Keywords
marijuana - cannabis - lung health
The cannabis plant is native to South and Central Asia and has been used in religious rituals, as a traditional medicine, and as a recreational drug for centuries.[1]
[2] Marijuana is a psychoactive drug derived from dried flowers, seeds, or leaves of the cannabis plant. Resin from plant buds is also used as a drug and is commonly referred to as hashish. The cannabis plant contains over 400 chemical entities of which more than 60 are cannabinoid compounds, including delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD).[3] THC represents the main psychoactive component of cannabis. Its content in marijuana has previously been around 2%, but with commercialization and development of the marijuana industry, recent strains contain much higher concentrations of THC, reaching up to over 25%.[4] The effects of THC on the human body are mainly driven through cannabinoid receptors CB1R, found in brain, and CB2R, found in the immune system.[5] The only U.S. Food and Drug Administration (FDA)-approved marketing application for plant-derived cannabis is Epidiolex (CBD), which is indicated for the treatment of seizures associated with Lennox–Gastaut syndrome, Dravet syndrome, or Tuberous Sclerosis Complex in patients 1 year of age or older. Approved synthetic cannabinoids include dronabinol (synthetic THC) and nabilone (a synthetic product with a chemical structure similar to THC) for treating nausea and vomiting associated with cancer chemotherapy; dronabinol also has an FDA-approved indication for its appetite stimulant effect in malnourished patients with acquired immunodeficiency syndrome.[6] Full discussion of medical marijuana is beyond the scope of this review, and we will focus mainly on the pulmonary effects of smoked marijuana.
Marijuana as a Recreational Drug
Marijuana as a Recreational Drug
Marijuana use leads to various psychological and physical effects which range from pleasant euphoria, a sense of relaxation, heightened sensory perception, altered perception of time, and increased appetite, to more negative effects including impaired short-term memory, impaired fine movement control, anxiety, fear, and distrust. More significant adverse effects include episodes of acute psychosis with hallucinations, delusions, and loss of sense of personal identity, as well as addiction and long-term cognitive effects.[6] Although detectable concentrations of THC remain in the body for days or even weeks after use, the effects of smoked marijuana generally last for several hours. While marijuana overdose is rarely fatal, toxicities include various neuropsychiatric effects, tachycardia, tachypnea, postural hypotension, seizures, and even respiratory depression and coma.[5]
[7]
[8]
Marijuana is available in many forms. It may be inhaled using joints (paper-wrapped marijuana), blunts (replacing cigar innards, about equivalent to 5 joints), spliffs (combined cannabis and tobacco rolled in paper), bongs (pipes or water pipes), or vaporizers (heating cannabis to release vapor without combustion). Its compounds can be extracted in oils that are vaped, smoked, or dissolved in vapors of flammable solvents such as butane and then inhaled (dabbing). Vaping is commonly performed through electronic cigarettes, hookahs, vape pens, and electronic nicotine delivery systems. Marijuana is also ingested in edible form such as chocolates, baked goods, candies, infused drinks, cannabis tea, and tinctures of cannabis. Although vaping marijuana has increased in popularity, this review will focus on the pulmonary consequences of smoked marijuana as this remains the most common mode of use. Moreover, while there is a significant body of recent literature regarding the acute or subacute impact of vaping marijuana on lung injury, overall knowledge about the impact of vaping marijuana is limited and the currently available literature on the pulmonary consequences of marijuana is dominated by the impact of smoked marijuana. That said, it is important to acknowledge that our understanding of the pulmonary effects of inhaled marijuana remain modest in comparison with those from tobacco smoking.
Increased Prevalence of Marijuana Use
Increased Prevalence of Marijuana Use
The clinical significance of marijuana smoking and vaping has burgeoning relevance as recreational use has increased significantly in the past two decades ([Fig. 1]). Marijuana has already been by far the most widely used illicit substance before its legalization.[9]
[10] In the United States alone, adult recreational use as of November 2023 was legalized in 24 states.[11] To date, there are only three states (Nebraska, Kansas, and Idaho) and one U.S. territory (American Samoa) where any context of use is completely illegal.[12] This leaves 47 states and four inhabited U.S. territories with varying degrees of medical or recreational legality ([Fig. 2]). This equates to approximately 99% of the U.S. population of some 336 million inhabitants having some degree of state or territorial law permitting marijuana usage.[13] Use in adults reached an all-time high in 2022 according to the National Institute on Drug Abuse-funded Monitoring the Future panel annual report.[6] Past-year cannabis use for 2022 was reported by 44% surveyed in the 19 to 30 age group (with 21% vaping), compared with 28% in 2012. In the 35 to 50 age group past-year use of cannabis was 28% (with 9% vaping) compared with 17% in 2017.[6] Use of marijuana is also prevalent in school-age children.[14] In 2019, according to a Youth Behavior Survey, 37% of U.S. high school students have used cannabis in their lifetime and 22% reported use within the past 30 days. Eight percent of 8th graders, 19% of 10th graders, and 22% of 12th graders reported vaping marijuana within the past year.[14] In a survey of 9,599 12th graders in 102 schools (both public and private) distributed throughout the United States, marijuana usage decreased in 12th grade students after the onset of the coronavirus disease 2019 (COVID-19) pandemic, from 35 to 36% in the immediate prepandemic years to 31% in 2021. Nicotine vaping also decreased from 35% in 2020 to 27% in 2021, possibly reflecting disruption in access or interaction with peers who would encourage use. National estimates from the 2022 National Survey on Drug Use and Health also supported a rising trend in the usage of lifetime marijuana in adults, with higher overall estimates (55% of males and 46% of females 18 and over in 2022).[15] First-time use of cannabis also increased across all age groups in people aged 12 years and over in 2021. 1.2 million adolescents aged 12 to 17, 1.2 million young adults aged 18 to 25, and 1.3 million adults aged 26 or older initiated marijuana use in 2022.[16]
Fig. 1 Past month substance use among people aged 12 year and older in the United States: Estimated numbers of current users of different substances are not mutually exclusive because people could have more than one type of substance in the past month; Rx = prescription. Modified from “Substance Abuse and Mental Health Services Administration. (2022). Key substance use and mental health indicators in the United States: Results from the 2021 National Survey on Drug Use and Health.”
