Theacrine

Theacrine is a purine alkaloid with structural similarity to caffeine which is found in a species of plant from which Kucha tea is made: Camellia assamica variant kucha, which shares its genus with that of green tea.^[1][2] Kucha tea also contains caffeine and theabromine,^[3] and it seems that theacrine is synthesized in the plant from caffeine.^[3] Another alkaloid, liberine (synthesized from theacrine in some plants^[4]) is not present in Kucha leaves, resulting in a relative accumulation of theacrine compared to liberine-synthesizing plants.^[3]

Theacrine is an alkaloid structurally similar to caffeine, and is produced from caffeine in some plants. It is known to occur in high levels in the plant used for Kucha tea, since the plant can produce theacrine but theacrine itself is not further metabolized, resulting in theacrine accumulation

Studies assessing the sources of theacrine have found them to be:

• Camellia assamica var. Kucha^[1] at 1.8+/-0.05% of the leaves (dry weight^[1]) or the range of 0.6-2.7% dry weight^[3]

Theacrine is found in respectable amounts in the leaves of_Camellia assamica variant kucha which are used to make the tea, and not much information exists on other sources of theacrine at this moment in time

Theacrine's chemical name is 1,3,7,9-tetramethyluric acid, in comparison to caffeine's 1,3,7-trimethylxanthine, with the only difference in structure being an additional methyl group on the 9-carbon and an additional ketone group, which changes caffeine's xanthine into a uric acid moiety.

The structure of theacrine is essentially caffeine with an additional methyl group (CH₃) and an additional ketone group (=0)

Theacrine appears to be a solubilizing agent, capable of increasing the solublilty of other molecules in solution,^[5] which appears to be a property of purines in general,^[6] but theacrine has twice the potency of caffeine in this regard (and even greater than sodium deoxychlorate).^[7][6]

Most purine molecules structured similarly to caffeine have a solubilizing ability, and theacrine appears to be better than caffeine at doing so.

The locomotor enhancing properties of theacrine appears to involve adenosine signalling, as the reduction of locomotion seen with adenosine antagonists (a combination of A1 and A2A inhibition) is attenuated with coadministration with 48mg/kg theacrine via intraperitoneal injections.^[2]

Although the role is not fully elucidated, theacrine appears to be capable of causing adenosine signalling changes similar to caffeine

Dopamine signalling appears to be involved in the locomotor properties of theacrine, as dopamine antagonists (D1 and D2 receptor antagonists) can partially attenuat the increase in locomotion seen with an infusion of 48mg/kg theacrine.^[2]

Similar to the role on adenosine signalling, theacrine may influence dopaminergic signalling in the same manner caffeine does through adenosine signalling

Oral ingestion of 8, 16, and 32mg/kg theacrine in mice appears to exert dose-dependent analgesic properties as assessed by a hot plate test (24.5-34.1% increase in latency) and acetic-acid induced writhing test (10.6-18.9% reductions in writhing; 8mg/kg ineffective) performed an hour after theacrine ingestion;^[8] the potency of theacrine was nonsignificantly less than the reference drug of 10mg/kg indomethacin.^[8]

Oral administration of theacrine in mice cause possible pain reduction in preliminary tests, with a potency comparable or lesser than indomethacin

One study in humans found that TheaTrim had no effect on two measures of cognition and working memory (Digit Symbol Substitution Test and Trail Making Test) when ingested immediately before the testing battery compared to both placebo and 150 mg caffeine controls.^[9] TheaTrim is a proprietary blend of theacrine (amount unspecified due to its proprietary nature), 150 mg caffeine, white willow bark, S-Adenosyl Methionine, Rauwolfia vomitoria extract, citrus bioflavonoid complex, and vitamin B12. However, subjective reports of attentiveness, focus, and alertness trended toward statistical significant for the TheaTrim group.^[9] These effects cannot be definitively attributed to theacrine, however, since the supplement did not contain pure theacrine alone, but a host of other ingredients.

The one human study on theacrine done to date found borderline subjective effects, but not objective effects, on attention and alertness, but these possible effects cannot be traced to theacrine specifically since a blend of supplements was used.

