Ground breaking Grewall

The earliest cited paper on caffeine (or 1,3,7-trimethylxanthine), a naturally sourced compound from coffee beans, cocoa beans, cola nuts and tea leaves was published in January, 2003. This alkaloid is primarily metabolized by the liver, reaches maximum concentration in the blood by 1-1.5hrs, is readily able to pass the blood-brain barrier and through the placenta and is present in breastmilk and semen¹. Unlike adults, children below 2 years of age are unable to metabolize caffeine as efficiently as adults. In infants < 2 years, 85% of the caffeine is excreted by the urine in its original form. Luckily, it is water-soluble and gets excreted out instead of collecting inside the body and causing harm?

Well, that’s the not the problem actually. The problem is repeated dosage, before the previous dose has washed off from the body, developing adverse side effects faster, like jitteriness, rapid heart rate, vomiting and sleep disruption.

Hepatocytes (liver cells), metabolize caffeine by a methylation reaction. The cytochrome P-450 enzyme (or CYP1A2) converts caffeine to paraxanthine, theobromine and theophylline (mainly). In chronic liver diseases, this activity is hampered, leading to some studies suggesting using caffeine metabolism as a marker for liver function⁵. In fact, a study observed lower hepatic lipidosis (fatty liver) in llamas and alpacas upon administering 3mg/kg IV of caffeine⁴. Does this mean caffeine can cure fatty liver in humans? There is no study yet hold your horses, people!

Caffeine binds to and selectively blocks adenosine receptors on neurons which results in downstream increase in cAMP (cyclic adenosine monophosphate, just another molecule that helps cell signalling or talking to each other). This leads to release of norepinephrine, dopamine and serotonin, keeping you alert².

Did you know, maple syrup, beef jerky and donuts also contain caffeine?

What are these adverse effects?

Briefly, the amount of caffeine per cup of coffee is provided in the table below (1cup = 237ml = 8 oz).

Beverage	Caffeine (mg/ cup)
Brewed Coffee (Pour-over, French press, drip)	96
Espresso	63
Brewed coffee, decaf; Espresso, decaf	1
Instant coffee	62
Instant coffee, decaf	2
Black tea	48
Green tea	29
Decaf tea	2 (4mg/cup acc. to Caffeine Informer)

According to the FDA, around 3-4 cups is considered “safe”. While caffeinism, or caffeine “abuse” is defined as having >500-600mg (or around 4-7 cups of coffee) leading to adverse effects.

Seriously, what’s the worst that could happen? Well, irregular (arrhythmia) or fast (tachycardia) heartbeat, elevated respiration, excessive peeing (diuresis) and gastrointestinal disturbances (farting, constipation or diarrhoea). It also decreases the calcium absorption by the intestines and increases urinary calcium excretion. This leads to an increased risk osteoporosis (reduced bone density) for older adults and postmenopausal women.

< 400mg/day of caffeine is safe for most healthy adults². What is “healthy adults”? A 2017 study on caffeine’s effects defines “healthy” as those that do not have any disease/ not hospitalized. So, if you have any metabolic disorders, allergies, autoimmune conditions, eh?

Technically, caffeine should be avoided if one has a predisposition for hypertension, any cardiac ailment, anxiety, bipolar disorder, among others. Although, one study has shown that having 1 cup of coffee a day helped patients suffering from atrial fibrillation⁸, most physicians still avoid caffeine for patients with heart ailments.

Caffeinated coffee consumption is associated with lower hyperglycemia and insulin sensitivity. While the cause-effect is still debatable, studies say that caffeine improved adiponectin levels- the hormone that regulates glucose catabolism, thereby improving type II diabetic health³. A long shot, I guess, with no understanding of which active component in coffee helped and no mechanism.

Components of coffee

So let me dial it back a little here, we’re talking about coffee as a whole, not only caffeine. Coffee comes from coffee beans from more than 120 plant species, but the two major species are Coffea arabica (Arabica) and Coffea canephora (Robusta). Brewed coffee, specifically, contains many other bioactive molecules, such as melanoidins, phenolic compounds, polysaccharides, lipids and dietary fibres, with caffeine representing only 2% of the beverage’s chemical profile. Some of the advantages and examples of these are given below.

