COVID-19 and SARS-CoV-2
In December 2019, a novel coronavirus, designated as SARS-CoV-2, emerged in Wuhan, Hubei Province, China, instigating an outbreak of acute respiratory ailments. This emergence was characterized by the virus belonging to the Coronaviridae family, with its transmission primarily facilitated through respiratory droplets and fomites . This new pathogen was later named COVID-19, marking the inception of a global health calamity. The primary mode of transmission for COVID-19 is through human-to-human interaction, and its rapid proliferation escalated it to a worldwide pandemic status, necessitating a global response aimed at reducing the transmission of SARS-CoV-2, expanding the scientific understanding of the virus, and improving health security particularly in low- and middle-income countries .
The alarming escalation in the number of fatalities related to this disease compelled nations to enact social distancing protocols and lockdowns as a stratagem to mitigate its dissemination. A pronounced challenge in addressing COVID-19 has been the dearth of targeted therapeutic agents. The quest for efficacious treatments and vaccines has galvanized a worldwide scientific enterprise. The application of basic scientific discoveries from studying the structure and modus operandi of related coronaviruses like SARS-CoV and MERS-CoV has facilitated the development of therapies that specifically target SARS-CoV-2, along with the development of vaccines to prevent COVID-19. Targeted therapies have included the use of antibodies to prevent virus entry among other strategies .
Epidemiological scrutinies have incessantly illustrated that elderly populations bear a heightened susceptibility to severe manifestations of COVID-19, with the case fatality rate rising notably with age, exhibiting a rate of less than 1% for individuals below 50 years, and escalating to 14.8% for octogenarians . This age-related severity gradient is purportedly underpinned by differences in innate, adaptive, and heterologous immunity, alongside disparities in endothelial and clotting function among other mechanisms . In contrast, pediatric populations generally manifest milder symptoms and a lower predilection for severe illness upon SARS-CoV-2 infection, with individuals under 20 years of age exhibiting roughly half the susceptibility to infection compared to adults over 20 years, and clinical symptoms manifesting in about 21% of this younger demographic.
The discernible disparity in symptom manifestation between pediatric and adult demographics has catalyzed a burgeoning interest in delineating the immune response to COVID-19 in pediatric cohorts. It is imperative to meticulously explore the immune response mechanisms in children, as the extant data on this subject remains sparse.
In summary, COVID-19, engendered by SARS-CoV-2, has precipitated a global pandemic hallmarked by its brisk transmission, substantial mortality, and impediments in engendering targeted therapies. The malady showcases a pronounced disparity in severity between pediatric and adult populations, thereby necessitating an in-depth examination of the immune responses across these diverse age groups. The amassed knowledge from such investigations will be pivotal in devising age-specific therapeutic and preventive strategies, thereby ameliorating the global efforts to control the pandemic and reduce its deleterious impact on various populations.
Alternative therapeutic avenues
The pursuit for efficacious therapeutic agents against COVID-19 persists as a cardinal imperative, notwithstanding the advent of preventive vaccines. Existing antivirals and repurposed drugs have demonstrated a spectrum of efficacy levels, with certain drugs such as nirmatrelvir (when co-dosed with ritonavir) reducing hospitalization and mortality, and molnupiravir demonstrating potential in averting death albeit not hospitalization [6; 7]. Additionally, AT-527, a repurposed nucleoside inhibitor for hepatitis C, showed promise in reducing viral loads within a hospitalized cohort, although it did not exhibit similar efficacy in outpatient settings . The evolution of SARS-CoV-2 variants, such as the Delta and Omicron variants, has further nuanced the therapeutic landscape, potentially impacting the effectiveness of certain therapeutic and preventive measures [9, 10].
In this convoluted real life scenario, delving into alternative therapeutic avenues assumes a heightened significance. Natural compounds have emerged as a compelling frontier in this regard, with cannabinoids particularly drawing attention due to their potential antiviral, anti-inflammatory, and immunomodulatory properties. Cannabinoids such as cannabidiol (CBD), cannabigerolic acid (CBGA), and terpenes have demonstrated anti-inflammatory and antiviral potential, which could be instrumental in managing the cytokine storm often observed in severe COVID-19 cases . The potential of natural cannabinoids in reducing ACE2 activity, a key facet of SARS-CoV-2 entry into host cells, has also been underscored . Moreover, CBD has exhibited promise in inhibiting critical proteins requisite for SARS-CoV-2 replication and in alleviating lung damage through its agonistic action on cannabinoid receptor 2 (CB-2) .
Cannabinoids and the endocannabinoid system
Cannabinoids operate within the framework of the body’s endocannabinoid system (ECS), a complex network comprising endogenous cannabinoids, CB1 and CB2 receptors, and enzymes, which modulates a myriad of biological processes including immune response, inflammation, and neural activity. The prospective utility of cannabinoids in modulating these processes could be pivotal in the context of COVID-19, where aberrant immune responses and inflammatory cascades play a substantial role in disease severity and progression.
