Continuing Education Activity
Medicinal marijuana is a medication currently undergoing research for its use in the management and treatment of several oncology-related symptoms. Such areas of potential use include chemotherapy-induced nausea, vomiting, analgesia, cachexia, and tumor suppression. This activity reviews the most up-to-date literature on the use of medicinal marijuana. This activity will highlight the history, mechanism of action, adverse event profile, and several study outcomes that will aid the interprofessional team in understanding the effects and potential uses of medicinal marijuana in the field of oncology.
Objectives:
Describe the pharmacodynamics of medical marijuana.
Identify the active compounds within the cannabis plant that hold potential therapeutic benefits within the field of oncology.
Outline the potential adverse events a patient may experience while consuming medical marijuana.
Identify four areas within the field of oncology that medical marijuana is being investigated as a possible therapeutic agent by an interprofessional team.
Introduction
Medicinal marijuana (Cannabis sativa) has become a topic of great debate within the oncology literature. There have been several proposed uses of cannabis by clinicians and researchers alike. As of April 2021, medical marijuana use has become legal in 36 states, and recreational use has been approved in 15 states and Washington, DC. With the increasing use of marijuana, it will likely become commonplace for patients to seek advice from medical providers in terms of potential therapeutic use. Clinicians should know the potential uses and side effects associated with marijuana to educate patients properly.
The history of cannabis within the medical community dates back to the 19th century when Dr. William Brooke O'Shaughnessy first published his data on the pharmacology and toxicology properties of cannabis. He found it to be a powerful analgesic, anti-convulsant, and muscle relaxant through his experimental treatment of patients suffering from rheumatism, cholera, tetanus, and seizures.[1] In 1964, Gaoni and Mechoulam successfully identified the active elements that comprised cannabis, namely cannabinoids such as delta-9-tetrahydrocannabinol (THC). This ultimately led to the discovery in the 1990s of the human endogenous molecules, Anandamide (ADA) and 2-arachidonoyl-glycerol (2-AG), that play a role in the endocannabinoid system by acting on cannabinoid receptors 1 and 2.[2]
As of January 22, 2021, the U.S. Food and Drug Administration has approved one purified form of CBD for seizure treatment as well as three medications that contain either dronabinol (THC) or nabilone (synthetically derived form of THC) for therapeutic use. Exogenous cannabinoids, such as THC and cannabidiol (CBD), and their effect on the endocannabinoid system will be discussed below regarding their role in oncology with chemotherapy-induced nausea/vomiting (CINV), analgesia, cachexia, and tumor suppression.
Function
Cannabis is composed of a variety of constituents, which include over one hundred different cannabinoids. Within the family of cannabinoids, delta-9-tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) can be decarboxylated via heat to produce delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).[3][4] The decarboxylated form has drawn the most interest within the medical community due to the suggested therapeutic benefits.
Cannabinoids exert their effect through their interaction with cannabinoid receptors, namely cannabinoid 1 (CB1) and cannabinoid 2 (CB2). CB1 receptors are predominately found within the central nervous system, though they are ever-present throughout the human body. Of note, it is the activation of CB1 receptors by THC that leads to the well-known psychoactive effects associated with cannabis use.[5] Conversely, CB2 receptors are found within the immune system, subsequently playing a role within immunomodulation, and are non-psychoactive.[6]
THC binds with these cannabinoid receptors acting as a weak partial agonist, whereas CBD has a low affinity for either receptor.[4] When THC and CBD are both within the vicinity of a CB1 receptor, CBD acts as an antagonist at the receptor site and modulates the effect of THC.[3] Specifically, CBD’s allosteric inhibition leads to the inability of THC to bind with CB1 receptors. This decreased the hallucinogenic effect caused by normal THC-CB1 interaction.[5]
Issues of Concern
Medicinal and recreational marijuana use comes with several reported side effects: dizziness, euphoria, somnolence, hallucinations, dry mouth, confusion, and nausea. Furthermore, there remains some uncertainty regarding the more severe side effects such as myocardial infarction and/or stroke being associated with cannabis use. In chronic excessive users, cannabinoid hyperemesis syndrome, in which marijuana use leads to the triad of nausea, vomiting, and abdominal pain, may occur.[7]
Another factor to consider is the method through which cannabis is delivered. Administration of cannabis may occur via oromucosal sprays, capsules, edibles food products, topical solutions, or inhalation. Smoke from the inhalation of marijuana has been found to contain several carcinogens that are also in tobacco smoke, such as formaldehyde, arsenic, and benzene. [8] Due to the presence of these carcinogens, the American Cancer Society Cancer Action Network recommends against smoking or vaping medicinal marijuana to prevent harm to the patient and mitigating the risk of secondhand smoke to bystanders.
Lastly, when utilizing medicinal marijuana to treat the side effects associated with oncology treatment regimens, clinicians must consider the possibility of cannabinoids interfering with the effectiveness of their patient's cancer therapy. Bar-Sela et al. evaluated the interaction between immunotherapy and cannabis use for patients with metastatic (stage IV) disease. The study found a significant decrease in overall survival rates (6.4 months for cannabis users vs. 28.5 months nonusers) and time to tumor progression (3.4 months for cannabis users vs. 13.1 months for non-users).[9] The endogenous cannabinoid, ADA, has been shown to inhibit mitogen-activated T and B lymphocyte proliferation in a dose-dependent fashion.[10]
Halting or restraining the body's immune response may inhibit the effectiveness of immunotherapy and weaken the body's ability to destroy cancer cells. Exogenous cannabinoids, specifically THC, were found to suppress CD8 T-cells and cytotoxic T lymphocytes. THC was also discovered to down-regulate the proliferation of lymphocytes and their maturation into cytotoxic T lymphocytes.[11]
Clinical Significance
Chemotherapy-induced Nausea and Vomiting (CINV)
CINV is a well-known side effect associated with chemotherapy regimens. The vomiting response consists of a complex system of afferent and efferent messengers traveling to and from regions within the medulla termed the "Chemotherapy Trigger Zone" and "Vomiting Center." Chemotherapy is believed to induce this signal cascade through two separate mechanisms: peripheral and central.[12]
The peripheral pathway is associated with acute emesis and vomiting that occurs within 24 hours of chemotherapy initiation. The mechanism involves the activation of serotonin/5-HT3 receptors within the gastrointestinal (GI) mucosa. The toxic effect of chemotherapy agents leads to the destruction and or injury to enterochromaffin cells within the GI tract, subsequently causing their release of serotonin. Serotonin receptors bind with the abundant release of serotonin molecules and send afferent signals to the Chemotherapy Trigger zone. Here, the culmination of afferent signals occurs and triggers an efferent signal from the Vomiting Center back to the periphery. The efferent signal leads to the contraction of abdominal muscles, diaphragm, and stomach. The outcome of such contractions is emesis.[12][13]
The central pathway is primarily involved in delayed emesis, vomiting that occurs greater than twenty-four hours after dosing of chemotherapy. The mechanism predominately occurs within the brain and is regulated by the neurotransmitter substance P and its affinity for Neurokinin-1 (NK-1) receptors. The presence of chemo agents leads to the body's release of substance P and its subsequent binding to NK-1 receptors within the brain. The substrate-receptor interaction leads to direct signaling of the Chemotherapy Trigger Zone within the medulla, which compiles the signal and triggers the Emetic Center to send efferent signals to induce emesis.
To date, clinicians have attempted to alleviate CINV through a combination of medications that act as antagonists at serotonin/5-HT3 and neurokinin1 receptor sites.[14] Despite medical advances in developing such antagonistic medications, 40% of patients receiving chemotherapy still report experiencing nausea and/or vomiting.[12] Other methods of eliminating such symptoms have been investigated, namely the use of cannabinoids THC and CBD and their interaction with CB1 and CB2 receptors.
Grimison et al. performed a crossover study of 72 patients experiencing refractory CINV despite receiving guideline-consistent antiemetics comprised of corticosteroids, NK-1 antagonists, 5-HT3 antagonists, and plus/minus olanzapine. Subjects were randomized to receive either placebo or oral THC:CBD (2.5 mg:2.5 mg) in cycle A and subsequently received the opposite trial drug in cycle B. For cycle C, participants remained blinded but received the medication that they felt was most beneficial. Results proved that supplementation of THC:CBD in conjunction with the already approved antiemetic regimen significantly decreased episodes of both nausea and vomiting. Additionally, the patients' rate of complete response (defined as no episodes of emesis) increased from 14 to 25% with the addition of THC:CBD. Despite the significant improvements in controlling CINV, 31% of participants experienced adverse events, including but not limited to sedation, dizziness, and disorientation as a byproduct of their use of cannabinoid therapy. Despite the significant increase in adverse events, 83% maintained a preference for THC:CBD over placebo.[15]
