Here, Dr. Dustin Sulak shares how stress is a major factor in the development and progression of autoimmune diseases and how cannabis can be a great tool in alleviating symptoms.
Autoimmune diseases often cause pain, inflammation, spasticity, itching, and gastrointestinal distress. Cannabis, well known for its analgesic, anti-inflammatory, antispasmodic, antipruritic (anti-itch), and gut-balancing effects, often works well for improving symptoms in people with autoimmune conditions. But can cannabis impact the underlying disturbance leading to these symptoms? This article reviews the clinical evidence examining the efficacy of cannabis in the treatment of common autoimmune conditions and takes a deeper look at the preclinical evidence suggesting that cannabis may be able to modify the autoimmune disease process. At the end of the article, I provide tips for implementing cannabis-based therapies in individuals with autoimmune diseases.
Inflammation is a normal physiological defense against infection and tissue damage; it serves its role in the healing process and quickly ends, under normal circumstances. Sometimes, however, the immune system becomes dysregulated, and inflammation persists, causing tissue and organ damage. In autoimmune diseases, inflammatory symptoms persist because one’s immune system attacks targets on otherwise healthy human cells. More than 80 conditions have been categorized as autoimmune, and the symptoms vary widely depending on the tissue or organ targeted by the aberrant immune activity.
There is no single cause of autoimmune diseases; most occur at the intersection of genetics and environment. For example, many autoimmune conditions run in families, but not in a clear pattern of genetic inheritance, and identical twins rarely manifest the same autoimmune disease (1). This suggests a genetic predisposition to autoimmune diseases, but environmental factors play a major role: microbial or viral infections, vaccinations (2), or major life stressors often precede autoimmune disorders.
Autoimmune conditions occur in about 8% of the population. The most common include type 1 diabetes, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), thyroid disease (Hashimoto’s thyroiditis and Grave’s disease), multiple sclerosis, rheumatoid arthritis, Sjögren disease, psoriasis, and lupus—among many others. Though not consistent among all autoimmune diseases, many individuals with one have a higher likelihood of developing a second autoimmune condition (3).
Many patients with autoimmune diseases are told that their immune system has become confused and is now attacking healthy tissue, but until recently the mechanisms of that confusion have been poorly understood. Recent research suggests molecular mimicry is one of the leading mechanisms by which infectious or chemical agents may induce autoimmunity. It occurs when the T or B cells of the immune system react to a foreign antigen with a similar molecular structure to peptides normally found in human cells. Under certain conditions such as genetic predisposition or psychological stress, the antibodies or T cells will continue to react to the human tissues long after the infection or foreign chemical is gone. Other immune malfunctions, such as impaired immune tolerance, likely also play a role (4).
Some autoimmune diseases impact specific organs, causing related problems and their downstream symptoms; for example, diabetes attacks the pancreas and results in loss of insulin production, which causes high blood sugar, which, without careful management, causes a host of other problems; and Hashimoto’s attacks the thyroid gland and results in loss of thyroid hormone production. When the immune system attacks the musculoskeletal system or the skin, symptoms usually include swelling, pain, and itching. When the immune system attacks the nervous system, symptoms often include spasticity, weakness, sensory disturbances, and psychiatric symptoms.
During the 13 years in which I’ve treated patients with cannabis, I’ve witnessed hundreds of people with autoimmune diseases report improvement in symptoms and quality of life when using this versatile medicine. But that’s not unexpected, as I could say the same about many categories of diseases. Why is cannabis so broadly effective across such wide variety of conditions? The main reason is its capacity to interact with the endocannabinoid system (ECS), a master regulator of the other bodily systems, including the immune system. Other reasons include non-ECS targets of compounds found in cannabis that also modulate inflammation, metabolism, nerve function, and more.
