Caffeine Metabolism

Do you start your day with a cup of freshly brewed coffee?

Does a cup of tea warm your insides and leave you feeling fresh in the evening? Do you stock up energy drinks in your fridge to help handle late nights?

All these beverages have one thing in common - caffeine.

Caffeine is an organic compound found in plant sources. Caffeine is a legally accepted and consumed psychoactive drug ( a chemical that alters nervous system functions). Caffeine alters a person’s mood, behavior, and energy levels.

Is caffeine good or bad for health? The controversial aspects of caffeine
While some studies have praised the beneficial effects of caffeine on human health, others warn about the health risks. Why does the same substance lead to different health outcomes?

The answer to these questions is not only applicable to caffeine but also to a lot of other substances.

We are all genetically unique. While some substances produce relatively similar effects on our bodies- many substances, including caffeine, are processed differently in different individuals.

When a drug fails a clinical trial- it does not mean that every individual who took that drug failed to respond. On the other hand, there is no approved drug that works equally well on every individual.

It is common knowledge that some drugs work really well for some, but not for others. We need higher doses of certain drugs and lower doses of others. There is a dose difference for certain drugs for men, women and children.

Caffeine is no different. Unless the genetics and other factors are accounted for, it will not be easy to say whether caffeine is good or bad for you. Keep reading to find out the unique genetic aspects of caffeine metabolism (processing in the body)

Benefits Of Consuming Caffeine

  • Keeps the person alert and focused
  • Prevents tiredness and fatigue
  • Can improve mood
  • Helps with better metabolism and weight loss
  • Improves the effectiveness of pain medications by up to 40%
Sources Of Caffeine
There are about 60 species of plants that can produce caffeine. Few top sources are:
  • Seeds of cocoa plants
  • Leaves of tea shrubs
  • Kola nuts
  • Seeds of the guarana berries
  • Leaves of the yaupon holly tree
Did you know that about 85% of Americans consume at least one caffeinated drink a day? Coffee remains the most consumed caffeinated drink among adults.

How much caffeine is too much? Do you have to give up on caffeine to lead a healthy lifestyle? Keep reading to know more.

The Story Behind Caffeine Consumption
The history of caffeine is closely associated with the histories of its plant sources.

It was 2437 BCE. The Chinese Emperor Shen Nung was relaxing in his garden. The wind blew a couple of leaves into his cup of boiling water. He noticed that the water changed color and smelled fragrant. The leaves were later identified to be from the tea shrubs. Tea leaves are considered a stimulant (a drink to energize the body).

There are many stories on the discovery of caffeine. Some scripts say the ethnic Oromo people of Ethiopia recognized coffee beans to have energizing properties.

The more popular version is of Kaldi, an Ethiopian goat herder. He noticed his goats getting all excited after consuming coffee beans. He mentioned this in a monastery and the first cup of coffee was brewed there.

The leaves of the yaupon holly tree were brewed as early as 8000 and 1000 BC. This was then known as the black drink.

In many West African cultures, it is still a regular practice to chew on kola nuts when people feel tired.

Caffeine At The Molecular Level- Getting Technical
Caffeine is very easily absorbed by the body. 99% of caffeine is absorbed in about 45 minutes.

Once you consume a caffeinated beverage, it enters the gastrointestinal tract. Caffeine is processed in the liver by an enzyme that breaks it apart into different chemicals like paraxanthine, theobromine, and theophylline.

Peak levels of caffeine are observed in the plasma between 15 minutes and 120 minutes after oral consumption.

Caffeine easily reaches the brain. Adenosine is a chemical in the brain that induces sleep. The structure of caffeine is similar to that of adenosine. Caffeine attaches itself to the adenosine receptors (a protein that responds to adenosine) and prevents people from feeling sleepy.

The more caffeinated beverages you drink, the more adenosine receptors your body will produce.

Over time, you will need more amounts of caffeine to keep you awake.

Did You Know?
Plant sources are not the only way to get your dose of caffeine. Caffeine is artificially synthesized in industries too.

The production of caffeine in industries began during World War II. Germans were unable to obtain caffeine because of various trading bans. They hence had to create caffeine artificially.

