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COVID-19 + Cannabis

Is it ethical not to investigate the use of phytocannabinoids?

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I have been very curious to see what experts had to say about cannabis use in the COVID-19 epidemic, and thus have been researching extensively. I have found only broad generalizations, along with the popular refrain “cannabidiol does not cure coronavirus”. I find it to be a very over-simplified statement (who is talking about treatment of the virus itself, anyway?) and so I decided to do my own research.

According to all the studies to date (Nichols & Kaplan, 2020), there is no doubt that CBD is immunomodulatory and anti-inflammatory. By “immunomodulatory” we mean basically immunosuppressive, since it generally suppresses the proliferation and activation of mitogen stimulated T-cells, as well as the production of pro-inflammatory cytokines (Chen et al., 2012); the point that should be made here is that the immuosuppressive action of CBD is in no way related to the immunosuppressive action in drugs such as methotrexate or cyclophosphamide. These drugs alter immunity as suppressors only, while CBD (and THC for that matter) modulates its response either by suppressing or by enhancing it, depending on the level of existing T-cell activation (Chen et al., 2012). These findings apply to HIV infections and it remains to be proven if they apply to other corona viruses as well; nevertheless, some data are available: In SARS-CoV infections (very similar to current SARS-CoV-2), a severe decrease in circulating T-cells was observed in the acute phase (Channappanavar et al, 2014). It is therefore possible and worth investigating whether the same applies to COVID-19, which would mean that the two basic phytocannabinoids, namely CBD and THC, would be indicated for the treatment of the acute phase. We have no definite proof at this point.

There is no doubt that CBD is immunomodulatory and anti-inflammatory.

In the COVID-19 epidemic, people are dying mainly of an inflammatory cytokine storm, leading to non-reversible ARDS (Acute Respiratory Distress Syndrome). Several drugs, new and old are tested in the pursuit of a means to contain the storm reaction of the immune system in a balanced way. Since bibliographical evidence suggests that CBD has multiple modes of anti-inflammatory action, very comparable to colchicine (Drugs.com) save the serious adverse side effects (Leung et al, 2015), it is only reasonable to have it tested in the present contingency. There is also some preclinical evidence that THC is useful in preventing the equivalent of ARDS in mice (Rao et al, 2015). I propose that it should be included in the therapeutic protocols on equal terms as colchicine and chloroquine.

Overall, phytocannabinoids manifest their effect by directly suppressing effector T-cells, and by inhibiting kinase cascades and transcription factors leading to production of pro-inflammatory molecules. One such example is the inhibition of phosphorylated p38, which leads to a decrease in the functionality of the inflammatory transcription factors AP-1 and NF-κB, thereby reducing inflammation. Another interesting aspect is the emergence of pro-inflammatory micro-RNAs (miRNAs) at the onset of ARDS (Umbrello et al, 2016), associated to Toll-like Receptor (TLR) and NF-κB signaling (Juknat et al, 2019). miRNA-induced inflammation is not amenable to corticosteroid treatment, but is responsive to CBD and THC (Umbrello et al, 2017). This is another line of research, very much worth pursuing.

In particular, the aforementioned actions of phytocannabinoids are manifested by the inhibition of the production and/or activity of important inflammatory cytokines such as, IFN-γ, IL-6, IL-1β, IL-2, IL-17A, TNF-α (mediated through enhancement of endogenous adenosine signaling (A2A receptors) (Nichols & Kaplan, 2020, Carrier et al, 2006), and chemokines such as CCL-2, which attracts monocytes, T-cells and dendritic cells to areas of inflammation. CBD, with its inhibitory effect on cryopyrin (NALP3), inhibits macrophage inflammasome activation, and thus the caspase-1 cascade is not activated or, were it activated, it would be controlled (Han & Mallampalli, 2015, Libro et al., 2016). Two pro-inflammatory interleukins, IL-1β and IL-6, are emerging as the decisive factors that dictate whether a COVID-19 case will evolve into ARDS (through the combination of macrophage activation syndrome and immune dysregulation [Hellenic Institute for the Study of Sepsis, 2020]) or will self-cure. IL-1β is responsible for 25% of cases, while IL-6 for 75% (Professor E. Giamarellos, personal communication). Interestingly, they are both mitigated by CBD (Nichols & Kaplan, 2020). There is less evidence for THC (Kozela et al, 2010, Keen et al, 2014). In view of this knowledge, not testing CBD as a preventive of ARDS in the context of COVID-19 might even be considered unethical.