Component	Example	Advantage
Polysaccharides	Cellulose, hemicellulose, pectins, arabinogalactose	Natural components in plants. Aid in viscosity of coffee brew
Alkaloids	Caffeine Trigonelline	Caffeine is the stimulant. Trigonelline adds to the coffee flavour and upon roasting forms niacin (Vitamin B3). Antioxidant and anti-inflammatory properties.
Phenolic compounds	Chlorogenic acid (CGA)	Imparts aroma and taste (bitterness) Antioxidant properties
Melanoidins	Melanoids/ Humic acid	Provides the colour to roasted coffee due to Maillard reaction
Lipids	Triglycerides, Diterpenes (cafestol, kahweol)	8-18% for viscosity of coffee brew, retention of flavour, stable foaming

How long can the effect last?

While the effects (wakefulness), may begin as early as 15 minutes, caffeine peaks in your bloodstream by the 1hour timepoint. Its half-life is around 6 hours². Since withdrawal symptoms occur by 12-24hrs, does it mean it is flushed out of the system by then? I’m still searching…

Caffeine and other drugs?

Not okay with other stimulants. So, no no, with amphetamines, cocaine (why would you even be thinking of doing coke? Bad!), medications of ADHD as it increases the side effects. There are reports that it can lower effects of beta blockers, diuretics and sedatives like benzodiazepines, diazepam and lorazepam, while have synergistic effects with antibiotics like azithromycin, cefepime and gentamycin⁵.

Caffeine reduces the absorption of levothyroxine, a hypothyroid medication and should be consumed after at least a 4hour gap (please contact your physician. I am not a medical practitioner. This is just from research studies).

Caffeine withdrawal

John Hopkins School of Medicine published a study in 1999, where they observed the following⁶–

1. Whether you consume 300mg of caffeine in 1 shot or throughout the day, the withdrawal effects will be similar.
2. Wether you have 100mg or 300mg of caffeine per day, the withdrawal effects will be similar.
3. Withdrawal effects occur with a substantial reduction in caffeine dose too (eg. for people having 300mg of caffeine per day, anything less than 100mg of caffeine resulted in onset of withdrawal).
4. Caffeine withdrawal can occur with even 3-day consistent exposure but the severity worsens if the exposure was for a week or more.

Caffeine withdrawal can occur even with low doses. So, are low doses better than high doses? Is the effect same if we have 25mg or 300mg?

Most people who shift to 25mg of caffeine per day are those trying to get off the coffee wagon. If you’re a beginner, it will take longer to develop tolerance or dependence over time. While the “effect” of coffee remains the same, it’s more difficult to quit/ reduce if you have a higher dose.

So, decaf?

One of the most effective ways to decaffeinate coffee is called a “supercritical CO₂ method”. Coffee beans are soaked in water, carbon dioxide is pumped through the beans under high pressure and temperature which dissolves the caffeine in liquid form, the caffeine-rich liquid passes through activated charcoal which absorbs the caffeine thereby removing 96-98% caffeine.

The internet likes decaf since it reduces risk of withdrawal, prevents disruption of sleep, reduces blood pressure spikes, safer for pregnancy and overall, is a good alternative for people with heart conditions, acid reflux and anxiety.

Since the polyphenols like chlorogenic acid are still present, decaf offers the same antioxidant benefits of caffeinated coffee. Further, one study checked the C-peptide levels (elevated in insulin-resistant type 2 diabetes) and observed reduced C-peptide levels after consumption of coffee- in caffeinated and decaffeinated. This leads me to believe that caffeine is probably not the component which is helping diabetics (which I was debating above)⁷. Again, there’s a study wherein caffeinated and decaffeinated coffee reduced risk of hepatocellular carcinoma, leading me to believe that it’s not just the caffeine which imparts benefits to coffee⁹.

