New Research Suggests Terpenes And CBD Work 2X’s Better For Covid-19 Inflammation Than Corticosteroid
In the fight against Covid-19, cytokine storms are one of the most deadly factors that doctors are battling. This symptom in severe cases of the novel coronavirus can lead to excessive inflammation, swelling, pain, and loss of organ function. It can even cause the immune system to ramp up so much that it starts killing the body’s own cells - instead of just fighting the infection. In serious cases, this can lead to death, as we’ve seen in many cases of severe Covid-19.
In the last few months, researchers have been looking at whether cannabis, or it’s many chemical compounds, might help to fight this deadly effect by bringing down inflammation. Recently, we’ve seen positive results from studies suggesting that CBD, a compound in cannabis, may help fight these cytokine storms.
Now early results from an ongoing Israeli study are adding to the chorus of researchers suggesting that cannabis’ ingredients could be a game changing treatment in the fight against Covid-19. But this study says that terpenes, compounds that provide the aroma and flavor in cannabis and many other plants, may lead to even better results than CBD alone, and might outperform conventional treatments like corticosteroids. Reports from the study show that a combination of CBD with terpenes was 2 times more effective at inhibiting cytokine activity than dexamethasone, a corticosteroid which a recent study found to be an effective treatment for Covid-19 cytokine storms.
The new terpene study is being performed by two Israeli research and development companies, Eybna which specializes in terpene based medicines, and CannaSoul Analytics which is led by Prof. David “Dedi” Meiri, PhD a well known cannabis researcher and biochemist who has studied cannabis’ use for conditions like cancer and Alzheimer's disease. This new study was designed to find out whether anti-inflammatory terpenes might help bring down dangerous cytokine storms, and if they could, how they compared to other available treatments.
The study looks at a proprietary terpene formulation called NT-VRL™, which was created by Eybna to treat inflammatory conditions such as the cytokine storm syndrome found in Covid-19 patients. The formulation contains 30 individual terpenes that are potential anti-inﬂammatory agents, and considered generally safe for consumption.
Data scientist Nadav Eyal, who is Co-Founder & CEO at Eybna, explains that they utilized “biological data mining, data processing and formulation design” to create a “formulation effectively targeting specific health conditions” such as cytokine storms. He says that this method of development “is opening a new world for synergistically-effective natural formulations - holding therapeutic capabilities in which single Active Pharmaceutical Ingredients will have difficulties to match.”
In other words, while most medicines contain one active ingredient, this formulation contains 30 different ingredients all working together to create beneficial effects.
To test this terpene formulaton, researchers used a “Cytokine Storm Assay” from Cannasoul, which Dr. Meiri says is well-established and allows for the “evaluation of Cytokine Storm Syndrome.” Using human blood cells, the assay helps researchers to assess the effect of different treatments on cytokine secretion - the major factor in cytokine storms in severe cases of Covid-19.
Along with the NT-VRL™ terpene formulation, researchers also tested CBD, CBD with NT-VRL™, and Dexamethasone using this assay. Dexamethasone was included because it is a corticosteroid often used to bring down inflammation. In a recent study in the UK, it was found to reduce mortality by one third in hospitalized Covid-19 patients using ventilators. The World Health Organization is currently updating their recommendations to include using dexamethasone or other corticosteroids in severe cases of Covid-19.
Each compound was tested to see how it impacted cytokine activity, and the results are somewhat shocking. Not only was the terpene formulation able to inhibit the cytokine activity, (with better results using higher doses), but it also outperformed both CBD and dexamethasone. CBD alone inhibited around 75% of the cytokines on average, while the terpenes alone inhibited around 80%, suggesting that Eybna’s terpene blend may be even more effective than CBD for inflammation reduction.
Still, the best results came from the combination of CBD and the NT-VRL™ terpene formulation, which was able to inhibit around 90% of the tested cytokines. In comparison, dexamethasone was only able to inhibit around 30% of the cytokines, suggesting that the combination of CBD and terpenes may be 2 times more effective than the current recommended treatment.