One of the most common autoimmune diseases I’ve treated with cannabis, multiple sclerosis (MS), is also one of the best studied. Nabiximols (brand name Sativex), a pharmaceutical oral spray containing plant-derived tetrahydrocannabinol (THC) and cannabidiol (CBD), has been extensively investigated in randomized, controlled trials: between 2000 and 2010, nabiximols trials included more than 2500 patients with MS, of whom more than 660 were treated continuously for at least 6 months. Nabiximols was approved in several countries for the treatment of MS spasticity, and vast clinical experience with nabiximols in the post-marketing setting accounts for more than 150,000 patient-years of use to date. A recent review of the post-marketing data concluded that (5), “nabiximols is a solid option for the management of MS spasticity in patients who fail to respond adequately to treatment with first-line anti-spasticity agents.” The authors also noted that (5), “nabiximols can provide noticeable relief of other symptoms associated with spasticity such as spasms, pain and disrupted sleep.”
It has always bothered me when researchers and medical authorities ascribe cannabis to the category of second-line therapies, considering it has a superior safety profile compared to most first-line agents, an extensive list of side benefits typically conveyed to patients, and as described below, the potential to beneficially impact the underlying cause of the condition. In my practice, cannabis is appropriately used as a first-line agent for spasticity and pain when patients come to me early enough in their health journey.
The American Academy of Neurology, in a 2014 review of 34 studies, supported the use of oral cannabinoids in the treatment of MS spasticity, pain originating in the central nervous system, and spasticity-related pain, and found that oral cannabinoids are probably also effective for reducing bladder complaints in patients with MS (6). The data supporting oral use is substantial and the benefits are moderate, but not impressive.
While majority of the data on cannabis for MS comes from trials using oral cannabinoids, in my clinical experience, I have found inhaled cannabis to be much more effective for producing improvements in spasticity. One placebo-controlled crossover trial on 30 patients with MS using low-quality cannabis cigarettes (4% Δ9- tetrahydrocannabinol [THC]) versus placebo cigarettes smoked once daily for 3 days confirmed my observations: reductions in objective measures of spasticity were greater than those observed in the oral cannabis trials, and subjects also experienced more significant reductions in pain (7).
Very little clinical trial data on the effects of cannabis for other specific autoimmune conditions is available, though plenty of data supports the use of cannabis to treat symptoms such as pain and itching. Readers of this publication didn’t need the 2017 National Academies of Sciences, Engineering, and Medicine report to tell us that they found conclusive evidence that cannabis could effectively treat chronic pain (8)—pain is the most common reason people use cannabis for therapeutic purposes (9), and with or without placebo-controlled trials, they probably wouldn’t be doing so if it wasn’t helping.
It’s important to note that without cannabis as a first-line or even second-line treatment for pain in people with autoimmune conditions, opioids are often the only effective option. One study found that 40% of patients with rheumatoid arthritis used prescription opioids regularly (10). The consequences of long-term opioid use, including increased sensitivity to pain, hormone disruption, disturbed sleep, problematic use, and overdose, are finally common knowledge among clinicians and patients alike. While cannabis has been shown again and again to work as a tool for helping patients decrease and discontinue opioids, it’s even better when it’s used to avoid the need to start opioids in the first place.
Less commonly known, however, are the benefits of cannabis for treating pruritis (itching), a common manifestation of autoimmune conditions in the skin. Substantial preclinical evidence indicates the cannabinoids work via CB1 and CB2 receptors in itch-related nerves fibers in the skin to suppress signaling and via CB1 receptors in the spinal cord and brain to decrease the intensity of the sensation. Human clinical studies in a variety of skin conditions, including psoriasis and eczema, have consistently shown significant reductions in itching and scratching using both topical and systemic cannabinoid treatments (11). Not surprisingly, the topical treatments also resulted in decreased signs of inflammation.
Crohn’s disease and ulcerative colitis, collectively known as inflammatory bowel disease (IBD), are autoimmune diseases that affect the gastrointestinal tract. People with IBD experience both gastrointestinal symptoms like abdominal pain, diarrhea, bleeding, and weight loss, as well as systemic symptoms like joint pain and fatigue. Symptoms can be present daily but typically cycle through “flares” of exacerbation. The goal of treatment is not only to address symptoms, but also to prevent the need for surgical removal of the intestines and other complications including nutrient deficiencies and weight loss, anemia, fistulas, and more.
