Cannabis use and head and neck cancer: a narrative review

Introduction

Background

Cannabis, referring to the products derived from the plant Cannabis sativa, has been the focus of an increasing amount of attention due to its complex pharmacological effects and evolving legal status (1,2). Recent reviews and clinical studies have highlighted the roles of its two principal compounds, or cannabinoids, Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Both are potent mediators of the endocannabinoid system, impacting the modulation of pain, mood, and inflammation within the body (3). Of the two, THC is the primary psychoactive component, causing altered perception and euphoria mainly through its effects on cannabinoid type-1 (CB1) receptors. At the same time, CBD, lacking significant psychoactivity, has demonstrated anti-inflammatory and potential neuroprotective effects (4,5). Cannabis and its derivatives have been increasingly adopted in clinical settings to manage symptoms including chronic pain, chemotherapy-induced nausea, and appetite loss, even as ongoing debates persist regarding the broader health implications of cannabis use (6). However, the study of cannabis use is complicated by the fact that there are over 550 unique compounds in the cannabis plant, with THC and CBD being just two of over 100 identified phytocannabinoids (7). Further complicating the study of cannabis in humans is the wide variety of methods by which cannabis can be consumed—including smoking, drinking, vaporizing, eating, and dabbing—with each method having its own unique chemical constituents involved (8).

Head and neck cancer (HNC) is a broad term describing a diverse group of malignancies that affect the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity, and salivary glands (9). Globally, when excluding thyroid cancers, HNC is the eighth most common cancer as of 2022 (10), and, in the United States, HNC accounts for an estimated 4% of all cancers (11,12). Traditionally, the etiology of HNC has been closely linked with well-established risk factors such as tobacco and alcohol consumption; however, the previous decade has seen a rising incidence of human papillomavirus (HPV)-related HNC, particularly with oropharyngeal cancers (13,14). Though not primarily implicated in this rise, lab-based studies have shown that cannabinoids can promote progression of HPV-related HNC through a distinct molecular pathway (15). This rise in HPV-related HNCs has not only reshaped the epidemiologic landscape due to HPV-positive tumors frequently presenting in younger, non-smoking populations, but also influences prognostic outcomes as HPV-positive HNC tend to have a better treatment response when compared to HPV-negative HNCs (16). With improving prognostic outcomes among a younger population, there has been an increasing focus on care and quality of life of HNC survivors—individuals previously diagnosed with a HNC who are undergoing treatment or are entering life after treatment (17-19).

Rationale and knowledge gap

Emerging evidence suggests that cannabis use may intersect with HNCs on multiple levels. Historically, early observational studies conducted in the 1980s and 1990s raised the possibility that cannabis use, ingested primarily through smoking, may be linked to malignancies in the head and neck region (20,21). Systematic reviews have assessed the association between these factors, though data remains inconclusive. Furthermore, while cannabis use has been suggested as a way to alleviate many of the morbidities associated with HNC survivorship, the safety and efficacy of cannabis used in this setting has been questioned, with clinicians currently being uncertain on its use (22).

To our knowledge, there has not been a review that synthesizes both the oncologic risks and therapeutic roles of cannabis specifically in the context of HNC. Prior reviews, where available, have either focused narrowly on cannabis and general cancer risk or have not addressed cannabis’ dual role in both potential carcinogenesis and symptom management. This represents a significant knowledge gap. A focused synthesis of current evidence is essential to identify research deficiencies, clarify the strength of existing associations, and guide future investigations on cannabis use across the cancer care continuum in HNC populations.

Objective

This manuscript critically reviews the current literature on cannabis in the context of HNC by examining epidemiologic studies exploring the association between cannabis use and the risk of developing HNC, evaluating the impact of cannabis on HNC treatment outcomes, and exploring patterns of cannabis utilization among HNC survivors. By integrating recent advances in cannabis pharmacology with evolving insights into HNC epidemiology and treatment, this review aims to provide a nuanced discussion of how cannabis use intersects with the care and survivorship of HNC patients. We present this article in accordance with the Narrative Review reporting checklist (available at https://joma.amegroups.com/article/view/10.21037/joma-25-9/rc).

Methods

The Scale for the Assessment of Narrative Review Articles (SANRA) was utilized as a quality control tool for this manuscript (Table S1) (23).