“The preliminary results were highly positive,” explains Eyal, adding that they are “demonstrating significant anti-inflammatory activity of terpenes and breaking the perception that terpenes are just flavorings and fragrances compounds with a placebo effect.”
Still, while this in-vitro study offers important insight into the potential to use terpenes and CBD in the fight against Covid-19, it’s important to note that these results are coming from an ongoing study that has yet to be completed, peer reviewed or published. These results still need to be reviewed and validated by the larger scientific community, but if they prove to be accurate, they could offer impetus for human trials looking into whether this combination of CBD and terpenes actually works for patients with Covid-19 related cytokine storm syndrome.
Hemp CBD oil is able to provide this protein during proliferation as a basic element of the whisker, especially when included in the diet. CBD oil also improves blood circulation on the scalp, which ensures that the Alopecia follicles are nourished enough to support hair growth.
Though there is not much anecdotal evidence on CBD for treating alopecia areata, people are finding this cannabinoid effective in treating hair and scalp loss issues. Moreover, the presence of fatty acids, terpenes and other vitamins in CBD oil makes it a potent solution for all our hair related problems.
CBD helps reduce oxidative stress, inflammation, cell death, and vascular hyperpermeability, commonly linked to diabetes. CBD for diabetics has been shown to help reduce the need for insulin among patients. Numerous studies have demonstrated the impact of CBD on diabetes.
CBD and blood pressure
A new study has found that CBD effectively reduces systolic blood pressure, suggesting it could be beneficial in the treatment of cardiovascular disorders. “Our data show that a single dose of CBD reduces resting blood pressure and the blood pressure response to stress, particularly cold stress, and especially in the post-test periods.
Gingivitis is the first stage of gum disease and is completely reversible with the right care, and CBD oil may be able to help. By putting CBD in your toothpaste, you may be able to help fight gingivitis because of cannabidiol’s antibacterial properties.
CB Receptors: What They Are and How
The cannabis plant has two primary cannabinoids, THC and CBD (or cannabidiol). These substances are
becoming more and more well known, but what surprises many people is that humans have receptors in our bodies and brains that are specifically receptive to cannabinoids. These are called CB receptors (cannabinoid receptors).
Even more surprising is that we can produce our own cannabinoids in our bodies without consuming any cannabis at all. Cannabis becomes useful when we want to increase a certain mechanism by feeding a cannabinoid receptor with more cannabinoids.
How do we know we make our own cannabinoids? For a long time, endorphins were believed to be the home-brewed opiates responsible for the feeling known as a “runner’s high” since elevated levels were observed in the bloodstream after intensive jogs. What they didn’t consider back then is that endorphins are made up of rather large molecules that don’t cross the blood-brain barrier. They were in the bloodstream, yes, effectively at work in reducing pain in the body, but they were not the ones responsible for that peaceful state of mind.
So what gives a person a runner’s high? Almost too coincidentally, turns out it is the same stuff that can actually get you high. A 2003 study published in the Journal of Neuroreport examined male college students running on a treadmill or cycling on a stationary bike for 50 minutes. They found the first evidence that exercise activates the endocannabinoid system.
Cannabinoid receptors are a part of this system, and they’re located throughout the body, including the brain. Their main function is to regulate physiological processes like appetite, mood, pain and memory.
Research History of CB Receptors
Who was the true discoverer?
Cannabis has an ancient history dating all the way back to 8,000 BCE, but it wasn’t until recently in the 20th century that we actually discovered these cannabinoid receptors. Most sources will tell you that THC was first isolated in 1964 by Raphael Mechoulam, Yechiel Gaoni, and Habib Edery from the Weizmann Institute of Science. With further investigation, however, an article published in the British Journal of Pharmacology as well as an article on Cannabis Digest’s site (“Setting the Record Straight”) reveal to us that the timeline is a little different.
THC was apparently already being experimented on for its potential as a truth serum in World War II and the Cold War era. So, as it turns out, while Mechoulam and his colleagues were first to synthesize THC, THC had already been extracted as early as 1942 by Wollner, Matchett, Levine and Loewe. This was all just the beginning for cannabis research.
