The number of states that have legalized medical marijuana has steadily increased in recent years, and cancer and cancer treatment-related symptoms (ie, nausea, vomiting, cachexia) are qualifying conditions for use of the drug in all 26 states, and the District of Columbia, where use is permitted by state law.1 Although large, randomized, double blind clinical trials evaluating the efficacy of medical marijuana to treat the symptoms of cancer are limited, many patients use it to treat nausea, vomiting, decreased appetite, anxiety, and insomnia. In addition, two synthetic, oral cannabinoid drugs (dronabinol [Marinol] and nabilone [Cesamet]) are approved by the Food and Drug Administration (FDA) for the treatment of chemotherapy-related nausea and vomiting (CINV) in patients who have not responded to standard therapy.^2-4

However, advocates claim medical marijuana is more efficacious than the synthetic derivatives due to the more than 400 chemicals and 60 cannabinoids (the active components of medical marijuana, also known as phytocannabinoids) contained in medical marijuana, compared to only one, delta-9-tetrahydrocannabinol (THC), primarily used in the synthetic drugs mentioned above.5 The majority of studies showing efficacy in treating patients for nausea, vomiting, decreased appetite, and neuropathic pain are based on synthetic marijuana drugs.6 In addition, multiple in vitro and in vivo studies have shown that cannabinoids, such as delta-9-THC and cannabidiol (CBD), have antiproliferative effects on certain tumors, while leaving normal tissue unaffected.7 The diminished side effects and symptoms from cancer treatment therapies associated with medical marijuana use, as well as the intriguing possibility of antiproliferation, are motivating factors for many cancer patients to try this medication.

Proper management of patients using medical marijuana requires pharmacy have an understanding of the general history of the drug (see SIDEBAR 18-11), its pharmacokinetics and pharmacodynamics, adverse events, possible interactions, hospital-federal issues, and uses in patients with cancer based on the most current clinical information, so that pharmacists and other health care providers can help patients with cancer effectively and safely use medical marijuana products.

Pharmacokinetics and Pharmacodynamics of Marijuana

Multiple human and animal studies demonstrate the important role of the endocannabinoid system in memory, mood, inflammation, brain reward systems, drug addiction, and metabolic processes.12,13 Endocannabinoids and their receptors are found throughout the body, in the brain, organs, connective tissues, glands, and immune cells. Researchers have identified two endocannabinoid receptors in the body: CB₁, located in the central nervous system, connective tissues, glands, and organs; and CB₂, found in the immune system and hematopoietic cells.9 The CB₁ and CB₂ receptors function as G protein-coupled receptors, which are activated by cannabinoids to cause intracellular signal transduction leading to myriad therapeutic effects.¹⁴

Cannabinoids, the plant molecules that stimulate the endocannabinoid receptors, include delta-9-THC, CBD, and cannabinol (CBN), as well as the 60-plus other cannabinoids mentioned previously. These molecules originated from the Cannabis sativa marijuana strain. Cross breeding has resulted in two main species of marijuana: Cannabis indica and C. sativa.15 C. indica exerts stronger sedative and pain relief effects on the body, while C. sativa exerts an uplifting, energetic high, which is better for daytime use. These cannabinoids exert a stronger effect on the endocannabinoid receptors than the natural endocannabinoids, anandamide and 2-arachidonoylglycerol. The abundance of endocannabinoid receptors throughout multiple organ systems and the immune system suggests that there could be a wide range of therapeutic potential for medical marijuana.

Medical marijuana is available in various forms, including the plant product, edibles, capsules, tablets, oral oil-filled syringes, vaporizer oils, concentrates, sublingual strips, oromucosal sprays, and topical preparations (lotions, creams, etc). Each patient requires different dosing and dosage forms depending on their qualifying condition, comorbidities, and tolerance that may develop. For example, a medical marijuana-naïve patient who has not used marijuana recreationally previously will have a lower tolerance and will require a lower starting dose relative to a patient who has used medical or recreational marijuana previously. Tolerance is thought to occur with increased use of marijuana and may require dose adjustment over time.16

The bioavailability of different dosage forms also must be taken into account. Oral and inhaled medical marijuana products have different absorption rates and bioavailability. Oral medical marijuana products can take hours to reach peak blood concentrations, versus minutes for inhaled medical marijuana products (TABLE 15,17,18). Inhaled medical marijuana products are available in varying percentages of cannabinoids, depending on the strain, and can either be smoked or vaporized. Vaporization is a much healthier option for the lungs, because it contains fewer carcinogens than smoked marijuana.19 Vaporization also increases the percentage of delta-9-THC and CBD extracted from the marijuana. Sublingual and oromucosal products are another option that bypass first-pass metabolism similar to inhalation routes. These routes have shown high bioavailability, eliminate the need to inhale smoke or vapor, and have a faster onset than oral medications, such as edibles or capsules.20

Click here to see FIGURE 1.

