Osteoarthritis (OA) is the number one cause of disability in older adults, leading not only to pain and reduced mobility, but to a host of other medical conditions, including increased anxiety and depression and poor quality of life. Managing OA symptoms is also a common reason many patients turn to medical cannabis. Until now, there has not been a clinical trial demonstrating efficacy of cannabis in the treatment of OA, however, studies highlighting the role of the endocannabinoid system, both in OA pathophysiology and as a possible therapeutic target for future OA drugs, suggest cannabis as an approved treatment for osteoarthritis may be closer than many think. Furthermore, cannabis has become an accepted, safe alternative for those suffering from chronic pain, which is a defining feature in osteoarthritis.
The Endocannabinoid System
Evidence highlighting an intimate relationship between the body’s endocannabinoid system (ECS) in the development of osteoarthritis and its role as a potential therapeutic target has opened up a new area of possibility for scientists researching OA drugs.
The endocannabinoid system was discovered at the beginning of the 1990s when researchers were trying to understand how tetrahydrocannabinol (THC), the psychoactive compounds in cannabis, affects the body. They found two main classes of receptors: CB1 cannabinoid receptors primarily in the brain and central nervous system and the CB2 receptors located mostly in the immune system, but also peripheral nerve terminals.
Binding with these cannabinoid receptors are fatty ligands called endocannabinoids; the most studied being anandamide and 2-AG, but may also include the related endogenous compounds arachidonic acid (AA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA)). Endocannabinoids are produced on demand when there is some imbalance in the body, after which they are broken down by special enzymes (FAAH and MAGL)
The ECS by its very nature is adaptive and dynamic, becoming altered in most pathological conditions, including pain. These changes can include alterations in cannabinoid receptor expression or their agonists, anandamide and 2-AG. However, this is thought to be protective in nature and is in effect our bodies trying to inhibit disease progression.
So far, most studies examining the role of the ECS in osteoarthritis have been carried out in animal models, usually rodents. While these give a strong indication of the relationship between the ECS and osteoarthritis, the results from the studies aren’t necessarily replicated in humans. In fact, one of the only human clinical trials targeting the endocannabinoid system for arthritis (blocking the enzyme responsible for breaking anandamide down in the body), failed to repeat the pain relieving results seen in animals.
That said, some useful clues to the role of the ECS in osteoarthritis have been highlighted through studies on mice and rats. Raised levels of anandamide, 2-AG and related compounds PEA and OEA were found in the spinal cord of rats induced OA knee pain. Another study found decreased CB1 and CB2 expression in the lumbar cord of mice induced with OA, which may be in response to increased ECS tone.
But how about in humans? While it’s a lot easier to measure endocannabinoid tone in rodents, one study did find OA patients had upregulated CB1 and CB2 expression as well as elevated 2-AG levels, suggesting a connection between the ECS, OA, and the higher rates of depression encountered by patients.
Could it be then that endocannabinoid dysregulation will become the osteoarthritis biomarker of the future, alerting doctors to the disease before too much joint damage has occurred?
What is certainly an area of exciting research is the development of drugs targeting the ECS as a way to reduce OA pain.
The role of the CB2 receptor, which when activated is known to have an anti-inflammatory effect, shows particular promise with scientists suggesting it may play a crucial role in modulating osteoarthritis. In one study, an increase in CB2 expression brought about a reduction in joint pain, while stimulating CB2 receptors in osteoarthritic rats reduced pain-associated behaviour. In fact, when scientists bred mice without any CB2 receptors at all, their OA was more severe than the control group.
Activating CB1 receptors also appears to suppress OA nociceptive pain, something scientists discovered using a synthetic CB1 agonist in a rodent model of osteoarthritis.
Cannabis & Osteoarthritis
With the ECS now an accepted therapeutic target for osteoarthritis drugs, this gives further foundation for the use of compounds within the cannabis plant to manage OA symptoms.
The cannabis plant contains more than 144 compounds called cannabinoids, with tetrahydrocannabinol (THC) perhaps the most widely studied. THC is a partial agonist for both CB1 and CB2 receptors, which could explain why patients find cannabis helps with their pain symptoms. Interestingly, one neuroimaging study in human subjects found THC reduced the unpleasantness of pain rather than changing pain sensations themselves.
As well as counteracting the “high” caused by THC, CBD is both analgesic and anti-inflammatory in its own right, through non-ECS mechanisms. However, CBD is thought to indirectly affect endocannabinoid tone by inhibiting the enzyme FAAH, responsible for breaking anandamide down in the body, which may bring about a further anti-inflammatory effect.
Indeed, one preclinical trial on rats found that CBD’s anti-inflammatory effect prevented pain and nerve damage associated with OA.
So far, cannabinoids have shown most efficacy in targeting neuropathic pain in humans, although anecdotal evidence from around the world suggests the cannabis plant is effective for chronic pain in general.
When it comes to osteoarthritis, clinical research has been limited, although right now two clinical trials using cannabinoids for OA are taking place.
The first, a randomised, double placebo trial, is studying the use of vaporized cannabinoids for arthritis of the knee joint. Different ratios of THC and CBD are being tested on 40 subjects for safety, efficacy and tolerability of the different cannabinoid combinations.
A second study, also random and placebo controlled, will study CBD as a treatment in osteoarthritis of the hand in 180 subjects.
Thankfully, more clinical research into cannabinoids for osteoarthritis is likely to take place worldwide as restrictions on researching compounds in cannabis become lifted.
Potential side effects of cannabis use
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