WHAT DOES A THORN IN THE FOOT, HEART DISEASE, AND A MEERSCHAUM OF MARIJUANA HAVE IN COMMON? PART FOUR OF A FOUR PART SERIES
Hey everyone sorry I’m late but I was on vacation. I am a contributing writer to another website that you will find very interesting. It’s called MEDICALMARIJUANA.CO.UK. Please give it a visit and add comments if you like. I’ll have a dozen articles on it by the end of May.
In part three we discussed the exciting results of several studies using cannabis ligands for their plaque punching use in treating atherosclerosis. In this final installment we’ll move beyond classic receptors and explore the uses of CBD.
The studies below indicate that there is more to it than stimulation of CB2 receptors (while blocking CB1), and that blocking CB2 also decreases inflammation. Furthermore, cannabidiol (CBD) exerts some or all of its anti-inflammatory effects outside of these receptors: From Mohanraj Rajesh et al:
Consistently, CBD has been shown to exert anti-inflammatory and antioxidant effects both in vitro and in various preclinical models of neurodegeneration and inflammatory disorders, independent from classical CB1 and CB2 receptors [11 citations].
Cannabidiol has been shown to be effective in protecting endothelial function and integrity in human coronary artery endothelial cells (HCAECs). The study demonstrated that CBD reversed the harmful effects of high glucose on HCAECs by inhibiting:
Reactive oxygen species production by mitochondria
Transendothelial migration of monocytes
Monocyte–endothelial adhesion in HCAECs [Emphasis mine]
Cannabidiol (CBD) is not psychoactive due to a low affinity for the CB1 & CB2 receptors. It has been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans since 2005.
In what can only be described as astonishing, Mohanraj Rajesh and his team were able to demonstrate that CBD may be the perfect anti-inflammatory for diabetics and cardiac patients. Its effects are so broad as to make one question the authenticity of this study. Basically CBD suppressed all of the adverse effects from excess serum blood sugar that they examined such as hyperglycemia induced free radical damage from NF-kB activation, and superoxide formation. Superoxide production plays a significant role in the pathogenesis of diabetes-associated endothelial dysfunction. From part two TARGETING CELLULAR INFLAMMATION:
Superoxide can also be converted to hydrogen peroxide (H2O2),…plays a central role in NF-κB activation in coronary artery endothelial cells [2 citations]. Hyperglycemia-induced superoxide generation might also favor increased expression of iNOSs through the activation of NF-κB, which increases the generation of nitric oxide. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium,…[2 citations]. [Emphasis mine]
And furthermore from the same authors:
We demonstrate that CBD attenuates HG [hyperglycemia]-induced mitochondrial superoxide generation, NF-κB activation, nitrotyrosine formation, upregulation of iNOS and adhesion molecules ICAM-1 and VCAM-1, TEM of monocytes, monocyte-endothelial adhesion, and disruption of the endothelial barrier function in [human coronary artery endothelial cells] HCAECs by a mechanism independent from CB1 and CB2 receptors. [Emphasis mine]
The above quote provides a shopping list of destruction formed from excessively high blood sugars typically seen in diabetics and prediabetics. You do not need to know all of the individual players listed above which might require a graduate level course in biochemistry to fathom. You need only know that all of these effects lead to the downstream formation of reactive intermediates which generate atherosclerosis and other complications such as neurodegeneration. Considering that over 80% of the American population has fasting blood sugars outside the ideal range (83-85 mg/dl), CBD may be a welcome addition to our paucity of anti-inflammatory/diabetic medicines.
In other words this study shows that CBD may behave as an antidote to diabetic hyperglycemic complications, and in those patients with prediabetes or who eat excessive quantities of refined carbohydrate.
In the conclusion of the above study the author’s state: Collectively, our results suggest that the nonpsychoactive cannabinoid CBD have significant therapeutic benefits against diabetic complications and atherosclerosis.
Of course, in medicine nothing is ever black and white. While scientists elucidate the role of CB2 stimulation leading to a decrease in the inflammatory response in plaque formation, others are finding that blocking the CB2 receptor with CBD leads to a decrease in the immune response. The authors suggest that these findings may lead the way toward development of a new class of anti-inflammatory drugs.
Turning now to CBD, an important recent finding is that this cannabinoid displays unexpectedly high potency as a CB2 receptor antagonist and that this antagonism….can ameliorate inflammation through inhibition of immune cell migration…raises the possibility that CBD is a lead compound from which a selective and more potent CB2 receptor inverse agonist [a type of antagonist] might be developed as a new class of anti-inflammatory agent. [Emphasis mine]
CBD acts as an antagonist to the CB1 (& CB2) receptor but it indirectly stimulates endogenous (pot-like molecules made in our brain) cannabinoid signaling by suppressing fatty acid amide hydroxylase (FAAH), which is the enzyme that metabolizes anandamide. Anandamide is an endogenous cannabinoid that activates the CB1 receptor. CBD therefore, indirectly leads to increased CB1 signaling through increasing the quantity of anandamide at the receptor in spite of the fact that CBD weakly antagonizes CB1. Incidentally, CBD in excess quantities, can decrease the high from THC since it is an antagonist of CB1 (located mostly in the brain).
But wait there’s more to it. CBD also stimulates the release of 2-AG another endogenous cannabinoid which stimulates both CB1 and CB2 receptors. Looking at the figure below we see that CBD also acts as an agonist at the 5HT1a receptor (a serotonin receptor), and an agonist at the vanilloid receptor known as TRPV-1. Lastly, it also stimulates adenosine receptors one of which acts as a powerful anti-inflammatory known as A2A, and CBD is a potent anti-inflammatory in its own right. For all you coffee drinkers take note that part of caffeine’s effect is to antagonize adenosine in the CNS thus leading to an alert response of heightened awareness. Coffee also contains exorphins which are morphine-like chemicals. No wonder why we all LOVE coffee! OK, settle down, now back to our discussion.