In addition, cannabidiol directly induces inflammatory immunocyte suppression by up-regulating the IκB kinase complex, which inhibits the activity of the NF-κB transcription factor (Nichols & Kaplan, 2020). CBD also plays a regulatory role in inflammation by triggering the production of Treg and MDSC (Myeloid Derived Suppressor Cells) (Dhital et al, 2017), as is the case in simple respiratory viral diseases, especially during the early phase.

All the above actions of CBD are related to the suppression of innate (primary) immunoreactivity. Innate immunoreactivity is extremely useful at the beginning of viral infections, but harmful when it eventually gets out of control in the course of the disease: In high risk groups, it can lead to ARDS (acute respiratory distress syndrome). This is what patients have been dying from in the ICUs of the world.

Apart from this, CBD exerts an immunoapoptotic activity (ie withdraws inflammatory immune cells by the programmed cell death mechanism that is called “apoptosis”), as well as an apoptotic activity on infected cells; both actions appear to be important in controlling the degree of inflammation and the progression of infection (Nichols & Kaplan, 2020).

In addition to treating uncontrolled inflammation in the context of viral disease in general, cannabinoids cause significant changes in epigenetic mechanisms (D’Addario et al, 2013), including methylation, histone modification, and non-coding RNA. The epigenetic regulation of viral infections through cannabinoids has received considerable attention in the literature, but this line of knowledge is not fully understood yet. With the increased methylation of host DNA under the influence of cannabis and methylating agents, the expression of many genes may be inhibited, and in particular of the genes related to cell-virus interaction, i.e., genes governing the entry of the virus into the cell, its structural integration, its output and subsequent inflammation (Tahamtan et al, 2016).

Based on the above theoretical / bibliographical data, CBD should be well suited for the exacerbation stage of COVID-19 infection, for exactly the same reasons as colchicine, which has already begun to be administered experimentally. The only difference is that CBD is free from important adverse effects. By the same token, its use as a prophylactic should be discouraged; the same applies to the initial phase of the infection: Full capacity of innate immunity is what is required initially. Concerning patients that already use CBD for other conditions; given the fact that immunosuppression is dose dependent, they should probably keep using it during the epidemic, but in small doses, arbitrarily estimated at less than 15mg/day in divided doses. If larger doses are needed, and in order to err on the safe side, then CBD combined with strict social distancing should suffice. Smoking and vaping should be discouraged altogether (Williams, 2020).

CBD should be well suited for the exacerbation stage of COVID-19 infection.

A final word of caution: Neither CBD nor any other cannabinoid and anti-inflammatory terpene have been systematically tested in the clinical setting of the present epidemic, and therefore cannot be formally recommended by clinicians. Cannabinoids can contribute to infectivity and/or pathogenicity in certain viral infections; in others, they can diminish make viruses less infective and/or less pathogenic. In both cases, multiple biochemical routes affect host immunity, cell signaling and effector mechanisms involved in the viral cell cycle. In this respect, the role of vitamin D is extremely important in the enhancement of public health, but beyond the scope of the present discussion. In any case, caution is in order and medical supervision as well (Reiss, 2010).


NOTES:

Note 1: CBG, other cannabinoids and terpenes have not been taken into account in this small review because a) they would greatly confuse understanding of an already complicated matter b) There is little research available in the literature of cannabis to date.

Note 2: In the literature, CBD and THC are considered as isolated substances, thus without the notorious “entourage effect” of preparations from whole plants (Russo, 2018). The main exception is a few studies with AIDS/HIV patients, who were also smoked cannabis users. There is a possibility that the use of whole spectrum oils would have a different effect on the immune response to viruses.

Note 3:
Other supportive measures (like vitamins D and C, glutathione, acetaminophene etc) that could enhance innate immunity are available, but have not been addressed here.


SELECTED REFERENCES:

Carrier, E. J., Auchampach, J. A., & Hillard, C. J. (2006). Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression. Proceedings of the National Academy of Sciences, 103(20), 7895–7900.

Channappanavar, R., Zhao, J., & Perlman, S. (2014). T cell-mediated immune response to respiratory coronaviruses. Immunol Res, 59(1–3), 118–128.

