marijuana users have a higher incidence of diseases such as infections, tumors, allergies, and autoimmune disease. Studies on resistance to bacterial and viral infection are clearly needed, and should involve the collaboration of immunologists, infectious disease specialists, oncologists, and pharmacologists.

b Cell lines are created by removing cells from an organism and then treating them so they are "immortalized,' meaning they will continue to divide indefinitely in culture. Cellular processes can then be studied in isolation from their original source.

3.34

Marijuana Smoke

Tobacco is the predominant cause of lung diseases such as cancer and emphysema, and marijuana smoke contains many of the same components as tobacco smoke. 7 Thus, it is important to consider the relationship between habitual marijuana smoking and certain lung diseases.

Given a cigarette of comparable weight as much as four times the amount of tar can be deposited in the lungs of marijuana smokers compared to tobacco smokers. 161 This is primarily due to the differences in filtration and smoking technique between tobacco and marijuana smokers. Marijuana cigarettes usually do not have filters, and marijuana smokers typically develop a larger puff volume, inhale more deeply, and hold their breath several times longer than tobacco smokers. 118 However, a marijuana cigarette smoked recreationally typically is not packed as tightly as a tobacco cigarette, and thus the smokable substance is about half that in a tobacco cigarette. In addition, tobacco smokers generally smoke considerably more cigarettes per day than do marijuana smokers.

Cellular Damage

Lymphocytes: T and B Cells

Human studies of the effect of marijuana smoking on immune agents are not all consistent with cannabinoid cell culture and animal studies. For example, antibody production was decreased in a group of hospitalized patients who smoked marijuana for four days (twelve cigarettes/day), but this decrease was seen in only one subtype of humoral antibody (IgG), while two other subtypes (IgA and IgM) remained normal and one (IgE) was elevated. 107 Additionally, T cell proliferation was normal in the blood of a group of marijuana smokers, although when evaluated more closely, there was an increase in one subset of T cells 160 and a decrease in a different subset (CD8). 156 From these studies it appears that marijuana use is associated with intermittent disturbances in T and B cell function, but the magnitude is small and other measures are frequently normal. 86

Macrophages

Alveolar macrophages are the principal immune-effector cells in the lung and are primarily responsible for protecting the lung against infectious microorganisms, inhaled foreign substances, and tumor cells. They are increased during tissue inflammation. In a large sample of volunteers, habitual marijuana smokers had twice as many alveolar macrophages as nonsmokers, and smokers of both marijuana and

3.35

tobacco had twice as many again. 11 Marijuana smoking also reduced the ability of alveolar macrophages to kill fungus such as Candida aIbicans, c pathogenic bacteria such as Staphylococcus aureus, and tumor target cells. This reduction in ability to destroy fungal organisms was similar to that seen in tobacco smokers. The inability to kill pathogenic bacteria was not seen in tobacco smokers. 10 Furthermore, marijuana smoking depressed pro-inflammatory cytokine production (such as TNF-a and IL-6), but not Immunosuppressive cytokines. 10 Since cytokines are important regulators of macrophage function, this marijuana-related decrease in inflammatory cytokine production might be a mechanism whereby marijuana smokers are less able to destroy fungal and bacterial organisms, as well as tumor cells.

The inability of alveolar macrophages from habitual marijuana smokers without apparent disease to destroy fungus, bacteria, and tumor cells, and to release pro-inflammatory cytokines, suggests that marijuana might be an immunosuppressant with clinically significant effects on host defense. Therefore, the risks of smoking marijuana should be seriously weighed before recommending ifs use in any patient with pre-existing immune deficits -- including AIDS patients, cancer patients, and those receiving immunosuppressive therapies (for example, transplant or cancer patients).

Bronchial-pulmonary Damage

Animal Studies

A number of animal studies have revealed certain respiratory tract changes and diseases associated with marijuana smoking, while others have not. Extensive damage to the smaller airways, which are the major site of chronic obstructive pulmonary disease (COPD), d as well as acute and chronic pneumonia have been observed in various species exposed to different doses of marijuana smoke. 41, 42, 127 In contrast, rats exposed to increasing doses of marijuana smoke for one year did not show any signs of COPD, whereas rats exposed to tobacco smoke did. 66

Chronic Bronchitis and Respiratory Illness

Human studies suggest that there is a greater chance of respiratory illness in individuals who smoke marijuana. In a survey of outpatient medical visits in a large HMO, marijuana users were more likely to seek help for respiratory illnesses than people who smoked neither marijuana nor tobacco. 119 However, the incidence of

c A yeast infection that is particularly prevalent among people whose immune systems are suppressed, such as in AIDS patients.

d A slow progressive obstruction of the airways, loss of their elasticity, and loss of lung volume. Characterized by chronic shortness of breath, chronic bronchitis and reduced oxygenation of blood.

3.36

seeking help for respiratory illnesses was not elevated for those who smoked marijuana for 10 years or more when compared to those who smoked for less than 10 years. One explanation for this is that people who experience respiratory symptoms are more likely to quit smoking, and the people who continue to smoke represent a set of survivors who do not develop or are indifferent to such symptoms. A limitation of this study is that no data were available on the use of cocaine, which when used with marijuana could contribute to the observed differences. Another limitation is that the survey relied on self-reporting, and tobacco, alcohol and marijuana use might have been underreported (S. Sidney, IOM workshop).

When marijuana smokers were compared to non-smokers and tobacco smokers in a group of 446 volunteers, 15-20 % reported symptoms of chronic bronchitis, including chronic cough and phlegm production. 145 Twenty to 25 % of the tobacco smokers also reported symptoms of chronic bronchitis. Despite a marked disparity in the amount of each substance smoked per day (3-4 joints of marijuana versus more than 20 cigarettes of tobacco), the difference in the percent of tobacco-smokers and marijuana-smokers experiencing symptoms of chronic bronchitis was insignificant. 145 Similar findings were reported by Bloom and coworkers, 15 and these investigators noted an additive effect of smoking both marijuana and tobacco.

Bronchial Tissue Changes

Habitual marijuana smoking is associated with changes in the lining of the human respiratory tract. Many marijuana or tobacco smokers have increased redness (erythema) and swelling (edema) of the airway tissues and increased mucus secretions. 43, 55 In marijuana smokers, the number and size of small blood vessels in the bronchial wall are increased, tissue edema is present, and the normal ciliated cells e lining the inner surface of the bronchial wall are largely replaced by mucus secreting goblet cells.. Moreover, the damage is even greater in people who smoke both marijuana and tobacco. 129 Overproduction of mucus by the increased numbers of mucus-secreting cells in the face of diminished numbers of ciliated cells tends to leave cough as the only major mechanism to remove mucus from the airways. This might explain the relatively high proportion of marijuana smokers who complain of chronic cough and phlegm production. 147

A 1998 study has shown that, compared to nonsmokers, both marijuana and tobacco smokers have significantly more cellular and molecular abnormalities in bronchial epithelium cells; those changes are associated with increased risk of cancer. 12 The tobacco-only smokers in that study smoked an average of 25 cigarettes per day, whereas the marijuana-only smokers smoked an average of 21 marijuana cigarettes per week. Despite the fact that the marijuana smokers smoked many fewer

e Ciliated cells have hair-like projections that function to transport mucus toward the mouth by rapid wave-like motion.

3.37

cigarettes, their cellular abnormalities were equivalent, or greater than, those seen in tobacco smokers. This and earlier studies have shown than such abnormalities are greatest in people who smoke both marijuana and tobacco, suggesting an additive effect of marijuana and tobacco smoke on airway tissue. 12 43 55 Tenant and coworkers 149 found similar results in U.S. servicemen who suffered from respiratory symptoms and were heavy hashish smokers. (Hashish is the resin from the marijuana plant).

Chronic Obstructive Pulmonary Disease

In the absence of epidemiological data, indirect evidence, such as nonspecific airway hyperresponsiveness and measures of lung function, offers an indicator of the vulnerability of marijuana smokers to COPD. 153 For example, the methacholine provocative challenge test, used to evaluate airway hyperresponsiveness, showed that tobacco smokers develop more airway hyperresponsiveness. But no such correlation has been shown between marijuana smoking and airway hyperresponsiveness.

There are conflicting results as to whether regular marijuana use harms the small airways of the lungs. Bloom found that an average of one joint smoked per day significantly impaired the function of small airways. 15 On the other hand, Tashkin and coworkers 145 did not observe such damage among heavier marijuana users (3-4 joints per day for at least 10 years), but did note a narrowing of large, central airways. Tashkin s long-term study, which adjusted for age-related decline in lung function (associated with an increased risk for developing COPD), showed an accelerated rate of decline in tobacco smokers, but not in marijuana smokers. 146 Thus the question as to whether usual marijuana smoking habits are enough to cause COPD remains open.

