Caffeine

Effects on alertness, vigilance, and performance, combined with a general cultural acceptance and popularity, means worldwide caffeine remains the most used psychostimulant: 85% of adults in the United States drink on average one-and-a-half cups of coffee per day.¹

A methylxanthine, caffeine is found in various plant seeds, fruits, and leaves: the coffee bean; the tea leaf; the cacao bean; yerba matte leaf; and in the guarana berry. It is more relevant, however, to represent these commodities through the consumer end-products they go into making classified according to concentration of caffeine.

Higher caffeine content

• Coffee
• Energy drinks
• Caffeine tablets

Intermediate caffeine content

• Tea

Lower caffeine content

• Soft drink

Coffee contains hundreds of biologically active phytochemicals apart from caffeine. Caffeine’s molecular structural similarity to adenosine affords it, at moderate doses of 40-300 mg, competitive inhibition of adenosine receptors, which normally tend to inhibit arousal and increase drowsiness.¹ The corollary of that is that caffeine consumption late in the day can extend sleep latency and hinder the quality of sleep,  and induce anxiety, particularly at higher doses (> 200 mg per dose or 400 mg per day). Withdrawal symptoms after habitual use can last just over a week but peak after 1-2 days of abstinence and include headache, fatigue, drowsiness, flattened mood, and flu-like symptoms; all of which can be mitigated by gradually tapering consumption.

Tolerance to the cardiovascular effects of caffeine, related to raised epinephrine levels, develops within a week although remains incomplete in some. Overall, however, the clinical effect on blood pressure from caffeine is considered minimal, perhaps because of counteracting phytochemicals present in coffee. And while coffee contains cafestol, levels of this cholesterol-raising chemical remain negligible in instant coffee.¹ Similarly, consumption of up to six cups of coffee per day has not been associated with atrial fibrillation, coronary artery disease, or stroke. On the contrary, coffee consumption is associated with reduced cardiovascular risk with maximal effect at 3-5 cups per day.¹ Moreover, modest effects on energy balance and tolerance to insulin resistance suggest caffeine is not harmful in matters of weight and metabolism. Coffee is not associated with an increased incidence of cancer, if anything perhaps the opposite, and caffeine seems to promote detoxification of the liver. Coffee consumptions is associated with a reduction in both cholesterol (biliary) stones and gallbladder cancer, and a reduction in risk of kidney stones. Caffeine intake is also associated with a lower risk of Parkinson’s disease without any evidence for a link with dementia or Alzheimer’s disease. In fact, cohort studies suggest that consumption of at least 2 cups of coffee per day is associated with a reduced all-cause mortality in Caucasians, Africans, and Asians.

In pregnancy, trials do however seem to reflect deleterious potential, including lower birth weight and higher risk of pregnancy loss (possible publication bias and confounding by smoking and nausea), as caffeine readily crosses the placenta and may pose a risk, especially in slow metabolisers.¹ Modest caffeine intake during pregnancy and lactation, below 200 mg per day, is prudent.

Metabolism

Absorption all but complete within 45 minutes, so that caffeine blood levels peak within 15 minutes to 2 hours of ingestion. Generally between 2.5 and 4.5 hours, the half-life of caffeine is, however, subject to large inter-individual (heritable) variation. This effect is partially offset by the tendency for slow caffeine metabolisers to lower habitual caffeine intake.¹ 

• Smoking greatly accelerates caffeine metabolism, reducing the half-life by up to 50%, whereas
• Oral contraceptive use: doubles the half-life of caffeine.
• Pregnancy: greatly reduces caffeine metabolism, especially in the third trimester, when the half-life of caffeine can be up to 15 hours.

Metabolised principally through CYP1A2 through the intermediaries paraxanthine, theophylline, and theobromine, caffeine is ultimately excreted as uric acid in the urine. CYP1A2 substrates: quinolones, cardiovascular drugs, bronchodilators, antidepressants (slow caffeine metabolism by competitive inhibition). Although caffeine stimulates urine output, this seems to occur with few detrimental effects to hydration when taken in moderate doses of < 400 mg per day.

Toxic effect

Consuming 1.2 g of caffeine is estimated to cause toxicity. Such high levels of caffeine consumption lead to anxiety, restlessness, nervousness, dysphoria, insomnia, excitement, psychomotor agitation, and rambling flow of thought and speech. Deaths from caffeine toxicity generally relate to tablet or supplement use—especially where no tolerance to caffeine has allowed to develop— and often in associated psychiatric disorders but occasionally in athletes as well.

Persons who consume energy drinks should thus be advised to check the caffeine content and avoid high consumption (>200 mg of caffeine per occasion) or consumption in combination with alcohol.¹

Moderate caffeine consumption appears consistent with a healthy lifestyle.

Reference

1. van Dam, Rob M.; Hu, Frank B.; Willett, Walter C. Coffee, Caffeine, and Health. N Engl J Med 383(4); July 23, 2020: 369–378.  DOI: 10.1056/NEJMra1816604.