March 2, 20150 Comments



We have been discussing the use of medical marijuana as an anti-inflammatory. In part two we discussed the devil of cellular inflammation: NF-kB, the various ways that can generate it, and the importance in finding better solutions for reducing this process. In the third and fourth parts of this series we will review some of the current research involving cannabis: its potential role as a powerful anti-inflammatory, and specifically how it may be utilized in the future as a treatment for atherosclerosis.


It turns out that cannabinoids, acting via both CB1 and CB2 receptor modulation, have an important role in immune system regulation. Because inflammation plays a key role in atherogenesis, cannabinoids can potentially affect atherogenesis via modulation of the immune system.[1] CB1 & CB2 receptors have been identified on many immune cells and endothelial cells. Let’s see what the data show:

Both CB1 and CB2 are G-protein coupled receptors that modulate second messengers and signaling components such as adenylate cyclase, mitogen activated protein kinases (MAPK), and members of the nuclear factor κ B (NF-κB) family, in addition to playing a role in direct modulation of cell membrane ion channels.[2] [Emphasis mine]

Let me clarify that for you. From above we see that the CB receptor system is part of a very large class of G-protein coupled receptors. For example the “fight or flight” system utilizes the same processes. It’s a commonly conserved way (evolutionarily speaking) that many animals use to communicate with other cells. And they (the CB receptors) have the right pedigree for addressing cellular inflammation-by modulating NF-kB.

In one study a synthetic cannabinoid agonist (stimulant) with CB2 selectivity was used. The decrease in extent of atherosclerosis was associated with a decrease in proinflammatory cytokine gene expression and attenuated oxidized low-density lipoprotein (ox-LDL)-induced NF-κB activation.[3] In other words a synthetic CB2 stimulant (agonist) decreased plaque formation through a reduction in NF-kB.

The monocyte is an immune cell that turns into a macrophage (big eater) in the subendothelial space where plaque forms. These cells are integral to the inflammatory response that is plaquing out Americans en masse. Several studies below used both types of cells in tissue culture for their experiments.

The same authors from above found in animal studies 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.[4] Risk factors, or what I and some investigators call Irritating Agents (IA), for atherosclerosis include bad habits (nicotine & sloth) or foods (sugar) 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 weaken and erode the thin, cobweb-like cap covering a young atheroma causing it to burst. The rupture of a Toxic Atheroma, which happens thousands of times a day all across America, can directly lead to sudden death or heart attack. In fact, depending on who you quote, up to 50% of all first-time heart attacks lead directly to sudden death, the type that does not involve Hail Mary passes.

While agonizing (stimulating) CB2 receptors using very low doses of THC (1 mg/kg/day), Steffens et al[5] showed an inhibition of progression of atherosclerotic lesions in the aortic root and abdominal aorta…by decreasing monocyte adhesion and infiltrating the subendothelial region via activation of CB2 receptors on these cells. Monocyte (macrophage) infiltration into the subendothelium is a hallmark for atherosclerosis. They gobble up oxidized LDL cholesterol in an effort to contain these IA’s.

A similar profile is encountered when scientists look at the endothelium, the single cell layer lining all blood vessels. A healthy endothelium, the absence of endothelial dysfunction, is necessary to prevent atherosclerosis. It’s ground zero. Look at the endothelium as the Appian Way of blood vessels: each endothelial cell is similar to one of the precision placed paving stones. IA’s can and do injure these “stones” and cause them to dislodge. This opens up the delicate basement membrane for oxLDL and other IA’s to damage it leading to the sub-endothelial infiltration of oxLDL and eventually toward making a fresh, young, atheroma. The new atheromas are dangerous since they are unstable and can burst open. 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]. [Emphasis mine]

In a similar fashion as with the endothelium when we examine lipid metabolism and vascular smooth muscle cells, both play roles in atherogenesis, we see once again that stimulation of CB1 is pro-atherogenic while stimulation of CB2 decreases the inflammatory response involved in plaque formation. Thus, the available evidence suggests a diverse role for CB1 and CB2 receptors in the progression of atherosclerosis.