Objective of the summary
The objective of the envisaged scientific summary is to provide a panoramic view of the current research landscape concerning the potential antiviral and immunomodulatory effects of cannabinoids against SARS-CoV-2 and COVID-19. This endeavor aims to delineate the mechanisms of action, clinical implications, risks, and future prospects of cannabinoids as therapeutic agents in managing COVID-19. Through a rigorous analysis of existing research, the summary seeks to contribute to a more nuanced understanding of cannabinoids’ therapeutic potential, fostering informed discussions and further research in this emergent field of study.
Antiviral Activities of Cannabinoids
Main protease (Mpro) as a therapeutic target
The main protease (Mpro) of SARS-CoV-2 is a key enzyme in the virus’s life cycle as it facilitates the virus’s replication and transcription, making it a promising therapeutic target for COVID-19. The mechanism posited is that by inhibiting the function of Mpro, the viral replication process can be halted, thus curbing the virus’s ability to propagate within the host . Recent investigations have delved into the potential inhibitory effects of cannabinoids on Mpro, with some cannabinoids exhibiting promising results in this regard.
Specifically, studies have spotlighted cannabinoids such as betacaryophyllene (BCP), which has demonstrated the potential to target SARS-CoV-2 Mpro, possibly preventing viral replication . Furthermore, it has been revealed that cannabinoids may have stable conformations with the binding pocket of the Mpro enzyme of SARS-CoV-2, which plays a crucial role in viral replication and transcription, suggesting that cannabinoids could suppress viral entry and activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in host cells .
Research has also explored the inhibitory effects of THC-type cannabinoids on SARS-CoV-2 Mpro, though the inhibitory effects of other cannabinoids in this group were found to be weak, with a range of inhibition from 2.6% to 13.8% . Additionally, in silico and in vitro experiments were conducted to evaluate the interactions between cannabinoids and the SARS-CoV-2 Mpro enzyme, with in vitro antiviral activity carried out for five cannabinoid molecules .
Moreover, cannabigerolic acid (CBGA) and cannabidiolic acid (CBDA) have been highlighted for their effectiveness against the SARS-CoV-2 alpha variant B.1.1.7 and the beta variant B.1.351, showcasing the potential of these cannabinoids to prevent as well as treat infection by SARS-CoV-2 .
Recent studies have screened a library of minor cannabinoids for their potential inhibitory effects on Mpro. Among the tested cannabinoids, tetrahydrocannabutol (THCB) and CBGA have shown the most promise. THCB exhibited an inhibitory concentration 50% (IC50) value of 3.62 μM, while CBGA displayed an IC50 value of 14.40 μM. Furthermore, CBGA demonstrated a binding affinity (Kd) of 2.16×10−4M .
Mechanisms of action
The cannabinoids THCB, CBGA and BCP have been proposed to inhibit the enzymatic activity of Mpro, potentially halting the viral replication cycle. These cannabinoids are believed to interact directly with the active site of Mpro, preventing it from performing its proteolytic functions essential for viral replication [14; 15].
Molecular docking studies and computational assays have further illuminated the mechanisms through which these cannabinoids may exert their inhibitory effects, elucidating the specific molecular interactions between the cannabinoids and the Mpro enzyme, thereby providing insights into their binding affinities and the stability of the formed complexes .
Cytokine storm in COVID-19
The severe complication of cytokine storm in COVID-19, characterized by a hyperinflammatory response, has been a key focus of investigation in the quest for effective treatments. This phenomenon involves an overproduction of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β, which can overwhelm the body’s regulatory mechanisms, leading to acute respiratory distress syndrome (ARDS) and other critical conditions . Cannabinoids, derived mainly from the Cannabis plant, have emerged as potential immunomodulators in this context due to their ability to modulate cytokine levels.
Cannabinoids as immunomodulators
Research has illustrated that cannabinoids such as CBD and THC can significantly inhibit the release of pro-inflammatory cytokines, including IL-6 and TNF-α, which may in turn help to mitigate the cytokine storm associated with severe COVID-19 cases [11; 12]. Additionally, cannabinoids have been shown to upregulate anti-inflammatory cytokines such as IL-10, thus fostering a more balanced cytokine profile that might be conducive to recovery.
The mechanistic insights into how cannabinoids modulate cytokine levels suggest the involvement of various cellular signaling pathways. For instance, cannabinoids have demonstrated the ability to inhibit the NLRP3 inflammasome and STAT3 signaling pathways, both of which are pivotal to the cytokine release process. The endocannabinoid system, particularly the CB2 receptor (CB2R), plays a significant role in these immunomodulatory effects. Activation of CB2R has been associated with a decrease in the release of pro-inflammatory cytokines and an enhancement of anti-inflammatory responses, thereby adding a layer of complexity to the intricate interplay between cannabinoids and the immune system .
