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top 10 cbd brands gummies Some, Since the protagonist expressed that he didn t mind, the others naturally had nothing to say, and the field finally calmed down. In a short period of time, there was no need to worry about Cbd Oil For Bronchitis cbd cream restricting the development of the territory due to population problems. Swain Jie Jie smiled: The Marshal s words shouldn t be a big problem.

When I saw the three corpses on the ground, I was already plus sleep cbd gummies furious, These people actually killed their own soldiers in their own territory. He commented that he thought the ship doctor was a magician who bewitched the people, but since he entered the town of Arutonga until now, he has not found anything wrong with the sun god sect. If other people forcibly ride, these your cbd store horses will lie on honest health cbd gummies the ground, motionless. The kingdom and the Sun God sect started a protracted war, and the war ended in victory for the kingdom, edible gummies weed but the strength of the kingdom of Avelyn also dropped sharply because of this war, and it never regained its former glory.

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More than that, continued, Even one of the three small cities occupied by the City Lord s Mansion was captured by the Blue Shirt Army. Believe in the gods? repeated, That s right, Kieran nodded, If the power of faith is strong enough, theoretically a peak fifteenth level, that daily gummies is, the peak of legend, can be conferred a god and become a god. He stepped forward and kicked Aljeev out with one kick, Aljeev gummies to sleep is just an ordinary person, how can he stop him? If he kicked him with all his strength, he could cbd gummy bears effects have killed him on the spot. At the same time, the six golden-robed priests behind the ship doctor also began to sing magic.

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After summoning Swain, to his surprise, the system cbd cream s voice sounded in his mind again. Select the lottery, the pointer flies around, and finally stops cbd oil for bronchitis on that mask. Butler York did not answer, but Aljeev suddenly He took two steps forward, glared, pointed his nose and said: What is the city lord sending us here, you want to call us the city lord, do you know? Even knowing 900 mg cbd oil that we are the envoys of the city lord s mansion, you dare to put on airs and not come out to greet you, you are despising the city lord s mansion. What divine power is obviously magic! Lux muttered in a low voice, Sometimes divine power and magic seem to be the same, but where to buy cbd gummies montreal their nature is completely different. Should you leave Alex cbd oil for bronchitis or Garen here and cut down the trees slowly? I ll try it. Without cbd gummies much hesitation, he chose to start the lottery, and the pointer on best cbd for anxiety the lottery disc began to spin like crazy.

However, in just a few seconds, Patrick has avoided far away, and his rotating figure has stopped. cbd gummies for pain 1000mg amazon Why the other party invaded medline cbd capsules our territory is no longer important, What is important is that since the war has already started, then we cbd products must find a way cbd oil for bronchitis to become the winner. In the impression of the old people reviews for cbd sleep gummies in Alutonga Town, the High Priest looked does cbd oil get you high like this when he first arrived in Alutonga Town.

This is an unsolvable proposition, and Arthur, someone must bow to the other s philosophy. But it won t give Patrick time to breathe, After one sword does cbd help anxiety is over, the other sword cbd oil for bronchitis platinum series cbd infused gummies 1200 immediately slashes cbd oil for bronchitis at Patrick. Before leaving, Ansier gave gummies delicious him a fierce look, apparently blaming him for all this. lloyds pharmacy cbd gummies The cavalry behind had no time to stop and could only step on them, The cavalry who fell to the ground counted arrows and were stepped on by their companions mounts.

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The goal is to grow the population of the territory to more gummy edibles than a thousand people before daily gummies planting next spring! With a population base of 1,000 cbd oil near me people, the territory can gather dozens of guardian armies with cultivation talents. There is a small town and five villages in the territory, In the eyes of Folkestone, the five villages are only tools used to collect taxes and raise money, and they do not have troops stationed, so the target of the attack is the only town in Folkestone, Folkestone Town.

Carus called a few ordinary cavalry warriors and pointed to the road ahead: You guys, form a line and ride your horses to the front! Others, keep up.

After the black figure reached the edge of the forest, it jumped down from the tree cbd oil for bronchitis trunk, landed more than ten meters in front of the others, and let out a loud roar at everyone. Look at the properties of the giant eagle, Gale Eagle: Wind attribute eighth-level monster, how to store cbd oil capsules born to master wind magic, flying very fast! The two claws are stronger than steel and can crush gold and stone. When choosing cbd oil for bronchitis cbd oil for bronchitis does work arms, he directly skipped the how long until cbd gummies kicks in first to third cbd oil for bronchitis orders, and set his sights cbd for sleep on the high-level soldiers. The solubility height is about 20 to 30 meters, the range is very large, the east and west are connected, and there is no edge at a glance. Getting through the tunnel will at most take some effort, thanks! The magician and two other gummies mg companions bowed deeply and sale gummies thanked, If I find the body of your companion, I will bring the body back to Huaxia Town, and then you can go to Huaxia Town to find me.

