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The pandemic caused by Sars-CoV-2 (COVID-19) has been a great concern for public and mental health systems worldwide. The identification of risk groups is essential for the establishment of preventive and therapeutic strategies, as for substance users. During COVID-19 pandemic, there was an increase in the use of psychoactive substances during the lockdown, including cannabis. This commentary reviews relevant findings and discusses scientific evidence on the risks of worse clinical and psychiatric complications due to coronavirus disease COVID-19 in subjects who use cannabis. Although they are not included as a risk group in the health recommendations for that disease, they may have a more vulnerable respiratory system to viral diseases. There are certain similarities between the harmful cardiovascular and respiratory effects of cannabis use and those of smoking. Due to the different modes of smoking, cannabis chemicals are retained in the body for longe and may also contain other toxic substances such as tar, a substance found in tobacco and which has been associated with the development of lung cancer, bronchitis and pulmonary emphysema. Therefore, we discuss if individuals who use cannabis regularly might be more vulnerable to COVID-19 infection. This population deserves more clinical attention worldwide and this manuscript can help clinicians become more aware of cannabis risks during pandemics and develop specific intervention strategies. It’s too early to tell whether CBD helps against Covid-19 — but researchers worry that won’t stop CBD makers.

Multiple clinical risks for cannabis users during the COVID-19 pandemic

The pandemic caused by Sars-CoV-2 (COVID-19) has been a great concern for public and mental health systems worldwide. The identification of risk groups is essential for the establishment of preventive and therapeutic strategies, as for substance users. During COVID-19 pandemic, there was an increase in the use of psychoactive substances during the lockdown, including cannabis. This commentary reviews relevant findings and discusses scientific evidence on the risks of worse clinical and psychiatric complications due to coronavirus disease COVID-19 in subjects who use cannabis. Although they are not included as a risk group in the health recommendations for that disease, they may have a more vulnerable respiratory system to viral diseases. There are certain similarities between the harmful cardiovascular and respiratory effects of cannabis use and those of smoking. Due to the different modes of smoking, cannabis chemicals are retained in the body for longe and may also contain other toxic substances such as tar, a substance found in tobacco and which has been associated with the development of lung cancer, bronchitis and pulmonary emphysema. Therefore, we discuss if individuals who use cannabis regularly might be more vulnerable to COVID-19 infection. This population deserves more clinical attention worldwide and this manuscript can help clinicians become more aware of cannabis risks during pandemics and develop specific intervention strategies.

Introduction

The pandemic caused by Sars-CoV-2 (COVID19) has caused the collapse of health systems worldwide. Alongside the clinical risk, the appearance or intensification of psychiatric symptoms has also been generating a mental health pandemic within another. The identification of risk groups is essential for the establishment of preventive and therapeutic strategies, for people who are infected by the COVID-19 virus, as well as for users os psychoative substances (PS). During the COVID-19 pandemic, it was identified that the consumption of PS, such as tobacco, cannabis, and cocaine increased the risk of contamination of influenza and was associated with a worse clinical prognosis [1]. A study found that patients with a recent use of PS were at significant risk greater risk of developing COVID-19 compared to patients without a recent substance use disorder (SUD) diagnosis, after adjusting for age, sex, race and types of insurance. Although cannabis users have a lower odds ratio than other drugs (opioids, tobacco, alcohol and cocaine) the risk is five times greater than in people who do not use PS [2]. Thus, cannabis users can be at risk of clinical complications if infected with COVID-19 due to deteriorating health status.

A review conducted in 2019 found that with the increasing increase in cannabis use in the population there has been an increasing number of studies associating cannabis use with serious and life-threatening cardiovascular complications, including acute coronary syndromes, potentially lethal cardiac arrhythmias and ischemic strokes. There are certain similarities between the harmful cardiovascular and respiratory effects of cannabis use and those of smoking. Despite the difference in active ingredients (tetrahydrocannabinol vs. nicotine), along with, due to the different modes of smoking, cannabis chemicals are retained in the body for longer [3]. Furthermore, cannabis may also contain other toxic substances such as tar, a substance found in tobacco and which has been associated with the development of lung cancer, bronchitis and pulmonary emphysema [4]. Although, it is necessary to consider that cannabis is widely used by young populations.

