National Academies Press: OpenBook

Marijuana and Health (1982)

Chapter: EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS

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Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
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Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
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Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 59
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 60
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 61
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 62
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 63
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 64
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 65
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 66
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 67
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 68
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 69
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 70
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 71
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 72
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 73
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 74
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 75
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 76
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 77
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
×
Page 78
Suggested Citation:"EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS." Institute of Medicine. 1982. Marijuana and Health. Washington, DC: The National Academies Press. doi: 10.17226/18942.
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EFFECTS OF MARIJUANA ON THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS RESPIRATORY SYSTEM Performance (Pulmonary Function) The lungs are the natural target for the harmful effects of smoked materials. This is as true for marijuana as for tobacco. In both instances, smoke is drawn into the lungs where it can harm not only the cells that line the airways (trachea, nasopharynx, bronchi, and alveoli) and constitute the lung tissue, but also impair such cells as lung macrophages, which are part of the immune system. As a result, the smoke may inflict injury directly on parts of the system and also make the lungs vulnerable to agents that normally are held at bay by self-cleansing and self-protecting mechanisms. Different effects would be expected from tobacco and marijuana smoking because of the striking differences in the way in which the two substances are smoked: marijuana smoke usually is drawn deeply into the lungs by one or a few deliberately deep breaths, whereas tobacco smoking is generally more automatic, repetitive, and variable in pattern. Moreover, because marijuana is a "street drug," it not only is inconsistent in its content but also is subject to contamina- tion. Also, filters are not usually used by marijuana smokers, although water pipes are used occasionally. Consequently, under natural conditions it is difficult to judge dosage of active ingredients, to sort out the influence of contaminants, and to compare the consequences of marijuana and tobacco smoke. Experience over the years with cigarette smoking has shown that continued exposure to tobacco smoke entails the risk of producing chronic bronchitis and/or carcinoma of the lung. But, although cannabis products have been smoked for centuries, remarkably little is recorded about their effects on the lungs. Whatever contemporary information exists is confounded by the fact that most marijuana smokers are also tobacco smokers. In recent years, interest has heightened in the smoking of marijuana as a therapeutic measure. The inhalation route takes advantage of the large surface area afforded by the lungs for administering the effective constituents of marijuana. However, this 57

58 practice entails the disadvantage of administering a therapeutic agent in a cloud of air pollutants. In brief, our appraisal must assess the impact of chronic bronchial irritation and inflammation on the airways and gas-exchanging surfaces of the lungs. Acute Effects Marijuana affects the control of the breathing pattern in different ways depending upon the dose, the preparation, and its psychotropic effect on the consumer. One marijuana cigarette generally stimulates ventilation (air exchange between the lungs and the ambient air) in conjunction with an increase in the metabolic rate and a heightened response to carbon dioxide (CC>2) as a regulatory stimulant (Vachon et al., l973; Zwillich et al., l978). On the other hand, larger doses of smoked marijuana may depress the ventilation and responsiveness to the CO2 stimulus (Weil et al., l968; Bellville et al., l975). The intravenous administration of A-9-THC in equivalent doses has much less of an effect either on the ventilation or on the effectiveness of CO2 as a respiratory stimulant (Malit et al., l975). Much more consistent and predictable is the effect of marijuana on the airways. The inhalation of small amounts of marijuana smoke causes bronchial dilation in persons without demonstrable lung disease (Tashkin et al., l973; Vachon et al., l973). The bronchodilation is easily demonstrable; the inhalation of isoproterenol (l250 ug), a potent bronchodilator, caused less of an improvement in airways conductance than the peak effect observed after smoking 2 percent marijuana (Tashkin et al., l973). Ingestion of A-9-THC is less effective than smoking marijuana in producing bronchodilation; the bronchodilator effects of smoked marijuana last as long as 60 minutes; that of ingested A-9-THC up to 6 hours. Aerosolized A-9-THC has a local irritating effect on the airways, which often overrides the bronchodilating effect to the point of making it unsuitable for therapeutic purposes (Tashkin et al., l977a). Except for bronchodilation, acute exposure to marijuana has little effect on breathing as measured by conventional pulmonary tests. Thus, in young marijuana smokers (2l-30 years of age) who smoked at least four cigarettes per week and no tobacco for at least 6 months before, ventilatory mechanics and gas exchange were normal by conventional tests (Tashkin et al., l976). In contrast, heavy marijuana smoking, i.e., at least 4 days per week for 6 to 8 weeks did cause mild airway obstruction (Tashkin et al., l976). Acute smoking of marijuana, as well as the ingestion of A-9-THC, also causes bronchodilation in individuals with mild to moderate asthma (Tashkin et al., l974). Marijuana smoking or ingestion of A-9-THC also dilated airways in asthmatics in whom bronchoconstriction was deliberately provided either by exercise or by the inhalation of methacholine, a bronchoconstrictor (Shapiro et al., l976a). The mechanism by which bronchodilation is effected is not clear, but does not involve stimulation of beta-adrenergic

