CRx MAGAZINE

Spring 2021

COVID-19: Does Medicinal Cannabis Help or Hurt?

The answer may be both.

Advances in research have led to increased interest in the properties and potential of cannabis to treat many illnesses that have alluded modern medicine. Now, practitioners and consumers turn their attention to the role that it may play in the treatment of COVID-19, the disease caused by the coronavirus SARS-CoV-2.

The focus has been on the immune modulation and vascular effects of cannabis.1,2 As with any pharmacological treatment, the effects will depend on patient specifics and the stage of disease. To grasp the current state of research, CRx evaluates the weight of evidence and speaks with experts in the field of medicinal cannabis. When working with medicinal cannabis in the age of COVID-19, it may help to think in wo separate categories: COVID-19 naïve (cannabis use in a population that is not and has no record of having been infected by COVID-19) and acute COVID-19.

Can Using Cannabis Make People More Susceptible to COVID-19 Infection?
David Bearman, MD, executive vice president of the American Academy of Cannabinoid Medicine and a certified cannabinoid medicine specialist, notes that it’s important to distinguish between adult and medicinal cannabis use. Concerning adult use, Bearman would err on the side of caution and recommends people “take an herbal vacation until they’ve been successfully vaccinated.” If a person is using cannabis to relieve symptoms of a serious illness, such as cancer or epilepsy, Bearman believes it may be beneficial for some patients to continue treatment but makes it clear that “risk assessment for cannabis during the COVID-19 pandemic needs to be made in conjunction with the health care provider on a case-by-case basis.” The intent is to ensure that potential benefits outweigh the risks. Bearman also emphasizes that any inhalation—whether via smoking or vaporizing—increases a person’s risk of COVID-19 because the respiratory route of cannabis increases both sputum and bronchial irritation, making a person more susceptible to infection. Essentially, if cannabis is being used medicinally, clinicians should discuss the immune modulation effects and route of administration with patients.

The endocannabinoid system is often called a “gatekeeper” to the immune system and can prevent an overwhelming immune response.3 While this can be useful in the treatment of autoimmune disorders and low-grade systematic inflammation, it may be problematic for a generally healthy individual—especially during a time of increased pathogens. A 2015 review published in the Journal of Neuroimmune Pharmacology examined the effects of cannabinoids on immune function, with a focus on the effects on T cells as well as on resistance to infection.4 The review looked at THC extracted from the Cannabis sativa plant and synthetic cannabinoids—specifically those that are CB2 receptor selective agonists, as CB2 receptors are principally expressed on cells of the immune system. Therefore, in conditions for which it’s beneficial to dampen an immune response—such as in autoimmune disorders—cannabis could be beneficial. However, this immunosuppressive effect can also sensitize some individuals to certain infections. There isn’t sufficient research to say whether COVID-19 is one of these infections. It’s also noteworthy that the study looked specifically at THC and synthetic CB2 binders. CBD seems to work by slowing reuptake of the body’s endogenous cannabinoids, and many researchers believe it works to modulate the immune system rather than to suppress it.

Researchers at the University of Lethbridge in Alberta, Canada, are using 3-D human tissue models to better understand the effect of cannabis on COVID-19. “By no means are our results encouraging smoking just any strain of marijuana. The point is that this plant has pharmacological promise, based on potentially controlling the entry point of the virus (by down-regulating angiotensin-converting enzyme 2 [ACE-2] receptors and serine protease transmembrane serine protease 2 [TMPRSS2]) and as an anti-inflammatory (via its immune modulatory effects),” says Olga Kovalchuk, MD, PhD, a professor and Board of Governors’ Research Chair at the University of Lethbridge and an author of the study.

