The proportion of older adults who use cannabis is only 18% that of younger adults, much lower than the comparable proportions for alcohol (89%) and tobacco cigarettes (60%). Moreover since the use of cannabis in young adults declined steadily between 1979 and 1998, whereas use in older adults remained stable, the observed low prevalence in older adults is unlikely to increase in the foreseeable future. Therefore, even diseases that might be related to long term use of cannabis are unlikely to have a sizeable public health impact because most people who try cannabis do not become long term users. This observation is relevant to lung cancer, which, although strongly related to cigarette smoking, typically only occurs after at least 20 years of smoking. Also, a typical regular cannabis user smokes the equivalent of one marijuana cigarette or less per day, whereas consumption of 20 or more tobacco cigarettes is common. Exposure to smoke is therefore generally much lower in cannabis than in tobacco cigarette smokers, even taking into account the larger exposure per puff.Hall and MacPhee (2002, p. 245) note similarly:
On current patterns of use, cannabis smoking will make, at most, a small contribution to the occurrence of respiratory cancers. This is so even if we assume that the risks of daily cannabis smoking are comparable to those of daily tobacco smoking (Hall 1998). The reason is that in most western societies there are many more daily tobacco (25–30%) than daily cannabis smokers (1–3%) (Hall 1995); most cannabis smokers stop in their mid- to late 20s (Bachman et al. 1997); and the 1% or fewer people who smoke cannabis daily over decades typically smoke 1–3 cannabis cigarettes per day rather than 10–30 tobacco cigarettes a day (Didcott et al. 1997). Among this minority, however, cannabis smoking into the fourth and later decades may increase the risk of respiratory cancer in tobacco smokers who concurrently smoke cannabis.Secondly, though cannabis and tobacco smoke are chemically similar in most ways, there are important differences. Cannabis smoke lacks nicotine and some nicotine-derived carcinogens which are thought to play a significant role in the etiology of smoking-related cancers (Hecht, 2003). Nicotine and the nicotine-derived, tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) inhibit apoptosis (programmed cell death) of airway epithelial cells via activation of an enzyme called AKT (West et al, 2003). Normally, damaged cells would undergo apoptosis, reducing the chances that further damage would initiate oncogenic mutations. Inhibition of apoptosis of these cells by nicotine/NNK may thus increase the likelihood of airway cancers. By contrast, cannabinoids such as THC appear to inhibit AKT selectively in cancer cells but not normal cells, producing a pro-apototic effect (Guzman, 2003).
| Critics of cannabis
as medicine have often argued that cannabis cannot be safe because
it contains a mixture of chemicals, some of which carcinogens.
For instance, this
webpage quotes NIH scientist's statement that "[m]arijuana
cigarette smoke contains a complex mixture of over 400 compounds
including polyareomatic hydrocarbons which are carcinogenic."
Yet, in itself,
this is hardly an argument for the danger of cannabis smoking,
since virtually every foodstuff consumed by humans, whether processed
or not, is a "complex mixture" of hundreds of chemicals,
including many that are carcinogenic. For example, Ames and Gold
(1997) point out that over 1000 chemicals are present in a cup of
coffee, only 28 or which have been tested in rodents, and 19 of which
were found to be carcinogenic in rodent tests (which typically involve
large doses not analogous to human coffee consumption). In fact, Ames
and Gold (1990) estimate that a single cup of coffee contains at least
10mg of rodent carcinogens. Like cannabis smoke, coffee and many cooked
foods contains polyaromatic hydrocarbons. Does this mean that coffee causes cancer
in humans? No. Epidemiological studies of human coffee drinkers fails
to reveal any significant increased cancer risk at reasonable daily doses. As Paracelsus noted long ago, the
dose makes the poison, and that is still true today (though it is now recognized
poison is not only a function of dose, but also of between-compound interactions
and individual susceptibilities). Kava (2000) provides an amusing commentary on carcinogens by pointing out some of the carcinogens present in the foods on a 'healthy' holiday menu. The carrots, cherry tomatoes, and celery contain caffeic acid, benzaldehyde, and quercetin glycosides. The salad with vinaigrette contains estragole and allyl isothiocyanate. The meat and bread stuffing contains benzopyrenes, ethyl carbamate, furfural, and safrole. The steamed broccoli spears contain allyl isothiocyanate; baked potatoes contain ethyl alcohol and caffeic acid. The sweet potatoes contain furfural. The pumpkin pie contains benzopyrene. The apple pie contains caffeic acid. Both pumpkin and apple pies contain safrole. Fresh fruits contain acetaldehyde, caffeic acid, and quercetin glycosides. Nuts contain aflatoxins and furfural. Red wine contains ethyl carbamate and methylglyoxal. Teas may contain symphytine, and "jasmine tea offers a hint of benzyl acetate" (Kava, 2000). All of these substances are carcinogenic, and this represents a very incomplete list of the carcinogenic substances present in these foods. Whether considering coffee, cannabis, or a holiday dinner, what is important are the effects at the doses humans take, in the manner humans take them, in interaction with other substances humans take. |
Experimentally, groups of 60-70 male and female rats were administered 0, 12.5, 25, or 50 mg THC/kg body weight (bw), and male and female mice were given 0, 125, 250, or 500 mg THC/kg bw in corn oil by gavage for 104-106 weeks (3,4). During this 2-year period, individual animal body weights were reduced compared to controls, although all groups consumed the same amounts of food. More importantly, survival in all THC groups of male and female rats was significantly greater than the controls. For mice, survival was comparable among groups except for the high-dose males. Clinical findings in the THC groups included lethargy followed by hyperactivity, convulsions, and seizures, which occurred typically during and immediately after dosing or handling.
