Key Points

QuestionÌý Is cannabis use associated with increased risk of head and neck cancer (HNC)?

FindingsÌý In this cohort study of 116 076 individuals, people with cannabis use disorder had an increased risk of any HNC, as well as oral, oropharyngeal, nasopharyngeal, salivary gland, and laryngeal cancer, compared with a group of matched individuals.

MeaningÌý The results of this study suggest that patients with cannabis-related disorder may be at an increased risk for HNC, and further studies are required to further explore the strength and potential mechanisms of this association.

ImportanceÌý Cannabis is the most commonly used illicit substance worldwide. Whether cannabis use is associated with head and neck cancer (HNC) is unclear.

ObjectiveÌý To assess the clinical association between cannabis use and HNC.

Design, Setting, and ParticipantsÌý This large multicenter cohort study used clinical records from a database that included 20 years of data (through April 2024) from 64 health care organizations. A database was searched for medical records for US adults with and without cannabis-related disorder who had recorded outpatient hospital clinic visits and no prior history of HNC. Propensity score matching was performed for demographic characteristics, alcohol-related disorders, and tobacco use. Subsequently, relative risks (RRs) were calculated to explore risk of HNC, including HNC subsites. This analysis was repeated among those younger than 60 years and 60 years or older.

ExposureÌý Cannabis-related disorder.

Main Outcomes and MeasuresÌý Diagnosis of HNC and any HNC subsite.

ResultsÌý The cannabis-related disorder cohort included 116 076 individuals (51 646 women [44.5%]) with a mean (SD) age of 46.4 (16.8) years. The non–cannabis-related disorder cohort included 3 985 286 individuals (2 173 684 women [54.5%]) with a mean (SD) age of 60.8 (20.6) years. The rate of new HNC diagnosis in all sites was higher in the cannabis-related disorder cohort. After matching (n = 115 865 per group), patients with cannabis-related disorder had a higher risk of any HNC (RR, 3.49; 95% CI, 2.78-4.39) than those without HNC. A site-specific analysis yielded that those with cannabis-related disorder had a higher risk of oral (RR, 2.51; 95% CI, 1.81-3.47), oropharyngeal (RR, 4.90; 95% CI, 2.99-8.02), and laryngeal (RR, 8.39; 95% CI, 4.72-14.90) cancer. Results were consistent when stratifying by older and younger age group.

Conclusions and RelevanceÌý This cohort study highlights an association between cannabis-related disorder and the development of HNC in adult patients. Given the limitations of the database, future research should examine the mechanism of this association and analyze dose response with strong controls to further support evidence of cannabis use as a risk factor for HNCs.

Head and neck cancer (HNC) is the sixth most frequent cancer type worldwide, with more than 870 000 new cases and 440 000 deaths in 2020.¹ In the US alone, HNC accounts for nearly 3% of all cancers and more than 1.5% of all cancer deaths.² HNCs include a diverse group of cancers from the mucosal epithelial linings of the upper aerodigestive tract, including the oral cavity, pharynx, and larynx, and adjacent salivary glands. Historically, HNC has been primarily associated with tobacco-derived carcinogens and/or excessive alcohol consumption,^3-5 although recent data have demonstrated a relative rise in human papillomavirus (HPV)–positive cancers.^6,7 With estimates demonstrating that many HNCs can be attributed to modifiable risk factors, it becomes even more paramount to detect and prevent these underlying risk factors to continue to decrease HNC prevalence.⁸

Tobacco consumption remains a primary risk factor for the development of HPV-negative HNCs. Tobacco contains numerous chemicals with carcinogenic potential, including polycyclic aromatic hydrocarbons and nitrosamines, which are some of the most well studied.^9,10 The reactive metabolites of these carcinogens can induce DNA damage and inflammatory responses that, if not properly dealt with, can promote neoplastic transformation.¹¹ The smoke content of cannabis contains carcinogens similar to those found in tobacco.¹² Furthermore, tetrahydrocannabinol, the major compound in cannabis, can activate the transcription of specific enzymes that convert polycyclic aromatic hydrocarbons into carcinogens.¹³ Given similarities in the delivery of cannabis smoke and tobacco smoke, there is concern about the adverse association cannabis may have with cancers in sites that receive the heaviest long-term exposure, ie, the aerodigestive tract (oropharynx, nasal and sinus epithelium, and larynx) and lungs.^14,15

