Medicinal Cannabis: What is the Evidence for Autoimmune Disease?

CLICK TO EXPAND // Glossary of Terms

Introduction

Over the last several years, our society has seen a relative explosion of interest and use of both recreational and medicinal cannabis and its associated cannabinoids. Many states have recently passed laws allowing the medicinal use of cannabis in addition to other states even allowing its use recreationally. Alongside these changes in legislation, we have also seen an even greater explosion in the use of the cannabinoid CBD, both as a medical drug and as an unregulated supplement. Given this relative explosion as well as the informational quagmire that has ensued regarding the potential benefits and harms of cannabis or cannabinoid use, I felt it was important to provide a concise assessment of the medical literature regarding the use of cannabis and cannabinoids to treat disease in humans and provide some helpful guidance on how one could use (or not use) cannabis and cannabinoid products in a safe and effective way.

Note: While I am writing as a medical professional, this article does not constitute professional medical advice or take into consideration the legality of cannabis and cannabinoids in your current state or country of residence. The contents of this article are strictly informational in nature and you should speak first with your medical professional prior to beginning any use of cannabis or cannabinoids for the treatment of a medical condition.

In an attempt to make this article briefer than my previous forays on Autoimmune Wellness, I will focus specifically on reviewing the clinical evidence and research for the use of cannabis and cannabinoids for the treatment of disease in humans. If you wish to have a more thorough discussion about the physiology of endocannabinoids and cannabinoids or about foundational research in animal or theoretical models of disease, I will direct you to other resources linked at the end of this article. In addition, if you have not done so already, read through the glossary of terms and points outlined in the beginning of the article to familiarize yourself with some of the terms regarding cannabis and cannabinoids that I will be using throughout the article. As a final organizational preface, while focusing on summarizing the current evidence for the medicinal use of cannabis and cannabinoids for treating autoimmune disease in humans. I have also included discussions regarding the treatment of secondary and associative conditions to numerous autoimmune diseases such as chronic pain, and insomnia. I have delineated in the article when the research was performed on humans with a specific autoimmune disease or if it was performed in a larger population of individuals diagnosed with secondary and non-specific conditions such as chronic pain and insomnia.

Is there any evidence for the use of cannabis and cannabinoids for the treatment of autoimmune disease in humans?

An extensive summary report by the National Academies of Science, Engineering and Medicine (NASEM): Health and Medicine Division called The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research was published in early 2017 to outline the current level of evidence for the use of cannabis and cannabinoids in the treatment of human disease (1). Prior to this report, the largest and most recent meta-analysis examining the efficacy of cannabinoids in clinical medicine was a meta analysis published in JAMA in 2015 by Whiting et. al (2). While research has continued to grow since the 2015 JAMA meta analysis, as well as the NASEM report in 2017, the extensive NASEM review (nearly 500 pages in length) will serve as one of our primary resources when it comes to assessing the current state of the evidence for medicinal cannabis/cannabinoids in humans.

All of this being said, as many of us know in the AIP community, simply because research is limited or non-existent regarding a certain intervention or therapy does not mean that there is evidence against the therapy or that the therapy itself is not effective, it simply means that there’s no scientific research at this point in time, and we should be cautious and tempered when making any types of statements or conclusions about the therapy or intervention.

Prefaces aside, was there any evidence from the 2017 NASEM report that cannabis or cannabinoids are effective treatments for any autoimmune condition? The short answer is yes, with the caveat that there is not as much disease specific evidence as you would think regarding the use of cannabis to treat autoimmune disease. Let’s dig into the research.

Cannabis and Cannabinoids in Multiple Sclerosis

The task force authors concluded that “there is conclusive or substantial evidence that cannabis or cannabinoids are effective for improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids).” Of all the conditions studied by the task force (outside of just autoimmune disease) the only other conditions with the same level or degree of evidence for the clinical utility of cannabis or cannabinoids were chronic pain and chemotherapy induced nausea and vomiting (we will talk a little more about chronic pain later).

CLICK TO EXPAND // Determining the Level of Evidence

So you may be asking, “What studies were assessed to make the above conclusions regarding spasticity in MS?”