In both rats and mice, no increased incidences of neoplasms were considered related to the administration of THC (3,4). In fact, for several organ systems the incidences of background tumors in these strains were actually reduced. The incidences of mammary gland fibroadenomas and uterine stromal polyps were decreased in THC groups of female rats, as were incidences of pituitary gland adenomas, interstitial cell adenomas of the testis, and pancreatic adenomas in THC-treated male rats. Concerning nonneoplastic lesions in mice, increases of thyroid gland follicular cell hyperplasia occurred in all THC groups, and increases of forestomach hyperplasia and ulcers occurred in THC groups of male mice; yet, no THC-related tumors were observed to progress from these toxic lesions. This common lack of correlation between toxicity and carcinogenicity has long been known (5-7). Regarding carcinogenic activity of THC in mice, thyroid gland follicular cell adenomas were somewhat increased only in the lowest THC-dosed group of mice (125 mg/kg); thyroid gland follicular cell adenomas were found in 0/62 control males versus 6/60, 3/61, and 1/57 mice treated with 125, 250, and 500 mg THC/kg bw, respectively, and in 4/60 control females versus 9/60, 3/60, and 1/60 mice); these were considered not significantly related to THC (3,4). However, there were significant decreases observed for both benign and malignant liver tumors in male and female mice.
. . .
Our 2-year studies (3,4) showed that the observed THC antitumor effects are not confined to the site of injection or administration, and these antitumor effects seem to affect a range of "spontaneous" tumors commonly found in rats and mice. Consequently, the THC-associated antitumor effects are systemically active and are applicable to different tumor types at different organ sites. Again, this lack of specificity might lend credence to the notion that these effects are hormonally mediated and likely related to the observed decreases in body weights. Nonetheless, there were significant reductions in total benign and malignant tumors in all organs combined for both species after THC exposure: in male rats, tumors were found in 98% of controls versus 98, 92, and 90% of groups treated with 12.5, 25, and 50 mg THC/kg bw, respectively; in female rats, tumors were found in 88% of controls versus 82, 86, and 70% of treated groups. Most strikingly, in male mice tumors were found in 73% of controls versus 55, 44, and 30% of male mice treated with 0, 125, 250, and 500 mg THC/kg bw, respectively, and in female mice, tumors were found in 77% of controls versus 52, 43, and 27% of treated groups (3,4).
Use of marijuana and cocaine is on the rise in the United States. Although pulmonary toxicity from these drugs has occasionally been reported, little is known about their effects on the lung microenvironment. We evaluated the function of alveolar macrophages (AMs) recovered from the lungs of nonsmokers and habitual smokers of either tobacco, marijuana, or crack cocaine. AMs recovered from marijuana smokers were deficient in their ability to phagocytose Staphylococcus aureus (p < 0.01). AMs from marijuana smokers and from cocaine users were also severely limited in their ability to kill both bacteria and tumor cells (p < 0.01). Studies using N G-monomethyl-L-arginine monoacetate, an inhibitor of nitric oxide synthase, suggest that AMs from nonsmokers and tobacco smokers were able to use nitric oxide as an antibacterial effector molecule, while AMs from smokers of marijuana and cocaine were not. Finally, AMs from marijuana smokers, but not from smokers of tobacco or cocaine, produced less than normal amounts of tumor necrosis factor-, granulocyte-macrophage colony-stimulating factor, and interleukin-6 when stimulated in culture with lipopolysaccharide. In contrast, the production of transforming growth factor-, an immunosuppressive cytokine, was similar in all groups. These findings indicate that habitual exposure of the lung to either marijuana or cocaine impairs the function and/or cytokine production of AMs. The ultimate outcome of these effects may be an enhanced susceptibility to infectious disease, cancer, and AIDS.Calignano et al, 2000. Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature 408, 96-101
Smoking marijuana or administration of its main active constituent, 9-tetrahydrocannabinol (9-THC), may exert potent dilating effects on human airways1-4. But the physiological significance of this observation and its potential therapeutic value are obscured by the fact that some asthmatic patients respond to these compounds with a paradoxical bronchospasm3, 5. The mechanisms underlying these contrasting responses remain unresolved. Here we show that the endogenous cannabinoid anandamide exerts dual effects on bronchial responsiveness in rodents: it strongly inhibits bronchospasm and cough evoked by the chemical irritant, capsaicin, but causes bronchospasm when the constricting tone exerted by the vagus nerve is removed. Both effects are mediated through peripheral CB1 cannabinoid receptors found on axon terminals of airway nerves. Biochemical analyses indicate that anandamide is synthesized in lung tissue on calcium-ion stimulation, suggesting that locally generated anandamide participates in the intrinsic control of airway responsiveness. In support of this conclusion, the CB1 antagonist SR141716A enhances capsaicin-evoked bronchospasm and cough. Our results may account for the contrasting bronchial actions of cannabis-like drugs in humans, and provide a framework for the development of more selective cannabinoid-based agents for the treatment of respiratory pathologies.Chan et al, 1996. Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. Fundamental and Applied Toxicology 30(1), 109-117.