Cannabis is the most commonly used illicit substance in the US and worldwide, with use rates incrementally rising during the last decade.¹⁶ It is primarily consumed through inhalation-based methods (among others), and its cannabinoid derivatives induce unique gene expression profiles, inflammatory pathways, and oxidative stressors.^17,18 Cannabis has been used for different medical conditions, including nausea, anorexia, and cancer pain.^19,20 In patients with newly diagnosed HNC, cannabis use has been associated with improved pain scores and overall well-being.^21,22 Despite its purported benefits, cannabis use remains controversial due to its harmful association with the development of psychotic disorders and cognitive defects as well as its addictive symptoms.^19,23,24

To date, studies investigating the association between cannabis and HNC risk are inconsistent.^25,26 Ultimately, it remains unclear if the association between cannabis use and HNC is similar to that of tobacco use. In this study, we sought to explore the clinical association between cannabis use and HNC by querying TriNetX, a globally federated database of deidentified electronic medical record data. We hypothesized that there would be an association between cannabis use and HNC due to the inflammatory effects of smoke on the upper airway and potential carcinogenic mechanisms of cannabis.

This study received exempt approval from the University of Southern California institutional review board. Informed consent was waived due to the use of deidentified data. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology () reporting guidelines.

This retrospective cohort study used a globally federated health research network that provided access to consistently updated deidentified electronic medical records (TriNetX).²⁷ We used the US Collaborative network, which provided access to data from 64 health care organizations that accounted for greater than 90 million individuals. The cohort consisted of tertiary care centers within the US. The database complies with the Health Insurance Portability and Accountability Act, as information is supplied only in aggregated counts of 10 or greater with deidentified information only.

Two cohorts were created to compare relative risk of various HNCs. Cohort 1 (cannabis-related disorder group) included individuals who received a diagnosis of cannabis-related disorder (International Statistical Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] F12) and had a recorded outpatient hospital clinic visit (Healthcare Common Procedure Coding System: G0463) with no prior history of HNC. Cannabis-related disorders are defined by the excessive use of cannabis with associated psychosocial symptoms, such as impaired social and/or occupational functioning.¹⁹ Cohort 2 (no cannabis-related disorder group) included individuals who had a recorded outpatient hospital clinic visit, never received a diagnosis of cannabis use disorder, and did not have a history of HNC. Each group was defined by diagnosis or hospital visit from April 19, 2004, to April 19, 2024. Similar groups were created, with stratification by age (younger than 60 years or 60 years or older, as per previous research).²⁶ The analysis was completed on April 19, 2024. The ICD-10 and Healthcare Common Procedure Coding System codes used are documented in the eTable in Supplement 1.

The primary outcome of interest was occurrence of a new HNC diagnosis. HNC diagnosis was further analyzed by primary subsite of cancer, including hypopharyngeal, laryngeal, nasopharyngeal, oral, oropharyngeal, and salivary glands. A description of the ICD-10 codes used for analysis is included in the eTable in Supplement 1.

Advanced analytics were used for all analyses.²⁸ First, baseline demographic characteristics of the cohorts were collected. Advanced analytics were then used to describe incidence of each HNC subtype at any time after the index event. In accordance with prior literature,^29,30 the index event for analysis was defined as the first recorded outpatient hospital clinic visit or, when applicable, the first time when recorded outpatient hospital clinic visit and diagnosis of cannabis-related disorder were met. Then, propensity score 1:1 matching (with greedy nearest neighbor matching and a caliper distance of 0.1 pooled SDs of the logit of the propensity score) was used to create cohorts with matched characteristics. Case and control individuals were paired in analyses. Characteristics used in matching included age, self-reported race and ethnicity, alcohol-related disorders (ICD-10-CM F10), and tobacco use (ICD-10-CM Z72.0). Finally, risk ratios (RRs) were calculated using Poisson regression analysis to compare the rate of HNCs between groups after propensity score matching. The analysis was completed to analyze the outcome (HNC) any time, at 1 year or longer, and 5 years or longer after the index event to search for a potential dose response through time. Because a previous study found higher epidermal growth factor receptor expression (likely associated with cannabis use) among a group of young patients with laryngeal cancer (younger than 60 years), this analysis was completed again for the young adult (<60 years) and older adult (≥60 years) groups to explore the possibility of effect size variation by age. Statistical significance was set at α = .05.