59 receptors or blockade of muscarinic receptors in airway smooth muscle (Shapiro et al., l976a). Adding to the difficulties of interpretation are the psychotropic effects of marijuana: four of the individuals who had previously used cannabis could distinguish the marijuana cigarette from the placebo on the basis of the intoxicating experience afforded by the marijuana smoke. Although the four subjects without previous cannabis experience did not experience any central nervous system effects, they did note mild somnolence or light-headedness after marijuana use. Among the experiments with induced asthma were some that employed the inhalation of cannabinoid-free marijuana smoke (Tashkin et al., l975). The results indicate that the smoke of the marijuana cigarette does not prevent methacholine-induced bronchospasm (Tashkin et al., l976). Smoking of marijuana did not aggravate or perpetuate bronchoconstriction in stable asthmatics, and it promptly reversed experimentally induced bronchospasm (Tashkin et al., l978). Addition of A-9-THC to placebo smoke caused a prompt, complete, and sustained reversal of methacholine-induced bronchospasm. Although ingestion of A-9-THC in a sesame oil vehicle has produced bronchodilation in asthmatic patients, less dilation was noted than after smaller doses of A-9-THC delivered by smoking (Tashkin et al., l974). Although it appears that the mechanism of A-9-THC-induced bronchial dilation is mediated by the autonomic nervous system, the process of dilation is not understood (Gill and Paton, l970; Cavero et al., l972; Shapiro et al., l973). Subacute Effects Pulmonary function tests in 28 healthy young experienced cannabis users before and after a 47-59-day period of heavier than customary marijuana usage (group daily average of 5.2 cigarettes, with a daily mean range of l.7 to l0 cigarettes per subject) disclosed the development of mild but significant decreases in specific airway conductance and forced expiratory flow as well as in diffusing capacity (Tashkin et al., l976). Cessation, by reduction in smoking, gradually restored the tests toward normal. The clinical significance of these abnormalities is uncertain. The marijuana smoked and the impairment in pulmonary function, coupled with the observation that reversibility of function was incomplete l week after marijuana smoking had stopped, suggests that heavy marijuana smoking over a much longer period could lead to clinically significant and less readily reversible impairment of pulmonary function. Chronic Effects A study of 3l American soldiers stationed in West Germany who smoked large quantities of hashish (lOO grams or more per month for periods

60 of 6 to l5 months) found their ailments to be principally respiratory, including bronchitis, sinusitis, asthma, and rhinopharyngitis (inflammation of the nasopharynx) (Tennant et al., l97l). In one-third of the soldiers, sputum-producing coughs, difficulty in breathing, and wheezing followed 3 to 4 months of regular use of hashish. However, they had a normal chest radiograph and normal sputum. Antibiotics failed to relieve the symptoms. The symptomatic patients could not work and four required hospitalization. An unspecified decrease in hashish consumption improved their symptoms. Pulmonary function tests in these individuals showed mild airway obstruction after 3 days of lessened hashish intake. Moreover, the response of these individuals to isoproterenol suggested that reversible bronchospasm and/or the accumulation of fluid in the bronchi was involved in the pathogenesis of the airway obstruction. Patch and serological tests failed to implicate allergy as a cause of the upper respiratory symptoms and signs. In Jamaica (Hall, l975), where marijuana usage is heavy, chronic bronchitis is frequent. However, marijuana smoking is usually associated with tobacco smoking, which confounds interpretation of the effects of marijuana alone. Adding to the uncertainty about the effects of marijuana as a cause of chronic regulatory abnormalities are two other studies, one in Jamaica (Rubin and Comitas, l975) and the other in Costa Rica (Hernandez-Bolanos et al., l976), which failed to find any difference in the prevalence of chronic respiratory disease between smokers and nonsmokers of marijuana. These results cannot be accepted as conclusive, because in each study the number of marijuana smokers was small, the subjects were not randomly selected, and the use of tobacco was not taken into account. Much more convincing is a recent study (Tashkin et al., l980) of 74 persons who smoked marijuana for 2 to 5 years, typically as frequently as several times per day, 3 to 6 days per week. Care was taken to obtain proper control groups. The results indicated that habitual smoking of marijuana causes a mild but significant increase in resistance to airflow in the large airways without an appreciable effect on conventional tests. Another study was of 200 American soldiers stationed in West Germany who voluntarily sought medical attention for such respiratory symptoms as pharyngitis, sinusitis, bronchitis, and asthma related to chronic heavy hashish smoking (Henderson et al., l972). Analysis of the hashish available and in use in the locale of this study showed concentrations of 5 to l0 percent A-9-THC. Two to 3 percent of samples were contaminated with cocaine, opium, morphine, spices, or feces. Two aspects of hashish smoking are relevant to the question of lung injury produced by hashish: l) hashish is usually smoked in a pipe (occasionally in a water pipe), although it is occasionally eaten, drunk as a tea, or rolled into a cigarette and smoked, and 2) hashish smoke generally is regarded by users as burning much hotter than tobacco smoke. Soldiers with pharyngitis usually smoked less than 25 grams of hashish monthly; those with bronchitis and asthma consumed more than 50 grams per month. The common complaint of sore throat in these

