Caffeine or Paraxanthine: What's the Difference

Paraxanthine is sold as "next-generation caffeine," although in reality it forms from caffeine in our liver after every cup of coffee. The editorial team explains how these substances differ chemically and pharmacologically and what among the marketing promises has confirmation.

Paraxanthine is caffeine "after the liver"

Paraxanthine (1,7-dimethylxanthine) is not an exotic new plant substance but the main product of caffeine's transformation in our body. Every time you drink coffee, most of the caffeine in the liver is converted precisely into paraxanthine. In recent years it has begun to be produced as a separate supplement and positioned as "the next generation of caffeine."

Chemically, paraxanthine differs from caffeine only by the absence of one methyl group at position 3. The liver's enzymes, primarily cytochrome CYP1A2, cleave off this group, and dimethylxanthine is formed. Other, less significant pathways yield theobromine and theophylline.

According to pharmacokinetic reviews, in particular the 2011 review by Arnaud, in humans paraxanthine accounts for roughly 70-80% of metabolized caffeine. This means that a significant part of the "coffee" effect in the late hours after a cup of coffee may be due precisely to paraxanthine.

So the question of "caffeine or paraxanthine" is really a question of whether it makes sense to take the active metabolite directly, bypassing the stage of hepatic conversion.

Mechanism of action: the shared and the distinct

Like caffeine, paraxanthine is an antagonist of adenosine receptors A1 and A2A. According to laboratory studies, its affinity for these receptors is comparable to that of caffeine or even slightly higher. It is precisely the blocking of adenosine that explains the reduction in fatigue and the increase in alertness.

Advocates of paraxanthine also point to other possible effects, for example an influence on dopamine transmission or on phosphodiesterase enzymes. However, these data were obtained mainly on cells and animals, and their significance for humans at real doses has not been established.

An important historical fact: as early as 1995 Benowitz and colleagues compared the intravenous administration of caffeine and paraxanthine to humans and showed that paraxanthine has sympathomimetic effects similar to those of caffeine, in particular affecting blood pressure. That is, paraxanthine is not a "mild" or "passive" metabolite but a full-fledged stimulant.

The claimed differences in "mildness" of action, such as less anxiety, are partly attributed to the fact that paraxanthine is not converted into theophylline and theobromine, as well as to a lesser dependence on individual CYP1A2 activity. However, there are so far few independent comparative studies in humans that would convincingly confirm this.

Pharmacokinetics and genetics

The rate of caffeine elimination varies several-fold between people. It is affected by genetic variants of CYP1A2, smoking (accelerates), pregnancy and oral contraceptives (slow it down), and certain medications. This is what explains why one person sleeps after an evening espresso while another cannot fall asleep after an afternoon coffee.

Paraxanthine is also metabolized with the participation of CYP1A2, but when taken directly the body bypasses the first stage - the conversion of caffeine. In theory this may make the blood concentrations of the active substance more predictable, although paraxanthine itself also has individual variability of elimination.

According to pharmacokinetic studies, the half-life of paraxanthine in humans is comparable to that of caffeine, that is, it too is measured in hours. So there is no basis for expecting that paraxanthine "will not affect sleep."

• Shared: antagonism to adenosine, a stimulating effect, involvement of CYP1A2.
• Distinct: paraxanthine does not require the first demethylation step and does not form theophylline and theobromine.
• Unknown: whether this yields a noticeable advantage in performance or tolerability.

Comparison table

The editorial team brought the main characteristics of the two substances together into one table.

The table clearly shows the main asymmetry: mechanistically the substances are very close, but in the volume of research caffeine is orders of magnitude ahead. For paraxanthine as a separate ergogenic supplement the number of randomized human studies is small, and some of them were carried out with the support of raw-material manufacturers.

From the standpoint of doping control the situation is specific: paraxanthine is a natural metabolite of caffeine that is detected in the urine of every person who drinks coffee. It is not itself separately listed in the Prohibited List, but tested athletes should check the position of their anti-doping organization.

Finally, price: caffeine remains one of the cheapest supplements, whereas paraxanthine so far costs significantly more.

Safety: what is known and what is not

For caffeine the safety limits are carefully assessed: EFSA considers up to 400 mg per day and up to 200 mg at once safe for healthy adults, and up to 200 mg per day for pregnant women. The side effects of excessive doses are also known: tachycardia, tremor, anxiety, insomnia.

Since paraxanthine is constantly present in the body of people who drink coffee, one may assume that at moderate concentrations it is not a foreign substance. However, taking a separate supplement creates a different concentration profile, and there are as yet few long-term safety studies of precisely this form.

It is important not to combine paraxanthine with a large amount of caffeine, believing them to be "different" substances. Pharmacologically they act on the same receptors, so their effects add up - and the side effects too.

People with cardiac arrhythmias, uncontrolled hypertension, anxiety disorders, pregnant women and those taking medications that interact with CYP1A2 (for example, some fluoroquinolone antibiotics or fluvoxamine) should take any methylxanthines only after consulting a doctor.

Editorial conclusions

Paraxanthine is not an alternative to caffeine "from another plant" but its main active metabolite, which with coffee is formed in the liver in large amounts.

The mechanism of action of both substances is shared - the blocking of adenosine receptors. The claimed advantages of paraxanthine (less anxiety, predictability of action) are logical but so far weakly supported by human studies.

Caffeine remains the best-studied substance with a proven effect and known safety limits. Paraxanthine is an interesting novelty that should be treated with moderate skepticism until independent data appear.

To understand the topic better, read also our articles on the genetics of caffeine metabolism, on theacrine as "caffeine without tolerance," and on caffeine and the athlete's sleep.

References

1. Arnaud MJ. Pharmacokinetics and metabolism of natural methylxanthines in animal and man. Handb Exp Pharmacol. 2011;(200):33–91.
2. Benowitz NL, Jacob P 3rd, Mayan H, Denaro C. Sympathomimetic effects of paraxanthine and caffeine in humans. Clin Pharmacol Ther. 1995;58(6):684–691.
3. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999;51(1):83–133.
4. Guest NS, VanDusseldorp TA, Nelson MT, et al. International society of sports nutrition position stand: caffeine and exercise performance. J Int Soc Sports Nutr. 2021;18(1):1.
5. Grgic J, Grgic I, Pickering C, et al. Wake up and smell the coffee: caffeine supplementation and exercise performance — an umbrella review of 21 published meta-analyses. Br J Sports Med. 2020;54(11):681–688.
6. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion on the safety of caffeine. EFSA Journal. 2015;13(5):4102.