The use of medical marijuana remains a hot topic in the United States. Although twenty states and the District of Columbia have enacted laws to legalize medical marijuana, in the majority of the country marijuana is still an illicit drug. Two states, Colorado and Washington, legalized the recreational use of marijuana in 2012. Despite state laws allowing for medical or recreational use of cannabis, the US federal government continues to list marijuana (cannabis) as a Schedule I substance under the Controlled Substance Act which makes it illegal to possess, use, or sell marijuana throughout the United States.
The Arthritis Foundation, an advocacy organization representing patients with all types of arthritis, featured a discussion on issues related to medical marijuana in its May/June 2013 issue of Arthritis Today. See “Medical Marijuana: RX or Risk?” (pdf) by Camille Noe Pagán.
What is Cannabis?
The Cannabis sativa L plant contains at least 60 active cannabinoids including the non-psychoactive component, cannabidiol (CBD), and the primary psychoactive element, tetrahydrocannabinol (THC). Cannabis plants are bred to contain different levels of these compounds to enhance their “get high” factor or their medicinal use. Cannabis products include marijuana (dried flowers and leaves), hashish (plant resin pressed into blocks), and hash oil (potent oil made from hashish).
Synthetic THC [Marinol® (dronabinol) or Cesamet® (nabilone)] has been used for the treatment of nausea, vomiting, and loss of appetite in chemotherapy and AIDS patients for years. Only one cannabis extract containing CBD [Sativex® (nabiximols)] has been approved for moderate to severe treatment-resistant spasticity in multiple sclerosis. Sativex contains equal amounts of THC and CBD in an oromucosal mouth spray and is approved for use in the treatment of MS spasticity in 24 countries, but not in the United States (Leussink 2012). Sativex is currently in clinical trials for cancer pain and neuropathic pain.
Cannabinoids in Clinical Trials
In more than 100 controlled clinical trials since 1975, different cannabis preparations have demonstrated antispastic, analgesic, antiemetic (anti-nausea), neuroprotective, and anti-inflammatory actions, and are effective against certain psychiatric diseases (Grotenhermen 2012; Sánchez 2012; Zuardi 2008). A recent systematic review of 18 randomized trials demonstrated that cannabinoids are a modestly effective and safe treatment option for chronic non-cancer (predominantly neuropathic) pain (Lynch 2011, Russo 2008). GW Pharmaceutical, the makers of Sativex, have sponsored a number of clinical trials, including one which investigated its use in the treatment of pain caused by rheumatoid arthritis (Blake 2006).
RA Pain, Disease Activity, and Cannabis
In a phase II double-blind, randomized, placebo-controlled, 5-week study of 58 rheumatoid arthritis patients, researchers assessed the efficacy of Sativex administered at night up to a maximum of 6 sprays per evening (16.2 mg THC + 15 mg CBD) in 31 patients compared with placebo in 27 patients. The primary outcome measure was morning pain on movement. Secondary outcomes included measures of pain at rest, sleep quality, morning stiffness, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the 28-joint disease activity score (DAS28). Baseline scores (an average of the last 4 days of a 14-day baseline period) were compared with the average of the last 14 days of treatment (Blake 2006).
Sativex produced statistically significant improvements in morning pain on movement, morning pain at rest, quality of sleep, disease activity (measured by DAS-28), and SF-MPQ pain at present, as compared to placebo. However, tesearchers found that Sativex had no effect on morning stiffness in this group of RA patients (Blake 2006). Authors did point out that baseline scores for morning stiffness had been low initially. No serious adverse effects occurred in the active treatment group and the large majority of adverse effects were mild or moderate, including dizziness, light-headedness, dry mouth, and nausea. More studies are warranted.
Cannabinoids and the Immune System
Animal studies have demonstrated that cannabinoids have immunomodulatory and neuroprotective properties. Through activation of CB2 receptors primarily found on immune cells, cannabinoids modulate peripheral blood lymphocytes, interfere with migration across the blood-brain barrier and control microglial/macrophage activation (Sánchez, 2012). CB2 select agonists are not psychoactive and could lead to promising therapies against autoimmune and inflammatory diseases, such as MS and RA (Rieder, 2010).
