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.

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.

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?

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).

Methylxanthines

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

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).

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):

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).

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.

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.

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).

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…

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).

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.

How does it affect sporting performance?

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

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.

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.”

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).

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.

To bear in mind…

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

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%.

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.

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).

Conclusions

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.

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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