Lastly, during myocardial ischemia the heart often times misbehaves and can develop serious rhythm disturbances such as ventricular tachycardia (V-tach). In a rat model CBD was shown to decrease the incidence of V-tach during coronary artery occlusion but just how it does that remains a mystery.
Figure 1 CBD How it works from Martin A Lee (O’Shaughnessy’s • Autumn 2011)
DARK HORSE: CANNABINOIDS AND HEART ATTACK
Just when you thought it was safe to light your spliff there remains a dark horse in the use of pot and heart disease. As you probably know there is a transient increase in heart rate with a subsequent mild increase in blood pressure when smoking pot. If you stand up too quickly you may also experience dizziness as your blood pressure takes a nose dive, called orthostatic hypotension. That’s about it as far as cardiovascular effects go with the average cannabis user.
At least one study is getting plenty of press, it has shown that pot smoking increases the risk for heart attack within the first hour of smoking. However, before your pants catch fire I think we can relax. This was a retrospective study involving a questionnaire on frequency of marijuana use which makes it notoriously unreliable. Moreover, those at greater risk after pot smoking tended to be more obese and smoked cigarettes (about two times as many smokers as the control group). Interestingly, they were also less likely to have a history of angina or hypertension. Researchers feel that it’s most likely the transient tachycardia in vulnerable patients that precipitated a heart attack. If a mild increase in heart rate was all that was needed to precipitate an infarct in the experimental group then these patients were going to infarct anyway regardless of pot smoking. A 10-20% transient increase in heart rate is not normally a major risk for heart attack unless these patients already suffered severe, stable angina, which apparently they did not. So it’s a conundrum of sorts.
Unless of course something else is at work causing these heart attacks. Some investigators have demonstrated that THC increases platelet stickiness, increasing the risk for thrombus formation and heart attack, through stimulation of both CB1 & CB2 receptors which was completely blocked by aspirin administration. Aspirin squashes platelet activity by preventing them from adhering to each other to form a platelet plug or clot. Coronary vasospasm (narrowing of the artery) precipitated by marijuana smoking has also been proposed as a mechanism for precipitation of acute myocardial infarction in individuals with either normal or minimally diseased coronary arteries. The underlying mechanism for coronary vasospasm following marijuana smoking may be related to an increase in sympathetic discharge. The increase in sympathetic discharge (as in the fight or flight response) is responsible for the slight increase in heart rate from pot smoking. And then right out of left field we see others speculate that THC actually decreases thrombus (clot) formation through some unknown mechanism. In other words, nobody knows what’s going on yet.
In summary, I have presented compelling animal, tissue culture, and human studies that strongly support a role for cannabinoids in moderating inflammation in general, and specifically in the treatment of cardiovascular disease (which includes stroke and heart attack) our number one killer. I have pointed out that drug companies do not currently have ways to treat chronic inflammation which is one of the reasons why Americans have become so sick. That’s why lifestyle modification, in other words, preventing inflammation is currently our best option. But, as any physician knows most patients simply are going to eat and do as they please-even if it’s killing them-and it clearly is. Therefore, telling Mabel to eat more salads, and to drop 60 pounds is often time a fool’s errand.
That’s why a new cannabinoid anti-inflammatory class of drugs would be embraced. Because of their unique, novel, and powerful, systemic anti-inflammatory actions these drugs could be applied as antidotes to Irritating Agents such as destructive habits and environmental toxins that are recognized risk factors for neurodegeneration and atherosclerosis.
Furthermore, these novel molecules, and many more just waiting for a fresh PhD student or MD to expose, appear to work far upstream of the inflammatory cascade right into the very heart (no pun intended) of cellular inflammation: the suppression of NF-kB.
Let me put this into perspective. If we had a drug that could effectively, and safely, attenuate or reverse the effects of our first-world, inflammatory lifestyle, while allowing patients to continue their destructive habits-the classic American way to approach healthcare-it would outsell statins within the first year. That’s at least 30 billion in sales per year (some sources quote 200 billion in annual sales). Moreover, by operating at the root level and suppressing NF-kB, a real cure for atherosclerosis could be realized, and with it cures for a hundred more diseases of affluence. That could change the face of medicine folks. It would be as important, if not more so, than when penicillin was first introduced 70 years ago in the treatment of that generation’s biggest killer-infectious disease.
There is still much needed work to be done before we’ll have it clear as to the role of cannabinoids in treating the numerous expressions of inflammatory disease. Regardless of where the chips finally fall there’s so much promise in the years to follow that I’ll leave you with this paradigm-shifting statement:
…cannabis is a source not only of D9-THC, CBD and D9-THCV but also of at least 67 other phytocannabinoids and as such can be regarded as a natural library of unique compounds. The therapeutic potential of many of these ligands still remains largely unexplored prompting a need for further preclinical and clinical research directed at establishing whether phytocannabinoids are indeed ‘a neglected pharmacological treasure trove’ (Mechoulam, 2005). [Emphasis mine]
Finally, let’s take the trillions wasted in drug interdiction and the prison system for non-violent drug offenders toward research into cannabinoids and you got yourself a “Going Jesse.” It only makes one wonder what bounty might already be available to our moribund masses had President Nixon or Carter legalized marijuana back when they should have.
 Mohanraj Rajesh et al., Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ Physiol. Jul 2007; 293(1)
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 Mittleman MA1, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial infarction by marijuana. Circulation. 2001 Jun 12;103(23):2805-9.
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 Journal of British Pharmacology (2008) 153, 199–215; 2008 Nature Publishing Group