Hotly debated by clinicians, legislators, medical associations, and patients for more than 30 years, the medical and legal issues surrounding medical marijuana use still lack clarity.
Backbone research supporting the majority of related clinical studies has proven marijuana’s efficacy in treating chemotherapy-induced nausea and vomiting (CINV), AIDS-related cachexia, pain, movement and neurological disorders, and glaucoma.
Even with these clinical findings, the Drug Enforcement Administration (DEA) has classified marijuana as a Schedule I agent with a high potential for abuse and no legitimate medical use. Despite recommendations from the Institute of Medicine, American College of Physicians, and American Medical Association to re-evaluate this current classification in order to enable further research on marijuana, the DEA has rejected rescheduling attempts.1
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FEDERAL VS STATE LAW
Further stifling the medicinal use of marijuana, state and federal policies are contradictory, yet evolving. Due to the Schedule I status of marijuana from a federal perspective, possession, use, sale, or cultivation of marijuana is illegal.2 Despite this federal law, 17 states as well as Washington DC have passed laws eliminating criminal penalties for using marijuana for medical purposes, and many other states are considering similar legislation.2,3
In 2009, the Department of Justice issued a memo stating that states should not prosecute individuals whose actions comply with their state’s laws regarding medical marijuana.2 This game-changing guidance, coupled with physicians’ recommendations for protection of marijuana use under the First Amendment, opened the door for states to design their own laws enabling access to medical marijuana while limiting its abuse and diversion.2
However, legislation varies widely from state to state on the following issues: legal quantities that patients may possess (dried marijuana: 1oz to 24oz; plants: 2 to 15); qualifying diseases that meet criteria for medical marijuana use; and whether a registry is established or ID cards are distributed for qualifying patients.2 Routes for obtaining medical marijuana also vary, with some states having dispensaries, others having alternate treatment facilities that “fill” physicians’ written instructions, and most other states remaining silent about ways to obtain medical marijuana.2
States with dispensaries typically have storefront facilities that provide medical marijuana to member patients and caregivers, verified by patient documentation verification. Although access to medical marijuana appears to be expanding, the relentless struggle to determine and maintain its legitimacy is expected to persist unless further, robust research is conducted. Specifically, well-controlled trials comparing marijuana to approved alternatives, establishing quality and potency standards (perhaps via dose-finding investigations), and clarifying risk/benefit information are needed.2
POTENTIAL INDICATIONS IN CANCER PATIENTS
One of the earlier recognized indications for medical marijuana is chemotherapy-induced nausea and vomiting (CINV). CINV, which may be acute, delayed, or anticipatory, has been reported by patients, nurses, and physicians as the most distressing side effect of chemotherapy.4 When poorly controlled, CINV may influence the patient’s willingness to accept scheduled chemotherapy or the oncologist’s treatment plan, thereby compromising tumor control and patient survival.5
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 administered. Although these treatments are efficacious, the complex pathophysiology of CINV necessitates that agents with differing mechanisms of action be explored. Cannabinoids are a commonly discussed class with diverse pharmacologic characteristics that have shown efficacy in patients with CINV.
Cannabinoids have modulatory effects at multiple control points for nausea and vomiting, which suggests that they may have significant effects in improving CINV symptoms.5 Cannabinoid receptors of the CB1 type are present throughout the CNS, and CB2 type receptors are thought to be localized exclusively in the periphery, primarily on immune cells.5 Whether through CB1 type receptor agonism or CB2 binding, cannabinoids directly or indirectly affect serotonin, neurokinin, dopamine, and opioid activity, all of which play a critical role in mediating the emetogenic response to toxins.5
In the GI tract, cannabinoids may function similarly to 5-HT3 antagonists in diminishing vagal excitation (via serotonin released by enterochromaffin cells), though effects on other neurotransmitters (eg, acetylcholine) may also be important.5 CB1 type receptors are particularly abundant in the area postrema, nucleus tractus solitarus, and dorsal motor nucleus, which are key in detection, integration, and efferent sites within the brainstem for emetogenic stimuli.5 In addition, similar to the 5-HT3 antagonists, cannabinoids appear to stabilize the enterochromaffin cells in the gut, which then decreases the vagal input to the brainstem regions that coordinate nausea and vomiting.5
FDA-APPROVED CANNABINOID MEDICATIONS
The FDA has approved two synthetic cannabinoids for the treatment of CINV in patients who do not respond to conventional antiemetics. Dronabinol (Marinol) and nabilone (Cesamet) are both synthetic versions of tetrahydrocannabinol (THC), the active ingredient in marijuana.6 Several limitations exist in the use of these compounds, including include high cost and the need for oral administration, which is associated with poor bioavailability and may be problematic for patients with frequent, uncontrolled vomiting.7
Bioavailability for Marinol is only 10% to 20% of the oral dose, with the peak effect generally being reached up to 2 to 4 hours after dosing.6 Moreover, because Marinol is metabolized slowly, its therapeutic and psychoactive effects may be unpredictable and considerably variable. Cesamet has limitations similar to Marinol, and both have proven mildly effective in preventing vomiting following cancer chemotherapy.7
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SAFETY AND EFFICACY
When compared to these FDA-approved cannabinoid medications, smoked or vaporized marijuana has been considered to be more effective.7 The THC in the inhaled smoke is absorbed within seconds and is delivered to the brain rapidly, as would be expected from a lipid soluble drug.7 Patients prefer the fast onset of action to help control the ongoing attacks of nausea or vomiting.
Maximum blood concentrations are reached at the time when smoking is finished and then rapidly dissipate, which also allows patients to self-titrate.7 In addition, the marijuana plant contains about 60 other cannabinoids, which may or may not produce additional benefits.6,7
In the near future, safer alternatives that eliminate the carcinogenic concern of smoking marijuana may become available, such as the marijuana patch. Medical Marijuana Delivery Systems LLC has acquired the patent to a medical marijuana patch (to be marketed under the name Tetracan) that may become available at dispensaries.8 Besides different delivery systems for medical marijuana being examined, published evidence also suggests that cannabinoids may have anticancer effects, including suppression of proliferative cell signaling pathways, angiogenesis inhibition, and apoptosis stimulation, which warrant further exploration.8