€1 heavy hashish smokers occurred most often in those who smoked hashish in a pipe without a screen or cotton filter; in them, the roof of the mouth and the back of the throat were inflamed. Persistent rhinitis (inflammation of the nasal mucous membranes) was present in 26 patients. As a rule, allergy could not be implicated in the nasopharyngeal manifestations. Treatment with antibiotics, decongestants, and phenylephrine (a vasoconstrictor) relieved the symptoms, but they recurred in those who continued smoking hashish. Twenty high-dose hashish smokers (more than 50 grams/month) had chronic bronchitis as manifested by a chronic sputum-producing cough, shortness of breath, and decreased exercise tolerance. On physical examination, abnormal respiratory sounds—rhonchi, wheezes, and rales—were present. Chest radiographs were consistently normal, but pulmonary function was abnormal; the vital capacity (the maximum volume of gas taken in) was l5 to 40 percent below normal. In six of these subjects who smoked 50 or more grams per month, biopsy of bronchial mucosa revealed changes that resembled the abnormalities that occur in older heavy smokers of tobacco (Auerbach et al., l96l). The biopsies also turned up atypical cells not found in tobacco smokers. The study of a respiratory disease in hashish or marijuana smokers is difficult because the great majority also smoke tobacco cigarettes. Also, the illegality of marijuana smoking prevents people from volunteering information and cooperating in experimental studies. Baseline physiological or clinical studies are difficult, because the subject is not identified until he seeks medical help. Rats (Fleischman et al., l979) and dogs (Roy et al., l976) have been exposed experimentally to marijuana smoke over long periods (l year and 900 days, respectively) to determine its morphological effects on the lungs. At autopsy, the animals demonstrated damage of the airways and also of the lung substance. However, it is difficult to relate the results of these animal experiments, in which the artificial pattern of smoking differed markedly from that of the human smoker, to the effects that chronic marijuana smoking might elicit in man. Defense Mechanisms (Alveolar Macrophages) Little is known about the effects of marijuana on the defense mechanisms of the lungs. Although some observations have been made on the alveolar macrophage, an important element in this system, the results have been inconsistent. For example, some studies of the rat lung found that macrophages obtained by washing out the lung and exposing them to marijuana smoke manifested a depression in bactericidal activity (Huber et al., l975, l979a,b, l980). On the other hand, another report failed to disclose a significant effect, not only of marijuana, but also of tobacco smoke on the bactericidal activity of macrophages (Drath et al., l979). Finally, others have found that alveolar macrophages differ slightly in their morphological responses to tobacco and to marijuana smoke. The significance of

62 these differences, especially in terms of their long-term effect on pulmonary defense mechanisms, remains to be defined. Explants of lung have also been examined after exposure in culture to marijuana smoke (Leuchtenberger et al., l973a,b; Leuchtenberger and Leuchtenberger, l976). Striking changes have been observed in the appearance and growth characteristics of exposed cells. Carcinoma of the Lung The effect of marijuana as a carcinogen for lung, airways, and upper respiratory organs has not been systematically explored. Evaluating the carcinogenicity of marijuana is difficult, because most marijuana smokers also are tobacco cigarette smokers and because such carcinogenicity could have a long period of latency; studies of tobacco carcinogenesis indicate that 20 to 30 years of exposure must occur before tumors appear in the lung. It is understandable that information concerning the carcinogenic properties of marijuana are not yet available, particularly in the United States, where the agent has come into extensive use only during the past two decades. An important problem in evaluating carcinogenicity is the fact that the leaf is used by igniting it and the inhaled products of its combustion may be carcinogenic, as in the case of tobacco products. Even if it proved to be carcinogenic, the question would still remain as to what constituent in marijuana smoke was at fault. The potency of a substance as a mutagen (ability to change genetic material) can provide a clue as to its possible role as a carcinogen. Induction of genetic mutations by a substance in test strains of bacteria correlates with induction of tumors in test animals. Fractions from extracts of marijuana smoke particulates ("tar") have been found to produce dose-related mutations in four out of five test strains of bacteria (Busch et al., l979; Seid and Wei, l979; Wehner et al., l980). By itself, A-9-THC was not active as a mutagen in bacterial strains (Glatt et al., l979) or in mammalian test systems (van Went, l978). The extent to which marijuana smoke differs from tobacco smoke is discussed in detail in Chapter l. In general, except for the presence of cannabinoids in one and tobacco alkaloids (nicotine) in the other, the combustion products of tobacco and marijuana are qualitatively similar. On occasion, however, differences that may be meaningful have been found. For example, one study (Hoffmann et al., l975) reports that tobacco smoke contains more isoprene and volatile phenols, whereas marijuana smoke contains about 5O percent more carcinogenic hydrocarbons. Tumorigenicity of marijuana and tobacco smoke condensates on mouse skin have been reported. In mice painted three times weekly with a tar suspension of smoke condensate, survival at 74 weeks was better in the marijuana group than in the tobacco group. Six of l00 mice painted with marijuana condensate developed skin tumors, all of which were benign, whereas l4 of l00 in the tobacco condensate group developed tumors, two of them malignant (Hoffman et al., l975).