delta 9-Tetrahydrocannabinol (delta 9-THC) was studied for potential carcinogenicity in rodents because it is the principal psychoactive ingredient in marihuana and it has potential medicinal uses. delta 9-THC in corn oil was administered by gavage to groups of male and female Fischer rats and B6C3F1 mice at 0, 5, 15, 50, 150, or 500 mg/kg, 5 days a week for 13 weeks and for 13-week plus a 9-week recovery period, and to groups of rats at 0, 12.5, or 50 mg/kg and mice at 0, 125, 250, or 500 mg/kg, 5 times a week for 2 years. In all studies, mean body weights of dosed male and female rats and mice were lower than controls but feed consumptions were similar. Convulsions and hyperactivity were observed in dosed rats and mice; the onset and frequency were dose related. Serum FSH and LH levels in all dosed male rats and corticosterone levels in 25 mg/kg female rats were significantly higher than controls at 15 months in the 2-year studies. delta 9-THC administration for 13 weeks induced testicular atrophy and uterine and ovarian hypoplasia; the lesions persisted in a 9-week recovery period. In the 2-year studies, survival of dosed rats was higher than controls; that of mice was similar to controls. Incidences of testicular interstitial cell, pancreas and pituitary gland adenomas in male rats, mammary gland fibroadenoma and uterus stromal polyp in female rats, and hepatocellular adenoma/carcinoma in male and female mice were reduced in a dose-related manner. Decreased tumor incidences may be at least in part due to reduced body weights of dosed animals. Incidences of thyroid gland follicular cell hyperplasia were increased in all dosed groups of male and female mice, and follicular cell adenomas were significantly increased in the 125 mg/kg group of males, but there was no evidence of a dose-related trend in proliferative lesions of the thyroid. There was no evidence that delta 9-THC was carcinogenic in rats or mice.Fligiel et al, 1991. Marijuana exposure and pulmonary alterations in primates. Pharmacology Biochemistry and Behavior 40(3), 637-642.
As part of a large multidisciplinary study, we examined lungs from 24 periadolescent male rhesus monkeys that were sacrificed seven months after daily marijuana smoke inhalation of 12 months duration. Animals were divided into four exposure groups: A) high-dose (one marijuana cigarette 7 days/week), B) low-dose (one marijuana cigarette 2 days/week and sham smoke 5 days/week), C) placebo (one extracted marijuana cigarette 7 days/week), and D) sham (sham smoke 7 days/week). Lungs, removed intact, were formalin inflated, sectioned and examined. Several pathological alterations, including alveolitis, alveolar cell hyperplasia and granulomatous inflammation, were found with higher frequency in all cigarette-smoking groups. Other alterations, such as bronchiolitis, bronchiolar squamous metaplasia and interstitial fibrosis, were found most frequently in the marijuana-smoking groups. Alveolar cell hyperplasia with focal atypia was seen only in the marijuana-smoking animals. These changes represent mostly early alterations of small airways. Additional follow-up studies are needed to determine their long-term prognostic significance.Fligiel et al, 1997. Tracheobronchial histopathology in habitual smokers of cocaine, marijuana, and/or tobacco. Chest 112, 319-326.
BACKGROUND: Marijuana and alkaloidal cocaine ("crack") are the two most commonly smoked substances in the United States after tobacco. While regular tobacco smoking has been found to be associated with extensive microscopic alterations in bronchial mucosa, little information is available concerning the effect of crack cocaine and marijuana on tracheobronchial histopathology. STUDY OBJECTIVE: To determine the relative impact of smoked substances (cocaine, marijuana, and tobacco) alone and in combination on the histopathology of the tracheobronchial mucosa and to assess whether the effects of habitual smoking of two or more substances (cocaine, marijuana, and/or tobacco) are additive. DESIGN: Observational cohort study. SUBJECTS: Fifty-three nonsmoking control subjects (NS), 14 current, habitual smokers of crack cocaine only (CS), 40 current, regular smokers of marijuana only (MS), 31 regular smokers of tobacco only (TS), 16 current smokers of both cocaine and marijuana (CMS), 12 current smokers of both cocaine and tobacco (CTS), 44 current smokers of both marijuana and tobacco (MTS), and 31 current smokers of cocaine, marijuana, and tobacco (CMTS). METHODS: After preliminary screening evaluation, including a detailed respiratory and general health questionnaire and routine pulmonary function studies, subjects underwent fiberoptic bronchoscopy with endobronchial biopsies of the mucosa of the primary carina and randomly selected secondary or tertiary carinae. Biopsy specimens were processed for light microscopy, stained with hematoxylin-eosin or periodic acid- Schiff, and examined to assess epithelial, basement membrane, and submucosal alterations by one or two pathologists who were masked to the smoking status of the subject. RESULTS: Smokers of cocaine, marijuana, or tobacco alone all exhibited more frequent abnormalities than NS in 10 (CS) or all 11 (MS and TS) of the histopathologic features assessed. For most features, MS and TS showed significantly more frequent alterations than NS (p < or = 0.02), while CS showed significantly more frequent abnormalities than NS in only three features (p<0.05) and nearly significant differences from NS in two additional features (p < or = 0.09). Alterations were noted most frequently in CTS (six features) and MTS (three features), while abnormalities were relatively infrequent in CMS. For 10 features, MTS had more frequent alterations than MS and TS. With a single exception, CMTS did not show more frequent alterations than CTS or MTS. CONCLUSION: Marijuana and tobacco smoking each produces significant bronchial mucosal histopathology and the effects of marijuana and tobacco appear additive. Cocaine appears to lead to fewer significant bronchial mucosal alterations than marijuana or tobacco when smoked alone and does not add to the changes associated with marijuana. When smoked together with tobacco, however, cocaine appears to augment the bronchial injury caused by tobacco smoking.Gieringer, 1996. Marijuana Water Pipe and Vaporizer Study. Newsletter of the Multidisciplinary Association for Psychedelic Studies 6(3).
Contrary to popular impression, waterpipes don't necessarily protect smokers from harmful tars in marijuana smoke, according to a new study sponsored by MAPS and California NORML (National Organization for the Reform of Marijuana Laws). The reason is that waterpipes filter out more psychoactive THC than they do other tars, thereby requiring users to smoke more to reach their desired effect. The study does not rule out the possibility that waterpipes could have other benefits, such as filtering out gases, but it suggests that other methods, such as the use of high potency marijuana, vaporizers, or oral ingestion are needed to avoid harmful toxins in marijuana smoke.Gieringer, 2001. Cannabis Vaporization: A Promising Strategy for Smoke Harm Reduction. Journal of Cannabis Therapeutics 1(3-4), 153-70.