Cohort characteristics are summarized in Table 1. Before propensity score matching, the cannabis-related disorder cohort contained 116 076 individuals who had mean (SD) age of 46.4 and were mostly male (61 434 [52.9%]), not Hispanic (101 191 [87.2%]), and White (69 595 [60.0%]) with relatively frequent alcohol (26 220 [22.6%]) and tobacco use (21 547 [18.6%]). The no cannabis-related disorder cohort contained 3 985 286 individuals who had mean (SD) age of 60.8 (20.6) years and were mostly female (2 173 684 [54.5%]), not Hispanic (3 185 445 [79.9%]), and White (2 971 832 [74.9%]) with relatively infrequent alcohol (94 955 [2.4%]) and tobacco use (99 529 [2.5%]). After propensity score matching (for the main analysis), each group contained 115 865 individuals. Matching minimized differences between groups, although age and ethnicity remained statistically significantly different, albeit with very small differences (postmatching standardized differences were 0.02 and 0.01, respectively). The presence of alcohol-related disorder (standardized difference, 0.005) and tobacco use (standardized difference, 0.003) were comparable between groups after matching.

When comparing the incidence of various HNCs between groups, incidence of any HNC and every location of HNC any time after the index event was greater in the cannabis disorder group compared with the no cannabis disorder group (Table 2). Specifically, the cannabis disorder group demonstrated higher rates of any HNC (0.285% vs 0.091%, respectively), hypopharyngeal cancer (0.016% vs 0.003%), laryngeal cancer (0.093% vs 0.015%), nasopharyngeal cancer (0.022% vs 0.007%), oral cancer (0.113% vs 0.049%), oropharyngeal cancer (0.081% vs 0.013%), and salivary gland cancer (0.023% vs 0.008%).

After propensity score matching, individuals in the cannabis disorder group had higher risk of developing any HNC (RR, 3.49; 95% CI, 2.78-4.39), laryngeal cancer (RR, 8.39; 95% CI, 4.72-14.90), nasopharyngeal cancer (RR, 2.60; 95% CI, 1.25-5.39), oral cancer (RR, 2.51; 95% CI, 1.81-3.47), oropharyngeal cancer (RR, 4.90; 95% CI, 2.99-8.02), and salivary gland cancer (RR, 2.70; 95% CI,: 1.31-5.58) but not hypopharyngeal cancer (RR, 1.70; 95% CI, 0.78-3.71; Table 3) any time after the index event. After limiting to cases of HNC developed 1 year or longer after the index event, the relative risk for developing HNC after cannabis disorder increased for any HNC (RR, 4.40; 95% CI, 3.21-6.01), oral cancer (RR, 3.11; 95% CI, 2.02-4.80), and oropharyngeal cancer (RR, 6.70; 95% CI, 3.45-13.03). At 1 year or longer, the relative risk decreased but remained significant for laryngeal cancer (RR, 7.10; 95% CI, 3.66-13.77), while the association lost significance with the outcomes of nasopharyngeal cancer and salivary gland cancer. After limiting to cases of HNC developed 5 years or longer after the index event, the relative risk for developing cancers after cannabis disorder diagnosis increased again for any HNC (RR, 5.00; 95% CI, 2.62-9.56), although significance was lost for HNC subsites (Table 3).

When considering only young adults, individuals with cannabis disorder demonstrated higher relative risk for any HNC (RR, 3.44; 95% CI, 2.32-5.10), laryngeal cancer (RR, 2.60; 95% CI, 1.25-5.39), oral cancer (RR, 2.00; 95% CI, 1.19-3.38), and oropharyngeal cancer (RR, 3.40; 95% CI, 1.68-6.88). Relative risks increased for any HNC (RR, 4.67; 95% CI, 2.67-8.16) and oral cancers (RR, 3.00; 95% CI, 1.47-6.14) when considering cancers only 1 year or longer from cannabis disorder diagnosis but decreased for oropharyngeal cancer (RR, 2.60; 95% CI, 1.25-5.39). No site was significant at 5 years or longer, although all findings were limited by sample size (Table 4).

