Medical marijuana for management of cancer pain: a narrative review

Introduction

Cancer remains the second leading cause of death in the United States (US), with over two million new diagnoses projected in 2025 alone (1). Cancer-related pain is highly prevalent with the incidence increasing as cancer advances; up to almost 70% in patients with metastatic cancer and between 40% and 55% of patients with non-metastatic cancer. Additionally, many patients (up to 40%) continue to experience pain after curative treatment (2-4). Cancer-related pain may severely impact quality of life, including daily physical functioning, emotional well-being, social interactions, and can contribute to sleep disturbances (5,6).

In 1986, the World Health Organization (WHO) introduced the analgesic ladder to help guide the management of cancer-related pain (7). The analgesic ladder recommends initial treatment of pain with non-opioids, followed by weak opioids and finally strong opioids if pain remains refractory. Significant side effects associated with opioids limit their use, including constipation, respiratory depression, sedation, as well as risk of opioid abuse/misuse. Interventional options are also readily utilized for treatment of cancer-related pain (2,8,9). Since the introduction of the WHO analgesic ladder, there have been significant advancements made in interventional pain management of cancer-related pain, including spinal cord stimulation, targeted drug delivery systems, vertebral body ablation, and vertebral augmentation (9).

One area of ongoing research is the potential role of medical marijuana in the treatment of cancer-related pain. Medical marijuana is defined as the use of non-pharmacological, herbal cannabis or cannabinoid-based products for the treatment of disease or symptoms, under the guidance or certification of a licensed health care provider in accordance with state regulations (10). In this article, medical marijuana will broadly refer to marijuana tetrahydrocannabinol (THC) as well as cannabidiol (CBD).

Medical marijuana is currently legal in 40 US states as well as the District of Columbia (11). Cancer pain is currently an indication for medical cannabis use in most legalized states, although there continues to be debate regarding efficacy. Medical marijuana is available in a variety of forms, making it an attractive treatment option to many of these patients (12). As the popularity of medical marijuana continues to grow, we want to highlight the prevalence of use, current understanding of mechanism of action, and clinical efficacy of marijuana use for treatment of cancer-related pain. We present this article in accordance with the Narrative Review reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-25-85/rc).

Methods

A research librarian conducted a literature search in PubMed and EMBASE for articles published between January 01, 2018 and date was June 6, 2025. An updated search prior to submission resulted in the addition of one additional article published in August 2025. Search terms included but were not exclusive to cancer Cannabis AND cancer pain; Marijuana AND cancer pain management; Cannabinoids AND cancer-related pain; Medical cannabis AND oncology pain; THC CBD AND cancer pain relief (see Appendix 1 for full list of search terms). Twenty articles were identified and three database reviewers (A.M.M., A.N., and L.R.K.) independently screened titles and abstracts for relevance. Full-text articles were then reviewed with full consensus for final inclusion (see Table 1).

Mechanism of action of medical marijuana

Cannabinoid type 1 receptor (CB1) and cannabinoid type 2 receptor (CB2) are found throughout the body. CB1 receptors can be found throughout both the peripheral as well as central nervous systems. CB2 receptors can be found in immune tissues and peripheral tissues (13). CB1 and CB2, both of which are G-protein receptors, inhibit adenyl cyclase and lead to a decrease in cyclic adenosine monophosphate (cAMP) production (13). The endocannabinoid system inhibits release of presynaptic neurotransmitters and activates descending inhibitory pathways modulating pain pathways (13).

Endocannabinoids, produced naturally by humans, bind to the cannabinoid receptors. Two major endocannabinoids are arachidonoyl ethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), both produced from membrane lipids (13,14). AEA is a partial agonist at the cannabinoid receptor, although more selective for CB1, and 2-AG binds to both CB1 and CB2 equally (13).

Phytocannabinoids are the cannabinoids found in marijuana plants. Marijuana is made up of over 100 phytocannabinoids (15). Delta-9-THC and CBD are the two major phytocannabinoids found in the marijuana plants (15). THC, the main psychoactive component in marijuana, acts as an agonist at the CB1 and CB2 receptors (12). THC also can modulate the pain response by modulating the transient receptor potential vanilloid (TRPV), TRPV2, TRPV3, TRPV4, and TRPM8 receptors (16). Unlike THC, CBD, a non-psychotropic phytocannabinoid, does not bind directly to cannabinoid receptors but rather modulates the receptor response, particularly CB1 (15). CBD is a direct agonist at the TRPV1, which can modulate pain response and inflammation to stimuli (15).

Prevalence and trends of marijuana use for cancer-related pain

Although still considered a Schedule I drug by the Drug Enforcement Agency, medical marijuana has emerged as an appealing option for cancer patients and providers due to its availability in various formulations, including oral, buccal, inhaled, and spray preparations (12). As it is a Schedule I medication, it is difficult to conduct randomized controlled trials due to legal issues.

