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This is Part I of a three-part series on using marijuana or cannabis as medicine for chronic fatigue syndrome (ME/CFS) and/or fibromaylgia (FM). The first two parts by Amber focus on the science behind using Cannabis and how to get started on it. The last part by Cort focuses on using CBD oils.

Summary

  • Cannabis plants contain compounds that mimic those produced by our own endocannabinoid system (ECS).
  • ME/CFS research suggests that an endocannabinoid deficiency may play a role in the disease, at least in women.
  • Cannabis – especially THC – decreases many pro-inflammatory cytokines and increases some anti-inflammatory cytokines.
  • Both THC and CBD help to limit mast cell degranulation, a problem that many individuals with ME/CFS and Ehlers Danlos Syndrome experience.
  • Cannabis is most effective at treating neuropathic pain and can help reduce the amount of opioid painkillers used to treat pain.
  • A second article explores how to get started with Cannabis to treat the many symptoms of ME/CFS.

Marijuana as medicine

cannabis sativa

Cannabis sativa (from Leonhard Fuchs “Das Kräuterbuch” (“The New Herbal”) 1543))

For centuries, marijuana, also called by its scientific name Cannabis, has been used as medicine. The plant was used extensively in China and India, where Westerners first encountered “gunjah”. By the second half of the 19th century, researchers in the United States and Europe published over 100 scientific articles looking at the therapeutic benefits of Cannabis. Amazingly, in 1924 Cannabis was listed in Sajous’s Analytic Cyclopedia of Practical Medicine as a sedative, pain killer, and treatment for many gastroenterological complaints. This all came to an end in 1937 with the Marihuana Tax Act, which placed heavy taxes and fines on medical uses of the plant. By 1941, Cannabis was removed from the United States Pharmacopeia.

Since the discovery of cannabinoid receptors in the 1980s, there has been a resurgence in Cannabis research documenting marijuana’s many therapeutic benefits, including treatment of neuropathic pain and spasticity in multiple sclerosis, nausea and vomiting associated with cancer chemotherapy, and anorexia and wasting seen in HIV/AIDS patients.

As more states and countries move to legalize both the recreational and medical uses of marijuana, interest has grown in using Cannabis to help manage the debilitating symptoms of chronic neuroimmune diseases such as ME/CFS. Although there is no direct research on the effects of Cannabis in ME/CFS, research on other related conditions with similar symptoms, like fibromyalgia and autoimmune diseases, may provide clues for how it can be used to manage symptoms.

In the first article of this series, I focus specifically on the effects of Cannabis on the immune system and pain treatment, for which there is strong scientific evidence for therapeutic uses. In a second article, I outline some general strategies for those wishing to explore further the use of Cannabis for treating symptoms of ME/CFS in particular.

First, a caveat about Cannabis research

Research involving Cannabis has been legally complicated over the years. Despite achieving legal status in an ever-increasing number of states and foreign countries, Cannabis is still arguably misclassified as a Schedule I drug under United States federal regulations. Schedule I drugs are those that have been found to have no therapeutic benefit and a high potential for abuse (examples of other Schedule I drugs include heroin and LSD). This means, by definition, that according to federal law, there are no accepted medical uses for marijuana. It isn’t normally possible to secure funding for the gold-standard randomized clinical trials involving human subjects using Schedule I drugs. As a result, research in the US has been limited largely to synthetic cannabinoids, such as dronabinol and nabilone.

While the use of synthetics may allow medical researchers to bypass federal laws and allow for greater experimental control, these studies are not able to capture the true chemical complexity of Cannabis, with its over 60 identified cannabinoids, to say nothing of the scores of other types of compounds, such as terpenes, which also have many documented health benefits and may bolster the efficacy of cannabinoids. Research has shown that full-spectrum compounds found in Cannabis behave differently than the isolated and patented compounds favored by pharmaceutical medicine, a phenomenon called the entourage effect.

The Cannabis flowers that are available for federally-approved research are still limited by regulations, and as such, do not allow for comparison of different strains, let alone different types of products, such as edibles or topical creams. While this research is a good start, it does not ultimately provide enough information on how to best use Cannabis to treat the symptoms of chronic disease. Changing Cannabis laws at the federal level is necessary for the research to progress in more meaningful directions.

