The Endocannabinoid System: From Coffee to Cardiovascular Health

Recently, I came across an article from Live Science titled “Why Coffee Could Be the Opposite of Cannabis”. I was immediately intrigued as to how these apparently dichotomous and unrelated recreational drugs (I’ll confess to being a heavy user of caffeine) could possibly be linked. I was even more baited by similar articles referring to the same study, claiming that coffee is “reverse weed”.

The things we do for clicks.

The article summarized a study published in 2018 which I’ll get into below. The study had nothing to do with marijuana, just coffee, but it did reference a particular set of compounds found in the marijuana plant — known as cannabinoids — and how these compounds might be influenced by your daily cup (or 8) of joe. Furthermore, this study provided a comprehensive look into the mechanisms by which coffee might be influencing health.

The study: Coffee metabolomics

The debate over whether coffee is good for or detrimental to human health is long-standing. I’ve written about the topic of genes, coffee, and fitness and about the observation that coffee is good for your health. A simple search for “coffee and health” on Google will probably give you pages of headlines hyping the latest study about how “people who drink more coffee live longer”.

People are very interested in this topic for a good reason — since caffeine is the drug of choice for many Americans and others around the world. As much as anyone, I want to know whether my coffee habit is doing anything to hurt or harm me.

However, what we lack is actual mechanistic data telling us how coffee might influence health. Most of the current literature is observational — meaning that it usually uses self-reported coffee consumption and associates it with “X” health condition. Hypothesis informing? Yes. Rigorous? Hardly.

Published in the Journal of Internal Medicine last March and titled “Metabolomic response to coffee consumption: application to a three-stage clinical trial”, the study sought to identify changes in individual metabolites in response to coffee abstinence (sounds awful) and consumption. While caffeine is the primary metabolite in coffee (and the one most studied), hundreds of other compounds in coffee might impact health and disease-related pathways in our bodies. These researchers wanted to find out which ones.

The design was simple. Participants (47) went through three different “phases”, each one month long. First, they refrained from drinking coffee for 1 month, after which they went another month consuming 4 cups/day followed by another month where they consumed 8 cups/day. The coffee was given to them by researchers and standardized — +1 for quality study control!

Methodological details non-withstanding, after each phase, serum (blood) samples were collected from each participant, and then put through metabolomic profiling. What this does is determine the relative levels of individual metabolites in the serum (see example output below) in response to each condition.

So, what happened? A lot. Coffee intake was associated with changes in115 individual metabolites, mapping to 33 different pathways in the body.

Sample clustering that includes all 115 metabolites identified in the study. The green represent low levels, and red represents high levels.

Not surprisingly, there was a strong association between coffee consumption and metabolites of the main constituents of coffee — caffeine, theyphylline, and theobromine. Xanthine metabolites are produced when these compounds are digested and broken down in the body.

Interestingly, there were several findings that the intake of coffee was associated with increases in compounds like chlorogenic acid (CGS) and polyphenols which might impact the gut microbiome. Perhaps this explains some of the recent data that coffee consumption is related to changes in gut microbiota and health. Additional key changes included metabolites associated with the steroid pathway in the body.

Perhaps more interesting, was the finding that 5 metabolites of the endocannabinoid (eCB) pathway were shown to significantly decrease with coffee consumption in a dose-response manner (they decreased more with 8 cups/day vs. 4). These compounds, known as N-acylethanolamines (NAEs), are related to and have similar actions to the “true” endocannabinoids which act on the cannabinoid (CB) receptors. Here, we have our coffee-pot “connection.”

Why would these metabolites decrease with coffee consumption? This is a hypothesis we will deal with later, after a brief discussion of what the endocannabinoid system actually does.

Unfortunately, the study doesn’t have an enormous take away like “coffee is good” or “coffee is bad”. We might need to wait for more experimental studies like this before conclusions can be drawn as to the up- and down-sides of coffee drinking. What it does tell us is that dose-response relationships with coffee consumption can be seen for several biological markers and tells us that this level of investigation is necessary to move to the next step in research. Rather than observations, we need to move on to direct experimental studies that test the impact of coffee on human health.

For now, let’s return to the cannabinoid story, briefly, and discuss what this system is, and how it might influence cardiovascular health.

The ECS

The endocannabinoid system (“endo” meaning within, since we produce our own CBs), helps maintain homeostasis within our body. This means that when things get thrown out of whack, or we are presented with some sort of external/internal stress, the ECS helps bring us back to center

We have receptors for this system in numerous areas throughout our body — including the brain, the nervous system, the immune system, and the cardiovascular system. There are two major endocannabinoids (as opposed to cannabinoids which are found in plants, i.e. THC), anandamide and 2-AG, which can bind to 2 different receptors — CB1 and CB2.

The ECS. Source: Leafly: https://www.leafly.com/news/science-tech/what-is-the-endocannabinoid-system

Binding of (endo)cannabinoids to each receptor exerts a variety of physiological effects. Many of these are involved in the regulation of cardiovascular function.