A study of cannabinoid receptor system in synovial tissue and fluid of patients with osteoarthritis (OA) and rheumatoid arthritis (RA) detected increased levels of the endocannabinoids AEA and 2-AG in the synovial fluid of OA and RA patients, compared with non-inflamed normal volunteers (Richardson 2008). Endocannabinoids are the substances our bodies naturally make to stimulate cannabinoid receptors. Researchers also found that levels of the anti-inflammatory substances PEA (almitoyl ethanolamide) and OEA (oleoyl ethanolamide), which have the ability to modulate the endocannabinoid system, were higher in the synovial fluid of normal volunteers compared with OA and RA patients. Richardson et al suggest that the loss of PEA may contribute to arthritic disease.
Use Caution with Cannabis
Although no safety concerns have arisen in clinical trials with RA patients, the use of medical cannabis is not without risk. Cannabinoids have been linked with depression, paranoia and hallucinations; people prone to mental illness may have more serious mental and emotional effects. Physical side effects can include low blood pressure, fast heartbeat, dizziness, slow reaction time and heart palpitations. Smoking marijuana carries similar risks as smoking tobacco products which is not recommended for RA patients.
A recent article in the journal Arthritis Care & Research, “The dilemma of medical marijuana use by rheumatology patients,” cautions against using herbal cannabis to reduce the pain associated with RA or other rheumatic diseases. However, it is important to distinguish between herbal cannabis, which can be cultivated specifically for recreational use or medicinal use, and synthetic cannabis derivatives.
One reason doctors caution against herbal cannabis for medical use is because dosing is difficult to control due to the variability of Cannabis sativa plants. It is important for people who consider using street cannabis (i.e. marijuana) or medical cannabis derivatives (i.e. Sativex) to reduce pain associated with RA or other rheumatic disease should always weigh the potential benefits against the potential side effects.
More research specific to rheumatoid diseases is needed to provide the evidence that cannabis may or may not be beneficial for patients with RA. It is difficult to conduct such research in the United States while cannabis is remains listed as a Schedule I substance. It seems that much of the related research that does exist has been supported by the same company that produces Sativex (which would logically be biased against herbal cannabis).
Blake DR, Robson P, Ho M, Jubb RW, McCabe CS. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford). 2006 Jan;45(1):50-2. Epub 2005 Nov 9.
Fitzcharles MA, Clauw DJ, Ste-Marie PA, Shir Y. The dilemma of medical marijuana use by rheumatology patients. Arthritis Care Res (Hoboken). 2014 Mar 3. doi: 10.1002/acr.22267. [Epub ahead of print]
Grotenhermen F, Müller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int. 2012 Jul;109(29-30):495-501. Epub 2012 Jul 23.
Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011 Nov;72(5):735-44. doi: 10.1111/j.1365-2125.2011.03970.x.
Parloff, Roger. “How marijuana became legal.” Fortune magazine, CNN Money, 11 Sep 2009, updated 18 Sep 2009. Web. Accessed 2 Apr 2014.
Richardson D, Pearson RG, Kurian N, et al. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):R43. doi: 10.1186/ar2401. Epub 2008 Apr 16.
Rieder SA, Chauhan A, Singh U, et al. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology. 2010 Aug;215(8):598-605. doi: 10.1016/j.imbio.2009.04.001. Epub 2009 May 20.
Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008 Feb;4(1):245-59.
Sánchez AJ, García-Merino A. Neuroprotective agents: cannabinoids. Clin Immunol. 2012 Jan;142(1):57-67. doi: 10.1016/j.clim.2011.02.010. Epub 2011 Mar 21.
Wright S, Ware M, Guy G. The use of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford). 2006 Jun;45(6):781; author reply 781-2. Epub 2006 Apr 18.
Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr. 2008 Sep;30(3):271-80.