63 Because marijuana smoke has adverse actions similar to tobacco smoke on cell function in the respiratory and cardiovascular systems, it has been proposed that marijuana smoke, rather than only the cannabinoid, should be used to obtain information about effects on cell injury and response (Leuchtenberger and Leuchtenberger, l97l). Exposure of human lung cells in culture to freshly generated marijuana smoke for up to 2 months resulted in increased mitotic indices, stimulation of ONA synthesis, and an increase in the population of cells with four times the DNA content of control cells or those exposed to tobacco smoke (Leuchtenberger et al., l973a,b). Long-term exposure of hamster lung cells to the smoke of either marijuana or tobacco led to abnormal proliferation and malignant transformation within 3 to 6 months of exposure (Leuchtenberger and Leuchtenberger, l976). Since malignant transformation was also noted in unexposed lung cells after l2-24 months of culture, it appears that the smoke of marijuana or tobacco accelerates, rather than initiates, the malignant change. Although no instance of human lung carcinoma attributable solely to marijuana smoking has yet been reported, abnormalities suggestive of cancerous lesions have been recorded. For example, in several of the U.S. servicemen who smoked 50 grams of hashish or more per month and developed upper respiratory disorders, mucosal biopsy showed extensive cellular abnormalities, including loss of cilia, proliferation of basal epithelial cells, and atypical cells (Tennant et al., l97l; Henderson et al., l972). Comparison of 30 American hashish smokers (25-l50 grams/month for 3-24 months; 23 also smoked tobacco and 7 did not), 3 tobacco smokers (l.6 packs/day for ll.3 years) who did not smoke marijuana and 3 nonsmokers of tobacco or hashish, indicated exposure to combined marijuana and tobacco smoke produced more harmful effects than that produced by either substance alone (Tennant et al., l980). In the hashish smokers who did not smoke tobacco, abnormalities in the tracheal biopsies were no more frequent or severe than in those persons who smoked only tobacco. Exception has been taken to the idea of an additive effect of tobacco and hashish smoke. A Greek study that compared chronic hashish and tobacco users with tobacco smoking controls found that although the hashish smokers had considerably more throat irritation and cough, the prevalence of bronchitis in both groups was about the same (Boulougouris et al., l976); no biopsies were taken. The differences between the Greek and American studies may reflect differences between the two populations: The American study, done in Germany, favored inclusion of men with severe respiratory disturbances (Tennant et al., l980), whereas the Greek study (Boulougouris et al., l976) appears to have included persons with less severe illness. The finding of known carcinogens in marijuana smoke and the presence of epithelial abnormalities known to be the precursors of lung cancer in heavy smokers of tobacco suggest the possible development of lung cancer in chronic, heavy users of marijuana and/ or hashish after a prolonged period of use, especially if they are also smokers of tobacco. However, evidence to support this hypothesis is not available. Because marijuana smoking is an ancient

64 custom in Asia and the Middle East, lung cancer would be expected to be more prevalent in these parts of the world if a causal relationship did exist. Unfortunately, no reliable data have been gathered to settle this question. Heavy smoking of marijuana, in quantities comparable to that of tobacco, has been relatively uncommon in the United States. Therefore, the contribution of marijuana smoking to the incidence of primary lung cancer cannot yet be answered with any authoritative data. Summary: Respiratory System Lung Function and Defense Mechanisms The most important question about the effects of marijuana on the health of the respiratory system is whether acute or chronic marijuana smoking cause detectable structural or functional impairment of the lungs. Mild but measurable airway obstruction, affecting both large and small airways, can be shown to exist after 6 to 8 weeks of smoking marijuana daily, averaging five marijuana cigarettes a day; this decrement in function is reversible, but does not return to normal within one week of abstaining from smoking. In persons with histories of heavy smoking, particularly of hashish, chronic inflammatory changes are seen in the bronchi and uvula, often in association with chronic sinusitis. These manifesta- tions of upper respiratory disturbance have been described in individuals with histories of marijuana smoking usually in excess of 3 years and are reversible when marijuana smoking is stopped. Acute exposure of alveolar macrophages in vitro to marijuana smoke causes a reduction in phagocytic activity, a cell defense mechanism. The agents responsible for this change in macrophage function are in the vapor phase of marijuana smoke and are not related to the presence of A-9-THC. Also, lung explants exposed to marijuana smoke in vitro show changes in the chromosomal structure of nuclei. There is as yet no information about the effects of prolonged smoking of marijuana, that is, beyond 5 years. Although some populations have been examined for the effects of chronic marijuana smoking, controlled studies are sparse and populations exposed to marijuana smoke only—without exposure to tobacco—apparently are not available. Particularly conspicuous is the lack of information about the effect of chronic marijuana smoking begun in late childhood or adolescence and continued to adulthood. Such studies would require morphological examination of biopsy material from the bronchi and respiratory passages to determine the presence of structural changes that indicate the development of chronic bronchitis and/or lung cancer. Morphological changes associated with smoking marijuana could be compared with the morphological abnormalities associated with chronic tobacco smoking. The acute response to inhalation of marijuana is an appreciable bronchodilation, both in normal subjects and in individuals with

