Different studies have suggested a correlation between marijuana smoking and the development of bullous emphysema. Johnson et al. described four young males with significant marijuana exposure but low tobacco exposure who were affected by large lung bullae [10]. Hii et al. reported that in a series of 10 regular chronic marijuana smokers (more than one year, continuously), 4 had a pneumothorax, and high-resolution chest CT revealed asymmetrical, variably sized, emphysematous bullae in 9 of them [11]. Fiorelli et al. found lung emphysematous bullae in 8/13 (62%) habitual marijuana smokers [12]. Habitual marijuana smokers are defined as users of more than 100 marijuana cigarettes (joints) during their lifetime and at least one in the previous month [13]. Feldman et al. described a case with an apical lung bulla in a marijuana and tobacco smoker [14]. Rawlins et al. reported two marijuana users, male patients with bilateral giant lung bullae [15]. In a study by Douglass et al., of 525 diagnoses of a pneumothorax, 113 (21.5%) occurred as a result of drug abuse in 84 patients [16].

Moreover, other recent studies have underlined that: the combination of smoking cannabis and tobacco significantly increases the risk of having a PSP in young men compared to both those who have never smoked and daily tobacco smokers [17]; cannabis smokers develop more severe chronic respiratory symptoms and bullous lung disease than both tobacco smokers and non-smokers [18]; cannabis use is associated with PSP recurrence and the eventual need for operative intervention [19].

Furthermore, in our other study we identified, for the first time in the literature, the principal cannabinoids in the lungs of a group of young patients who underwent operations for a PSP and were former or current tobacco smokers with a history of cannabis consumption. Additionally, we compared these patients with a group of patients of the same mean age without a history of cannabis abuse who were surgically treated for a PSP, supporting a correlation between this disease and cannabis abuse [9].

Our finding of these drugs in lung tissue opened the way for the study of their pathogenic mechanisms.

A previous study by Beshay et al. [4] reported the largest case series of spontaneous pneumothorax in habitual marijuana smokers with upper-lobe severe bullous lung disease and therefore suggested considering cannabis abuse as a cause of emphysema in young patients.

However, the mechanism for bullae development in cannabis smokers is not well-known, and various hypotheses have been put forward: the direct action of toxic components in marijuana, prolonged breath holding producing high inspiratory pressure, and the activation of inflammatory cells triggering the loss of lung elastic recoil [9,12]. It should also be noted that in marijuana smokers, barotraumas with a consequent pneumothorax, pneumomediastinum, and subcutaneous emphysema may occur with deep inhalation involving breath holding or Valsalva maneuvers [9].

Nevertheless, while suggesting the responsibility of cannabis for the development of bullous lung disease in young subjects and the consequent risk of a pneumothorax, none of the aforementioned studies examined the presence of cannabinoids in lung tissues and related pathologic findings of bullous emphysema. Thus, our research was innovative, investigating this correlation for the first time.

In our study, we described 21 male patients who underwent operations for a PSP and had a history of cannabis smoking (in 19/21 cases, this was associated with tobacco smoking).

Cannabinoids were detected in the lung tissue of about 67% of the patients, and bullous emphysema was present in 93%. Of the patients, 69% smoked one cannabis cigarette per day, and all were tobacco smokers too, showing that in young people even a single cannabis cigarette smoked per day seems to contribute to the development of bullous emphysema, especially if accompanied by tobacco smoking.

On the other hand, in most patients (86%) with lung tissue negative for cannabinoids, no bullous emphysema was found, and 50% of these patients smoked one cannabis cigarette per month and were tobacco smokers too, suggesting that smoking fewer cannabis cigarettes is related to a lower risk of developing bullous emphysema, even if accompanied by tobacco smoking.

The evaluation of the association between the presence of cannabinoids in resected lung tissue and the presence of bullous emphysema produced statistically significant results (p < 0.0009), thus supporting (although the prevalence of bullous emphysema in cannabis-only smokers is unknown [20]) the responsibility of cannabis for the development of bullous emphysema, as hypothesized in other studies [2,10,11,12,13,14,15,16]. However, the presence of cannabinoids in lung tissue was not determined in these studies.

The retention time of cannabinoids in lung tissue was calculated by considering the declared last instance of cannabis consumption. In 12/14 (86%) patients with lung tissue positive for cannabinoids, the last consumption of cannabis was <3 months before PSP onset, and in 2/14 (14%) it ranged from 3 to 12 months before PSP onset, while in 5/7 (71%) patients with lung tissue negative for cannabinoids, it varied from 1 to 3 years before PSP onset. This observation suggested that the maximum retention time of cannabinoids in lung tissue is about 1 year, while in the urine of chronic smokers, it can remain for about 77 days [21]. Regarding the other 2/7 (29%) patients negative for cannabinoids who reported that they had last consumed cannabis < 3 months prior to PSP onset, these were patients with psychiatric disorders, and so they may have not provided totally reliable historical data.