The endocannabinoid system and Cannabis

The interest in Cannabis to help manage a diverse range of health conditions stems from its role in the endocannabinoid system (ECS). Much like soy and other plant estrogens are able to mimic natural human reproductive hormones, Cannabis plants contain molecules that mimic human endocannabinoids. Called phyto-cannabinoids (phyto = plant), these molecules interact with a wide variety of systems and have been found to have neuroprotective, anti-inflammatory, and immunomodulatory benefits.

Endocannabinoids initiate a diversity of functions by binding to cannabinoid receptors, called CB1 and CB2, found in both immune and nerve cells, two systems greatly impacted in ME/CFS. The most studied endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Palmitoylethanolamide (PEA), while not technically an endocannabinoid, can enhance AEA activity. These cannabinoid receptors are involved in a variety of physiological processes, including energy metabolism, immune function, pain modulation, stress response, mood, and memory.

CB1 and CB2 Receptors

The CB1 and 2 cannabanoid receptors affect different parts of the body (from Williams – http://sites.utexas.edu/pharmacotherapy-rounds/files/2018/10/Williams_Final-Handout-without-pic-Oct-2018.pdf )

CB1 receptors are located primarily in the nervous system and some immune cells, where they play a role in pain perception and immune regulation. CB2 receptors are found mostly in immune cells. Their activation can lead to both anti- and pro-inflammatory effects, depending on the type of endocannabinoid and immune cell type involved. Research on multiple sclerosis has shown that CB2 receptors are also found in the central nervous system in neurons, microglial cells, and astrocytes – all likely sources of brain inflammation seen in ME/CFS, according to Jared Younger’s recent work.

The two most widely-studied phyto-cannabinoids in Cannabis are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC has a strong affinity for binding to CB1 receptors and is responsible for the “high” feeling typically associated with Cannabis.

In contrast, the non-psychoactive CBD blocks (versus binds) the CB2 receptor. Studies suggest that by blocking CB2 receptors, CBD may help correct endocannabinoid deficiencies indirectly by encouraging the body to use its own endocannabinoids more effectively.

Dysregulation of the ECS has previously been linked to chronic diseases such as fibromyalgia, autism, migraine, and irritable bowel syndrome. A 2016 paper by Naviaux and colleagues found that the endocannabinoid 2-AG was deficient in ME/CFS patients, but in females only. A decrease in 2-AG could explain, in part, the patterns of altered fatty acid and carnitine metabolism found in this study.

How does Cannabis influence immunity?

Endocannabinoids influence immunity directly and indirectly through their role in cell-to-cell signaling among many different kinds of immune cells. Endocannabinoids influence the production of inflammatory molecules called cytokines, the action of mast cells and many other types of immune cells. Because the immune system is largely a bunch of single cells found throughout the body, such communication is essential and provides checks and balances on the immune system, helping to modulate it so it functions more efficiently.

cannabis interactions with immune cells

Cannabis interactions with immune cells (Fig. 1, from Chiurchui 2016).

Overall, based on the research available, which is still mostly done in mice or on cell lines in a test tube, cannabinoids are typically viewed as broadly immunosuppressive agents. Both endo- and phyto-cannabinoids are potent anti-inflammatories that can induce cell death (apoptosis), inhibit cell proliferation, suppress cytokine production, and induce T-regulatory cells (Tregs), which help to keep the immune system from overreacting.

Because of these properties, THC has been used as a novel anti-inflammatory drug to manage autoimmune conditions such as multiple sclerosis, rheumatoid arthritis, colitis, and cancers with inflammatory components.

Like these other conditions, ME/CFS is an inflammatory disease. Recent research provides evidence for possible autoimmunity in ME/CFS, including T-cell clonal expansion (which could also suggest infection or cancer) and evidence for autoantibodies at adrenergic and muscarinic receptors. Many with ME/CFS have a mixed autoimmune picture.

