Mean Muggin' Part I

Exploring the mud in your mug.

Feb 06, 2022

What do you see when you picture a drug addict? Does your mind jump straight to what society might call hard-core drugs, like heroin or crystal meth, or do you see the more mainstream and less feared addictions, like cigarettes and alcohol? Statistically speaking, drug use is most ordinarily exhibited by everyday Joe’s and Jane’s wielding mugs and to-go cups at breakfast tables and on morning commutes.

With some research showing that 85% of Americans consume at least one caffeinated beverage per day, it is safe to say that drug use via caffeine consumption is the status quo in modern society; yet, the ways in which we implement this status quo in daily life vary widely from the meathead’s pre-workout essential to the high schooler’s caramel-swirl, sugar-tooth satisfaction.1 Of course, the holy grail of caffeine rituals is the morning Cup O’ Joe that warms morning bus stop shifts and wards off sleep deprivation long enough to endure calculus lectures. So, what’s going on that keeps modern society so hooked on coffee and caffeine as a whole?

Medical Disclaimer: I am not a medical professional, and nothing in the post serves as medical advice in any way, shape, or form; rather, this post serves as a summary of the data and information I found in my own research. You should consult a medical professional and conduct your own research before making any decisions regarding any of the information in this post.

Side note: If you couldn’t care less about my silly analogies or biochemistry break downs and are mostly interested in the, “So what?” of this post, feel free to skip past my antics and go straight to the summarizing key points sections.

Adenosine 101

Similar to my previous deep dive on hangover science, understanding how coffee affects your body begins with understanding its biological mechanisms, of which its impact on adenosine receptors is most prominent with regards to the decreased fatigue, increased alertness, disrupted sleep, and enhanced mood that we commonly associate with coffee consumption. You can envision the concepts of adenosine activity through the scope of a pizza shop where trash accumulation — instead of clocks or watches — serves as a marker for the passing of time during the workday. When you, the business owner, arrive to work, the pizza shop is void of trash; however, as the day goes on, customers flood in and out, devouring your delicious and cheesy pepperoni, sausage, and vegetable productions — none of which contain ham and pineapple because you are a logical and sane business owner. As the day progresses, the shop’s activity leads to a gradual build-up of trash, and you use this trash accumulation to gauge the time of day, in that the more the trash piles up the closer you know you are to closing up and heading home. You are able to leverage this system to track the time every day because overnight trash crews come and clear all of the trash out of your shop, leaving you with a fresh, “trash clock,” at the start of the next day.

In the case of your sleep-wake cycle, adenosine molecules are analogous to trash, in that they are by-products of cellular activity that build up in your brain throughout the day and signal to surrounding cells when it is time to refresh the system. In terms of human physiology, this refreshing rest comes in the form of sleep, where our brain flushes itself out via the glymphatic system, a network of support cells that clears your brain of toxins and metabolic by-products, including adenosine. Now, imagine that the gradual trash build-up within the shop’s bins, buckets, and dumpsters throughout the day progressively reduces your shop workers’ productivity and ultimately results in an overall decrease in activity during the refresh period. This is analogous to how adenosine gradually accumulates in your brain throughout the day and interacts with receptors (trash containers) of both wake-promoting and sleep-promoting neurons to bias your body towards sleep. Neuroscientists describe this sleep-promoting force as sleep pressure, and, interestingly, adenosine’s role in this process emerges out of complementary inhibition of wake-promoting neurons paired with excitation of sleep-promoting neurons. Specifically, activity in Adenosine 1 Receptors (A1R) functions to inhibit certain neurons associated with wakefulness, and activity in Adenosine 2 Receptors (A2AR) functions to activate certain neurons associated with sleep; additionally, research suggests that these receptors further exhibit cross-talk through their sleep-promoting functions, in that studies point to A2AR activity as a catalyst for sleep initiation and A1R activity as a propagator of the slow-wave activity present in deep sleep.2