Conclusion

Chronic marijuana smoking might lead to acute and chronic bronchitis and extensive microscopic abnormalities in the cells lining the bronchial passageways, some of which may be pre-malignant. These respiratory symptoms are similar to that of tobacco smokers, and the combination of marijuana and tobacco smoking augments these effects. At the time of this writing, it has not been established whether chronic smoking marijuana causes COPD, but there is probably an association.

HIV/AIDS Patients

The relationship between marijuana smoking and the natural course of AIDS is of particular concern because HIV patients are the largest group who report using

3.38

marijuana for medical purposes. Marijuana use has been linked to both increased risk of progression to AIDS in HIV-seropositive patients, and to increased mortality in AIDS patients.

For reasons as yet unknown, marijuana use is associated with increased mortality among men with AIDS, but not among the general population. 137 (The relative risk of AIDS mortality for current marijuana users in this 12-year study was 1.90, indicating that, compared to non-current marijuana users, almost twice as many marijuana users died of AIDS.) Never married men used twice as much marijuana as married men and accounted for 83% of the AIDS deaths in the study. The authors of the study note that, while marital status is insufficient to adjust for lifestyle factors -particularly, homosexual behavior - a substantial proportion of the never married men with AIDS were likely homosexuals or bisexuals. This raises the possibility that the association of marijuana use with AIDS deaths might be related to indirect factors, such as use of other drugs or high risk sexual behavior, both of which increase risks of infection to which AIDS patients are more susceptible. The higher mortality of AIDS patients who were current marijuana users also raises the question as to whether this was because patients increased their use marijuana at the end-stages of the disease to treat their symptoms. However, the association between marijuana use and AIDS deaths was similar even when the subjects who died earliest in the first 5 years of this 12 year study, and who were presumably the most sick, were excluded from the analysis. In sum, it is premature to conclude what the underlying causes of this association might be.

For the general population, the risk of mortality associated with marijuana use was lower than that associated with cigarette smoking, and tobacco smoking was not an independent risk factor in AIDS mortality in this study. Interestingly, the authors of this study concluded that therapeutic use of marijuana did not contribute to the increased mortality among men with AIDS.

Marijuana use has been associated with a higher prevalence of HIV seropositivity in cross-sectional studies,(Ostrow 1994) 83 but the relationship of marijuana to the progression to AIDS in HIV-seropositive patients is a reasonable question. It remains unclear whether marijuana smoking is an independent risk factor in the progression of AIDS in HIV-seropositive men. Marijuana use did not increase the risk of AIDS in HIV-seropositive men in the Multicenter AIDS Cohort Study, in which 1,795 HIV-seropositive men were studied for 18 months, 83 or in the San Francisco Men's Health Study, in which 451 HIV-seropositive men were studied for 6 years. 34 In contrast, the Sydney AIDS Project in Australia (386 HIV seropositive men were studied for 12 months) 151 reported that marijuana use was associated with increased risk of progression to AIDS. But the results of the 1988 Sydney study are less reliable than the other two studies described. For one, this was the shortest of the studies; and, second, according to the 1993 definition of

3.39

AIDS, many of the subjects probably already had AIDS at the beginning of the study. f

The most compelling concerns regarding marijuana smoking in HIV/AIDS patients are the possible effects of marijuana on human immunity. 110 Reports of Opportunistic fungal and bacterial pneumonia in patients with AIDS who used marijuana suggest that marijuana smoking either suppresses the immune system, 33 or that it exposes patients to an added burden of pathogens. 21 In sum, patients with preexisting immune deficits due to AIDS should be expected to be vulnerable to serious harms caused by smoking marijuana. The relative contribution of marijuana smoke versus THC or other cannabinoids is not known.

Carcinogenicity

The gas and tar phases of marijuana and tobacco smoke contain many of the same compounds. Furthermore, the tar phase of marijuana smoke contains higher concentrations of polycyclic aromatic hydrocarbons (PAHs), such as the carcinogen benzopyrene. The higher content of carcinogenic PAHs in marijuana tar and the greater deposition of this tar in the lung might act in conjunction to amplify the exposure of the marijuana smoker to carcinogens. For these reasons the carcinogenicity of marijuana smoke is an important concern.

Compared to studies on tobacco smoke, it is more difficult to collect the epidemiological data necessary to establish or refute the link between marijuana smoke and cancer. Far fewer people smoke only marijuana than who smoke only tobacco, and marijuana smokers are more likely to underreport their smoking.

Case Studies

Several case-series suggest that marijuana might play a role in the development of human respiratory cancer. Those reports indicate an unexpectedly large proportion of marijuana users among cases of lung cancer 140, 148 and cancers of the upper aerodigestive tract - that is, the oral cavity, pharynx, larynx, and esophagus - that occur before age 45 years. 36, 39, 148 Respiratory tract cancers associated with heavy tobacco and alcohol consumption are not usually seen before the age of 60 years, 153 and the occurrence of such cancers in marijuana users younger than 60 years suggests that long-term marijuana smoking potentiates the effects of other risk factors, such as tobacco smoking, and is a more potent risk factor than tobacco and alcohol use in the early development of respiratory cancers. Unfortunately, most studies lack the necessary comparison groups to calculate the isolated effect of marijuana use on cancer risk. Many marijuana smokers also smoke tobacco, so when studies lack information regarding cigarette smoking status, there is no way to separate the effects of marijuana smoke from tobacco smoke.

f In 1993, the diagnosis of AIDS was expanded to include anyone with a CD4 count less than 200. Prior to 1993, this alone would have been insufficient for a diagnosis of AIDS.

3.40

Epidemiological Evidence

As of this writing, Sidney and coworkers 138 have conducted the only epidemiological study to evaluate the association between marijuana use and cancer. The study included a cohort of approximately 65,000 men and women between the ages of 15 and 49 years. Marijuana users were defined as those who had used marijuana on six or more occasions. Among the 1,421 cases of cancer in this cohort, marijuana use was associated only with an increased risk of prostate cancer in men who did not smoke tobacco. In these relatively young HMO clients, no association was found between marijuana use and other cancers, including all tobacco-related cancers, colorectal or melanoma. The major limitation associated with interpreting this study is that the development of lung cancer requires a long exposure to smoking, and most marijuana users quit before this level of exposure is achieved. Additionally, marijuana use has only been widespread in the U.S. since the late 1960s; therefore, despite the large cohort size there might not have been a sufficient number of heavy and/or long-term marijuana smokers to observe an effect.

Cellular and Molecular Studies

In contrast to clinical studies, the evidence from cellular and molecular studies provides strong evidence that marijuana smoke is carcinogenic. Cell culture studies implicate marijuana smoke in the development of cancer. Prolonged exposure of hamster lung cell cultures to marijuana smoke led to malignant transformations, 93 and human lung explants exposed to marijuana smoke resulted in chromosomal and DNA alterations. 153 Additionally, the tar from marijuana smoke induced mutations similar to those produced by tar from the same quantity of tobacco in a common bacterial assay for mutagenicity. 157

Molecular studies also implicate marijuana smoke as a carcinogen. Protooncogenes and tumor suppressor genes are a group of genes that affect cell growth and differentiation. Normally, those genes code for proteins that control cellular proliferation. Once mutated or activated, these genes produce proteins which cause cells to multiply rapidly and out of control, resulting in tumors or cancer. g When the production of these proteins was evaluated in tissue biopsies taken from marijuana, tobacco, marijuana plus tobacco smokers, and non-smokers, respectively, two of them (EGFR and Ki-67) were markedly increased in the marijuana smokers compared to non-smokers and tobacco smokers. Moreover, the effects of marijuana and tobacco were additive. 130 Thus, in relatively young smokers of marijuana, and

g Some of the genes involved in the development of lung cancer include those that encode for Ki-67 (a nuclear proliferation protein responsible for cell division), the p53 tumor suppressor (a protein that normally suppresses cell growth), and epidermal growth factor receptor (EGFR) (a receptor found on a variety of cell types, especially epithelia, and which promotes cellular growth and proliferation when bound to epidermal growth factor).

3.41

particularly in those who smoke both marijuana and tobacco, marijuana is implicated as a risk factor for lung cancer.

DNA alterations are known to be early events in the development of cancer, and have been observed in the lymphocytes of pregnant marijuana smokers, as well as in those of their newborns. 4 This is an important study because the investigators were careful to exclude tobacco smokers - a problem in previous studies that cited mutagenic effects of marijuana smoke. 26, 53, 62, 141 These same investigators found similar effects in previous studies among tobacco smokers, 5, 6 so the effects cannot be attributed solely to THC or other cannabinoids. Although it can only be determined by experiment, it is likely that the smoke contents - other than cannabinoids - are responsible for a large part of the mutagenic effect.