Your heart and eCBs

While research is lacking in this area (for obvious reasons), there are data to suggest that cannabinoids may have a role in cardiovascular health. For one, several studies in mice show that activation of the ECS is able to induce vasodilation (relaxation) and cause a blood-pressure lowering effect. Giving mice pot to smoke sounds like a fun job for any research assistant.

Unfortunately, this isn’t usually what happens. Many of these studies used injection of CB1/CB2 activators (a.k.a agonists) or anandamide directly to investigate the effects of the ECS on blood pressure and the vascular system, rather than THC.

Instead of providing health benefits in “normal” situations, the protective effects of endocannabinoids for might be more potent during a “challenge” to the cardiovascular system such as cardiac injury (e.g. heart attack). Remember, the ECS is a homeostatic-regulator; it wants to make things normal and for this reason, plays a protective role. It has been shown that CB2 activation reduces the damage after heart ischemia, and ECS activation improves cardiac function and structure after chemo-therapy treatment; perhaps by reducing oxidative damage and stress, reducing cell proliferation, and lowering infammation.

Interestingly, in chronic disease states, the ECS might be over-activated. While it might seem odd that a protective system could switch roles to cause pathophysiology, it makes sense. Chronic over-activation of a stress response system might render it useless; too much cell signaling may lead to disruption rather than balance. Under normal conditions, CB receptor activation is a good thing. But, ECS overactivation leads to dysregulation, and dysregulation leads to disease, or vice-versa.

This concept is illustrated below — the divergent effects of different receptors in different conditions.

That’s right, CB1 and CB2 may have divergent roles, depending on whether the system is over-activated or not. For instance, CB1 receptor activation and expression have been shown to be increased in patients with signs of coronary atherosclerosis, in vulnerable artery plaques, and in oxidative-stress related diabetes and arterial dysfunction. In this case, chronic overactivation. But, anandamide (which modulates CB1) can reduce heart contractility while lowering vascular resistance and blood pressure. What happens when CB1 receptors are blocked in these diseases? Conditions improve.

CB2 is a different story. Activation of CB2 might actually help reduce dysfunction and inflammation associated with many vascular diseases. Increased CB2 expression has shown to inhibit the progression of atherosclerosis in animals and mice; it also protected against lymph cell proliferation and immune hyper-responsiveness. This might perhaps be one strategy whereby disease progression can be reduced in certain individuals by use of (e)CBs or related compounds.

Anandamide molecule

Whether we will be able use THC or cannabinoids/cannabinoid-like compounds to manipulate the ECS to our favor, who knows. There is definitely an interest in these pathways and compounds for the treatment of many diseases, but studies aren’t currently being conducted, especially not on THC (other than in mice). Certain drugs that target the ECS might be used to effectively treat high blood pressure, vascular dysfunction, or improve heart conditions. For now, it’s mostly assumptions and theory.

Coffee: A link to Cannabinoids?

Back to the study presented at the beginning of this post. Given the findings that coffee consumption led to a decrease in some of the same cannabinoid compounds that are impacted by smoking marijuana, it begs the question — why, and what does this mean, if anything?

The lead researcher from the study is quoted as saying that the decrease in cannabinoids due to coffee consumption might be the body’s response to increased stress, a way to try and normalize stress levels of certain molecules (perhaps endocannabinoids) that were overactive in the high-dose caffeine group. Perhaps, she quotes, “the increased coffee consumption over the two-month span of the trial may have created enough stress to trigger a decrease in metabolites in this system.”

In short, the body may have adapted to reduced cannabinoid levels to arrive back a homeostasis.

Maybe this makes sense? We saw before that over-activation of the ECS is observed in certain cardiovascular diseases (i.e. chronic stress). So, maybe a month-long coffee abstinence followed by a two-month binge resembles a cannabinoid overactivation, one to which the body responded by decreasing overall levels of these metabolites. In this way, it may have also been protecting against a chronic over-activation of the stress and eCB response. This is (my) mere hypothesis, which could be completely off.

Like all of us, I’m just trying to make sense of things. For now, we can agree to not refer to coffee as “reverse weed.”

References

Cornelis MC, Erlund I, Michelotti GA, Herder C, Westerhuis JA, Tuomilehto J. Metabolomic response to coffee consumption: application to a three-stage clinical trial. J Intern Med. 2018;283(6):544–557.

Alfulaij N, Meiners F, Michalek J, Small-howard AL, Turner HC, Stokes AJ. Cannabinoids, the Heart of the Matter. J Am Heart Assoc. 2018;7(14)

Montecucco F, Di marzo V. At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction. Trends Pharmacol Sci. 2012;33(6):331–40.

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PhD candidate at the University of Florida — Science writing with a particular focus on exercise and nutrition interventions, aging, health, and disease.

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Brady Holmer

Brady Holmer

PhD candidate at the University of Florida — Science writing with a particular focus on exercise and nutrition interventions, aging, health, and disease.

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