A recent review shows a significant association between cannabis use and symptoms of chronic bronchitis after adjustment for tobacco. Some studies have found a modest reduction in specific airway conductance in relation to marijuana, probably reflecting endoscopic evidence of bronchial mucosa edema among habitual cannabis smokers [5]. The immunosuppressive effects of delta-9 tetrahydrocannabinol (THC) increase the possibility of an increased risk of pneumonia, but further studies are needed to assess this potential risk. Several case series have demonstrated pneumothorax / pneumomediastinum and bullous lung disease in cannabis smokers, but these associations require epidemiological studies for firmer evidence of possible causation. Another recent study reports that the use of vaping causes lung injuries similar to COVID-19 symptoms [6].

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Moreover, most of the people who use cannabis also report tobacco use concurrently. This fact may increase the risk of exposure to toxic substances, as certain co-users (for example, blunt users) tend to have higher levels of carbon monoxide in exhaled air and cannabis smoke may have higher levels of some carcinogens than tobacco smoke [7]. Previous studies have indicated that long-term cannabis use is associated with high mortality rates, heart disease [8], metabolic syndromes and changes in the immune system [9]. In this sense, when compared to the general population, we can consider that this population may be more vulnerable to infection morbidity and mortality.

In addition to worsening the clinical outcome (especially involving respiratory risk) [10], cannabis use can generate or increase psychiatric disorders (mainly psychotic symptoms) [11], intense emotional and behavioral reactions were reported during the pandemic, such as fear, boredom, loneliness, anxiety, insomnia, anger and aggression [12]. These symptoms might be especially intense in people who use cannabis, as it is a population that has high rates of psychiatric comorbidities, is particularly sensitive to dysphoric emotional states and has a low tolerance for frustration and stress [13]. Futhermore, it has been described that people who use cannabis may have high rates of psychiatric disorder comorbidities such as simultaneous substance use (mainly tobacco and alcohol), anxiety disorders, mood disorders and personality disorders, potentiating higher risk symptoms in the current scenario [14].

A study conducted in the USA found that 36% of adults had symptoms of anxiety disorders compared to 8% of adults in January–June 2020 (N = 17,067). Anxiety can lead to increased substance use, beginning to use SPA, relapses or even increasing the amount of SPA used. [15]. Another study, carried out with 1054 Canadian adolescents, for a previous period and after the beginning of the practices of social distancing, showed that there was an increase in the use of alcohol and cannabis by this population and although 43% of the sample reported using cannabis and alcohol alone, 23% of the sample reported using it with friends during the period of social isolation, thus placing adolescents at risk of contracting COVID-19. Besides, solitary substance use in adolescence during the pandemic, which is associated with mental health problems and coping, can also be a notable concern, worthy of further investigation [16].

Nevertheless, recent studies also report that the use of cannabinoids offers good results in the treatment of COVID-19, although the endocannabinoid system (ECS) is involved in the regulation of several physiological processes, including sleep and the immune response, its role during infections has not been fully studied. It is well known that the use of this substance increases the susceptibility to infections due to the impact on the modulation of the immune system. Regarding the medicinal or recreational use of cannabis, its influence on the course of an infection, whether caused by bacteria, viruses, parasites, and fungi, has been reported. In this sense, there is evidence to suggest the involvement of ECS in the control and elimination of infectious agents but few studies are available to date. The question therefore arises as to whether ECS increases the severity of viral or bacterial infections and whether consumption of cannabis or synthetic cannabis derivatives / products can influence this risk.

The ECS has a modulating effect on the immune system, but subjects who take cannabinoids or cannabis are not considered immunosuppressed [17]. There are currently no studies available on the incidence and course COVID-19 infection in individuals taking cannabinoids. Pre-existing non-medical consumption of cannabinoids should not be increased, but decreased, during the COVID-19 pandemic, considering potential respiratory complications. One should avoid sharing cigarettes, pipes, or any equipment used for the use of cannabis, as well as any psychoactive substance, as it might be a potential form of transmission of the virus, since the greatest form of dissemination is through droplets of saliva. Likewise, cannabidiol (CBD) cannot be recommended as a possible medication, as the impact on immunity in the case of COVID-19 infection is unclear [18].