Preliminary findings suggest that marijuana smoke activates cytochrome P4501A1 (CYPlA1), the enzyme that converts PAHs, such as benz[a]pyrene, into active carcinogens 98 Bronchial epithelial cells in tissue biopsies taken from marijuana smokers show more binding to CYP1A1 antibodies than do comparable cells in biopsies from nonsmokers (D.Tashkin, IOM workshop). This suggests that there is more of the carcinogen-producing enzyme, CYP1A1, itself in bronchial cells of marijuana smokers, but different experimental methods will be needed to definitely establish that possibility.

Conclusions

At this time, there is no conclusive evidence that marijuana causes cancer in humans, including cancers usually related to tobacco use. However, cellular, genetic and human studies all suggest that marijuana smoke maybe an important risk factor for the development of respiratory cancer. More definitive evidence that habitual marijuana smoking does or does not lead to respiratory cancer awaits the results of well-designed case-controlled epidemiological studies. It has been 30 years since the initiation of widespread marijuana use among young individuals in our society, and such studies should now be feasible.

The following studies or activities would be useful in providing data that could more precisely define the health risks of smoking marijuana.

1. Case-control studies to determine whether marijuana use is associated with an increased risk of respiratory cancer: Despite the lack of compelling epidemiological evidence to date, findings from the biochemical, cellular, immunologic, genetic, tissue and animal studies cited above strongly suggest that marijuana is a risk factor for human cancer. What is required to address this hypothesis more convincingly is a population-based case-controlled study of sufficiently large numbers of lung cancer cases and cases of upper aerodigestive tumors (cancers of the oral cavity and pharynx, larynx and esophagus), as well as non-cancer controls, to demonstrate a statistically significant association, if one exists. Because of the long time period required for induction of human carcinomas and the infrequent use of marijuana in the general U.S. population prior to 1966, no

3.42

epidemiological studies so far have been extensive enough to adequately measure the association between marijuana and cancer. However, epidemiological investigation of this association is probably possible now, since approximately 30 years have elapsed since the start of widespread marijuana use in the U.S. among teenagers and young adults.

2. Molecular markers of respiratory cancer progression in marijuana smokers. If an epidemiological association between marijuana use and risk of respiratory cancer is demonstrated, then studies are warranted to explore the presence of molecular markers that may be predictive of genetically increased risk of carcinogenesis in marijuana users, such as TP53, p16, NATZ and GSTML.

3. Prospective epidemiological studies of populations with HIV-seropositivity or at high risk for HIV infection. Because HIV/AIDS patients are largest group that reports smoking marijuana for medical purposes and they are particularly vulnerable to immunosuppressive effects, there is a pressing need for a better understanding of the relative risk and rewards of smoking marijuana. Such studies should include history of marijuana use in the analysis of potential risk factors for seroconversion and acquisition of opportunistic infections/progression to AIDS. h These studies could be carried out in the context of any federally approved clinical trials of medicinal marijuana in immunocompromised patients and should provide a sufficiently long period of follow-up to capture any potential adverse events.

4. Regularized recording of marijuana use by patients. Although marijuana is the most commonly used illicit drug, medical providers often do not question patients about marijuana use and rarely document its use. 101 Among 452 Kaiser Permanente patients who reported daily or almost daily marijuana use, physicians recorded marijuana use in only 3 % of their medical records (S. Sidney, IOM workshop).

5. Additional cellular, animal and human studies to investigate further the impact of THC and marijuana on immune function, including their effects on proinflammatory versus immunosuppressive cytokines, and on the function of leukocytes that present antigen to T cells.

The question that needs to be addressed is whether THC or marijuana is a risk factor for HIV infection, for progression to more severe stages of AIDS, or for opportunistic infection among HIV-positive patients. Studies are needed to determine the effects of marijuana use on the function of alveolar macrophages. It would be important to compare the HIV infectivity and replication of alveolar macrophages harvested from habitual marijuana users with those harvested from non- or infrequent marijuana users. Cell culture studies could be used to compare the

h A prospective study is one in which a group of subjects is identified and then studied over the course of time. Such a study allows an experimenter to balance different factors that may contribute to the study outcome. For example, age, family history, and smoking are risk factors for lung cancer. In a prospective study these factors can be balanced to measure how much smoking increases the risk of lung cancer. A retrospective study is one in which people with a particular disease are identified and their histories are studied. Such studies are easier and less expensive to conduct, but they generally lack the explanatory power of prospective studies.

3.43

susceptibility of HIV-infected alveolar macrophages to additional infection with Opportunistic pathogens. Similarly, further studies on cell cultures of peripheral blood mononuclear cells could be used to assess the impact of exposure to THC on HIV infectivity and replication.

Cardiovascular System

Marijuana smoke and oral THC can cause tachycardia (elevated heart rate) in humans, usually 20 - 100 % above baseline. 56, 84 The increase in heart rate is greatest in the first 10-20 minutes after smoking, and decreases sharply and steadily; depending on whether smoked marijuana or oral THC are used, these side effects can last 3 or 5 hours, respectively. 67, 94 In some cases, blood pressure can be increased while a person is in a reclining position, but can decrease inordinately on standing, resulting in postural hypotension. i In contrast to acute administration of THC, chronic oral ingestion of THC reduces heart rate in humans. 13

In animals, THC decreases heart rate and blood pressure. 56, 155 However, most such animals studies are conducted in anaesthetized animals, and anesthesia causes hypertension. Thus, those studies should be interpreted as reports on the effects of cannabinoids in hypertensive subjects. The results of the animal and human studies are consistent with the conclusion that cannabinoids are hypotensive at high doses in animals, as well as humans (see 1998 review by Wagner and coworkers). 155

Tolerance can appear after a few days of frequent daily dosing (2 - 3 times per day) of oral THC or marijuana extract with heart rate slowing, reclining blood pressure falling, and postural hypotension disappearing. 72 Thus, the intensity of these effects depends on the frequency of use, dose, and even body position.

The cardiovascular changes have not been a health problem for healthy, young users of marijuana or THC. However, such changes in heart rate and blood pressure could present a serious problem for older patients, especially those with coronary artery or cerebrovascular disease. Since cardiovascular diseases are the leading causes of death in the United States (coronary heart disease is first, stroke is third), any impact of marijuana use on cardiovascular disease could have a substantial impact on public health (S. Sidney, IOM workshop). The magnitude of this impact remains to be determined as chronic marijuana users from the late 1960s enter the age where coronary artery and cerebrovascular diseases become common. Additionally, smoking marijuana is known to decrease maximal exercise performance. This, along with the increased heart rate, could theoretically induce angina (S. Sidney, IOM workshop). Therefore, this raises the possibility that patients with symptomatic coronary artery disease should be advised not to smoke marijuana, and THC might be contraindicated in patients with restricted cardiovascular function.

i Decreased blood pressure due to changing posture from a lying or sitting position to a standing position, which can cause dizziness and faintness.

3.44

Reproductive System

Animal studies

Marijuana and THC can inhibit many reproductive functions on a short-term basis. In both male and female animals, THC injections suppress reproductive hormones and behavior.106, 158 Studies have consistently shown that injections of THC result in rapid, dose-dependent suppression of serum luteinizing hormone (LH) levels. 69 (LH is the pituitary hormone that stimulates release of the gonadal hormones, testosterone and estrogen.) Embryo implantation also appears to be inhibited by THC. But it does not necessarily follow from this that marijuana use will interfere with human reproduction. With few exceptions, the animal studies are based on acute (i.e., single injections) or short-term treatments (i.e., THC injections given over a series of days). The results are generally observed for only several hours, or sometimes in females for only one ovulatory cycle.

Acute treatments of cannabinoids, including THC, CBD, and cannabinol, and anandamide can decrease the fertilizing capacity of sea urchin sperm. 134, 135, 136 While the sea urchin is only a distant relative of humans, the cellular processes that regulate fertilization are similar enough that one can expect a similar effect in humans. However, the effect of cannabinoids on the capacity of sperm to fertilize eggs is reversible, and is observed at 6-100 µM concentrations, 135, 136 which are higher than those likely to be experienced by marijuana smokers. At the same time, the presence of cannabinoid receptors in sperm suggests the possibility of a natural role for anandamide in modulating sperm function during fertilization. However, it remains to be determined whether smoked marijuana or oral THC taken in prescribed doses has a clinically significant effect on the fertilizing capacity of human sperm.