€5 bronchial asthma. However, the bronchodilator effects of marijuana are a response to acute exposure; chronic exposure usually evokes bronchoconstriction. With respect to therapeutic application, the effects of smoking marijuana in producing bronchial dilatation do not exceed those that follow the inhalation of beta-agonist drugs. Moreover, the doses required for bronchodilatation usually elicit the psychotropic effects of marijuana and may be associated with changes in the structure of bronchial and parenchymal lung cells, the significance of which remains to be assessed. For these reasons therapeutic usefulness as a bronchodilator drug is open to serious question (see Chapter 7). Carcinoma of the Lung One of the great uncertainties about marijuana smoking is its neoplastic potential. No reliable data are available concerning the incidence of carcinoma of the lungs and upper respiratory passages in long-term users of cannabis. But a variety of experimental studies has sounded the alert that marijuana smoking—just as tobacco smoking—may be carcinogenic and that a combination of tobacco and marijuana smoke may have greater neoplastic potential than either one alone. Although the experimental observations have raised the suspicion, long-term observations on human subjects—and possibly on smoking animals—will be necessary to settle the issue. Recommendations for Research Lung Function and Defense Mechanisms With respect to the performance and defenses of the lungs, these studies would be informative: * the physiological, biochemical, and morphological interactions of combined exposures of the respiratory tract to tobacco and marijuana smoke; * the interactions of cannabis and alcohol on the function of the respiratory tract; * the long-term effects, i.e., l0 to 30 years, of exposure of the respiratory tract to frequent use of cannabis in the absence and pressure of exposure to tobacco smoke (for this purpose, large-scale epidemiological studies may be required); * the physiological effects and clinical consequences of exposure of alveolar macrophages and other lung cells to long-term exposure to marijuana smoke; * the immunologic effects of marijuana smoke exposure on cells and on the entire body.

66 Carcinoma of the Lung With respect to carcinoma of the lung, these studies seem essential: * an epidemiological survey to determine over the next 20 to 30 years if there will be an increased incidence of primary lung, laryngeal, oropharyngeal, esophageal, nasal, or sinus cancer in chronic marijuana smokers; * epidemiologic and pathological studies in humans and experimental studies in animals to evaluate the carcinogenic potential of chronic marijuana smoking on the lung, larynx, oropharynx, nasal, and sinus epithelium. CARDIOVASCULAR SYSTEM Normal Heart and Circulation Heart (Direct Effects) With respect to the heart and circulation, the most evident effect in human beings of smoking marijuana, or of ingesting the active ingredient (A-9-THC), is a brisk increase in heart rate (tachycardia). Although this is not threatening to the normal heart, the rapid heart action can be harmful to the heart in which the circulation is compromised by atherosclerosis or is on the verge of failing. The responses of the cardiovascular system to acute exposure to marijuana differ between human beings and most other mammals in that the human subject typically responds with an increase in heart rate (Bright et al., l97l; Beaconsfield et al., l972; Perez-Reyes et al., l973), whereas most mammals show a slowing in rate (bradycardia) (Cavero et al., l973; Graham and Li, l973; Rosenkrantz and Braude, l974; Vollmer et al., l974; Adams et al., l976; Hardman and Hosko, l976; Kawasaki et al., l980). Human blood pressure usually increases moderately on acute administration of A-9-THC, but in monkeys and dogs acute administration is followed by a decrease in systemic arterial pressure. Typical effects on heart rate and blood pressure have been attributed to altered autonomic function (Loewe, l944; Joachimoglu, l965; Ames, l968; Gill and Paton, l970). Effects on the cardiovascular system are to some extent a function of dose, route of administration, and duration of exposure. Tolerance to some of the cardiovascular effects in human beings develops with chronic use (Benowitz and Jones, l975, l977a,b; Nowlan and Cohen, l977), but continued use does not result in any persistent alteration in cardiovascular function after cessation of exposure (Dornbush and Kokkevi, l976). Effects on Heart Rate In healthy young adults, acute administration of marijuana by smoking (l0 mg total dose) causes a prompt increase in heart rate (increasing by up to 90 beats/minute) for about l hour.