The task force evaluated two systematic reviews (pooling of independent trials) conducted in 2014 and 2015 respectively that only looked at randomized controlled trials for the use of cannabis and cannabinoids for treating spasticity in MS. While employing slightly different methodological designs, these systematic reviews concluded that “nabiximols, oral cannabis extract and orally administered THC are probably ineffective for reducing objective measures of spasticity in the short term (6–15 weeks), while oral cannabis extract and orally administered THC are ‘possibly effective’ for objective measures at 1 year.” As you can see from these conclusions, the story is a lot more nuanced as there appears to be variations in the types of cannabis/cannabinoids providing benefit as well as the duration of use required to see benefit. In addition, the authors noted that there was no clear change in clinician assessed markers of spasticity (doctor’s impression of spasticity vs. the patient) and that this weakened the support for the benefit of cannabis and cannabinoids. That being said, I personally find great value in the “subjective” patient experience and still find meaning (as the task force illustrates) in what the patient acknowledges about their condition as compared to strict objective markers alone.

The other area of research and conclusions provided by the task force as they relate to cannabis and cannabinoid use for MS involved symptoms of depression. The task force found that “there is limited evidence that cannabis or cannabinoids are ineffective for reducing depressive symptoms in individuals with chronic pain or multiple sclerosis (nabiximols, dronabinol, and nabilone).”

Not wanting to paint a rosier picture than we currently have from the scientific literature, but also not wanting to simply ignore the evidence we have up to this point, I hope you can see that even for MS, a condition in which the task force stated there was substantial/conclusive evidence regarding the use of cannabis and cannabinoids, there does not appear to be large therapeutic changes associated with its use, at least as it pertains to the formulations, dosages and vehicles currently used to deliver cannabis and cannabinoid constituents.

As strange as it may sound, when we look at the rest of the NASEM report, there are no conclusions or summaries about any other autoimmune diseases. Not even conclusions stating there is insufficient or limited evidence. Zero. Drawing a conclusion from the paucity of research and thus the lack of concluding statements from the task force, I simply want us all to acknowledge that the formal scientific study of cannabis and cannabinoids for the treatment of autoimmune disease is in its infancy and perhaps, one could argue, even slightly behind the growing body of literature for the efficacy of AIP for autoimmune diseases (read more about the AIP IBD, AIP Hashimoto’s, and AIP Eczema/Psoriasis studies published or currently in-progress).

As the task force authors point out, there are several barriers to growing research into medicinal cannabis and cannabinoid use for more health conditions, including autoimmune disease and I provide a few of their primary points below.

1. “There are specific regulatory barriers, including the classification of cannabis as a Schedule I substance, that impede the advancement of cannabis and cannabinoid research.”
2. “It is often difficult for researchers to gain access to the quantity, quality, and type of cannabis product necessary to address specific research questions on the health effects of cannabis use.”
3. “A diverse network of funders is needed to support cannabis and cannabinoid research that explores the beneficial and harmful effects of cannabis use.”

As you can see, cannabinoid research faces an uphill battle, just as our efforts to study dietary and lifestyle approaches including the AIP diet face financial and societal challenges.

The research barriers and the lack of conclusive findings from the NASEM report regarding the use of cannabis or cannabinoids for autoimmune diseases aside, are there any other studies looking at the use of cannabis or cannabinoids for the treatment of an autoimmune condition?

Cannabis and Cannabinoids in Crohn’s Disease

A 2018 Cochrane Database Systematic review published in 2018 identified 3 randomized controlled studies totalling 93 patients with active Crohn’s disease and concluded: “the effects of cannabis and cannabis oil on Crohn’s disease are uncertain. Thus no firm conclusions regarding the efficacy and safety of cannabis and cannabis oil in adults with active Crohn’s disease can be drawn. The effects of cannabis or cannabis oil in quiescent Crohn’s disease have not been investigated. Further studies with larger numbers of participants are required to assess the potential benefits and harms of cannabis in Crohn’s disease.” (4)

As you can see, a few small studies looking at the use of cannabis or cannabis oil for individuals with active Crohn’s disease have revealed no consistent findings (5,6). Let’s look a little deeper at the three studies included in the systematic review, however, to assess the rationale for these conclusions.

Between the three studies, there did appear to be some trends for the cannabis groups with regards to improvements in quality of life, clinical disease activity and even rates of remission when compared to the placebo groups. The cannabis groups, however, in the studies that tracked adverse events, did experience more side effects and adverse events when compared to the placebo groups.