Research suggests that Cannabis might benefit someone with a chronic inflammatory disease, but not someone who has a chronic or smoldering infection. A suppressed immune system can lead to increased susceptibility to infectious agents, increased duration of infection, and a reduced ability to identify and destroy cancer cells. Research on the effects of cannabinoids on T-cells show that THC suppresses the number of CD8 T-cells, cells that play an important role in fighting infections and cancer.

This presents a conundrum for ME/CFS patients because the mechanism underlying this disease is still unclear. It may be that ME/CFS has both an infectious component and an inflammatory/autoimmune component. Whether the net effect of Cannabis is positive or negative will likely depend on the precise mechanism driving immune dysfunction in this disease. ME/CFS patients with a mixed immunological picture will, unfortunately, have a harder time prioritizing whether to capitalize on the immunosuppressive properties of Cannabis or focus instead on fighting chronic or reactivated infections.

Cannabis and Cytokines

Cytokines, proteins that help coordinate immune responses to infection and inflammation, are considered to be the “bosses” of the immune system. As such, they are responsible for both initiating and turning off the immune response. Many researchers believe that chronically-elevated cytokine levels play a role in many of the symptoms experienced in ME/CFS and other inflammatory diseases. Both THC and CBD have been shown to affect the immune system by increasing immunosuppressive cytokines and decreasing T-cell activating cytokines.

In a 2017 study, Montoya and colleagues found that certain elevated cytokines correlate with ME/CFS severity as well. THC inhibits at least two of the inflammatory cytokines found elevated in this study, interleukin-12 (IL-12), and interferon-gamma (IFN-γ), a cytokine that plays an especially important role in fighting viral infections.

Strategies for using an anti-inflammatory like THC may also depend on where someone is in the arc of their illness.  Disease duration is a factor, where the longer patients are sick with ME/CFS, the more altered the cytokine associations become. Interestingly, cytokine levels appear to be higher during the first few years of this disease, but then taper off. Research by Hornig et al. (2016) found a stronger correlation between cytokine alterations and illness duration than with illness severity, and this pattern is consistent with that seen in immune exhaustion.

Due to limitations on Cannabis research, few studies have looked at the effects of Cannabis use on the immune system in humans. A very small Italian study found Cannabis use was associated with a decreased number of NK cells, increased IL-10 (an anti-inflammatory cytokine) and TGF-𝛽 (both a potent regulatory and inflammatory cytokine), and decreased IL-2 (a growth factor produced by NK cells). These findings are consistent with mouse and test tube studies and also suggest immunosuppressive effects of Cannabis.

Cannabis and mast cells

Cannabis also affects mast cells, which are another important type of immune cell. Mast cells are considered “immune sentinels” as they are located throughout the body but typically are found in greater numbers in the skin, airways, and gut, where the body meets the external environment. When mast cells degranulate, they release a variety of inflammatory compounds, including histamines, cytokines, serotonin, and among other compounds. Mast cell degranulation promotes inflammation and may contribute to many of the symptoms found in ME/CFS.

cannabis mast cells

Cannabis may be able to tamp down mast cell activation

Because mast cells have both CB1 and CB2 receptors, it is possible that both THC (binding to CB1 receptors) and CBD (blocking CB2 receptors) could have a beneficial therapeutic effect on allergic-type symptoms. The suppressive effects of cannabinoids on mast cells are limited to cannabinoids binding CB1 and those that interact with both CB1 and CB2, suggesting that THC and CBD could suppress mast cell degranulation.

Cannabis, as well as many other unrelated plant species, have a number of compounds that inhibit pro-inflammatory cytokine production. Perhaps the best example of this is β-caryophyllene, a type of terpene that is a major component of Cannabis, as well as in the essential oils of some spices and food plants, including clove, oregano, basil, and black pepper.

How can Cannabis be used to manage pain? 

Pain is no stranger to sufferers of ME/CFS for fibromyalgia. Whether it occurs in the form of muscular pain, joint pain, neuropathic pain or migraine headaches, pain is one of the most common symptoms. Types of pain can be classified as nociceptive, such as the pain that follows an acute injury, or as neuropathic. While nociceptive pain is often responsive to common pain medications, neuropathic pain is far harder to treat, because it is caused by damage to peripheral and autonomic nerves, which then send inaccurate pain information to the brain. This damage can be caused by many factors, including medications, spinal stenosis caused by cranial/cervical instability, vitamin deficiencies, infections, and more.