67 The change in heart rate caused by A-9-THC appears to result from alterations in both sympathetic and parasympathetic efferent activity to the normal cardiac pacemaker (Beaconsfield et al., l972; Martz et al., l972; Sulkowski et al., l977). The results of studies designed to determine whether beta-adrenergic stimulation is responsible for the tachycardia have not been consistent: In one series of reports, prior administration of propranolol,* in a dose sufficient to block the heart's beta-adrenergic receptors, prevented the increase in heart rate (Bright et al., l97l; Beaconsfield et al., l972; Perez-Reyes et al., l973), whereas in other reports, propranolol failed to block the marijuana-induced tachycardia (Kanakis et al., l976; Tashkin et al., l978). Although part of the discrepancy may be attributable to differences in dosages, not all of it can be rationalized this way, leaving an unexplained disparity. Hemodynamic Effects Effects of marijuana on blood pressure and cardiac output, as mentioned above, are a function of the nature of exposure (acute or chronic), of the dose, and of the body position; also, there are differences among human beings and a number of mammalian species. In human beings lying supine, acute exposure to A-9-THC typically causes a modest increase in blood pressure, although in some instances no significant change in pressure has been observed (Beaconsfield et al., l972; Kanakis et al., l976; Benowitz et al., l979). On assuming the upright posture, blood pressure may drop considerably. Cardiac output, in the supine position following an injection of A-9-THC, has been found to increase by as much as 30 percent (Malit et al., l975; Tashkin et al., l977b). The increase in cardiac output in the face of only a modest increase in blood pressure clearly results in a substantial decrease in peripheral vascular resistance. The change in resistance varies among the different vascular beds, being greatest in the vessels to the skeletal muscles. Chronic administration of quite large oral doses of A-9-THC exerts different effects (than the acute) on the circulation (Bernstein et al., l974; Benowitz and Jones, l975; Benowitz et al., l979). Systolic and diastolic pressure usually fall slightly, but these changes are not always sustained. As the blood pressure falls, the heart rate slows from the high levels caused by initial marijuana administration. The decrease in blood pressure can be accentuated if the subject assumes an upright posture. The extent to which it drops appears to be a reciprocal function of the extent to which plasma volume has increased. Effects on Heart Muscle Data about changes in human left ventricular function caused by marijuana are not entirely convincing because most studies have relied on noninvasive measurements and *Propranolol is an agent that blocks beta-adrenergic neurotransmitters and is used in treatment of cardiac arrhythmias.

68 because it has not been possible to control separately the several variables that modify left ventricular function and are changed by administration of A-9-THC. Changes in heart rate, afterload (systemic vascular resistance, blood pressure), or preload (plasma volume, venous return) individually can cause changes in heart size and ventricular performance. In spite of these limitations, conclusions can be drawn from the observations on human beings. Definitive animal studies of A-9-THC effects on ventricular performance have not been done. Indices of cardiac performance usually improve after marijuana or A-9-THC. Almost invariably this improvement can be attributed to the increase in heart rate (Gash et al., l978). The acute administration of A-9-THC (25 ug/kg intravenously) to healthy young males elicits, in association with the increase in heart rate, changes in the ventricular contraction periods (an increase in ejection time and shortening of the preinjection period), while systemic arterial pressure is unaffected (Weiss et al., l972; Kanakis et al., l976). Beta-adrenergic blockade by propranolol is followed by less striking changes in the contraction time intervals. Another study of l7 subjects who smoked two to three cigarettes (20 mg A-9-THC per cigarette) found cardiac output increased by 28 percent and heart rate by 30 percent, in conjunction with a slight decrease in stroke volume, which affects pulse pressure (Tashkin et al., l977b). Autonomic Nervous System Marijuana could influence autonomic function in several ways: (l) by changing the sensitivity of reflexes that influence and control cardiovascular function; this effect could result either from changes in the processing of nerve impulses in the central nervous system or autonomic ganglia (a group of nerve cells outside the central nervous system), from changes in the liberation or metabolism of transmitters at the autonomic nerve terminals, or from changes in the sensitivity of the pre- or postjunctional receptors; (2) by a change in the levels of neurotransmitters, the catecholamines (norepinephrine, epinephrine) in the blood as a result of actions on the adrenal medulla, which secretes these neurotransmitters; activation of the adrenals could be a direct effect or by reflexes or by a central action of A-9-THC; and (3) by exerting effects on dopamine activity (an intermediate product in the synthesis of norepinephrine) either in the central nervous system or periphery. Unfortunately, it is unclear how the effects of A-9-THC are exerted on the autonomic nervous system (Truitt and Anderson, l97l; Beaconsfield et al., l972; Weiss et al., l972; Englert et al., l973; Ho et al., l973; Howes and Osgood, l974; Ho and Johnson, l976; Huot, l976; Benowitz and Jones, 1977a,b; Gash et al., l978; Stefanis, l978). The data are insufficient to determine if the effects come by way of the central nervous system, or by peripheral neural structures, or by the adrenal medulla. It is also difficult to assess the role of

