Preventing & Treating Cancer — The Potential Role of Cannabis

There are more than 100 different types of cancer. At the most basic level, cancer occurs when abnormal or damaged cells grow, multiply, and spread into healthy tissues.1

Although their use depends on the specific type and stage of cancer, therapeutics include surgery, chemotherapy, radiation therapy, immunotherapy, antiangiogenic treatment, hormone therapy, targeted drug therapy, and radiofrequency ablation, among others.1 All these strategies attempt to kill cancerous cells or stop their growth and spread. The unifying factor in successful cancer treatment is that early detection—and prevention—is even better.

Although certain substances such as nicotine and alcohol have been cited as increasing cancer risk, some researchers believe cannabis may decrease risk, despite its classification as a Schedule I drug. However, there isn’t enough research on cannabis to make conclusions. Second, prevention is difficult to define and nearly impossible to prove. But that’s not to say the question—whether cannabis can be used in the prevention of cancer and as an early-stage intervention—is without merit, nor is it without certain answers.

Fresh Look at the Evidence
Many lifestyle adjustments are recommended to prevent cancer, including use of supplements such as vitamins C, D, and E. These nutrients are mainly touted for their role as antioxidants, and, while there’s no proof of their efficacy, their unregulated status keeps them on the shelves and in people’s cabinets. The issue is the potential for toxicity—and it’s much the same question with cannabis.

Might vitamin C supplements reduce the risk of cancer? Perhaps, but if not, the result is simply more expensive urine. On the other hand, vitamin D and vitamin E, being fat soluble, can build up in the body and potentially cause side effects such as kidney stones. Likewise, cannabis is fat soluble, making its health effects gradual, and knowledge about its potential for side effects is dependent on robust clinical studies.

“Whether or not CBD can be toxic is still not definitively known—for example, how high of a dose we can recommend,” says Dong Zhang, MD, director of the New York Institute of Technology Center for Cancer Research and senior author of the review “Cannabidiol (CBD) as a Promising Anti-Cancer Drug,” recently published in the journal Cancers.2 “Pharmacokinetics, pharmacodynamics, and toxicology studies are potentially underexplored research areas.” Given the lack of research and outstanding potential of cannabis to modify the biological mechanisms of cancer, Zhang is clear on the limitations of the current research: “Based on the biology of CBD and its physiological function, there is the potential for CBD to prevent the occurrence of cancer or even the spread of the cancer, but I must emphasize that in order to recommend CBD to patients, or to healthy individuals, you really need rigorous clinical trials, which we don’t have. This is one of the reasons that we decided to explore the CBD research—to convey the research that we do have for the application of CBD.”

Zhang and colleagues’ comprehensive review included 134 scientific publications and focused on the biological mechanisms by which CBD could stop the growth and spread of cancer cells without poisoning healthy cells, as most cancer treatments do. Major themes in the review include CBD’s potential to increase the amount of reactive oxygen species (ROS) in the cancer microenvironment, improve the body’s immune response, and activate endoplasmic reticulum (ER) stress. Each of these research areas is explored in detail in this article.

ROS Modulation
Beginning with ROS, the dual nature of CBD is evident. Low-level increases in ROS can increase the likelihood of DNA mutations, and the accumulation of mutations could promote the abnormal cell growth that leads to cancer. By this measurement, it’s easy to assume that anything that promotes oxidative stress is bad. Here, it’s necessary to differentiate between the interaction of CBD with healthy cells vs with invasive cells and to be aware that different compounds in the plant result in different interactions. “Cannabis is more like a Chinese medicine; you have a potential mixture of active ingredients within that, which is also a potential issue for FDA approval. The FDA likes to approve more isolated chemicals, so they know definitively the active ingredients in the drug that causes specific effects,” Zhao says.

Under normal circumstances, CBD has been shown to decrease oxidative stress in healthy tissues. A vast body of studies (predominantly in animal models) report CBD’s proclivity to act as a free radical scavenger, exhibiting behaviors similar to more commonly known antioxidants.3 CBD has been shown to broadly affect tumor necrosis factor in an array of anti-inflammatory models and may regulate the enzymatic activity of copper and zinc, which metabolize superoxide radicals.4,5 Indeed, many medical uses of CBD focus on its antioxidative and anti-inflammatory properties (such as in the treatment of pain and neurological disorders).6

As with any therapeutic, CBD’s actions are likely specific to certain conditions. Some examples include preventing hydroperoxide-induced oxidative damage in neurons,7 ameliorating lipopolysaccharide-induced ROS production in microglia,8 and inhibiting mitochondrial superoxide generation in high glucose–stimulated human coronary endothelial cells.9

Regarding the pro-oxidant potential of CBD, the compound has been shown to increase intracellular ROS production in isolated human monocytes, breast cancer cells, human glioma cells, and human leukemia cells.10-13 This pro-oxidative effect on monocytes may account for the anti-inflammatory effects and immunomodulation in autoimmune conditions.

