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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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GRAM Mag Sets NOW AVAILABLE!

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GIVE THE GIFT OF GRAM

You can now order sets of our
printed magazines. Give the gift of
knowledge this year to your friends,
family, or yourself and only pay
the shipping and handling.

What a deal!

Set includes 9 vintage GRAM Mags
(2019-2020)

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Turmeric

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Turmeric is a root vegetable commonly used as a spice in various Indian and other cultures’ dishes. Turmeric is in the zingiberaceae family, as is ginger. The turmeric plant is native to the southeastern region of Asia and commonly harvested in places like India, Sri Lanka, China, Indonesia, and Taiwan. It is responsible for curry’s signature orange color, and its vibrant pigment will give essentially any meal an orange hue. 

Turmeric contains a substance called curcumin, and curcumin has been shown through research to offer anti-inflammatory and other therapeutic benefits. The scientific name for the turmeric plant is Curcuma Longa, and likely where the name curcumin comes from. When people are talking about the health benefits of turmeric, they are referencing curcumin so you may hear the two names used interchangeably. Curcumin is part of a group called curcuminoids, with curcumin being the most active and the most beneficial for health. Flavonoids are another substance found in various plants and give these plants their color. Curcumin is a flavonoid and is responsible for providing that bright orange color to turmeric. In addition to providing aesthetic value, flavonoids are also strong antioxidants with anti-inflammatory and immune-boosting properties.

The Journal of Biological Chemistry published a study done by Sanjaya Singh and Bharat B. Aggarwal of the Cytokine Research Laboratory at the world-renowned cancer hospital, M.D. Anderson. The study found that curcumin suppressed NF-κB, a protein complex responsible for controlling inflammatory responses. In other words, turmeric shuts off the body’s inflammatory response. Anti-inflammatories can be beneficial for many different ailments, including chronic pain and digestive disorders. A lot of CBD companies even put curcumin in their products because of its benefits. It is believed to be a synergistic pair with complementary therapeutic properties. The thought is that the two plant medicines are powerful on their own; as a combination, they can deliver even more anti-inflammatory and medicinal benefits. 

Many people simply add turmeric to their dishes as a way to easily incorporate it into their daily routine. It is pretty mild in flavor and can be added to many dishes without changing the overall taste too drastically. Some say that turmeric isn’t strong enough on its own to receive the anti-inflammatory properties that curcumin provides, and therefore recommend a curcumin supplement. Research varies on that, so in the end it is just up to personal preference and your doctor’s approval. Curcumin supplements come most available in capsules. Pregnant women can safely use turmeric as an addition to their food, but should avoid taking high-dosage supplements. Those who are interested in supplementing with curcumin products should talk with their doctor first. 

M.D. Anderson Cancer Center did another study in 2007 exploring curcumin for cancer treatment. The study found that curcumin inhibits ovarian cancer growth and angiogenesis (the development of new blood vessels). It does this by targeting and manipulating the NF-κB pathway, the same protein complex responsible for controlling inflammatory response. According to a report published by the National Center for Biotechnology Information, “The nuclear factor NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules.”  

The trend with curcumin seems to be it’s ability to control inflammatory responses in the body. It does this by multiple pathways, but a commonly researched one is the NF-κB protein complex. Because this pathway is able to be manipulated by curcumin to encourage anti-inflammatory expressions, its potential for successfully treating various ailments is there.

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Psilocybin + Magic Mushrooms

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When many think of plant medicine, specifically those plants with psychoactive effects, they think of “magic mushrooms,” or fungi containing psilocybin and psilocin that can cause hallucinations depending on the dosage consumed. In many states, there are active efforts to decriminalize these otherwise scheduled substances, lowering penalties for their use and possession. But what value do psilocybin-containing mushrooms offer? New research suggests a range of therapeutic and psychological value ranging from the treatment of substance abuse to anxiety and depression management.  

What are Magic Mushrooms?