Kovalchuk and colleagues set out to identify which high-CBD Cannabis sativa extracts could transiently down-regulate ACE-2 receptors and TMPRSS2, critical proteins required for SARS-CoV-2 entry into host cells. The study, published in Aging, used Western Blot analysis to measure the effects of specific Cannabis sativa extracts on the 3D tissue models of oral, intestinal, and airway tissues. Certain cannabis extracts showed down regulation of both ACE-2 and TMPRS2, however, some cultivations caused an up-regulation of ACE-2 receptors. Moreover, some extracts down-regulated ACE-2 receptors in certain tissues (such as the airway), but up-regulated ACE-2 receptors in other areas, such as intestinal tissues. The study was intended to model oral cavity applications, encapsulated extracts, dosed oils, and inhalers or nebulizers but didn’t model respiratory uptake and doesn’t apply to smoking cannabis, especially due to the controversial effects of smoking on ACE-2 receptors.4

Could Cannabis Be a Valuable Treatment for Patients With Acute COVID-19?
The potential for cannabis to help patients infected by COVID-19 is promising. The same immunosuppression that may (or may not) make some people more susceptible to COVID-19 infection could quell the cytokine storm that leads to acute respiratory distress syndrome (ARDS) in severe cases of infection.5 Concerning the anti-inflammatory effects of cannabis, in a study published in June 2020, researchers at the University of South Carolina used mice models to research the effect of THC on ARDS. During the study, mice were divided into two groups. Both the A group and the B group were infected with Staphylococcus aureus, which is known to cause ARDS via a cytokine storm similar to that seen in COVID-19. The A group was injected with THC immediately after infection with S aureus, then again after 24 and 48 hours, while the B group received no treatment. All of the mice in the A group (receiving THC) survived, whereas all of the mice in the B group died. The researchers further found that THC functioned to suppress inflammatory cytokines, elevated the induction of regulatory T-cells, and caused the induction of myeloid-derived suppressor cells. The researchers also note that pharmacological inhibitors of CB2 receptors blocked these anti-inflammatory effects, suggesting that these immune suppression effects occur via THC activation of CB2 receptors.6

Bearman suggests that cannabis-based therapies could be useful in the treatment of acute COVID-19 due to their anti-inflammatory effects. He also notes that cannabis comes with far fewer side effects than those associated with steroids such as dexamethasone. The implication is that cannabis-based therapies may be useful in patients with an overactive immune response to COVID (the cytokine storm). Whether cannabis could be used to prevent this reaction is unclear.

Concerning immune suppression, practitioners may be informed by the impact of cannabis on other viruses, such as HIV. For years, cannabis-based treatments have been used in patients with HIV to suppress lymphocyte proliferation and inflammatory cytokine production. In vitro studies have shown that CB2 receptor activation can reduce CD4 T-cell infection and can reduce HIV replication. In cross-sectional human studies, THC hasn’t been shown to reduce cluster of differentiation 4 (CD4) T-cell counts.7 As with HIV, lymphopenia and drastic reduction of CD4 T-cell counts have been associated with poor clinical outcomes in COVID-19 cases.8 The decision to use cannabis-based treatments as immune-modulators must happen on a patient-to-patient basis and can only be based on a clear interpretation of the available evidence; Bearman suggests that physicians consult with, or direct their patients to, certified cannabis specialists.

The long-term consequence of COVID- 19 infection is also a concern, especially as there is a growing number of COVID “long-haulers.” In a study published in the Journal of Cellular and Molecular Medicine, researchers sought to show that CBD may ameliorate the symptoms of ARDS through up-regulation of apelin, a peptide with the potential to improve blood and oxygen flow, potentially limiting the lung damage caused by COVID-19. To test their hypothesis, researchers divided adult mice into three groups. Group one received once-daily intranasal administration of sterile saline for three consecutive days to serve as a control. Group two received a synthetic analogue of double-stranded RNA called polyinosinic:polycytidylic acid (POLY I:C) to mimic ARDS. Group three received once-daily intranasal administration of POLY I:C with intraperitoneal administration of CBD isolate (5 mg/kg body weight).9

After nine days, blood and lung tissue were harvested and subjected to flow cytometry, immunofluorescence, and histological analysis. The ARDS-induced mice (group two) exhibited a pattern of lymphopenia, lower frequency of T cells, and elevated rates of neutrophils in addition to a significant reduction in apelin production. Group three (administered CBD isolate) showed increased T-cells, increased neutrophils, and enhanced apelin levels in the blood flow. Concerning organ damage, histological examination of lung tissues showed significant perivascular and peribronchiolar interstitial inflammatory infiltrate, fibrosis, hypertrophy, and pulmonary edema in the ARDS-induced group. Immunofluorescence analysis showed that these pathological features were partially or completely abolished in the CBD-treated group. Additionally, apelin levels in the lungs were increased toward control levels. This study may suggest that CBD exerts a potent anti-inflammatory effect and upregulates apelin levels, increasing oxygenation following experimental ARDS. As the number of COVID long-haulers grows, finding ways to decrease the risk for ARDS and mitigate organ damage is crucial in the fight against COVID-19.

