Marijuana and the lung: hysteria or cause for concern?

Cannabis is the most widely used illicit substance, and the second most widely smoked, in the world. Cannabis refers to products of the cannabis plant including marijuana (the flowers and tops of the plant; bud) and the resin (hash). Other terms in common use include “weed”, “dope”, “grass”, “hemp”, “ganga”, “reefer”, “spliff”, “toke” and “blunt”.

Although alcohol, caffeine and tobacco indulgence are more widespread, illicit recreational drug use polarises opinion more. Cannabis is seen as harmless on the one hand and as a gateway to hard drug use on the other. Dependence is associated with cannabis use disorder which is increasing in prevalence. Cannabis as a public health issue has risen up the political agenda. With an aim to disrupt an illicit industry funding organised crime, Canada began regulating tetrahydrocannabinol (THC) content in July 2018 in an attempt to improve safety and protect the young. Not surprisingly, there are vocal critics and cries for much more research [1].

As healthcare professionals, we deal with tobacco all the time but we also need to know about the respiratory effects of marijuana to be able to advise our patients and colleagues. This brief review aims to summarise what is known and how concerned we should be, particularly with regards to the lungs.

The cannabis genus includes three species: Cannabis sativa, Cannabis indica and Cannabis ruderalis. Each species contains varying concentrations of the two major psychoactive compounds: delta-9-THC and cannabidiol [2]. The concentrations of psychoactive compounds in recreational marijuana also vary over time, with concentrations higher now than they were 50 years ago due to selective breeding. Positive psychoactive effects of cannabis include euphoria and relaxation [3]. However, negative psychological side-effects range from anxiety to psychosis [3]. Commonly available high potency cannabis, dubbed skunk (based on its distinct smell), is associated with a high risk of psychosis due to its high concentration of delta-9-THC [2, 3].

Pharmacology

The high number of cannabinoids recognised (perhaps over 90) means that cannabis pharmacology is necessarily complex; and a full discussion is not warranted here.

Traditional CB1 receptors, belonging to the G-protein coupled family, were identified in 1988 and cloned in 1990. The concept of an endogenous cannabinoid system was developed after the discovery of an endogenous arachidonic acid metabolite ligand (N-arachidonylethanolamide (anadamide) and subsequently a much more selective agonist 2-arachidonylglycerol). delta-9-THC and synthetic derivatives are CB1 agonists. The CB2 receptor subtype was originally described in differentiated myeloid cells and shows 44% amino acid homology with CB1 but a distinct, though similar, binding profile. Five classes of cannabinoid compounds show activity at CB1 and CB2 receptors with minor selectivity for the agonists delta-9-THC and cannabidiol but major selectivity (>1000-fold) and nanomolar affinity shown by antagonists [4]. Other cannabinoid receptor subtypes have been postulated but not confirmed [5].

Cannabis use is increasing

Recent data from the 2016 Crime Survey for England and Wales on drug misuse suggest that around 2.1 million adults have used cannabis in the past year [6]. In addition, one-third of those surveyed thought it was acceptable for people of their own age to use cannabis occasionally. These figures are unsurprising given the global shift in attitudes towards cannabis and the growing number of countries relaxing legislation on both medical and recreational marijuana use (table 1).

Epidemiology

While we know that marijuana use is increasing, legality remains a major problem for epidemiological studies. In the UK, it is a class B drug meaning it is illegal for UK residents to possess cannabis in any form.

Cannabis can be smoked in a variety of ways, usually without a filter and burned at a higher temperature, and with users generally holding their breath for longer periods of time, compared to tobacco smokers [2]. Joints can be made using just cannabis leaves or can be mixed with tobacco in spliffs. Many cannabis users also concurrently smoke tobacco cigarettes. Routes of administration vary by geographical region as well, with European countries mostly smoking spliffs while the Americans largely smoke cannabis only joints [7]. Aside from joint smoking, users may also use water bongs, pipes and, more recently, vaporisers [7, 8].