Fig. 2 Degrees of marijuana legalization in the United States map provided by Julie Werner-Simon, JD, LLM (2024), used with permission.
Similarities and Differences Comparing the Smoke Contents of Tobacco versus Marijuana
Similarities and Differences Comparing the Smoke Contents of Tobacco versus Marijuana
Tobacco smoke components have been well characterized[17] and linked to adverse health effects. Chromatographic analysis of smoke from marijuana compared with that of tobacco indicated that the smoke from both substances was comprised almost entirely of over 500 semivolatile chemical species, a third in common to both. At least 110 compounds in marijuana and 173 compounds in tobacco smoke have been implicated in carcinogenic, teratogenic, or mutagenic mechanisms (69 common to both).[18] Systematic evaluation identified mutagenic and carcinogenic compounds such as polycyclic aromatic hydrocarbons (PAHs) and formaldehyde in both marijuana and tobacco and found even higher concentrations of ammonia, hydrogen cyanide, and procarcinogenic PAHs in cannabis smoke compared with tobacco smoke.[19]
[20] A major difference between the smoke contents of marijuana and those of tobacco is that the latter contains nicotine, while the smoke of marijuana contains more than a hundred cannabinoids that are not found in tobacco. Smoking one joint of marijuana has been found to be associated with a nearly fivefold greater increment in the blood carboxyhemoglobin level and increased respiratory tract delivery and retention of inhaled tar compared with that of a single tobacco cigarette (p < 0.001), potentially reflecting the method of marijuana inhalation, namely deeper inhalation and fourfold longer breath-holding times compared with tobacco smoking, in addition to the lack of filter tips and decreased rod filtration of the more loosely packed marijuana joint compared with tobacco.[21]
Effects of Inhaled Marijuana on Systemic Inflammation and Risk of Respiratory Infections
Effects of Inhaled Marijuana on Systemic Inflammation and Risk of Respiratory Infections
Cannabis contains over 60 cannabinoids. The best characterized is delta-9 THC, which harbors immunomodulatory and anti-inflammatory properties mediated by cannabinoid-2 (CB-2) receptors and endogenous ligands.[22]
[23]
[24] CB-2 receptors are expressed in immune tissues; in vitro studies have demonstrated suppression of cytotoxic T-lymphocyte activity as well as B- and T cell proliferation, however, mainly with very high doses. Suppression of α and β interferons has been suggested in animal models with unclear conclusions on ramifications of virus susceptibility.[25] THC activation of CB2 receptors has shown downstream effects resulting in impaired bactericidal and fungicidal activity of alveolar macrophages harvested from bronchoalveolar lavage (BAL) of heavy marijuana smokers,[26] suggesting the possibility of greater susceptibility to respiratory infections.
