Throughout its long history, coffee has endured both accolades and opposition.

Over the ages, some of the world’s greatest composers, thinkers and statesmen have extolled coffee’s virtues, while others have denounced it as a poisonous, mind-corrupting drug. Coffee has been praised by certain religions and prohibited by others.

Some governments have subsidized coffee crops; others have imposed steep taxes and duties on them. Doctors vali­date coffee’s health benefits yet worry about its contribution to cardiovascu­lar disease, diabetes, and even cancer.

Coffee is more popular than ever, which contributes to its contradictory status. In moderation, coffee poses minimal health risks for most people. In some cases, coffee even appears to be protective.

But many North Ameri­cans now consume coffee in large quantities, which can significantly damage our neuroendocrineimmune system over the long term.

Neuro-what?

The neuroendocrineimmune system consists of the processes and structures that form our central nervous systems, our hormonal systems, and our immune systems, all of which are linked in complex relationships.

For example, many of us know that when we are stressed, we get sick more easily. Emotional and mental demands, especially if prolonged, cause our stress hormones to increase, which means our immune systems don’t work as well.

The complicated interplay of our neuroendocrineimmune systems suggests that there is no clear division between mind and body. What we think and experience is as much “us” as what our body does.

How do we know what we know?

It’s hard to get a clear picture of coffee’s health effects. Epidemiological studies, which try to find relationships between multiple lifestyle factors, can be hard to interpret.

For one thing, coffee drinking is correlated with other dietary and lifestyle behaviours such as alcohol and nicotine consumption and a sedentary lifestyle. In other words, people who drink a lot of coffee also tend to drink and smoke, and be out of shape.

On the other hand, people who avoid coffee often do so for health-related reasons. They’re also more likely to be health-conscious in other ways, making health-promoting lifestyle choices such as exercise. Comparing coffee drinkers with non-coffee drinkers thus misses a number of important variables.

Second, there are vast differences in coffee’s pharmacological constituents depending on the type of bean used in the study, the methods of roasting, and the varying ways of preparing coffee, not to mention the differences between commercially available instant coffee versus freshly roasted organic coffee.

There are also differences in individual sensitivity to caffeine, likely due to the genetic traits related to caffeine metabolism (see “Coded for Caffeine”, in the Spezzatino Coffee issue), as well as lifestyle influences. For example, the half-life of caffeine is shorter in smokers than non-smokers, while the half-life of caffeine is doubled in women taking oral contraceptives.

Finally, most research studies observe and measure the effects of a single dose of caffeine rather than the effects of chronic ingestion. Yet most coffee drinkers drink coffee daily.

As a number of studies have shown, single-dose experiments don’t necessarily reflect the effects of our regular routines. For example, researchers have shown that we can build tolerance to the cardiovascular effects of caffeine within two to three days. Therefore, research studies that show a given effect on the body from an acute single dose bear little relevance to the chronic ingestion of caffeine.

In my naturopathic practice, I use evidence from epidemiological and experimental studies. But I also draw on experience and a systematic understanding of how our nervous, endocrine, and immune systems interact in order to make educated guesses about coffee’s potential effects on my patients.

Caffeine and your brain

Caffeine is one of coffee’s primary constituents with psychoactive activities. It’s part of a group of substances collectively referred to as methylxanthines. These alkaloids are well known for their ability to increase cognitive abilities, improve energy, enhance well-being, and increase arousal and alertness.

As mentioned elsewhere in the Spezzatino Coffee issue (see “Lab to Lunch”), these effects occur largely because of caffeine’s ability to block adenosine receptor sites throughout the body. However, there are other neurochemical effects that are worth noting.

Once again, studies demonstrating the effects of caffeine on neurotransmitters (chemicals that allow the cells of our nervous system to communicate) don’t always give us a realistic picture.

First, the dose used in neurochemical studies generally exceeds quantities ingested during normal everyday life.