In this context, it is essential that this population is recognized according to their clinical and psychiatric vulnerability. It is vital to think about prevention and protection strategies, as well as the recovery of clinical and mental symptoms. In order to prevent the period of social distance from intensifying consumption and all other risks related to it, several measures must be taken. Among them, one must consider: the information must be used as a form of prevention, damage reduction policy, pharmacological approach, brief intervention, possibly online, during the most critical peak of the pandemic. Therefore, it is relevant to refer these patients to highly complex health treatment centers to evaluate and treat them according to the specificity of this population. The clinical and psychiatric aspects of addiction and its relationship with COVID-19 should be noted. There are few studies conducted to date on the increased risk of COVID-19-related morbidity and mortality in this population, although the gray literature has shown data showing the increase in cannabis use in the United States during this period. Epidemiological studies should be carried out to assess a potential increase in cannabis use by the population and investments should be intensified, as well as directed to psychoeducation, to preventive and therapeutic approaches to this substance and its consequences, enhanced by the inherent pandemic risks.

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Conclusion

Our manuscript contains clinically relevant notes on the risks of worse clinical complications due to COVID-19 in marijuana users. Although not included as a risk group in global health recommendations, marijuana users may be more vulnerable to contagion and worsening of their clinical condition due to covid-19 infection are at high risk, this can be explained both by the action of the psychoactive substance on central nervous system and not immune system, as well as due to the method of use that this substance is usually used. In addition, the behavior of marijuana users can make them even more vulnerable to SARS-CoV-2 infection. At this stage that Pandemia is in, with increasing rates of morbidity due to contagion by COVID-19, this population deserves more clinical attention worldwide. Therefore, our letter manuscript can help doctors become more aware of this group and can develop a specific approach.

It’s too early to tell whether CBD helps against Covid-19 — but researchers worry that won’t stop CBD makers

T he scientists stressed the caveats that early-stage research demands: the compounds they had studied showed hints — in cells in lab dishes and in animals — of being able to combat the coronavirus. Definite answers could only come from clinical trials.

But the compounds were CBD and other marijuana and hemp derivatives, so the news took off. Kimmel and Colbert cracked jokes. The studies received coverage in outlets from Fox News to The Daily Beast.

The latest hubbub is an example of both the promise of cannabinoids — components of cannabis — as potential therapies, but also the hype around them, which can far outpace the evidence that they work. It’s left researchers and consumer advocates scrambling to warn people that patients shouldn’t be turning to over-the-counter products or recreational marijuana in hopes that it might protect them from Covid-19.

“We don’t want people running out taking random cannabinoids,” said Marsha Rosner of the University of Chicago, the senior author of one of the new studies.

The research also presents a new challenge for the Food and Drug Administration, which is already struggling to police the rapidly growing CBD market. While the agency has said CBD makers can’t market their products as medical treatments without conducting a clinical trial and submitting an application to the agency, few companies have actually invested in conducting those trials. Instead, companies have tried to tiptoe around the FDA rules by selling their products as dietary supplements and making only modest claims. Experts fear that the FDA’s job will only get harder with the increased hype around cannabinoids and Covid-19.

“These kinds of studies are what these companies look for to promote their products — that’s the scary part,” said Jeanette Contreras, director of health policy at the National Consumers League, which runs a campaign called Consumers for Safe CBD. “This gives them more fuel to make false claims about their products.”

Related: The FDA is finalizing its long-awaited rules for CBD

R osner and her team were initially skeptical that CBD could have any potential effect for Covid-19. They thought that if there was going to be any benefit, it might be in the late-stage illness that occurs when the immune response to the virus goes into hyperdrive.

But then they found something that surprised them: While CBD couldn’t block the virus from entering human epithelial cells in lab dishes, it prevented the pathogen from hijacking the cell’s internal Xerox machines to make copies of itself. It also lowered viral levels in infected mice.

Rosner and her team’s paper was published in Science Advances this month, soon after researchers in Oregon reported in the Journal of Natural Products that two chemicals found in hemp, CBGA and CBDA, could bind to the virus’ spike protein and thus prevent it from infecting cells in lab dishes.

Together, the two studies earned attention for the suggestion that cannabinoids might have a role to play in the pandemic.

But since the work was published, Rosner has been trying to inject caveats and nuances into the discussion around CBD for Covid.

As she emphasizes: experiments in mice and cells in lab dishes regularly seem like breakthroughs, whether for Covid-19 or just about any other ailment. But only rarely do they go on to demonstrate any actual effectiveness in human trials.

Outside researchers also noted that the two papers reported sometimes opposing results for how cannabinoids interacted with the coronavirus, indicating that any potential effect needs to be further studied.