Inclusion and exclusion criteria

Studies were included if they addressed at least one of the following objectives through primary research in a clinical setting: (I) the association between cannabis use and risk of developing HNC; (II) the effects of cannabis use on HNC treatment outcomes; or (III) the utilization of cannabis among HNC survivors with quality-of-life implications. Studies that did not specifically report on cannabis use in HNC populations, focused exclusively on non-malignant head and neck conditions (e.g., benign tumors), or involved patients outside the head and neck oncology spectrum were not required for inclusion. Conference abstracts, editorials, commentaries, reviews, and manuscripts not in English were excluded from this review due to limited data quality or lack of original research.

Search methods

A literature search was conducted using PubMed to identify primary studies published between January 1, 1990, and December 31, 2024 that reported original data on cannabis use in the context of HNC. As this is a narrative review, we limited our search to the PubMed database, which provides broad coverage of relevant biomedical literature. 1990 was selected as the lower cutoff, as this is when the first case reports regarding a potential association between cannabis use and HNC were published (20,21). The search strategy incorporated the following combination of search terms: “Cannabis” or “Marijuana” and “Head and Neck Cancer” or “Head and Neck Cancer Survivor” or “Head and Neck Cancer Surgery”. Each combination of search terms was utilized (six in total), and all studies meeting inclusion criteria were included. Additionally, the authors reviewed the reference lists of retrieved articles to identify additional eligible studies. If the initial literature search revealed information about cannabis use among non-HNC survivors that addressed gaps in HNC-related literature, those manuscripts were included to enhance the narrative discussion. No restrictions were imposed on the search concerning publication country or sample size.

Data collection

Two independent reviewers initially screened the titles and abstracts of the identified records. Then, full-text articles of all potentially eligible studies were retrieved and assessed against the inclusion criteria. Any ambiguous studies identified by the reviewer were discussed with the study team (all authors) and resolved by consensus. After assessment, data from selected studies were extracted onto a standardized collection form that captured details of each study’s design, patient demographics, definitions and methods of assessing cannabis exposure, details of HNC diagnosis and treatment, and reported outcome measures. A summary of this search strategy is outlined below in Table 1 and Figure 1.

Figure 1 Schematic representation of search strategy. HNC, head and neck cancer.

Outcome measures

The primary outcome measures for this review were defined as: (I) the association between cannabis use and the risk or incidence of HNC; (II) the impact of cannabis use on HNC treatment outcomes, including any reported effects on perioperative or surgical metrics; and (III) quality-of-life outcomes among HNC survivors, as reflected by patient-reported outcomes in domains such as pain, mood, and overall well-being.

The literature regarding cannabis use and HNC

Likelihood of an association of cannabis use and HNC

Cannabis use, particularly via smoking, has been postulated to be a contributor to the development of HNC since the 1980s, when multiple studies noted early cases of HNC among individuals without other traditional risk factors (20,21). Despite significant advancements in technology and data accessibility, a consensus regarding the potential of an association between cannabis use and HNC has not been reached (24). This has raised concerns that society may be repeating a past mistake—permitting the expansion of cannabis use and the cannabis industry without fully considering its potential cancer risks, much like what happened with the tobacco industry decades ago (25).

While the potential cancer risks of expanded cannabis use are substantial, lab-based and clinical data on the association between cannabis and HNC is not indisputable. The study of cannabis use is particularly challenging from a molecular perspective, as the cannabis plant produces greater than 550 unique chemical compounds and over 100 phytocannabinoids with varying effects (26). Cannabis’ diverse chemical composition has led to its investigation as both a potential carcinogen and a therapeutic agent in cancer care.

In a study of 24 cannabis extracts, Blal et al. were able to demonstrate significant anti-tumoral effects of one particular CBD extract on samples of head and neck squamous cell carcinoma (SCC) (27). The cytotoxic effect of CBD has been demonstrated in oral SCC cells through real-time monitoring utilizing electric cell-substrate impedance sensing (28). Though such work is primarily preliminary, these lab-based studies are among a growing literature that demonstrates the potential anti-tumor effects of cannabinoids (29,30).