In cancer cells, CBD’s pro-oxidative effects have been shown to cause apoptosis. For example, CBD has been shown to increase ROS in human colorectal cancer cells, inducing cell death.14 CBD has also been shown to up-regulate oxidative stress and induce cell death in human breast cancer cell lines, with no significant effect on healthy breast epithelial cells.15 This increased ROS production seems to happen at an intracellular level in the cancer cells, leading to apoptosis and cell death—a primary mechanism by which CBD shows promise as an early-stage cancer treatment.

In their review, Zhang and colleagues note that while CBD has a pro-oxidant effect in many cancer cells, it typically did not exert the same effects on healthy cells.

ER Stress
ER stress is another important actor in apoptosis and cancer cell death. The ER plays a crucial role in intracellular calcium homeostasis as well as in the in the posttranslational modification and folding of proteins. When there is an accumulation of misfolded or unfolded proteins, the unfolded protein response is triggered—temporarily halting protein synthesis. This process creates high levels of stress on the cell, increasing the transcription factor CHOP, which induces apoptosis via the generation of ROS, increased cytoplasmic calcium levels, and increases in the extrinsic cell death pathway, promoting the release of cytochrome C. Cancer cell death mediated by ER stress has been observed in breast cancer,15 colorectal cancer (in combination with TRAIL therapy),16 and lung cancer,17 among others.

During development, tumors rely heavily on the unfolded protein response; by overwhelming this system, cannabis could be an important early therapeutic to inhibit tumor growth.

The Immune Response
Many studies indicate there’s potential for cannabis to bolster the immune response to cancer, while others suggest that cannabis could suppress the host immune response. Cannabinoids (including both CBD and THC) seem to increase anti-inflammatory cytokines and decrease proinflammatory cytokines.

In a murine model of lung cancer, THC was shown to inhibit the host’s immune response to cancer cells; similar findings have been reported in a murine breast cancer study. The findings indicated that THC suppressed the T helper 1 cell–mediated response, enhancing proinflammatory cytokines mediated by T helper 2 cells.15

Is there a reason for hope? In the review, Zhang and colleagues reported CBD’s ability to disrupt the protumorigenic cytokine production, thus leading to ineffective immunosuppression and promoting tumor cell death. Cannabis also interacts differently with various cancer cells. In the review, there was positive evidence for CBD’s ability to inhibit cancer cell migration in breast cancer, lung cancer, and glioma. Studies suggest that CBD binds to the CB1 and CB2 receptors on infiltrating inflammatory cells, thereby disrupting protumorigenic cytokine production.

As researchers focus more on the tumor-suppressive potential of cannabis, the science points toward the tumor-suppressive benefits. Studies concerning the immune-modulatory role of the endocannabinoid system have shown that CB2 activation inhibits the production of tumor necrosis factor-alpha, interleukin 6, and interleukin 8 in monocytes and macrophages.2

Antiangiogenetic Effects
Antiangiogenic therapies are relatively new in cancer treatment. In essence, they “starve” the cancer cells by stopping the generation of new blood vessels that serve the tumor. Various studies have indicated that CBD may promote antiangiogenic activities. Vascular endothelial growth factor (VEGF) is activated in the microtumor environment.18 Cannabis shows promise in attenuating VEGF production, which may decrease angiogenesis in cancer cells. One review specifically showed the antiangiogenic effects of cannabis on glioblastomas.19 CBD has been reported to inhibit angiogenesis related to the proliferation of estrogen receptor–positive breast cancer by inactivating proangiogenic factors such as VEGF, integrins, and angiopoietins, or by activating inhibitory effectors such as thrombospondins or interferons.20

Cannabis as an Adjunct Therapy
Cannabis is widely accepted as a modulator of symptoms associated with chemotherapy, such as nausea and pain. But can cannabis improve the efficacy of already approved cancer treatments? Some research suggests it can. While existing studies are slim, there’s evidence that CBD can augment treatment with temozolomide (TMZ) in glioma patients.21 Patients who were treated with a Sativex 1:1 oro-mucosal in conjunction with dose-intense TMZ had an increased one-year survival rate compared with study participants given a placebo. The observed indication was that resistance to TMZ treatment may be reduced by using combinations of CBD and delta-9-THC.

As an adjunct therapy for colorectal cancer patients receiving immunotherapy, cannabis may improve survival rates by increasing immunogenicity and reversing tumor immunosuppression.22

Cannabinoids, the Endocannabinoid System, and Prevention
The endogenous cannabinoid system has gained considerable attention for its role in health and disease states. About the potential role of cannabis in prevention, Eloise Theisen, RN, MSN, AGPCNP-BC, cofounder and CEO of Radicle Health and Radicle Health Clinical Network, says, “Often, we are talking about deficiency in endocannabinoid tone—which is something we haven’t been able to test for yet. We cannot test for a dysfunctional endocannabinoid system; we cannot test to know if it is unregulated or down-regulated, so we look for clinical indications to make a differential diagnosis,” says Theisen, who refers to a theory first introduced by Russo and colleagues in 2001. The theory links many diseases states to alterations in a person’s endocannabinoid levels or receptors; more recent evidence has linked it to chronic illnesses such as migraine.23 Theisen recommends providers look for a strong family history of conditions such as fibromyalgia, irritable bowel disease, and migraines, and take a full history of patient health, drug use, cannabis use, social interaction, alcohol intake, exercise, diet, sleep habits, and comorbidities. “The issue is that you could have 20 other differential diagnoses, but when someone comes to cannabis, usually those other diagnoses have been ruled out,” she says.