“These are the seeds of our knowledge related to how cannabinoids might interact with the SARS-Cov-2 virus,” said Ziva Cooper, the director of the UCLA Cannabis Research Initiative. “We have a long way to go.”

Related: A spate of new class-action lawsuits threaten the CBD industry. Will they force Washington to act?

T he new studies are adding to the FDA’s existing CBD headache, too.

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The agency has already grappled with companies trying to use early research into CBD and Covid-19 to promote their products — it has sent 13 official warning letters demanding that companies stop selling their CBD products as Covid-19 treatments.

Some of those companies did not explicitly call their products cures, but instead included outside research on their websites that could lead consumers to believe CBD was a proven treatment for Covid-19, STAT found when it reviewed the FDA’s warning letters. Other companies explicitly noted that their product was not a treatment for Covid-19 but suggested, for example, that “ the best thing you can do is boost your immune system.”

This has been a long-running issue with CBD, which the FDA regulates the same way it does other prescription drugs. That means anything with CBD in it must go through the agency’s rigorous approval process if companies want to suggest it can treat or cure anything at all.

Few companies have been willing to invest the time and effort needed to actually get a CBD drug through the regulatory odyssey. Instead, most market their products as dietary supplements in hopes that the FDA will not crack down on their individual products.

Related: The company behind the first-ever CBD-based drug is now eyeing everything from multiple sclerosis to autism

Research is hard for other reasons, too. Just a few years ago, researching cannabidiol was heavily restricted because of marijauna’s legal status, and the trials are still hard to conduct — one researcher called the system a “nightmare.”

That means there’s hardly any infrastructure or investment into actually testing whether CBD has an impact on Covid-19.

In fact, there’s still not much late-stage clinical research into whether CBD really does much of anything at all.

“The status quo is challenging,” said Lowell Schiller, the former co-lead of the FDA’s CBD working group. “When we see potentially promising research coming out of the laboratory setting, where are the dollars coming from to do the kind of rigorous clinical research that we need to genuinely understand whether there’s a there there ?”

It’s an open question whether new trials looking at cannabinoids and Covid will take off. Scientists have hypothesized that CBD or other cannabinoids might have some role to play against Covid-19 for much of the pandemic, but a STAT review of clinicaltrials.gov identified just seven trials that have tested CBD as a therapy for Covid-19, the majority of which are early-stage studies that would not produce the type of results necessary to conclude whether CBD can help combat the pandemic.

Rosner said she and her colleagues have been in touch with various companies about clinical trials, but so far, nothing’s set up. “Our hope is we can get some traction in the near future,” she said.

Related: These four companies are betting big on CBD-based prescription drugs

Richard van Breemen, a professor of medicinal chemistry at Oregon State University and one of the scientists involved with the other paper, told the Boston Globe this month that he expected data from clinical trials later this year. He did not respond to a question from STAT about whether clinical trials based on his team’s research had started or when they might.

Not all clinical trials are created equally, either — a fact that has dogged scientists’ efforts to test potential Covid-19 treatments. Going back to the heady days of hydroxychloroquine mania, dozens of trials of different treatments were launched based on preclinical hope, but they were ultimately too small or too poorly designed to come up with definite answers. The pileup of unhelpful U.S. clinical trials stands in stark contrast to something like the Recovery trial out of the United Kingdom, where a cohesive strategy and a national health system led to clear findings about treatments like dexamethasone (which worked) and convalescent plasma (which didn’t).

“It’s not just, is there a clinical trial, but what kind of clinical trial?” Rosner said, adding that her team was hoping to conduct a rigorous trial.

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In the meantime: Rosner is urging consumers not to go buy CBD to try to prevent Covid-19. For one, it’s not clear the products available at convenience stories contain pure CBD, or at what levels. The clinical trial Rosner envisions would test a pharmaceutical-grade CBD — something like the FDA-approved Epidiolex, an epilepsy treatment.

There’s another reason why people shouldn’t smoke marijuana or pop an edible and think it might be helping protect them from Covid-19, Rosner added: While her team reported an effect from CBD, the scientists found that the added presence of THC — the component of marijuana that makes people high — counteracted whatever benefits CBD may provide.

“The last thing we would like to see is for someone to say, ‘I’m going to go out and take CBD,’ and say, ‘I’m not going to get vaccinated, I’m not going to get boosted, I’m going to take off my mask,’” she said.

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