Israeli researchers from The Medical Cannabis Research and Innovation Center at Haifa’s Rambam Health Care Campus are leading research that suggests the effects of medical cannabis could be used as a method for treating some symptoms of seriously ill COVID-19 patients.
As the novel coronavirus continues to spread, clinical trials at Rambam hospital for the use of medical marijuana in treating and preventing the rapid, life-threatening inflammation in patients with COVID-19 are scheduled to begin in the next few months.
Preliminary investigations have already indicated as much, according to the hospital. The researchers aim to prove these theories with evidence-based trials.+
Leading the team of researchers is Dr. Igal Louria-Hayon, scientific director of The Medical Cannabis Research and Innovation Center.
“For the first time in Israel, a laboratory experiment has been undertaken to explore the effect of various types of cannabinoids on the white blood cells of COVID-19 patients,” .
Dr. Louria-Hayon says the focus currently is just how much cannabis influences the inflammation process.
“We began to understand that cannabinoids take part in the communication network of cells in the immune system. While working full force on these findings, the corona[virus] outbreak suddenly broke,” Dr. Louria-Hayon said, “As we are situated in one of the biggest hospitals in Israel, naturally, our team became part of the worldwide efforts to fight the pandemic.”
Current research indicates that when the body’s immune system recognizes a new and threatening invader, a large number of white blood cells are activated and release inflammatory “communication molecules” called cytokines, which activate even more white blood cells and regulate the inflammation process, he explains.
This storm of cytokines which can result in the out-of-control inflammatory response which worse the illness and can even lead to death.
“Based on our experimental data, we hypothesize that cannabis may affect the cytokine storm which occurs during COVID-19 disease. Our goal is to apply cannabis treatment to downregulate the inflammation storm before the patients develop severe lung inflammation,” Dr. Louria-Hayon said.
The center aims to treat the inflammatory “storm” as it develops and before the patient’s condition deteriorates and a ventilator is needed.
Active components in cannabis activate an internal system in the body called the endocannabinoid system. Since the body naturally produces and utilizes substances similar in structure to the active components of cannabis, it may also respond broadly to the cannabis plant itself.
“We hope that by decoding the cannabinoid activity mechanism during inflammatory storms, we can treat COVID-19 patients where conventional drugs have failed,” Dr. Louria-Hayon said in the statement from Rambam.
The researchers are using a complex composed of more than a hundred cannabinoids in each cannabis plant. The concentration of cannabinoids differs between the strains.
“We first have to identify the relevant strains and cannabinoids combinations which target and thus treat inflammation,” Dr. Louria-Hayon tells.
Inflammation is also not a simple process with approximately 20 different cells participating in inflammation progression and different pathogens may induce different components of the inflammation.
“Thus, not every cannabis strain that showed anti-inflammatory properties, can also treat COVID-19 disease. Our challenge and goal is to identify the specific strain or cannabinoids combination, which can treat the specific COVID-19 related pattern of inflammation.,” he said.
A biobank database of COVID-19 patients at Rambam will help facilitate research into the possible therapeutic effects of cannabis in battling some symptoms of the deadly virus.
“We saw the establishment of a biobank pool for COVID-19 research as essential to securing rapid answers and accelerating critically needed research. Blood samples are the most accessible resource for continuous sampling-to understand biological processes during the disease and to develop vaccines and drugs,” Dr. Shlomit Yehudai-Reshef, director of the Clinical Research Institute at Rambam hospital, said in the statement.
“At Rambam, dozens of COVID-19 patients have been hospitalized in recent weeks, from whom blood samples were collected for clinical and research purposes”, she said, noting that “despite the complexity and high risk, we found a safe way to separate the white blood cells, including the immune cells from verified patients.”
The researchers took blood samples from the COVID-19 patients and kept them in a way that they could isolate the immune cells on demand, Dr. Louria-Hayon explained. These will serve as samples for the first stage of experiments.
The scientists divided their clinical experiments into two different investigations. The first experiment will isolate the immune cells from the blood of COVID-19 patients, which cause the cytokines storm, and will identify the strains and cannabinoids that affect inflammation properties of the patient’s cells, according to Dr. Louria-Hayon.
“This experiment will begin in a few months, and based on its analysis, we will progress to the second clinical experiment where we will treat COVID-19 patients with the candidate strains that presented anti-inflammatory potential on human-derived cells (the first experiment).”
This course of examination will secure the accuracy of treatment, Dr. Louria-Hayon .
“The aim is to be ready for the second clinical experiment when the next pandemic will break.”
Researchers of the cannabis research center investigated multiple cannabis strains and were able to narrow the field to about 15 species strains that appear to have the ability to prevent the intense inflammatory response experienced by some COVID-19 patients.
“We detected signs that cannabinoids contribute to the sophisticated fabric network of intercellular communications,” Dr. Louria-Hayon explained.
“Intercellular communication based on cannabis-like substances also exist in the immune system. If we understand how cannabinoid components are used in intercellular communication, we can help influence this communication in the event of a disease, to disrupt it or empower the communication to convey desired messages.”
Each cannabis strain has hundreds of active substances. The researchers want to examine the receptors to which these substances bond, the cellular messages that are communicated, and the extent to which cannabinoids reduce the inflammatory response.
“We believe that we will be able to accelerate the pace of investigation and move more rapidly to clinical applications, due to access to the National Biobank at Rambam,” said Dr. Louria-Hayon.
