My foray in to circadian biology over the last few years has given me a fresh perspective on a number of things.  There are a few things I’ve told people with gut and adrenal problems to avoid because they can make those issues worse.  Most of the time, this has to do with how things affect digestion.

However, circadian biology has given me a much more big picture approach.  Time adds a whole new layer of complexity that allow for a much more nuanced approach to addressing gut and adrenal issues.  Not only can this be used to prevent needlessly avoiding things that you like or that are healthy, it can also identify common foods and beverages that goose you back in to a healthier state by tweaking your circadian rhythms.

Well, it turns out that looking at one of the most commonly loved and consumed beverages in the World through these circadian-colored glasses indicates that it doesn’t necessarily need to be avoided by people with gut and adrenal problems.  In fact, it could be used therapeutically to improve adrenal function and eliminate brain fog.

But before we dig in to the goodies, we have to dig in to sleep.  If you’ve ever experienced poor sleep, you know how it can cause major problems with anxiety, depression, your ability to deal with stress, and your ability to focus.  So it should come as no surprise that the factors that help regulate your sleep cycle also exert powerful control over your adrenal and brain function.

Dual regulation of sleep

Before we dig in to the beverage du jour, it’s important to understand the 2-way street that regulates our sleep-wake cycle.  Most people who’ve read this blog are familiar with the circadian regulation of sleep where circadian changes in cortisol and melatonin levels help regulate sleep by promoting wakefulness.

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As you can see, the basics of this are pretty simple.  In the morning, cortisol levels should be high and melatonin levels low to promote arousal and thus, wakefulness.  As day turns in to night, cortisol levels begin to drop and melatonin levels rise, decreasing wakefulness.  Both of these effects are regulated to a large extent by light exposure from the day/night cycle.

However, the circadian regulation of sleep isn’t the only game in town.  There’s also the homeostatic regulation of sleep which involves the neurotransmitter adenosine.  Again, this is pretty straightforward.  As we stay awake, levels of adenosine in the brain increase and begin stimulating adenosine receptors in the brain.  This causes us to feel tired and helps induce sleep.

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In this image, the circadian regulation of the sleep cycle is called the wake drive and the homeostatic regulation the sleep drive.  In the morning, high cortisol and low melatonin promote wakefulness.  Assuming you just woke up would mean that adenosine levels are very low and thus your drive to be awake is high and your drive to sleep low.  As we approach nighttime, your drive to be awake is low and your drive to sleep high as adenosine accumulates.

This is important because sleep is important.  The longer you stay awake, the more you’re driven to sleep.  If you failed to go to sleep the night before, your circadian drive may be attempting to promote wakefulness based on light exposure from the Sun, but the homeostatic drive will be pushing you to sleep and chances are that’s exactly what you’ll do.

Obviously we get our best sleep when we put the brakes on wakefulness and the accelerator on sleep.  That’s not to say you can’t fall asleep if your circadian and homeostatic drives aren’t aligned properly.  But it does draw in to question whether your sleep will be ideal.

Fortunately they tend to work together on all fronts to make sure that your sleep is regulated properly.   Well, not just your sleep, your brain and adrenals as well.

Adenosine, melatonin, & cortisol: Perfect circadian bedfellows

As we spend the daylight hours awake, adenosine builds up and stimulates adenosine receptors in the brain to help induce sleep.  One particularly interesting location where this happens is in the pineal gland, best known for melatonin synthesis.  In fact, stimulating adenosine receptors increases melatonin synthesis by the pineal gland by 3-4 fold.

But the crossover fun doesn’t end there, melatonin also appears to help regulate the effects of adenosine.  In order for the circadian clock protein Per1 to cycle properly in the pituitary gland, cells in the pituitary gland need to be sensitized to adenosine, which occurs during stimulation of melatonin receptors by melatonin.

If that seems confusing to you, let me break it down in the simplest of terms.  The pituitary gland functions as the master regulator of hormonal output of things such as thyroid hormone, cortisol, growth hormone, and sex hormones.  During the nighttime, melatonin functions as a brake on the circadian oscillator, but makes it sensitive to adenosine.  As night turns in to day, the melatonin brake is lifted and adenosine functions as an accelerator, allowing the Per1 gene to cycle.

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You can see why this is important with regard to adrenal function because the pituitary regulates cortisol output by producing adrenocorticotropic hormone(ACTH) which travels to the adrenal glands and causes the release of cortisol.  Stimulation of adenosine receptors in the pituitary causes the pituitary to increase ACTH output, and thus, cortisol levels.

Unfortunately, things get a little murky here for some people.  You see, early life stressors can have a transformative effect on the way people deal with stress.  The down and dirty physiology behind why this happens involves an increase in adenosine receptors in the brain.

