The Use of Cannabis as a Potent Anti-Inflammatory Medication – Part 3

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.

RIMONABANT-NOT

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:

–Part 1

-Part 2

The Use of Cannabis as a Potent Anti-Inflammatory Medication – Part 2

In part 1 of this article, some of the general applications of cannabinoids both synthetic and natural were covered. The power in these mysterious substances, comes at least in part, from their anti-inflammatory effects. In this article, we’ll cover the chronic immune response, where it lurks, the definition of cellular inflammation, and active areas of research where cannabis plays a special role.

Many would argue, myself included, that nearly all disease of affluence are inflammatory. Chronic inflammation is the bane of civilization. This is the response that we are trying desperately to decrease or eliminate among those that suffer from its torpor. The biggest problem is that, with few exceptions, it doesn’t respond well to our pharmaceuticals either. As a result we have an enormous number of people suffering from chronic, degenerative diseases for which there is no cure. It has been shown that cannabis reduces pain and inflammation under these circumstances.

This is one of the main reason why and how medical marijuana came to be legalized in certain states of America.

So what exactly is it that cannabis helps?

Let’s start first with a general definition so that we can all speak the same language. Chronic inflammation is an unchecked biological reaction to tissue injury producing a smoldering, cascade of immuno-vascular responses in an attempt to heal, leading to a pathologic change in the cell population of the affected tissue. It is characterized by repeated healing and injury.

Arterial plaque (and much more) is a result of the above response. Simply living La Vida Industria is all it takes sometimes. It is real tissue injury. Here I’m referring to atherosclerosis because of its textbook presentation, but we could just as easily be describing other pandemics like metabolic syndrome, neurodegeneration like Alzheimer’s disease, or chronic pain. In total there are three main regions where inflammation prefers to occur: blood vessel, brain and as an excess of visceral fat.

Let me saturate you in acronyms for a moment as we devil into the details. One of the 30 or so maligned products of visceral fat cells (belly fat as it is sometimes called), TNF-alpha, is a known cytokine (immune cell messenger) that activates NF-kB. This odd sounding chemical messenger is at the core of chronic inflammation.

The definition of cellular inflammation is increased activity of the gene transcription factor known as Nuclear Factor-kappaB (NF-kB). This is the gene transcription factor found in every cell, and it activates the inflammatory response of the innate immune system.[ref]Barry Sears PhD. What is Cellular Inflammation? (http://www.zonediagnostics.com/cellular-inflammation/) 08/06/2013[/ref]

CANCER

This immune response can be triggered by anything that stimulates the activity of NF-kB. It also paves the way for the third biggest killer in the western world – cancer.

The role of inflammation in evolution of certain types of cancer has been strongly suggested, linking the inflammatory response to 15–20% of all deaths from cancer worldwide….If genetic damage is the “match that lights the fire” of cancer, some types of inflammation may provide the “fuel that feeds the flames.”[ref]Lancet. 2001 Feb 17;357(9255):539-45.[/ref]

Cellular inflammation is the initiating cause of chronic disease because it disrupts hormonal signaling networks throughout the body.[ref]Barry Sears PhD. What is Cellular Inflammation? (http://www.zonediagnostics.com/cellular-inflammation/) 08/06/2013 p. 1[/ref]

TARGETING CELLULAR INFLAMMATION WITH CANNABIS

Unfortunately, for many with chronic, degenerative diseases in advanced stages we need bigger guns which we do not have. Patients with high levels of silent or overt inflammation (pain) are often left in the lurch. These are the patients I would see who have been through a dozen doctors, taking 20 or more medications, and are no better off.

Wouldn’t it be amazing if we had drugs that operated on the cellular level to help these patients? A drug or supplement that might suppress NF-kB?

Well, we already have some, but most are not commercially available yet. Can you say cannabinoids?

While there is a paucity of good anti-inflammatory prescription medications that a doctor can treat you with, current research demonstrates that several classes of cannabinoids can influence many of the inflammatory mechanisms mentioned above.

Let’s look at the classic model of inflammation once again: atherosclerosis.

CB1 BLOCKADE & CB2 STIMULATION DECREASE PLAQUE

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[ref]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[/ref]. CB1 & CB2 receptors have been identified on many immune cells and endothelial cells. Let’s see what the data shows:

Both CB1 and CB2 are G-protein coupled receptors that modulate second messengers and signalling components such as adenylate cyclase,…and members of the nuclear factor κ B (NF-κB) family. [ref]IBID[/ref]

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 pro-inflammatory cytokine gene expression and attenuated oxidized low-density lipoprotein (ox-LDL)-induced NF-κB activation[ref]IBID[/ref].

In other words a synthetic CB2 stimulant (agonist) decreased plaque formation through a reduction in NF-kB.

What these studies suggest is that we may have a new, powerful, and potentially game-changing syllabus of cannabinoids that may actually “cure” heart disease, and by inference dozens of other chronic inflammatory diseases.

In part three more compelling evidence of the use of cannabis in suppressing inflammation will be provided.

You can read Part 1 of Dr. Christopher Rasmussen’s articles on Cannabis and Inflammation here.