He could convert all the soldiers of the cbd near me auxiliary army into second-order light infantry. From the innkeeper s point of view, these nobles, especially young nobles like this, are all big spenders, and it is no exaggeration to cbd gummies say that they are the God of cbd oil for bronchitis Wealth. For a while, the Huaxia collar actually ushered in a period of peaceful development. Our road ahead will be different, let s just leave it, To Cornell, At this time, it was already the second day after waiting for the people to leave the underground world. I don t know if it s because of the prize plus cbd oil draw for achievement rewards, so the quality of the prizes this time is relatively good, and there is no wooden box that occupies at least two grids in the past.

Follow your orders, young master! Alex said, It is conceivable what kind of brutal training the soldiers of the Guardian Army will experience in the pikachu cbd gummies coming days. The discussion was intense, and a guard opened the curtain of the recommend best cbd gummies review main tent and walked in. boom! northern scents cbd gummies The giant sword slammed into Patrick, marijuana gummies and it exploded, blowing dust into the sky. You know, it s time to start, In a flash, he came to the front of the two guards, and punched out. cbd oil for bronchitis In addition to the legendary powerhouses, a group of powerhouses who are aiming to protect the cbd gummy Hariland nation have also joined the Guardian of Light, making the Guardian of Light continue cbd oil for bronchitis to grow. Don t mess around! The, snack merchant rarely gave Belle a serious face. As the direct descendant cbd for pain of the Sen Lan family, is it strange to have the title of baron in the kingdom? Did Aljeev tell you about my origins? he said to Ans El with a smile. The Huaxia collar and the blue shirt army s highest cbd oil gummies commander, Carus, have a feud for killing their sons. Hello Kenny, smiled after returning a cbd oil for bronchitis salute: We are not some adventurers, my cbd oil for bronchitis name is Sen Lan, I come from the Chinese collar in the Nice City area, these are my friends.

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In fact, he has no ill tacoma farm cbd oil intentions towards you, young master, But even Steward York himself did not believe what he said. Then please move to the exterior of the hall, Cornell said, cbd oil topical versus oral The nobles in the banquet hall walked just cbd gummies out of the banquet hall with a smile, and stood scattered around, waiting for the start of the fight.

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Pioneer knight, charge! With a blank face, he ordered that if he refused to surrender, he would still be 8 gummies the enemy, and he would not show any mercy to the enemy, even if it was someone he admired.

After entering the system, take a look at the territory attributes, Territory Name: Tru Village (Large Village. That is to say, even if I lead you to upgrade after leveling up, you Will the experience points obtained from killing monsters still be saved to the current level? said happily.

The two soldiers each carried a bag, which contained monster materials and bright silver. What s the panic! What happened? Cornell asked sharply, The news gummy edibles came from the intelligence department just now that the city of Saint Zeer was captured by the blue shirt army, and the territory of Saint Zeer was completely occupied. If it wasn t for the other party s unintentional killing of him in the last attack, he would have been killed by now. Don t drop! Dozens of surviving blue shirt soldiers shouted in unison. However, I heard from the cbd oil for bronchitis Sen Lan family that their eyes have been black since birth, not because of their own time travel. In front, more than 20 soldiers who were originally guarding the town entrance, after blowing the warning cbd oil for bronchitis whistle, saw the iron cavalry rushing towards him, hugging their heads and squirming.

Nodding with satisfaction: Exactly, I have a task for you, As he said, he took out the information of the stack of magic energy machines from the space ring: I will cbd sleep gummies give you the information of this stack of magic energy machines, and you can copy and copy it as soon as possible.

The light infantry had not yet been trained, and the plan to counterattack Folkestone could only wait cbd oil for bronchitis a few more days. Cbd Oil For Bronchitis The two who passed the initial test are Arthur and Stuart, The village chief read royal cbd gummies out the names of the two people aloud. In fact, with the speed at which Rek Sai digs the tunnel, the short distance between the barracks and the city of Saint Zeil, why does it take one night. Also, the troops that have been secretly trained over the years, except cbd oil for bronchitis the Blood Wolf Knights, have all been transferred to me! I want the Blue Shirts to perish completely. Yasuo rushed to Alex s side as soon as possible, He lifted Alex s head slightly, observed it carefully, and said, The injury is too serious and he is in a coma.

hawaiian haze cbd hemp flower Eric and cbd oil for sundowning Spike, who had been standing at cbd oil for bronchitis the back to watch the battle, were shocked by taco bell cbd gummies the sudden appearance of the Vanguard Knights. On the afternoon of the 7th, he finished all the exam papers, I have to say that the ideas of these candidates taking the test are very different, some of which are eye-catching, some are bland, some are extreme, and some are childish. This kid named Sen Lan is probably crazy! During the battle, Yasuo and Lux immediately felt the improvement of their strength. With a slight smile: You are a nobleman, but not your two guards, Besides, what about nobles? Do you think I would not dare to fight. I am cannabis gummies in favor of attacking the territory occupied by the blue shirt army, but the lord cannot attack other people s territory for no reason. You were sent by that old fellow Alfred? the ship doctor asked with a gloomy face. .

