Cannabis in Cancer Care
D.I. Abrams and M. Guzman
Clinical Pharmacology & Therapeutics, 2015, 97, (6), 575-586.
Doi : 10.1002/cpt.108
Cannabis has been used inmedicine for thousands of years prior to achieving its current illicit substance status. Cannabinoids, the active components of Cannabis sativa,mimic the effects of the endogenous cannabinoids (endocannabinoids), activating specific cannabinoid receptors, particularly CB1 found predominantly in the central nervous system and CB2 found predominantly in cells involved with immune function. Delta-9-tetrahydrocannabinol, themain bioactive cannabinoid in the plant, has been available as a prescriptionmedication approved for treatment of cancer chemotherapy-induced nausea and vomiting and anorexia associated with the AIDS wasting syndrome. Cannabinoidsmay be of benefit in the treatment of cancer-related pain, possibly synergistic with opioid analgesics. Cannabinoids have been shown to be of benefit in the treatment of HIV-related peripheral neuropathy, suggesting that they may be worthy of study in patients with other neuropathic symptoms. Cannabinoids have a favorable drug safety profile, but their medical use is predominantly limited by their psychoactive effects and their limited bioavailability.
Although long recognized for its medicinal values and widely used by millions throughout the world, cannabis receives little attention in the standard literature because of its status as a controlled substance and classification in the United States as a Schedule I agent with a high potential for abuse and no known medical use. Data on the potential effectiveness of medicinal cannabis is difficult to find due to the limited numbers of clinical trials that have been conducted to date. As a botanical, cannabis shares those difficulties encountered in the study of plants that are grown in many climates and environments from diverse genetic strains and harvested under variable conditions.
CANNABIS AS MEDICINE: A BRIEF HISTORY
The use of cannabis as medicine dates back nearly 3,000 years.1 Employed widely on the Indian subcontinent, cannabis was introduced into Western medicine in the 1840s by W.B. O’Shaughnessy, a surgeon who learned of its medicinal benefits first-hand while working in the British East Indies Company. Promoted for reported analgesic, sedative, antiinflammatory, antispasmodic, and anticonvulsant properties, cannabis was said to be the treatment of choice for Queen Victoria’s dysmennorhea. In the early 1900s, medicines that were indicated for each of cannabis’ purported activities were introduced into the Western armamentarium, making its use less widespread.
Physicians in the United States were the main opponents to the introduction of the Marihuana Tax Act by the Treasury Department in 1937. The legislation was masterminded by Harry Anslinger, director of the Federal Bureau of Narcotics from its inception in 1931 until 1962, who testified in Congress that
“Marijuana is the most violence-causing drug in the history of mankind.” The Act imposed a levy of one dollar an ounce for medicinal use and one hundred dollars an ounce for recreational use, which in 1937 dollars was a prohibitive cost. By using the Mexican name for the plant and associating it with nefarious South-of-the-Border activities, the proponents fooled many physicians. The Act was singly opposed by the American Medical Association, who felt that objective evidence that cannabis was harmful was lacking and that its passage would impede further research into its medical utility. In 1942, cannabis was removed from the U.S. Pharmacopoeia. In 1970, with the initiation of the Controlled Substances Act, marijuana was classified as a Schedule I drug. Where both Schedule I and Schedule II substances have a high potential for abuse, Schedule I drugs are distinguished by having no accepted medical use. Other Schedule I substances include heroin, LSD, mescaline, methylqualone, and, most recently, gammahydroxybutyrate (GHB). Despite efforts to change the scheduling of cannabis, it remains a Schedule I substance at this time.
Delta-9-THC is one of the 100 cannabinoids found in the cannabis plant and is felt to be the main psychoactive component. Overall, the plant contains about 400 compounds derived from its secondary metabolism, many of which may contribute to its medicinal effect. Synthetic delta-9-THC in sesame oil (dronabinol, Marinol) was first licensed and approved in 1986 for the treatment of chemotherapy-associated nausea and vomiting. Clinical trials done at the time determined that dronabinol was
as effective, if not more so, than the available antiemetic agents.2 Dronabinol was investigated for its ability to stimulate weight gain in patients with the AIDS wasting syndrome in the late 1980s. Results from a number of trials suggested that although patients reported an improvement in appetite, no statistically significant weight gain was appreciated.3,4 Nabilone (Cesamet) is another synthetic delta-9-THC that is also available by prescription. More recently, nabiximols (Sativex), a whole plant extract delivered as an oromucosal spray, has been developed and approved for medical use in Europe and Canada. This article will review the biology and pharmacology of cannabis and cannabinoids and focus on their use in symptom management, particularly in patients with cancer.
CANNABINOID CHEMISTRY AND BIOLOGIC EFFECTS
Cannabinoids are a group of 21 carbon terpenophenolic compounds produced uniquely by Cannabis sativa and Cannabis indica species.1 With the discovery of endogenous cannabinoids and to distinguish them from pharmaceutical compounds, the plant compounds may also be referred to as phytocannabinoids. Although delta-9-THC is the primary active ingredient in cannabis, there are a number of non-THC cannabinoids and noncannabinoid compounds that also have biologic activity. Cannabidiol (CBD), cannabinol, cannabichromene, cannabigerol, tetrahydrocannabivirin, and delta-8-THC are just some of the additional cannabinoids that have been identified. It is postulated that the secondary compounds may enhance the beneficial effects of delta-9-THC, for example by modulating the THC induced anxiety, anticholinergic, or immunosuppressive effects, and may reduce the unwanted effects of delta-9-THC, for example by attenuating seizures, psychoses, or motor discoordination. In addition, cannabis-associated terpenoids and flavonoids may increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide antiinflammatory activity.1,5
The neurobiology of the cannabinoids has only been identified within the past 25 years, during which time an explosion of knowledge has occurred.1 In the mid-1980s, researchers developed a potent cannabinoid agonist to be used in research investigations. In 1986 it was discovered that cannabinoids inhibited the accumulation of 30-50 cyclic adenosine monophosphate (cAMP), suggesting the presence of a receptor-mediated mechanism. By attaching a radiolabel to the synthetic cannabinoid, the first cannabinoid receptor, CB1, was pharmacologically identified in the brain in 1988. The CB1 receptor is coupled to Gi proteins (Figure 1). Its engagement inhibits adenylyl cyclase and voltagegated calcium channels, and stimulates rectifying potassium conductances and mitogen-activated protein kinase cascades. By 1990, investigators had cloned the CB1 receptor, identified its DNA sequence, and mapped its location in the brain, with the largest expression being in the basal ganglia, cerebellum, hippocampus,
and cerebral cortex. Nowadays, CB1 is known to be a ubiquitous protein that is present in basically all body tissues. In 1993 a second cannabinoid receptor, CB2, was identified outside the brain. Originally detected in macrophages and the marginal zone of the spleen, the highest abundance of CB2 receptors is
located on the B lymphocytes and natural killer cells, suggesting a role in immunity.