What changed the consensus on how THC works?
Here is a little preliminary chemistry. The way many things work in our bodies on a microscopic scale is according to chemical shape. Many drugs are made by creating chemical shapes (like a key) that will fit into specific receptors in your body (the lock).
Initially, there was hot debate over whether receptors for cannabinoids existed. It seemed intuitive, though, partly because the effects of psychotropic cannabinoids seemed to be largely influenced by their chemical structure.
Yet other researchers thought that THC worked by being hydrophobic enough to interact with cell membrane lipids; in other words, they thought it interacted simply with our body’s cells. Ultimately, this was shown to be false, and that gave scientists cause to inquire about just how THC functioned in the body. They began the search for receptors.
The First Cannabinoid Receptors Found and Identified
What finally settled the question of CB receptors was the work of Allyn Howlett in his St. Louis University lab in the mid 80s. He discovered that psychotropic cannabinoids had in common an ability to inhibit adenylate cyclase by acting through Gi/o proteins.
Then, in collaboration with Bill Devane in 1988, Howlett conducted experiments with radio labeled CP55940, and the first of these receptors was identified: CB1. Not long after, cloning of such receptors began in 1990 and well into 1993, when CB2, the other cannabinoid receptor, was successfully cloned. Research since then has focussed their location and exactly what turns them on or off.
Where Are They?
Most cannabinoid receptors are located in the brain. According to information from Medical News: Life Sciences and Medicine, CB2 receptors are found mostly on white blood cells and in the spleen while CB1 receptors can be found on nerve cells abundantly in parts of the brain such as the cerebellum, basal ganglia, hippocampus and dorsal primary afferent spinal cord regions. These receptors spread throughout the body are referred to collectively as the endocannabinoid system, which we mentioned earlier.
It is because of the specific locations of the cannabinoid receptors that we observe specific effects from cannabinoids. For example, one study illustrates how THC can create an immunosuppressant response by reacting with CB2 receptors. Additionally, since the cerebellum is primarily responsible for smooth motor function and movement, when THC binds to receptors in that area, motility can be affected.
How THC Affects Receptors
THC can both activate and deactivate receptors, as another article published in the British Journal of Pharmacology points out. The efficacy of THC on a cannabinoid receptor can sometimes depend on the density and activation efficacy, or receptiveness, of the cannabinoid receptor itself. But this receptiveness varies greatly within the brain’s receptors.
According to the article, THC has relatively low cannabinoid receptor efficacy, but, to quote, “THC can inhibit depolarization-induced suppression of excitation, and hence presumably it may inhibit endocannabinoid-mediated retrograde signaling in at least some central neuronal pathways.”
What this means overall is that THC can cause excitation, act as an antagonist rather than an agonist in some receptors, or cancel out agonists. Whether or not THC is an agonist or antagonist also depends on whether those cannabinoid receptors are being down- or up-regulated. Up-regulation can occur as a result of some disorders. When this happens, THC typically acts as a partial agonist.
Another interesting thing to consider is that CB1 receptors generally have an inhibitory effect on any ongoing transmitter release from the neurons on which they are located. However, when these receptors are activated in vivo, this sometimes leads to increased transmitter release from other neurons. More specifically, there is evidence that in vivo administration of THC produces CB1-mediated increases in the release of acetylcholine in rat hippocampuses; of acetylcholine, glutamate and dopamine in rat prefrontal cortexes; and of dopamine in mouse and rat nucleus accumbens.
How CBD Affects Receptors
CBD usually acts by affecting different receptors. According to an article published in Epilepsia in early 2016, CBD is unlike THC in that it does not activate CB1 and CB2 receptors. This partially explains its lack of psychotropic effect. However, it interacts in other signaling systems. For example, in a study on mice, CBD protected against cocaine-induced seizures through the mTOR pathway and by reducing glutamate. The article lists the following receptors affected by CBD.
the equilibrative nucleoside transporter (ENT),
the orphan G-protein-coupled receptor GPR55, and
the transient receptor potential of the melastatin type 8 (TRPM8) channel.