69 reflex adjustments in the heart and systemic circulation. Finally; other possibilities, such as desensitization or blockade of peripheral adrenergic receptors, have not been examined. Although the data on human beings are not adequate to determine how marijuana influences autonomic function* evidence that it does has been obtained. For example, A-9-THC appears to reduce a number of autonomic reflexes: After marijuana, the typical changes in heart rate and blood pressure elicited by the Valsalva maneuver (a forced exhalation effort against the closed glottis) are decreased, and so are the reflex circulatory responses to immersion of the hand in cold water (Beaconsfield et al., l972; Benowitz et al., l979). However, during chronic administration of A-9-THC, no change occurs in the reflex decrease in heart rate caused by infusion of a dose of the vasoconstrictor phenylephrine sufficient to increase the blood pressure (Benowitz and Jones, l975; Benowitz et al., l979). Exercise Acute exposure to A-9-THC modifies exercise performance by human beings. Smoking (20 mg of A-9-THC) decreased the duration of exercise but caused no change in any cardiopulmonary parameter at any work load except for heart rate, which increased (Shapiro et al., l976b). Other Effects (Plasma Volume, Sodium Retention) Acute administration of A-g-THC would not be expected to have prominent effects on sodium balance or plasma volume. Chronic administration, on the other hand, has distinct effects. With chronic ingestion of large doses of A-9-THC there is a consistent gain in body weight and plasma volume, the latter caused by sodium retention (Benowitz and Jones, l975, l977a,b). The change in plasma volume seems to be causally related to the decrease in orthostatic hypotension during chronic exposure. The mechanisms responsible for the retention of salt and water have not been explored and may include changes in renal perfusion, inhibition of prostaglandin (a substance that affects blood pressure) synthesis by A-9-THC (Burstein and Raz, l972; Howes and Osgood, l976), or some modification in pituitary-adrenal function (Birmingham and Bartova, l976). Abnormal Heart and Circulation Although smoking marijuana or the introduction of A-9-THC into the body is apparently without deleterious effect on the normal heart and circulation, the possibility is great that the abnormal heart and circulation will not be as tolerant of an agent that speeds up the heart, sometimes unpredictably raises or drops the blood pressure,

70 and modifies the activities of the autonomic nervous system. Therefore, it is pertinent to examine the prospects that marijuana (or A-9-THC) may be harmful in individuals with coronary heart disease, cerebrovascular disease, hypertension, and heart failure. Moreover, it may be important to determine if A-9-THC interacts in its effects on the abnormal heart or circulation with other agents that are being administered for therapeutic purposes. Coronary Heart Disease Data on this topic are sparse, presumably because of the relatively short time that marijuana has been available in this country. Those who have smoked marijuana are just entering the age when coronary atherosclerosis is common. However, it has been shown both in normal individuals and in individuals with coronary artery disease that the acute administration of A-9-THC by smoking or injection can cause changes in the electrocardiogram (ECG) (Johnson and Domino, l97l; Beaconsfield et al., l972; Kochar and Hosko, l973). Premature beats have also been noted. The reasons for the changes are unclear. Also not understood is the contribution of the increase in heart rate itself to the ECG changes and to the premature beats. In some patients with coronary artery disease, increased catecholamines can induce arrhythmias. It seems likely that in such patients A-9-THC could have the same effect. Also, in patients with coronary artery disease a large increase in heart rate can induce angina (pain) and even ischemic damage from insufficient oxygen as a result of an obstructed blood vessel. If A-9-THC were to increase heart rate markedly in such patients, and at the same time increase the need for cardiac perfusion because of the increased cardiac work and because of the intensified effect of catecholamines on the heart, it seems reasonable that there could be induction of angina and potentially precipitation of ischemic damage. Furthermore, if A-9-THC dulled the appreciation of pain and the appropriate responses to pain, the patient might not take suitable measure to relieve the angina, thereby increasing the risk of damage or arrhythmias. A decrease in oxygen-carrying capacity of blood because of formation of carboxyhemoglobin could also be troublesome. Exercise tolerance has been reported to decrease in individuals with angina after smoking marijuana; this decrease is in contrast to the unaffected exercise tolerance after smoking a placebo marijuana cigarette (Aronow and Cassidy, l974). Oral ingestion of A-9-THC or smoking marijuana apparently can cause marked hypertension in association with an increase in systemic vascular resistance (Benowitz et al., l979), which would place the heart with coronary artery disease at risk of damage. These observations concur in indicating that marijuana and A-9-THC increase the work of the heart, often in many ways. The conclusion seems inescapable that this increased work, coupled with stimulation by catecholamines, may tax the heart to the point of clinical hazard.

7l Cerebrovascular Disease There are few, if any, indications that A-9-THC has direct effects on the cerebral circulation that would be important in patients with cerebrovascular disease. In the occasional patient who develops hypertension after smoking, there would be an increased risk of a cerebral vascular accident (stroke). Also, because A-9-THC administered after atropine can cause marked increases in blood pressure, this combination would place the patient with cerebro- vascular disease at risk, as would smoking after ingestion of other muscarinic blockers. In some patients, postural hypotension could be a problem, not only for persons with abnormal cerebral circulations, but also with abnormal coronary circulations. Hypertension The factors that act to intensify angina would be of importance in hypertensive patients. Although data are lacking on the magnitude of change in blood pressure caused by A-9-THC in hypertensives, it seems reasonable to assume that hypertensives smoking marijuana might have a greater increase in blood pressure than normals do. The increase in plasma volume and sodium retention that are associated with chronic exposure to A-9-THC could increase blood pressure in hypertensives and the mechanisms responsible for these changes very likely would interfere with the action of a number of antihypertensive medications. Heart Failure Because marijuana can cause tachycardia, a decrease in systemic vascular resistance (required for increased cardiac output to sustain blood pressure) and salt and water retention might place patients with severe heart failure at a disadvantage by exposure to A-9-THC. Data on such patients are lacking. In older patients treated by A-9-THC or who have smoked marijuana for glaucoma or cancer, orthostatic hypotension has been both disabling and a threat of cardiovascular complications (Merritt et al., l980). However, tolerance to orthostatic hypotension seems to develop during continued intake of A-9-THC or continued smoking of marijuana. Dehydration, as during vomiting or diuretic therapy, predisposes to the orthostatic hypotensive effects and resists the development of tolerance because it prevents expansion of blood volume. Interactions with Cardioactive Drugs Few studies evaluate interactions between A-9-THC and other drugs that act directly or indirectly on the heart. Propranolol usually attenuates the increase in heart rate caused by A-9-THC. Atropine