The primary health hazard of medical cannabis is respiratory damage from marijuana smoke. Aside from oral ingestion and other non-smoked delivery systems not yet commercially available, strategies for reducing the harm of smoking include: (1) use of higher potency cannabis and (2) smoking devices aimed at eliminating toxins from the smoke. Studies have found that waterpipes and solid filters are ineffectual at improving the THC/tar ratio in cannabis smoke. The most promising alternative appears to be "vaporization," in which cannabis is heated to a point where cannabinoids are emitted without combustion. A feasibility study by NORML and MAPS has demonstrated that an electric vaporizer can successfully generate THC at 185°C while completely suppressing benzene, toluene, and naphthalene formation. Further studies are needed to evaluate how effectively vaporizers suppress other toxins, and how their performance varies using different samples, temperatures, and device designs.Gong et al, 1987. Tracheobronchial changes in habitual heavysmokers of marijuana with and without tobacco. American Review Respiratory Disorders 136, 209-216.
We performed flexible fiberoptic bronchoscopy in 29 habitual, heavy marijuana smokers 25 to 45 yr of age, with and without concomitant tobacco smoking, to inspect and biopsy their proximal tracheobronchial tree for the evaluation of histopathologic changes. Control tobacco smokers (TS) and nonsmokers (NS) residing in the same metropolitan area were similarly studied and compared with the marijuana smokers (MS) and marijuana-tobacco smokers (MTS). Respiratory and drug histories, physical examination, and pulmonary function tests were obtained prior to bronchoscopy. The prevalence of respiratory symptoms and pulmonary function abnormalities was generally higher in the 3 smoking groups than in the NS group but was not statistically different across all groups. However, bronchoscopic inspection revealed airway hyperemia and other visible abnormalities in 32 (91%) subjects in the 3 smoking groups, unlike the unremarkable findings in the NS group. Light microscopy showed 2 or more histopathologic changes in the bronchial epithelium of all MS, MTS, and TS. Squamous metaplasia was observed in all MTS, a prevalence that was significantly different from that in MS, TS, and NS. Hyperplasia of basal and goblet cells was more prevalent in the MS than in the NS, whereas cellular disorganization was more prevalent in the MS than in the TS. A direct relationship between cumulative marijuana use (joint-years) and bronchoscopic and histopathologic changes was not apparent in this study sample. These results indicate that relatively young, habitual, heavy marijuana smokers have a high prevalence of abnormal airway appearance and histologic findings, irrespective of concomitant tobacco smoking.Guzman, 2003. Cannabinoids: Potential Anticancer Agents. Nature Reviews Cancer 3, 745 -755.
The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (-)Delta9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-D-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-D-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or alpha-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia.Hecht, 1999. Tobacco smoke carcinogens and lung cancer. Journal of the National Cancer Institute 91, 1194-1210.
The complexity of tobacco smoke leads to some confusion about the mechanisms by which it causes lung cancer. Among the multiple components of tobacco smoke, 20 carcinogens convincingly cause lung tumors in laboratory animals or humans and are, therefore, likely to be involved in lung cancer induction. Of these, polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are likely to play major roles. This review focuses on carcinogens in tobacco smoke as a means of simplifying and clarifying the relevant information that provides a mechanistic framework linking nicotine addiction with lung cancer through exposure to such compounds. Included is a discussion of the mechanisms by which tobacco smoke carcinogens interact with DNA and cause genetic changes—mechanisms that are reasonably well understood—and the less well defined relationship between exposure to specific tobacco smoke carcinogens and mutations in oncogenes and tumor suppressor genes. Molecular epidemiologic studies of gene-carcinogen interactions and lung cancer—an approach that has not yet reached its full potential—are also discussed, as are inhalation studies of tobacco smoke in laboratory animals and the potential role of free radicals and oxidative damage in tobacco-associated carcinogenesis. By focusing in this review on several important carcinogens in tobacco smoke, the complexities in understanding tobacco-induced cancer can be reduced, and new approaches for lung cancer prevention can be envisioned.Hecht, 2003. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nature Reviews Caner 3. 733-744.
We provide anatomic and functional evidence that nicotine induces angiogenesis. We also show that nicotine accelerates the growth of tumor and atheroma in association with increased neovascularization. Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated fibrovascular growth in vivo. In a mouse model of hind-limb ischemia, nicotine increased capillary and collateral growth, and enhanced tissue perfusion. In mouse models of lung cancer and atherosclerosis, we found that nicotine enhanced lesion growth in association with an increase in lesion vascularity. These effects of nicotine were mediated through nicotinic acetylcholine receptors at nicotine concentrations that are pathophysiologically relevant. The endothelial production of nitric oxide, prostacyclin and vascular endothelial growth factor might have a role in these effects.Huber and Mahajan, 1988. The comparative response of the lung to marihuana or tobacco smoke inhalation. In: Chesher, G.; Consroe, P.; and Musty, R. eds. Marijuana: An International Research Report. Proceedings of Melbourne Symposium on Cannabis 2 - September, 1987. National Campaign Against Drug Abuse. Monograph Series No. 7. Canberra: Australian Government Publishing Service, pp. 19-24.
Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-alpha in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS.