This led investigators to try Rimonabant, a CB1 antagonist, as a possible solution for decreasing plaque burden in human volunteers.

In one study CB1 blockade did not appear to reduce plaque in obese patients with metabolic syndrome according to O’Leary the main author. There was no difference in atherosclerosis progression between patients receiving rimonabant for 30 months, and those receiving placebo for the primary efficacy measure (absolute change in carotid intima-media thickness, CIMT) in the AUDITOR Trial which used Rimonabant a CB1 antagonist.[6] CIMT is a very reliable surrogate for coronary artery atherosclerosis measurement. It’s used since it is easier to ultrasound the carotids that to angiocath a patient. It sure would have been nice to see but apparently blocking CB1 doesn’t help much as far as plaque goes. The authors remarked that perhaps 30 months isn’t long enough to see plaque regression. However, I am in possession of at least three studies that show how pomegranate juice reduces plague by 30% in only 12 months. I believe 30 months is long enough to show whether a drug is effective or not.


In a phrase reperfusion injury is where the real damage occurs in stroke and heart attack.

Coronary and carotid arterial occlusion due to thrombosis after atherosclerotic 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. A large number of experimental studies has been performed in the past aimed at targeting individual mediators of reperfusion injury such as treatment with anti-oxidants or anti-inflammatory agents. Although many agents proved beneficial in animal models of myocardial or cerebral ischemia/reperfusion, the attempts to translate these protective effects into clinical practice were mostly disappointing. Elucidating the complex cellular and molecular mechanisms involved in ischemic cell death is crucial for the development of more efficient drugs in order to improve current treatment strategies.

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.[7] [Emphasis mine]

The massive free radical cascade, and autoimmune response that occurs from reperfusion injury during stroke follows the same activity profile of the CB receptors. That is, blocking the pro-inflammatory CB1 receptor while stimulating the CB2 receptor led to significant reductions in reactive oxygen species (ROS).

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 proinflammatory responses of the macrophages.[8] [Emphasis mine]


It appears that the CB2 receptor system is a protective arrangement in which IA’s 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).[9] [Emphasis mine]

The authors Sabine Steffens and Pal Pacher speculate that the CB2 signaling is part of a protective response against human plaque vulnerability, which is impaired in patients with acute vascular events (like heart attack or stroke). This is witnessed in other end stage diseases such as advanced kidney nephropathy. The authors list ten additional animal studies providing compelling evidence for a protective role of CB2 stimulation in cardiovascular disease.

In the final installment 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 pot in a pretty light; and some of the exciting things that await us in the very near cannabis future.

[1] Sandeep Singla MD. Cannabinoids and Atherosclerotic Coronary Heart Disease .Clinical Cardiology

Volume 35, Issue 6 pages 329–335, June 2012 (online: http://onlinelibrary.wiley.com/doi/10.1002/clc.21962/full) 11/23/2014

[2] IBID

[3] IBID

[4] 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.

[5] Steffens S, Veillard NR, Arnaud C, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature. 2005;434:782–786.

[6] 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.

[7] Tuma RF, Steffens S. Current pharmaceutical biotechnology 13:1 2012 Jan pg 46-58

[8] 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

[9]Sabine Steffens and Pal Pacher Targeting cannabinoid receptor CB2 in cardiovascular disorders: promises and controversies. Br J Pharmacol. Sep 2012; 167(2): 313–323.

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About the Author ()

Christopher Rasmussen MD, MS is Founder and Professor at AdaptiveTCM where helps Traditional Chinese Medicine Practitioners treat complex patients with confidence through providing online CEUs and research. Dr. Rasmussen is currently writing a comprehensive, preventive medicine book, with an emphasis on inflammatory components of disease prevalent in today's patients.

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