72 can greatly potentiate the ability of A-9-THC to increase systemic arterial pressure (Benowitz and Jones, l977a,b). A number of possible interactions can be imagined. If a patient were taking a drug that blocked uptake of catecholamines by nerve terminals, then those effects of A-9-THC that are mediated by catecholamines would be intensified. Because a great many psychotropic and antihypertensive drugs modify metabolism of neurotransmitters in the central nervous system and periphery, a wide variety of interactions with A-9-THC seems possible. Summary: Cardiovascular System The smoking of marijuana causes changes in the heart and circulation that are characteristic of stress. But there is no evidence to indicate that it exerts a permanently deleterious effect on the normal cardiovascular system. Neither is there convincing evidence that marijuana would be of particular benefit in treating any of the major forms of cardiovascular disease. The situation is quite different for those with an abnormal heart or circulation. Evidence abounds that marijuana increases the work of the heart, usually by increasing heart rate, and in some persons by increasing blood pressure. This increase in workload poses a threat to patients with hypertension, cerebrovascular disease, and coronary atherosclerosis. The magnitude and incidence of the threat remains to be determined because marijuana smoking has largely been confined to younger adults who are only now entering the age of serious complications of atherosclerosis on the heart, brain, and peripheral vessels. Marijuana also can cause postural hypotension. This drop in blood pressure could be hazardous in those individuals with compromised blood flow to the heart or brain, especially if they are volume-depleted (dehydrated) or if other drugs have impaired reflex control of their blood vessels. Marijuana appears to intensify the effects of the sympathetic nervous system on the heart, an undesirable consequence in patients with coronary artery disease and in those susceptible to arrhythmias. Many of the undesirable effects of marijuana on the cardiovascular system seem to become less severe following chronic exposure. Whether the relative paucity of reports of the ill-effects of marijuana on the abnormal cardiovascular system is a consequence of adaptation to chronic usage or to lack of exposure to marijuana of a population that is sufficiently advanced in years to be susceptible to its untoward effects remains to be determined. Recommendations for Research Additional studies are needed both (l) to provide information on the mechanisms responsible for the observed effects of marijuana on the cardiovascular system and (2) to provide new data on the effects of marijuana in patients with known forms of cardiovascular disease.

73 * The manner in which A-9-THC acts on the heart to change the rate and force of contraction needs clarification. Direct effects on the heart are not likely to differ among species, and thus experiments can be planned for a "standard" heart preparation. * Direct effects on electrical activity, which might relate to reports of changes in electrical activity and production of premature impulses as well as changes in sinus rate, should be evaluated with standard methods and standard preparations. * Direct effects of A-9-THC on vascular smooth muscle should be explored. For this purpose, it would be essential to use some vessels that did, and others that did not, have functioning nerve terminals. It would be important here to include studies on selected coronary vessels and on vessels which play a dominant role in the regulation of systemic vascular resistance. * A number of related studies are needed before the effects on humans can be explained in full, particularly the effects of A-9-THC on the renin-angiotensin system in the kidney, which provides control of arterial pressure, and on the several sequences of prostaglandin metabolism. Studies also are indicated to obtain new data about the effects of marijuana on: ' persons with hypertension, coronary artery disease, and cerebrovascular disease; * increases in systemic arterial pressure in low- and high-renin hypertension and the interactions between A-9-THC and several classes of antihypertensive medications; * the interactions between the salt and water-retaining effect of A-9-THC and diuretics that could be employed both in hypertensives and those with heart failure. Additionally, studies should be done on the use of standard monitoring techniques to quantify any effect of marijuana smoking on tendencies toward arrhythmias, and on interactions of A-9-THC with drugs that modify synaptic transmission in the central nervous system. REFERENCES Adams, M.D., Earnhardt, J.T., Dewey, W.L., and Harris, L.S. Vasoconstrictor actions of A-8- and A-9-tetrahydrocannabinol in the rat. J. Pharmacol. Exp. Ther. l96:649-656, l976. Ames, F. A clinical and metabolic study of acute intoxication with cannabis sativa and its role in the model psychoses. J. Ment. Sci. l04:972-999, l968. Aronow, W.S. and Cassidy, J. Effect of marihuana and placebo- marihuana smoking on angina pectoris. N. Engl. J. Med. 29l:65-67, l974. Auerbach, 0., Stout, A.P., Hammond, E.G., and Garfinkel, L. Changes in bronchial epithelium relation to cigarette smoking and in relation to lung cancer. N. Engl. J. Med. 265:253-267, l96l.

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