Although some patients had also used cocaine and heroin, these substances were not detected in the resected lung tissue, likely due to their more rapid elimination compared to cannabinoids.

Most of our patients were also tobacco smokers, but since emphysema usually develops at around 50–60 years in tobacco smokers, while bullous emphysema appeared at a younger age in the studied patients, we believe that cannabis has a decisive impact in its development, while tobacco smoking has a minor role at a younger age. Moreover, the fact that we identified patients who were negative for cannabinoids in the lung tissue and did not present bullous emphysema but smoked 5 to 50 tobacco cigarettes per day supported the responsibility of cannabis for the development of bullous emphysema in these young patients. The study by Bense et al. supports our thesis, reporting that, in 27 chronic tobacco smokers with a previous spontaneous pneumothorax, chest CT revealed the absence of bullous emphysema in all, the presence of areas of focal emphysema in 22 (81%), and the absence of emphysema in 10 non-smoking control subjects [22]. Moreover, in our patients, other diseases characterized by the presence of bullous emphysema, such as Marfan syndrome, Ehlers–Danlos syndrome, HIV infection, and the intravenous use of illicit drugs, were absent. Furthermore, as all patients in our study were young and healthy, only five of them underwent a blood test to detect the values of the alpha-1-antitrypsin enzyme, which turned out to be normal.

In reference, then, to the rupture of bullae, we believe that this is favored not only by the deep inhalation used by cannabis smokers [23,24] who, in order to increase the absorption surface of the airways, practice the Valsalva maneuver [16,24,25,26], but also by the inflammatory process, evidence of which we found during the histological examination of the operative specimens. In fact, pleural-interstitial fibrosis, non-specific chronic inflammation, and DIP-like reactions were detected in the majority of patients with lung tissue positive for cannabinoids.

Hartman [27] and Carrington [28] suggested the responsibility of marijuana for the genesis of desquamative interstitial pneumonia (DIP); in some of our patients (7/14 cannabinoid-positive and 2/7 cannabinoid-negative patients), a DIP-like reaction was detected in the lung tissue. Thus, in our study, the role of cannabis smoking in causing DIP-type lung lesions was supported by not only the age of our patients (ranging from 18 to 51 years, while for DIP induced by other causes, the age usually ranges from 40 to 60 years [29]) but also the finding of a large number of macrophages within the alveoli. In fact, DIP-like reactions are characterized by the accumulation of many macrophages, presenting a light brown pigment, in the alveolar spaces.

When lung tissue is damaged by the chronic irritative insult caused by tobacco and cannabis smoke, neutrophils and monocytes are activated, with the release of toxic factors, such as proteases, elastases, and collagenases. This chronic irritative stimulus could be an etiopathogenetic factor favoring the formation of emphysematous bullae. This process, as emerged in our study, could occur earlier in patients with cannabinoid-positive lung tissue. The endoalveolar presence of macrophages (DIP-like reactions), histiocytes, or foreign-body giant cells, indicative of a chronic inflammatory process, supports the role of cannabinoids in favoring the chronic non-specific inflammatory process with the secondary lysis of the interalveolar septa, which in turn become the sites of the chronic inflammatory process with interstitial fibrosis and the consequent formation of bullous emphysema. Therefore, in our study, the factor that differentiated cannabinoid-positive subjects from cannabinoid-negative ones, with all subjects being drug users, was the time of the development of bullous emphysema, and both groups presented the same pathogenetic mechanism, as was also suggested by Cagle et al. [30].

With reference, then, to concomitant tobacco smoke, Gong et al. report a study comparing subjects between 25 and 45 years of age (non-smokers, tobacco smokers, marijuana smokers, and tobacco and marijuana smokers) and concluded that habitual, heavy marijuana smokers had a high prevalence of abnormal airway appearance and histologic findings, irrespective of concomitant tobacco smoking; they also found that smoking 3–4 joints per day produced in the airways the same histological changes as smoking 20 tobacco cigarettes per day [31].

According to some authors [16], symptoms of a pneumothorax generally appear within 24 h from the consumption of illicit drugs, as we also observed in 7/14 (50%) of the cannabinoid-positive patients and in only 1/7 (14%) of the cannabinoid-negative patients. Therefore, considering their positivity for cannabinoids in the resected lung tissue, the pneumothorax with bullous emphysema we observed in these young patients was not considered of unknown cause (primary) but secondary to cannabis.

This study had some limitations: some of our patients declared the use of other illicit drugs, and their possible role and contribution to the development of bullous emphysema was not investigated; positivity for cannabinoids in the lung tissue was not correlated to the eventual presence of cannabinoids in the urine and/or blood, as this was not investigated in these patients; most of our patients were active tobacco smokers, which could have been a confounding or contributing factor in the pathologic findings of bullous emphysema; we encountered difficulties in recruiting patients, who were reluctant to provide informed consent for the toxicological examination of their lung tissue.