Theacrine, the next Caffeine?

Theacrine, the next Caffeine?

We tell you all about Theacrine, a substance considered a new form of caffeine, albeit with some differences.

Society demands something clearly:

Substances that increase psychomotor performance.

In the search for central nervous system modulator complexes, many dopaminergic, catecholaminergic, cholinergic agonists have appeared… all with a particular mechanism of action and specific targets of action.

Today we will analyse in depth what Theacrine is and what its effects are, as well as whether its use is recommended. Stay and we’ll tell you!

What is Theacrine?

Theacrine (Acid 1,3,7,9-Tetramethyluric) is a caffeine-homologous molecule, except for the addiction of a ketone and a carboxyl group to the imidazole ring.

Caffeine vs theacrine

Figure I. Molecular structure of Theacrine and Caffeine.

And what does this mean?

Well, thanks to its chemical structure, like the rest of the methylxanthines, it possesses the capacity to stimulate the central nervous system.

But how much? How can we know?

Indeed, what will determine the activity of Theacrine will be its ability to cross the blood-brain barrier.

Since it is the main limiting factor of purines to reach the receptors of neurones that “keep us active”.

Where is it found?

In the search for an alkaloid with similar effects, we have found tetramethyuric acid (or theacrine), a methylated purine which was unknown until a few years ago; that we have succeeded in extracting from kucha tea and, of course, have learned to synthesise it in the laboratory.


Figure II. Graph representation of the Theacrine obtained from kucha tea (Camellia assamica var. Kucha). (Li et al., 2015).

But why is it special?

Because thanks to its chemical structure, which is tremendously similar to the caffeine molecule, it has been postulated that it may be the future substitute for caffeine.

Are we onto the next caffeine? Keep reading…


Substances with purine structure (such as caffeine, theobromine, or theophylline) are methylxanthines, natural (and legal) substances with the following properties:

  • Catecholaminergic effects (stimulating the secretion of epinephrine and norepinephrine);
  • Direct mechanism of vasoconstriction (by agonism of α1 and α2 receptors);
  • Cardiorespiratory stimulation (by agonism β1);
  • Coronary dilation, bronchodilation (by agonism, β1);
  • Diuresis (by increasing uric acid secretion in the proximal contoured tubing); and
  • Central nervous system stimulation (by antagonism A2A receptors, increased density of D2r and increased glutamic metabolism).
The ability to stimulate central nervous system activity is dependent on the permeability of the substance at crossing the blood-brain barrier.

This is why caffeine is superior to the rest of methylxanthines to stimulate the central nervous system, promote concentration, and speed of reaction; the reason is that it has a more lipophilic structure than the rest of methylxanthines, which improves the transport and agonism of the substance (Monteiro et al., 2016).


Figure III. Effects on the central and peripheral of the action of the methylxanthines. (Monteiro et al., 2016).

Caffeine is, possibly, the most used supplement to improve activity function. We tell you here.

Properties of Theacrine

Theacrine has the ability to cross the blood-brain barrier easily.

In the following graph we can see as from 15’ to 2h, the concentrations of Theacrine in plasma and in the brain are correlated in a quasi-perfect way (Li et al., 2015):

Theacrine plasm

Figure IV. Correlation between plasma (filled columns) and brain (empty columns) Theacrine concentrations; 15 min, 30 min, 1h, and 2h after consumption. (Li et al., 2015).

This indicates that Theacrine is able to access our brain without any problems; possibly because, like caffeine, it is more lipophilic than other xanthines.

The lipophilic character of a substance is the one that gives it a greater conductive force and therefore greater capacity to reach the target receptor, or to spread the lipid bilayer; that is… more potency.

However, an extremely lipophilic substance can lead to strong toxicity; due to its high transport, binding and retention capacity; it can be a substance that requires longer metabolisation time and therefore we have longer acting in the body.

That is why pharmacologic substances are often recommended as more hydrophilic (as long as they are capable of acting) as better; because they are simply safer.

Logic tells us that since Theacrine has a more methyl group it should be more lipophilic and therefore more powerful, right?