To determine whether smoking more, compared to less, potent marijuana (MJ) cigarettes to a desired level of intoxication ("high") reduces pulmonary exposure to noxious smoke components, in 10 habitual smokers of MJ, we measured respiratory delivery and deposition of tar and delta9-tetrahydrocannabinol (THC), carboxyhemoglobin (COHb) boost, smoking topography, including cumulative puff volume (CPV) and breathholding time, change in heart rate (deltaHR) and "high" during ad lib smoking of 0, 1.77, and 3.95% MJ cigarettes on 3 separate days. At each session, subjects had access to only a single MJ cigarette. On average, smoking topography and COHb boost did not differ across the different strengths of MJ, while THC delivery, as well as HR, were significantly greater (p < 0.01) and tar deposition significantly less (p < 0.03) for 3.95% than 1.77% MJ. Although individual adaptations in smoking topography for 3.95% compared to 1.77% MJ were highly variable, three subjects with the lowest 3.95% MJ:1.77% MJ ratios for CPV also displayed the lowest 3.95% MJ:1.77% MJ ratios for tar deposition. In vitro studies using a standardized smoking technique revealed a mean 25% lower tar yield from 3.95% than 1.77% MJ (p < 0.05), but no difference between 1.77% and 0% marijuana. Under the conditions of this study, we conclude that tar delivery is reduced relative to THC content in a minority of subjects, and this reduction appears to be due to a reduced intake of smoke (decreased CPV) and/or a reduced tar yield from the stronger MJ preparation.Mittleman et al, 2001. Triggering myocardial infarction by marijuana. Circulation 103, 2805-2809.
Lewis lung adenocarcinoma growth was retarded by the oral administration of delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta-9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta-8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta-9-THC, delta-8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg;, respectively), whereas CBD did not. Delta-9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 X DBA/2) F (BDF) mice hosting the L1210 murine leukemia. However, delta-9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta-8-THC and delta-9-THC showed a dose-dependent (10 -4 10 -7) inhibition (80-20%, respectively) of tritiated thymidine and 14C -uridine uptake into these cells. CBD was active only in high concentrations (10 -4).Pacifici et al, 2003. Modulation of the immune system in cannabis users. Journal of the American Medical Association 289, 1989-1991.
Even though marijuana smoke contains carcinogens and more tar than tobacco smoke and marijuana intoxication has been implicated as a risk factor for injuries, relatively little epidemiologic evidence has identified marijuana use as a risk factor for ill health. This study is the first to examine the health effects of smoking marijuana by comparing the medical experience of "daily" marijuana smokers who never smoked tobacco (n = 452) with a demographically similar group of nonsmokers of either substance (n = 450). Marijuana smoking status was determined during multiphasic health checkups at Kaiser Permanente medical centers between July 1979 and December 1985. Medical records were reviewed for as long as 2 years after the checkups. Frequent marijuana smokers had small increased risks of outpatient visits for respiratory illnesses (relative risk [RR] = 1.19; 95% confidence interval [CI] = 1.01, 1.41), injuries (RR = 1.32; CI = 1.10, 1.57), and other types of illnesses (RR = 1.09; CI = 1.02, 1.16) compared with nonsmokers; their risk of being admitted to a hospital was elevated but not statistically significant (RR = 1.51; CI = 0.93, 2.46). Analyses were adjusted for sex, age, race, education, marital status, and alcohol consumption. Daily marijuana smoking, even in the absence of tobacco, appeared to be associated with an elevated risk of health care use for various health problems.Roth et al, 2001. Induction and Regulation of the Carcinogen-Metabolizing Enzyme CYP1A1 by Marijuana Smoke and delta 9 Tetrahydrocannabinol. American Journal Respiratory Cell and Molecular Biology 24, 339–344.
Human alveolar macrophages (AMs) were recovered from the lungs of healthy nonsmokers (NS) or smokers of tobacco (TS), marijuana (MS), or crack cocaine (CS) and challenged in vitro with Staphylococcus aureus. AMs from NS and TS exhibited potent antibacterial activity that correlated with the production of nitric oxide (NO) and induction of NO synthase without the requirement for priming with exogenous cytokines. In contrast, AMs from MS and CS exhibited minimal antibacterial activity and failed to produce NO unless primed with additional cytokines. These results confirm that NO plays a significant role as an effector molecule used by normal human AMs, but this capacity is suppressed in AMs from MS and CS because of a lack of intrinsic cytokine priming.Sidney et al, 1997a. Marijuana use and mortality. American Journal of Public Health 87, 585-590.
The purpose of this retrospective cohort study was to examine the relationship of marijuana use to cancer incidence. The study population consisted of 64,855 examinees in the Kaiser Permanente multiphasic health checkup in San Francisco and Oakland (California, United States), between 1979-85, aged 15 to 49 years, who completed self-administered questionnaires about smoking habits, including marijuana use. Follow-up for cancer incidence was conducted through 1993 (mean length 8.6 years). Compared with nonusers/experimenters (lifetime use of less than seven times), ever- and current use of marijuana were not associated with increased risk of cancer of all sites (relative risk [RR] = 0.9, 95 percent confidence interval [CI] = 0.7-12 for ever-use in men; RR = 1.0, CI = 0.8-1.1 in women) in analyses adjusted for sociodemographic factors, cigarette smoking, and alcohol use. Marijuana use also was not associated with tobacco-related cancers or with cancer of the following sites: colorectal, lung, melanoma, prostate, breast, cervix. Among nonsmokers of tobacco cigarettes, ever having used marijuana was associated with increased risk of prostate cancer (RR = 3.1, CI = 1.0-9.5) and nearly significantly increased risk of cervical cancer (RR = 1.4, CI = 1.0-2.1). We conclude that, in this relatively young study cohort, marijuana use and cancer were not associated in overall analyses, but that associations in nonsmokers of tobacco cigarettes suggested that marijuana use might affect certain site-specific cancer risks.Sidney, 2002. Cardiovascular consequences of marijuana use. Journal of Clinical Pharmacology (11 suppl) 42, s64-s70.