Now that you understand the basics of adenosine and its receptors, you can connect the dots of how caffeine — a competitive adenosine antagonist — allows you to fight off your morning grogginess, mid-class head-bobbing, and post-lunch snooze comas. Caffeine holds a structure similar enough to that of adenosine to enter adenosine receptors but different enough to avoid activating those receptors. In this way, caffeine’s principal effect differs from those of chemical agonists — like anabolic steroids and alcohol that exhibit their effects by activating their target receptors — and matches those of other antagonists, like Narcan, that block but do not trigger their target receptors. So, caffeine can knock off and block adenosine molecules from their receptors and, as a consequence, prevent those molecules’ sleep-inducing and wake-reducing effects. At the neurochemical level, this means that caffeine encourages certain neurons in your brain to release neurotransmitters — neuronal signaling molecules that act like hormones of the nervous system — associated with alertness and focus, such as dopamine, acetylcholine, histamine, and epinephrine, and discourages other neurons from releasing neurotransmitters associated with calmness and drowsiness, such as GABA. Lastly, one pivotal aspect of this antagonistic interaction is that it is partial, in that caffeine only out-competes adenosine 25-50% of the time, depending upon genetics, adenosine concentrations, and caffeine concentrations. (2)

In relation to the pizza shop analogy from above, caffeine acts as a blinder to you, in that it prevents you from noticing some of the trash build-up, leading you to operate as if it were earlier in the workday. Of course, this blinding effect can only last so long, at which point you finally peel back the curtains, recognize an overwhelming accumulation of trash, and rapidly reduce the shop’s productivity. In terms of the physiology associated with caffeine, you may have experienced a similar rapid movement towards shut down: the caffeine crash. Theoretically, a caffeine crash is most likely to occur if you consume caffeine during a prolonged state of sleep deprivation — such as working the overnight shift or pulling an all-night study session — at the end of which the wave of adenosine that built up in the process crashes down, like a tsunami, as the departing caffeine frees up a host of adenosine receptors.

Key Points

1. Adenosine is a by-product of cellular energy metabolism that builds up throughout the day and plays a role in encouraging sleep.
2. During sleep, the glymphatic system, a drainage network in the brain, clears the adenosine that builds up in your brain when you are awake.
3. Caffeine functions as a competitive adenosine antagonist, meaning that it competes to kick off and block adenosine molecules from adenosine receptors. In this process, caffeine does not activate the adenosine receptors, and it blunts the sleep-inducing effects of adenosine.
4. In theory, the infamous caffeine crash occurs when the caffeine in your brain eventually departs and leaves adenosine receptors available for the tsunami of adenosine that has built up over time.

Caffeine 101

So, we covered caffeine’s main mechanism of action once it hits your brain, but we still need to look at the factors impacting how caffeine gets to your head and how effective it is when it does. In terms of bioavailability, caffeine is about as good as it gets, in that the gastrointestinal tract absorbs roughly 99% of the caffeine you consume orally.3 From there, caffeine disperses throughout your body in your bloodstream, out of which it readily diffuses across your blood-brain barrier — the protective layer of endothelial tissue that regulates what can and cannot enter your brain — to gain access to your brain and the previously mentioned adenosine receptors within it. Sooner or later, those caffeine molecules make their way into the liver, where they are metabolized by a series of enzymes known as the P450 Oxidase System.4 In particular, the CYP1A2 enzyme handles most of the primary caffeine breakdown, of which paraxanthine and dimethyluricacid are the major primary and ultimate by-products respectively.5 Once this metabolic process is complete, the by-products, along with the remaining iota (about 3%) of unmetabolized caffeine, are excreted in your urine.