Concern has also been raised for direct pulmonary inoculation from marijuana cigarettes contaminated by fungal spores or bacteria due to the lack of quality control. A study from the 1980's found that 11/12 marijuana cigarette samples contained Aspergillus organisms and that 11/21 smokers had positive Aspergillus precipitins compared with 1/10 controls (p < 0.03).[27] Although there have been case reports in which the authors concluded that marijuana cigarettes were implicated in fungal infections such as aspergillosis in immunocompromised patients,[28] no available studies have robustly proven or disproven this concern. A Centers for Disease Control and Prevention-sponsored review of health insurance claims from 2016 sought to ascertain an association between the prevalence of fungal infection diagnosis codes and marijuana use and concluded that persons who used cannabis were 3.5 (95% confidence interval [CI]: 2.6–4.8) times more likely than never users to have a fungal infection. However, this study had significant limitations including reliance on proper coding, inability to distinguish the mode of delivery (including ingestion), and inability to determine the degree of immunosuppression.[29]
Alveolar macrophages harvested by BAL from habitual marijuana smokers have demonstrated impaired production of proinflammatory cytokines (TNF-a, IL-6, and GM-CSF) after lipopolysaccharide stimulation,[24] a finding that implies a possible protective effect against inflammation-driven lung tissue injury from marijuana smoke, as well as against a hyperimmune response to infection. In a retrospective cohort study of 1,831 patients with severe COVID-19 pneumonia, active cannabis users had lower levels of inflammatory markers on admission, lower intensive care unit admission rates, and less need for mechanical ventilation, although there was no difference in overall survival.[30]
The above-noted BAL findings also imply an impairment in the lung's defense against pulmonary infection that has been illustrated by in vitro evidence of the reduced ability of alveolar macrophages derived from habitual marijuana smokers to phagocytose and kill Staphylococcus aureus.[24] However, evidence of a direct link between marijuana smoking and community-acquired pneumonia is lacking.[31]
[32] While Lorenz et al reported an association between marijuana use and opportunistic pneumonia (Pneumocystis jirovecii) in human immunodeficiency virus (HIV) seropositive patients,[32] no association of community-acquired pneumonia was observed in a larger sample of HIV seronegative subjects derived from the same cohort.[31]
Given the widespread use of cannabis in cancer patients, a relevant question is whether these same immunomodulatory effects of cannabis can reduce the efficacy of immunotherapy. A murine tumor model was used to examine the interaction between THC and an immune checkpoint inhibitor (pembrolizumab). Survival was not affected, suggesting that THC did not have deleterious effects on anti-PD-1 antibody therapy. Examination of 201 patients with nonsmall cell lung cancer (NSCLC) on pembrolizumab monotherapy, using multivariate analyses, did not identify cannabis use as an independent predictor for mortality.[33]
Long-Term Effects of Regular Marijuana Smoking on Respiratory Symptoms
Long-Term Effects of Regular Marijuana Smoking on Respiratory Symptoms
Several studies have examined the association of marijuana smoking with chronic respiratory symptoms in comparison with nonusers of marijuana after adjustment for concomitant tobacco smoking in dual users[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41] ([Table 1]). The majority of these studies demonstrated a statistically significant increase in chronic cough, sputum production, and wheeze compared with controls, although three studies did not.[35]
[40]
[42] While in the study of Wenger et al[40] marijuana smoking was associated with an increase in these symptoms of chronic bronchitis, the difference from nonsmoking controls did not reach statistical significance. In contrast to the general association of marijuana smoking with chronic bronchitis symptoms, no increase in self-reported dyspnea in marijuana smokers compared with nonusers was found in most of the studies in which this symptom was evaluated,[35]
[36]
[37]
[38]
[39]
[40]
[42] although two groups reported an increase in dyspnea.[34]
[41] The finding of symptoms of chronic bronchitis in association with marijuana smoking is consistent with the parallel finding of histopathologic evidence of goblet cell hyperplasia and loss of ciliated epithelium in the bronchial epithelium of marijuana-only smokers (MS) who underwent bronchoscopy as part of a cohort study of smokers of marijuana with and without tobacco and nonsmoking control subjects.[43] The increased burden of mucus secreted by hyperplastic mucus-secreting surface epithelial cells in conjunction with the loss of ciliated epithelium would be expected to result in increased cough and phlegm as a mechanism to cleanse the airways of excess mucus in the absence of an effective mucociliary escalator.
Table 1
Associations of regular marijuana (MJ) smoking with chronic respiratory symptoms compared with nonsmokers of any substance or with smokers of both MJ and tobacco (T) controlling for concomitant tobacco smokers
|
Author
|
Total
|
Age (y)
|
MJ use amount
|
Cough
|
Sputum
|
Wheeze
|
Shortness of breath
|
|
Bloom et al 1987[38]
|
990
|
15–40
|
Mean 58.2 joints-years
|
Numeric ↑
|
↑
|
↑
|
NS
|
|
Tashkin et al 1987[39]
|
446
|
25–49
|
Mean 54.4 joint-years
|
↑
|
↑
|
↑
|
NS
|
|
Sherrill et al 1991[64]
|
1,239
|
20–60
|
Not reported
|
↑[a]
|
↑[a]
|
↑[a]
|
NS
|
|
Taylor et al 2000[34]
|
943
|
21 (birth cohort
|
Mean 230 uses past year
|
↑
|
↑
|
↑
|
↑
|
|
Moore et al 2005[36]
|
6,728
|
20–59
|
Use on mean of 10.2 days past month (always with T)
|
↑
|
↑
|
↑
|
NS
|
|
Aldington et al 2007[52]
|
339
|
25–75
|
Mean 54.2 joint-years
|
↑
|
↑
|
↑
|
NR
|
|
Tan et al 2009[35]
|
878
|
Mean 54.3 (no COPD) to 65.4 (COPD)
|
Lifetime median no. of joints: No COPD (n = 708): 80.5; COPD (n = 148): 208
|
No significant increase in symptoms consistent with COPD
|
|
MacLeod et al 2015[37]
|
500
|
Mean 36.5–38 (MJ/T) to 43–47 (T only)
|
Mean 53.2 (females) to 104.5 (males) joint-years
|
↑
|
↑
|
↑
|
NS
|
|
Hancox et al 2010[41]
|
933
|
36 (birth cohort)
|
99 frequent users[b]; 146 occasional users[c]
|
↑
|
↑
|
↑
|
↑
|
|
Morris et al 2018[42]
|
2,643
|
Mean 58.5–65.9
|
Mean 10.6 joint-years (former MJ) Mean 49 joint-years (current MJ)
|
NS
|
NS
|
↑ (former MJ); NS (current MJ)
|
NS
|
|
Wenger et al 2021[40]
|
300
|
48–60
|
Median (IQR) 42 (13–72) HIV+ Median (IQR) 14 (5–72) HIV-
|
NS
|
NS
|
NS
|
NS
|
Abbreviations: ↑, significant increase; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; IQR, interquartile range; joint-years, average number of marijuana joints smoked per day times the number of years marijuana was smoked; NS, no significant association; T, tobacco.
a The significant increase in cough and sputum was observed in each of the three follow-up surveys of this longitudinal study.
b Frequent = ≥52 times in previous year (weekly).
c Occasional = 1 to 51 occasions previous year.