Little high-quality human research has examined the impact of cannabis in these conditions, and the studies that have been performed, in my opinion, have not used practical cannabis dosing strategies—low dose CBD isn’t going to cut it (12). Surveys of patients with these conditions, however, confirm what I’ve observed in my clinical practice: most patients with IBD who try cannabis, find it helpful and continue to use it. A survey of US patients with IBD found that 80% of those who tried cannabis reported benefits in their condition. Interestingly, 21% of those living in states with both medical and adult-use cannabis laws used adult-use products specifically for IBD without their clinician’s knowledge. The most commonly reported benefits (13) were related to pain (68%), appetite (49%), anxiety (48%), fatigue (26%), stool frequency (23%), weight gain (20%), and blood in stool (5%).
In a large, recent survey of people with IBD in Australia (14), 25% of respondents had used cannabis for their condition, and 93% of them endorsed cannabis as effective in symptom management. The most common symptoms helped by cannabis were abdominal pain, stress, sleep issues, cramping, anxiety, bloating, depression, reduced appetite, and diarrhea—amongst many others. The authors noted, “the magnitude of self-reported symptom improvement in the present survey was surprisingly high. Symptom improvements of the magnitude reported in this study are rarely seen in any therapeutic intervention.”
For symptomatic treatment, cannabis often sounds too good to be true. When asked if cannabis can help with—fill in the blank: pain, itching, stiffness, spasms, redness, hypersensitivity, diarrhea, cramping, anxiety, fatigue, insomnia, anxiety, and so forth—the answer is yes, in most people. Of course, not everyone responds to cannabis, and in some, the results are modest. In others, the benefits are profound, life-changing, and often allow patients to discontinue other treatments that have significant side effects. While treating symptoms is important, preventing them may be even more helpful for people with these conditions.
Anyone with an autoimmune disease will confirm that psychological stress plays a major role in their symptoms, and that high stress events can trigger a flare-up or even a relapse of their condition. Most clinicians who treat patients with autoimmune diseases will confirm that they see more flare-ups during times of major stress. It’s well-known that stress impacts the function of the immune system, but the association of stress and stress-reduction techniques with symptom severity in autoimmune diseases has not yet received substantial attention of researchers in the field, and seldom receives the attention of clinicians caring for these patients. In one study of 92 patients with rheumatoid arthritis, psychologic stress was reported to be the most common reason for disease flares (15).
As mentioned above, psychological stress is also implicated in the development of autoimmune diseases. A recent retrospective Swedish cohort study compared the incidence of autoimmune disease in more than 100,000 people with stress-related disorders such as post-traumatic stress disorder (PTSD), adjustment disorder, and acute stress reaction with the incidence of autoimmune disease in more than 126,000 of their full siblings and over 1 million matched control subjects without a stress-related disorder. During an average follow-up of 10 years after the stress-related disorder was diagnosed, and after controlling for confounding factors, the risk of developing an autoimmune disease was 36% higher in those with the stress-related disorder. Some conditions, such as autoimmune thyroid disease, had a stronger association with stress-related disorders, while rheumatoid arthritis was still increased in those with stress-related disorders but not as much as the other autoimmune conditions studied (16).
Why might severe life stress predispose individuals to the development of autoimmune disease? At a biological level, activation of the sympathetic (fight or flight) nervous system and increased levels of the stress hormone cortisol can impair immune function, potentially increasing susceptibility to and preventing recovery from infections that could trigger autoimmune disease. In patients with PTSD and other types of chronic stress, particularly related to early life trauma, “adrenal burnout” or chronically low cortisol levels can lead to over-activation of the immune system and increased levels of inflammatory cellular signals. Severe life stress also indirectly influences the risk for autoimmune disease via lifestyle factors such as sleep disruption, alcohol or substance abuse, and increased smoking.
