Jul 6, 2018, 11:36 AM by Connie Bruno; Sara Jane Ward, PhD; Rany Abdallah, MD, PhD, MBA

Marijuana (Cannabis sativa) has been used for medical purposes throughout recorded history.^[1] The plant was prescribed historically for myriad purposes, including appetite stimulation, treating epilepsy, managing grief, and assuaging labor pain, headaches, and sore muscles.^[2] The Cannabis genus of flowering plants has also provided nutrition from its seeds and fiber for rope, paper, and textiles from its stem.^[1] In the United States, however, the Marihuana Tax Act of 1937 imposed a registration tax and strict regulations on cannabis distribution that effectively dissuaded its prescription.^[3] Subsequently, the Controlled Substances Act of 1970 classified cannabis as a schedule I drug with no accepted medicinal value.^[4]

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“We have much to learn about the benefits and side effects of medical cannabis and our ability to regulate its safe usage, but we have a body of knowledge from which to start.”

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Despite cannabis prohibition in the United States and many countries worldwide, it has been widely produced and used unabated. In the scientific community, however, designation as a schedule I drug greatly limits cannabis research. In fact, the few investigators authorized to conduct clinical research with cannabis are limited to one strain from the University of Mississippi.^[1] As an illegal drug with harsh federal restrictions, the taboos about marijuana continue.

Recently, though, insight into the endocannabinoid system (ECS) and rising public awareness have renewed interest in exploring therapeutic and social potentials for cannabinoids. Beginning in 2009, the Department of Justice decided against enforcement of the federal laws, and most states in the United States have legalized either medical or recreational use.^[5],[6] Congress has since continued to uphold the Rohrabacher-Farr amendment, which prohibits the Justice Department from spending funds to interfere with the implementation of state medical cannabis laws. Despite this, stigma against cannabis is still widely prevalent, including within the medical community.

How can we create a paradigm shift about medical cannabis? Perhaps we can restructure our decisions by reexamining our knowledge base. In the age of the opioid epidemic, the need for redefining chronic pain treatments is ever present, and medical cannabis is a promising group of agents for chronic pain patients. We have much to learn about the benefits and side effects of medical cannabis and our ability to regulate its safe usage, but we have a body of knowledge from which to start.

Medical cannabis is an overarching term that describes all serviceable cannabinoids and a vast assortment of cannabis products that are consumed as smoke, vapors, oil, or capsules. Botanical cannabis and medical cannabis are notably overlapping terms, because botanical cannabis use is frequently reported for medical purposes. Cannabinoids are a chemical class of neuromodulators that function in the ECS, which participates in “relax, eat, sleep, forget, and protect” and may also play a role in ameliorating refractory nausea, muscle spasticity, seizures, pain, and inflammation.^[7] Cannabinoids are recognized in 3 groups: endocannabinoids (naturally synthesized by our bodies from membrane-bound lipid precursors), phytocannabinoids (derived from the Cannabis sativa plant species, that is, botanical), and synthetic cannabinoids (designed in the laboratory to mimic the effects of endo- or phytocannabinoids).^[2]

Phytocannabinoids represent more than 100 lipid molecules found in botanical cannabis and are a subset of more than 400 natural compounds found in the Cannabis sativa plant, including potentially bioactive terpenes and flavonoids. Two major active phytocannabinoids of interest are δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), through which medical cannabis participates in the ECS.^[4]

THC acts on 2 well-defined G-protein–coupled receptors: CB1 and CB2. CB1 receptors are most common in the central nervous system but also found in peripheral tissues; CB2 is a central and peripheral neuronal and nonneuronal receptor that modulates inflammatory and neuropathic pain.^[4],^[7] Therefore, medical cannabis modulates pain at supraspinal, spinal, and peripheral levels, by modifying pain transmission and inflammatory responses. Interestingly, CB1 receptors are infrequently found in brain stem respiratory centers, explaining a low risk of respiratory depression from marijuana use.^[4]

CBD, while producing some pharmacological effects similar to THC, such as attenuating inflammation, does not work primarily through CB1 or CB2 receptors. Instead, its anti-inflammatory, anxiolytic, and antiseizure effects are likely mediated through one or several other mechanisms, such as interactions with serotonin, adenosine, glycine, or transient receptor potential channel receptors.

As mentioned, cannabis use has a low risk of respiratory depression, and no lethal cannabis overdose has been reported in humans to date.^[1],^[4] Cannabis use, however, does not come without consequence. THC is a psychoactive analgesic that can have shortterm side effects on learning, memory, and attention, and it can cause euphoria; long-term side effects are not yet established.^[8],^[9] Cannabis use before driving increases the risk of having a motor vehicle accident. In addition, prescription of medical cannabis to adults inadvertently exposes children to the risks from the compound. Cannabis legalization may even decrease the perception of its risks to adolescents, who have developing brains and are at greatest risk for experimenting with substances of abuse.^[8]

In a nationwide study in the United States, 10% of all adult cannabis users reported taking the drug exclusively for medical purposes, and 36% reported a mixture of recreational and medical purposes.^[8] Accordingly, understand that the levels of individual chemical constituents in most botanical cannabis products—and consequently in medical cannabis products—are currently greatly variable and unregulated.