Exposure to THC in utero can result in long-term changes. Many in utero effects interfere with embryo implantation (see review by Wenger and coworkers 158). Exposure to THC: close to the time of, or shortly after, their birth can also result in impaired reproductive behavior in adult mice: females are slower to show sexual receptivity and males are slower to mount. 106

Although THC can act directly on endocrine tissues, such as the testes or ovaries, it appears to affect reproductive physiology through its actions on the brain, but somewhere other than the pituitary. Some, but not all, of the effects of THC are through its effect on stress hormones such as cortisol. 69

Human Studies

The few human studies are consistent with the acute animal studies: THC inhibits reproductive functions. However, studies of men and women who use marijuana regularly have yielded conflicting results, and show either depression of

3.45

reproductive hormones, effect, or only a short-term effect. Overall, the results from human studies are consistent with the hypothesis that THC inhibits LH on a short-term basis, but not in long-term marijuana users. In other words, long-term users develop tolerance to the inhibitory effect of THC on LH. The results in women are similar, with the added consideration of the menstrual cycle; the acute effects of THC appear to vary with cycle stage. THC appears to have little effect during the follicular phase (the phase after menses and before ovulation), and to inhibit the LH pulse during the luteal phase (the phase after ovulation and before menses).102 In brief, although there are no data on fertility per se, marijuana or THC would likely decrease human fertility - at least in the short-term-for both men and women. And it is reasonable to predict that THC can interfere with early pregnancy, particularly implantation of the embryo. Like tobacco, marijuana smoke is highly likely to be harmful to fetal development and should be avoided by pregnant women as well as those who might become pregnant in the near future. Nevertheless, although fertility and fetal development are important concerns for many, they are unlikely to be of much concern to people with seriously debilitating or life-threatening diseases. The well-documented inhibition of reproductive functions by THC is thus not a serious concern for evaluating the short-term medical use of marijuana or specific cannabinoids.

Developmental impact of use during pregnancy

Among the studies that have investigated the relationship between prenatal marijuana exposure and birth outcome, the results have been inconsistent (reviewed by Cornelius and coworkers 30 in 1995). Except for adolescent mothers, there is little evidence that gestation is shorter in mothers who smoke marijuana. 30 Several studies of women who smoked marijuana regularly during pregnancy show that they tend to give birth to lower weight babies.46, 64 Mothers who smoke tobacco also give birth to lower weight babies, and the relative contributions of smoking versus THC are not known from these studies.

Babies born to mothers who smoked marijuana during pregnancy weighed, on average, 3.4 ounces less than babies born to the study's control group of mothers who did not smoke marijuana; there was no significant difference in either gestational age or frequency of congenital abnormalities.163 These results were based on women whose urine tests indicated recent marijuana. However, when the analysis was based only on self-reports of marijuana use (without verification by urine tests), there was no difference between the weight of babies born to women who reported themselves as marijuana smokers and those born to women who reported they did not smoke marijuana. This raises an important concern about the methods used to measure the effects of marijuana smoking in any study, and perhaps even more so in studies on the effects of marijuana during pregnancy when subjects might be even less likely to admit to smoking marijuana. (The study was conducted in the last trimester of pregnancy, and there was no information about the extent of marijuana use earlier in the pregnancy).

For most of these studies, much of the harms associated with marijuana use are consistent with those associated with tobacco use, and smoking is a significant

3.46

factor so the contribution of cannabinoids cannot be confirmed. However, Jamaican women who use marijuana rarely smoke it, but instead prepare it as tea. 37 In a study of neonates born to Jamaican women who either did or did not ingest marijuana during pregnancy, there was no difference in neurobehavioral assessments made at 3 days after birth and at one month. 38 A limitation of this study is that there was no direct measure of marijuana use. Estimates of marijuana use were based on self reports, which might be more accurate in Jamaica than in the U.S. since there is less social stigma associated with marijuana use in Jamaica, but are nonetheless less reliable than direct measures

Newborns of mothers who smoke either marijuana or tobacco have significantly higher mutation rates than those of non-smokers. 4, 5 Since 1978, the Ottawa Prenatal Prospective Study has been measuring the cognitive functions of children born to mothers who smoked marijuana during pregnancy. 47 Children of mothers who smoked either moderately (1-6 marijuana cigarettes per week) or heavily (more than 6 marijuana cigarettes per week) have been studied from age four days to 9-12 years. It is important to keep in mind that studies like this provide important data about the risks associated with marijuana use during pregnancy, but they do not establish the causes of any such association.

The children in the different marijuana exposure groups showed no lasting differences in global measures of intelligence such as language development, reading scores, and visual or perceptual tests. Moderate cognitive deficits were detectable among these children when they were four days old and again at four years, but these deficits were no longer apparent at five years.

Prenatal marijuana exposure was not, however, without lasting impact. By comparison, at both ages 5-6 and 9-12, children in the same study who were prenatally exposed to tobacco smoke scored significantly lower on tests of language skills and cognitive functioning.48 In another study, 49, 50 nine-to-twelve years olds who were exposed to marijuana prenatally scored lower than control subjects on tasks associated with "executive function," a term used by psychologists to describe an individual's ability to plan ahead, anticipate, and suppress behaviors that are incompatible with a current goal. 50 This was reflected in how the mothers described their children. The mothers of the marijuana-exposed children were more likely to describe their offspring as hyperactive or impulsive than did mothers of control children. This alteration in executive function was not seen in children born to tobacco smokers. The underlying causes might be the marijuana exposure, or might be more closely related to the reasons underlying their mothers' use of marijuana during pregnancy.

Mice born to dams injected with the endogenous cannabinoid, anandamide, during the last trimester of pregnancy also showed delayed effects. No effect of anandamide treatment during pregnancy was detected until the mice were adults (40 days of age), at which time they showed behavioral changes that are common to the effects of other psychotropic drugs or prenatal stress. 45 As with the children born to mothers who smoked marijuana, it is not known what aspect of the treatment caused the effect. The dams might have found the dose (20 mg/kg of body weight) of

3.47

anandamide aversive, in which case, the effect could have resulted from generalized stress, as opposed to a cannabinoid-specific effect. Either case is possible.

Despite the uncertainty as to the underlying causes of impact of prenatal exposure to cannabinoid drugs, it is, nonetheless, prudent to advise against smoking marijuana during pregnancy.

Summary and Conclusions

This chapter summarizes the harmful effects of marijuana to the individual user and, to a lesser extent, to society. The harmful effects to individuals were considered from the perspective of possible medical use of marijuana, and can be divided into acute and chronic effects. The vast majority of data on harmful effects of marijuana is based on smoked marijuana, and except for the psychoactive effects that can be reasonably attributable to THC, it is not possible to distinguish the drug effects from the effects of inhaling smoke of burning plant material.

For most people, the primary adverse effect of acute marijuana use is diminished psychomotor performance, it is inadvisable to operate any equipment that might put the user or others in danger (such as driving and operating or monitoring complex equipment under the influence of marijuana). While most people can be expected to show impaired performance of complex tasks, a minority experience dysphoria. Individuals with or at risk of psychiatric disorders (including substance dependence) are particularly vulnerable to developing marijuana dependence and marijuana use would be generally contraindicated in those individuals. The short term immunosuppressive effects are not well-established and, if they exist at all, are not likely great enough to preclude a legitimate medical use. The acute side effects of marijuana use are within the risks tolerated for many medications.

The chronic effects of marijuana are of greater concern for medical use and fall into two categories: the effects of chronic smoking, and the effects of THC. Marijuana smoke is like tobacco smoke in that it is associated with increased risk of cancer, lung damage, and poor pregnancy outcomes. Smoked marijuana is unlikely to be a safe medication for any chronic medical condition. The second category is that associated with dependence on the psychoactive effects of THC. Despite past skepticism, it has been established that, although it is not common, a vulnerable subpopulation of marijuana users can develop dependence. Adolescents, particularly those with conduct disorders, individuals with psychiatric disorders, or problems with substance abuse appear to be at greater risk for marijuana dependence than the general population.

As a cannabinoid drug delivery system, marijuana cigarettes are not ideal since they deliver a variable mixture of cannabinoids, as well as a variety of other biologically-active substances, not all of which are desirable or even known. Unknown substances include possible contaminants such as fungus or bacteria

Finally, there is the broad social concern that sanctioning the medical use of marijuana might lead to an increase in its use among the general population. At this point there are no convincing data to support this concern. The existing data are

3.48

consistent with the idea that this would not be a problem if the medical use of marijuana were as closely regulated as other medications with abuse potential, but we acknowledge that there are no data that directly address this question. Even if there were evidence that the medical use of marijuana would decrease the perception that it can be a harmful substance, this is beyond the scope of laws regulating the approval of therapeutic drugs. Those laws concern scientific data concerning safety and efficacy drugs for individual use, and do not address perceptions or beliefs of the general population.