Metaphorically, severe stress is usually related to the perception of uncontrollable threatening elements in one’s external environment, or the absence of a safe personal environment. This is reflected in autoimmune disease, where the immune system’s perception of threat invades its recognition of self.
The ECS has been extensively studied and shown to be a major player in the development of stress-related disorders as well as in their treatment and resolution. The ECS controls excessive activity in the emotional and memory centers of the brain, and the therapeutic use of cannabinoids have been shown to help extinction of fear memories, prevent reinforcement of fear memories after trauma reminders, reduce the impact of stress on cortisol levels and immune function, and relieve symptoms of stress-related disorders such as anxiety and insomnia (17). Interestingly, there’s evidence that people with ECS dysfunction, such as a mutation in the gene that codes for the CB1 receptor (18) or lower levels of circulating endocannabinoids (19) have an increased likelihood of developing PTSD; there’s also evidence that the ECS is dysregulated in autoimmune conditions such as MS (20).
In medicine we often speak about “stress reduction” with an assumption that all psychological stress is damaging, but this is certainly not the case. It’s well-known that certain types of physical stress, like exercise, are healthy, but what defines healthy psychological stress, and what does this have to do with cannabis?
Eustress is a form of stress that has a beneficial effect on our health, motivation, performance, and emotional well-being. This type of stress feels challenging but exciting and within our coping ability. Eustress usually occurs when we embrace both the challenging and supportive aspects of an event or situation.
Distress is another form of stress that leads to anxiety, depression, impaired performance, and feeling overwhelmed. It typically occurs when one perceives the challenging aspects of an event or situation without simultaneously perceiving the supportive aspects. Eustress and distress are associated with vastly different responses in brain function and physiology.
I find it fascinating that the stressful situation itself doesn’t determine the type of stress, but our perception of the situation does. Nearly every situation has both challenging and supportive aspects, but we so often chose to fixate on the challenge while ignoring the support. Why? We all have the power to transform distress into eustress and spare ourselves the emotional and physiological consequences, so why do we so seldomly exercise this choice?
Because our environment is full of far more stimuli than our capacity for perceiving, our brains develop perceptual filters that help us focus on certain things and ignore others. Over time, and especially if left unattended, our filters often orient toward threatening aspects of our environment and away from supportive ones. This is especially true for those of us that have experienced trauma, which is generally everyone. Rigid perceptual filters limit our capacity to make the choice to perceive both sides of the situation and experience eustress instead of distress.
Why so much discussion about stress in an article on autoimmune disease? Among my patients with these conditions, many find that beyond the symptom-relief that cannabis provides, which they celebrated early in their use of the medicine, the perceptual flexibility learned from their long-term cannabis use is its most valuable gift. My patients find that cannabis helps them experience acceptance of stressful situations and their disease itself, feel as if they are a part of something greater than themselves like nature or God, and at the same time feel more like themselves.
Interestingly, qualitative research on cannabis-using patients has also found this common theme. Authors proposed the term “restored self” to describe this benefit of cannabis, defined as “the experience of regaining one’s sense of self, sense of normality, and sense of control over one’s life,” (21). Remarkably, this benefit was experienced independently of whether or not the individual experienced symptom relief with cannabis.
My patients with autoimmune disease often describe, in other words, an enhanced capacity to experience eustress instead of distress, which decreases the frequency of symptom flares and improves their overall quality of life. While the increased perceptual flexibility is often first experienced during the acute psychoactive effects of THC, after some time repeatedly using cannabis, they are able to maintain this flexibility with or without cannabis on board, suggesting a long-lasting transformation in stress resilience. In this way, perhaps cannabis strikes closer to the cause of the autoimmune disease, healing a dysfunctional perception of support and challenge, a dysfunctional sense of self and non-self.