When considering only older adults, individuals with cannabis-related disorder demonstrated higher risk for any HNC (RR, 3.21; 95% CI, 2.44-4.21), laryngeal cancer (RR, 6.92; 95% CI, 3.78-12.67), oral cancer (RR, 2.46; 95% CI, 1.66-3.64), and oropharyngeal cancer (RR, 3.28; 95% CI, 1.94-5.57). Relative risks for developing HNC were similar with cases only 1 year or longer from cannabis disorder diagnosis, as was association with any HNC (RR, 3.14; 95% CI, 2.25-4.40), laryngeal cancer (RR, 5.70; 95% CI, 2.91-11.16), oral cancer (RR, 2.70; 95% CI, 1.62-4.52), and oropharyngeal cancer (RR, 3.16; 95% CI, 1.69-5.89) remained similar compared with any time after cannabis disorder diagnosis. Although limited by sample size, cannabis disorder remained associated with any HNC (RR, 3.60; 95% CI, 1.79-7.26) at 5 years or longer (Table 5).

In this cohort study, cannabis disorder diagnosis was independently associated with greater risk of subsequent development of any HNC, as well as cancers in various subsites of the head and neck among US adults. When limited to cases of HNC occurring greater than 1 year after cannabis use disorder diagnosis, many of the associations increased, demonstrating additional strength in the association. When limited to cases of HNC at 5 or more years after cannabis use disorder, many associations fell in magnitude, possibly due to poor sample sizes, inconsistent cannabis use, and other uncontrolled factors, although several of the associations, including between cannabis use and any HNC, oral cancer, oropharyngeal cancer, and laryngeal cancer, remained. Each of these associations were generally consistent when considering only young adult (age <60 years) and older adult (age ≥60 years) samples. This study potentially contributes to the literature that has previously found some evidence regarding the association between cannabis use and HNC.^26,31,32

Clinical studies have had mixed results in assessing the association between cannabis use and HNC. Nearly all clinical studies have relied on single-site or regional samples and used a case-control format for analysis. Most of these studies did not find an association between cannabis use and HNC, perhaps due to a lack of association but also possibly due to a combination of small sample size and relatively small cannabis exposure, as measured by surveys.^5,31,33 One cohort study followed up cannabis users for 8 years and did not find any association, although that study was limited by short follow-up and relatively little cannabis consumption in the cohort.²⁵ However, 1 study was able to find an association, demonstrating a strong link between cannabis use and HPV-16–positive squamous cell carcinoma.³¹ However, a 2019 systematic review demonstrated limited clinical evidence for association between cannabis use and development of HNC.³⁴

This study builds on the existing literature on the association between cannabis and HNC, reinforcing the possibility of an association between cannabis consumption and development of HNC. By using a relatively new electronic medical record database, we were able to use national data to examine the association between cannabis and HNC. With this method, to our knowledge, this study used a far greater sample than any previous study on this topic, affording greater power to detect a potential association than previous studies. Furthermore, while this study was not able to measure the amount of cannabis consumption, it overcame the problem of limited cannabis consumption that was described by a previous cohort study.²⁵ Because individuals in our cohort had the cannabis-related disorder diagnosis, each individual had cannabis exposure substantial enough to cause physical or emotional symptoms with the inability to cease cannabis use.¹⁹

In this study, we found that the relative risk of developing HNC for those with cannabis-related disorders ranged from 3.5 to 5 times that of those without cannabis-related disorders, depending on time from diagnosis of cannabis-related disorder. Previous studies into the relative risk of developing HNC for people who use alcohol and tobacco ranged from 2 to 10 times that of those without use, with the association varying greatly based on frequency and dosage of use.^35-37 Given that our cohort included those with the highest use of cannabis, we can estimate that the association of cannabis use seen in this study with risk of developing HNC was slightly less than that of alcohol and tobacco use. However, these results should be interpreted cautiously due to potential for lack of complete controlling for alcohol and tobacco use, as well as HPV status, although this would primarily affect interpretation of the relative risk of oropharyngeal cancer in our study. Additionally, our finding of a lack of increased risk of developing hypopharyngeal cancer after cannabis use disorder may be due to underpowering of results.