Administration Method Matters
Smoking is still a lung irritant, even if a person is smoking cannabis, and it’s associated with large airway inflammation, increased airway resistance, and lung hyperinflation.10 Vaporizing can also harm respiratory health, as vitamin E acetate may have adverse effects on the lungs.11 Bearman advises using tinctures or edibles unless there’s an overriding reason for vaping, such as the need for rapid absorption to prevent migraines during the prodrome phase. Bearman also recommends using whole plants extracts rather than isolates.

As was shown by Kovalchuk’s study, different strains of cannabis will have different results. Future studies need to be done before practitioners can be prescriptive with cannabis—there simply isn’t enough evidence. However, it’s worth noting that many of the successful cannabis extracts in Kovalchuk’s study were high CBD, with less than 0.3% THC content. In other words, the strains were hemp varietals.

Key Takeaways
We’ve grown accustomed to synthetic and single compound medicines; it can be easy to forget that pharmacological treatments used to be mostly plant based. With that in mind, cannabis can be approached for its medicinal properties, with an understanding that not all strains and extracts will have the same effects. At the same time, attention should be paid to the whole plant, including the role of terpenes and the full cannabinoid profile. The overriding takeaway is that we need more controlled studies to evaluate the role of cannabis in health care and disease treatment. For now, clinicians can rely on the golden wisdom of the Hippocratic Oath—”Do no harm”—and, as Paracelsus said, “Medicine is not only a science; it is also an art.”

— Jennifer Lutz is a freelance journalist who covers health, politics, and travel. She has written for both consumer and professional medical magazines, as well as popular newspapers. Her writing can be found in Practical Pain Management, EndocrineWeb, Psycom Pro, The Guardian, New York Daily News, Thrive Global, BuzzFeed, and The Local Spain. In addition to journalism, Lutz works as a strategies and communications consultant for nonprofits focused on improving community health.

References

1. Hernández-Cervantes R, Méndez-Díaz M, Prospéro-García Ó, Morales-Montor J. Immunoregulatory role of cannabinoids during infectious disease. Neuroimmunomodulation. 2017;24(4-5):183-199.

2. Richter JS, Quenardelle V, Rouyer O, et al. A systematic review of the complex effects of cannabinoids on cerebral and peripheral circulation in animal models. Front Physiol. 2018;9:622.

3. Oláh A, Szekanecz Z, Bíró T. Targeting cannabinoid signaling in the immune system: "high"-ly exciting questions, possibilities, and challenges. Front Immunol. 2017;8:1487.

4. Wang B, Kovalchuk A, Li D, et al. In search of preventive strategies: novel high-CBD Cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues. Aging. 2020;12(22):22425-22444.

5. Eisenstein TK, Meissler JJ. Effects of cannabinoids on T-cell function and resistance to infection. J Neuroimmune Pharmacol. 2015;10(2):204-216.

6. Mohammed A, Alghetaa H, Sultan M, Singh NP, Nagarkatti P, Nagarkatti M. Administration of Δ9-tetrahydrocannabinol (THC) post-staphylococcal enterotoxin B exposure protects mice from acute Respiratory Distress Syndrome and toxicity. Front Pharmacol. 2020;11:893.

7. Costiniuk CT, Jenabian MA. Cannabinoids and inflammation: implications for people living with HIV. AIDS. 2019;33(15):2273-2288.

8. Peng X, Ouyang J, Isnard S, et al. Sharing CD4+ T cell loss: when COVID-19 and HIV collide on immune system. Front Immunol. 2020;11:596631.

9. Salles ÉL, Khodadadi H, Jarrahi A, et al. Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome. J Cell Mol Med. 2020;24(21):12869-12872.

10. Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc. 2013;10(3):239-247.

11. Blount BC, Karwowski MP, Shields PG, et al. Vitamin E acetate in bronchoalveolar-lavage fluid associated with EVALI. N Engl J Med. 2020;382(8):697-705.

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