Today, synthetic caffeine is very cheap and tastes just like natural caffeine. It would not be surprising if you cannot tell the difference between the two.

While synthetic caffeine is safe when had in small amounts, the problem is with the manufacturing process. Ammonia goes through a lot of steps and chemical interactions to turn into caffeine.

The synthetic caffeine industry is also unregulated in most countries. All this makes synthetic caffeine a slightly worrying product in the market.

Recommended Daily Intake
What Are The Symptoms of Caffeine Overdose
  • Caffeine overdose may cause anxiety, mood swings, and irritability
  • Too much caffeine can cause insomnia
  • Coffee is a laxative and too much coffee can lead to diarrhea
  • For people with gastroesophageal reflux disease (GERD), excess coffee can worsen the condition
  • Excess caffeine can lead to irregular heartbeats and dizziness in people with cardiac problems
  • Excess caffeine stimulates the nervous system and leads to high blood pressure
  • Caffeine overdose can cause polyuria (excessive urination) and dehydration
  • Extreme overdoses can cause seizures
What Are The Symptoms Of Caffeine Withdrawal
Caffeine is addictive. Your body goes through withdrawal symptoms when you try to reduce your caffeine intake. Few popularly noticed symptoms of caffeine withdrawal are:
  • Headaches
  • Irritability
  • Depression and mood swings
  • Excess tiredness and fatigue
  • Tremors (shaky hands and legs)
  • A general lack of energy
Withdrawal symptoms can start 24 hours after giving up caffeine and can last for up to 9 days.

Non-Genetic Factors That Cause Caffeine Sensitivity
Caffeine sensitivity refers to having an adverse reaction to consuming caffeine. For most people, consuming more than 400 mg of caffeine can cause physical and mental discomforts.

Few others can be hypersensitive to caffeine and cannot tolerate it even in small quantities. Here are some non-genetic factors causing caffeine sensitivity.

  • Gender - Studies show that men are more sensitive to caffeine than women.
  • Being on the pill - If you are a woman on birth control pills, you may be sensitive to caffeine. The enzymes needed for processing caffeine in the body are used by estrogen in the pills. If you are on the pill, talk to your doctor about the right amounts of caffeine for you.
  • Medications - Certain medications and herbal supplements can increase the effects of caffeine. You can get the side effects of an overdose very quickly.
  • Psychological disorders - You may be extra sensitive to caffeine if you are already diagnosed with psychological disorders like baseline anxiety, depression, or mood swings.
  • Not being used to caffeine - Like any other drug, your tolerance to caffeine increases with time. If you are not used to caffeine, you can get hypersensitive with very low doses.
How Genetics Influences Caffeine Intake
How are some people able to process caffeine better than others? Genetics is the answer.

CYP1A2 gene - The CYP1A2 gene influences how fast caffeine is processed in your body and how you react to it. One particular SNP that can increase or decrease the effects of caffeine consumption is the rs762551.