Drug-Drug Interactions

Cannabinoids, such as delta-9-THC, are primarily metabolized by the cytochrome P450 CYP2C liver enzyme.17,18 Delta-9-THC is converted to 11-hydroxy-THC (11-OH-THC), which is primarily eliminated in the feces with secondary elimination in the urine, to a lesser degree. It also is believed that CBD more potently inhibits the CYP3A4 liver enzyme than delta-9-THC.

This information allows one to infer that any drug that is metabolized through the CYP3A4 enzyme would have an increased effect if taken concomitantly with marijuana products containing CBD. It also is important to consider any other medications the patient is taking that may cause drowsiness, such as benzodiazepines, barbiturates, narcotics, and some antidepressants, as using marijuana in addition to any of these drugs can increase drowsiness. Moreover, marijuana may increase the risk of bleeding if taken with drugs that increase the risk of bleeding, such as aspirin, warfarin, heparin, ibuprofen, or antiplatelet medications.21

Efficacy of Medical Marijuana in Cancer

Chemotherapy-Induced Nausea and Vomiting

As previously mentioned, two synthetic forms of marijuana have been approved by the FDA for CINV.2-4 Dronabinol (Marinol) is approved for CINV that fails to respond to other antiemetic therapies and to increase appetite in patients with acquired immune deficiency syndrome (AIDS), while nabilone (Cesamet) is approved for CINV in patients who fail other antiemetic therapies. It is important to note that many studies that show the effectiveness of marijuana for cancer symptoms are principally based on these synthetic forms of marijuana. Current therapeutic options commonly prescribed for CINV are 5-hydroxytryptamine (5HT₃) antagonists, neurokinin-1 (NK-1) antagonists, and corticosteroids, either as monotherapy or combination therapy, depending on the emetogenic potential of the chemotherapy regimen. While CINV often can be controlled with these therapies, some patients still have refractory CINV that may respond to cannabinoids.

Cannabinoids exert effects at multiple sites in the body that control nausea and vomiting. Whether through CB₁ agonism or CB₂ binding, cannabinoids directly or indirectly affect dopamine, neurokinin, serotonin, and opioid activity, which all play critical roles in controlling the emetogenic response to toxins.22 CB₁ receptors also are located in the nucleus tractus solitarius, postrema, and dorsal motor neurons, which are key sites within the brain that effect emetogenic stimuli. Additionally, similar to 5-HT₃ antagonists, cannabinoids appear to stabilize the enterochromaffin cells in the gut, which decreases the vagal input in the brainstem regions that coordinate nausea and vomiting.

An important benefit for patients using inhaled medical marijuana versus oral synthetic derivatives or standard antiemetic therapies is the capacity for dose titration. Taking an oral antiemetic medication may take longer to be absorbed and can leave the patient in a state of nausea or vomiting without relief for an increased period of time. Fast absorption into the blood through the lungs via inhalation allows patients to feel the effects of the cannabinoids, such as delta-9-THC, immediately, and to quickly determine whether additional inhalation is required.

Appetite Stimulation

One of marijuana’s well-known effects is increased appetite. Animal studies have demonstrated that delta-9-THC and other cannabinoids increase appetite and food intake.23 To date, the CB₁ receptor has been found to be active in several areas of the body known to stimulate eating behavior, including sections of the hypothalamus and hind brain that regulate food intake, the reward center of the brain that helps eating improve our mood, and the limbic forebrain that makes food taste more palatable.24 The CB₁ receptor also is believed to increase the levels of two key hunger-regulating hormones, ghrelin and leptin, without significantly altering insulin levels.25

Dronabinol improves taste, appetite, and increases the number of protein calories consumed.5,17,18 The results of one study comparing dronabinol versus megestrol acetate versus combination therapy (dronabinol and megestrol acetate) in the treatment of cancer-associated anorexia showed that megestrol acetate is more effective in inducing appetite, although dronabinol increased appetite as well.26 It is important to note that dronabinol only includes delta-9-THC, while the other 60-plus cannabinoids in marijuana may synergistically play a role in appetite stimulation as well. Also, the dronabinol dose (2.5 mg) used was low compared to what patients may experience with the various forms and dosages of medical marijuana products. However, one smaller cancer study demonstrated that dronabinol enhanced chemosensory perception and taste of food compared to the placebo group.27 The dronabinol group also experienced increased appetite and caloric intake in this study.