Despite these studies, investigation into the potential molecular mechanism linking cannabis use to HNC are robust. Among the strongest suggested links is a study demonstrating the ability of cannabinoids to promote progression of HPV-positive head and neck SCC progression through p38 MAPK pathway activation (15). This mechanism is particularly concerning due to the known association between cannabis use and HPV-positive status (31). In-vitro evidence indicates that THC promotes progression by aiding in the invasion of carcinogenic HPV into cells without directly affecting proliferation (32). Administration of THC also actives the p38 MAPK pathway as well as the ERK MAP kinase pathways, both of which are implicated in carcinogenesis (15,32,33).

However, there are several more potential molecular connections between cannabis and HNC–multiple studies have utilized samples of laryngeal cancer to uncover genetic pathways related to epidermal growth factor receptor (EGFR) that may connect cannabis to laryngeal cancer (34,35). Additionally, a separate lab-based study found that CBD may diminish the anti-tumor effect of activated natural killer cells (36). Other studies have suggested that indirect mechanisms may be at play as well. Cannabis use has been shown to significantly alter the oral microbiome of frequent cannabis users, though the induced microbiome is not similar to the characteristics of an individual with HNC (37,38). Furthermore, adults with frequent cannabis use were associated with higher likelihood of periodontitis (39), which itself is associated with HNC (40).

Given the literature that suggests a link between cannabis use and HNC, a variety of retrospective and prospective clinical studies have been performed; similar to lab-based studies, the results have been mixed. A summary of ten related studies included in this manuscript as well as their strengths and weaknesses are listed in Table 2. Due to low reported use of cannabis and relative infrequency of HNCs, many of these studies are in a case-control format. As analyzed by a 2019 systematic review (24), three studies did not report a significant association with head and neck SCC (44,46,48), while two studies did (45,51). Additionally, one study reported an association with oral cancer (43) while one did not (42). When combined in a random effects model, these studies did not collectively find significant evidence of an association between cannabis use and HNC (24). Not included in this systematic review were three more case control studies, one demonstrating an association with nasopharyngeal cancer (47), another demonstrating a lack of association with HPV-positive oropharyngeal SCC but a negative association with HPV-negative oropharyngeal SCC (49), and a final one not finding a significant association between cannabis use and oral cancer (41).

While the aforementioned systematic review and meta-analysis did not reveal an association between cannabis use and HNC, most of these studies were limited by a moderate-to-high risk of bias as well as relatively low numbers of cases of individuals with cannabis use and limited cannabis use among those users (24,52). In an effort to overcome the limitations of low levels of use and the small samples in case-control formats, a recent study utilized diagnosis of cannabis use disorder—indicating high long-term levels of cannabis exposure—to explore the potential for an association. This retrospective cohort study among individuals with cannabis use disorder found those with heavy cannabis use were at nearly 3.5 times greater risk of any HNC, 2.5 times greater risk of oral cavity cancer, 4.9 times greater risk of oropharyngeal cancer, and 8.4 times greater risk of laryngeal cancer (50).

Unfortunately, this study was significantly limited by utilization of medical record coding data for grouping and controls, which is likely an incomplete control for co-use of tobacco as well as other environmental risk factors. Additionally, there was no clear dosing information—either temporality or method of use—in this study. However, this study demonstrates the next needed advancement in clinical research of cannabis use—large study samples of heavy cannabis users. Prospective information on dosing, cannabis product contents, and method of use are needed to further investigate this association.

While the current evidence to support the presence of an association between cannabis use and HNC is incomplete, there is substantial clinical and molecular data to suggest that a connection is possible. The connection between the two is particularly likely when cannabis is ingested via smoking, as cannabis smoke is often inhaled through deeper and unfiltered breaths than tobacco (53), likely causing an acute inflammatory reaction. Furthermore, there is substantial evidence that cannabis smoke in particular is mutagenic (54-57), and it is known that cannabis smoke has many similar carcinogens to tobacco smoke (54,58). Given this collection of evidence, definitive statements about this association are not warranted, but clinicians should consider advising patients about the potential association between cannabis use and HNCs, particularly in the case of ingestion by smoking.