When animals are used, they are non-coffee drinkers. (It’s hard to make mugs that small, and without opposable thumbs… well, let’s just say there’ve been some unfortunate spills of hot liquid. Luckily, no legal cases against McDonalds are pending.) Therefore, researchers use a single dose of caffeine, which may not reflect the neurochemical effects of chronic consumption of caffeine.

Second, neurotransmitters are produced in different amounts in different areas of the brain simultaneously, and have very different effects on mood and personality depending on where in the brain they’re used.

Quick overview: serotonin is involved in mood and appetite regulation; gamma-aminobutyric acid (GABA) typically inhibits neuronal activity to cause relaxation and sleep; and acetylcholine is involved in muscle contraction.

Chronic caffeine intake has been shown to increase the receptors of serotonin (26-30% increase), GABA (65% increase), and acetylcholine (40-50%). This may contribute to the elevated mood and perceived increase in energy we feel after a coffee (which makes espresso a handy pre-workout drink). Despite increasing receptors, caffeine also inhibits the release of GABA, which contributes to our feeling of alertness.

Chronic caffeine intake also increases the sensitivity of serotonin receptors. In other words, receptors specific to serotonin are more responsive to serotonin present in the synaptic cleft — it’s sort of like installing a bigger satellite dish to catch more of an existing signal. One study showed a decrease in serotonin release, but an increase in serotonin reuptake, leading to an overall increase in serotonin levels. (Think of it as the brain’s natural recycling.)

In the human body, when neurotransmitter receptors increase in number, or if they increase their sensitivity, it generally suggests a reduction in functional capacity and activity of neurons associated with those receptors.

Either the brain needs more chemicals to do the job, or the neurons involved aren’t working as hard. This might mean that a certain neurotransmitter is in short supply, or that its activity needs to increase. In the case of caffeine and serotonin, this can partly explain the mood-enhancing effects of drinking coffee.

Caffeine has also been shown to increase serotonin levels in the limbic system, a relatively primitive part of our brain involved in regulating basic functions such as hormonal secretions, emotional responses, mood regulation and pain/pleasure sensations. This has a similar mode of action as some antidepressant medications.

The increase in serotonin levels, combined with the increase in serotonin receptors, cause the characteristic withdrawal symptoms (such as agitation and irritability) when coffee intake is stopped. The brain has come to expect more action in its serotonin receptors, and when its abundant supply of happy chemicals is abruptly cut off, it gets crabby.

Indirectly, chronic caffeine intake may impact neurochemistry by reducing cofactors – chemical partners – necessary for neurotransmitter synthesis.

For example, coffee inhibits the absorption of iron, a key mineral involved with the synthesis of serotonin and dopamine. Additionally, we need the activated form of vitamin B6, pyridoxal-5-phosphate, to synthesize serotonin, dopamine and GABA. Coffee consumption can decrease amounts of circulating B-vitamins, which could affect neurotransmitter synthesis in another way.

Thus, caffeine impacts whether certain chemicals are available; how receptive our brains are to them; and whether we’re even making those chemicals in the first place.

Caffeine and your hormones

Both scientists and lay people know the effects of caffeine consumption on hormones relatively well.

For example, quickly perusing the internet brings up numerous sites claiming that caffeine “wears out the adrenal glands”. But not surprisingly, this may not be entirely accurate. While we know many things about the impact caffeine has on human’s stress physiology, certain mechanisms of how it occurs are still relatively mysterious.

Caffeine strongly affects the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the linked system of hypothalamus and pituitary glands in the brain, and the adrenal glands that sit atop the kidneys. The HPA axis influences the body’s ability to manage and deal with stress, both at rest and during activity.

The adrenal glands secrete two key hormones: epinephrine and cortisol. Epinephrine, or adrenaline, increases respiration rate, heart rate and blood pressure; while cortisol frees up stored glucose, which we need in greater amounts during times of perceived stress.

As you can imagine, for our early hominid ancestors, the ability to quickly access and use stored energy was a helpful feature. However, while this is an excellent acute response to an immediate stress (such as being chased by a bear), it’s a damaging response when the stress is chronic (such as the cumulative demands of our daily modern lives).