Source: Modified from [Table 1] in Tashkin and Tan.[93]
Short-Term Effects of Marijuana Smoking, Aerosol Inhalation of Delta-9 Tetrahydrocannabinol, and Oral Ingestion of Tetrahydrocannabinol and Other Cannabinoids on Lung Function
Short-Term Effects of Marijuana Smoking, Aerosol Inhalation of Delta-9 Tetrahydrocannabinol, and Oral Ingestion of Tetrahydrocannabinol and Other Cannabinoids on Lung Function
Earlier studies have shown that marijuana smoking produced modest, but significant, short-term bronchodilation in healthy persons,[8]
[44] as well as in persons with asthma.[7] The attribution of this bronchodilator effect to delta-9 THC was validated by the absence of a bronchodilator effect when cannabinoids were extracted from marijuana with ethanol to produce a “placebo” marijuana joint, in contrast to the restoration of a bronchodilator effect when placebo marijuana was spiked with delta-9 THC and then smoked. Similar results have been demonstrated with aerosolized delta-9 THC from a nebulizer[45] or a metered-dose inhaler.[46] In contrast to the bronchodilator effect of marijuana, smoking tobacco has been shown to produce modest, but significant, acute, vagally mediated bronchoconstriction.[47] Marijuana smoking has also been shown to inhibit experimentally induced bronchoconstriction in asthmatic subjects.[48]
Oral delta-9 THC has also been shown to produce bronchodilation, but the magnitude of the bronchodilator effect and time of onset (1 hour) and duration (4–6 hours)[7] after ingestion differs from the greater magnitude, time of onset (immediately after smoking), and shorter duration (approximately 2 hours) observed after smoking marijuana.[8] Oral delta-8 THC, a less potent CB1 agonist than delta-9 THC, produced a lesser degree of acute bronchodilation, whereas other oral cannabinoids, including CBD and cannabinol (CBN), had no demonstrable bronchodilator action.[49] The acute bronchodilator effect of marijuana appears to be caused by inhibition of the release of acetylcholine by efferent vagal nerve endings adjacent to bronchial smooth muscle mediated by peripheral prejunctional CB-1 receptors.[50] The clinical significance of these findings is unclear, although it is possible that the acute bronchodilator effect of marijuana might make marijuana smoke more tolerable to asthmatics than tobacco smoke, which causes acute, transient bronchoconstriction.[47]
Long-Term Effects of Marijuana Smoking on Lung Function
Long-Term Effects of Marijuana Smoking on Lung Function
Given the qualitative similarity between the smoke contents of marijuana and those of tobacco,[19]
[51] several observational studies in cohorts or convenience samples of smokers of marijuana and/or tobacco as well as control nonsmokers (NS) of either substance have explored the possibility that habitual smoking of marijuana might contribute to long-term impairment in lung function, analogous to the well-known deleterious effects of regular tobacco smoking on the lung ([Table 2]). Of these, several cross-sectional studies of convenience samples or population-based cohorts have uniformly failed to find any statistically significant decrement in forced expiratory volume in 1 second (FEV1) in regular marijuana smokers in comparison with nonsmoking controls when examined in MS or dual smokers of marijuana and tobacco with adjustment for the effect of tobacco,[38]
[39]
[41]
[42]
[52]
[53]
[54]
[55]
[56] but several have reported an increase in forced vital capacity (FVC) in marijuana smokers,[42]
[53]
[54] while one study of persons living with HIV (PLWH) and HIV-negative controls found a significant increase in FVC only in PLWH.[56] Such increases in FVC have been thought to account for the decrease in the FEV1/FVC ratio, found by several authors,[34]
[36]
[38]
[53]
[54] presumably a spurious indicator of airflow obstruction due to a denominator effect of the elevated FVC, while several other groups have reported no significant reduction in the FEV1/FVC ratio.[35]
[39]
[41]
[42]
[55]
[56]
[57] The observed increases in FVC reported by some groups are believed to be analogous to the observations of increases in lung volumes in elite swimmers,[58] possibly related to the deep inhalations and lung breath-holding times during competitive swimming that is analogous to the increased inhaled volumes and prolonged breath-holding at end-inspiration characteristic of the smoking profile during smoking marijuana that is distinctly different from the smoking technique commonly used in smoking tobacco.[20] However, this potential explanation for the association of marijuana smoking with a “puzzling” increase in FVC has recently been disputed.[59]