Cannabis use may be particularly attractive to cancer patients and survivors due to its potential to manage symptoms of cancer itself or its treatment. THC use amongst cancer patients has been increasing with a recent study suggesting a doubling of past 30-day use between 2005 and 2014 (17). A recent systematic review examined trends in cannabis use amongst cancer patients and survivors (10). The prevalence of cannabis use in this patient population was reported to range from almost 5% to over 20% (18). Another study suggested a prevalence range from 8% to 25% of marijuana use in the past 12 months (19). Modes of consumption, including smoking (73%), vaping (12%), topical application (80%), and ingestion of edible products (10%), were all reported. Studies indicated that cancer patients who used cannabis tended to use more than one type of product (18). Patients reported using both CBD and THC either alone or in combination. Most patients reported obtaining cannabis through medical dispensaries, followed by family and friends, and less frequently from recreational dispensaries. Studies suggest that most patients learned about cannabis from the media, friends and family, clinicians, and advertisements; with websites (57.6%), medical professionals (47.8%), and friends and family (46.8%) being the most commonly cited sources (18).

The types of cancers in which cannabis was utilized varied extensively; however, almost half of participants reported having advanced cancer (stage 3 or 4). Younger patients used cannabis more frequently than older patients. Lower socioeconomic status was found to be associated with a lower prevalence of cannabis use (18).

The majority of patients reported using cannabis to help manage their symptoms, including pain, loss of appetite, nausea, insomnia, and anxiety. Some of the benefits of cannabis use included reduction in pain, reduced need for opioids, decreased itching, reduced anxiety, and improvement in sleep. Reported side effects included mental cloudiness, decreased energy, and paranoid thinking; however, some studies found that most patients (92%) reported no side effects. While cannabis may help cancer patients and cancer survivors manage symptoms, more studies are needed to understand the mechanisms of efficacy as well as whether the positive effects outweigh adverse events (18).

Another study examined the impact of state medical THC legalization on opioid-related and pain outcomes for adult cancer patients. They found that medical THC legalization was associated with reduced opioid prescriptions and decreased pain-related hospitalizations amongst patients with newly diagnosed cancer (20). Possible reasons for these findings include legal access to medical THC, resulting in oncologists and other clinicians prescribing fewer opioids and lower demand from patients to be prescribed opioids secondary to perceiving THC as a viable alternative. Studies have found, however, that despite an increased number of patients’ inquiries about THC, a large variation in physician knowledge and willingness to recommend or prescribe THC existed (21). A survey amongst US oncologists found that although 80% discussed THC with their patients and or families, only 46% recommended it clinically, and 50% indicated they did not feel they had sufficient expertise to recommend it (22). More and more patients are likely to inquire about medical THC, and more research and education are needed amongst clinicians in order to be able to appropriately advise patients on its role in their treatment plan.

Clinical efficacy of marijuana for the management of cancer-related pain

One of the earliest studies evaluating use of marijuana for treatment of cancer-related pain was by Noyes et al. in 1975. His group compared the analgesic effect of 5, 10, 15, and 20 mg THC doses versus placebo in 10 patients with advanced cancer. Significant analgesic benefits were observed at 15 and 20 mg doses of THC compared to placebo (23).

Since this early study, there have been numerous other trials completed to evaluate medical marijuana’s use in treatment of cancer-related pain.

Johnson et al. in 2010 expanded on Noyes et al. and evaluated the efficacy of nabiximol (Sativex), one of the first approved THC:CBD combination cannabinoid system modulators. They studied THC:CBD extract and THC extract in the pain management of patients with moderate to severe cancer-related pain. After 2 weeks, their study with 177 advanced cancer patients found that the THC:CBD extract group showed a statistically significant reduction in pain severity (24). Furthermore, Johnson et al. found that the mean daily use of opioids for breakthrough pain reduced in the treatment group over the 2-week span (24). Although these findings were seminal in directing the field toward THC:CBD combinations, questions remained regarding its dose response and safety in a population with advanced cancer and associated opioid-refractory pain.

In 2012, Portenoy et al. looked at nabiximol for treatment of patients with opioid refractory cancer pain. This was a randomized, double-blind, placebo-controlled, graded trial where 360 patients were randomized to receive either placebo or nabiximols at either low-, medium-, or high-dose. There was no statistically significant difference between the number of patients in the placebo group and the nabiximols group who received >30% pain relief (25). There was, however, a larger proportion of patients reporting pain relief in the low- and medium-dose nabiximols groups versus the patients who received the placebo (25). This demonstrated that lower doses of nabiximols may be more efficacious for treatment of pain (25).

