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.
The Endocannabinoid System
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.
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 5-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.
Despite increasing evidence that cannabis may have anti-inflammatory effects in patients living with rheumatoid arthritis there are no recommendations to prescribe cannabis for this reason. Patients therefore are treated with medical cannabis for symptomatic relief (particularly pain). It is possible that in the future medical cannabis will also prescribed for its anti inflammatory effects.
While cannabis is still illegal in the USA according to federal law, a majority of states have legalized medical cannabis. Currently the following states have legalized medical cannabis for rheumatoid arthritis and chronic or intractable pain: Connecticut, Hawaii and Illinois. In the following states chronic or intractable pain are indications with no specific mention of rheumatoid arthritis: Alaska, Arizona, Arkansas, California, Colorado,, Delaware, District of Columbia, Florida, Georgia, Iowa, Louisiana, Maine, Maryland, Massachusetts, Michigan, Minnesota, Missouri, Montana, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Dakota, Ohio, Oregon, Pennsylvania, Rhode Island, South Carolina, Vermont, Virginia, Washington, West Virginia.
Other countries in which rheumatoid arthritis or chronic pain are a legal indication for prescription include Australia, Chile, Colombia, Canada, Czech Republic, Germany, Greece, Israel, Italy, The Netherlands, Norway, Poland, Romania, and Uruguay.
Regulations regarding medical cannabis are changing very rapidly and so this list is constantly changing and being added to.
Rheumatoid arthritis is an autoimmune disease, like fibromyalgia and lupus. If you have RA, your body’s immune system attacks your joints, instead of (or as well as) attacking germs, viruses, and other foreign substances to protect your body from infection. In response, your joints become inflamed and painful. This makes the tissue that lines the joints get thicker and stop the joints from moving smoothly.
If you don’t treat the inflammation, it can cause damage to the cartilage, which is the soft, slippery tissue that covers the ends of the bones in the joint to make them move easily. Eventually, the cartilage can wear away, leaving the bones to rub painfully against each other. Your joints can get loose and unstable. Over time, your joints could become deformed, causing permanent physical disability.
There are several different types of arthritis. They all cause pain and inflammation in the joints, but each type of arthritis progresses in a different way and has different treatments and causes. Rheumatoid arthritis (RA) is among the most common forms of arthritis. It is estimated to affect as much as 1% of the global population.
Although rheumatoid arthritis commonly affects the joints, it’s impact can be felt throughout the body and is a systemic disease. That means that it can also attack entire body systems, like your eyes, blood vessels, skin, or even your lungs or your heart.
The main symptoms of rheumatoid arthritis are pain and swelling in the joints. It usually progresses slowly, but it can also get worse quickly. Rheumatoid arthritis tends to appear in the smaller joints first, like the fingers, hands, and toes, and it usually affects your joints symmetrically, meaning that if one hand is affected, the other one probably will be as well. The first symptoms of RA in the joints are:
- Throbbing, aching pain in the joints that’s usually worse in the mornings
- Joints that are swollen, red, or feel warm to the touch
- Joints that are stiff in the morning, and take more than 30 minutes for the stiffness to wear off
You might also see more general symptoms, including feeling tired and fatigued, losing your appetite, weight loss, and low-grade fever.
Around 40% of people with rheumatoid arthritis also see symptoms in other parts of their body, depending on which body systems are attacked. These symptoms can include:
- Eyes that are dry, red, and painful. You might be sensitive to light and have impaired vision
- A dry mouth, with irritated gums and infections
- Small lumps underneath your skin in bony areas, called rheumatoid nodules
- Inflammation and scarring in your lungs, causing shortness of breath
- Inflamed blood vessels that damage your nerves, skin, and other organs
- Lowered red blood count, leading to anemia
- Morning stiffness for a prolonged period of time
When to see a doctor
It’s important to go to your doctor if you have persistent swelling and pain in your joints, or if you have other symptoms of rheumatoid arthritis. The progression of rheumatoid arthritis can be slowed down, but once the joints have been damaged there’s no way to heal them.
There’s no single test that proves rheumatoid arthritis, and there are many other reasons why you might have stiff and painful joints, so your doctor will ask a lot of questions to rule out other possible causes for your symptoms.