Table 2
Lung function abnormality associated with regular marijuana use versus nonuse of marijuana controlled for concomitant tobacco smoking (cross-sectional studies)
|
Author
|
N
(total)
|
Age, y
(range[a])
|
FEV1
|
FVC
|
FEV1/ FVC
|
FEF25–75%
|
TLC
|
FRC
|
RV
|
SGaw
|
DLCO
|
|
Tashkin et al 1980[94]
|
74
|
Mean 24.1
|
NS
|
NS
|
NS
|
NS
|
–
|
NS
|
–
|
↓
|
–
|
|
Tilles et al 1986[95]
|
83
|
Mean 28.5
|
|
|
|
|
|
|
|
|
NS[b]
|
|
Bloom et al 1987[38]
|
990
|
15–40
|
NS
|
–
|
↓
|
–
|
–
|
–
|
–
|
–
|
–
|
|
Tashkin et al 1987[39]
|
446
|
25–59
|
NS
|
NS
|
NS
|
NS
|
NS
|
NS
|
NS
|
↓
|
NS
|
|
Taylor et al 2000[34]
|
943
|
21 years (birth cohort)
|
–
|
–
|
↓
|
–
|
–
|
–
|
–
|
–
|
–
|
|
Moore et al 2005[36]
|
6,728
|
20–59
|
–
|
–
|
↓
|
–
|
–
|
–
|
–
|
–
|
–
|
|
Aldington et al 2007[52]
|
339
|
25–75
|
NS
|
–
|
NS
|
NS
|
NS
|
NS
|
NS
|
↓
|
NS
|
|
Hancox et al 2010[41]
|
967
|
32 years
(birth cohort)
|
NS
|
Trend to↑
|
NS
|
–
|
↑
|
↑
|
↑
|
↓
|
NS
|
|
Tan et al 2009[35]
|
856
|
Mean 54.3 (COPD); 65.4 (no COPD)
|
–
|
–
|
NS
|
–
|
–
|
–
|
–
|
–
|
–
|
|
Kempker et al 2015[54]
|
7,716
|
18–59
|
NS
|
↑
|
↓
|
–
|
–
|
–
|
–
|
–
|
–
|
|
Papatheodorou et al
2016[56]
|
10,327
|
18–≥50
|
NS
|
↑
|
↓
|
NS
|
–
|
–
|
–
|
–
|
–
|
|
Morris et al 2018[42]
|
2,641
(all COPD)
|
Mean 58.5–65.9
|
Trend to ↑ (p < 0.06)
|
↑ (ex-
MS)
|
NS
|
–
|
–
|
–
|
–
|
–
|
–
|
|
Wenger et al 2021[40]
|
300[c]
|
Mean 55–56
|
NS
|
↑PLWH
NSw/oHIV
|
NS
|
–
|
NS
|
–
|
NS
|
–
|
↓PLWH NSw/oH
|
|
Hancox et al 2022[53]
|
839–881
|
45 y (birth cohort)
|
NS
|
Trend to ↑
|
↓
|
↓
|
↑
|
↑
|
↑
|
↓
|
↓
|
|
Najman et al 2023[55]
|
2,601
|
21 and 30 (birth cohort)
|
NS
|
NS
|
NS
|
–
|
–
|
–
|
–
|
–
|
–
|
Abbreviations: ↑, significant increase attributed to marijuana adjusted for tobacco use; ↓, significant decrease attributed to marijuana adjusted for tobacco use; –, not studied or results unclear; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; FEF25-75%, forced expiratory flow between 25% and 75% of vital capacity; TLC, total lung capacity; FRC, functional residual volume; RV, residual volume. MS, marijuana smoker; NS, no significant effect of marijuana; SGaw, long-term effect of marijuana smoking on specific airway.
a Range (unless otherwise stated).
b NS for comparison of heavy marijuana-only smokers with nonsmoking controls.
c
N = 162 persons living with HIV (PLWH); N = 138 persons without HIV (w/oH).
Sources: Modified from [Table 1] and [Table 2] Tashkin and Tan.[93]
Moreover, seven longitudinal studies with follow-up times of 5 to 27 years in cohorts or convenience samples of marijuana only and/or dual smokers of marijuana and tobacco, as well as nonsmokers, have been conducted to examine the change in FEV1 over time in association with marijuana and/or tobacco use compared with nonusers of either substance, controlling for the effect of tobacco among the dual users of marijuana and tobacco ([Table 3]). In all of these studies, tobacco use was associated with a significant decline in FEV1 compared with nonsmokers.[41]
[53]
[60]
[61]
[62] In contrast, in four of these seven studies, no significant decline in FEV1 was observed in marijuana smokers.[41]
[53]
[60]
[61]
[62]
[63] In one additional study, a significant decline in FEV1 was observed in former but not current marijuana smokers.[64] In two other studies a significant decline in marijuana smokers was observed only in those marijuana users with a cumulative lifetime history of more than 20 joint-years[65]
[66] (1 joint-year equals an average of one joint per day times the number of years regularly smoked). One of the latter studies, which followed middle-aged and older adults, reported that marijuana smokers (most of whom also smoked tobacco) experienced a decline in FEV1 that was even greater than that of tobacco smokers after adjustment for the alternative substance.[66] However, in contrast to the latter findings, which have been criticized for limitations in design and analysis,[67]
[68] another longitudinal cohort study that also was comprised of older persons failed to find any impact of marijuana on FEV1 decline over several years of observation.[60] This disparity regarding the long-term impact of marijuana on lung function in older persons underscores the need for additional study.