Bookshelf

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington (DC): National Academies Press (US); 2017 Jan 12.

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.

National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda.

7 Respiratory Disease

Chapter Highlights

It is unclear whether cannabis use is associated with chronic obstructive pulmonary disorder, asthma, or worsened lung function.

Environmental exposures are the leading causes of respiratory disease worldwide. Exposures to tobacco smoke and household air pollution consistently rank among the top risk factors not only for respiratory disease burden but also for the global burden of disease (Lim et al., 2012). Less is known, however, about the attributable effects of cannabis use on respiratory disease despite shared similarities with that of cigarette use and the fact that cannabis is the most commonly used inhaled drug in the United States after tobacco, with an estimated 22.2 million people ages 12 years and older reporting current use (CBHSQ, 2015). Moreover, it is estimated that more than 40 percent of current users smoke cannabis on a daily or near daily basis (Douglas et al., 2015). Given the known relationships between tobacco smoking and multiple respiratory conditions, one could hypothesize that long-term cannabis smoking leads to similar deleterious effects on respiratory health, and some investigators argue that cannabis smoking may be even more harmful than that of tobacco smoking. Indeed, data collected from 15 volunteers suggest that smoking one cannabis joint can lead to four times the exposure to carbon monoxide and three to five times more tar deposition than smoking a single cigarette (Wu et al., 1988). This may be, in part, because cannabis smokers generally inhale more deeply and hold their breath for longer than do cigarette smokers (Wu et al., 1988) and because cannabis cigarettes do not commonly have filters as tobacco cigarettes often do. On the other hand, cannabis cigarettes are not as densely packed as tobacco cigarettes (Aldington et al., 2008), and cannabis users usually smoke fewer cannabis cigarettes per day than tobacco users smoke tobacco cigarettes per day.

The committee responsible for the 1999 Institute of Medicine (IOM) report Marijuana and Medicine: Assessing the Science Base (IOM, 1999, p. 6) concluded that cannabis smoking was an important risk factor in the development of respiratory disease and recommended that “studies to define the individual health risks of smoking marijuana should be conducted, particularly among populations in which marijuana use is prevalent.” The literature search conducted by the current committee did not identify any fair- or good-quality systematic reviews for cannabis use and respiratory disease published since 2011 (the cutoff established by the current committee); however, the committee identified—and elected to include—a systematic review by Tetrault et al. (2007) that provides a detailed synthesis of the available literature through 2005. A review by Tashkin (2013) and a position statement by Douglas et al. (2015), which summarized current evidence of the link between cannabis smoking and respiratory disease, were also considered by the committee. Fourteen primary articles published since 1999 that were not included in the systematic review from Tetrault et al. (2007) provided additional evidence on the association between smoking cannabis and respiratory diseases (Aldington et al., 2007; Bechtold et al., 2015; Hancox et al., 2010, 2015; Kempker et al., 2015; Macleod et al., 2015; Papatheodorou et al., 2016; Pletcher et al., 2012; Tan et al., 2009; Tashkin et al., 2012; Van Dam and Earleywine, 2010; Walden and Earleywine, 2008; Weekes et al., 2011; Yadavilli et al., 2014).

PULMONARY FUNCTION

Pulmonary function refers to lung size and function. Common measures of pulmonary function include forced expiratory volumes, lung volumes, airways resistance and conductance, and the diffusion capacity of the lung for carbon monoxide (DLCO). Spirometry values include the measurements of forced expiratory volumes, including forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC. The latter is a measure of airflow obstruction and, when combined with bronchodilator therapy, is used in the diagnosis of chronic obstructive pulmonary disorder (COPD).

Is There an Association Between Cannabis Use and Pulmonary Function?

Systematic Reviews

Tetrault et al. (2007) systematically reviewed the evidence found in 34 publications, of which 12 reported on the effects of airway response and 14 reported on the effects of pulmonary function. The authors found that short-term exposure to cannabis smoking resulted in bronchodilation. Specifically, acute cannabis smoking was consistently associated with improvements in specific airway conductance, peak flow measurements, and FEV1, as well as reversed bronchospasm from challenges by either methacholine or exercise. Any short-term benefits, however, were offset by the effects of long-term cannabis smoking. Specifically, regular cannabis smoking was associated with a lower specific airway conductance on average by 16 percent and also with a lower FEV1. There was also a dose–response effect between average daily quantity of cannabis and a lower specific airway conductance. However, the clinical significance of the association between regular cannabis smoking and a lower specific airways conductance is not known. Other studies that examined the association between long-term cannabis smoke exposure and pulmonary function have inconsistently found lower or no change in FEV1, FVC, FEV1/FVC, DLCO, and airway hyperresponsiveness (Tetrault et al., 2007).