Studies in humans have shown that caffeine increases cortisol and epinephrine at rest, and that levels of cortisol after caffeine consumption are similar to those experienced during an acute stress. Drinking coffee, in other words, re-creates stress conditions for the body.

While scientists have some ideas about how caffeine increases HPA hormones, the exact mechanism still remains unclear.

Compounding the problem, people tend to consume more caffeine during stressful periods (as nearly every student during exam season knows well). They add stress to stress, potentially making things even worse.

Rat studies have shown that caffeine consumption during chronic stress increased cortisol, blood pressure, and other negative hormonal events. Chronically stressed rats who consumed caffeine ended up sicker, and died sooner, than rats experiencing chronic stress without caffeine consumption.

However, again, chronic caffeine consumption leads to a degree of physiological tolerance and thus among people who drink coffee regularly, blood pressure, heart rate, excessive urination, epinephrine production, and even anxiety and stimulation may not be as strongly affected.

Other hormonal effects of caffeine appear to be related to competitive actions for metabolism in the liver. Like a gridlocked city, the liver only has so many “roads”, or metabolic pathways, available. More “cars” (i.e. chemicals) on the “roads” slow things down.

For instance, the liver detoxifies caffeine using the CYP1A2 enzyme system, which is also responsible for initial metabolism of estrogen during Phase I clearance by the liver. This is one reason caffeine is likely metabolized more slowly in women taking oral contraceptives or postmenopausal hormone replacement therapy.

While research showing the effects of chronic caffeine consumption on circulating levels of estrogen isn’t yet available, researchers have suggested that caffeine consumption may lower the risk of breast cancer by upregulating the CYP1A2 isoenzyme and thus improving estrogen metabolism.

Caffeine and your immune system

The immune system is a vast and complex system that communicates extensively with itself and connects to every other system of the body.

For simplicity’s sake, we’ll separate the immune system into two sections: the Th1 side (T-cell mediated system) and the Th2 side (B-cell mediated antibody system). The Th1 side is our innate immune system – the system that develops early in life – and is our first line of defense against pathogens such as viruses and bacteria.

On the other hand, the Th2 system is acquired: as we are exposed to pathogens throughout our lives, we produce antibodies to them. Antibodies recognize foreign invaders if exposed to them repeatedly, and will launch a stronger and swifter attack if a second invasion takes place. Because of this system, someone will experience a reaction to poison ivy only after their second exposure.

The two sides of this system act as a seesaw: when one side is dominant, the other side is suppressed.

Research suggests that chronic caffeine exposure shifts the immune system to a Th2 dominance. This may help the treatment of Th1 dominant autoimmune conditions, but in the average person, it may elevate the Th2 system excessively, creating an overzealous Th2 immune response. A dominant Th2 system predisposes individuals to hypersensitivity reactions such as asthma and allergies.

To date, there have not been any correlations between chronic caffeine consumption and increased prevalence of Th2 associated conditions, but based on existing knowledge of caffeine and the immune system, the link seems plausible.

In my clinical naturopathic practice, we have seen certain autoimmune conditions improve with caffeine consumption, while others get worse.

If someone with rheumatoid arthritis (an autoimmune condition that causes joint pain and inflammation) says they get significantly more joint pain when they drink coffee, one could hypothesize that their Th2 system is dominant, and the caffeine is promoting destruction of their joints by further stimulating this already overzealous Th2 system.

Putting it all together

No known studies demonstrate statistically significant correlations between coffee over-consumption and the unwinding of the neuroendocrineimmune system. We just don’t know for sure yet how all the puzzle pieces fit together.

However, certain theoretical pathways can be created, and have been observed clinically. We can also make some informed speculation based on what we already know of the neuroendocrineimmune system’s interrelationships.

Effects on metabolism

Chronic coffee consumption increases insulin resistance, a situation in which the body cannot effectively deliver glucose into the cells of the body. In this situation, insulin, which helps transport glucose into the cells, cannot do its job well because the body’s cells are less receptive.