As the authors of the systematic review rightly conclude, there is a small amount of inconsistent evidence that shows cannabis and cannabis oil may be of some clinical utility for individuals with active Crohn’s disease, but we need much more research as well as clinical examinations of its use in those with stable/quiescent disease to establish a more firm understanding of the role of cannabis in the treatment of Crohn’s.

Cannabis and Cannabinoids in Ulcerative Colitis (UC)

The same study authors from the 2018 Cochrane Database Systematic Review for Cannabis in Crohn’s Disease also published a connected Cochrane Database Systematic Review for the use of cannabis in UC (7). Let’s look at their conclusions.

“The effects of cannabis and cannabidiol on UC are uncertain, thus no firm conclusions regarding the efficacy and safety of cannabis or cannabidiol in adults with active UC can be drawn.There is no evidence for cannabis or cannabinoid use for maintenance of remission in UC. Further studies with a larger number of patients are required to assess the effects of cannabis in UC patients with active and quiescent disease.”

As you can see, the authors, drawing from 2 randomized controlled studies including 92 total participants make similar conclusions to the conclusions provided for cannabis and cannabinoid use in Crohn’s disease (8,9).

Looking at the specific study results in greater detail, the study authors point out that 1 of the studies included in the review looked at various doses of CBD versus placebo (8). The CBD group experienced more mild to moderate side effects/adverse events than the placebo group. The mean C-reactive protein (CRP) level (a marker of inflammation) after the 10- week study was clinically and statistically similar in both groups with the CRP level in the CBD group actually being a little bit higher. There was a small trend for improved quality of life in the CBD group as compared to the placebo group. Overall, the study showed very unimpressive therapeutic benefits. From this study, given the increased rate of adverse effects, the overall cost of the CBD and the lack of change in inflammatory markers, I would very likely forgo the use of CBD in ulcerative colitis and instead focus on other more validated and efficacious therapies.

The other study included in the systematic review looked at the use of cannabis cigarettes with a standardized amount of THC (9). The authors of that study found a statistically significant difference in the mean fecal calprotectin level (inflammatory stool marker in UC) between the THC users versus the placebo group after 8 weeks. There were also trends noted for decreased clinical disease activity in the THC group as compared to the placebo group. The mean change in CRP levels were similar between both groups. From these findings we see that perhaps there is more clinical utility with the cannabis cigarettes containing a standardized amount of THC as compared to isolated CBD capsules. In following with the authors of the systematic review, however, with only the 1 study of 32 patients showing trends for clinical benefit, I do not feel that cannabis or cannabinoids should be included as a primary therapy in IBD, including both UC and Crohn’s disease.

Cannabis and Cannabinoids in Rheumatoid Arthritis (RA)

A small 2006 study published in Rheumatology looked at the treatment of joint pain and quality of life in individuals with active RA (10). The study authors compared the use of Sativex (the combined THC-CBD medication) to placebo over 5 weeks of treatment. A total of 58 participants (31 Sativex, 27 placebo) were included. The study authors reported “in comparison with placebo, the CBM (Sativex) produced statistically significant improvements in pain on movement, pain at rest, quality of sleep… The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group.”

Upon closer examination of the results, it does appear that there were clinically significant changes (albeit small) in the domains of pain and quality of life previously noted, however, following my correction for multiple hypothesis testing, it does not appear that any of the findings stated by the study authors should actually be considered statistically significant.

There is currently an on-going study (not published) enrolling participants with either RA or Ankylosing Spondylitis (AS) that is examining the safety and efficacy of CBD as well as THC for the treatment of chronic pain in these conditions (11).

Cannabis and Cannabinoids in Systemic Lupus Erythematosus (SLE)

I am not aware of any randomized and controlled interventional studies that have been conducted to date for cannabis or cannabinoids in SLE. A 2014 meeting abstract entitled: Medical Marijuana Related Outcomes in Patients with Systemic Lupus Erythematosis commenting on a multi-year prospective study of over 200 individuals from New Mexico (⅓ of which reported marijuana use) and various measures of clinical disease activity, medication use, etc. (12).

The study authors concluded “this 5-year outcome study indicates that marijuana use in SLE is not associated with reduced pain, use of prednisone, narcotic analgesics or SLE disease activity. However, marijuana use in SLE is associated with an increased incidence of neuropsychiatric SLE, death, narcotic use, end stage renal disease, and noncompliance/nonadherence to recommended therapy. These epidemiologic data are not supportive of a beneficial role for medical cannabis in SLE.”