We initially hypothesized that cannabis use may be associated with HNC due to various cellular mechanisms linking cannabis use to cancer. The clearest potential association between the 2 lies in the inflammatory pathways that are triggered by cannabis smoke, as smoking is the most common method of cannabis consumption.³⁸ Compared with smoking tobacco, smoking cannabis may be even more proinflammatory. Cannabis smoking is typically unfiltered and consumed through deeper breaths than tobacco.³⁹ Additionally, cannabis burns at a higher temperature than tobacco, increasing the risk of inflammatory injury.⁴⁰ On a cellular level, cannabis smoke increases the expression of epidermal growth factor receptor, which has been found to be overexpressed in most cases of squamous cell carcinoma in the head and neck,⁴¹ as well as in laryngeal cancer specimens from people who smoke cannabis.²⁶

Direct effects of cannabinoids may also be associated with carcinogenesis of the head and neck, although studies of these mechanisms are more mixed. Some studies have demonstrated antitumor properties of cannabinoids, including suppression of cancer proliferation and decreased angiogenesis of tumors.^42,43 Meanwhile, other studies have shown tumor-promoting activities, such as increased oxidative stress and inhibition of tumor-specific immune mechanisms.^44-46 Such a mixed effect is to be expected with the cannabis plant producing more than 400 unique chemical entities and more than 60 cannabinoids with various (and often opposite) effects.⁴⁷ However, genetic-based studies have also found an association between cannabis use and laryngeal cancer,⁴⁸ leading us to suspect an association between cannabis and HNC.

Our study had limitations. This study has limited information about cohort composition, including health care organizations included, population characteristics, and payer status. Length of follow-up with adequate sample size was a limitation, particularly at longer than 5 years after initial diagnosis. This prevents analysis of dose effect, as the increased risk of HNC after diagnosis is likely based on large consumption of cannabis before diagnosis. While this study had high power overall, type II error was possible for relatively infrequently observed HNCs, such as hypopharyngeal cancer. Potential inconsistency of diagnosis and reliance on medical record codes was another limitation. Cannabis use is likely to be underreported. This could decrease relative risks discovered if individuals were using cannabis in the noncannabis group, although this effect may be overcome by the high use in the cannabis use disorder group. This study was further limited by lack of information on dosage and frequency of cannabis use, as well as some controls, including alcohol and tobacco use. There was possibility for bias, as cannabis use disorder is likely associated with alcohol and tobacco use. While we controlled for alcohol use disorder and tobacco use, differences in dosage between groups may remain. In addition, it is possible that some diagnoses may have been missed entirely if an individual received an HNC diagnosis outside of a health care organization participating in the database, although these missed diagnoses are likely to be randomly apportioned between groups. Additionally, while we were able to the specify subsite of HNC, we were unable to specify the histology of HNC or assess its potential association with cannabis use.

The possibility of an association between cannabis use and HNC has substantial public health implications given that cannabis use is rising among young adults with trends toward legalization.⁴⁹ Future studies should seek to use similarly large cohorts to analyze the association between cannabis use and HNC but can demonstrate additional strength of the association by using more thorough data on cannabis use, including dosage, frequency, and method of use.

This cohort study suggests that there is an association between excessive cannabis use and HNC, particularly oral, oropharyngeal, and laryngeal cancers. These findings were consistent regardless of the age group studied. Further research is necessary to confirm the existence of this association and understand the mechanism of this potential association.

Accepted for Publication: June 17, 2024.

Published Online: August 8, 2024. doi:10.1001/jamaoto.2024.2419

Corresponding Author: Niels C. Kokot, MD, Department of Otolaryngology–Head and Neck Surgery, University of Southern California, 1450 San Pablo St, #5100, Los Angeles, CA 90033 (niels.kokot@med.usc.edu).

Author Contributions: Drs Gallagher and Kokot had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Gallagher, Lin, Kim, Kokot.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Gallagher, Chung, Lin.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Gallagher, Chung, Kim.

Administrative, technical, or material support: Lin, Kokot.

Supervision: Lin, Kokot.

Conflict of Interest Disclosures: None reported.

Meeting Presentation: This paper was presented as a poster at the 2024 Meeting of the American Head and Neck Society; May 15, 2024; Chicago, Illinois.

Data Sharing Statement: See Supplement 2.