Lynch et al. conducted a small pilot study evaluating the efficacy of nabiximols for the treatment of chemotherapy-induced neuropathic pain in 2014. Sixteen patients were randomized to receive either nabiximols or placebo in a crossover design. Following the completion of the first treatment phase, patients who received nabiximols would then receive a placebo. The study found no statistically significant differences in NRS pain scores between the treatment and placebo groups (26). The study determined there was a low number needed to treat of five, demonstrating there may in fact be efficacy for treatment of cancer-related pain (25). Importantly, their findings remained consistent with previous literature, indicating significant variation in patient response to nabiximols.

More recently, in 2023, Hardy et al. aimed to elucidate the effects of pure CBD oil as an adjunct therapy to standard palliative care in advanced cancer patients. While previous studies, such as Johnson et al., found that THC:CBD extract improved pain and reduced opioid prescriptions, there was little known about pure CBD oil. Their randomized dose-escalated placebo-controlled study included 121 patients (58 on CBD and 63 on placebo). Their primary outcome was a change from the patient baseline Edmonton Symptom Assessment System (ESAS) Total Symptom Distress Score (TSDS), which is a commonly used tool to measure physical and psychological well-being of cancer patients. Overall, Hardy et al. concluded that pure CBD oil did not significantly improve symptom control compared to standard palliative care alone (27). Moreover, their secondary findings failed to indicate improvement in anxiety, depression, or quality of life (27). It is possible that the use of pure CBD, without THC, led to sub-therapeutic benefits and that CBD is mainly used to reduce THC toxicity (28). Hardy et al. note that further research must be conducted on this particular topic (27).

Hardy et al. also published a more recent study evaluating the effectiveness of THC:CBD versus placebo for treatment of cancer-related pain. In this multicenter double-blind, randomized placebo-controlled trial, 144 patients who were under management of the palliative care team received either 1:1 THC and CBD oil or placebo in addition to standard of care (28). The primary objective of the study was to examine differences in TSDS between the two groups; however, they also examined other variables, including pain scores, opioid reduction, and adverse effects. Overall, the study concluded there were no differences in TSDS or opioid reduction between the two groups; however, there was a statistically significant reduction in pain scores among the patients who received THC:CBD (28). The experimental group also experienced increased adverse events versus the placebo group with the most common side effect being confusion (28). Hardy et al. concluded that while there was a mild benefit in pain scores in the THC/CBD oil group, it came with significant adverse effects without reduction in overall symptom burden in patients with advanced cancer (28).

Meng et al. conducted a review in response to increased popularity among patients in the use of cannabis and cannabinoids for management of cancer-related pain. While there was some promising preclinic data, the authors acknowledged the current lack of high-quality randomized controlled trials assessing effectiveness and safety of cannabis among cancer patients (29).

In 2023, Häuser et al. published a Cochrane review on medical cannabis for adults with cancer pain, aiming to reevaluate the benefits and harms of cannabis-based medicine for patients with advanced cancer. They selected 14 studies involving 1,823 participants and found moderate-certainty evidence that “nabiximols and THC” used as additional treatment for opioid-refractory cancer pain did not differ from placebo in reducing mean pain intensity (30). Their findings did not significantly differ based on route of administration, as mouth sprays with a combination of THC and CBD still did not outperform placebo in reducing pain in patients with severe cancer pain (30). Häuser et al. also concluded that a single dose of an artificial cannabinoid mimicking the effects of THC, while more effective at reducing pain than a single dose placebo, still did not significantly differ from a single small dose of “morphine-like” medication in reducing cancer-related pain (30). The authors note that their evidence is incomplete as the included studies on THC analogues date back to the 1970s, and associated “study design limitations” often exhibiting a high risk of bias. Häuser et al. confirm that future studies following more up-to-date guidelines for both palliative care and medical marijuana may elucidate more clear findings.

Also in 2023, the Multinational Association of Supportive Care in Cancer (MASCC) released guidelines for use of cannabis for cancer-related pain (31). To et al. looked at 34 systemic reviews and randomized trials analyzing analgesic benefits of cannabis as well as adverse events related to cannabis use. The authors concluded that they do not recommend the use of cannabis for cancer-related pain outside of randomized controlled trials citing lack of efficacy, risk of harm, and other available medications to treat pain (23). Furthermore, they specifically recommend against cannabis use in patients receiving checkpoint inhibitors, as there are two retrospective studies showing decreased time to tumor progression and decreased survival (31).

A recent meta-analysis investigated the role of medical cannabis on therapeutic potential, safety, and role in cancer treatment. The findings suggest a role for cannabis in managing cancer-related symptoms as well as possibly exerting an anticarcinogenic effect. Of note, THC was found to have potent anti-inflammatory properties, an important finding given the prevalence of inflammatory-related pain in many cancers. Thus, the authors concluded that while more research is needed, there does appear to be support for the use of cannabis as a palliative adjunct to cancer treatments (32).

