A 42-year-old woman with metastatic breast cancer being treated with a combination of cyclophosphamide, doxorubicin, and fluorouracil (5-FU) complains of pain due to chemotherapy-induced peripheral neuropathy. She has been unwilling to eat due to nausea and vomiting induced by her medications. She is receiving heavy doses of oxycodone for pain, but this has resulted in severe constipation. Upon her visit with the oncologist she shows physical signs of cachexia and reports ongoing pain in her back and hips. Friends suggest medical marijuana as a strategy for controlling her present symptoms. What evidence supports this approach? What might be the unwanted effects of this strategy?
The medical use of cannabinoids and crude marijuana has been controversial, but like many other pharmaceuticals, there is a long history of their use in a variety of illnesses. There are numerous reports of cannabinoids being used for pain relief, nausea, and glaucoma, and for inhibiting excitatory disorders such as epilepsy, Parkinson disease, and Tourette syndrome. In the USA, 33 states have legalized cannabis for medicinal use. Although the use of cannabis remains illegal in the USA under Drug Enforcement Agency (DEA) rules, some of its derivative compounds have been approved by the US Food and Drug Administration (FDA). Medical marijuana contains approximately 50–70 different cannabinoids termed phytocannabinoids, and two of these components have received careful scientific study. The first, delta-9 tetrahydrocannabinol (THC), is believed to be the most psychoactive and is responsible for the symptoms of euphoria. The second component, cannabidiol (CBD), does not demonstrate psychoactive or euphoric activity, appears to have an unknown mechanism of action, and has been reported to be useful for a variety of disorders.
The discovery of cannabinoid receptors has generated interest in the therapeutic potential of marijuana, and the identification of widespread cellular production of endogenous cannabinoids in humans and animals has revitalized the science of medicinal cannabinoids.
Cannabinoid receptors were identified pharmacologically in the 1980s and confirmed by cloning in 1990. Studies identified two unique G protein-coupled receptors termed CB1 and CB2, which demonstrated Gi/o coupling and a corresponding decrease in cAMP levels when activated. In spite of similar coupling, the receptors have very different expression patterns, with CB1 demonstrating widespread expression in the majority of the organs of the body as well as high expression on the neurons of the central and peripheral nervous system. CB2 receptor expression is far less extensive, demonstrating activity mainly on immune cells (ie, macrophages, monocytes, organ-specific resident immune cells), spleen, lymph nodes, microglia of the CNS, and specialized immune cells such as osteoclasts. Since the discovery of the CB receptors, numerous studies have identified their function in a variety of tissues as well as changes of receptor expression due to diseases, hormone alterations, and sustained activation. However, only a few cannabinoid molecules have been approved by the ...