Chronic pain conditions are common, debilitating, and notoriously difficult to treat using opioids, nonsteroidal anti-inflammatory agents, anticonvulsants, antidepressants, local anesthetic or steroid injections, and nonpharmacologic methods.^[10] Medical cannabis can act as an adjuvant agent for refractory pain, with meaningful improvement in pain reported for 1 of every 3.5 to 9 patients with chronic, noncancer pain^{.[4],[9],[10]}

In 2017, the National Academies of Sciences, Engineering, and Medicine (NASEM) released a comprehensive review of studies titled Health Effects of Cannabis and Cannabinoids. The NASEM committee found that chronic pain patients treated with medical cannabis can experience a significant reduction in pain symptoms, short-term use of synthetic oral cannabinoids improves multiple sclerosis-related muscle spasms, and synthetic oral cannabinoids can prevent and improve chemotherapy-induced nausea and vomiting.^[8]

Patients with a variety of different diseases may someday benefit from medical cannabis. The hundreds of natural components in botanical cannabis should be studied, and novel, therapeutic, cannabinoid-derived agents may be discovered. Many of our present-day pain medications were actually derived from the plant world, including opioids, salicylates, and capsaicin. Unfortunately, cannabis's unyielding federal status as a schedule I drug continues to limit effective research.

In 1994, California was the first state to legalize medicinal cannabis use. Since the Rohrabacher-Farr amendment, medical cannabis is now legalized in 29 states and Washington, DC. Our state of Pennsylvania passed its legislation in April 2016 and continues to solidify the rules and regulations. Pennsylvania's law has taken a highly medicalized approach, requiring staffing of dispensaries by physicians and pharmacists and the incorporation of funded research collaborations between select medical cannabis entities and the state's medical and research institutions. In addition, clinicians involved in recommending and dispensing cannabis will be required to complete at least 4 hours of continuing medical education. Current indications for medical cannabis prescription in Pennsylvania are 17 serious medical conditions, including pain listed on its own, as well as amyotrophic lateral sclerosis, cancer, Crohn disease, spinal cord injury, HIV/AIDS, inflammatory bowel disease, multiple sclerosis, neuropathy, and sickle cell anemia.

As we await cannabis reclassification at a federal level, pain physicians should leverage what we do know about cannabis to benefit our patients with chronic pain. Only half of chronic pain patients describe their pain as “under control.”^[4] Until blinded, randomized studies are conducted, pain physicians can prescribe medical cannabis to patients whose pain is refractory to conventional medical therapies. Institution of multimodal pain regimens can be used to minimize medical cannabis dosages and its potential side effects. Certainly, all patients should have the opportunity to ease their unrelenting and debilitating conditions.

References

1. Bostwick JM. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc. 2012;87(2):172–186.
2. Pertwee RG, ed. Handbook of Cannabis. 1st ed. Oxford, United Kingdom: Oxford University Press; 2014.
3. Anderson DM, Hansen B, Rees DI. Medical marijuana laws, traffic fatalities, and alcohol consumption. IZA Discussion Paper Series. 2011;6112:1–28.
4. Burns TL, Ineck JR. Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain. Ann Pharmacother. 2006;40:251–260. 34 American Society of Regional Anesthesia and Pain Medicine 2018
5. Spahos C, Zahnd E, Arnold D, et al. Marijuana Policy: The State and Local Prosecutors' Perspective. Arlington, Virginia: National District Attorneys Association; 2017.
6. State Marijuana Laws in 2017 Map. Available at: http://www.governing. com/gov-data/state-marijuana-laws-map-medical-recreational.html. Accessed October 8, 2017.
7. Russo EB, Hohmann AG. Role of cannabinoids in pain management. In: Deer TR, Leong MS, Buvanendran A, et al. Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. New York, New York: Springer; 2013:181–197.
8. NASEM News. Nearly 100 conclusions on the health effects of marijuana and cannabis-derived products presented in new report; one of the most comprehensive studies of recent research on health effects of recreational and therapeutic use of cannabis and cannabis-derived products [press release]. Washington, DC: National Academies of Sciences Engineering Medicine. Available at: http://www8.nationalacademies.org/onpinews/newsitem. aspx?RecordID=24625. Accessed October 12, 2017.
9. Deshpande A, Mailis-Gagnon A, Zoheiry N, Lakha SF. Efficacy and adverse effects of medical marijuana for chronic noncancer pain. Can Fam Physician. 2015;61:e372–e381.
10. Andreae MH, Carter GM, Shaparin N, et al. Inhaled cannabis for chronic neuropathic pain: an individual patient data meta-analysis. J Pain. 2015;16(12):1221–1232.