Anxiety and Sleep

The stress that patients experience from a life-threatening disease, such as cancer, can lead to increased anxiety as well as decreased sleep. Animal studies have shown delta-9-THC and CBD to have anxiolytic properties.28,29 The endocannabinoid system also has demonstrated an important role in the mediation of the sleep-waking cycle in rodents.30 One of the main side effects recognized in marijuana users is euphoria, which may contribute to anxiety relief. The dronabinol study that increased chemosensory perception mentioned above also noted other effects of dronabinol, including increased relaxation and sleep quality.27

Analgesia

Oncology patients may experience chemotherapy– or cancer-induced neuropathic pain. Animal studies, as well as some placebo-controlled studies in humans, have shown that inhaled marijuana and dronabinol can decrease pain sensitivity and increase pain tolerance.5,17,18 One patient study compared nabiximols (delta-9-THC and CBD) oral mucosal spray, delta-9-THC 2.7 mg oromucosal spray, and placebo.31 The study found that cancer pain was significantly decreased from baseline (>30%) with the nabiximols product, while the delta-9-THC oromucosal spray showed no improvement.

Cannabinoids and opioids share several pharmacologic properties and may act synergistically. Another study evaluated 21 patients receiving twice-daily sustained-release morphine or oxycodone over 5 days. Vaporized marijuana was administered to the patients at night on day 1, three times daily on days 2 through 4, and in the morning on day 5. No significant pharmacokinetic changes in the AUC for either opioid were observed, but with the addition of vaporized marijuana, pain significantly decreased by 27% on average.32

These studies suggest that marijuana may be an important adjuvant option for pain and that delta-9-THC may exert stronger effects when combined with other cannabinoids, such as CBD.

Anticancer Effects

Multiple in vivo and in vitro studies have shown that delta-9-THC and CBD may have antiproliferative and antiangiogenesis effects on tumor cells. A pilot phase 1 trial assessed the safety of intracranial delta-9-THC and the cannabinoid antitumoral action of delta-9-THC in recurrent glioblastoma multiforme.33 Delta-9-THC was administered intracranially to 9 patients. The results of this study showed that delta-9-THC does not facilitate tumor growth or decrease patient survival. The effects of delta-9-THC on survival were unclear due to the characteristics of the study and would require a larger trial, which is now ongoing. Due to the safety profile and possible antiproliferative potential of delta-9-THC, it was concluded that it would be desirable to run additional trials on gliomas and other types of tumors.

Adverse Effects

A systematic review evaluating the adverse effects of marijuana found that the majority of side effects present as mild to moderate and include dizziness, tachycardia, coughing, wheezing, sedation, slowed reaction time, and visual disturbances.34 The most common adverse effect was dizziness, which is important to mention when counseling patients. This effect may be more likely in elderly patients who are already at risk for postural hypotension. The risks for short-term adverse effects tend to diminish with the addition of CBD to delta-9-THC; it is believed that CBD may counter some of the effects of delta-9-THC.35 The toxicity of medical marijuana also is very low. This could be due to the fact that unlike opioid receptors, the cannabinoid receptors are sparse in the lower brain stem so marijuana does not cause respiratory depression with increased dose titration.

Studies have shown that marijuana inhalation through combustion, unlike vaporization, is carcinogenic. Vaporization is the process of heating marijuana via the surrounding air in a closed chamber so no direct flame touches the drug, which allows the cannabinoids to vaporize at a much lower temperature. Combustion, on the other hand, burns the cannabinoids and plant material at a much higher temperature, leading to the formation of carcinogens. Paradoxically, it is believed that the cannabinoids in marijuana have an antagonistic effect with the carcinogens of marijuana, leading to a decreased risk of lung damage compared with using a substance such as cigarettes.19 To improve the efficacy and safety of medical marijuana, it is important to counsel patients on the benefits of using vaporization compared with combustion methods.36,37 Although marijuana may exert therapeutic effects via delta-9-THC and CBD through combustion, it is not the healthiest delivery form of this medication and can be avoided.