No, we do not know for sure why, but in fact it is slightly “softer” than caffeine itself; perhaps it is because of the addition of ketone to the molecule or, possibly, because of a mixture that has a lower logarithmic distribution coefficient, coupled with lower bioavailability (He et al., 2017).

What does this say…?

Theacrine with Caffeine, for Greater Effectiveness

Co-administration of caffeine with Theacrine significantly increased activity.

The data in the table below are clear: Theacrine alone takes time to reach its maximum concentration in the blood, is cleaned out before the body and requires more doses to achieve the effects.

Theacrine methabolism

Figure V.Metabolism of Theacrine after consumption of 25mg (condition 1), 125mg (condition 2), and 125mg+150mg of caffeine (condition 3). (He et al., 2017).

Caffeine dependence to Theacrine decreases the time to maximum concentration, increases the substance’s half-life by more than 10h, and this makes the area under the curve per unit of time 50% greater.

What am I saying?

That considering that 150mg of caffeine reaches a maximum concentration of 33.4ng/mL; and that Theacrine alone reaches 34.1ng/mL (about the same), but is more hydrophilic and therefore less potent; and 150mg is a low dose of caffeine, whereas 125mg is a high dose of Teacrine…

Theacrine is NOT a substitute for Caffeine…

Theacrine, consumed alongside caffeine, or not at all.

Genetic question

Moreover, it’s always worth remembering that those who express a CYP1A2 genotype with one or both C alleles, are considered “slow metabolisers” (an incorrect term, by the way) and show minor ergogenic effect (in case of AC) and non-existent or even negative (in case of CC) before caffeine consumption.

This association appears to be dependent on regular consumers of metabolisable xenobiotics in this way (smokers and regular coffee consumers).

Caffein table

Figure VI. Time in a speed test after consuming a placebo (full bars), and low-dose caffeine (2mg/kg, grated bars), and at moderate doses (4mg/kg, empty bars); based on the genotype expressed from rs762551. Shows the positive effect of caffeine expressed on the genotype (A; A) and negative in (C; C). (Guest et al., 2018).

This is why we potentially are born with our predefined individual response.

But if you had the luck of falling into the world with the rs762551 AA genotype, the consumption of Theacrine, presumably having a metabolisation by this cytochrome isoenzyme, will help us significantly enhance the effects of caffeine, and this in turn, of Theacrine. They are complementary.

How does it affect sporting performance?

As virtually no study analyses the genotype expressed in the subjects involved, we can find results like these:

Bench press squat

Figure VII. Changes in 1RM of bench press and squat after consumption of placebo, 300mg of Theacrine, 300mg of caffeine and 150mg of each substance; in trained subjects. (Cesareo et al., 2019).

Neither 300mg of caffeine, nor 300mg of Theacrine, nor its combination (a fairly high dose), have been shown to increase the performance of participants in strength tests.

But then the 125mg combination of Teacrine + 150mg of caffeine was 7% higher than the equivalent dose of caffeine and 11% higher than the equivalent dose of Teacrine in a run-to-exhaustion test.

Only Theacrine (less than half the dose of the study in the graph above) increased athletes performance by 27%; these subjects were mostly clear “fast metabolisers.”

Effort test

Figure VIII. Changes in time until exhaustion in a maximum intensity stress test after consuming a placebo, theacrine, caffeine or a combination. (Bello et al., 2019).

Do you realise that these are very strange results? What’s going on?!

Explanation of the results of the studies

Caffeine is one of the most potent (acute) ergogenic aids on the market, be sure to note that it’s powerful enough that the WADA (World Anti-Doping Agency) has been trying to ban it for years, and there are currently maximum concentrations of metabolites in urine from which it is considered doping.

However, our genetics will determine our individual response to methylxanthines consumption, alleles expressed in different SNPs (parts of the genome that we know vary between individuals) associated with certain genes will determine the metabolisation and positive effects of caffeine (CYP1A2), side effects (ADORA2A), dopaminergic effects and anxiety (DRD2), or effects on fat loss (ADRB2), among many others known and unknown.