While the data is only observational in nature and cannot be used to make causative claims, it is indeed at least concerning to see that marijuana use in this isolated sample was actually associated with more troubling health outcomes. While it is indeed possible that individuals in the marijuana group were self-medicating as a result of poorer health, the study does not lend much support for the regular use of marijuana in the treatment of SLE.

Positively, there has been some biochemical research thus far indicating disturbances in the endocannabinoid system in patients with SLE (13) and there is currently an on-going clinical trial looking at the use of a compound called BT-101 (also known as lenabasum) which is a synthetic endocannabinoid receptor type 2 (CB2) agonist in individuals with SLE (14).

Cannabis and Cannabinoids for Secondary Conditions including Chronic Pain, Insomnia and IBS

As I begin to bring this article to a close, I wanted to share some of the other conclusions provided by the NASEM report as they relate to secondary conditions often associated with autoimmune disease (2).

Here are some of their primary conclusions regarding cannabis and cannabinoid use for the respective condition mentioned.

1. “There is conclusive or substantial evidence that cannabis or cannabinoids are effective for the treatment for chronic pain in adults (cannabis).”
2. “There is moderate evidence that cannabis or cannabinoids are effective for improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis (cannabinoids, primarily nabiximols).”
3. “There is limited evidence that cannabis or cannabinoids are effective for improving symptoms of posttraumatic stress disorder (nabilone; one single, small fair-quality trial).”
4. “There is no or insufficient evidence to support or refute the conclusion that cannabis or cannabinoids are an effective treatment for symptoms of irritable bowel syndrome (dronabinol).”

With regards to the effects of cannabis and cannabinoids for mental health disturbances and overall cognition, the evidence is much more murky and difficulty to entangle. There is a moderate level of evidence for an association between acute cannabis use and impairments in cognition and learning.

With regards to risk factors for the development of problem cannabis use, the task force authors go on to list several different domains with the most likely associative risk factors being: 1) being male and smoking cigarettes, 2) initiating cannabis use at an early age, 3) a history Major Depressive Disorder, 4) childhood anxiety and depression.

As previously stated, these are simply associations and do not imply causation, however, such conclusions may be helpful to identify individuals who may be at higher risk of problem cannabis use and who may be less likely to benefit from medicinal cannabis.

Final Thoughts

Cannabis and cannabinoid research is very much in its infancy, suffering from federal regulations restricting its availability for clinical research. Given these limitations, much of the current medical practice regarding cannabis and cannabinoids has been driven by extensive physician (clinical) use in the fields of integrative oncology and pain management. Following the 2017 NASEM report, it is clear that the expansion of medicinal cannabis and cannabinoid use across most of the US is likely premature. While the passing of such legislature is a positive step for increasing the availability of cannabis and cannabinoids for clinical care and research, it would be difficult to universally endorse the use of cannabis and cannabinoids in the manner that is implied by the adoption of state regulated medicinal cannabis programs.

My greater worry, however, beyond the increasing scope of the potentially premature medicinal cannabis practice across the country, is the increasing utilization of CBD products, non-regulated supplements with massive variations in their production and composition. Of the research reviewed and included in the NASEM report, only a small percentage of the studies included looked at CBD isolate drugs or supplements, and as you may recall, the CBD Crohn’s disease study previously mentioned showed no major therapeutic benefit from the CBD. I should also point out that nearly all of the CBD studies performed to date, including the Crohn’s disease study, are using doses of CBD in the 100’s of milligrams (mg), some as much as 500 or 1000 mg. The typical therapeutic dose of the CBD drug Epidiolex used in the treatment of genetic based seizure disorders is 5 mg/kg two times daily. For an average person weighing 60 kg, this is 300 mg two times daily for a total of 600 mg daily. With the current price of most CBD products, administering a dose of this size is absolutely impractical for nearly everyone. While the therapeutic dose of CBD for other conditions may be much different than it is for the dose utilized for its current seizure disorder indications, I do worry greatly that many people are currently using subtherapeutic doses of CBD that are acting essentially as very expensive placebos.