Finally, schizophrenia is an important consideration before recommending medical marijuana to a patient. Some studies, as well as anecdotal evidence, suggest that delta-9-THC may exacerbate the positive (eg, hallucinations, delusions, paranoia) and negative (eg, amotivation, social withdrawal, emotional blunting) symptoms patients with schizophrenia experience.38 The administration of delta-9-THC (0, 2.5, and 5 mg) in one randomized, double-blind, placebo-controlled study, demonstrated that 80% of patients with schizophrenia, compared with 35% of the control group, had an increase in positive symptoms using the 2.5 mg dose; the 5-mg dose elicited an increase in 75% in the patients with schizophrenia and a 50% increase in the control group. The patients with schizophrenia were taking antipsychotic medications and were clinically stable. Pharmacists and health care providers should be wary of this possible interaction and must determine whether the risks outweigh the benefits in using medical marijuana in these patients.

Click here to see TABLE 2.

Practical Considerations for Use in Health Systems

Schedule I Status

Although many states have legalized medical marijuana, according to federal law it is still considered Schedule I under the Controlled Substance Act, meaning it has no medicinal value and a high potential for abuse. Therefore, federally funded hospitals and health care institutions may find it risky to implement the use of medical marijuana due to the potential loss of federal funding. The Schedule I nature of medical marijuana also limits the ability to conduct research to further support the body of scientific evidence elucidating its potential medicinal benefits.

Unlike other drug therapies, acquisition of medical marijuana by health care institutions is not permitted under current federal regulations. State laws typically require either the patient or patient’s caregiver to obtain the medical marijuana from the dispensary at which they are registered. This requires the patient to bring “their own meds” to the health care institution. Health care institutions will need to consider whether medical marijuana will be considered a patient’s own medication and whether additional security/storage is warranted for the medical marijuana. Additionally, most health care institutions do not allow smoking; therefore, smokable forms of medical marijuana would likely not be allowed. This must be stipulated in hospital policies and procedures (P&Ps).

Health care facilities seeking to implement internal protocols for patients using or bringing medical marijuana into the hospital also need to address processes for documentation, monitoring, and the education of health care providers.

• Documenting Use. When a patient is admitted to the hospital and reports using medical marijuana, the information should be documented in the patient’s medication list. If the patient is not able to specify the dosage form, strength, dose, and frequency, health care providers should contact the dispensary to get specifics, similar to calling a pharmacy to confirm other patient medications.
• Monitoring. Additional programming of the electronic medical record software may be required to allow for ordering and patient self-administration of medical marijuana.
• Staff Education. Educating health care professionals (eg, physicians, nurses, medical assistants) and those involved with policy making (eg, the P&T committee) is necessary to ensure that appropriate assessment and monitoring of patients consuming medical marijuana occurs. Pharmacists can play an integral role in education efforts regarding medical marijuana due to their knowledge of pharmacodynamics, pharmacokinetics, dosage forms, bioavailability, efficacy, and safety. (Medical marijuana educational resources for pharmacists are available in SIDEBAR 2.)

Finally, it is important that all health care providers stay up-to-date with their state regulations as well as federal laws in order to mitigate repercussions.

The Role of the Pharmacist

In Connecticut, Minnesota, and New York, pharmacists are required to dispense medical marijuana to qualifying patients.39 Using knowledge gleaned from this experience, pharmacists in these three states have a unique opportunity to pave the way for a health care model for medical marijuana use that is beneficial for patients. Although pharmacists in other states may not be responsible for dispensing medical marijuana, it is possible that patients will have questions for pharmacists about marijuana.

For example, in Connecticut pharmacists are on the receiving end of the recommendation made by the physician. In order to become a registered medical marijuana patient, a physician who is registered in Connecticut’s medical marijuana program must first diagnose an individual with one of the 22 qualifying conditions. The physician certifies the patient in the state program, and may authorize one caregiver to pick up the patient’s medical marijuana if the patient is unable to do so. It is important to note that physicians are not permitted to write prescriptions for medical marijuana because Schedule I drugs, such as marijuana, are prohibited by federal law; rather, physicians certify patients for medical marijuana use through state programs. Next, the patient registers with the Connecticut Department of Consumer Protection and chooses which dispensary they will use (patients must register with one, although they are permitted to switch dispensaries up to four times per year).40,41 After the patient receives a valid Connecticut medical marijuana identification card, they can schedule an appointment for an initial consultation with a dispensary pharmacist.