Overall, there remains limited evidence to support the use of medical cannabis for cancer-related pain. Evaluating the efficacy of cannabis in cancer is complicated by the larger heterogeneity of both cannabis extracts as well as types of cancer in which cannabis is used. There also continues to be limitations in conducting studies as federal regulations classify marijuana as a Schedule I drug, limiting large-scale clinic research. These issues further highlight the necessity for high-quality research.

Potential limitations/cautions for marijuana use

Although there are various therapeutic benefits from cannabis use for patients with cancer pain, Woerdenbag et al. performed a narrative review with studies from 2016-2022 to provide more comprehensive limitations and cautions regarding marijuana use. Their review starts by acknowledging the importance of THC:CBD ratio along with key plan constituents, including terpenes and flavonoids in contributing to the cannabis therapeutic effect, known as the “entourage effect” (33). Importantly, however, Woerdenbag et al. note that medical cannabis products must be rigorously controlled and held to high qualitative standards to ensure clinical efficacy and safety for clinical studies (33). The researchers’ claim is not unfounded as studies in the Netherlands found that street-market quality cannabis 10 out of 10 times exceeded the limits for “microbiological purity” with occasional presence of Escherichia coli, Cladosporium, and Aspergillus. Fortunately, pharmaceutical-grade cannabis products met the requirements for safe use without the presence of any microbial impurities (33).

Despite numerous ways of administering marijuana, including orally in the form of tea, inhalation by smoke or vapor, application by cannabis oil, there are clear pharmacokinetic differences between each route of administration that may affect therapeutic benefits. Cannabis, when taken orally, has a low bioavailability of THC and CBD due to first-pass metabolism in the gastrointestinal tract and liver (33). Maximal plasma concentrations of THC are reached after “several hours”, while the same plasma concentrations are reached within 10 minutes through inhalation of vapor (33). The authors comment that additional considerations, such as the “taste” of cannabis tea and cannabis oil, may be “unpleasant” and hinder the acceptance of the therapy by the patient, while an inhalation device may be preferable but expensive and a “burden” for the user. These concerns should be taken into account for each patient, given their specific uses and needs.

Possible interactions of marijuana with anticancer drugs

Woerdenbag et al. remark that another limitation of marijuana is the potential for interactions with anticancer drugs. In theory, based on in vitro models, marijuana products have the potential to impact numerous biological membrane components, including adenosine triphosphate (ATP)-binding cassette (ABC) transmembrane proteins, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins (MRPs) (33). Given these interactions with transmembrane channels, researchers have found elevated concentrations of anticancer drugs such as topotecan, which utilizes the BCRP transporter, when given to in vitro models along with cannabis. Other studies have also found that Cannabinoids bind with high affinity to plasma proteins. As such, other anticancer drugs that bind to plasma proteins, such as platinum drugs and 5-fluorouracil, may also be impacted by cross effects with cannabis (33). Further research into drug interactions between cannabis and other cancer therapeutics, including immunomodulatory cancer drugs (nivolumab, atezolizumab), nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids (dexamethasone, prednisone, prednisolone, and triamcinolone), is warranted (33).

Adverse effect and safety profile

Marijuana products are generally well-tolerated with limited adverse effects. The most common self-reported side effects include dry mouth, drowsiness, and dizziness (33). There is also emerging data regarding effects of marijuana on the cardiovascular system and cognitive function; however, this has not been fully assessed in the cancer population (34,35). The researchers acknowledge that providers and patients must be vigilant when prescribing or using cannabis, as known side effect profiles remain limited. The majority of marijuana use has been recreational. As more legislation is passed on the use of medical marijuana, further research regarding marijuana-drug interactions and side effects will elucidate more appropriate monitoring and management protocols (33).

Conclusions

Medical marijuana continues to be an attractive option to many patients due to its perceived limited side effect profile as well as many formulations available for patients. Although some studies suggest potential benefits, there is overall limited evidence to support the use of medical cannabis for treatment of cancer-related pain. Federal regulations classify marijuana as a Schedule I drug, posing a significant barrier to large scale clinic research. As more states move toward legalization for medicinal use, it is essential to further investigate both the efficacy and safety profile of medical cannabis.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Alaa Abd-Elsayed) for the series “Pain Management Options for Incurable Cancer”, published in Annals of Palliative Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-25-85/rc

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-85/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-85/coif). The series “Pain Management Options for Incurable Cancer” was commissioned by the editorial office without any funding sponsorship. L.R.K. reports the grants from FUSmobile, NIH, Averitas, and Vertex; consulting fees from Avanos; Support for attending meetings from UVA; and participation on a Data Safety Monitoring Board of Reliev-CM2; Leadership or fiduciary role in ASRA BOD, AAPM BOD, SAAAPM BOD, APPD BOD, and Purpose Network BOD. The authors have no other 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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