In vitro studies have also elucidated the anti-inflammatory activity of cannabis compounds in COVID-19-related inflammation, particularly in lung epithelial cells, while also showing pro-inflammatory activity in macrophages . Furthermore, CBD has been reported to reduce pro-inflammatory cytokine levels, ameliorating symptoms of ARDS induced in a murine model, and to down-regulate the expression of ACE2 and TMPRSS2, two receptors exploited by SARS-CoV-2 to enter cells  .
In summary, cannabinoids show promise in moderating the deleterious effects of cytokine storms in COVID-19, exhibiting the ability to downregulate pro-inflammatory cytokines and upregulate anti-inflammatory cytokines. The involvement of specific signaling pathways and receptors like CB2R further highlights the complexity and potential efficacy of cannabinoids as therapeutic agents in the context of COVID-19.
The clinical implications of cannabinoids in the context of COVID-19 are multi-dimensional, and several observational studies and analyses have pointed towards potential benefits associated with cannabis use among COVID-19 patients:
Clinical Outcomes and Mortality
A recent retrospective study conducted on over 320,000 individuals demonstrated that cannabis users who contracted COVID-19 had better outcomes and reduced mortality compared to non-users. Specifically, cannabis users had lower rates of complications associated with COVID-19, such as intubation, acute respiratory distress syndrome (ARDS), acute respiratory failure, and multiorgan failure. The mortality rate among cannabis users was significantly lower (2.9%) compared to non-users (13.5%) .
Severity of Symptoms
A noteworthy randomized, double-blind, placebo-controlled clinical trial, dubbed the CANDIDATE Study, was conducted to investigate the safety and efficacy of CBD in treating patients with mild to moderate COVID-19. While CBD was well-tolerated with mostly mild and transient side effects, its administration at 300 mg daily for 14 days did not alter the clinical evolution of COVID-19. The authors posited that future trials might explore CBD’s therapeutic effect in severe COVID-19 cases, potentially at higher doses .
A retrospective cohort study published in August 2022 found that cannabis consumers experienced less severe COVID-19 symptoms and improved clinical outcomes .
Some studies have suggested the use of cannabinoids for the prophylaxis and treatment of COVID-19 due to their anti-inflammatory effects. While the benefits of cannabinoids seem promising to modulate the immune system, inhaled cannabis is reported to increase the progression and severity of the infection .
A 2021 survey indicated that heavy lifetime cannabis consumers reported being less likely to get vaccinated, although this does not provide insight into the impact of cannabinoids on vaccine efficacy .
Neurological manifestations in COVID-19
The spectrum of neurological manifestations associated with COVID-19 is vast, encompassing symptoms such as headache and anosmia to more severe conditions like encephalopathy, Guillain-Barré syndrome, myopathy, neuromuscular disorders, and cerebrovascular diseases. These manifestations could arise from direct viral invasion or indirect effects like systemic inflammation and cytokine storms, which could inflict collateral damage on the nervous system.
Cannabinoids as neuroprotective agents
Cannabinoids, particularly cannabidiol (CBD), have been explored for their neuroprotective potential, especially in the context of chronic neurodegenerative diseases. Their neuroprotective capabilities could extend to COVID-19 patients, attenuating not only the immediate inflammatory responses but also safeguarding neural tissues from long-term degenerative consequences .
Direct vs. indirect pathways
The neuroprotective effects of cannabinoids may be mediated through both direct and indirect pathways. Directly, cannabinoids can interact with neural cells to attenuate oxidative stress and modulate neurotransmitter release. Indirectly, they can inhibit the activation of immune cells in the brain, thereby reducing inflammation and consequent neural damage [19;29].
The endocannabinoid system, featuring receptors like CB1 and CB2, along with non-canonical receptors such as GPR55 and TRPV1, play a pivotal role in mediating the neuroprotective effects of cannabinoids.
Particularly, the activation of CB2 receptor (CB2R) has shown promise in reducing pro-inflammatory cytokine release, which is crucial in the context of COVID-19 as the expression of CB2R is induced during inflammation triggered by SARS-CoV-2 infection in the central nervous system .
Risks and Limitations
Frequency and dosage considerations
Cannabinoids exhibit a therapeutic potential; however, the fine line between their beneficial and possibly detrimental effects necessitates thorough investigation. For instance, regular cannabis users who smoked more than once per month were reported to have poorer COVID-19-related survival outcomes . This highlights the critical need for rigorous clinical exploration to ascertain the optimal frequency and dosage of cannabinoid administration.