Table 3
Change in FEV1 over time associated with marijuana use[a] and tobacco use (longitudinal studies)
|
Author
|
N
|
Follow-up time interval
|
Marijuana (MS)
|
Tobacco (TS)
|
|
Sherrill et al 1991[64]
|
856
|
Up to 5 y
|
Significant decline in former but not current MS
|
Significant decline in current TS
|
|
Tashkin et al 1997[62]
|
394
|
Up to 8 y
|
No significant decline in MS
|
Significant decline in TS
|
|
Hancox et al 2010[41]
|
779
|
14 y
|
No significant decline in MS
|
Significant decline in TS
|
|
Pletcher et al 2012[65]
|
5,016
|
20 y
|
Borderline significant decline in MS with >10 joint-years (p = 0.079)
Significant decline in MS with >20 joint-years (p = 0.017)
|
Significant decline in TS with >1 pack-year
|
|
Tan et al 2019[66]
|
1,285
|
3 y
|
No significant decline in MS with 1–5 or >5 to 20 joint-years
Significant decline in MS with >20 joint-years—OR 2.45 (95% CI: 1.55 to 3.88)
|
Significant decline in TS with >5 pack-years
|
|
Hancox et al 2022[53]
|
871
|
27 y (age 18 to age 45 y)
|
No significant decline in MS
|
Significant decline in TS
|
|
Barjaktarevic et al 2022[60]
|
1,803
|
4.2 (2.2 SD) y
|
No significant decline in either current or former MS, including those with >20 joint-years
|
Significant decline in TS with ≥20 pack-years
|
Abbreviations: CI, confidence interval; joint-years, average number of marijuana joints smoked per day times the number of years marijuana was smoked; FEV1, forced expiratory volume in 1 second; MS, marijuana smokers; OR, odds ration; TS, tobacco smokers.
a All analyses in MS were adjusted for concomitant tobacco smoking in pack-years.
Sources: Modified from [Table 1] and [Table 3] in Tashkin and Tan.[93]
All four studies that examined the long-term effect of marijuana smoking on specific airway (SGaw) conductance demonstrated a modest, but statistically significant reduction in (SGaw), averaging around 25%, a degree of change that may not be clinically meaningful.[39]
[41]
[53]
[57] SGaw is believed to reflect airflow obstruction mainly in large airways, consistent with bronchoscopic findings of mucosal edema and vascular congestion in central airways that narrow their lumen.[69]
Few studies have focused on the possible association of marijuana smoking with measures of lung function sensitive to abnormalities in smaller airways. Of five such studies, two reported no association of marijuana with an abnormal FEF25–75%,[39]
[52]
[56] but a more recent study observed a significant decrease in FEF25–75% in association with marijuana,[53] and another paper from the same cohort reported findings from oscillometry indicating an increase in peripheral airway resistance and reactance associated with marijuana use.[70] Again, disparities in these findings argue for additional research regarding the long-term impact of marijuana smoking on lung function, especially among heavy habitual smokers with >20 joint-years of use.
Similarly, measurements of the diffusing capacity of the lung for carbon dioxide (DLCO) have been conducted in only a handful of studies. While four of these studies showed no significant reduction in DLCO in relation to marijuana smoking,[39]
[41]
[52] one recent study has shown a modest, but statistically significant, marijuana-associated reduction in DLCO both with and without adjustment of alveolar volume (VA),[53] while another study found a reduction in DLCO in PLWH, but not in HIV-negative subjects.[56] The finding in PLWH in the latter study could be attributed to the increased susceptibility of persons with HIV to develop chronic obstructive pulmonary disease (COPD) independent of cigarette smoking status.[71] Since DLCO is a sensitive, albeit nonspecific, indicator of emphysema, it is noteworthy that no evidence of macroscopic emphysema in relation to marijuana has been noted on high-resolution computed tomography (HRCT) in a convenience sample of adults from New Zealand[52] or in a study of PLWH in which data were adjusted for tobacco pack-years and marijuana joint-years in analyzing the possible association of marijuana or tobacco, respectively, with the presence of emphysema.[56]
Effects of Marijuana on the Lung Structure Assessed by High-Resolution Computed Tomography
Effects of Marijuana on the Lung Structure Assessed by High-Resolution Computed Tomography
As already noted, two studies failed to find increased evidence of emphysema on HRCT in relation to marijuana smoking.[52]
[56] In a more recent study of older ever-smokers with a history of ≥20 pack-years of tobacco use and evidence of COPD who participated in the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS), both current and former marijuana smoking participants were found to have a significantly lower extent of emphysema on HRCT than nonmarijuana smoking subjects after adjustment for age, height, gender, race and pack-years of tobacco.[42] Moreover, marijuana smoking was not found to be associated with the progression of emphysema in a longitudinal analysis of the latter cohort.[60] Recently, Murtha et al[72] reported the results of a retrospective case-control study of HRCT examinations in age- and sex-matched marijuana smokers (n = 56), control NS (n = 57), and tobacco-only smokers (TS; n = 33) among whom they found that rates of bronchial wall thickening, bronchiectasis and mucoid impaction, as well as rates of emphysema, were significantly higher in the marijuana than age-matched TS (p = 0.006–0.009). Furthermore, the authors also found a significant difference in the paraseptal predominant pattern of emphysema in the marijuana group compared with the tobacco-only group (p = 0.01). However, the authors' interpretation of their results was flawed by the failure to account for the fact that only 6 of the 56 marijuana smokers on whom their analysis was based smoked only marijuana, while the vast majority (50 of 56) also smoked tobacco, suggesting that their findings might very well be due to the impact of tobacco among their dual smokers. Consequently, a larger population of marijuana smokers is required with adjustment for relevant covariates, especially concomitant tobacco use, to determine whether marijuana smoking itself is associated with abnormalities in the lung structure on HRCT.