Caffeine’s half-life — the amount of time it takes for your body to metabolize 50% of the caffeine you consume — fluctuates depending upon multiple variables, such as your genetics and the amount of caffeine you consume in a given sitting; however, most sources suggest that the average caffeine half-life is around 5 hours. (3, 5, 6) Interestingly, some studies report a 20-30% increase in caffeine half-life in women, as well as roughly 100% and 450% increases in caffeine half-life in women using oral contraceptives and traversing their third trimester of pregnancy respectively. (6) In addition, smoking appears to have a major impact on caffeine metabolism, in that smokers seem to exhibit a 50% reduction in caffeine half-life. (6) Sex, oral-contraception use, pregnancy, and smoking all appear to impact caffeine metabolism by altering CYP1A2 concentration/activity, the former three of which may be associated with how estrogen impacts the CYP1A2 enzyme. (5, 6)

Shortly after exploring the world of caffeine, you will encounter statements like, “Caffeine gives me anxiety,” and, “I could drink coffee all day long and sleep like a baby,” which evidence the wide range of human responses to caffeine consumption. Much of this variability is attributable to a host of genetic alleles in genes associated with dopamine receptors, epinephrine clearance, adenosine receptors, and caffeine metabolism. (2, 5, 7, 8 ) Certain combinations of these alleles can lead one to be caffeine sensitive and experience sleep disturbance, anxiety, prolonged caffeine effects, and intensified cardiovascular caffeine effects; contrarily, other combinations can lead one to be a, “rapid metabolizer,” who experiences short and rapid caffeine effects or none at all. In particular, it seems that there is evidence supporting certain alleles for the CYP1A2 enzyme and the A2A receptor that exhibit significant impacts on a caffeine consumer’s physiologic and conscious experiences following caffeine consumption. (2, 5, 8)

Key Points

1. Caffeine is very bioavailable, in that 99% of orally consumed caffeine is absorbed in the gastrointestinal tract.
2. The P450 Oxidase System, especially the CYP1A2 enzyme, is responsible for metabolizing caffeine and does so in the liver.
3. Genetic variations in genes corresponding to dopamine receptors, adenosine receptors, P450 enzymes, and catecholamine metabolism can impact caffeine sensitivity.

What’s the Catch?

If you’ve made it this far, it’s likely because you’re looking for an answer to the big caffeine question: So, what are those great coffee shits costing me with my health? Whether it be due to sleepless and jittery caffeine sensitivity traumas or society’s general stigmatism on drugs, I find that more people than not assume that caffeine is bad for you; however, most of the data I found on this deep dive indicates otherwise, in that it suggests that caffeine has either neutral or positive effects on a host of health parameters when consumed within the recommended daily allowance (RDA) of 400 mg. To put things into perspective, that RDA represents the equivalent of drinking about 4-5 cups of coffee, 9.5 cups of English breakfast tea, or 1.3 Bang energy drinks per day. Of course, the vast majority of the data from caffeine and coffee research is epidemiological and inherently complicated by confounding variables; consequently, we must ask clarifying questions, like, “What type of people tend to drink more coffee?” and, “What else do coffee drinkers do on a regular basis that could impact their health?”. In addition, most of these observational studies utilize dietary recall surveys to collect data, which leaves that data vulnerable to inaccurate consumer reporting; furthermore, data collection becomes more complicated for coffee consumption when considering the varying cup sizes, coffee types, and caffeine concentrations. For example, one cup of coffee that you brewed from a Keurig and one cup of coffee from Dunkin Donuts could differ in caffeine content by anywhere from 50-250 mg, but sub-optimal survey designs may miss that distinction. Then, you also have to consider the manner in which that daily caffeine is being consumed. Are the subjects drinking all of their coffee in one sitting or multiple? At what time of day are those subjects consuming caffeine? If there are effects, could they be connected to how a caffeine crash or a late-night cup of coffee impacts the subjects’ sleep? How about the potential effect the caffeine has on what, when, and how much the subjects’ eat? My point is that, although abundant, fairly consistent, and in some cases thorough, it is nearly impossible to make conclusive statements about how coffee — and almost anything else we eat or drink — impacts our health due to the constraints on the study methods.

