In a new study, scientists have shown that one of the non-psychoactive cannabinoids in cannabis – CBD – reduces lung damage induced by cytokine storms caused by COVID-19 through enabling an increase in levels of a natural peptide.
The scientists, from the Dental College of Georgia (DCG) and the Medical College of Georgia, demonstrated earlier this year that CBD has the ability to improve oxygen levels and reduce inflammation and physical lung damage related to adult respiratory distress syndrome (ARDS). This new study has now shown the mechanisms behind these results, demonstrating that CBD normalises levels of a peptide named apelin, which is known to reduce inflammation. Levels of this peptide are low during a COVID-19 infection.
While the researchers say the peptide clearly has an important role to play, they do not attribute all CBD’s benefits to apelin. The results have been published in the Journal of Cellular and Molecular Medicine.
Reducing inflammation with CBD
Blood levels of apelin, which is an important regulator in bringing both blood pressure and inflammation down, dropped close to zero in the authors’ ARDS model and increased 20 times with CBD. When blood pressure gets high, for example, apelin levels should go up to help reduce the pressure. Apelin should do the same to help normalise inflammation in the lungs and related breathing difficulties associated with ARDS.
“Ideally with ARDS it would increase in areas of the lungs where it’s needed to improve blood and oxygen flow to compensate and to protect,” said Dr Babak Baban, DCG immunologist. But when the authors looked at their ARDS model, apelin did not do either, and instead decreased in both the lung tissue itself and the general circulation. However, this changed when they administered CBD.
The authors emphasise that they do not yet know whether the novel coronavirus or CBD have a direct effect on apelin, or if these are downstream consequences, however, they are already working to find out.
“It is an association; we don’t know yet about causative, but it is a very good indicator of the disease,” Baban said.
The authors note that the finding of dramatic reductions in apelin in the face of ARDS, makes levels of the protective peptide a potential early biomarker for ARDS and response to treatment efforts.
The COVID-19 virus enters human cells via the also pervasive angiotensin-converting enzyme 2, otherwise known as the ACE2 receptor, with plenty of common ground between ACE2 and apelin, including the fact that many cell types and tissues have both, including the lungs.
Apelin and ACE2 normally work together to control blood pressure, and upregulation of both may be helpful in cardiovascular disease, including heart failure, by decreasing blood pressure while increasing the heart’s ability to pump.
The COVID-19 virus appears to upset this positive partnership, with the virus having the ability to bind to the receptor for ACE2. This has been shown to decrease ACE2 levels and increase levels of the powerful blood vessel constrictor angiotensin II, because less angiotensin II gets degraded and fewer vasodilators (chemicals that widen blood vessels) get produced, which worsens the patient’s prognosis.
“Instead of ACE2 helping blood vessels relax, it helps the virus get into the host where it makes more virus instead of helping the lungs relax and do their job,” says Yu.
CBD as a natural apelin agonist
The next steps in the research include better understanding the interaction between CBD, apelin, and the novel coronavirus, including why apelin goes down in the face of the virus and why CBD brings it up.
The researchers will be exploring how eliminating apelin affects ARDS and if CBD produces the same lung benefit without apelin. The authors note that it is likely the virus suppresses something that suppresses apelin and CBD interferes with this process, however, they also they doubt the apelin-CBD interaction is the only way the compound works in this and other scenarios.
To carry out the studies, the authors developed a safe, relatively inexpensive model of ARDS by giving a synthetic analogue of double-stranded RNA called POLY (I:C). The novel coronavirus also has double-stranded RNA, while human DNA is single-stranded. The model produced a response similar to the virus, including the extreme lung damage and the “cytokine storm” that reflects an over-the-top immune response in the lungs.
For these studies, a control group received intranasal saline for three consecutive days while the COVID-19 model received POLY (I:C) intranasally for three days. A third group, the treatment group, received POLY (I:C) and CBD over the same timeframe. The researchers found significantly reduced apelin levels in the mice that developed COVID-like symptoms compared to controls, and treatment with CBD normalised the immune response and apelin levels, along with oxygen levels, swelling, and scarring in the lungs.
“The apelinergic system is a very, very ubiquitous signalling system,” Yu says. The authors note that apelin has diverse jobs in different places and that its levels are consistently measurable in the lungs, one of the reasons it should be a good biomarker.
They add that CBD appears to be a natural apelin agonist.