Marijuana is not a completely benign substance. It is a powerful drug with a variety of effects. However, except for the harms associated with smoking, the adverse effects of marijuana use are within the range tolerated for other medications. Thus the safety issues associated with marijuana do not preclude certain medical uses. But the question remains: is it effective? This topic is covered here in two chapters: chapter 2 summarizes what has been learned about the biological activity of cannabinoids in the past fifteen years from research in the basic sciences, chapter 4 reviews the clinical data on the effectiveness of marijuana and cannabinoids for the treatment of a variety of medical conditions.

Three factors influence the safely of marijuana or cannabinoid drugs for medical uses: the delivery system, the use of plant material, and the side effects of cannabinoid drugs. (l) Smoking marijuana is clearly harmful, and especially for chronic conditions, and is not an ideal drug delivery system. (2) Plants are of uncertain composition which render their effects equally uncertain, hence an undesirable medication. (3) The side effects of cannabinoid drugs fall within the acceptable risks for approved medications. Indeed, some of the 'side effects', such as anxiety reduction and sedation, might be desirable for certain patients. As with many medications, there are people for whom they would likely be contraindicated.

CONCLUSION: Present data on drug use progression neither support nor refute the suggestion that medical availability would increase drug abuse. However, this question is beyond the issues normally considered for medical uses of drugs, and should not be a factor in evaluating the therapeutic potential of marijuana or cannabinoids.

CONCLUSION: A distinctive marijuana withdrawal syndrome has been identified, but it is mild and short-lived. The syndrome includes restlessness, irritability, mild agitation, insomnia, sleep EEG disturbance, nausea, and cramping.

CONCLUSION: Numerous studies suggest that marijuana smoke is an important risk factor in the development of respiratory disease.

3.49

RECOMMENDATION: Studies to define the individual health risks of smoking marijuana should be conducted, particularly among populations in which marijuana use is prevalent.

3.50

References

1. Adams IB, Martin BR. 1996. Cannabis: pharmacology and toxicology in animals and humans. Addiction 91:1585-1614.

2. American Psychiatric Association. 1987. Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R). 3rd ed. revised. Washington, D.C.: American Psychiatric Association.

3. American Psychiatric Association. 1994. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Fourth edition. Washington, D.C.: American Psychiatric Association.

4. Ammenheuser MM, Berenson AB, Babiak AK, Singleton CR, Whorton Jr EB. 1998. Frequencies of hprt mutant Iymphocytes in marijuana-smoking mothers and their newborns. Mutation Research 403:55-64.

5. Ammenheuser MM, Berenson NJ, Stiglich EB, Whorton Jr EB, Ward Jr JB. 1994. Elevated frequencies of hprt mutant Iymphocytes in cigarette-smoking mothers and their newborns. Mutation Research 304:285-294.

6. Ammenheuser MM, Hastings DA, Whorton Jr EB, Ward Jr JB. 1997. Frequencies of hart mutant Iymphocytes in smokers, non-smokers, and former smokers. Environmental and Molecular Mutagenesis 30:131-138.

7. Anthenelli RM, Schuckit MA. 1992. Genetics. In: Lowinson JH, Ruiz P. Millman RB, eds. Substance abuse: A comprehensive textbook. 2nd Edition. Baltimore, MD: Williams & Wilkins. Pp.39-50.

8. Anthony JC, Warner LA, Kessler RC. 1994. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey. Experimental and Clinical Psychopharmacology 2:244-268.

9. Bailey SL, Flewelling RL, Rachal JV. 1992. Predicting Continued Use of Marijuana Among Adolescents: The Relative Influence of Drug-specific and Social Context Factors. Journal of Health and Social Behavior 33:51-66.

10. Baldwin GC, Tashkin DP, Buckely 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 156:1606-1613.

11. Barbers RG, Gong HJ, Tashkin DP, Oishi J. Wallace J M. 1987. Differential examination of bronchoalveolar ravage cells in tobacco cigarette and marijuana smokers. American Review of Respiratory Disease 135:1271-1275.

12. 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 Institute 90:1198- 1205.

13. Benowitz NL, Jones RT. 1975. Cardiovascular effects of prolonged delta-9-tetrahydro-cannabinol ingestion. Clinical Pharmacology and Therapeutics 18:287-297.

3.51

14. Block Rl, Ghoneim MM. 1993. Effects of chronic marijuana use on human cognition. Psychopharmacology 110:219-228.

15. Bloom JW, Kaltenborn WT, Paoletti P. Camilli A, Lebowitz MS. 1987. Respiratory effects of non-tobacco cigarettes. British Medical Journal 295:516-518

16. Bornheim LM, Kim KY, Li J. Perotti BY, Benet LZ. 1995. Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metabolism and Disposition (United States) 23:825-831 .

17. British Medical Association. 1997. Therapeutic uses of cannabis. Amsterdam, The Netherlands: Harwood Academic Publishers.

18. Brook JS, Cohen P. Brook DW. 1998. Longitudinal study of co-occurring psychiatric disorders and substance use. Journal of the American Academy of Child and Adolescent Psychiatry 37:322-330.

19. Budney AJ, Radonovich KJ, Higgins ST, Wong CJ. 1998. Adults seeking treatment for marijuana dependence: a comparison with cocaine-dependent treatment seekers. Experimental and Clinical Psychopharmacology 6:419-426.

20. Burns LA, Meade BJ, Munson AK. 1996. Toxic Responses of the Immune System. In: Casarett, Doul, Toxicology: The Basic Science of Poisons. 5th Edition. New York: McGraw-Hill. Pp. 355-402.

21. Caiaffa WT, Vlahov D, Graham N. Astemborski J. Solomon L, Nelson KE, Munoz. 1994. Drug smoking, Pneumocystis carinii pneumonia, and immunosuppression increase risk of bacterial pneumonia in Human Immunodeficiency Virus-seropositive injection drug users. American Journal of Respiratory and Critical Care Medicine 150: 1493-1498.

22. Campbell AM, Evans M, Thompson JL, Williams MR. 1971. Cerebral atrophy in young cannabis smokers. Lancet 2:1219-1224.

23. Chait LD, Pierri J. 1992. Effects of smoked marijuana on human performance: A critical review. In: L Murphy and A Bartke, Eds Marijuana/Cannabinoids: Neurobiology and Neurophysiology. Boca Raton FL: CRC Press. Pp. 387-424.

24. Charalambous A, Marciniak G. Shiue C Y. Dewey SL, Schlyer DJ, Wolf AP, Makriyannis A. 1991. PET studies in the primate brain and biodistribution in mice using (-)- S'18F-delta 8-THC. Pharmacology Biochemistry and Behavior 40: 503-7.

25. Chen K, Kandel DB, Davies M. 1997. Relationships between frequency and quantity of marijuana use and last year proxy dependence among adolescents and adults in the United States. Drug and Alcohol Dependence 46:53-67.

26. Chiesara E, Rizzi R. 1983. Chromosome damage in heroin-marijuana and marijuana addicts. Archives of Toxicology Supplement 6:128-130.

27. Cleeland CS, Gonin R. Hatfield AK, Edmonson JH, Blum RH, Stewart JA, Pandya KJ. 1994. Pain and its treatment in outpatients with metastatic cancer. New England Journal of Medicine 330:592-596.

3.52

28. Co BT, Goodwin DW, Gado M, Mikhael M, Hill SY. 1977. Absence of cerebral atrophy in chronic cannabis users by computerized transaxial tomography. Journal of the American Medical Association 237:1229-1230.

29. Cohen MJ, Rickles Jr WH. 1974. Performance on a verbal learning task by subjects of heavy past marijuana usage. Psychopharmacologia 37:323-330.

30. Cornelius MD, Taylor PM, Geva D, Day NL. 1995. Prenatal tobacco and marijuana use among adolescents: Effects on offspring gestational age, growth, and morphology. Pediatrics :738-743.

31. Crowley TJ, Macdonald MJ, Whitmore EA, Mikulich SK. 1998. Cannabis Dependence, Withdrawal, and Reinforcing Effects Among Adolescents with Conduct Symptoms and Substance Use Disorders. Drug and Alcohol Dependence 50:27-37.

32. Crowley TJ, Rhine MW. 1985. The Substance Use Disorders. In: Simons RC, Editor Understanding Human Behavior in Health and Illness. 3rd Edition. Baltimore, MD: Williams & Wilkins. Pp. 730-746.

33. Denning DW, Follansbee SE, Scolaro M, et al. 1991. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. New England Journal of Medicine 324:654-662.

34. Di Franco MJ, Sheppard HW, Hunter DJ, Tosteson TD, Ascher MS. 1996 The lack of association of marijuana and other recreational drugs with progression to AIDS in the San Francisco Men's Health Study. AEP 6:283-289.