This typically occurs with a diet high in refined sugars and starches. Thus, the body must release ever-larger amounts of insulin to do the job. Like parents tuning out their screaming toddler, the body becomes less and less sensitive to insulin’s effects, which means more circulating glucose, which means more insulin release… and so on.

It’s a vicious cycle. And, unfortunately, it’s a cycle that currently occurs in the majority of North Americans. Combine the standard Western diet high in refined carbohydrates with stress and a high caffeine intake, and you have a potential recipe for metabolic disaster.

Insulin stimulates the release of interleukin-6 (IL-6), which is a Th2 cytokine (a cell signaling molecule).

If IL-6 is chronically elevated (in this case, from high insulin levels), it may lead to a Th2 dominance and potential hypersensitivity from an overzealous antibody response. This can result in acquired sensitivities to foods and chemicals.

Interleukin-6 also stimulates the release of cortisol, which, as a glucocorticoid hormone, increases the body’s glucose level. This leads to an increased demand for insulin, which is problematic because of the insulin resistance that started the cascade in the first place.

Let’s recap: a diet high in refined sugars and starches leads to more circulating glucose.

More glucose means more insulin needed to dispose of it.

More insulin means cells tune out, which means even more insulin dumped into the bloodstream (especially if people continue to eat this high-carbohydrate diet).

More insulin means insulin resistance — possibly aggravated by high caffeine consumption.

More insulin means more IL-6 and more inflammation and hypersensitivity.

More IL-6 means more cortisol, which means more glucose… and here we are, back at the beginning of a very nasty cycle.

Consider this as you cradle your extra-large coffee and glazed donut this morning during your white-knuckle commute to work.

Effects on brain function and mood

The elevated blood sugar and insulin don’t just stop at inflammation. They can create imbalances in the neurotransmitters serotonin, dopamine and GABA, which can lead to sub-clinical mood problems such as mild depression (aka “the blues”), low motivation, irritability, and impaired cognition.

People with chronically high glucose, insulin resistance, systemic inflammation, and stress typically have “fuzzy brain”, memory loss, lethargy, and/or a short fuse.

Coupled with the potential iron and B-vitamin deficiencies created by coffee, which, again, cause impaired synthesis of key neurotransmitters, this may result in mood states where people feel the need for coffee to keep themselves functioning properly.

Have you ever felt that you desperately needed coffee for a pick-me-up? Do you tell people, “I’m a grouch until I get my coffee?” If so, you may be experiencing this situation.

Caffeine in moderation is likely not an issue for most people. Indeed, it may actually have health benefits. (See the article on traditional Chinese medicine and coffee, in the Spezzatino Coffee issue) Problems occur when we drink coffee all day long and combine it with sedentary lifestyles, poor diets, and chronically elevated stress.

We drink much more caffeine than our great-grandparents did. Not only has our coffee consumption increased, but the market is saturated (pardon the pun) with other sources of caffeine. There is much more refined sugar available to us, and our lives move at a much faster pace.

The industry standard size for a cup of coffee is six ounces. If you’re North American and under 40, I bet you don’t even own a six-ounce glass of anything – never mind finding a cup that size at the local coffee shop!

It’s the perfect storm: caffeine, stress, sugar, and sedentary living. This combination and its complex relationships with your neuroendocrineimmune system may be affecting you more than you realize.

Systems in our body are closely interconnected. Stimulation of one area can have far-reaching effects, especially if the stimulation is dramatic and/or prolonged.

Large amounts of caffeine likely have numerous negative impacts on the body that research has not yet elucidated, but if we piece the available studies together, such impacts appear to be very real possibilities.

Follow the evidence that your body offers you. Pay attention to how you feel when you drink coffee.

Do you feel good for a short period, then shaky and irritable? Do you notice more pain or other kinds of physical distress?

If you’re experiencing any of the symptoms I’ve mentioned above, ranging from anxiety to inflammation, consider bringing a little decaf into your life.

Eat, move, and live…better.©

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