Primary Studies

Aldington et al. (2007) examined the cross-sectional relationship between long-term cannabis smoking and pulmonary function in a convenience sample of 339 participants in the Wellington Research Study. The inclusion criteria for cannabis and tobacco smokers were a lifetime exposure of at least 5 joint-years of cannabis (defined as smoking 1 joint per day for 1 year) or at least 1 pack-year of tobacco, respectively. Cannabis smoking was based on self-report. The researchers did not find an association between long-term cannabis smoking and pulmonary function variables. However, when cannabis smoking was analyzed in terms of joint-years, Aldington et al. (2007) found a significantly lower FEV1/FVC, lower specific airways conductance, and a higher total lung capacity per joint-year smoked in cannabis smokers compared to nonsmokers. Based on their analyses, the authors estimated that the negative association between each cannabis joint and a lower FEV1/FVC was similar to that of 2.5 to 5 tobacco cigarettes. The committee identified a couple of problems with the analyses and the presentation of the results in the paper by Aldington et al. (2007). First, the authors reported main effects only from their analysis of covariance. A more conservative analysis would have considered the examination of interaction effects between cannabis smoke (or joint-years) and tobacco smoke (or pack-years) in a regression model to better dissect the contribution of cannabis smoke (or joint-years) versus tobacco smoke (or pack-years). Second, the authors incorrectly labeled the association with continuous measures of pulmonary function with cannabis smoke (or joint-years) as odds ratios (ORs) in tables 3 and 4; however, their methods correctly state that a multivariable analysis of covariance methods was used for continuous data.

Papatheodorou et al. (2016) analyzed cross-sectional data from 10,327 adults who participated in the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2012. Cannabis smoking was based on self-report, but the researchers could not quantify joint-years. Cannabis smokers were categorized as never smokers (n = 4,794), past cannabis smokers (n = 4,084), cannabis smokers in the past 5–30 days (n = 555), and cannabis smokers in the past 0–4 days (n = 891). Current cannabis smokers were heavier tobacco smokers than were past and never smokers of cannabis, as measured by mean pack-years. In multivariable analyses, the investigators found that current smokers had a smaller FEV1/FVC than never smokers (−0.01 and −0.02, respectively), and they observed moderate to large increases in FEV1 (49 mL and 89 mL, respectively) and FVC (159 mL and 204 mL, respectively) when comparing current smokers to never smokers. There was also an important decrease in exhaled nitric oxide among current smokers when compared to never smokers (−7 percent versus −14 percent), but it is unclear if this effect was confounded by the high prevalence of tobacco smoking in current cannabis users or if it represented a true decrease in exhaled nitric oxide due to cannabis smoking. The study by Papatheodorou et al. (2016) has some shortcomings. First, the researchers’ analyses were based on cross-sectional data. Second, cannabis use was obtained by self-report and there may have been a bias of underreporting. Finally, there was a lack of data on the method of smoke inhalation and the frequency of cannabis smoking, thus not allowing for an analysis of the relationship between the frequency of cannabis use and pulmonary function.

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Pletcher et al. (2012) analyzed longitudinal data from 5,115 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study and concluded that occasional and low cumulative cannabis smoking was not associated with adverse effects on pulmonary function. The investigators noted that there was a trend toward decreases in FEV1 over 20 years only in the heaviest cannabis smokers (≥20 joint-years). Similar to the findings of Papatheodorou et al. (2016), CARDIA investigators found a higher-than-expected FVC among all categories of cannabis smoking intensity. Despite the large sample size, the study by Pletcher et al. (2012) had a small number of heavy cannabis smokers. Other limitations include the risk of bias due to the self-reporting of cannabis use, a lack of data on the method of cannabis smoke inhalation, and bias due to unmeasured confounders as cannabis smoking was not the main objective of this study.

The study by Hancox et al. (2010) analyzed data of a cohort of 1,037 adult participants in Dunedin, New Zealand, followed longitudinally since childhood and asked about cannabis and tobacco use at ages 18, 21, 26, and 32 years. Cumulative exposure to cannabis was quantified as joint-years since age 17 years. Spirometry was conducted at 32 years. Cumulative cannabis use was associated with higher FVC, total lung capacity, and functional residual capacity and residual volume, but not with lower FEV1 or FEV1/FVC.

A small feasibility study by Van Dam and Earleywine (2010) found that the use of a cannabis vaporizer instead of smoking cannabis in 12 adult participants who did not develop a respiratory illness was associated with improvements in forced expiratory volumes at approximately 1 month after the introduction of the vaporizer; however, this study did not have a control group.