Utility of cannabis use for HNC survivors

As previously mentioned, while there are many in vitro studies and mechanistic insights into the potential ability to utilize cannabis products to treat HNC (27-30), there were no published clinical studies identified that are investigating the utilization of cannabis products to treat HNC. However, there are several studies within the literature that highlight cannabis use among HNC and cancer survivors, with many patients reporting use and benefit. Recent data suggests that approximately 9.2% of adult cancer survivors report cannabis use, with 51.3% using only for medical reasons and most (65.2%) report use via smoking (59). Due to high reported use and suggestion of its benefits, cannabis and its products are currently being studied for their ability to improve a variety of treatment-related conditions and improve quality of life among HNC survivors. Seven articles were found regarding this topic, and a discussion of these studies is below (summarized in Table 3).

Perhaps first among the proposed benefits of cannabis use for HNC survivors is pain relief, which is often a long-term and critical problem for survivors (67,68). Non-controlled qualitative and quantitative studies demonstrate significant patient-reported benefit from cannabis for HNC treatment-related pain (60,64,66). However, higher-quality studies are mixed on the matter. In a prospective cohort study, users of cannabis matched for cancer and treatment characteristics, cannabis users had lower pain and discomfort based on related domains in the validated Edmonston Symptom Assessment System (ESAS) and EuroWol-5D (EQ5D) surveys (62). However, a randomized controlled trial that utilized nabilone (a synthetic cannabinoid) did not find relative reduction in pain scores among HNC survivors (61). A 2023 Cochrane review of the effect of THC on HNC pain management found moderate evidence that THC does not relieve pain among HNC survivors (65). However, a systematic review and meta-analysis among all cancer survivors that included several randomized clinical trials did show a benefit of medical cannabis for pain control (63).

Two other proposed benefits of cannabis use include appetite stimulation and mental health support. Patients with HNC may deal with a broad array of symptoms that can decrease ability to eat and appetite, including primary or treatment-related dysphagia, xerostomia, dysgeusia, nausea, and vomiting, often resulting in sustained weight loss (69,70). These symptoms, along with a wide variety of other factors, often contribute to poor mental health in the form of anxiety disorders, depressive disorders, and even suicide, which contributes to mortality from HNC (71-73). Similar to pain management, self-reported improvement in levels of anxiety (64,66) and appetite (60,64) have been reported with cannabis use. While the previously mentioned prospective cohort study of cannabis use among HNC survivors did not examine appetite stimulation, there was an observed improvement in validated measures of mental health symptoms, such as anxiety and depression, as measured by ESAS (62). Again, nabilone was not shown to be effective in improving either mood or appetite (61).

When examining data with outcomes specific to quality of life, one study of cannabis users found an increased general wellbeing score based on the ESAS questionnaire (62), while a randomized controlled trial of nabilone did not find benefit (61).

Overall, these data present substantial evidence of quality-of-life benefit for HNC survivors who are users of cannabis. However, comparative data are largely incomplete, as only one prospective trial found significant quality of life benefit. The inconsistency of support for the use of cannabinoids for pain and other symptom management for head and neck survivors appears partially driven by inconsistency in the substance being studied, with some studying cannabis generally, others studying THC or CBD, and another studying nabilone. Additionally, the quality of several of the studies is limited, and many in the field are simply qualitative without control groups, providing very weak support for the hypothesis. Still, given the clear potential for benefit, there is a need for careful examination of the potential harms of cannabis use among this population.

Two published studies found in the literature search investigated these potential harms, though others outside of the HNC-specific literature suggest the need for further examination in the field. One concern of cannabis use among HNC survivors is worse response to treatment, given that continued tobacco smoking after HNC diagnosis is associated with lower treatment response to radiation therapy, higher rates of gastrostomy tube dependence after treatment, higher recurrence rates, higher rates of second primary lesions, and decreased overall survival (74,75). To date, limited studies have been published on this topic, but these studies do not report such a problem being present for HNC survivors. One prospective study compared a group of 47 cannabis users to a matched group of 47 non-users and found no difference in 5-year overall, disease-specific, disease-free, and metastasis-free survival (76). Another single-center retrospective cohort study including 59 cannabis users and 454 non-users also found no difference in rate of development of a second primary HNC among users (77).

Though studies have not occurred among HNC survivors, there is some evidence that cannabis use may decrease the effectiveness of immunotherapy. While the human body endocannabinoid receptors CB₁ and CB₂ are the primary studied targets of cannabinoids, there are a variety of other pathways through which endocannabinoid signaling regulates the immune system (78). Two clinical studies investigating factors impacting success rates of immunotherapy have identified cannabis as a factor that may negatively impact response to treatment (79,80). With more investigations into the efficacy of neoadjuvant immunotherapy for HNC (81), this is an area of need for additional research.