With this increase in adenosine receptors comes an increase in cortisol and a decrease in brain glucocorticoid receptors.  The glucocorticoid receptor binds cortisol and allows it to perform its many functions including setting your circadian rhythm, responding to stress properly, and memory.  It also causes a decrease in cortisol output by the adrenals via negative feedback.  It doesn’t matter whether cortisol levels are high or low if tissues don’t respond to it, and this appears to be what we’re dealing with here.

As you can see by this simple yet complex inter-relationship, the circadian clock has a lot of interlocking arms.  Hormones such as melatonin and cortisol, as well as neurotransmitters such as adenosine play a powerful role in proper circadian signaling between multiple organs and tissues.

If we look at these interlocking features we can see why fatigue, depression, stress, and memory problems tend to couple together.  Adenosine directly affects fatigue and depression/motivation by promoting fatigue and indirectly affects stress and memory by regulating cortisol release and glucocorticoid receptor expression.

Putting it all together

It may come as no surprise to readers of this blog, but the above situation ends up causing a loss of the circadian cortisol rhythm.  But most people look at something like elevated cortisol or a disturbed rhythm and assume this means they’re making too much cortisol or making it at the wrong time.

This reductionist thinking very rarely works because high cortisol can also mean you have low receptor expression, and a disturbed rhythm can mean the same thing.  Since cortisol can’t bind to receptors because they aren’t being expressed, you get none of the beneficial effects of cortisol and higher levels of it in the blood.  This means that the adrenals aren’t the problem receptor expression is, and blocking cortisol production is probably a mistake.

While this throws off everything involving sleep, it also throws off adrenal and brain function.  You can throw in fatigue and depression as well, which makes sense given the role adenosine plays in promoting sleep.  Fortunately, we can play around with adenosine signaling and cover both bases.

Blocking the adenosine receptor with an adenosine antagonist prevents adenosine from producing its effects.  Adenosine receptor antagonists not only prevent fatigue, but they also re-establish the circadian rhythm of glucocorticoid signaling by restoring proper glucocorticoid release and glucocorticoid receptor expression in the brain.  This has been shown to work in mice who have high adenosine activity due to early life stress as well as mice with age-related increases in adenosine levels associated with Alzheimer’s disease.

The best part of this situation is that we have a super common and heavily studied adenosine antagonist with a long track record of safety and multiple other health benefits: coffee.  The caffeine in coffee is a pretty good adenosine receptor antagonist that can help re-establish proper glucocorticoid signaling.

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Using your morning cup as a zeitgeber

It’s important to point out that your morning cup of coffee is more than just a jolt to your system, it’s actually useful as a zeitgeber to help entrain your circadian clocks.  Keeping this in mind, properly timing your morning cup(s) of Joe is something you can use to help establish proper circadian rhythms.  If you were exposed to early life stress or are getting up there in the years, it may be an indispensable tool to establish a healthy rhythm.

The biggest obstacle for most people is how it affects their digestion.  My former position was that one should avoid coffee if it causes loose stools.  However, after researching the topic I realized that the problem with loose stools was probably not simply due to the ability of coffee to speed up motility.  It likely has more to do with premature bile release affecting the gut clock.

With caffeine affecting multiple layers of the clock including adenosine signaling, cortisol signaling, and gut motility, it’s obvious that its role as a zeitgeber is probably a bigger deal than just the effects on motility.   Rather than simply being dose or sensitivity related, the problem is when it falls out of sequence with other zeitgebers because it confuses the clock.

The problem is exacerbated when other zeitgebers are also out of sequence with one another, which disrupts signaling throughout the gut.  This not only causes loose stools, it also affects digestion and absorption as well.

Conclusion

It’s my personal opinion that most people chasing symptoms of adrenal dysfunction, fatigue, depression & brain fog are dealing with some form of circadian disruption, particularly if they have sleep problems as well.  For some people, the solution is as simple as addressing things such as light exposure, physical activity, and the feeding/fasting cycle.

For other people, early life stressors or simply the aging process in general cause physiological disturbances that promote adrenal dysfunction, fatigue, and brain fog.  In other words, factors outside of their control makes re-establishing a healthy rhythm difficult.  These people absolutely need to address the above exposures, but need further assistance to address things that are beyond their control, specifically increased adenosine receptor expression in the brain.

For these people, coffee or caffeine consumption can be a useful tool to re-establish their ability to set proper circadian rhythms.  By looking at coffee consumption as a zeitgeber, most people can reap these benefits of coffee without the negative consequence of loose stools.  I’ve been finding out more and more as I delve in to circadian research that when is becoming a very important variable for almost everything we do.