If you have bad luck, neither Caffeine nor Theacrine will help you… ;(

To bear in mind…

With all the above, here’s a brief summary of this data:

  • Theacrine shares a mechanism of action with caffeine (and possibly metabolisation), but has a different pharmacokinetics:
  • Takes longer to reach maximum concentration (1 hour longer).
  • Its relative power is lower, and the concentration reached does not compensate for it.
  • The half-life of caffeine lasts 6 hours, that of Theacrine between 16.5h and 26.1h; as you express the genotype (T; T) in rs5751876 and (C; C) in rs762551; with a high dose of Theacrine you can be eating a roof for two days…
  • The combination of caffeine and Theacrine exerts a synergistic effect and increases the stimulating potency of the substances.

Potential of Theacrine

Teacrine, unlike caffeine, “does not generate tachyphylaxis”, i.e. does not produce tolerance from use.

However, this conclusion is formulated on the basis of reports of mood report scales, which, although validated, are the most imprecise (Taylor et al., 2016). Until we assess the physiological response to continued consumption of Theacrine, we cannot conclude this with a safety of 100%.

That is why Theacrine is an “impoverished” caffeine, with the ability, through its joint administration, to increase the effects of both.

And although they share mechanisms of action, by their very long half-life (especially in combination with caffeine), Theacrine has shown to be useful by inhibiting phosphodiesterase in mouse neurones, and improving cortical glucose metabolism, after subjecting them to stressful factors.

It improves serotonin/dopamine balance, allowing mice to be “calmer”, improving their learning and memory.

Theacrine potential

Figure IX. Mechanism of action showing the potential of Theacrine attenuating cognitive deficit after exposure to stressful stimuli by controlling glucose metabolism (increased activity of GLUT1 and 3; inhibition of LDH, increased synthesis of 5HT and balance in inhibitory/excitatory neurotransmitters). (Li et al., 2015).


The potential of Theacrine in the future is its nootropic action more than its own stimulating profile, relieving the latter to mere combination with caffeine.

Further research will be needed as the pharmacokinetics of this purine are interesting and possibly not all of its potential effects have yet been discovered.

Personally, I would use it as a reducer of caffeine-induced excitotoxicity in times of high academic stress.

Bibliography Sources

  1. Cesareo, K. R., Mason, J. R., Saracino, P. G., Morrissey, M. C., & Ormsbee, M. J. (2019). The effects of a caffeine-like supplement, TeaCrine®, on muscular strength, endurance and power performance in resistance-trained men. Journal of the International Society of Sports Nutrition, 16(1), 47.
  2. Di, L., & Kerns, E. H. (2016). Chapter 10 – Blood-Brain Barrier. In L. Di & E. H. Kerns (Eds.), Drug-Like Properties (Second Edition) (Second Edition, pp. 141–159).
  3. Guest, N., Corey, P., Vescovi, J., & El-Sohemy, A. (2018). Caffeine, CYP1A2 Genotype, and Endurance Performance in Athletes. Medicine and Science in Sports and Exercise, 50(8), 1570–1578.
  4. He, H., Ma, D., Crone, L. B., Butawan, M., Meibohm, B., Bloomer, R. J., & Yates, C. R. (2017). Assessment of the Drug-Drug Interaction Potential Between Theacrine and Caffeine in Humans. Journal of Caffeine Research, 7(3), 95–102.
  5. Li, Y.-F., Chen, M., Wang, C., Li, X.-X., Ouyang, S.-H., He, C.-C., … He, R.-R. (2015). Theacrine, a purine alkaloid derived from Camellia assamica var. kucha, ameliorates impairments in learning and memory caused by restraint-induced central fatigue. Journal of Functional Foods, 16, 472–483.
  6. Monteiro, J. P., Alves, M. G., Oliveira, P. F., & Silva, B. M. (2016). Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks. Molecules (Basel, Switzerland), 21(8).
  7. Taylor, L., Mumford, P., Roberts, M., Hayward, S., Mullins, J., Urbina, S., & Wilborn, C. (2016). Safety of TeaCrine(R), a non-habituating, naturally-occurring purine alkaloid over eight weeks of continuous use. Journal of the International Society of Sports Nutrition, 13, 2.

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About Alfredo Valdés
Alfredo Valdés
He is a specialist in metabolic physiopathology training and in the biomolecular effects of food and physical exercise.
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