35. Dixon L, Haas G. Weiden PJ, Sweeney J. Frances AJ. 1991. Drug Abuse In Schizophrenic Patients: Clinical Correlates and Reasons for Use. Am J Psychiatry 148:224-230.

36. Donald PJ. 1991. Advanced malignancy in the young marijuana smoker. Advances in Experimental Medicine and Biology 288:33-56.

37. Dreher M. 1987. The evolution of a roofs daughter. Journal of Psychoactive Drugs 19:165-170.

38. Dreher MC, Nugent K, Hudgins R. 1994. Prenatal marijuana exposure and neonatal outcomes in Jamaica: an ethnographic study. Pediatrics 93:254-260.

39. Endicott JN, Skipper P. Hernandez L. 1993. Marijuana and head and neck cancer. In: Friedman et al, Editors Drugs of Abuse, Immunity and AIDS. New York: Plenum Press. Pp. 107-113.

40. Fehr K, Kalant H. 1981. Cannabis and health hazards. Proceedings of an ARF/WHO scientific meeting on adverse health and behavioral consequences of cannabis use. Editors Fehr K, Kalant H. Toronto, Canada: Addiction Research Foundation.

41. Fleischman RW, Baker JR, Rosenkrantz H. 1979. Pulmonary pathologic changes in rats exposed to marijuana smoke for one year. Toxicology and Applied Pharmacology 47:557-566.

42. Fligiel SE, Beals TF, Tashkin DP, Paule MG, Scallet AC, Ali SF, Bailey JR, Slikker WJ. 1991. Marijuana exposure and pulmonary alterations in primates. Pharmacology, Biochemistry and Behavior 40:637-642.

3.53

43. Fligiel SEG, Roth MD, Kleerup EC, Barsky SH, Simmons M, Tashkin DP. 1997. Tracheobronchial Histopathology in Habitual Smokers of Cocaine, Marijuana, and/or tobacco. Chest 112:319-326.

44. Foley K. 1997. Competent care for the dying instead of physician-assisted suicide. New England Journal of Medicine 336:54-58.

45. Fride E, Mechoulam R. 1996. Ontogenetic development of the response to anandamide and delta-9-tetrahydrocannabinol in mice. Brain Research, Developmental Brain Research 95:131-134.

46. Fried PA. 1982. Marihuana use by pregnant women and effects on offspring: An update. Neurobehavioral Toxicology and Teratology 4:451 -454.

47. Fried P A. 1995. The Ottawa Prenatal Prospective Study (OPPS) Methological issues and findings - it's easy to throw the baby out with the bath water. Life Sciences 56:21592168.

48. Fried PA, O'Connell CM, Watkinson B. 1992. 60- and 72-month follow-up of children
prenatally exposed to marijuana, cigarettes, and alcohol: cognitive and language
assessment. Developmental and Behavioral Pediatrics 13:383-391.

49. Fried PA, Watkinson BSLS. 1997. Reading and language in 9- to 12-year olds prenatally
exposed to cigarettes and marijuana. Neurotoxicology and Teratology 19: 171-183.

50. Fried PA, Watkinson B. Gray R. 1998. Differential effects on Cognitive Functioning in 9- to 12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicology and
Teratology 20:293-306.

51. Gardner EL. 1992. Brain reward mechanisms. In: Lowinson JH, Ruiz P. Millman RB, Editors Substance Abuse: A Comprehensive Textbook. 2nd Edition. Baltimore, MD. Williams and Wilkins. Pp. 70-99.

52. Georgotas A, Zeidenberg P. 1979. Observations on the effects of four weeks of heavy marijuana smoking on group interaction and individual behavior. Comprehensive Psychiatry 20:427-432.

53. Gilmore DG, Blood AD, Lele KP, Robbins ES, Maximillian C. 1971. Chromosomal aberrations in users of psychoactive drugs. Archives of General Psychiatry 24:268272.

54. Goldstein A. 1994. Tolerance and Dependence. In: Goldstein A, Addiction: From Biology to Drug Policy. New York: W.H. Freeman and Company. Pp. 73-84.

55. Gong HJ, Fligiel S. Tashkin DP, Barbers RG. 1987. Tracheobronchial changes in habitual, heavy smokers of marijuana with and without tobacco. American Review of Respiratory Disease 136:142-149.

56. Graham JDP. 1986. The cardiovascular action of cannabinoids. In: Mechoulam R. Editor Cannabinoids as therapeutic agents. Boca Raton, FL: CRC Press, Inc. Pp. 159-166.

57. Grant S. London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, Phillips RL, Kimes AS, Margolin A. 1996. Activation of memory circuits during cue-elicited cocaine craving. Proceedings of the National Academy of Sciences 93: 12040- 12045.

3.54

58. Hall W. Solowij N. 1998. Adverse effects of cannabis. The Lancet 352:1611-1616.

59. Hall W. Solowij N. Lemon J. 1994. The health and psychological consequences of cannabis use. Department of Human Services and Health, Monograph Series, No. 25. Canberra, Australia: Australian Government Publishing Service.

60. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. 1999. Abstinence symptoms following oral THC administration to humans. Psychopharmacology 141:385-394.

61. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. 1999 Abstinence symptoms following smoked marijuana in humans. Psychopharmacology 141 :395-404.

62. Herha J. Obe G. 1974. Chromosomal damage in chronical users of cannabis: in vivo investigation with two-day Iymphocyte cultures. Pharmakopsychiatric 7:328-337.

63. Herring AC, Koh WS, Kaminski NE. 1998. Inhibition of the cyclic AMP signaling cascade and nuclear factor binding to CRE and kappa B elements by cannabinol, a minimally CNS-active cannabinoid. Biochemical Pharmacology 55:1013-1023.

64. Hingson R. Alpert JJ, Day N. Dooling E, Kayn H. Morelock S. Oppenheimer E, Zuckerman B. 1982. Effects of maternal drinking and marihuana use on fetal growth and development. Pediatrics 70:539-546.

65. Hollister LE. 1986. Health aspects of cannabis. Pharmacological Reviews 38:1-20.

66. Huber GL, Mahajan VK. 1988. The comparative response of the lung to marihuana or tobacco smoke inhalation. In: Chesher G. Consroe P. Musty R. Editors Marijuana: An International Research Report: Proceedings of Melbourne Symposium on Cannabis 2-4 September, 1987. National Campaign Against Drug Abuse Monograph Series No 7 Edition. Canberra: Australian Government Publishing Service. Pp. 19-24.

67. Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ. 1992. Characterization of the absorption phase of marijuana smoking. Clinical Pharmacology and Therapeutics 52:31-41.

68. IOM (Institute of Medicine). 1982. Marijuana and Health. Washington, DC National Academy Press.

69. Jackson AL, Murphy LL. 1997. Role of the hypothalamic-pituitary-adrenal axis in the suppression of luteinizing hormone release by delta-9-tetrahydrocannabinol. Neuroendocrinology 65:446-452.

70. Johnson V. 1995. The relationship between parent and offspring comorbid disorders. Journal of Substance Abuse 7:267-280.

71. Johnston LD, O'Malley PM, Bachman JG. 1989. Marijuana decriminalization: the impact on youth, 1975-1980. Journal of Public Health Policy 10:456.

72. Jones RT, Benowitz NL, Herning Rl. 1981. Clinical relevance of cannabis tolerance and dependence. Journal of Clinical Pharmacology 21: 143S- 152S.

3.55

73. Jones RT, Benowitz N. Bachman J. 1976. Clinical studies of tolerance and dependence. Annals of the New York Academy of Sciences 282:221 -239.

74. Kaklamani E, Trichopoulos D, Koutselinis A, Drouga M, Karalis D. 1978. Hashish smoking and T-lymphocytes. Archives of Toxicology 40:97-101

75. Kandel DB 1992 Epidemiological Trends and Implications for Understanding the Nature of Addiction. In: O'Brien CP, Jaffe JH, Editors Addictive Studies. New York: Raven Press, Ltd. Pp. 23-40.

76. Kandel DB, Chen KWLA, Kessler R. Grant B. 1997. Prevalence and demographic correlates of symptoms of last year dependence on alcohol, nicotine, marijuana and cocaine in the U.S. population. Drug and Alcohol Dependence 44:1 1-29.

77. Kandel DB, Davies M. 1992. Progression to Regular Marijuana Involvement: Phenomenology and Risk Factors for Near-Daily Use. In: Glantz M, Pickens R. Editors Vulnerability to Drug Abuse. Washington, D.C.: American Psychological Association. Pp. 211-253.

78. Kandel DB, Johnson JG, Bird HR, Canino G. Goodman SH, Lahey BB, Regier DA, Schwab-Stone M. 1997. Psychiatric Disorders Associated with Substance Use Among Children and Adolescents: Findings from the Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study. Journal of Abnormal Child Psychology 25.121-132.