Overall, my understanding of this debate leads me to something very simple – decaf is a way to get over your caffeine addiction. The “benefits” of coffee are similar in both cases. So why not study about the other components of coffee- chlorogenic acid or trigonelline?

Although, there are some interesting studies going on. One study argues that while black coffee and caffeinated coffee with milk and sugar did not have any effect on the glycaemic index post-60 minutes of meals, having decaffeinated coffee with milk and sugar 30 minutes prior significantly reduced glycaemic responses after meals¹⁰. While the authors admit that this effect may be due to the consumption of milk and sugar by itself- they have still not studied black decaffeinated coffee.

But wait, there is a plus side. Decaffeinated coffee reduces cortisol levels- so it does help in managing stress and anxiety while you need to get work done¹¹.

REFERENCES (not a comprehensive list)

1. Nawrot, P., Jordan, S., Eastwood, J., Rotstein, J., Hugenholtz, A., & Feeley, M. (2003). Effects of caffeine on human health. Food Additives & Contaminants, 20(1), 1-30. https://doi.org/10.1080/0265203021000007840
2. Wikoff, D., Welsh, B. T., Henderson, R., Brorby, G. P., Britt, J., Myers, E., … & Doepker, C. (2017). Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children. Food and chemical toxicology, 109, 585-648. https://doi.org/10.1016/j.fct.2017.04.002
3. Natella, F., & Scaccini, C. (2012). Role of coffee in modulation of diabetes risk. Nutrition reviews, 70(4), 207-217. https://doi.org/10.1111/j.1753-4887.2012.00470.x
4. Lakritz, J., Middleton, J. R., Anderson, D. E., Linden, D. R., Sams, R. A., Tessman, R. K., & Tyler, J. W. (2006). Pharmacokinetics of intravenously administered caffeine in healthy alpacas (Lama pacos) and llamas (Lama glama). American journal of veterinary research, 67(6), 1063-1069. https://doi.org/10.2460/ajvr.67.6.1063
5. Reddy, V. S., Shiva, S., Manikantan, S., & Ramakrishna, S. (2024). Pharmacology of caffeine and its effects on the human body. European Journal of Medicinal Chemistry Reports, 10, 100138. https://doi.org/10.1016/j.ejmcr.2024.100138
6. Evans, S. M., & Griffiths, R. R. (1999). Caffeine withdrawal: a parametric analysis of caffeine dosing conditions. The Journal of pharmacology and experimental therapeutics, 289(1), 285-294. https://doi.org/10.1016/S0022-3565(24)38135-2
7. Wu, T., Willett, W. C., Hankinson, S. E., & Giovannucci, E. (2005). Caffeinated coffee, decaffeinated coffee, and caffeine in relation to plasma C-peptide levels, a marker of insulin secretion, in US women. Diabetes care, 28(6), 1390-1396. https://doi.org/10.2337/diacare.28.6.1390
8. Wong, C. X., Cheung, C. C., Montenegro, G., Oo, H. H., Peña, I. J., Tang, J. J., … & Marcus, G. M. (2026). Caffeinated coffee consumption or abstinence to reduce atrial fibrillation: the DECAF randomized clinical trial. JAMA, 335(4), 317-325. https://doi.org/10.1001/jama.2025.21056
9. Kennedy, O. J., Roderick, P., Buchanan, R., Fallowfield, J. A., Hayes, P. C., & Parkes, J. (2017). Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose–response meta-analysis. BMJ open, 7(5), e013739. https://doi.org/10.1136/bmjopen-2016-013739
10. Wong, T. H. T., Wan, J. M. F., Tse, I. M. Y., Sit, W. H., & Louie, J. C. Y. (2021). Consumption of decaffeinated coffee with milk and sugar added before a high-glycemic-index meal lowers postprandial glucose surge when compared with consuming it after the meal. Human Nutrition & Metabolism, 24, 200124. https://doi.org/10.1016/j.hnm.2021.200124
11. Niu, Y. (2024). Effects of Coffee Consumption on Physiological Responses to Acute Mental Stress. North Carolina State University.