Association of Habitual Marijuana Smoking with Bullous Lung Disease, Pneumothorax, and Pneumomediastinum
Association of Habitual Marijuana Smoking with Bullous Lung Disease, Pneumothorax, and Pneumomediastinum
Several isolated cases and case series of pneumothorax, pneumomediastinum, pneumopericardium, and subcutaneous emphysema have been reported in association with marijuana smoking over the past several decades.[73]
[74]
[75]
[76]
[77]
[78] It has been suggested that the technique of deep inhalation followed by prolonged breath-holding commonly used during the smoking of marijuana, especially if it is associated with a Valsalva or Mueller maneuver, might predispose to alveolar rupture and leakage of air into the pleural or mediastinal space. In addition, individual cases and case series of large lung bullae have been reported in marijuana smokers.[79]
[80]
[81] However, a causal relationship between marijuana use and lung bullae cannot be established based on case series alone since the prevalence of bullous lung disease in the general population is unknown.[82]
Independent Association of Marijuana with Visual and Microscopic Evidence of Lower Airway Injury
Independent Association of Marijuana with Visual and Microscopic Evidence of Lower Airway Injury
Video bronchoscopy performed on 10 MS, 10 TS, 10 combined marijuana and tobacco smokers (MTS), and 10 control NS revealed similar degrees of central bronchial mucosal edema and vascular congestion (with narrowing of the airway lumen) and of increased mucoid secretions in MS, TS, and MTS compared with the NS group, suggesting an independent effect of marijuana on bronchial mucosal inflammation and injury.[69] This conclusion was supported by central airway mucosal biopsies from all these same subjects, which showed vascular hyperplasia and ectasia, submucosal edema, mononuclear cell infiltrates, and goblet cell hyperplasia in the smoking groups that correlated with the visual findings. Moreover, these findings might help explain the underlying cause of the chronic cough and sputum production that has been consistently documented in association with habitual marijuana smoking.
Association of Marijuana Smoking and Lung Cancer
Association of Marijuana Smoking and Lung Cancer
The data on lung cancer risk and smoked marijuana remain sparse. A clear link to causality for lung cancer or head and neck cancer has not been established, although there remains significant suspicion for risk given procarcinogenic components in the inhaled smoke. Moreover, bronchial biopsies from MS and TS, in contrast to those from healthy nonsmoking controls, have shown similar histopathologic abnormalities, including squamous metaplasia, cellular atypia, and increased nuclear cytoplasmic ratio that have long been thought to be precursors to the subsequent development of lung cancer.[42]
In total, 2,159 lung cancer cases and 2,985 controls were pooled from six case-control studies within the International Lung Cancer Consortium, and the association between lung cancer and marijuana smoking was studied using logistic regression adjusting for tobacco smoking and other variables. The odds ratio was 0.94 (95% CI: 0.67–1.32) for those with at least 10 joint-years compared with habitual or never-users and 1.74 (95%CI: 0.85–3.55) for adenocarcinoma cases.[83] Individually, five of these six studies failed to find any significant association of marijuana use with lung cancer. In contrast, one of the six studies that was conducted on adults ≤55 years of age in New Zealand (where there is a high prevalence of lung cancer especially in the Maori population), using interviewer-administered questionnaires for risk factors and logistic regression, concluded that the relative risk for lung cancer increased 8% for each joint-year of marijuana smoking after adjustment for cigarette smoking.[56] Although marijuana use was not significantly associated with lung cancer in lesser smokers, those with ≥10.5 joint-years of exposure had a significantly increased risk (risk ratio 5.7 [95%CI: 1.5–21.6]) after adjustment for age, sex, ethnicity, pack-years of cigarette smoking, and a family history of lung cancer. However, these findings were seriously limited by the small number of cases with >10.5 joint-years (n = 14) and an even smaller number of controls (n = 4), suggesting imprecise and probably inflated estimates of risk.
A Swedish population-based cohort study followed 49,321 men over 40 years for lung cancer outcomes. “Heavy” use (lifetime use over 50 times) using Cox regression analysis was associated with more than a twofold risk (hazard ratio: 2.12, 95% CI: 1.08–4.14) of developing lung cancer after adjustment for baseline tobacco use and socioeconomic status.[84] However, this study was significantly flawed due to the lack of information on continuing marijuana smoking as well as continuing tobacco smoking during the 40-year follow-up period.