Rheumatologists are specialists in diagnosing and managing rheumatoid arthritis. They will also do a thorough physical examination, checking the condition of your joints. You’ll also go through a number of tests. Blood tests will measure levels of inflammation in your blood by checking your Erythrocyte sedimentation rate (ESR, or “sed rate”) and C-reactive protein (CRP) level.
Your blood test results also show the level of rheumatoid antibodies in your blood, called rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) antibodies.
Your doctor might also send you for joint imaging tests, like X-rays and MRIs, to check for damage to your joints.
If you get a positive result to any of these tests, it’s still not definite proof that you have rheumatoid arthritis. All the tests, combined with your medical history, symptoms, and a physical exam, help your doctor to make a confident diagnosis.
Rheumatoid arthritis is caused by your immune system attacking the synovium lining your joints, but scientists aren’t sure what makes your immune system behave this way. It seems to be multifactorial, meaning there is more than one single cause. Causes are likely a combination of genetic and environmental factors.
Some of the risk factors that make it more likely that you’ll develop rheumatoid arthritis include:
- Gender. Rheumatoid arthritis affects almost 3 times as many women as men.
- Age. Women tend to develop it between 30 and 60 years old, but it affects men at an older age.
- Genes. Researchers found that people with a particular genetic marker called HLA are 5 times more likely to develop rheumatoid arthritis. HLA controls your immune responses. You’re also more likely to develop RA if someone in your close family has had it.
- Being overweight or obese, especially in women aged 55 or older.
- Exposure to environmental toxins, like cigarette smoke, air pollution, silica, asbestos, insecticides, and mineral oil.
- Exposure to certain bacteria or viruses can trigger RA in people who are already more likely to develop it.
- Stress or trauma can trigger RA
There are ways to treat rheumatoid arthritis in order to stop the inflammation that damages joints and organs, relieve the symptoms, reduce long-term complications, and improve your overall quality of life. Over the past two decades, new treatments have made astounding progress in the treatment of rheumatoid arthritis. That said, it’s not possible to cure RA entirely.
Once your joints or organs have been damaged by rheumatoid arthritis, the damage can’t be undone. That’s why doctors try to diagnose it as early as possible, and use aggressive initial treatments in order to prevent initial joint damage.
In the early stages, you’ll probably be given some of these types of medications to slow down or stop inflammation:
- Corticosteroids include prednisone, prednisolone, and methylprednisolone. They work fast to reduce inflammation, but they can have serious side effects, so they won’t be prescribed to you long-term. They’re usually used to get quick results against major inflammation while waiting for slower-acting, long-term medications like NSAIDs and DMARDs to kick in. These can be given in pill form or by injection.
- DMARDs stands for disease-modifying antirheumatic drugs, like methotrexate, hydroxychloroquine, and sulfasalazine. They can be taken orally, or given by injection or infusion.
- Biologics are a type of DMARDs that can work more quickly than traditional DMARDs. They’re usually given by injection or as an infusion in your doctor’s office. Biologics target specific steps in your immune response, instead of wiping out your entire immune system. They often work when other medications have failed.
For dealing with day-to-day pain and inflammation that causes significant disability, you can also take regular painkillers, or NSAIDs (nonsteroidal anti-inflammatory drugs), with or without a prescription. NSAIDs include ibuprofen and naproxen sodium. These medications reduce pain and inflammation, and can be taken as a pill, or applied as a cream or gel directly to the joint area.
Complementary and alternative therapies
Rheumatoid arthritis can affect your life and mood in many ways, so many people who live with it use different supplements and therapies to keep up their overall physical and mental health and cope with the anxiety of having a chronic illness. Some of the most popular options include:
- Acupuncture and acupressure, which helps stiff muscles to relax and relieves pain.
- Massage to ease tight, stiff muscles and relieve the stress and anxiety that can come with living with RA.
- Turmeric, fish oil, and/or plant oil supplements which can help to reduce pain and morning stiffness.
- Heat pads and warm baths to ease stiff and aching muscles.
- Gentle exercise and careful stretching, like tai chi or yoga, to strengthen your muscles and keep them as flexible as possible. Physical therapy can guide you to the best ways to strengthen your joints without overworking them.
- Eating foods that are rich in antioxidants, including oily fish, fruit and vegetables, and olive oil, and avoiding processed foods that feed inflammation.