You may be thinking after this discussion that I am anti medicinal cannabis/cannabinoid, but that is far from the truth. I simply want us all to be as informed as possible regarding the current state of the evidence regarding medicinal cannabis and make appropriate conclusions and subsequent treatment decisions. If you choose to pursue the use of CBD supplements, it is imperative to inquire about third party, independent testing in order to determine the specific types and amounts of cannabinoids in the CBD product in question. Asking the producer to provide a certificate of such testing is thus both reasonable and essential for safe use. You can also additionally inquire about further testing from the manufacturer regarding levels of other toxic constituents such as heavy metals, but this is less commonly performed and available. If you live in a state allowing medicinal cannabis use, please establish and maintain a relationship with a trusted health care provider to see if medicinal cannabis is appropriate for you. While randomized controlled studies are great tools to begin to more rigorously assess the potential benefits of cannabis for various conditions, studies of this nature cannot predict a given individuals personal response to its use. I am very hopeful that as the research and clinical use of cannabis/cannabinoids continues to grow, we will accumulate more evidence and anecdotal insight into the proper vehicles and doses to achieve therapeutic effects for a number of autoimmune conditions.

Additional Articles on Cannabis and Cannabinoids

• The Promising Potential of Medical Marijuana, Dr, Chris Kresser
• CBD: Panacea, Snake Oil or Somewhere In Between?, Dr. Sarah Ballantyne
• Chemistry, Metabolism, and Toxicology of Cannabis: Clinical Implications, Iranian Journal of Psychiatry

References

1. National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. https://doi.org/10.17226/24625.
2. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73.
3. Sharma P, Murthy P, Bharath MM. Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry. 2012;7(4):149–156.
4. Kafil TS, Nguyen TM, MacDonald JK, Chande N. Cannabis for the treatment of Crohn’s disease. Cochrane Database of Systematic Reviews 2018, Issue 11. Art. No.: CD012853.
5. Naftali T, et al. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013 Oct;11(10):1276-1280.e1.
6. Naftali T, Mechulam R, Marii A, Gabay G, Stein A, Bronshtain M, Laish I, Benjaminov F, Konikoff FM. Low-Dose Cannabidiol Is Safe but Not Effective in the Treatment for Crohn’s Disease, a Randomized Controlled Trial. Dig Dis Sci. 2017 Jun;62(6):1615-1620.
7. Kafil TS, Nguyen TM, MacDonald JK, Chande N. Cannabis for the treatment of ulcerative colitis. Cochrane Database of Systematic Reviews 2018, Issue 11. Art. No.: CD012954.
8. Irving PM, Iqbal T, Nwokolo C, Subramanian S, Bloom S, Prasad N, Hart A, Murray C, Lindsay JO, Taylor A, Barron R, Wright S. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis. Inflamm Bowel Dis. 2018 Mar 19;24(4):714-724.
9. T Naftali, L Bar Lev Schlieder, F Sklerovsky Benjaminov, I Lish, J Hirsch, F M Konikoff, P398 Cannabis induces clinical and endoscopic improvement in moderately active ulcerative colitis (UC). Journal of Crohn’s and Colitis, Volume 12, Issue supplement_1, February 2018. Page S306.
10. D. R. Blake, P. Robson, M. Ho, R. W. Jubb, C. S. McCabe. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology. Volume 45, Issue 1, January 2006, Pages 50–52.
11. Hendricks O, Andersen TE, Christiansen AA, et al. Efficacy and safety of cannabidiol followed by an open label add-on of tetrahydrocannabinol for the treatment of chronic pain in patients with rheumatoid arthritis or ankylosing spondylitis: protocol for a multicentre, randomised, placebo-controlled study. BMJ Open. 2019;9(6):e028197.
12. https://acrabstracts.org/abstract/medical-marijuana-related-outcomes-in-patients-with-systemic-lupus-erythematosis/
13. Navarini L, Bisogno T, Mozetic P, Piscitelli F, Margiotta DPE, Basta F, Afeltra A, Maccarrone M. Endocannabinoid system in systemic lupus erythematosus: First evidence for a deranged 2-arachidonoylglycerol metabolism. Int J Biochem Cell Biol. 2018 Jun;99:161-168.
14. https://clinicaltrials.gov/ct2/show/NCT03093402
15. White CM. A Review of Human Studies Assessing Cannabidiol’s (CBD) Therapeutic Actions and Potential. J Clin Pharmacol. 2019 Jul;59(7):923-934.