79. Kandel DB, Raveis VH. 1989. Cessation of Illicit Drug Use in Young Adulthood. Archives of General Psychiatry 46:109-116.

80. Kandel DB, Yamaguchi K. 1993. From Beer to Crack: Developmental Patterns of Drug Involvement. American Journal of Public Health 83:851-855.

81. Kandel DB, Yamaguchi K, Chen K. 1992. Stages of Progression in Drug Involvement from Adolescence to Adulthood: Further Evidence for the Gateway Theory. J. Stud Alcohol 53:447 - 457.

82. Kaplan H B. Martin S S, Johnson R J. Robbins C A. 1996. Escalation of marijuana use: application of a general theory of deviant behavior. Journal of Health and Social Behavior 27:44-61.

83. Kaslow RA, Blackwelder WC, Ostrow DG, et al. 1989. No evidence for a role of alcohol or other psychoactive drugs in accelerating immunodeficiency in HIV-1 positive individuals: a report for the multicenter AIDS cohort study. Journal of the American Medical Association 26 1 :3424-3429.

84. Kelly T H. Foltin R W. Fischman M W. 1993. Effects of smoked marijuana on heart rate, drug ratings and task performance by humans. Behavioral Pharmacology 4: 167-178.

85. Kendler, K. S., C. A. Prescott. 1998. Cannabis Use, Abuse, and Dependence in a Population Based Sample of Female Twins. American Journal of Psychiatry 155:1016.

86. Klein TW, Friedman H. Specter SC. 1998. Marijuana, immunity and infection. Journal of Neuroimmunology 83:102-115.

3.56

87. Koob GF, Le Moal M. 1997. Drug abuse: Hedonic homeostatic dysregulation. Science 278:52-58.

88. Kuehnle J. Mendelson JH, Davis KR, New PF. 1977. Computed tomographic examination of heavy marihuana smokers. Journal of the American Medical Association 237:1231 1231-.

89. Labouvie E, Bates ME, Pandina RJ. 1997. Age of first use: Its reliability and predictive utility. Journal of Studies on Alcohol 58:638-643.

90. Lau RJ, Tubergen DG, Barr MJ, Domino EF, Benowitz N. Jones RT. 1976. Phytohemagglutinin-induced lymphocyte transformation in humans receiving delta-9-tetrahydrocannabinol. Science 192:805-807.

91. Lepore M, Liu X, Savage V, Matalon D, Gardner EL. 1996. Genetic differences in delta-9-tetrahydrocannabinol-induced facilitation of brain stimulation reward as measured
by a rate-frequency curve-shift electrical brain stimulation paradigm in three different rat strains. Life Sciences 58:365-372.

92. Lepore M, Vorel SR' Lowinson J. Gardner EL. 1995. Conditioned place preference induced by delta-9-tetrahydrocannabinol: Comparison with cocaine, morphine, and food reward. Life Sciences 56:2073-2080.

93. Leuchtenberger C, Leuchtenberger R. 1976. Cytological and cytochemical studies of the effects of fresh marijuana cigarette smoke on growth and DNA metabolism of animal and human lung cultures. In: Braude MC, Szara S. Editors The Pharmacology of Marijuana New York: Raven Press.

94. Lindgren JE, Ohlsson A, Agurell S. Hollister LE, Gillespie H. 1981. Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis. Psychopharmacology (Berl) 74:208-12.

95. Linzen DH, Dingemans PM, Lenior ME. 1994. Cannabis abuse and the course of recent onset schizophrenic disorders. Archives of General Psychiatry 51 :273-279.

96. Lyons Michael J., Toomey R. Meyer J M, Green AI, Eisen S A, Goldberg J. True W R. Tsuang M T. 1997. How do genes influence marijuana use? The role of subjective effects. Addiction 92:409-417.

97. MacCoun R. Reuter P. 1997. Interpreting Dutch cannabis policy: Reasoning by analogy in the legalization debate. Science 278:47-52.

98. Marques-Magallanes JA, Tashkin DP, Serafian T. Stegeman J. Roth MD. 1997. In vivo and in vitro activation of cytochrome P4501A1 by marijuana smoke. Symposium on the Cannabinoids of the International Cannabinoid Research Society Program and Abstracts. Stone Mountain, GA, June, 1997.

99. Martellotta MC, Cossu G. Fattore L, Gessa GL, Fratta W. 1998. Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug-naive mice. Neuroscience 85:327-330.

3.57
100. Mathew RJ, Wilson WH, Humphreys DF, Lowe JV, Wiethe KE. 1992. Regional cerebral blood flow after marijuana smoking. Journal of Cerebral Blood Flow and Metabolism 12:750-758.

101. Mathre ML. 1998. A Survey on Disclosure of Marijuana Use to Health Care Professionals. Journal of Psychoactive Drugs 20: 117- 120.

102. Mendelson JH, Cristofaro P. Ellingboe J. Benedikt R. Mello NK 1985 Acute effects of marihuana on luteinizing hormone in menopausal women. Pharmacology, Biochemistry, and Behavior 23 :765-768.

103. Meyer RE, Pillard RC, Shapiro LM, Mirin SM. 1971 Administration of marijuana to heavy and casual marijuana users. American Journal of Psychiatry 128: 198-204.

104. Model KE. 1993. The effect of Marijuana decriminalization on hospital emergency room drug episodes: 1975-1978. Journal of the American Statistical Association 88:737- 747.

105. Moulin DE, Iezzi A, Amireh R. Sharpe WKJ, Boyd D, Merskey H. 1996. Randomised trial of oral morphine for chronic non-cancer pain. Lancet 347:143- 147.

106. Murphy LL, Gher J. Szary A. 1995. Effects of prenatal exposure to delta-9-tetrahydrocannabinol on reproductive, endocrine and immune parameters of male and female rat offspring. Endocrine 3:875-879.

107. Nahas GG, Osserman EF. 1991. Altered serum immunoglobulin concentration in chronic marijuana smokers. Advances in Experimental Medicine and Biology 288:25-32.

108. Nesse RM, Berridge KC. 1997. Psychoactive Drug Use in Evolutionary Perspective. Science 278:63-66.

109. Nestler EJ, Aghajanian GK. 1997. Molecular and Cellular Basis of Addiction. Science 278;58-63.

I10. Newell GR, Mansell PW, Wilson MB, Lynch HK, Spitz MR, Hersh EM. 1985. Risk factor analysis among men referred for possible Acquired Immune Deficiency Syndrome. Preventive Medicine 14:81-91.

111. NIH (National Institutes of Health). 1997. Workshop on the medical utility of marijuana. Report to the Director, National Institutes of Health by the ad hoc group experts. Bethesda, MD, February 19-20, 1997. Publisher: National Institutes of Health, Bethesda, MD.

112. O'Brien CP. 1996. Drug addiction and drug abuse. In: Harmon JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman A G. Editor Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th Edition. New York: McGraw-Hill. Pp. 557-577.

113. O'Brien CP. 1996. Recent developments in the pharmacotherapy of substance abuse. Journal of Consulting and Clinical Psychology 64:677-86.

114. O'Brien CP. 1997. A range of research-based pharmacotherapies for addiction. Science 278:66-70.

3.58

115. O'Leary DS, Andreasen NC, Hurtig RR, Torres IJ, Flashman LA, Kesler ML, Arndt SV, Cizadlo TJ, Ponto LLB, Watkins GL, Hichwa RD. 1997. Auditory and visual attention assessed with PET. Human Brain Mapping 5:422-436.

116. O'Leary D, Block RI, Flaum M, Boles Ponto LL, Watkins GL, Hichwa RD. 1998. Acute marijuana effects on rCBF and cognition: A PET study. Abstracts - Society for Neuroscience: 28th Annual Meeting. Los Angeles, CA, November 7- 12, 1998. Washington, DC Society for Neuroscience.

117. Ohlsson A, Lindgren J-E, Wahlen A, Agurell S. Hollister L E, Gillespie HK. 1980. Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clinical Pharmacology and Therapeutics 28:409-416.

118. Peterson RC. 1979. Importance of inhalation patterns in determining effects of marijuana use. Lancet 1 :727-728.

119. Polen MR, Sidney S. Tekawa IS, Sadler M, Friedman D. 1993. Health care use by frequent marijuana smokers who do not smoke tobacco. The Western Journal of Medicine
158:596-601.

120. Pope HG, Gruber AJ, Yurgelun-Todd D. 1995. The residual neuropsychological effects of cannabis: The current status of research. Drug and Alcohol Dependence 38:25-34.

121. Pope HG, Yurgelun-Todd D. 1996. The residual cognitive effects of heavy marijuana use in college students. Journal of the American Medical Association 275:521 -527.