CBD enhances the activity of….
the 5-HT1a receptor,
the ?3 and ?1 glycine receptors, and
the transient receptor potential of the ankyrin type 1 (TRPA1) channel
Other effects include…
a bidirectional effect on intracellular calcium,
activation of the nuclear peroxisome proliferator-activated receptor-? and the transient receptor potential of vanilloid type 1 (TRPV1) and 2 (TRPV2) channels, and
Inhibition of cellular uptake and fatty acid amide hydrolase-catalyzed degradation of anandamide.
Of course, if you’re not an organic chemist or biologist, it is hard to know what all of that means, so let’s use the 5-HT1a receptor as an example.
The 5-HT1a receptor is a subtype of the 5-HT receptor that binds the endogenous neurotransmitter serotonin. Serotonin is something we are all a bit more familiar with these days with the epidemic levels of depression and sleep problems. Serotonin plays contributing roles in mood and sleep. So, if CBD enhances receptivity to serotonin, this might explain some of its usefulness.
The human body contains a complex system that produces its own forms of cannabinoids at small doses. The effects of CBD and THC on this natural system are of great interest to researchers and enthusiasts alike.
Endogenous Cannabinoids: Homemade Cannabinoids Live Inside You
It comes as a surprise to many people that we have a system in our bodies capable of producing its own cannabinoids without you ever picking up a hemp or cannabis product. According to the Journal of Nature Reviews Drug Discovery, the discovery of this system occurred some time in the mid-1990s, after scientists found membrane receptors (known as CB receptors) used by the psychoactive compound delta9-tetrahydrocannabinol or THC. Some scientists thought that THC acted on individual body cells, but this discovery proved that notion wrong. As it is understood now, we wouldn’t actually get “high” from THC in cannabis plants at all if we did not have an endocannabinoid system. Other species in the world cannot get “high” because they lack this feature in their anatomy.
According to the Journal of Comparative Neurology, such a system is common in many creatures including in mammals, birds, amphibians, fish, sea urchins, leeches, mussels, and even the most primitive animal with a nerve network, the Hydra. However, the presence of CB receptors has not been seen in terrestrial invertebrates (or any member of the Ecdysozoa). Surprisingly, no specific bindings of the synthetic CB ligands [(3)H]CP55,940 and [(3)H]SR141716A were found in a panel of insects: Apis mellifera, Drosophila melanogaster, Gerris marginatus, Spodoptera frugiperda, and Zophobas atratus.
Another study confirming the endocannabinoid system in humans was one done on runners in 2003. This study showed that male college students running on a treadmill or cycling on a stationary bike for 50 minutes had their endocannabinoid system activated. This study was among the first evidence to suggest alternative explanations for exercise’s ability to induce analgesia, or “runner’s high,” in people.
Other good preliminary knowledge to have before we dive into endogenous cannabinoids is about the four subtypes of receptors in the endocannabinoid system upon which they can act. We usually only talk about two, but these four types are…
CB1 (first cloned around 1990),
CB2 (first cloned around 1993),
abnormal-cannabidiol receptors (abn-CBD) or anandamide receptor.
Some might be yet to be discovered, since truncated forms of the CB1 receptor (like CB1A) have also been found.
Also important is knowing where CB1 and CB2 receptors are generally located. According to an article in the Journal of Current Neuropharmacology, “CB1 receptors are abundant and widely dispersed throughout the brain. Their distribution has been mapped by autoradiographic studies, immunohistochemical techniques, in situ histochemistry, and electrophysiological studies. CB1 receptors have shown particularly high levels of expression in cortex, basal ganglia, hippocampus, and cerebellum and low levels of expression in brainstem nuclei.” In contrast, CB2 receptors are found mostly on white blood cells and in the spleen.
Endogenous Cannabinoids – What are these chemicals you make?