AA genotype
  • Benefits from regular caffeine consumption.
  • Drinking caffeinated beverages have lower risks for high blood pressure and heart diseases.
  • Caffeine increases athletic performance
AC and CC genotype
  • Increased anxiety and irritability after consuming caffeine
  • Increased risk of heart diseases and high blood pressure on consuming caffeine
  • Caffeine decreases athletic performance
Recommendations For Healthy Caffeine Consumption
  • The right amount of caffeine may be beneficial to adults and keep them healthy, active, and focused.
  • Individual tolerance to caffeine can vary. Start with minimal quantities of caffeinated beverages and see what works for you.
  • While carbonated drinks and energy drinks may seem tastier options, they are full of sugar. You have to be cautious when choosing the kind of beverage you opt for.
  • Green and black tea are healthier anti-oxidant rich choices for caffeinated beverages.
  • Decaffeinated coffee contains very little caffeine and can help with caffeine withdrawal.
What does the CYP1A2 gene do?
  • CYP1A2 codes for the production of 21-hydroxylase, which is part of the cytochrome P450 family of enzymes.
  • This family of enzymes is quite important as it is a part of many processes, that include breaking down drugs, production of cholesterol, hormones, and fats.
  • The adrenal glands secrete the enzyme, 21-hydroxylase.
  • Situated on the top of the kidneys, the adrenal glands also produce hormones like epinephrine and cortisol.
  • Incidentally, 21-hydroxylase plays a role in the production of cortisol and another hormone named aldosterone.
  • Cortisol is a stress-related hormone and plays a role in protecting the body from stress, as well as reducing inflammation.
  • Cortisol also helps in maintaining blood sugar levels.
  • Aldosterone, also known as the salt-retaining hormone, regulates the amount of salt retained in the kidneys.
  • This has a direct consequence on blood pressure, as well as fluid retention in the body.
  • There seems to be an interesting trend in the activity of the CYP1A2 gene and caffeine intake.
  • The consequence of being a “rapid” or a “slow” metabolizer of caffeine can have effects on an individual’s cardiovascular health.
  • This article explains the wide-ranging effects of this gene, caffeine intake, cardiovascular health, hypertension, and even pregnancy!
  • Analyze your CYP1A2 gene variants for Caffeine Metabolism
What is the association between CYP1A2 and caffeine metabolism?
  • In the body, CYP1A2 accounts for around 95% of caffeine metabolism.
  • The enzyme efficiency varies between individuals.
  • A homozygous, that is, AA genotype represents individuals that can rapidly metabolize caffeine.
  • Some individuals have a mutation in this locus and thus have the AC genotype.
  • These individuals are “slow” caffeine metabolizers.
CYP1A2 and cardiovascular health
  • There seems to be a link between CYP1A2, the incidence of myocardial infarction (MI), and coffee intake.
  • The positive effects of coffee include lowering a feeling of tiredness and increasing alertness; however, it can also narrow the blood vessels.
  • This increases blood pressure and could lead to cardiovascular disease risk.
  • Rapid metabolizers of coffee have the AA genotype and may unravel the protective effects of caffeine in the system.
  • However, the individuals that are slow metabolizers have a higher risk of MI.
  • This suggests that the intake of caffeine has some role in this association.
  • Yet another study associated DNA damage due to mutagens found in tobacco smoking could contribute to MI.
  • The study included participants who were genotyped at the CYP1A2 gene.
  • They found a group of ‘highly inducible’ subjects that had a CYP1A2*1A/*1A genotype.
  • These individuals have a greater risk for MI, independent of their smoking status.
  • This also means that there is some intermediary substrate that the CYP1A2 gene decomposes, and if this gene has a mutation, it could lead to a higher risk of MI.
  • In a study conducted on 2014 people, people who were slow metabolizers of caffeine (C variant) and who consumed more than 3 cups of coffee per day had an association with increased risk for myocardial infarction.
  • In a similar study on 513 people, increased intake of coffee, among slow metabolizers, has an association with an increased risk for hypertension.
Summary
Caffeine is a legally consumed drug that can alter the mood and increase attention and focus. It is naturally present in up to 60 plant sources. It is also artificially produced in industries. Normal adults have to limit their caffeine intake by up to 400 mg. Caffeine overdose can lead to mood disorders, rapid heartbeats, and high blood pressure. Caffeine withdrawal has to be handled gently and causes symptoms like depression, anxiety, and low energy levels. Genetically, some people can show high caffeine sensitivity and need to monitor their caffeine consumption.

Reference
  1. https://pubmed.ncbi.nlm.nih.gov/24189158/
  2. https://medium.com/@macromoltek/caffeine-the-good-the-bad-and-the-history-a1bad46fcd06
  3. https://www.cnet.com/news/this-is-your-brain-on-caffeine/
  4. https://www.trueprotein.com.au/blogs/nutrition/natural-vs-synthetic-caffeine
  5. https://www.ncbi.nlm.nih.gov/books/NBK223808/
  6. https://www.fda.gov/consumers/consumer-updates/spilling-beans-how-much-caffeine-too-much
  7. https://www.everydayhealth.com/diet-nutrition/diet/reasons-youre-sensitive-caffeine-what-have-instead/
  8. https://my.clevelandclinic.org/health/articles/15496-caffeine-tips-for-breaking-the-habit
  9. https://www.unitypoint.org/livewell/article.aspx?id=e3fb9e25-fc1e-4390-a6a7-6114dd83ea55