Introduction: Marijuana smoking induces increases in heart rate and blood pressure, and may acutely trigger angina pectoris and myocardial infarction. Myocardial oxygen delivery is impaired as a result of the even greater boost in blood carboxyhemoglobin from marijuana than tobacco smoking, and cannabinoids in marijuana smoke have been shown to contribute to cellular oxidative stress. However, few data on the association of marijuana use with the development of coronary artery disease are available. Objective: To examine the cross-sectional association of lifetime marijuana use with coronary artery calcium (CAC). Methods: Computed tomography in 2,855 African American and white men and women, ages 33-45 years, and self-reported lifetime marijuana use, at the 15-year follow-up exam (2000-2001) of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Results: Never use of marijuana was reported by 30% of participants, while lifetime use of 1-10, 11-99, 100-499, and >500 times was reported by 23%, 21%, 13%, and 13% of participants, respectively. The overall prevalence of CAC (nonzero score) was 10% (15% in men, 5% in women). The prevalence of CAC was 8% in never users of marijuana and was 7%, 10%, 13%, and 15% in lifetime marijuana use categories of 1-10, 11-99, 100-499, and >500 times, respectively (p<0.001 trend). After adjustment for age, race/gender, and cigarette smoking, the odds ratio (OR) associated with lifetime use >100 times relative to never use was 1.0 (95% confidence interval [CI] 0.7, 1.4), and was 1.0 (0.6, 1.5) for lifetime use >500 times relative to never use. These ORs were not significantly different from one within race/gender or cigarette smoking strata. Conclusion: We conclude that lifetime marijuana use is directly associated with the prevalence of CAC in this study group of young to middle age adults, but that this association is the result of confounding by age and tobacco cigarette use.Sidney et al, 2002. Marijuana use and hospitalization for cardiovascular diseases. Presented at the 2002 American Heart Association Scientific Session, Chicago, IL, November 20.
Marijuana smoking acutely increases heart rate and blood pressure, and may trigger MI. Though marijuana is the most commonly used illegal substance in the U.S., few data are available on the association of its use with cardiovascular disease (CVD). We examined the relationship of marijuana use to CVD hospitalization in a cohort of 62,012 men and women, aged 15 to 49 years (mean 33 years), who participated in multiphasic health checkups in the Kaiser Permanente Medical Care Program (a large prepaid medical care program) medical centers in San Francisco and Oakland (California) from 1979 through 1985. Participants underwent physical examination and completed self-administered research questionnaires on tobacco, marijuana and alcohol use. Followup for CVD hospitalizations was conducted through 12/31/1991 (mean length 6.6 years) using computer stored ICD9 primary discharge codes. Ever marijuana use was reported by 42% of the cohort (22% current, 20% former users). There were 979 hospitalizations for CVD. Current and former marijuana use were unassociated with MI, all CHD, stroke and all CVD hospitalizations (see table). Though it may trigger MI, we conclude that marijuana use was unassociated with the risk of hospitalization for major CVD endpoints in this relatively young study population.
After experimental induction of acute bronchospasm in 8 subjects with clinically stable bronchial asthma, effects of 500 mg of smoked marijuana (2.0 per cent delta9-tetrahydrocannabinol) on specific airway conductance and thoracic gas volume were compared with those of 500 mg of smoked placebo marijuana (0.0 per cent delta9-tetrahydrocannabinol), 0.25 ml of aerosolized saline, and 0.25 ml of aerosolized isoproterenol (1,250 mug). Bronchospasm was induced on 4 separate occasions, by inhalation of methacholine and, on four other occasions, by exercise on a bicycle ergometer or treadmill. Methacholine and exercise caused average decreases in specific airway conductance of 40 to 55 per cent and 30 to 39 per cent, respectively, and average increases in thoracic gas volume of 35 to 43 per cent and 25 to 35 per cent, respectively. After methacholine-induced bronchospasm, placebo marijuana and saline inhalation produced minimal changes in specific airway conductance and thoracic gas volume, whereas 2.0 per cent marijuana and isoproterenol each caused a prompt correction of the bronchospasm and associated hyperinflation. After exercise-induced bronchospasm, placebo marijuana and saline were followed by gradual recovery during 30 to 60 min, whereas 2.0 per cent marijuana and isoproterenol caused an immediate reversal of exercise-induced asthma and hyperinflation.Tashkin et al, 1977. Bronchial effects of aerosolized delta 9-tetrahydrocannabinol in healthy and asthmatic subjects. American Journal of Respiratory Critical Care Medicine 115(1), 57-65.
Effects on airway dynamics, heart rate, and the central nervous system of various doses of delta9-tetrahydrocannabinol administered in a random, double blind fashion using a Freon-propelled, metered-dose nebulizer were evaluated in 11 healthy men and 5 asthmatic subjects. Effects of aerosolized delta9-tetrahydrocannabinol were compared with aerosolized placebo and isoproterenol and with 20 mg of oral and smoked delta9-tetrahydrocannabinol. In the normal subjects, after 5 to 20 mg of aerosolized delta9-tetrahydrocannabinol, specific airway conductance increased immediately, reached a maximum (33 to 41 per cent increase) after 1 to 2 hours, and remained significantly greater than placebo values for 2 to 3 hours. The bronchodilator effect of aerosolized delta9-tetrahydrocannabinol was less than that of isoproterenol after 5 min, but significantly greater than that of isoproterenol after 1 to 3 hours. The magnitude of bronchodilatation after all doses of aerosolized delta9-tetrahydrocannabinol was comparable, but 5 mg of delta9-tetrahydrocannabinol caused a significantly smaller increase in heart rate and level of intoxication than the 20-mg dose. Smoked delta9-tetrahydrocannabinol produced greater cardiac and intoxicating effects than either aerosolized or oral delta9-tetrahydrocannabinol. Side effects of aerosolized delta9-tetrahydrocannabinol included slight cough and/or chest discomfort in 3 of the 11 normal subjects. Aerosolized delta9-tetrahydrocannabinol caused significant bronchodilatation in 3 of 5 asthmatic subjects, but caused moderate to severe bronchoconstriction associated with cough and chest discomfort in the other 2. These findings indicate that aerosolized delat9-tetrahydrocannabinol, although capable of causing significant bronchodilatation with minimal systemic side effects, has a local irritating effect on the airways, which may make it unsuitable for therapeutic use.Tashkin et al, 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.