Discussion of Findings

Overall, acute cannabis smoking was associated with bronchodilation, but many of the authors agreed that any benefits may be offset when cannabis is smoked regularly. The current findings are inconclusive on a variety of pulmonary function measurements, and the findings may be affected by the quality of the studies, a failure to adjust for important confounders, including tobacco and other inhaled drugs, and other occupational and environmental exposures. The committee’s findings are consistent with those reported in another recent review (Tashkin, 2013) and a position statement (Douglas et al., 2015).

The majority of studies, including those evaluated in the systematic review, relied on self-report for cannabis smoking. Many studies failed to control for tobacco smoking and occupational and other environmental exposures; did not control for the dose or duration of cannabis smoking; and did not use joint-years and instead based heavy cannabis smoking on having exceeded a specific threshold of joints. Even among studies that used joint-years, it is unclear how generalizable their findings are, given the potential high variability in lung-toxic content from joint to joint. Prior studies have inconsistently documented decreases or no change in FEV1, FEV1/FVC, DLCO, and airway hyperresponsiveness. Moreover, neither the mechanism nor the clinical significance of the association between cannabis smoking and pulmonary function deficits is known beyond the possible impact of a high FVC in lowering the FEV1/FVC ratio. While elevated lung volumes could be indicators of lung pathology, an elevated FVC by itself has not been associated with any lung pathology.

7-1(a) There is moderate evidence of a statistical association between cannabis smoking and improved airway dynamics with acute use, but not with chronic use.

7-1(b) There is moderate evidence of a statistical association between cannabis smoking and higher forced vital capacity (FVC).

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

COPD is a clinical syndrome that consists of lower airway inflammation and damage that impairs airflow. Ranked as the fourth-leading cause of death worldwide by the World Health Organization, COPD has been estimated to cause more than 3 million deaths worldwide annually and has an estimated global prevalence of 10 percent in adults (Buist et al., 2007; Diaz-Guzman and Mannino, 2014). COPD is diagnosed with spirometry and is defined by a post-bronchodilator forced expiratory volume at 1 second divided by forced vital capacity (FEV1/FVC) 1/FVC below the 5th percentile of a reference population (lower limit of normal). The committee responsible for Marijuana and Medicine: Assessing the Science Base (IOM, 1999) suspected, but did not conclude, that chronic cannabis smoking causes COPD.

Is There an Association Between Cannabis Use and COPD?

Systematic Reviews

There is no discussion about the association between cannabis and COPD in the systematic review by Tetrault et al. (2007). In the position statement of the American Thoracic Society (Douglas et al., 2015), workshop members concluded that there was minimal impairment in occasional cannabis smokers when controlling for tobacco use. In contrast, there was a trend toward higher prevalence in heavier users based on studies of lung function decline (Pletcher et al., 2012; Tashkin et al., 1987); however, workshop members determined that this association was incompletely quantified.

Primary Studies

The study by Aldington et al. (2007) examined high-resolution computed tomography scans among the subgroups of participants with cannabis smoking only, cannabis and tobacco smoking, tobacco smoking only, and never smokers. They found inconsistent results: a decreased mean lung density, which is suggestive of emphysematous changes (mean percent of area below −950 Hounsfield units in three slices at 2.4 percent [95% confidence interval (CI) = 1.0%–3.8%] for cannabis smokers, but −0.6 percent [−2.0%–0.8%] for tobacco smokers when compared to nonsmokers), but almost no evidence of macroscopic emphysema (1.3% versus 16.5% versus 18.5% versus 0% in cannabis-only smokers versus cannabis and tobacco smokers versus tobacco-only smokers versus non-smokers, respectively).

Tan et al. (2009) analyzed cross-sectional data collected in 878 adults ages 40 years and older from Vancouver, Canada, who participated in the Burden of Obstructive Lung Disease study on COPD prevalence. Current smoking of either tobacco or cannabis was defined as any smoking within the past year. Participants who had smoked at least 50 marijuana cigarettes but had no history of tobacco smoking were not at significantly greater risk of having COPD or more respiratory symptoms. There was inconsistent evidence for whether synergy from combined cannabis and tobacco smoking might affect the odds of having COPD or worse respiratory symptoms.

Specifically, the mean estimates for the tobacco and cannabis smoking versus tobacco-only smoking groups do not appear to be different, and the 95% CI for the tobacco and cannabis smoking group appears to overlap significantly with the tobacco-only smoking groups when evaluating either COPD or respiratory symptoms as the outcome.