Betser et al conducted a retrospective analysis of all persons ≤50 years of age (n = 77) who underwent surgical resection of NSCLC at three university hospitals in France between 2018 and 2020 and retrospectively obtained detailed information from these patients (by phone interview or contact with their physician) concerning their marijuana and/or tobacco smoking behavior (starting age, quantity, frequency and duration of use) prior to their surgery for NSCLC.[85] In univariate analysis, the authors found that dual smokers of both MTS (n = 33) compared with TS (n = 26), despite having accumulated a similar number of pack-years of tobacco, were of younger age, predominantly male, and had a significantly higher percentage of large cell carcinomas that were more often located in an upper lobe and were of larger size requiring more extensive resection, although no significant difference in the overall incidence of lung cancer between MTS and TS was found. The authors concluded that the co-use of marijuana and tobacco may lead to more severe and advanced forms of lung cancer in young men. However, their study was limited by the small number of patients and the authors' inability to adjust for potential confounders. Also of interest is that the proportion of marijuana users in this NSCLC population appeared to be larger than that reported in surveys of the general population, although it is possible that this difference might be attributable to more truthful reporting in the context of a life-threatening smoking-related disease in focused postoperative interviews compared with general population surveys. This finding is in fact similar to a much older report that found a disproportionately higher percentage of young lung cancer patients with a self-reported history of marijuana use in comparison with the proportion of self-reported marijuana users in the general population.[86] Similar findings have been reported for young patients with head and neck cancer. Additional studies are warranted to examine whether marijuana smoking is an independent risk factor for the development of lung cancer, particularly including large cell carcinoma, a rare form of lung cancer, and particularly in young to middle-aged smokers who are co-users of both tobacco and marijuana. As of now, lung cancer screening criteria[87] do not include guidelines for those who smoke marijuana heavily. More studies are necessary to determine how these other suspected risk factors can be incorporated into preventative care.
Pulmonary Effects of Vaping Marijuana
Pulmonary Effects of Vaping Marijuana
Marijuana e-cigarettes in particular have been associated with cases of acute lung injury (EVALI) which peaked in September 2019. THC products that contained vitamin E acetate, a thickener that increases the miscibility of the oily product of cannabinoids, were heavily implicated as this compound was identified in BAL samples of affected patients.[88] Histopathologic findings in lung biopsies from 17 patients clinically suspected to have EVALI, all of whom had a history of vaping, mainly with cannabis oils, were consistent with patterns of airway-centered acute lung injury with diffuse alveolar damage, acute pneumonitis, or organizing pneumonia, accompanied by bronchiolitis.[89] There were over 2,800 hospitalizations of patients with EVALI in the United States and 68 confirmed deaths ranging in ages 15 to 75 from EVALI as of February 2020.[90]
In an online school-based prospective survey of e-cigarette use over 4 years compared with nonuse conducted in 2,097 participants in the Southern California Children's Health Study, self-reported e-cigarette use was associated with increased wheeze and dyspnea adjusting for age, sex, concurrent cigarette use, and lifetime asthma diagnosis.[91] Unfortunately, however, the long-term effects of vaping are otherwise not well documented.
Future Directions
Studies of pulmonary consequences of marijuana have been significantly limited compared with those of tobacco smoking in the past. This is due in large part to marijuana's federal illegality and its placement in Schedule I of the Controlled Substances Act of 1970, which landed marijuana in the same category as other drugs including heroin and lysergic acid diethylamide which are defined as having “no currently accepted medical use and a high potential for abuse.” This has resulted in a half-century of limitations on federal marijuana research.[92] Only recently are such restrictions being discarded with the current administration's reassessment of research at the executive level with the DEA since 2021, and more recently, with the passage in 2022 of President Biden's bipartisan Medical Marijuana and Cannabidiol Research Expansion Act.[92] Other factors significantly limiting currently available data are heavy reliance on self-reporting of uncertain accuracy and confounding of data due to concurrent tobacco use. As marijuana use is rising with more widespread legalization of recreational use, it is even more critical to understand the pulmonary consequences of both short- and long-term use in all inhaled forms. In the forefront, further research is required to better characterize long-term risks of marijuana for airway and pulmonary parenchymal damage, immune dysfunction, infectious complications, and lung cancer. Future studies relating to long-term effects on the lung will need to obtain a lifetime history of the quantity of marijuana use (since long-term effects of the cumulative lifetime use appear to be dose dependent), in addition to both taking into account the mode of inhalation (in particular smoking and/or vaping) and adjusting for the amount of concomitant inhalation of other potential confounders, primarily tobacco. The scope of this article does not address potential nonpulmonary consequences (cognitive, behavioral, etc.) of marijuana. Marijuana, however, has not always been completely vilified and, although not evidence-based, it has been used therapeutically by the general public for mood disorders, insomnia, nausea, anorexia, and chronic pain, in addition to the very limited FDA-approved indications previously mentioned in this review. Clinical extrapolation of the theoretical benefits of its immunomodulatory effects has been suggested in small studies during the COVID-19 pandemic. Further research is key to determine any potential therapeutic role particularly in this and other acute pulmonary infectious disorders, in chronic inflammatory conditions, and for symptom palliation.