Long-lasting perceptual flexibility isn’t the only benefit of cannabis that impacts autoimmune disease deeper than symptom reduction. For most patients, temporary symptom relief isn’t enough; a treatment that prevents disease progression, prevents tissue damage, and perhaps promotes remission is crucial. In conventional medical care for several autoimmune diseases, a category of otherwise unrelated drugs, called disease-modifying antirheumatic drugs (DMARDs) is defined by the capacity to slow down disease progression. Many of the DMARDs work by suppressing the production or activity of the immune systems’ inflammatory signals such as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), interleukin-6, and by inducing apoptosis (death and recycling) of B cells and T cells.
Not surprisingly, given its broad ability to replace multiple classes of pharmaceuticals, cannabis is able to perform many of the same functions as the DMARDs. The ECS is already working via some of these same mechanisms to prevent and regulate autoimmune diseases, and many of the effects of cannabis are simply enhancing this inherent function.
Specifically, THC has been shown to induce apoptosis reduce proliferation of B cells and T cells, while increasing the number of T regulatory cells, which are beneficial in autoimmune disease; CBD also triggers apoptosis of certain T cell subtypes that contribute to autoimmune inflammation. THC and CBD both inhibit release of the pro-inflammatory Th1 cytokines such as IL-1 and TNF-α; tetrahydrocannabinolic acid (THCA) also has potent anti-TNF-α activity. THC and CBD have been shown to increase production of Th2 cytokines that counteract the effects of Th1 cytokines. Cannabinoids have also been shown to decrease the activity of metalloproteinases, which are enzymes implicated in cartilage destruction in autoimmune conditions like rheumatoid arthritis (22).
Remarkably, the immune systems of people who regularly use cannabis may be more responsive to its anti-inflammatory effects than new users, demonstrated in a study in which phytocannabinoids inhibited the migration of monocytes taken from the blood of regular users, but did not affect migration of the monocytes taken from non-users. The regular users’ monocytes had four times higher expression of CB1 mRNA, indicating the cells had more CB1 receptors and therefore a stronger response to THC (23).
“Treat the individual, not the diagnosis” is my most common answer when people ask me how to use cannabis to treat a specific condition or category of conditions such as autoimmune disease. With its diverse range of chemical compositions, delivery methods, safe and effective dosages, and significant interindividual variability, cannabis requires us to take a more individualized approach to medicine—a benefit to patients. Nevertheless, there are certain strategies I suggest for most patients with autoimmune disease:
In summary, autoimmune diseases are common and originate in the immune system’s (and often one’s conscious) dysfunctional perception of self and non-self. Cannabis can provide excellent symptom relief for pain, sleep disturbance, itching, spasticity, anxiety, gastrointestinal, and many other symptoms. Some conditions, like MS, have significant clinical trial data supporting the effectiveness of cannabis, while most autoimmune diseases have little data beyond patient surveys, which usually indicate excellent results. Stress is a major factor in the development and progression of autoimmune diseases; cannabis can improve resilience to stress via its acute anti-anxiety effects and via long-lasting improvements in perceptual flexibility and ability to experience eustress instead of distress. Finally, cannabis also treats many underlying factors of autoimmune disease, conveying many of the benefits of DMARDs without the side effects and likely reducing the progression and damage caused by these conditions.
Dustin Sulak, DO, one of the first physicians in Maine to incorporate the legal use of cannabis as a medicine in 2009, is the founder of Integr8 Health, a medical practice that follows more than 8000 patients using medical cannabis. Today he is globally recognized by his peers as a pioneer of clinical applications, formulations, and usage protocols. He is the author of the first foundational text on the clinical use of cannabis and cannabinoid therapies, titled Handbook of Cannabis for Clinicians: Principles and Practice. Dr. Sulak is co-founder of Healer, a medical cannabis brand founded to address the challenges of helping patients and health providers get the best results with safe, reliably dosable products and education on how to best use them. Healer’s distinctive product formulations and educational material are based on his work. Healer Whole Plant Hemp CBD, CBDA and CBG products are available nationwide at www.HealerCBD.com. Healer medical cannabis products are currently available in Maine and Maryland and for more information visit www.Healercannabis.com. For free education on how to use cannabis as medicine and for Healer's online training and certification program for healthcare providers, industry professionals and consumers, visit www.Healer.com.