122. Rachelefsky G. Opelz G. Mickey M, Lessin P. Kiuchi M, Silverstein M, Stiehm E. 1976. Intact humoral and cell-mediated immunity in chronic marijuana smoking. Journal of Allergy and Clinical Immunology 58:483-490.

123. Rickles Jr WH, Cohen MJ, Whitaker CA, McIntyre KE. 1973. Marijuana induced state- dependent verbal learning. Psychopharmacologia 30:349-354.

124. Robins LN. 1980. The natural history of drug abuse. Acta Psychiatrica Scandinavica Suppl 284:7-20.

125. Robins. L.N. 1998. The intimate connection between antisocial personality and substance abuse. Social Psychiatry and Psychiatric Epidemiology 33:393-399.

126. Robins LN, McEvoy LT. 1990. Conduct problems as predictors of substance abuse. In: Robins L, Rutter M, eds. Straight and devious pathways from childhood to adulthood. New York Cambridge: Cambridge University Press. Pp. 182-204.

127. Rosenkrantz H. Fleischman RW. 1979. Effects of cannabis on lung. In: Nahas GG, Payton WDH, Editors Marijuana: Biological Effects. Oxford, England: Pergamon Press. Pp. 279-299.

128. Rosenzweig MR, Leiman AL, Breedlove SM. 1996. Biological Psychology. Sunderland, MA: Sinauer Associates, Inc.

3.59

129. Roth MD, Arora A, Barsky SH, Kleerup EC, Simmons MS, Tashkin DP. 1998. Airway inflammation in young marijuana and tobacco smokers. American Journal of Respiratory and Critical Care Medicine 157: 1 -9.

130. Roth MD, Kleerup EC, Arora A, Barsky SH, Tashkin DP. 1996. Endobronchial injury in young tobacco and marijuana smokers as evaluated by visual, pathologic and molecular criteria. American Review of Respiratory Critical Care Medicine 153 (part 2): 100A.

131. SAMHSA (Substance Abuse and Mental Health Services Administration). 1998. National Household Survey on Drug Abuse: Population Estimates 1997. DHHS Pub No. (SMA) 98-3250. Rockville, MD: SAMHSA, Office of Applied Studies.

132. Scheier LM, Bovtin GJ. 1996. Cognitive effects of marijuana. Journal of the American Medical Association 275:JAMA Letters.

133. Schneier F Et, Siris SG. 1987. A review of psychoactive substance use and abuse in schizophrenia: patterns of drug choice. Journal of Nervous and Mental Disease 175:641 -652.

134. Schuel H. Berkery D, Schuel R Chang MC, Zimmerman AM, Zimmerman S. 1991.Reduction of the fertilizing capacity of sea urchin sperm by cannabinoids derived from marihuana. I. Inhibition of the acrosome reaction induced by egg jelly. Molecular Reproduction and Development 29:51-59.

135. Schuel H. Chang MC, Berkery D, Schuel R. Zimmerman AM, Zimmerman S. 1991. Cannabinoids inhibit fertilization in sea urchins by reducing the fertilizing capacity of sperm. Pharmacology, Biochemistry, and Behavior 40:609-615.

136. Schuel H. Goldstein E, Mechoulam R. Zimmerman AM, Zimmerman S. 1994. Anandamide (arachidonylethanolamide), a brain cannabinoid receptor, agonist, reduces sperm fertilizing capacity in sea urchins by inhibiting the acrosome reaction. Proceedings of the National Academy of Sciences 91:7678-7682.

137. Sidney S. Beck JE, Tekawa IS, Quesenberry CP, Jr, Friedman GD. 1997a. Marijuana Use and Mortality. American Journal of Public Health 87:585-590.

138. Sidney S. Quesenberry CP, Jr, Friedman GD, Tekawa IS. 1997b. Marijuana use and cancer incidence (California, United States). Cancer Cause and Control 8:722-728.

139. Solowij N. 1995. Do cognitive impairments recover following cessation of cannabis use? Life Sciences 56:2119-2126.

140. Sridhar JS, Raub WA, Weatherby NL, et al. 1994. Possible role of marijuana smoking as a carcinogen in the development of lung cancer at a young age. Journal of Psychoactive Drugs 26:285-288.

141. Stenchever MA, Kunysz TJ, Allen MA. 1974. Chromosome breakage in users of marijuana. American Journal of Gynecology 118:106-113.

142. Stephens RS, Roffman RA, Simpson EE. 1993. Adult marijuana users seeking treatment. Journal of Consulting and Clinical Psychology 61: 1100- 1104.

3.60

143. Tanda G. Pontieri FE, Di Chiara G. 1997. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a commonu1 opioid receptor mechanism. Science 276:2048-2049.

144. Tart CT. 1971. On being stoned: A psychological study of marijuana intoxication. Palo Alto, CA: Science and Behavior Books

145. Tashkin DP, Coulson A H. Clark V A, Simmons M, Bourque L B. Duann S. Spivey C} H. 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 135:209-216.

146. 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 155:141-148.

147. Tashkin E. 1999. Effects of marijuana on the lung and its defenses against infection and cancer. School Psychology International 20:23-37.

148. Taylor FM. 1988. Marijuana as a potential respiratory tract carcinogen: A retrospective analysis. Southern Medical Journal 81: 1213-1216.

149. Tennant F S. 1980 Histopathologic and clinical abnormalities of the respiratory system in chronic hashish smokers. Substance and Alcohol Actions/Misuse 1:93-100.

150. Thornicroft G. 1990. Cannabis and psychosis: Is there epidemiological evidence for an association? British Journal of Psychiatry 157:25-33.

151. Tindall B. Cooper D, Donovan B. Barnes T. Philpot C, Gold J. Penny R. 1988. The Sydney AIDS Project: Development of Acquired Immunodeficiency Syndrome in a Group of HIV Seropositive Homosexual Men. Australian and New Zealand Journal of Medicine 18:8-15.

152. Tsou K, Patrick SL, Walker JM. 1995. Physical withdrawal in rats tolerant to delta-9- tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist. European Journal of Pharmacology 280:R13-R15.

153. Van Hoozen BE, Cross CE. 1997. Respiratory tract effects of marijuana. Clinical Reviews in Allergy and Immunology 15:243-269.

154. Volkow ND, Gillespie H. Mullani N. Tancredi L, Grant C, Valentine A, Hollister L. 1996. Brain glucose metabolism in chronic marijuana users at baseline and during
marijuana intoxication. Psychiatry Research 67:29-38.

155. Wagner JA, Varga K, Kunos G. 1998. Cardiovascular actions of cannabinoids and their generation during shock. Journal of Molecular Medicine 76:824-836.

156. Wallace JM, Tashkin DP, Oishi JS, Barbers RG. 1988. Peripheral blood lymphocyte subpopulations and mitogen responsiveness in tobacco and marijuana smokers. Journal of Psychoactive Drugs 20:9-14.

3.61

157. Wehner FC, Van Rensburg SJ, Theil PF. 1980. Mutagenicity of marijuana and Transkei tobacco smoke condensates in the Salmonella/microsome assay. Mutation Research 77:135-142.

158. Wenger T. Croix D, Tramu G. Leonardelli J. 1992. Effects of delta-9-tetrahydrocannabinol on pregnancy, puberty, and the neuroendocrine system- In: Murphy L, Bartke A, Marijuana/Cannabinoids: Neurobiology and Neurophysiology. Boca Raton, FL: CRC Press.

159. White SC, Brin SC, Janicki BW. 1975. Mitogen-induced blastogenic responses of lymphocytes from marijuana smokers. Science 188:71-72.

160. Whitfield RM, Bechtel LM, Starich GH. 1997. The impact of ethanol and marinol/marijuana usage on hiv+/aidspatients undergoing azidothymidine, azidothymidine/dideoxycytidine, ordideoxyinosine therapy. Alcohol Clin Exp Res 21:122-7.

161. Wu TC, Tashkin DP, Djahed B. Rose JE. 1988. Pulmonary hazards of smoking marijuana as compared with tobacco. New England Journal of Medicine 318:347-351.

162. Yesavage JA, Leirer VO, Denari M, Hollister LE. l985. Carry-over effects of marijuana intoxication on aircraft pilot performance: a preliminary report. American Journal of Psychiatry 142:1325-1329.

163. Zuckerman B. Frank DA, Hingson R. Amaro H. Levenson S. Kayne J. Parker S. Vinci R. Aboagye K, Fried L, Cabral J. Timperi R. Bauchner H. 1989. Effects of maternal marijuana and cocaine use on fetal growth. New England Journal of Medicine 320:762-768.

3.62

Chapter 4 ----->>>>>