Polito et al. investigated the effect of cannabis therapy within the pediatric oncology population suffering from CINV. Nabilone, a synthetic THC analog that acts as an agonist at CB1 and CB2 receptor sites, was provided to subjects in addition to their antiemetic regimen that most commonly consisted of a 5-HT3 antagonist. Results showed that patients receiving highly emetogenic chemotherapy and moderately emetogenic chemotherapy achieved complete acute chemotherapy-induced vomiting control in 50.6% and 53.8% of subjects, respectively.[16] In comparison, Polito et al. cited a prior meta-analysis by Dupuis et al. that demonstrated similar outcomes in pediatric patients solely receiving a 5-HT3 receptor antagonist with complete resolution of vomiting in 56% and 54% of those with high and moderately emetogenic chemotherapy treatments, respectively.[17] Additionally, adverse events within Polito et al.'s study attributed to the use of Nabilone were experienced by 34%, with the most common symptoms being sedation, dizziness, and euphoria. Given the increase in adverse events caused by Nabilone, while achieving similar results as patients treated with a 5-HT3 antagonist alone, the investigators were unable to recommend the addition of the synthetic THC analog Nabilone therapy to the 5-HT3 antagonist in pediatric oncology patients.[16]
Analgesia
There are many sources of pain for oncology patients. Pain can be associated with chemotherapy, radiation treatment, or the disease itself. Patients with metastatic disease and those receiving anticancer treatment report prevalence of pain in 64% and 59% of cases, respectively.[18] Opioid medications have become a common analgesic for treating the discomfort associated with an oncologic disease. Unfortunately, opioid medications come with side effects, including but not limited to sedation, respiratory depression, constipation, nausea/vomiting, and dependence/addiction.[19] Attention has been drawn to the potential use of cannabinoids to alleviate pain and subsequently reduce the use of opioid medications.
Johnson et al. evaluated the efficacy of cannabinoid therapy when supplemented with opioid treatment for patients with advanced cancer over a two-week span. Subjects were randomly divided to receive either THC:CBD extract, THC extract, or placebo. The study drug was provided as an oromucosal spray, with each spray containing 2.7 mg THC and 2.5 mg of CBD. Results showed a statistically significant decrease in pain reduction compared to placebo in the THC:CBD group, but not the THC group. Additionally, 43% of THC:CBD subjects demonstrated a greater than 30% decline in pain on the NRS pain scale, which is deemed a clinically significant improvement. Interestingly, despite the addition of the experimental drug, none of the groups demonstrated a change in the median dose of their baseline opioid medication. Based on the results, the study's authors recommended supplementation of the tested THC:CBD extract to improve pain control in patients with advanced cancer when symptoms are unrelieved by opioid medication.[20]
Pawasarat et al. retrospectively reviewed morphine milliequivalent (MME) consumption in oncology patients using and not using medicinal marijuana. Their results showed that patients utilizing medicinal cannabis had a significantly lower daily intake of MME at both the onset and culmination of the study compared to patients receiving only opioid medication for pain control. As they trended MME intake throughout the study, it was noted that the rate of increase of opioid consumption was decreased in medical marijuana users compared to non-users.[21] Such findings suggest that medicinal marijuana not only serves as an aid in pain control but that medical marijuana may also prolong the effectiveness of an opioid dose. The authors hypothesize that this enhanced effectiveness may delay developing opioid tolerance.
Cachexia
The hormone Leptin triggers afferent signals to the brain leading to decreased appetite and increased energy expenditure. When the body is in a state of starvation, Leptin levels are suppressed, and the hormone ghrelin and appetite-stimulating neuropeptides such as neuropeptide Y are upregulated. Tumors possess the ability to release cytokines mimicking leptin and subsequently suppressing ghrelin and neuropeptide Y signals. The effect of this pathologic process is anorexia (loss of appetite) and cachexia (loss of muscle with or without loss of adipose tissue).[22] As we discussed earlier, the ability of cannabinoids to reduce CINV is one method to counteract malnourishment associated with oncology treatment. An additional perceived benefit of cannabinoid therapy is the notion that it stimulates appetite. Dronabinol (THC) has been utilized in AIDS patients since May of 1985 when it was first approved by the US Food and Drug Administration to combat anorexia associated with AIDS.[23] Interest has subsequently carried over to the field of Oncology to determine whether patients burdened by a neoplastic disease would achieve similar enhancements in appetite.