Yadavilli et al. (2014) examined data from 709 participants over a 33-month period for hospital readmissions of COPD in illicit drug users and tobacco smokers. These investigators found that cannabis users had similar readmission rates to ex-tobacco or current tobacco users (mean readmissions at 0.22 versus 0.26) and much lower readmission rates than other illicit drug users (mean readmissions at 1.0). The unit for mean readmissions was not specified in either the tables or methods of this paper. The limitations of the study by Yadavilli et al. (2014) include a lack of spirometry data on all patients to confirm diagnosis of COPD, the self-report of tobacco use, the risk for potential underreporting of illicit drug use, and the lack of outpatient visit frequency.

Kempker et al. (2015) analyzed data from the 2007–2010 NHANES cohorts, similar to the work done by Papatheodorou et al. (2016). Kempker et al. (2015), however, also examined the information on cumulative lifetime use of cannabis available in the 2009–2010 NHANES cohort. Main findings were that 59 percent reported using cannabis at least once during their lifetime, and 12 percent reported use during the last month. When evaluating cumulative lifetime cannabis use, those with >20 joint-years had a two times higher odds (OR, 2.1; 95% CI = 1.1–3.9) of having a pre-bronchodilator FEV1/FVC 1, which would spuriously reduce the ratio FEV1/FVC. Beyond the limitations noted above for the paper by Papatheodorou et al. (2016), who also used NHANES data, the authors were limited to use pre-bronchodilator spirometry instead of using post-bronchodilator spirometry as commonly done in COPD studies.

Discussion of Findings

It is unclear whether regular cannabis use is associated with the risk of developing COPD or exacerbating COPD. Current studies may be confounded by tobacco smoking and the use of other inhaled drugs as well as by occupational and environmental exposures, and these studies have failed to quantify the effect of daily or near daily cannabis smoking on COPD risk and exacerbation. There is no evidence of physiological or imaging changes consistent with emphysema. The committee’s findings are consistent with those of a recent position statement from the American Thoracic Society Marijuana Workgroup which concluded that there was minimal impairment in light and occasional cannabis smokers when controlled for tobacco use and that the effects in heavy cannabis smokers remain poorly quantified (Douglas et al., 2015). The review by Tashkin (2013) concluded that the lack of evidence between cannabis use and longitudinal lung function decline (Pletcher et al., 2012) argues against the idea that smoking cannabis by itself is a risk factor for the development of COPD. This is further supported by the findings of Kempker et al. (2015), who concluded that smoking cannabis was not associated with lower FEV1 after adjusting for tobacco smoking. However, smoking cannabis was associated with a higher FVC, which may have led to a spuriously lower FEV1/FVC. Therefore, their analyses also do not support an association between heavy cannabis use (>20 lifetime joint-years) and obstruction on spirometry. The position statement by Douglas et al. (2015) concluded that the lack of solid epidemiologic association suggests that regular cannabis smoking may be a less significant risk factor for the development of COPD than tobacco smoking.

Cross-sectional studies are inadequate to establish temporality, and cohort studies of regular or daily cannabis users are a better design to help establish COPD risk over time. Better studies are needed to clearly separate the effects of cannabis smoking from those of tobacco smoking on COPD risk and COPD exacerbations, and better evidence is needed for heavy cannabis users.

7-2(a) There is limited evidence of a statistical association between occasional cannabis smoking and an increased risk of developing chronic obstructive pulmonary disease (COPD) when controlled for tobacco use.

7-2(b) There is insufficient evidence to support or refute a statistical association between cannabis smoking and hospital admissions for COPD.

RESPIRATORY SYMPTOMS, INCLUDING CHRONIC BRONCHITIS

Respiratory symptoms include cough, phlegm, and wheeze. Chronic bronchitis is defined as chronic phlegm production or productive cough for 3 consecutive months per year for at least 2 consecutive years (Medical Research Council, 1965). Chronic bronchitis is a clinical diagnosis and does not require confirmation by spirometry or evidence of airflow obstruction. The committee responsible for Marijuana and Medicine: Assessing the Science Base (IOM, 1999) concluded that acute and chronic bronchitis may occur as a result of chronic cannabis use.

Is There an Association Between Cannabis Use and Respiratory Symptoms, Including Chronic Bronchitis?

Systematic Reviews

The systematic review by Tetrault et al. (2007) summarized information from 14 studies that assessed the association between long-term cannabis smoking and respiratory symptoms. Nine of these studies were cross-sectional, 3 were case series, 1 was a case-control study, and 1 was a longitudinal cohort study. Data were relatively consistent in both cross-sectional and cohort studies in indicating that long-term cannabis smoking worsens respiratory symptoms, including cough (ORs, 1.7–2.0), increased sputum production (ORs, 1.5–1.9), and wheeze (ORs, 2.0–3.0). Other studies have reported effects on more episodes of acute bronchitis and pharyngitis, dyspnea, hoarse voice, worse cystic fibrosis symptoms, and chest tightness.