It follows that the long-term health effects of marijuana smoking are less understood compared to traditional cigarette smoking.

Chronic respiratory effects

Tobacco smoking is well known to increase the risk of chronic bronchitis, emphysema and small airways disease (all components of chronic obstructive pulmonary disease; COPD), as well as the development of various forms of lung cancer. It might be expected that chronic cannabis smoking would have similar sequelae considering that the contents and properties of tobacco and cannabis smoke are similar [2]. However, observational studies tell a different story.

Symptoms

Respiratory symptoms such as cough, sputum production and wheeze are increased in current cannabis users [2, 9, 10]. Importantly, associations with shortness of breath were not found in larger studies [9, 10]. This suggests that cannabis smoke causes chronic bronchitis in current smokers but not shortness of breath or irreversible airway damage.

This is supported by studies examining the effect of quitting marijuana smoking. They show a significant reduction in morning cough, sputum production and wheeze compared to those who continue to smoke [2, 10]. Quitters also had no increased risk for developing chronic bronchitis compared with nonsmokers at follow-up 10 years later [2, 10].

Vaping cannabis is increasingly popular among young adults [8]. While we don't know the long-term respiratory health effects of e-cigarette use, for either tobacco or cannabis, it has been suggested that vaping may reduce the symptoms associated with smoking [8].

Lung function

COPD is conventionally diagnosed when a patient has an irreversible reduced forced expiratory volume in 1 s (FEV₁) compared with forced vital capacity (FVC) on spirometry. Several large, recently published observational studies (table 2) have reported that long-term marijuana only users have an increase in their FVC with little or no change in FEV₁, even after 20 joint-years of smoking (1 joint-year is equivalent to 365 joints per year) [2, 27, 29]. A reduced FEV₁/FVC ratio due to increased FVC clearly differs from the classical spirometric changes seen in tobacco smoking. The cause of this increase in FVC is unclear. Respiratory muscle training by the breath-holding techniques used during marijuana smoking has been proposed as a cause; however, there is little evidence that training can increase FVC [2, 30]. Additional lung function measurements have only been examined in smaller studies [2]. Very small changes in total lung capacity have been reported in several studies. Small effects on specific airways conductance and resistance have been interpreted as consistent with central airways inflammation. The transfer factor of the lung for carbon monoxide has been reported to be reduced only in smokers of cannabis and tobacco. Interestingly marijuana use within 0–4 days of lung function measurement showed a 13% reduction in exhaled nitrous oxide, though the clinical manifestation of this acute effect is unknown [29].

Acute airway effects of cannabis

Experimentally, the acute bronchodilator effect of inhaled cannabis is well described as an effect of THC [2]. However, since cannabinoids can have partial agonist, or even antagonist, effects little is known about differences in airway effects from different strains of cannabis containing varying concentrations of cannabinols.

We do not know why cannabis smoking does not produce COPD. Possible explanations include a persistent bronchodilator effect (offsetting airway narrowing) or anti-inflammatory or immunomodulatory effects of THC [2].

Bullous lung disease

Bullous lung disease, usually presenting with pneumothorax, is widely recognised as a possible consequence of marijuana smoking. However, while well-established anecdotally, there is actually a paucity of relevant data [2]. As of 2018, there have been seven case series and 11 case reports published. A total of only 57 individual cases were described. Concurrent tobacco smoking was recorded in all but four of the cases. Patient details are summarised in table 3. The majority were heavy marijuana users, up to 149 joint-years. Most of the cases had predominantly upper lobe involvement with added peripheral emphysema and most presented with pneumothorax, presumably due to rupture of a bulla. They are therefore not representative of the general marijuana smoking population. We have found only a single cross-sectional study (n=339) looking at radiological changes among marijuana smokers in New Zealand [23]. Interestingly they reported an increase in macroscopic emphysema in tobacco smokers compared with nonsmokers but not in cannabis only smokers. Low-density lung regions on high-resolution computed tomography in cannabis smokers were interpreted as hyperinflation rather than microscopic emphysema. This is in contrast to a case series of 10 patients which found asymmetrical bullous changes on CT among chronic marijuana smokers but with normal spirometry and chest radiographs [37]. A study looking at smoking status and the presence of emphysematous computed tomography changes of spontaneous pneumothorax patients found no difference in emphysema prevalence among tobacco smokers and tobacco plus cannabis smokers (there were no cannabis only smokers); however, concurrent smokers were significantly younger [49]. While the authors have suggested that cannabis added to tobacco leads to emphysema at a younger age, there are too many confounders such as the subject population, to come to a definitive conclusion.