Recent research by Thomas M. Clark, PhD, of the department of biological sciences at Indiana University, looks at the role of cannabis in chronic inflammation as it relates to obesity, metabolic syndrome, and cancer. Clark is studying the role of the Western diet in dysregulating the endocannabinoid system—particularly the increased intake of omega-6 fatty acids and a decreased intake of omega-3 fatty acids. Clark proposes that this overstimulates CB1 receptors, which can be rebalanced by exogenous cannabinoids, decreasing the inflammatory state as well as markers of obesity and metabolic disease—which put people at greater risk of cancer. “When you use cannabis, you rapidly down-regulate the CB1 receptor, which can be overstimulated by high levels of omega-6 intake,” Clark says.

Both theories, that of cannabinoid tone and of an up-regulation of CB1 receptors, focus on the importance of a balanced cannabinoid system in relation to the overall disease state. In Clark’s paper, “Scoping Review and Meta-Analysis Suggests that Cannabis Use May Reduce Cancer Risk in the United States,” he additionally cites the antitumorigenic potential of cannabis.24 At the same time, Clark doesn’t recommend individuals approach cannabis as they do vitamin C, for example. Exogenous cannabinoids could be beneficial for individuals who show signs of a dysregulated endogenous cannabinoid system, such as obesity, metabolic syndrome, and multisystem chronic illnesses.

When working with patients, Theisen is mindful of down-regulation. “What I see with down-regulation is usually symptoms that are outweighing any benefits. Depression, anxiety, and psychosis are likely indicators of overconsumption and down-regulation.” While Theisen believes cannabis has great potential in disease modulation, she’s clear that individuals should work with an expert and avoid trusting “Dr. Google.” “The one thing we don’t understand are the long-term effects of CBD. It’s the same thing as with vitamin D right now—everyone wants to take vitamin D, but what if your levels are good? You need to check in with an expert and determine if your dosage needs to be adjusted,” she says.

Practical Implications
As with any drug, cannabis comes with certain risks, but when it comes to cancer, there seem to be clear potential benefits. The American Cancer Society now lists cannabis and cannabis-based drugs as potential adjunct treatments for cancers but warns against relying on cannabis to replace proven medical interventions.25 “We have a limited amount of research on cannabis in general, and when talking about prevention, it’s difficult to say anything with certainty,” Theisen says. “That being said, when cannabis may be advised is when we see clinical symptoms of endocannabinoid dysregulation, in which case [patients] could be recommended to a specialist. When taking cannabis, it’s important to be aware of clinical signs of down-regulation, and a CBD-dominant approach would be recommended.”

There’s a clear need for increased funding for cannabis research. Despite strong research in animal models, there’s a lack of robust studies in humans. “This is one reason we decided to research the effect of CBD on cancers, using the cancer cell line. This is usually the clinical development; for a drug to be approved by the FDA, it has to go through certain stages. Before animal models, we typically begin with cell lines and eventually make our way to clinical trials,” says Zhang, who’s begun studying the effects of CBD on melanoma. “In our labs, we’ve done analysis on melanoma cell lines and have unpublished data supporting the claim that the CBD can induce ER stress. We find that CBD can exacerbate the response to unfolded proteins and induce ER stress, which in turn induces ROS in the melanoma cell lines, which we believe could be the mechanism that induces cell death in the melanoma cell lines,” he says. Although no two tumors are the same, the researchers believe that studying the impacts of CBD on melanoma could offer valuable insights into how CBD interacts with the tumor cells.

But is there any reason to begin a cannabis or CBD regimen in patients with a higher risk of developing cancer? “We don’t have enough data to say there’s a cannabinoid you should take at ‘X’ dose to prevent cancer,” Theisen says, adding, “CBD is Generally Recognized As Safe, so for most people I would say a CBD [regimen] can do more benefit than harm, but again, it always depends on the person. Most people tolerate CBD well, even in high dosages, but the million-dollar question is whether it’s worth it.”

In the United States, CBD products are treated as supplements, meaning they aren’t regulated. For patients who are interested in a CBD regimen, it’s important to understand that CBD’s effects build over time and supervision by a qualified professional is an important part of care.

— Jennifer Lutz is a freelance journalist who covers health, politics, and travel. She’s written for both consumer and professional medical magazines as well as popular newspapers. Her writing can be found in Practical Pain Management, Endocrine Web, Psycom Pro, The Guardian, New York Daily News, Thrive Global, BuzzFeed, and The Local Spain. In addition to journalism, Lutz works as a strategies and communication consultant for nonprofits focused on improving community health.

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