All of that said, we don’t need to throw the baby out with the bathwater and can still use the observational data we have to formulate decent guesses about whether regular coffee consumption is harmful, beneficial, or neutral with respect to our health. In this regard, I found that there are three concerns that stand out from the rest: cardiovascular health, neurological health, and mortality.

The Heart of the Question

Other than decreasing fatigue and increasing alertness, caffeine is most commonly known for its effects on the cardiovascular system, which are driven by its interactions with adenosine receptors on the heart and the associated increase in serum epinephrine levels.9 However, caffeine also acts on adenosine receptors within blood vessels, where antagonizing those receptors increases vasodilation and stimulates nitric oxide release, both of which work to relax those blood vessels. (9) In this way, caffeine exhibits an interesting net effect on the cardiovascular system, in that some of its mechanisms work to increase blood pressure and heart rate, while others work to do the opposite. (9) In one study, authors suggest that, “as there are multiple constriction and dilatation mechanisms at work, the overall result [of caffeine consumption] is individualized and dependent upon caffeine dose, the frequency of use, and comorbidities such as diabetes or hypertension.” (9) Furthermore, they address the potential difference in cardiovascular reactions to caffeine consumption between regular and irregular caffeine consumers, discussing how, “caffeine seems to increase systolic blood pressure by approximately 5 to 10 mmHg in individuals with infrequent use. However, there is little to no acute effect on habitual consumers.” (9) Authors from another study also found that caffeine’s acute cardiovascular effects disappeared in habitual coffee drinkers and that this habituation appeared after 2 weeks of consistent coffee consumption; additionally, they proposed that a slight and acute increase in blood pressure or heart rate may not be significant on the grand scale anyways, similar to how, “measuring BP in habitual joggers while they are running would lead to erroneous conclusions about the effect of regular physical activity on BP.”10

During my research, I found that data from long-term studies with larger population sizes, as well as data from meta-analyses, supported the aforementioned hypotheses that coffee and caffeine’s acute impacts on cardiovascular metrics do not lead to chronic or overall detriments in cardiovascular health when consumed within the RDA. (6, 8, 11, 12, 13, 14) Of these larger and longer-term studies, one found an inverse association between cardiovascular disease mortality and coffee consumption, meaning that higher coffee consumption was associated with a lower risk of dying from cardiovascular disease. (12) Researchers from that study stipulated that their results could be attributed to, “the possible beneficial effects of coffee on inflammation, endothelial function, and risk for type 2 diabetes.” (12)

Key Points

1. Caffeine induces multiple opposing cardiovascular effects through multiple mechanisms and pathways, including increasing blood pressure and heart rate by binding to adenosine receptors on the heart and reducing blood pressure and heart rate by binding to adenosine receptors in blood vessels. (9)
2. Some data suggest that caffeine and coffee’s effects on blood pressure and heart rate decrease or disappear in regular caffeine or coffee consumers. (9, 10)
3. Epidemiological data suggest that caffeine and coffee consumption do not negatively impact cardiovascular health if consumed within the RDA of 400 mg of caffeine per day — the equivalent of 4-5 cups of coffee.
4. Some researchers hypothesize that, “the possible beneficial effects of coffee on inflammation, endothelial function, and risk for type 2 diabetes,” overpower the potential negative effects of coffee and caffeine on the cardiovascular system. (12)
5. Other researchers propose that caffeine’s acute increases in blood pressure and heart rate do not correlate with long-term or chronic detrimental effects, similar to how acute increases in blood pressure during exercise do not correlate to long-term or chronic detriments in cardiovascular effects. (10)

The Brains of the Operation

Out of all aspects of health, the brain seems to pose a unique concern when it comes to drug use. If you have ever heard somebody talk about how alcohol, marijuana, nicotine, or *insert virtually any other recreational drug* are going to, “rot your brain,” then you know what I’m talking about. So, is there reason to believe that caffeine is going to turn your brain into a browned and mushy, overripe banana? (Side note: slightly overripe bananas are the best kind of bananas)

Similar to that on caffeine and coffee’s effects on cardiovascular outcomes, the data I found on neurological outcomes generally suggest a positive or neutral effect, especially in regards to Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). (15, 16, 17, 18, 19, 20) For example, researchers from one study proposed multiple pathways through which caffeine could potentially thwart Alzheimer’s development; particularly, those researchers highlighted caffeine’s ability to induce signaling cascades that alter intracellular activity and gene expression in a manner that reduces the production of beta-amyloid — a protein scientists and medical professionals believe possesses a causal relationship with AD. In terms of caffeine and coffee’s potential protective functions for PD, researchers from one study proposed that caffeine’s ability to promote and preserve dopaminergic signaling through antagonizing adenosine receptors could explain the epidemiological data that suggests an inverse relationship between caffeine/coffee consumption and PD. This hypothesis is grounded on the widely supported idea that impaired dopamine signaling lies at the heart of PD.

As previously mentioned, this data does not point to caffeine nor coffee consumption as definitive tools to reduce or expunge AD or PD risk, nor does it address the endless other factors and outcomes associated with neurological health; however, it does weaken the argument that caffeine and coffee consumption within the RDA disrupt brain health, at least with regards to AD and PD — the two most common neurodegenerative diseases globally.

Key Points

1. There are mechanistic data that suggests caffeine poses a potential role in ameliorating the central mechanisms in both Alzheimer’s Disease (AD) and Parkinson’s Disease (PD).
2. Some epidemiological data demonstrate negative correlations between coffee consumption and both AD and PD.

The Mortal Sin?

Now, cardiovascular and neurodegenerative diseases are no joke, but, at the end of the day, there is one outcome that rules all the rest: mortality. My deep dive results on this front matched those of the results for cardiovascular disease and neurological health, in that the data generally points to coffee and caffeine as having neutral or slightly positive impacts on mortality, especially mortality via CVD. (11, 12, 14, 21) Notably, one study that analyzed data from over 120,000 male and female subjects found that coffee consumption was associated with a decrease in all-cause mortality, but only after adjusting for confounding variables, such as, “smoking status, body mass index, physical activity, alcohol intake, use of hormone therapy for women, parental history of myocardial infarction, and dietary factors (total energy intake; use of multivitamin and vitamin E supplements; polyunsaturated, saturated, n-3, and trans fat intake; glycemic load; and folic acid intake).” (12) In particular, the authors of that study emphasized smoking status as a key contributor to their adjusted analysis and their ultimate findings; additionally, they attribute the overall reduction in mortality to the negative correlation between coffee consumption and death from CVD. Interestingly, the study also found that decaffeinated coffee produced similar effects on mortality, which they believe suggests coffee offers mortality benefits independent from those potentially associated with caffeine.

Although I think mortality — along with healthspan — serves as the king of health endpoints, it is inherently the most difficult to interpret through observational data, in that it is affected by virtually endless confounding variables; involves long and difficult research; and requires researchers to incorporate mechanistic data, in vitro results, and biological theories for all diseases. In contrast, studying an endpoint on one disease often allows for better control over variables, requires shorter study durations, and only demands mechanistic and theoretical understanding with regards to the disease of concern. For these reasons, I think it is wise to take observational data on mortality, including the aforementioned research on how caffeine and coffee consumption impact mortality, with a bit more than a grain of salt.

Key Points

1. The epidemiological data regarding coffee and caffeine consumption generally suggests a negative correlation after adjusting for confounding variables(i.e. Obesity, age, alcohol consumption, Type 2 Diabetes, etc.) — especially smoking status.
2. Epidemiological and observational studies on mortality in particular are vulnerable to many confounding variables and inherently difficult to design and run effectively. For these reasons, I think it is wise to take this data with a bit more than a grain of salt.