Strasser et al. investigated the effects of a cannabis extract consisting of 2.5 mg of THC and 1 mg of CBD vs. 2.5 mg THC vs. placebo in terms of their ability to improve appetite and quality of life over a 6-week timeframe. Cannabis extract proved to be the most beneficial in improving appetite in 73% of patients, whereas THC and Placebo were less effective at 58% and 69%, respectively. Despite such improvements, statistically significant values were not met by either group in terms of improvement in appetite or quality of life.[24]
A 20 institution, double-blind, randomized trial of 469 advanced cancer patients was performed assessing the usefulness of Dronabinol (2.5 mg BID) in isolation vs. combined with megestrol acetate (orexigenic agent) vs. isolated megestrol acetate. Subjective improvement in appetite proved superior in the single-agent megestrol acetate arm compared to the single-agent dronabinol group (75% vs. 49% of patients, respectively). A significant increase in the percentage of patients gaining > 10% from their baseline body weight was found when comparing the megestrol acetate group to the isolated dronabinol group, at 14% and 5%, respectively. Combination therapy (11%) vs. megestrol acetate (14%) showed no significant difference in terms of weight gain. The authors concluded that megestrol acetate was superior in inducing appetite and increasing weight gain compared to dronabinol. Furthermore, combination therapy of dronabinol and megestrol acetate did not demonstrate a significant difference in terms of appetite or weight gain compared to megestrol acetate alone.[25]
Bar-Sela et al. performed a similar study evaluating the efficacy of THC:CBD capsules in producing weight gain > 10% from baseline over a 6 month period. Despite a high rate of dropout (most commonly due to disease progression or side-effects from the study drug), 50% (n= 3) of the patients completing the 6-month study achieved a > 10% weight gain, while the remaining 50% of patient's weight remained stable.[26] Further investigation is warranted on a larger scale to help define the most appropriate dosage and effectiveness of cannabinoids in treating cancer-related cachexia and anorexia syndrome.
Tumor Suppressor
Several studies have investigated the effectiveness of cannabis use and its anti-tumor properties with specific cancer cell lines. Results of these studies have found evidence for inhibition of tumor cell proliferation and invasion, induction of apoptosis, and enhancement of the body's immune surveillance of tumor cells.[27] However, it is critical to note that despite the promising results found in such studies, the outcomes should not be interpreted to hold true for every cancer cell line.
Dr. Baram et al. investigated the effect of various combinations of cannabis extracts and their effect on 12 different cancers. Results demonstrated a variable response depending upon the cancer type and content profile of the specific cannabis extract. Of the 12 cancer varieties tested, components of THC were found to be successful in inducing cell death. Apoptotic features and/or inhibition of proliferation were found to be the underlying mechanism. Interestingly, two extracts consisting of equal amounts of THC but varying levels of other cannabinoids (i.e., CBD, Cannabigerol [CBG], THCA, etc.) had different outcomes in terms of cell death. Such findings indicate the likelihood that the interplay of the combination of cannabinoids may be the true determining factor of the extract's effectiveness rather than the presence or amount of THC. Therefore, the authors recommend whole extract cannabinoid therapy as opposed to single-agent THC formulations that have higher anti-tumor properties.
Another pertinent finding of the study discovered that each cancer type possessed unique cannabinoid receptors and had varying responses to specific cannabinoid extracts. Of the 12 cancer cell lines evaluated, breast and colon cancer had the lowest reported rate of tumor cell death.[28] The study suggests that the efficacy of cannabis to induce tumor suppression was based on varying ratios and combinations of a cannabinoid receptor and cannabis extracts. This indicates that the interaction between tumor and extract is unique and more research is needed to determine which combinations are most efficacious.
Other Issues
Other Issues
Since April 14, 2021, 17 states, the District of Columbia, and 2 territories have enacted regulations for medical marijuana dispensaries to abide by (https://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx). Regulations are state-dependent and may or may not entail product safety testing, labeling, and packaging requirements. Specifics for labeling may include listing the strain of marijuana, potency, and or health risks associated with its use. Packaging requirements may mandate the use of childproof and tamper-resistant material.[29]
However, until marijuana is approved at the federal level, the regulation of dispensaries will remain at the state level. Despite such variation amongst states, a controlled and legislated environment offers a sense of security to patients seeking medicinal marijuana to alleviate their ailments. In states where marijuana use has not been legalized, patients are faced with the risks involved with obtaining the substance illegally. Such risks may include fines, imprisonment, and alteration of the product that decreases the therapeutic benefits patients seek and, in some cases, causing detrimental effects to their health. As marijuana use continues to gain acceptance and approval within the United States, it may be beneficial to impose regulations to ensure safe and effective products capable of providing the therapeutic benefits sought after with medicinal use.
Enhancing Healthcare Team Outcomes
As medical marijuana becomes a more acceptable pharmaceutical care option, the entire interprofessional team needs to be prepared to recommend and/or counsel patients regarding its use, risks, and benefits to optimize patient outcomes. This interprofessional team includes clinicians, mid-level practitioners, oncology specialists, nurses, and pharmacists. Pharmacists can play a critical role in identifying and dispensing the appropriate dose of medicinal marijuana. All team members need to be vigilant and monitor patient use when interacting with patients on medical marijuana. [Level 5]
Medical Cannabis Use in Oncology