Primary Studies

Aldington et al. (2007) reported higher prevalence of wheeze (27 percent versus 11 percent), cough (29 percent versus 5 percent), chest tightness (49 percent versus 35 percent), and chronic bronchitis symptoms (19 percent versus 3 percent) among cannabis smokers than among nonsmokers. There were no clear additive effects observed in the combined cannabis and tobacco smoking groups on respiratory symptoms.

Hancox et al. (2015) conducted a study in a cohort of 1,037 adults (52 percent male) in the Dunedin Multidisciplinary Health and Development Study. Cannabis and tobacco smoking histories were obtained at the ages of 18, 21, 26, 32, and 38 years. At each assessment, participants were asked how many times they had used cannabis in the previous year. Frequent cannabis users were defined as those who reported using marijuana ≥52 times over the previous year. Quitters were defined as a frequent cannabis user at the previous assessment but less than frequent at the current assessment. Because it was possible to quit frequent cannabis use more than once during the follow-up from 18 to 38 years of age, only the first recorded episode of quitting was used in analyses. In this study, the investigators found that frequent cannabis use was associated with morning cough (OR = 1.97, p <0.001), sputum production (OR = 2.31, p <0.001), and wheeze (OR = 1.55, p <0.001), but not dyspnea (p = 0.09) (see Figure 7-1). Quitters (open triangles) also had fewer respiratory symptoms than those who did not quit (solid squares).

FIGURE 7-1

Prevalence of symptoms before and after quitting regular cannabis use (open triangles) and among those who used cannabis for two consecutive phases (solid squares). Vertical bars show 95% confidence level. SOURCE: Hancox et al., 2015.

Limitations of the study by Hancox et al. (2015) include its reliance on self-reported data of cannabis use without objective confirmation, the classification of nonusers as those with

Walden and Earleywine (2008) conducted a cross-sectional Internet survey of 5,987 adults worldwide who used cannabis at least once per month. They quantified frequency, amount, and degree of usual and maximal intoxication, and they also asked about respiratory symptoms using a composite score produced from the answers to six standard questions about cough, morning phlegm, dyspnea, chest wheezing other than during colds, and nighttime awakenings because of chest tightness. They found that the frequency of use, the amount used (in quarter bags per month), and the degree of usual intoxication were all positively associated with more respiratory symptoms. Limitations for this study include its recruitment of participants from organizations that advocate drug policy reform, its reliance on self-reported data of cannabis or tobacco use without objective confirmation, and the lack of data about cannabis use for medical versus recreational purposes.

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Tashkin et al. (2012) followed 299 participants from a longitudinal cohort study for at least two visits over 9.8 years and examined the relationship between symptoms for chronic bronchitis and cannabis use. They found that current cannabis users were more likely to have cough (OR = 1.7), sputum (OR = 2.1), increased bronchitis episodes (OR = 2.3), and wheeze (OR = 3.4) when compared to never users. They also found that current cannabis users were more likely to have cough (OR = 3.3), sputum (OR = 4.2), or wheeze (OR = 2.1) than former users. Similar to the studies by Hancox et al. (2015) and Walden and Earleywine (2008), these findings demonstrated the benefit of cannabis smoking cessation in resolving preexisting symptoms of chronic bronchitis. The limitations of this study include its reliance on self-reported data of cannabis or tobacco use without objective confirmation and high rates of loss to follow-up or variable follow-up periods.

A small feasibility study by Van Dam and Earleywine (2010) of 12 adult participants who did not develop a respiratory illness during the trial found that the use of a cannabis vaporizer instead of smoking cannabis was correlated with the resolution of cannabis-related respiratory symptoms at approximately 1 month after the introduction of the vaporizer; however, this study did not have a control group.

Discussion of Findings

Regular cannabis use was associated with airway injury, worsening respiratory symptoms, and more frequent chronic bronchitis episodes. There were no clear additive effects on respiratory symptoms observed from smoking both cannabis and tobacco. Cannabis smoking cessation was temporally associated with the resolution of chronic bronchitis symptoms, and a small feasibility study suggests that use of a vaporizer instead of smoking cannabis may lead to the resolution of respiratory symptoms. The committee’s findings are consistent with those reported in a recent review (Tashkin, 2013) and position statement (Douglas et al., 2015).

The majority of studies relied on self-report for cannabis smoking. Many studies failed to control for tobacco, occupational, and other environmental exposures; did not control for the dose or duration of the cannabis smoke exposure; and did not use joint-years and instead based heavy cannabis exposure on exceeding a specific threshold of cigarettes. Even among studies that used joint-years, it is unclear how generalizable the findings are, given the potential high variability in tetrahydrocannabinol (THC) content from joint to joint and from year to year.

7-3(a) There is substantial evidence of a statistical association between long-term cannabis smoking and worse respiratory symptoms and more frequent chronic bronchitis episodes.

7-3(b) There is moderate evidence of a statistical association between cessation of cannabis smoking and improvements in respiratory symptoms.