During the initial consultation, pharmacists conduct a thorough medication therapy review to ascertain information from the patient about their condition and goals of therapy. The patient also is counseled on the different forms of medical marijuana and the effects they will have. The pharmacist then determines an appropriate product, dose, and dosage form, and educates the patient on possible side effects and any possible interactions with concurrent medications. For example, patients using C. indica strains may experience drowsiness, especially if they are concomitantly using any other sedating drugs (eg, benzodiazepines, zolpidem) with medical marijuana. Patients report the efficacy of the dose and dosage form used at subsequent visits so that pharmacists can tailor the regimen to improve effectiveness and minimize side effects. Physicians continually provide follow-up care and evaluation of medical marijuana’s effectiveness of the condition.

Recent changes have occurred in Connecticut’s state medical marijuana program. As of October 1, 2016, the Department of Consumer Protection will begin accepting applications for medical marijuana research programs. Hospitals or health care facilities licensed under Chapter 368v, institutions of higher education as defined in Section 10a-55 of the General Statutes, licensed medical marijuana producers, and licensed medical marijuana dispensaries may apply. The department may approve a program that is intended to increase knowledge or information regarding the growth, processing, medical attributes, dosage forms, administration, or use of marijuana to treat or alleviate symptoms of any medical conditions or the effects of such symptoms.^₄₂ In addition, nurses in Connecticut will be able to administer medical marijuana to qualifying patients or research program participants in a hospital or health care facility licensed by the Department of Public Health.

Other specifics of Connecticut’s medical marijuana program are delineated in TABLE 2.40

Medical Marijuana Policies and Procedures

Although not yet common, developing and implementing a P&P delineating appropriate use of medical marijuana in a health system is a goal for many organizations where state medical marijuana programs exist.

Stanford Health Care & Lucile Packard Children’s Hospital in Stanford, California, has developed and implemented a P&P on medical marijuana use during admissions (personal communication, Sun Ah Chung, Lucile Packard Children’s Hospital). The policy categorizes medical marijuana as separate from other marijuana, which is destroyed per their Alcohol and Drug policy. To use medical marijuana in the hospital, the patient must sign the P&P. Specifics of the P&P include:

• The patient understands that due to federal regulations the Stanford Hospital and Clinics pharmacy department cannot guarantee the potency, safety, and efficacy of the product
• The patient understands the benefits versus the risks of using medical marijuana
• The route of administration is through ingestion only; smoking or vaporizing marijuana in the hospital is not permitted
• The patient acknowledges that all related entities of the hospital are not responsible for any and all effects of the use of medical marijuana, and that the hospital did not provide it to patient

This legal agreement acts as a safeguard for the hospital, aimed at preventing federal repercussions. Protocols such as these will have to be implemented in health care institutions in the future if more states legalize medical marijuana.

Conclusion

Medical marijuana is an increasingly common treatment option for patients with cancer, and the benefits suggest this drug has a place in other disease states as well. Although we can extrapolate the effects that cannabinoids, such as delta-9-THC and CBD, have on patients from in vitro, in vivo, and small clinical studies, larger studies need to be performed. However, before that occurs, the federal government will have to adjust its stance on marijuana and/or ease the regulations that surround Schedule I research. Until then, hospital administrators must enact hospital-wide protocols as more patients taking medical marijuana are treated in hospitals. Additionally, state medical marijuana laws, such as those in Connecticut, are also important in protecting hospital employees and patients until the federal government reschedules marijuana.

Engaging with local government officials to determine the risks of implementing such protocols is an important first step. Discussing the potential of medical marijuana with all hospital committees and health care providers is required to help define how patients will use this medication in the hospital. Currently, pharmacists are at the forefront in dispensing medical marijuana in just three states, but it can be expected that pharmacists in other states may receive questions as medical marijuana continues to emerge as a new medication. As one of the most accessible health care professionals, it is essential that pharmacists stay up-to-date on information regarding medical marijuana so that they can assist patients with medication concerns.

Camden E. Svec, PharmD, is a dispensary pharmacist at Arrow Alternative Care Medical Marijuana Wellness Center. His professional interests include the development of medical marijuana in health care and oncology pharmacology.

Lisa M. Holle, PharmD, BCOP, FHOPA, is an assistant clinical professor of pharmacy practice at the University of Connecticut School of Pharmacy, and practices at the University of Connecticut Health’s Carole & Ray Neag Comprehensive Cancer Center in Farmington. Her professional interests include supportive care and pain management in patients with cancer.