To assess the possible role of daily smoking of marijuana in the development of chronic obstructive pulmonary disease (COPD), we evaluated the effect of habitual use of marijuana with or without tobacco on the age-related change in lung function (measured as FEV1) in comparison with the effect of nonsmoking and regular tobacco smoking. A convenience sample of 394 healthy young Caucasian adults (68% men; age: 33 +/- 6 yr; mean +/- SD) including, at study entry, 131 heavy, habitual smokers of marijuana alone, 112 smokers of marijuana plus tobacco, 65 regular smokers of tobacco alone, and 86 nonsmokers of either substance were recruited from the greater Los Angeles community. FEV1 was measured in all 394 participants at study entry and in 255 subjects (65 %) on up to six additional occasions at intervals of > or = 1 yr (1.7 +/- 1.1 yr) over a period of 8 yr. Random-effects models were used to estimate mean rates of decline in FEV1 and to compare these rates between smoking groups. Although men showed a significant effect of tobacco on FEV1 decline (p < 0.05), in neither men nor women was marijuana smoking associated with greater declines in FEV1 than was nonsmoking, nor was an additive effect of marijuana and tobacco noted, or a significant relationship found between the number of marijuana cigarettes smoked per day and the rate of decline in FEV1. We conclude that regular tobacco, but not marijuana, smoking is associated with greater annual rates of decline in lung function than is nonsmoking. These findings do not support an association between regular marijuana smoking and chronic COPD but do not exclude the possibility of other adverse respiratory effects.Tashkin et al, 1997b. Effects of ‘crack’ cocaine on pulmonary alveolar permeability. Chest 112, 327-335.
Background: Lung clearance of 99mTc-labeled diethylenetriamine pentaacetate (DTPA) is a sensitive test of altered alveolar epithelial permeability that has been found to be increased in smokers of tobacco, as well as a small number of healthy smokers of crack cocaine, suggesting the possibility of subclinical crack-related lung injury. Study objective: To evaluate further whether habitual smoking of cocaine alone alters alveolar permeability, whether crack smoking adds to or potentiates the effects of tobacco and/or marijuana, and whether experimental cocaine smoking acutely alters DTPA lung clearance. Design: Observational cohort study (habitual cocaine smoking) and single-blind crossover study (experimental cocaine administration). Subjects: Fourteen habitual smokers of cocaine alone (CS), 19 smokers of cocaine and tobacco (CTS), 3 smokers of cocaine and marijuana, 12 smokers of cocaine, tobacco, and marijuana (CMTS), and 5 smokers of marijuana plus tobacco (MTS). Results obtained in the crack-smoking subjects were compared with data previously obtained in 10 nonsmokers (NS), 9 smokers of tobacco alone (TS), 10 smokers of marijuana alone (MS), and 4 additional MTS. Methods: Subjects underwent measurements of DTPA radioaerosol lung clearance after refraining from marijuana and/or cocaine for >12 h and from tobacco for >2 h. Ten of the 48 crack users were tested on two days 1 to 2 weeks apart within 2 h of experimental smoking of three physiologically active or inactive doses (total 98.8615.5 or 8.562.5 mg, respectively) of cocaine base. Lung clearance half-times (T1⁄2) were computed from time-activity curves for each lung. Results: T1⁄2 values for each lung in CS and MS were comparable to those of NS, while TS, MTS, CTS, and CMTS had significantly shorter clearance rates than NS (p<0.01; three-way analysis of variance). No additive or interactive effects on T1⁄2 were noted among tobacco, cocaine, and/or marijuana. No acute effect of experimental cocaine smoking on T1⁄2 was noted. Conclusion: Whereas regular smoking of tobacco alone or with other substances increases alveolar epithelial permeability, habitual smoking of cocaine and/or marijuana has no measurable effect on alveolar permeability in the absence of tobacco nor any additive effect to that of tobacco alone.
Rhesus monkeys exposed to marijuana smoke either 7 or 2 days/weeks (HI and LO groups, respectively), or ethanol-extracted marijuana smoke for 7 days/week (EM) or sham treatment (SH) for 1 year were sacrificed 7 months following the last exposure. Pulmonary levels of carcinogen-DNA adducts were determined. Although mean or median adduct levels were not statistically different, 15 of 22 adduct measures were highest in the EM group and lowest 12 of 22 times in the SH group. The levels of aromatic carcinogen-DNA adducts seem no higher in the lungs of animals exposed to marijuana smoke than in untreated animals. Ethanol-extracted marijuana may have effects greater than marijuana itself.Taylor et al, 2002. A longitudinal study of the effects of tobacco and cannabis exposure on lung function in young adults. Addiction 97, 1055–1061.