Similarly, central pain, the kind thought to underlie much of the pain in fibromyalgia, is also more difficult to treat. This type of pain originates from the central nervous system and occurs when the brain receives inaccurate information and thus perceives an exaggerated pain response to stimuli.

Evidence for Cannabis in pain management

Typically, neuropathic and chronic central pain are treated in conventional medicine with antidepressant drugs, such as Cymbalta, or prescription opioid-type painkillers. These drugs can carry heavy side effects and are often very difficult to discontinue. While consuming too much THC can certainly produce unwanted side effects, Cannabis carries little risk for addiction and has no associated withdrawal syndrome. There is even evidence that Cannabis and opioids can work synergistically, meaning that a lower dose of opioids is required to relieve pain when used with Cannabis.

Cannabinoids have shown relief against inflammatory and neuropathic pains, conditions that are often stubborn in their response to most pain medications. Agonists, like CBD, provide pain relief through modulating nociceptive pain thresholds, inhibiting the release of inflammatory molecules, and have combined effects with other systems that influence pain relief.  A recent report by the National Academies of Sciences, Engineering, and Medicine concluded that there is “conclusive or substantial evidence” to support the use of Cannabis as an effective treatment for neuropathic and chronic pain in adults.

Fibromyalgia studies that have examined the relationship between Cannabis use and symptom relief found that patients who use Cannabis experienced a significant reduction of pain and stiffness, enhanced relaxation, and increased somnolence and feeling of well-being relative to those who do not use Cannabis. The mental health scores were also significantly higher in Cannabis users compared to non-users. A research trial with nabilone – a synthetic CB1 agonist similar in structure to THC – also showed similar reductions in pain and anxiety scores.

THC - the part of Cannabis which can get you high - has the strongest pain-killing characteristics as well. (THC relieve pain without producing a high)

THC – the part of cannabis which can get you high – also has the strongest pain-killing characteristics. (Note – THC can relieve pain without producing a high)

THC has the greatest analgesic (painkilling) activity of the various natural cannabinoids, but it also has the greatest psychoactive potency, making it less than ideal for patients who do not want to be high while managing their pain. However, if administered in small doses it can be well tolerated and still be somewhat effective in treating neuropathic pain, without heavy psychoactive effects. Lower doses are also less likely to suppress blood pressure and elevate heart rate. Most people find that CBD is most effective at treating pain with a little THC (at least 1-3%). Synthetic THC analogs also hold promise and lack the euphoric high, but are not widely available.

CBD, a CB2 receptor agonist, interacts both directly and indirectly with other receptors that influence pain, including vanilloid, opioid, and serotonin receptors. Thus, CBD treats pain without the side effect of feeling high as with THC. CBD competes with endocannabinoids and in doing so acts as a reuptake inhibitor by impairing the process that breaks down the endocannabinoid AEA, thereby raising endocannabinoids in the brain’s synapses. Increased levels of AEA (e.g., via CBD or PEA supplementation) in the bloodstream may reduce the amount of pain a person feels. There is much to learn about the role that cannabinoids play in cell signaling beyond the CB receptors.

If you are in a state or country where Cannabis is illegal, options may be limited to CBD oil made from hemp. CBD is substantially more expensive than THC; if you seek a product with a high CBD content, be prepared to pay more money. In general, quality Cannabis products are very expensive.

Conclusion

The medical literature offers ample evidence for many therapeutic benefits of Cannabis, especially related to immune suppression in autoimmune diseases and pain management. Because of the widespread influence of the endocannabinoid system on a diversity of systems in the human body, Cannabis has the potential to help with treating many symptoms of ME/CFS. The next part in this series explores how patients might approach using cannabis to manage their own personal ME/CFS symptoms.

Acknowledgements

I am deeply grateful for the superb feedback I received on this piece from Emily St. Claire, Hall Cushman, and Cort Johnson.

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