Chen, W., Kaplan, B. L. F., Pike, S. T., Topper, L. A., Lichorobiec, N. R., Simmons, S. O., Ramabhadran, R., et al. (2012a). Magnitude of stimulation dictates the cannabinoid-mediated differential T cell response to HIVgp120. Journal of Leukocyte Biology, 92(5), 1093–1102.

Chen, W., Kaplan, B. L. F., Pike, S. T., Topper, L. A., Lichorobiec, N. R., Simmons, S. O., Ramabhadran, R., et al. (2012b). Magnitude of stimulation dictates the cannabinoid-mediated differential T cell response to HIVgp120. Journal of Leukocyte Biology, 92(5), 1093–1102.

D’Addario, C., Di Francesco, A., Pucci, M., Finazzi Agrò, A., & Maccarrone, M. (2013). Epigenetic mechanisms and endocannabinoid signalling. FEBS J, 280(9), 1905–1917.

Dhital, S., Stokes, J. V., Park, N., Seo, K. S., & Kaplan, B. L. F. (2017). Cannabidiol (CBD) induces functional Tregs in response to low-level T cell activation. Cellular Immunology, 312, 25–34.

Han, S., & Mallampalli, R. K. (2015). The Acute Respiratory Distress Syndrome: From Mechanism to Translation. J.I., 194(3), 855–860.

Hellenic Institute for the Study of Sepsis. (2020, April 9). Personalised Immunotherapy For SARS-CoV-2 (COVID-19) Associated With Organ Dysfunction — Full Text View — ClinicalTrials.gov. https://clinicaltrials.gov. Retrieved April 14, 2020, from https://web.archive.org/web/20200414135606/

Juknat, A., Gao, F., Coppola, G., Vogel, Z., & Kozela, E. (2019). miRNA expression profiles and molecular networks in resting and LPS-activated BV-2 microglia — Effect of cannabinoids. PLoS ONE, 14(2), e0212039.

Keen, L., Pereira, D., & Latimer, W. (2014). Self-reported lifetime marijuana use and interleukin-6 levels in middle-aged African Americans. Drug and Alcohol Dependence, 140, 156–160.

Kozela, E., Pietr, M., Juknat, A., Rimmerman, N., Levy, R., & Vogel, Z. (2010). Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells. J. Biol. Chem., 285(3), 1616–1626.

Leung, Y. Y., Yao Hui, L. L., & Kraus, V. B. (2015). Colchicine — Update on mechanisms of action and therapeutic uses. Seminars in Arthritis and Rheumatism, 45(3), 341–350.

Libro, R., Scionti, D., Diomede, F., Marchisio, M., Grassi, G., Pollastro, F., Piattelli, A., et al. (2016). Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front. Physiol., 7.

Nichols, J. M., & Kaplan, B. L. F. (2020). Immune Responses Regulated by Cannabidiol. Cannabis and Cannabinoid Research, 5(1), 12–31.

Rao, R., Nagarkatti, P. S., & Nagarkatti, M. (2015). Δ9Tetrahydrocannabinol attenuates Staphylococcal enterotoxin B-induced inflammatory lung injury and prevents mortality in mice by modulation of miR-17–92 cluster and induction of T-regulatory cells. Br J Pharmacol, 172(7), 1792–1806.

Reiss, C. S. (2010). Cannabinoids and Viral Infections. Pharmaceuticals, 3(6), 1873–1886.

Russo, E. B. (2018). The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain,” No Gain. Front. Plant Sci. , 9.

Tahamtan, A., Tavakoli-Yaraki, M., Rygiel, T. P., Mokhtari-Azad, T., & Salimi, V. (2016). Effects of cannabinoids and their receptors on viral infections. J. Med. Virol., 88(1), 1–12.

Umbrello, M., Formenti, P., Bolgiaghi, L., & Chiumello, D. (2016). Current Concepts of ARDS: A Narrative Review. IJMS, 18(1), 64.

Williams, V. (2020, March 24). What Smokers Should Know About COVID-19. Https://newsnetwork.mayoclinic.org/ . Mayo Clinic News Network. Retrieved April 14, 2020, from

Colchicine Uses, Side Effects & Warnings — Drugs.com. Retrieved from https://www.drugs.com/mtm/colchicine.html, Apr 14, 2020

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