Magic Mushroom use dates back to 10,000 BCE and references continue throughout the era. Their modern popularity began when the term “magic mushroom” was coined by two etnomycologists who learned of a Harvard study on local doctors in Mexico using these substances, noting the substance’s ability to affect the nervous system. These findings were eventually published in Life magazine in 1957, and the term became the universal reference for psychoactive fungi and truffles, specifically those containing high concentrations of psilocybin and psilocin.

Psilocybin & Psilocin: The “Magic” in Magic Mushrooms

Psilocybin and psilocin are part of a family of psychedelic compounds found in magic mushrooms. Psilocin is pharmacologically active, and psilocybin is converted into psilocin when consumed or activated. Similar in structure to serotonin, there are more than 50 species of mushrooms and a variety of truffles that produce both the precursor, psilocybin, and the psychoactive compound, psilocin. Unlike LSD, magic mushrooms do not affect dopamine receptors, solely targeting serotonin sites

How are Magic Mushrooms used?

Magic mushrooms are often used for recreational, therapeutic and medicinal reasons. “Effects range from mild feelings of relaxation, giddiness, euphoria, visual enhancement (seeing colors brighter), visual disturbances (moving surfaces, waves), to delusions, altered perception of real events, images and faces, or real hallucinations.” Recreationally, this is often known as “tripping.” As an alternative health option, these fungi are being used for anxiety, depression, PTSD, and trauma, as well as psychological disorders such as substance abuse disorders, and science is beginning to back the potential for these applications.

Research on Mushrooms

Evaluations of currently available scientific studies suggest a growing number of therapeutic benefits and treatment options. “In the past few years, a growing number of studies using human volunteers have begun to explore the possible therapeutic benefits of drugs such as psilocybin…looking at psilocybin and other hallucinogens to treat a number of otherwise intractable psychiatric disorders, including chronic depression, post-traumatic stress disorder, and drug or alcohol dependency.”

Magic mushrooms have been respected as a “safe & natural healing sacrament for millennia throughout Mexico, Central America and the world,” and are known to be beneficial for depression, recidivism (the tendency to repeat past transgressions), and encourages openness, creativity, as well as personal and spiritual growth. UCLA and NYC have done studies on the applications of magic mushrooms in the treatment of end-of-life anxiety and other studies have backed up the use of psilocybin and psilocin in the treatment of substance use disorders, depression (especially in cases of terminal conditions like cancer as well as treatment-resistant depression), and reducing depression and anxiety overall.

Best way for people to consume?

When it comes to the consumption of mushrooms, advice on dosage is about as specific as it was with cannabis under prohibition. Consumers must purchase on the black market and are subject to whatever may be available. 

“Recreational doses range from 1–5 grams of dry mushrooms depending on the species and individual strength of the specimens… After ingestion, the psilocybin is enzymatically converted to psilocin. Absorbed from the gastro-intestinal tract, hallucinogenic effects usually occur within 30 minutes of ingestion with a duration of effect of 4–6 hours.” 

My recommendation as someone who has used magic mushrooms both for recreational and therapeutic purposes, is to grind the mushrooms into a fine powder and either encapsulate them in small increments and/or combine with lemon juice. Capsules will allow you to titrate your dosage as needed with a recognizable increment, while lemon juice will expedite onset time.  

The Legality of Magic Mushrooms

In the United States, psilocybin is a Schedule I controlled substance, with no accepted medicinal value and a high potential for abuse. In contrast, the Drug Policy Alliance states that “Physically, psilocybin mushrooms are considered to be one of the least toxic drugs known.” With that being said, local efforts such as Decriminalize Nature – Oakland and Decriminalize Denver have pushed for and successfully passed initiatives and legislation to reduce penalties and make enforcement a low priority, as was done in the early days of cannabis activism. This has spurred multiple local and international efforts to “Decriminalize Nature,” efforts that we learn more about in this month’s feature.

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