The diverse interactions of cannabinoids with numerous physiological pathways and receptors, some of which are not fully elucidated, pose potential contraindications. For example, certain cannabinoids are known to interact with hepatic enzymes, potentially affecting the metabolism of other medications . This scenario warrants caution, especially in patients on antiviral or immunosuppressive therapies, underscoring the importance of thorough pharmacological profiling.
Gaps in current research
Much of the current evidence supporting the potential utility of cannabinoids in treating Much of the evidence hinting at the potential utility of cannabinoids in treating COVID-19 stems from in vitro studies, animal models, or retrospective analyses [14; 25;32]. While these studies offer valuable insights, they lack the rigor and conclusive power of randomized controlled trials. Moreover, the focus has primarily been on well-known cannabinoids like CBD and THC, leaving a plethora of other cannabinoids and terpenes unexplored. The mechanistic intricacies of how cannabinoids interact with SARS-CoV-2 and the immune system remain murky, thus hindering the full exploitation of their therapeutic potential.
Potential for drug development
Based on recent studies, cannabinoids have demonstrated interactions with the Mpro enzyme of SARS-CoV-2, an enzyme crucial for viral replication and transcription. Specifically, cannabinoids were found to inhibit viral entry and activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in host cells .
Cannabidiol (CBD) has shown preclinical promise in inhibiting SARS-CoV-2 replication. In a study, human lung carcinoma cells were pretreated with CBD, which led to a reduction in SARS-CoV-2 infection. Mechanistically, CBD acted post-viral entry, impeding viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. The inhibition of viral replication was partly attributed to the upregulation of the host’s IRE1α ribonuclease endoplasmic reticulum (ER) stress response and interferon signaling pathways .
Furthermore, cannabinoids such as CBGA and CBDA have demonstrated the ability to block SARS-CoV-2 entry into human epithelial cells, as evidenced by virus neutralization assays . In a separate study, cannabidiolic acid (CBDA) was identified as highly active against a panel of SARS-CoV-2 variants. To enhance the stability of CBDA, its methyl ester was synthesized and tested, showcasing antiviral activity .
The broader immunomodulatory, anti-inflammatory, and antiviral properties of cannabinoids render them a promising avenue in the fight against COVID-19, extending beyond the traditional antiviral therapeutic modalities .
The ‘Entourage Effect’
Cannabis harbors a plethora of cannabinoids, flavonoids, and terpenes, conjectured to work in concert, manifesting the ‘entourage effect.’ This notion suggests that the therapeutic prowess of the plant is optimally harnessed when its constituents are administered collectively rather than in isolation. This presents a riveting frontier for drug development, wherein formulations could be fine-tuned to leverage this synergistic effect, augmenting efficacy while potentially attenuating adverse effects.
Areas needing further investigation
While the therapeutic potential of cannabinoids is beguiling, certain domains necessitate rigorous exploration. Foremost, robust clinical trials are imperative to corroborate the insights garnered from preclinical and observational analyses. Secondly, discerning the long-term safety profile of cannabinoids, especially among specific demographics like individuals with pre-existing ailments or those on concurrent medications, is crucial. Lastly, mechanistic studies are vital for elucidating the molecular interplay between cannabinoids and both viral and host factors, a comprehension instrumental for the judicious design of novel therapies.
Summary of key findings
The amassing body of evidence articulates that cannabinoids harbor a diverse therapeutic potential against COVID-19, manifesting antiviral, immunomodulatory, and potentially neuroprotective effects. Noteworthy among these are cannabinoids like cannabidiol (CBD), cannabigerolic acid, and cannabidiolic acid, which have shown inhibitory actions on the main protease (Mpro) of SARS-CoV-2, a pivotal step toward obliterating viral replication [16; 18]. Moreover, cannabinoids demonstrate a capacity for modulating immune response, particularly in allaying the cytokine storm, a salient factor in the severity of COVID-19 .
Implications for healthcare providers and researchers
For healthcare providers, these insights unveil a prospective adjunctive therapeutic avenue that could ameliorate patient outcomes. Grasping the pharmacology and therapeutic potential of cannabinoids could be cardinal in concocting more efficacious treatment regimens. For researchers, the data bellows a clarion call to delve deeper into the intricate mechanisms through which cannabinoids wield their effects. This inquiry is particularly pertinent for drug development and discerning how cannabinoids could be assimilated into extant therapeutic paradigms.
Call to action for further research
While the preliminary data is promising, it is quintessential to navigate these findings with scientific rigor. A lack of know-how persists in our understanding of the optimal dosages, potential contraindications, and long-term effects of cannabinoid use, especially in the milieu of COVID-19. High-caliber clinical trials, exhaustive mechanistic studies, and thorough safety profiles are exigent to transmute these findings from bench to bedside [20; 34].
Stefan Broselid, Ph.D.
Editor-In-Chief, Aurea Care Medical Science Journal
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