Coronavirus disease-2019 (COVID-19), caused by Severe Acute Respiratory Syndrome coronoavirus-2 (SARS-CoV2) has emerged as a global pandemic, which was first reported in Wuhan, China.
Recent reports have suggested that acute infection is associated with a cytokine superstorm, which contributes to the symptoms of fever, cough, muscle pain and in severe cases bilateral interstitial pneumonia characterized by ground glass opacity and focal chest infiltrates that can be visualized on computerized tomography scans (Rothan and Byrareddy, 2020).
Currently, there are no effective antiviral drugs or vaccines against SARS-CoV2. In the recent issue of BBI, Zhang et al. (Zhang et al., 2020) thoroughly summarized the current status of potential therapeutic strategies for COVID-19.
One of them, anti-IL6 receptor (Tocilizumab) antibody, resulted in clearance of lung consolidation and recovery in 90% of the 21 treated patients (Fu et al., 2020). Although promising, it has also produced adverse effects like pancreatitis and hypertriglyceridemia (Morrison et al., 2020), which make it imperative to explore effective alternative anti-inflammatory strategies.
Here, we intend to highlight the potential effects of cannabinoids, in particular, the non-psychotropic cannabidiol (CBD), that has shown beneficial anti-inflammatory effects in pre-clinical models of various chronic inflammatory diseases and is FDA approved for seizure reduction in children with intractable epilepsy (Nichols and Kaplan, 2020).
Like Δ9-tetrahydrocannabinol (Δ9-THC), the most well-studied cannabinoid, CBD decreased lung inflammation in a murine model of acute lung injury potentially through the inhibition of proinflammatory cytokine production by immune cells and suppressing exuberant immune responses (Ribeiro et al., 2015).
CBD can inhibit the production of proinflammatory cytokines like interleukin (IL)-2, IL-6, IL-1α and β, interferon gamma, inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α (Nichols and Kaplan, 2020) (Fig. 1 ) that have been associated with SARS-CoV2 induced multi-organ pathology and mortality.
In a murine model of chronic asthma, CBD reduced proinflammatory cytokine production, airway inflammation and fibrosis (Vuolo et al., 2019). Moreover, CBD can effectively inhibit the JAK-STAT pathway including the production and action of type I interferons without leading to addiction, alterations in heart rate or blood pressure and adverse effects on the gastrointestinal tract and cognition (Nichols and Kaplan, 2020).
In simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs), we reported THC mediated attenuation of IFN stimulated gene expression in the intestine (Kumar et al., 2019). Similar to CBD, chronic THC administration blocked inflammation induced fibrosis in lymph nodes of chronically SIV-infected RMs (Kumar et al., 2019).
Unlike THC, CBD has a high margin of safety and is well tolerated pharmacologically even after treatments of up to 1500 mg/day for two weeks in both animals and humans (Nichols and Kaplan, 2020), which suggests its feasibility to reduce SARS-CoV2 induced lung inflammation/pathology and disease severity.
The many uncertainties associated with the COVID-19 pandemic such as status of the economy, employment and loss of connection can fuel depression, fear and anxiety. CBD has shown promise as an alternative therapy for the clinical management of anxiety disorders (Nichols and Kaplan, 2020).
Based on its anxiolytic and anti-depressant properties, it has been suggested that CBD could be used to improve the mental and somatic health of patients suffering from anxiety and emotional stress after recovering from Ebola disease (Reznik et al., 2016).
Like Ebola, patients recovering from COVID-19 may experience various psychological and social stressors that may be triggered by residual chronic inflammation and autoimmune reactions.
Therefore, randomized clinical trials to test the efficacy of CBD on alleviating anxiety and fear associated with COVID-19 infection and its consequences on people’s physical, social and psychological well-being may be beneficial in the future.
Additionally, severely ill COVID-19 patients exhibited neurological symptoms like cerebrovascular disease, headache and disturbed consciousness (Reviewed in (Wu et al., 2020)). Brain edema, neuronal degeneration and presence of SARS-CoV2 in the cerebrospinal fluid (CSF) were confirmed at autopsy (Wu et al., 2020).
Therefore, longitudinal CSF sampling using non-human primate (NHP) studies may help clarify whether and when SARS-CoV2 invades the brain, and if this happens, does it result in neuroinflammation and more importantly, whether cannabinoids can modulate these events (Kumar et al., 2019).
Being a negative allosteric modulator of the cannabinoid receptor-1, CBD can counter the psychotropic effects of THC when co-administered with THC (Nichols and Kaplan, 2020).
Although Remdesivir reduced the mortality rate of seriously ill COVID-19 patients needing invasive ventilation (Zhang et al., 2020), similar studies in rhesus macaques revealed minimal subpleural inflammatory cellular infiltrates in the lungs of clinically recovered Remdesivir treated RMs at necropsy (Williamson et al., 2020).
This suggests persistence of inflammation and may partly explain the 20–30% reduction in lung function in COVID-19 patients after recovery, which if left unresolved may lead to pulmonary fibrosis. Collectively, these findings support the investigation of cannabinoids as a plausible option to be added as an adjunct to Remdesivir or any new antivirals on SARS-CoV2 induced lung inflammation.
This work was supported by the National Institutes of Health Award Numbers R01DA042524, R01DA050169 and R56DE026930 to MM, and P51OD0111133. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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