Various mechanisms have been proposed to explain an observed association [2, 23]; the main one relating to breath-holding techniques employed during smoking, resembling a Valsalva manoeuvre. It is suggested that this could precipitate barotrauma increasing bulla formation and predisposing to pneumothorax. There is currently no direct evidence for this hypothesis.

It is possible that the lack of published data on bullous lung disease in marijuana smokers relates to its widespread recognition and familiarity. However, it is difficult to draw any firm conclusions on an association, its frequency, other epidemiological characteristics, mechanisms, etc. More studies, preferably prospective series, are required to gather epidemiological data. It falls to health professionals to recognise possible cognitive bias, and to fully investigate pneumothorax and bullous disease rather than simply relating it to drug history.

Lung cancer

The clear association of tobacco smoking and lung cancer and the similar carcinogens present in burning cannabis plant material have long raised the possibility of an association of marijuana use and lung cancer. Furthermore, premalignant changes in bronchial biopsies from marijuana smokers have been shown histologically [2]. However, as with chronic lung disease, there is currently little evidence of a definite link. A Swedish cohort study of almost 50 000 army conscripts reported a two-fold increased risk of lung cancer among marijuana smokers, compared with nonsmokers after 40 years. Unfortunately, and critically, smoking history was only assessed at the time of conscription and there was no data on smoking status before conscription or in the 40 years afterwards [50]. A pooled analysis of six case–control studies found no increased risk of cannabis compared to non-habitual smokers [51]. Other epidemiological studies investigating cancer risk suffered from methodological limitations including small sample sizes or short follow-up [2].

We do not know why cannabis smoking does not appear to be carcinogenic. Various factors might contribute, e.g. potential anti-inflammatory and anti-neoplastic properties of THC and other cannabinoids [52].

Pneumonia

Cannabis has been shown to have immunosuppressive effects on alveolar macrophages and to cause loss of ciliated bronchial epithelium [53]. An increased incidence of pneumonia in cannabis users might be expected. One cross-sectional study surveyed current marijuana users regarding a diagnosis of pneumonia within the previous 12 months and found no increased risk compared to nonsmokers [9]. Otherwise, we have found only isolated case series and studies on immunocompromised patients [53]. Such cases include invasive aspergillosis from spores which were found in contaminated leaves and Pseudomonas associated with bong smoking [54, 55].

Interstitial lung disease

Reports of cannabis-associated interstitial lung disease are few and far between. There are occasional reports of eosinophilic pneumonia (as with smoking generally) and a case of pneumoconiosis associated with talc-adulterated marijuana [52].

Medical use of cannabis

Medical use of cannabis by mouth/orally dates back to 2737 BC in China [56]. Raw herbal cannabis, cannabis oil extracts including products prepared in a pharmacy (magistral preparations), and cannabinoids are all used. There has been increasing recent interest with wide acceptance and authorisation of use of herbal preparations in many European countries and even more widespread authorisation of oral cannabinoid medications in most European countries and the USA and Canada (table 4). The most accepted indications include chronic pain, spasticity in multiple sclerosis, certain rare epilepsy syndromes, and chemotherapy-induced nausea and vomiting [57]. There has also been experimental evidence in the anti-neoplastic effect of cannabinoids [19], as well as in palliative care. It has been recommended in a large variety of other conditions and for improving sleep quality including in obstructive sleep apnoea, although with limited evidence [58].