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    Why are we waiting 20 years for official recognition that cannabinoids have anti-inflammatory effects?

    The available scientific evidence can often be conflicting depending on the model used (cells, animals, health condition, etc.) but there is sufficient evidence showing that cannabinoids influence how the cytokine network is regulated. 

    Since the appearance of COVID-19 in our lives, a lot more focus within the field of cannabinoid research has been placed on the potential therapeutic effects of cannabis and cannabinoids as anti-inflammatory drugs.

    I’ve been reading about how cannabinoids regulate the immune system since 2010. Here we are, ten years later, and it appears to me that scientists are still trying to convince each other that, without a shadow of doubt, cannabinoids can have anti-inflammatory and immunosuppressive effects. Scientific data from pre-clinical studies continuously shows us that cannabinoids have massive potential in the development of new treatments. This is especially relevant for diseases for which other available treatments have not been effective. Still, “we” (mostly the US governmental research funding body, NIH) prefer to spend 20 times more money on researching the harmful effects of cannabis and its constituents rather than their therapeutic potential.

    There is clearly a wide-spread reluctance to accepting Cannabis for its health benefit. This is partially due to a lack of clinical studies, but also due to another big factor. In the US, where the vast majority of funding originates, the Drug Enforcement Administration refuses to remove Cannabis from their list of Schedule I Substances, which comprises “dangerous drugs with no acknowledged medical benefits”. This creates a vicious cycle where scientists face serious challenges in getting their study proposals accepted (and funded!) with which they would have the opportunity to demonstrate the medical benefits of cannabis.

    I want to present you with a list of scientific evidence that was published in a review by Dr Klein and colleagues in 2000, exactly 20 years ago. This was my “go-to” reference when I started to study the involvement of the endocannabinoid system in the regulation of the immune system.

    The anti-inflammatory properties of synthetic cannabinoids

    • Dexanabinol (HU-211) is a THC derivative that does not activate the cannabinoid receptors. 

    In several models of brain injury, Dexanabinol reduced mortality and improved clinical outcomes. In the brain, it reduced the levels of Tumour Necrosis Factor-alpha (TNF-alpha), an inflammatory cytokine produced by immune cells during acute inflammation.

    • Ajulemic Acid (AJA, DMH-11C) is a synthetic cannabinoid that activates the cannabinoid receptor 2 (CB2).

    In an acute inflammation model, AJA reduced recruitment of white blood cells (also called leukocytes), and it reduced joint swelling in an adjuvant arthritis model. Some evidence suggested AJA inhibited cyclooxygenase-2 (COX-2), an enzyme involved in inflammation.

    The effect of smoking marijuana on the production of cytokines

    At the time of writing, only one study had been published concerning the effects of smoking marijuana on the production of cytokines (small proteins that synchronise immune system responses) in humans. It included four groups: non-smokers, smokers of cigarettes, marijuana and cocaine. Only the immune cells of the marijuana smokers had a decrease in the production of TNF-alpha, GM-CSF (a cytokine that promotes the production of several immune cells) and Interleukin 6 (IL-6, a pro-inflammatory cytokine).

    IL-6 was identified as an inflammatory marker for severe COVID-19. It means that doctors can predict that a patient with high levels of IL-6 in their blood will likely develop severe COVID-19 symptoms. 

    The pro and anti-inflammatory effects of THC

    Animal studies described in this review all involved injecting mice with THC. These studies already indicated that THC lowers resistance to infections. THC injections decreased the production of Th1 cytokines (the ones involved in the destruction of microbial pathogens), IFN-gamma (interferon gamma, a pro-inflammatory cytokine that activates immune cells), IL-12 (a cytokine produced in response to antigen stimulation) and the receptor for IL-12. This effect of THC treatment was brought about by activation of the cannabinoid receptors 1 and 2. In a separate animal study where animals were infected with Legionella pneumophila (the bacteria that causes Legionnaires’ disease), THC injection caused shock and death within a few hours.

    In a single study where several cell types of the immune system were analysed, THC was demonstrated to have both pro- and anti-inflammatory effects, likely dependent on the cell population. It decreased production of TNF-alpha, GM-CSF and IFN-gamma, but it also decreased production of IL-10 (an anti-inflammatory cytokine) and increased IL-8 (important in the recruitment of immune cells to the site of infection).

    For some reason, this review did not mention the effects of CBD on inflammation, even though this same study also tested for that. Similar to THC, CBD also showed widespread effects on cytokine production that differed depending on the type of immune cell investigated.

    The effects of the anandamide cannabinoid

    Anandamide (AEA), an endogenous cannabinoid, has been shown to change cellular responsiveness in the presence of various cytokines:

    • AEA decreased the proliferation of human breast cancer cells by reducing the number of prolactin receptors. Prolactin is a hormone that stimulates breast cell growth.
    • In the presence of IL-3 (a cytokine that regulates blood cell production) the proliferation of mouse bone marrow cells was higher in cultures with AEA than without.
    • In cultures of hematopoietic cells, the cells that give rise to all types of blood cells, AEA increased proliferation in the presence of IL-3 and IL-6.

    At the same time, AEA had been shown to regulate the production of some cytokines:

    • In brain cells infected with Theiler’s virus, the presence of AEA increased production of IL-6.
    • In human immune cells, adding AEA to the cell culture decreased IL-4, IL-6, IL-8, TNF-alpha and IFN-gamma under various conditions.

    The available scientific evidence can often be conflicting depending on the model used (cells, animals, health condition, etc.). That is why it is essential to repeat studies to confirm new findings and to investigate the effects of any substance in a wide range of conditions. Regardless, there was plenty of evidence 20 years ago showing that cannabinoids influence how the cytokine network is regulated. 

    Dr. Kenneth Finn, an experienced Pain Medicine specialist in Colorado Springs, published a commentary expressing his concerns with the observed outcomes of using cannabis as a drug of abuse.

    “It is critical to differentiate between what is cannabis-based medications and medical cannabis. Cannabis-based medications have met the muster of scientific research and dosing guidelines are available to the medical community. Medical cannabis bypassed the pathway of required research and study to be proven effective.

    The medical community should support FDA drug development protocols and provide providers with cannabis-based medications we can use safely for our patients. Physicians should be pro-science and public policy should be driven by that, not public opinion.

    There is a mountain of evidence of harm related to marijuana use and a paucity of evidence of benefit, particularly with medical cannabis.

    All of the above was known 20 years ago, and in the meantime our knowledge about the effects of cannabinoids in the human body has grown. Still, to this day, there is reluctance in the medical community to consider cannabinoids as alternative therapeutic compounds, even when dealing with medical conditions for which there are no known effective treatments. 

    Seeing that the gap between pre-clinical and clinical studies is still of considerable size and that there is no real prospect of approved pharmaceutical grade sources becoming available in the near future, the general population has few options, and many turn to medical cannabis. Though I believe they are not the ones to blame, the vast majority of medical professionals are mostly confused about whether cannabis is beneficial or not, and were never taught about the endocannabinoid system during their training, making it harder for them to comprehend the implications of cannabis consumption.

    In conclusion, as the title of this article suggests, it is frustrating that we are still spending energy on convincing medical professionals of the anti-inflammatory effect that cannabinoids can have on the body. This has been proven many times over in various models and studies. It can feel like a broken record when we repeat that what we require is much further research into specific use cases for cannabinoid application, especially for issues involving inflammation, but that is what we need! In the meantime, we will continue to highlight noteworthy research here on the Ardoa blog.

    CARINA PINTO KOZMUS
    Author


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