Further, there are a variety of other potential side effects to weigh when considering the use of cannabis among HNC survivors. One consideration is the possibility of subsequent reliance on cannabis for social and physical functioning; a recent study found that approximately 0.45% of cancer survivors meet the criteria for diagnosis of cannabis use disorder, while 0.34% of laryngeal cancer patients meet these criteria (82). Additionally, there are multiple well-known side effects of cannabis use among all users, which may be particularly harmful to HNC survivors, including fatigue, confusion or mental fogging, and paranoia (65,83). It is important to counsel patients who desire to use cannabis that these symptoms may be the result of cannabis use rather than HNC and its related treatments.

Based on the above information, there are limited recommendations for the use of cannabis as a therapy among survivors of HNC. The most recent HNC survivorship consensus statement only makes brief mention of cannabis as a potential contributor to HNC (84). However, the American Society of Clinical Oncology does provide guidelines for the use of cannabis among cancer survivors generally. These guidelines recommend non-judgmental discussion of cannabis use among cancer survivors, with cannabis use being an option for augmentation of an antiemetic regimen among those undergoing treatment with emetogenic neoplastic agents. Evidence for inclusion of cannabis and cannabinoids in managing other cancer and treatment-related toxicities—including pain—remains insufficient for recommendation outside of these specific circumstances (85).

Strengths and limitations

There are a variety of strengths and limitations to this manuscript. In regard to weaknesses, the lack of a systematic approach and strict exclusion of articles allows for risk of bias in selection and interpretation of studies. Furthermore, in analysis of any potential association, there is inherent risk of bias within the literature itself, as articles demonstrating a significant association are more likely to be published than those without. There is limited quantitative analysis produced by a narrative work. Furthermore, there is potential for incompleteness on a topic, particularly if the data fell outside of the time frame of the inclusion criteria or if the publication is not listed on PubMed.

However, the narrative format of this manuscript allows for a broad, cutting-edge overview of cannabis use and its relation to HNC and use among survivors. Without the strict exclusion criteria of a systematic review, this review has greater ability to provide thematic and thoughtful analysis of the topic. The narrative format also allows for flexibility in style and identification of the variety of knowledge gaps that currently exist in this space within the literature; these knowledge gaps and study proposals have been documented in Table 4.

As discussed throughout this manuscript, the limited quality and heterogeneity of existing studies prevent definitive conclusions about the relationship between cannabis use and HNC. Nonetheless, this narrative review highlights critical gaps in the literature. Notably, no study to date has combined detailed cannabis use data—including duration, type, and method of use—with longitudinal HNC incidence. While such a study would be time-consuming and expensive, integrating cannabis use questions into ongoing national cohort studies may make it feasible. Moreover, randomized controlled trials and prospective cohort studies evaluating the effectiveness of cannabis for managing HNC or treatment-related symptoms remain sparse. Even fewer studies examine the potential adverse effects of cannabis use following HNC diagnosis, further limiting the ability to assess its therapeutic utility. Expanding this literature is essential to inform appropriate counseling and decision-making for HNC survivors, especially as cannabis use becomes increasingly common and legalized.

Conclusions

There is substantial but inconclusive evidence for an association between cannabis use and HNC. Given this uncertainty, clinicians should counsel patients on the potential risks of cannabis use—particularly when consumed via smoking—while emphasizing the need for further research before definitive conclusions. Future studies should include larger samples of cannabis users with detailed information on cannabis dosing, product composition, and method of use to better inform public health recommendations.

There is also considerable evidence that cannabis may alleviate common symptoms experienced by HNC survivors, such as pain, appetite loss, anxiety, and diminished quality of life. Unlike continued tobacco use, current data do not indicate that cannabis use following a HNC diagnosis is associated with poorer treatment outcomes. Clinicians should weigh these potential benefits against the known and possible adverse effects of cannabis when discussing its use with HNC survivors.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://joma.amegroups.com/article/view/10.21037/joma-25-9/rc

Peer Review File: Available at https://joma.amegroups.com/article/view/10.21037/joma-25-9/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://joma.amegroups.com/article/view/10.21037/joma-25-9/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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