Chronic Cannabis Smoking, Oxidative Stress and the Pulmonary Innate Immune Response

I. Hypotheses and Specific Aims:

With changing legislation, the landscape of cannabis use is shifting; data demonstrates that public perception of marijuana's "safety" has contributed to increasing usage most commonly via the inhaled route (smoking). The effects of habitual cannabis smoking on lung health, however, remains unclear. Spirometric data has been inconclusive regarding risk of airflow limitation and development of chronic obstructive pulmonary disease, a finding that may be attributable to inaccurate reporting due to its former illegal nature. It seems clear, however, that these patients suffer from an increased incidence of bronchitis symptoms from an uncertain pathophysiologic mechanism. Animal data from the 1990s demonstrates that cannabinoid exposure (of which Tetrahydrocannabinol (THC) is an example) results in increased intra-pulmonary oxidative stress indices and immunomodulatory effects resulting in abnormal macrophage function; a finding that may be related the aforementioned symptoms. However, this data is likely now outmoded given the markedly increased (THC) content of today's cannabis for sale (12 percent Tetrahydrocannabinol (THC) compared to 3 percent in the 1990s). Furthermore, most of these findings have not been validated in human subjects. Thus, the investigators hypothesize that habitually smoked cannabis increases intrapulmonary oxidative stress resulting in impaired alveolar macrophage (AM) phagocytosis, elicits an attenuated AM response to pathogen-associated molecular patterns (PAMPs) and promotes AM apoptosis thereby increasing risk of upper and lower airway infections.

II. Background and Significance:

Cannabis use in the United States is rising since legalization for medical and, more recently, recreational purposes. The United Nations Office on Drugs and Crime estimates that in 2012, when cannabis was legal for medical purposes in 17 states, but illegal for recreational consumption nationally, cannabis use among the American population increased from 11.5% to 12.1%. Over the past 2 years, an additional seven states have legalized medical cannabis, and Colorado and Washington have recently legalized its sale for recreational use. Since January 2014, publicly available Colorado data indicate increasing tax revenue from cannabis sales (both medical and recreational), suggesting a rise in state-wide consumption in a relatively short period of time.

Effects of modern inhaled cannabis on lung health are not established. Published epidemiologic data collected prior to the widespread legalization of cannabis and commercialization of the cannabis industry demonstrate consistent associations between "regular" (e.g. near daily) and "heavy" (e.g. for multiple years) cannabis use with poorer lung health. Clinically, regular inhaled cannabis users complain of increased chronic bronchitis symptoms (eg. wheeze, chronic cough) compared to non-smokers; an increased use of medical services for respiratory infections due to immunosuppressive effects of the drug has also been reported. However, characterization of cannabis use in these investigations varies widely, ranging from 7 joint-years (1 joint per day for 1 year) 12 to 117 joint-years in cohorts examined. These studies were also potentially confounded by under-reporting of cannabis use due to the drug's illegal status, and concomitant use of inhaled tobacco in some study populations. Moreover, the quantity of THC in modern cannabis products has been increasing over the past two decades. Therefore, it remains unclear what use patterns of modern inhaled cannabis are harmful to lung health, although more cannabis is being consumed now than ever before, both for medical and recreational purposes. Today, due to the decriminalization of cannabis sale and purchase, the accuracy of self-reported cannabis use is likely much greater than in prior investigations, providing a novel opportunity to more accurately establish patterns of use associated with ill effects on health. Importantly, no study to date has utilized time series analyses, such as the time line follow-back (TLFB), to quantitate the effects of regular cannabis consumption in association with lung health. TLFB techniques are used extensively to quantitate substance use among chronic users of alcohol, tobacco, and more recently, cannabis. TLFB are calendar-assisted, structured interviews that cue memory to enhance accurate recall, and have been determined to be both reliable and valid in quantitating current substance use in detail. TLFB interviews to characterize past 30 day cannabis use have been routinely conducted in research subjects by Dr. Corsi's (co-mentor to Dr. Biehl) research group since 2010, and longer term joint-year data has been collected as well.