First thing to know regarding endogenous cannabinoids is that they are synonymous with endocannabinoids. “Endo” simply means “within” or “internal” while “genous” comes from the same root word as “generate” or “genesis” – in other words, “make” or “create.” The words “endogenous cannabinoids” and “endocannabinoids” will be used interchangeably. Endocannabinoids serve as intercellular “lipid messengers” signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. The first endogenous cannabinoid to be isolated and structurally characterized in 1992 was arachidonylethanolamide, commonly known as anandamide, and it was taken from a pig brain.
Fun fact: The name for this chemical comes from the Sanskrit word ananda, which means “bliss.” This study published in the Journal of Neurochemistry shows how anandamide works. Anandamide can bind to membranes in two ways. Either it does this transiently, quickly passing, or it does so when it is “transfected with an expression plasmid carrying the cannabinoid receptor DNA.” Transfection, in biology terms, is a method of introducing genetic material. An expression plasmid can affect the gene expression in cells. The anandamide also inhibits the forskolin-stimulated adenylate cyclase in the transfected cells. What all this means is that “anandamide is an endogenous agonist that may serve as a genuine neurotransmitter for the cannabinoid receptor.” Anandamide affects how CB1 receptors do or don’t get activated.
Anandamide is synthesised by the hydrolysis of the precursor N-arachidonoyl phosphatidylethanolamine, which is catalysed by the enzyme phosphodiesterase phospholipase D. After release from the postsynaptic terminal, which is the receiving part of the connection (synapse) between two nerve cells (neurons), anandamide interacts with presynaptic cannabinoid receptors. Deficiencies can have unpleasant results, as this study about neuropathic pain in mice shows. Anandamide plays a role in pain, mood, appetite, and memory and is the most extensively studied endogenous cannabinoid.
Like anandamide, 2-AG is also an endogenous ligand for CB1 receptors. According to a study published in the Journal of Neuroscience, it is the most prevalent endogenous cannabinoid ligand in the brain. The study, which observed self-administered injections of squirrel monkeys, also pointed to data suggesting that 2-AG plays a role in drug-taking behaviors. The monkeys were shown to exhibit an addictive behavior when given 2-AG. Its role in the organism overall is still being established, but recent studies show that it plays a role in the regulation of the circulatory system via direct and/or indirect effects on blood vessels and/or heart. It is synthesised by cleavage of an inositol-1,2-diacylglycerol, which is catalysed by phospholipase C.
This endogenous cannabinoid is a CB1 partial agonist but is a CB1 antagonist in vivo (in the body). It was discovered in June of 2002. Virodhamine is arachidonic acid and ethanolamine joined by an ester linkage. In the hippocampus, its concentrations are similar to those of anandamide. In peripheral tissues that express the CB2 receptor, however, it was found in amounts that were 2- to 9-fold higher than anandamide.
At the CB2 receptor, it acts as a full agonist. It sometimes can antagonize other endocannabinoids in vivo; for example, it can inhibit anandamide transport. In a study published in the British Journal of Pharmacology, it was shown to relax rat mesenteric arteries through endothelial cannabinoid receptors. It can do this to the human pulmonary artery via two mechanisms: It activates the putative endothelial cannabinoid receptor, and it initiates the hydrolysis of virodhamine to arachidonic acid and subsequent production of a vasorelaxant prostanoid through COX.
In Retrospect: Clearing Up Misinformation
Here are some things you need to understand about how CBD relates to these endogenous cannabinoids. CBD is not itself an endogenous cannabinoid; however, it acts on CB receptors in a similar manner to some endogenous cannabinoids, like OAE. THC and CBD both influence the way that natural endocannabinoids carry out their jobs. Sometimes, they are agonists in one spot and antagonists for another.
We hope that this helps clear up some information about the endogenous cannabinoids involved in the endocannabinoid system. It is perhaps commonly thought when hearing about this system that we produce things like CBD in our bodies, but this isn’t quite so. We produce very similar chemicals that do very similar things that also influence how cannabinoids like CBD and THC will interact with our CB receptors or other receptor sites. Some are ligands for synaptic reactions, and some are agonists/antagonists.