ASTHMA

Asthma is a clinical syndrome that is associated with airways inflammation, airflow limitation, bronchial hyperresponsiveness, and symptoms of episodic wheeze and cough. It is predominantly an allergic disease. Worldwide, asthma is thought to affect 300 million people, and it is responsible for more disability-adjusted life-years lost than diabetes mellitus. Asthma was not specifically addressed in Marijuana and Medicine: Assessing the Science Base (IOM, 1999).

Is There an Association Between Cannabis Use and Asthma?

Systematic Reviews

The systematic review by Tetrault et al. (2007) referred to only one study that described the association between cannabis use and asthma exacerbations. Upon retrieving this study, the committee found that this was a letter to the editor which reported findings of a case-control study of 100 participants ages 18–55 years, with and without asthma, admitted to the emergency department. In this study, the authors found no association between THC and asthma (Gaeta et al., 1996).

Primary Studies

Bechtold et al. (2015) reported on a follow-up of a cohort of boys who participated in the Pittsburgh Youth Study. A total of 506 boys were followed longitudinally: 257 scored at or above the 70th percentile of a multi-informant conduct problem score, and 249 scored below the 70th percentile. This study found no link between cannabis use and self-reported asthma symptoms. The limitations of this study include a lack of generalizability to the general population, given the selection criteria for conduct problems, a lack of inclusion of women in their study, and the fact that health outcomes were based on self-report and biased to those who had sought care for health problems.

Weekes et al. (2011) studied a cohort of 110 black urban adolescents with asthma. In this study, the investigators found that 16 percent of the adolescents smoked cannabis, but there was no association between cannabis use and asthma concern or asthma severity or asthma symptoms. The limitations of this study include the reliance on the self-report of cannabis use, which the study authors speculated may be underreported in black adolescents when compared to whites, and a lack of data on asthma medication adherence.

Discussion of Findings

The committee did not find evidence for an association between cannabis use and either asthma risk or asthma exacerbations, and current studies failed to control for other important confounders, including adherence to asthma medications.

The evidence linking cannabis use with asthma risk or exacerbation is limited by the scope and sample size of available studies and by the use of more standardized approaches to measure asthma prevalence or exacerbations of asthma. Few studies have examined the link between cannabis and asthma, and no clear evidence exists of a link between asthma or asthma exacerbation and cannabis use. However, asthma symptoms such as wheeze appear to be common among cannabis users.

CONCLUSION 7-4 There is no or insufficient evidence to support or refute a statistical association between cannabis smoking and asthma development or asthma exacerbation.

RESEARCH GAPS

The effects of cannabis smoke on respiratory health remain poorly quantified. Further research is needed to better elucidate the influence of exposure levels to cannabis smoke on respiratory outcomes, the chronicity of cannabis smoking, the effects of an underlying predisposition to respiratory disease, and possible interaction effects with tobacco smoke to promote airway inflammation, worsen respiratory symptoms, accelerate lung function decline, or increase exacerbation of COPD and asthma. Previous studies have not been able to adequately separate cannabis smoke effects from tobacco smoke effects, and this has meant that some important questions remain unanswered. It is unknown whether or not:

Long-term cannabis smoking, above and beyond that of tobacco smoking, leads to a more rapid decline in lung function and to the development of chronic bronchitis or COPD.

To address the research gaps relevant to respiratory disease, the committee suggests the following:

Design better observational studies with both self-reported and quantitative measures of cannabis smoking and systematic approaches to measure the duration and dose to determine if long-term exposure to cannabis smoke, above and beyond exposure to tobacco smoke, leads to the development of chronic bronchitis or COPD or to a higher rate of COPD exacerbation.

Design longitudinal studies to determine if long-term cannabis smoking is associated with the development of allergic disease and risk of asthma.

Conduct clinical trials of alternative inhaled delivery methods versus cannabis smoking to determine if they reduce respiratory symptoms.

SUMMARY

This chapter summarizes all of the respiratory disease literature that has been published since 1999 and deemed to be good or fair by the committee. Overall, the risks of respiratory complications of cannabis smoking appear to be relatively small and to be far lower than those of tobacco smoking. While heavy cannabis users may be at a higher risk for developing chronic bronchitis and COPD or at an increased risk of exacerbating COPD and asthma, current studies do not provide sufficient evidence for a link. Limitations of reviewed studies are that it is difficult to separate the effects of cannabis smoking from those of tobacco smoking from current available data; that exposures have generally been measured by self-report of cannabis smoking; and that there is a lack of cohort studies of regular or daily cannabis users, of adequate controls for environmental factors, and of generalizability of findings. The committee has formed a number of research conclusions related to these health endpoints (see Box 7-1); however, it is important that each of these conclusions be interpreted within the context of the limitations discussed in the Discussion of Findings sections.

BOX 7-1

Summary of Chapter Conclusions .

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