In part 3 of this article. we’ll continue on our informative journey through the labyrinthine rabbit hole of current medical marijuana research as it pertains to slaking inflammation. Once again I’ll refer to atherosclerosis as our “model” of inflammation. This is perhaps marijuana’s greatest application. If it can help with cardiovascular disease it will also affect many apparently unrelated disorders.
When I speak of inflammation, think “immune system.” One of the most vital components of immunity is an unassuming cell called the monocyte. When signalled to do so, this cell becomes a voracious eater of many things harmful to the organism. This “big eater” or macrophage (in science speak) plays a fundamental role, in this case in the blood vessel where plaque forms. These cells cause the inflammatory response that is decimating first-world inhabitants en masse.
BLOCKING CB1, AND STIMULATING CB2 IS GOOD FOR YOU
The same team I referred to in part 2 found that antagonizing (blocking) CB1 leads to decreased expression of several key inflammatory markers intimately involved in the generation of plaque. Sugamura et al, demonstrated using cultured human macrophages that antagonizing CB1 led to a decrease in the expression of an enzyme known to induce heart attack and sudden death, the MMP-9 enzyme[ref]Sugamura K, Sugiyama S, Nozaki T, et al. Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation. 2009;119:28–36[/ref]. There are about 15 risk factors, or what I call Irritating Agents (IA), for atherosclerosis. They include bad habits (nicotine & sloth) or foods (sugar, omega 6 oils) that lead to increased expression of MMP-9 from macrophages. These immune cells, located within the core of an atheroma (plaque), produce this enzyme via CB1 receptor activation which can erode the thin cap covering a young atheroma causing it to burst.
You might say who cares? Well, I care and here’s why: the rupture of a Toxic Atheroma, which happens thousands of times a day all across the developed world, can directly lead to sudden death, stroke, or heart attack.
While agonizing (stimulating) CB2 receptors using very low doses of THC (1 mg/kg/day), Steffens et al[ref]Steffens S, Veillard NR, Arnaud C, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature. 2005;434:782–786[/ref] showed an inhibition of progression of atherosclerotic lesions by decreasing monocyte activity via activation of CB2 receptors on these cells. Monocyte infiltration into the blood vessel is a hallmark for atherosclerosis. When they transform into macrophages they gobble up oxidized LDL cholesterol (the ‘bad’ cholesterol) in an effort to contain the damage.
Here’s another new term. The endothelium, is the single cell layer lining all blood vessels. The absence of endothelial dysfunction, is necessary to prevent atherosclerosis. Imagine the endothelium as the Appian Way of blood vessels: each endothelial cell is similar to one of the precision placed paving stones. IA’s injure these “stones” and cause them to dislodge eventually forming a fresh, young, atheroma. The new atheromas are very dangerous since they are unstable and can burst open. Well, guess what? CB2 stimulation seems to counteract this process by a mechanism as yet to be discovered. That’s remarkable news!
The dichotomy of the CB1 and CB2 receptor on endothelial function is similar to effects on macrophages, where CB1 agonism promotes a proatherogenic profile [increases plaque growth], and CB2 agonism prevents atherogenesis [decreases plaque].
I mentioned earlier in the article that CB1 blockage led to decreased inflammation. Now in these studies we see that stimulation of CB1 is pro-atherogenic (not good) while stimulation of CB2 decreases the inflammatory response in plaque formation (very good).
So it sounds as if a drug which blocks CB1 and stimulates CB2 may be a powerful tool for cardiac patients. Thus, the available evidence suggests a diverse role for CB1 and CB2 receptors in the progression of atherosclerosis and inflammation.
This led investigators to try Rimonabant, a CB1 antagonist, as a possible solution for decreasing plaque burden in human volunteers. In this study CB1 blockade was about as well received as a mendacious mother-in-law. After 30 months in the AUDITOR Trial which used Rimonabant a CB1 antagonist[ref]O’Leary DH et al. Effect of rimonabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR Trial. Heart. 2011 Jul;97(14):1143-50. Epub 2011 May 24.[/ref], it did not reduce plaque in the experimental group according to O’Leary the main author.
REPERFUSION INJURY AND THE ENDOCANNABINOID SYSTEM
Coronary and carotid arterial occlusion…after plaque rupture is the major cause of myocardial and cerebral infarction [stroke]. Together these acute events represent the leading cause of death worldwide. Early reperfusion is the best method to salvage the ischemic organ; however, it leads to additional damage known as reperfusion injury. …targeting the endocannabinoid system might evolve as a novel therapeutic concept to limit the devastating consequences of these acute vascular events through a wide variety of mechanisms, including lowering inflammation, oxidative stress, fibrosis, and excitotoxicity, and enhanced blood flow.[ref]Tuma RF, Steffens S. Current pharmaceutical biotechnology 13:1 2012 Jan pg 46-58[/ref]
The colossal damage that occurs from reperfusion injury during stroke, and heart attack is attenuated by blocking the pro-inflammatory CB1 receptor while stimulating the CB2 receptor leading to significant reductions in inflammation as seen below.
In this investigation it was demonstrated that CB1 activation promoted pro-inflammatory responses of macrophages through the production of reactive oxygen species. Blocking the CB1 receptor in conjunction with activation of the CB2 receptor suppressed the pro-inflammatory responses of the macrophages.[ref]Ronald F. Tuma et al. Targeting the Endocannabinod (sic) System to Limit Myocardial and Cerebral Ischemic and Reperfusion Injury. Current Pharmaceutical Biotechnology, 2012, 13, 46-58[/ref]
CB2 RECEPTORS PROTECT
In summary, the above studies suggest that blocking CB1 and stimulating CB2 decreases the inflammatory response. Furthermore, it appears that the CB2 receptor system is a protective arrangement in which IA’s like nicotine or oxidized fats, stimulate the proliferation of CB2 receptors which in turn limit the extent of inflammatory damage, as seen:
…under pathophysiological conditions such as inflammatory stimulation or tissue injury, increased CB2 receptor expression levels have been reported in the cardiovascular system, which probably reflects a protective response to limit cell or tissue injury (Pacher and Mechoulam, 2011). For example, up-regulation of CB2 receptor expression [increased number of receptors] has been described in primary human endothelial and smooth muscle cells stimulated by pro-inflammatory triggers and/or mitogens [IA’s] (Rajesh et al., 2007a; 2008; Ramirez et al., 2012), in human and mouse atherosclerotic plaques (Steffens et al., 2005), neointimal lesions following balloon injury (Molica et al., 2012) and in the myocardium of chronic heart failure patients (Weis et al., 2010).[ref] Sabine Steffens and Pal Pacher Targeting cannabinoid receptor CB2 in cardiovascular disorders: promises and controversies. Br J Pharmacol. Sep 2012; 167(2): 313–323. [/ref]
The authors Sabine Steffens and Pal Pacher (yes, that’s his real name) speculate that the CB2 signalling is part of a protective response against human plaque vulnerability, which is impaired in patients with acute heart attack or stroke.
In the final instalment of this series, we will discuss what lies outside of CB 1 & 2 receptor pharmacology and some of the properties of CBD a phytocannabinoid with some very interesting chattels. Lastly, we’ll discuss the results of one study that didn’t paint medical marijuana in a pretty light; and some of the exciting things that await us in the very near cannabis future.
You can read Parts 1 & 2 of Dr. Chris Rasmussen’s articles by clicking on the links below: