Cannabis affects the immune system and also can reduce pain levels. As a result, it has become increasingly of interest in diseases such as rheumatoid arthritis (RA), which is an autoimmune disease — meaning the immune system is dysfunctional and overactive causing inflammation. RA classically causes joint damage and chronic musculoskeletal pain. There are numerous immune cells and signals involved in RA such as antibodies.
How Cannabis Works on Rheumatoid Arthritis
Medical cannabis comes from the plant cannabis sativa and affects the body by interacting with the endocannabinoid system (ECS). The ECS system is broadly made up of cannabinoid molecules that activate the system, receptors that are distributed all over the body and are activated by the cannabinoid molecules and enzymes that play an important role in the synthesis and degradation of the cannabinoids.
The ECS can be activated by cannabinoids that are naturally produced in the body — “endocannabinoids” — or those produced externally (outside of the body) and consumed. These external cannabinoids include plant-based cannabinoids from cannabis sativa known as “phytocannabinoids” or cannabinoids that are synthesized in a pharmaceutical setting for example Nabilone. Much of our understanding of the ECS on the body has come from studying the effects of endocannabinoids, phytocannabinoids (cannabis) and synthetic cannabinoids. The most-studied phytocannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD), which are thought to cause the main effects of cannabis. Nonetheless, there are at least 140 phytocannabinoids identified in cannabis sativa and though these other cannabinoids are not as well studied as THC and CBD they are also likely to also have some effect on the body.
The enzymes of the ECS help regulate endocannabinoids levels and can clear the endocannabinoids very quickly, unlike phytocannabinoids which are usually longer lasting. Pharmaceutical companies have also started to develop drugs that can prevent the enzymes breaking down the endocannabinoids, so increasing and maintaining their levels.
ECS receptors & RA
Two ECS specific receptors have been identified, though as research moves forward more are likely to be found. The receptors identified are called CB1 and CB2, and they are distributed differently around the body and also affect the body differently. Cannabinoid molecules may activate or block either receptor or both of them to varying degrees. THC and CBD each interact and affect CB1 and CB2 receptors. The ECS has receptors all over the body with high concentrations on immune cells and in the nervous system. This allows the ECS to influence inflammation and pain. There is ongoing research to try to establish the precise functions of both the CB1 and CB2 receptors.
CB1 receptors, which have higher concentrations in the nervous system, seem to be responsible for the psychoactive (feeling “high”) and neurological effects of the ECS, including its effects on pain. CB1 activation helps regulates neurotransmitter (signalling of the nervous system) release, and it is this action that results in a decrease in pain and also has positive effects on depression and anxiety. CB2 receptors, on the other hand, are present in higher concentrations on the surface of immune cells. They also are expressed on bone cells and connective tissue cells. Studies have found that activating the CB2 receptors can reduce immune cell multiplication and movement, processes that are central in inflammation. This is why cannabis may act as an anti-inflammatory to reduce inflammation. CB2 activation also affects immune cell production of antibodies. This is especially relevant to RA as the majority of patients will be antibody positive.
A small study of 13 RA patients found both CB1 and CB2 receptors to be present on diseased joint tissue, and this was associated with increased endocannabinoid levels. Both CB1 and CB2 receptors have been identified on a type of cell in joints that is thought to be central to the rheumatoid disease process called “synovial fibroblasts.” The presence of the receptors in the diseased tissue suggest that they may have a role in the development and regulation of the disease. It is also possible that the presence of these receptors can be taken advantage of to directly affect diseased tissue.
Despite evidence that activation of the ECS seems to decrease inflammation there are also studies showing that CB1 activation can lead to increased inflammation. Interestingly, a recent study showed that if a CB2 receptor is not functioning normally due to a genetic mutation, the person has a 10-fold increased risk of developing RA. This suggests that CB2 activation may play a role in immune regulation that helps prevent the development of RA.
Endocannabinoids and synthetic cannabinoids have been shown to decrease the levels of immune and connective tissue cells that are thought to be involved in joint damage and destruction in RA(4). Endocannabinoids are usually undetectable in healthy joints, however there seems to be increased levels in the joints of patients with RA. Synthetic cannabinoids have also been shown to decrease specific inflammatory signalling by cells taken from diseased joints in RA patients by activating the CB2 receptor.
Medical Studies on Cannabis and Rheumatoid Arthritis
Cannabis has been used to treat pain for thousands of years. There are broadly two equally important aims in RA treatment. The first is to control inflammation and prevent irreversible damage to the body – this is known as disease-modifying treatment. The other aim is to improve symptoms, especially pain and quality of life. THC and CBD, the main components of medical cannabis, have different effects on the ECS and therefore play different roles in achieving these goals. Nonetheless it is also thought that THC and CBD may have a synergistic effect (meaning that that CBD and THC can positively influence each other’s effects). This “entourage effect” is an advantage in medical cannabis that is not currently seen with the synthetic preparations.
One study has shown that ingestion of medical cannabis in humans decreased the activity of immune cells and reduced antibody levels. In studies using animal models CBD has also been shown to reduce antibody levels.
THC’s effect on immune cells is unclear, and the effects it has on immunity may not be through the cannabinoid receptors but rather through a different mechanism entirely (non-cannabinoid receptors). In studies, high concentrations of THC were required in order to have an impact on inflammatory response. In addition, when medications were added that block the cannabinoid receptors, these anti-inflammatory actions were not affected. This suggests that the THC was having its effect on inflammation via a different non-cannabinoid pathway. CBD, on the other hand, has shown encouraging results influencing inflammation in RA. Some of these anti-inflammatory effects are due to activation of the cannabinoid system and some are likely to be through activation of receptors other than CB1 & CB2 receptors, involving different receptors and pathways. The hope is that further research will shed light on this, potentially opening up the potential for new types of therapies.
Different studies have also examined the effects of treatment with cannabinoids in arthritis in mouse models. CBD and synthetic cannabinoids that activated the CB2 receptor all reduced the arthritis severity and the amount of inflammation and musculoskeletal damage.
A small five-week randomised control trial (high quality methodology) was conducted with 58 RA patients. The patients were divided into groups and received either Nabiximols or placebo. Nabiximols is an oral spray which contains cannabis extracts of CBD and THC in equal quantities, while the placebo was a spray that looked the same but contained no active components. After 5 weeks, the patients that received Nabiximols reported significantly improved pain on movement and rest, quality of sleep, and disease activity scores compared to those patients that received the placebo. In terms of adverse effects, the most common were dizziness, lightheadedness and dry mouth. The side effects were all mild to moderate and did not cause any of the patients to stop taking the medication. This is currently the only clinical randomised control trial that has been performed examining the use of cannabinoids in patients with RA. However, there is a larger European study underway examining both CBD and THC in patients with RA.
There is increasing evidence that ECS plays a role in balancing the immune system in rheumatoid arthritis. There is currently only one high quality randomized clinical trial examining using cannabinoids as a treatment for RA in people; it has encouraging results and further trials are being conducted. Aside from potential beneficial effects that cannabis may have on inflammation there is also its well-known effects on pain. When deciding whether to start a new medication it is always a balance between potential benefits and harms. The majority of side effects from cannabis tend to be mild to moderate and usually do not result in the need to stop treatment. However, there are concerns regarding potential the psychotropic effects, and other possible complications including psychiatric complications.
Potential side effects of cannabis use
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