AIM: To assess the possible effects of tobacco and cannabis smoking on lung function in young adults between the ages of 18 and 26. SETTING AND PARTICIPANTS: A group of over 900 young adults derived from a birth cohort of 1037 subjects born in Dunedin, New Zealand in 1972/73 were studied at age 18, 21 and 26 years. MEASUREMENTS: Cannabis and tobacco smoking were documented at each age using a standardized interview. Lung function, as measured by the forced expiratory volume in one second/vital capacity (FEV1/VC) ratio, was obtained by simple spirometry. A fixed effects regression model was used to analyse the data to take account of confounding factors. FINDINGS: When the sample was stratified for cumulative use, there was evidence of a linear relationship between cannabis use and FEV1/VC (P < 0.05). In the absence of adjusting for other variables, increasing cannabis use over time was associated with a decline in FEV1/VC with time; the mean FEV1/VC among subjects using cannabis on 900 or more occasions was 7.2%, 2.6% and 5.0% less than non-users at ages 18, 21 and 26, respectively. After controlling for potential confounding factors (age, tobacco smoking and weight) the negative effect of cumulative cannabis use on mean FEV1/VC was only marginally significant (P < 0.09). Age (P < 0.001), cigarette smoking (P < 0.05) and weight (P < 0.001) were all significant predictors of FEV1/VC. Cannabis use and daily cigarette smoking acted additively to influence FEV1/VC. CONCLUSIONS: Longitudinal observations over 8 years in young adults revealed a dose-dependent relationship between cumulative cannabis consumption and decline in FEV1/VC. However, when confounders were accounted for the effect was reduced and was only marginally significant, but given the limited time frame over which observations were made, the trend suggests that continued cannabis smoking has the potential to result in clinically important impairment of lung function.Veugelers et al, 1994. Determinants of HIV disease progression among homosexual men registered in the Tricontinental Seroconverter Study. American Journal of Epidemiology 140(8), 747-758.
STUDY OBJECTIVES: To examine the significance of previously suggested risk factors and assess outcomes associated with Aspergillus identification in respiratory specimens from HIV-seropositive individuals. DESIGN: This was a nested case-control study. Patients who had Aspergillus species identified in respiratory specimens were matched at the time of study entry 1:2 with control subjects according to study center, age, gender, race, HIV transmission category, and CD4 count. SETTING: The multicenter Pulmonary Complications of HIV Infection Study. PARTICIPANTS: HIV-seropositive study participants. MEASUREMENTS AND RESULTS: Between November 1988 and March 1994, Aspergillus species were detected in respiratory specimens from 19 (1.6%) participants. The rate of Aspergillus identification among participants with CD4 counts <200 cells per cubic millimeter during years 2 through 5 after study entry ranged from 1.2 to 1.9%. Neutropenia, a CD4 count <30 cells per cubic millimeter, corticosteroid use, and Pneumocystis carinii infection were associated with subsequent identification of Aspergillus in respiratory specimens. Cigarette and marijuana use, previously suggested risk factors, were not associated with Aspergillus respiratory infection. A substantially greater proportion of patients with Aspergillus compared with control subjects died during the study (90% vs 21%). Excluding four cases first diagnosed at autopsy, 67% died within 60 days after Aspergillus was detected. CONCLUSIONS: Although Aspergillus is infrequently isolated from HIV-infected persons, the associated high mortality would support serious consideration of its clinical significance in those with advanced disease and risk factors.West et al, 2003. Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. Journal of Clinical Investigation 111 (1), 81–90.
To compare the pulmonary hazards of smoking marijuana and tobacco, we quantified the relative burden to the lung of insoluble particulates (tar) and carbon monoxide from the smoke of similar quantities of marijuana and tobacco. The 15 subjects, all men, had smoked both marijuana and tobacco habitually for at least five years. We measured each subject's blood carboxyhemoglobin level before and after smoking and the amount of tar inhaled and deposited in the respiratory tract from the smoke of single filter-tipped tobacco cigarettes (900 to 1200 mg) and marijuana cigarettes (741 to 985 mg) containing 0.004 percent or 1.24 percent delta 9-tetrahydrocanabinol. As compared with smoking tobacco, smoking marijuana was associated with a nearly fivefold greater increment in the blood carboxyhemoglobin level, an approximately threefold increase in the amount of tar inhaled, and retention in the respiratory tract of one third more inhaled tar (P less than 0.001). Significant differences were also noted in the dynamics of smoking marijuana and tobacco, among them an approximately two-thirds larger puff volume, a one-third greater depth of inhalation, and a fourfold longer breath-holding time with marijuana than with tobacco (P less than 0.01). Smoking dynamics and the delivery of tar during marijuana smoking were only slightly influenced by the percentage of tetrahydrocanabinol. We conclude that smoking marijuana, regardless of tetrahydrocannabinol content, results in a substantially greater respiratory burden of carbon monoxide and tar than smoking a similar quantity of tobacco.Zhang et al, 1999. Marijuana Use and Increased Risk of Squamous Cell Carcinoma of the Head and Neck. Cancer Epidemiology Biomarkers and Prevention 8, 1071-1078.
In this study, we show that D-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, suppresses host immune reactivity against lung cancer. In two different weakly immunogenic murine lung cancer models, intermittent administration of THC (5 mg/kg, four times/wk i.p. for 4 wk) led to accelerated growth of tumor implants compared with treatment with diluent alone. In contrast to our findings in immunocompetent mice, THC did not affect tumor growth in tumor-bearing SCID mice. The immune inhibitory cytokines, IL-10 and TGF-b, were augmented, while IFN-g was down-regulated at both the tumor site and in the spleens of THC-treated mice. Administration of either anti-IL-10- or anti-TGF-b-neutralizing Abs prevented the THC-induced enhancement in tumor growth. Both APC and T cells from THC-treated mice showed limited capacities to generate alloreactivity. Furthermore, lymphocytes from THC-treated mice transferred the effect to normal mice, resulting in accelerated tumor growth similar to that seen in the THC-treated mice. THC decreased tumor immunogenicity, as indicated by the limited capacity for tumor-immunized, THC-treated mice to withstand tumor rechallenge. In vivo administration of a specific antagonist of the CB2 cannabinoid receptor also blocked the effects of THC. Our findings suggest the THC promotes tumor growth by inhibiting antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway.