How coffee affects the brain – body and overall health


You’re reading this with a cup of coffee in your hand, aren’t you? Coffee is the most popular drink in the world. Americans drink more coffee than soda, juice, and tea — combined.

How popular is coffee?

When news first broke that Prince Harry and Meghan were considering Canada as their new home, Canadian coffee giant Tim Hortons offered free coffee for life as an extra enticement.

Given coffee’s popularity, it’s surprising how much confusion surrounds how this hot, dark, nectar of the gods affects our biology.

Coffee’s ingredients

The main biologically active ingredients in coffee are caffeine (a stimulant) and a suite of antioxidants. What do we know about how caffeine and antioxidants affect our bodies?

The fundamentals are pretty simple, but the devil is in the details and the speculation around how coffee could either help or harm us runs a bit wild.

The stimulant properties of caffeine mean that you can count on a cup of coffee to wake you up. In fact, coffee, or at least the caffeine it contains, is the most commonly used psychoactive drug in the world.

It seems to work as a stimulant, at least in part, by blocking adenosine, which promotes sleep, from binding to its receptor.

Caffeine and adenosine have similar ring structures. Caffeine acts as a molecular mimic, filling and blocking the adenosine receptor, preventing the body’s natural ability to be able a rest when it’s tired.

This blocking is also the reason why too much coffee can leave you feeling jittery or sleepless. You can only postpone fatigue for so long before the body’s regulatory systems begin to fail, leading to simple things like the jitters, but also more serious effects like anxiety or insomnia. Complications may be common; a possible link between coffee drinking and insomnia was identified more than 100 years ago.

The National Film Board of Canada produced a documentary on the cultural history of coffee called ‘Black Coffee: Part One, The Irresistible Bean’. Credit: exotickd.

Unique responses

Different people respond to caffeine differently. At least some of this variation is from having different forms of that adenosine receptor, the molecule that caffeine binds to and blocks. There are likely other sites of genetic variation as well.

There are individuals who don’t process caffeine and to whom drinks like coffee could pose a medical danger.

Even away from those extremes, however, there is variation in how we respond to that cup of coffee. And, like much of biology, that variation is a function of environment, our past coffee consumption, genetics and, honestly, just random chance.

We may be interested in coffee because of the oh-so-joyous caffeine buzz, but that doesn’t mean that caffeine is the most biologically interesting aspect of a good cup of coffee.

In one study using rats, caffeine triggered smooth muscle contraction, so it is possible that caffeine directly promotes bowel activity. Other studies, though, have shown that decaffeinated coffee can have as strong an effect on bowel activity as regular coffee, suggesting a more complex mechanism involving some of the other molecules in coffee.

Antioxidant benefits

What about the antioxidants in coffee and the buzz that surrounds them? Things actually start out pretty straightforward. Metabolic processes produce the energy necessary for life, but they also create waste, often in the form of oxidized molecules that can be harmful in themselves or in damaging other molecules.

Antioxidants are a broad group of molecules that can scrub up dangerous waste; all organisms produce antioxidants as part of their metabolic balance. It is unclear if supplementing our diet with additional antioxidants can augment these natural defences, but that hasn’t stopped speculation.

Antioxidants have been linked to almost everything, including premature ejaculation.

Are any of the claims of positive effects substantiated? Surprisingly, the answer is again a resounding maybe.

Coffee and cancer

Coffee won’t cure cancer, but it may help to prevent it and possibly other diseases as well. Part of answering the question of coffee’s connection to cancer lies in asking another: what is cancer?

At its simplest, cancer is uncontrolled cell growth, which is fundamentally about regulating when genes are, or are not, actively expressed.

My research group studies gene regulation and I can tell you that even a good cup of coffee, or boost of caffeine, won’t cause genes that are turned off or on at the wrong time to suddenly start playing by the rules.

This is a photo of a woman drinking coffee

From drip coffee to pourovers to stovetop espresso, the variations in coffee-based drinks are plenty. Image is in the public domain.

The antioxidants in coffee may actually have a cancer-fighting effect. Remember that antioxidants fight cellular damage. One type of damage that they may help reduce is mutations to DNA, and cancer is caused by mutations that lead to the misregulation of genes.

Studies have shown that consuming coffee fights cancer in rats. Other studies in humans have shown that coffee consumption is associated with lower rates of some cancers.

Interestingly, coffee consumption has also been linked to reduced rates of other diseases as well.

Higher coffee consumption is linked to lower rates of Parkinson’s disease and some other forms of dementia. Strikingly, at least one experimental study in mice and cell culture shows that protection is a function of a combination of caffeine and antioxidants in coffee.

Higher coffee consumption has also been linked to lower rates of Type 2 diabetes. Complexity, combined effects and variation between individuals seems to be the theme across all the diseases.

At the end of the day, where does all this leave us on the biology of coffee? Well, as I tell my students, it’s complicated. But as most reading this already know, coffee will definitely wake you up in the morning.

Funding: Thomas Merritt receives funding from Natural Sciences and Engineering Research Council of Canada.

Caffeine is a naturally occurring, central nervous system (CNS) stimulant of the methylxanthine class and is the most widely taken psychoactive stimulant in the world.

This drug is most commonly sourced from the coffee bean, but can also be found naturally occurring in certain types of tea and cacao beans. It is also an additive to soda and energy drinks. The primary goal of caffeine consumption is to combat fatigue and drowsiness, but there are many additional uses.[1]

The FDA has approved caffeine for the use in the treatment of apnea of prematurity and prevention and treatment of bronchopulmonary dysplasia of premature infants.[2][3][4] Non-FDA approved uses of caffeine include treating migraine headaches and post-dural puncture headaches and enhancing athletic performance, especially in endurance sports.[5][1] Caffeine has links with decreased all-cause mortality. It is also under investigation for its efficacy in the treatment of depression and neurocognitive declines, such as those seen in Alzheimer and Parkinson disease.[6][7][8][9][10]

Mechanism of Action

Caffeine’s primary mechanism of action is on the adenosine receptors in the brain. As it is both fat and water-soluble, it readily crosses the blood-brain barrier, resulting in antagonism to all four adenosine receptor subtypes (A1, A2a, A2b, A3).

Specifically, the antagonism of the A2a receptor is responsible for the wakefulness effects of caffeine.[11][12]

Adenosine receptors are not limited to the CNS but found throughout the body. In cardiac muscle, direct antagonism of receptor A1 results in positive inotropic effects. Likewise, adenosine receptor antagonism stimulates the release of catecholamines, which contributes to the systemic stimulatory effects of caffeine and further stimulates cardiac inotropy and chronotropy.

At the vascular level, caffeine undergoes a complex interaction to control vascular tone, which includes direct antagonism of vascular adenosine receptors to promote vasodilation, as well as stimulation of endothelial cells to release nitric oxide. This action promotes further relaxation of vascular smooth muscle cells.

This vasodilation becomes counteracted by the increase in sympathetic tone via catecholamine release and positive cardiac inotropic and chronotropic effects, which promotes vasoconstriction.As there are multiple constriction and dilatation mechanisms at work, the overall result is individualized and dependent upon caffeine dose, the frequency of use, and comorbidities such as diabetes or hypertension.

Overall, 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.[13][12]

Furthermore, adenosine receptor blockage stimulates respiratory drive by increasing medullary ventilator response to carbon dioxide, stimulating central respiratory drive, and improving diaphragm contractility. Caffeine increases renal blood flow, glomerular filtration, and sodium excretion resulting in diuresis. It is also a potent stimulator of gastric acid secretion and gastrointestinal (GI) motility.[12][14]

Metabolism of caffeine primarily occurs in the liver via the cytochrome P450 oxidase system, specifically enzyme CYP1A2. Metabolism results in 1 of 3 dimethylxanthine, including paraxanthine, theobromine, and theophylline, each with unique effects on the body. These metabolites are then further metabolized and excreted in the urine.[13][15]

The half-life of caffeine is approximately 5 hours in the average adult. However, multiple factors can influence metabolism. Half-life is reduced by up to 50% in smokers compared to nonsmokers. Conversely, pregnant patients, especially those in the final trimester, will have prolonged half-life upwards of 15 hours. Newborns will also have a significantly prolonged half-life, up to 8 hours for full-term and 100 hours for premature infants, due to reduced activity of cytochrome P450 enzymes and immature demethylation pathways. Children older than 9 months will have similar half-life eliminations to that of adults. Additionally, patients with liver disease or those taking cytochrome inhibitors will also experience prolonged half-lives due to reduced enzyme activity. [16][17]


Caffeine has nearly 100% oral bioavailability and is the primary route of administration. Caffeine can be sourced from coffee beans, cacao beans, kola nuts, tea leaves, yerba mate, the guarana berry, as an additive to sodas and energy drinks, or consumed as powder or tablets.[1] When taken orally, onset typically occurs in 45 to 60 minutes and lasts approximately 3 to 5 hours. Absorption is somewhat delayed when taken with food. It administrable via the parenteral route, which is a common method when treating apnea of prematurity in newborns or post-dural puncture headaches.

Alternatively, caffeine can be absorbed rectally, insufflated, or inhaled. Consumption via insufflation or inhalation is generally that of abuse with the intention of getting high. These routes lead to significantly faster absorption, usually within minutes, and bypass the first-pass metabolism. Although this route can lead to a faster onset of action, multiple studies have shown lower bioavailability from inhalation of caffeine; approximately 60% to 70%. When taken via this route, the duration of action is shorter.[15][18]

Adverse Effects

As with most drugs or medications, there comes a long list of adverse effects associated with its use, and caffeine is no different. The adverse effects of caffeine range from mild to severe to even fatal and are generally related to the dose consumed and an individual’s sensitivity to the drug. The most common side effects are listed below. Mortality is usually associated with cardiac arrhythmia, hypotension, myocardial infarction, electrolyte disturbances, and aspiration.[19][7]


Anxiety, restlessness, fidgeting, insomnia, facial flushing, increased urination, muscle twitches or tremors, irritability, agitation, elevated or irregular heart rate, GI upset


Disorientation, hallucinations, psychosis, seizure, arrhythmias, ischemia, rhabdomyolysis

Caffeine can also cause withdrawal symptoms if habitual users abruptly stop.  These symptoms usually begin 12 to 24 hours from last consumption, peak in 1 to 2 days and may persist for up to 1 week.  Withdrawal is preventable if caffeine is tapered off instead of abruptly discontinued. If symptoms do arise, they are promptly reversible by re-administration of caffeine.[20]

Lastly, when used for the treatment of apnea of prematurity, there is evidence of an increased risk of necrotizing enterocolitis in neonates.[21]


Although there are no absolute contraindications to caffeine, there are some medical conditions in which caution is necessary, which includes[7][22][14][17]:

  • Severe anxiety
  • Cardiovascular disease or symptomatic cardiac arrhythmias
  • Peptic ulcer disease or gastroesophageal reflux disease
  • Hepatic impairment
  • Renal impairment
  • Seizures (as may lower seizure threshold)
  • Pregnancy

American College of Obstetricians and Gynecologists (ACOG) considers 200 mg daily safe during pregnancy.[23] There is no evidence to suggest caffeine increases the risk of congenital malformations, although some studies have concluded that high caffeine consumption during pregnancy (more than 400 mg per day) may be associated with lower birth weights from intrauterine growth restriction, increased risk of miscarriage, but not preterm birth.[24][25][26] However, the evidence regarding lower birth weight and miscarriage is inconclusive at this time and pending further investigation.[27] Caffeine is considered a pregnancy class C drug.[23]


The average dose of caffeine is 2.4 mg/kg per day for adults; however, daily doses of up to 400 mg are considered safe.[28] Consumption of 100 mg of caffeine generally increases blood levels by 5 to 6 mg/L. There are reports of severe intoxication that causes altered mentation, vomiting, and hypotension at levels of 80 mg/L. The average blood level of patients who succumb to caffeine toxicity is 180 mg/L (+/- 97 mg/L).[29][30]

For the treatment of apnea of prematurity, caffeine is administered at 20 mg/kg loading dose, followed by 5 to 10 mg/kg per day of caffeine citrate via enteral or parenteral routes with therapeutic index goals of 5 to 25 mg/L.[31][32]


Caffeine consumption is generally recognized as safe. Most substances do not require FDA approval for additive caffeine as long as it falls within safe levels dictated by the statue. The typical dose of caffeine is roughly 70 to 100 mg per drink. Although there is no specific daily allowance for caffeine, doses of up to 400 mg a day are considered safe.[33]

The exact LD50 for humans is variable and largely dependent on sensitivity to caffeine. However, it is estimated to be 150 to 200 mg/kg. There are, however, case reports of doses as low as 57 mg/kg being fatal. A toxic dose of caffeine, or a dose at which significant unfavorable side effects begin to occur, for example, tachycardia, arrhythmia, altered mentation, and seizure, is estimated to be approximately 1.2 grams while estimates of a life-threatening dose are in the range of 10 to 14 grams.[19][34]

Ultimately, treatment is primarily supportive for mild ingestions. For more severe ingestions, additional interventions may be necessary. Patients may require intubation for airway protection from vomiting or altered mental status. Benzodiazepines can be given to abort any seizures that develop.

Patients may require vasopressors to combat persistent hypotension if intravenous (IV) fluid resuscitation alone fails. The first-line vasopressor should be either phenylephrine or norepinephrine. However, phenylephrine is the ideal choice due to its pure alpha agonism as well as reflex bradycardia.

Magnesium and beta-blockers can be used to combat cardiac arrhythmias secondary to the hyperadrenergic response. The ultra-short acting beta-1 selective blocker esmolol has been used successfully in several case reports for this indication. In the event of lethal arrhythmias, patients will require defibrillation and resuscitation per ACLS protocol.[22] Activated charcoal, intralipid infusion, and hemodialysis can assist in preventing further metabolism and subsequent effects of caffeine overdose.[34][19][35]

Enhancing Healthcare Team Outcomes

Caffeine consumption is relatively safe in limited amounts. The problem is that many people today are consuming high energy drinks that contain massive amounts of caffeine, which can lead to complications. Today the issue of caffeine toxicity has been worsened with high energy drinks.

These concentrated caffeinated beverages are not only toxic themselves, but the problem becomes exacerbated when the individual combines it with other illicit agents, tobacco, and alcohol. Over the past few years, there have been reports of many deaths following the consumption of such combinations.

Dealing with The nurse practitioner and primary care physician caffeine toxicity or side effects, or using caffeine therapeutically, require an interprofessional healthcare team for optimal results. For therapeutic use, a pharmacist or nurse should query the patient about other potential sources of caffeine in their life, so that toxicity is not an issue with therapy.  Team members are in a prime position to educate the public on the dangers of high energy drinks and related foods.

Clinicians, nursing staff, and pharmacists must be prepared to offer counsel to patients who may be overindulging in caffeine. While there are no absolute contraindications to caffeine, the public requires education that if they have cardiac disorders, panic disorder, anxiety, or too much stress, to avoid caffeine. An interprofessional team is the best means by which to convey this message. [Level V]

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