Subjective reports of grogginess were significantly lower immediately after taking TheaTrim, a proprietary supplement containing an unspecified amount of theacrine along with 150 mg caffeine and several other ingredients (listed in Attention and Focus section above), compared to both a 150 mg caffeine and placebo control. Subjective feelings of lethargy for the TheaTrim group trended toward significance versus both placebo and caffeine.^[9]

A proprietary blend of supplements containing both theacrine and caffeine may improve subjective feelings of grogginess. However, this putative effect cannot be attributed to theacrine alone since the blend contained a host of other supplements.

In mice subject to acute restraint stress following seven days of theacrine supplementation of 10-30mg/kg, adverse changes in liver enzymes and antioxidant enzymes seen with immobilization stress was attenuated, suggesting an anti-stress property.^[1]

There may be stress reducing properties with low doses of theacrine. These doses are thought to be at comparible levels to that which humans would ingest when consuming tea that contains theacrine

In rats injected with 24 or 48mg/kg theacrine, it was noted that the higher tested dose was able to increase locomotion in a manner dependent on both adenosinergic and dopaminergic signalling (similar to caffeine) while the lower dose trended to do so;^[2] as these effects were replicated by direct infusion into the nuclear accumbens, it is possible that theacrine's mechanism of action involves stimulation of this brain region,^[2] again similar to how caffeine acts.^[10]

Chronic administration of theacrine (for seven days) did not appear to cause any significant sensitization to the locomotor enhancing properties of theacrine, as the increase in locomotion seen on day one (294%) was similar to day seven (259% enhancement) which exceeded control groups at both time points.^[2] In contrast, administration of caffeine via infusion over seven days tends to induce sensitization;^[11] the reason for this difference between theacrine and caffeine is not yet known as long-term tests have not yet been conducted.

High doses of theacrine via infusion appear to be capable of causing an increase in locomotion in rats, thought to be due to acting on the same brain area as caffeine. Theacrine, for unknown reasons, has not yet been associated with sensitization to these effects in contrast with caffeine, even though the theacrine dose where locomotion is enhanced was higher than what would be ingested through a moderate consumption of tea

Theacrine at more practical doses (10mg/kg orally) has been associated with sedative properties but without significant alteration in locomotion,^[12] which has led to the hypothesis of a biphasic curve occurring with theacrine where low doses suppress locomotion and high doses enhance it.^[2] This has been noted with caffeine where low (3mg/kg) and high (100mg/kg) doses suppress activity while the midrange of dosing enhances activity.^[13][14]

Lower does of theacrine are implicated in a minor sedating property, and this general notion (low and high doses being suppressive but the midrange being enhancing) is another similarity with caffeine. The dose that is sedating is more likely to be seen with consumption of Kucha tea in humans

Theacrine at 10 and 30mg/kg (oral ingestion) appears to prolong phenobarbital induced sleep time suggesting a sedative property when taken 30 minutes prior to sleep, with the same dose of caffeine having a notable anti-sleep property in the same test.^[12]

Doses of theacrine likely found in tea produced from Kucha leaves may be able to have sedating properties, although the mechanisms underlying this are not yet known

The liver damage that is seen in mice subject to acute restraint stress (a model for acute stress in humans) appears to be attenuated in a dose-dependent manner with pretreatment of 10-30mg/kg theacrine for seven days prior to stress.^[1] The alterations seen in mRNA levels for antioxidant enzymes (SOD, catalase, and glutathoine) and inflammatory biomarkers (IL-1β, IL-6, TNF-α, and IFN-γ) also appeared to be normalized with the highest oral dose.^[1]

One study noted benefits to the liver secondary to anti-stress properties of theacrine, although any direct effects on liver function with theacrine has not yet been investigated

Theacrine at 8-32mg/kg oral ingestion to mice appears to have acute antiinflammatory properties in ear edema and carrageenan-induced paw edema tests.^[8]

The direct antioxidant capacity of theacrine appears to be significantly lower than the reference drugs used in one study (trolox and Vitamin C) at the same concentration.^[1]

Theacrine appears to have a low potency direct antioxidative property when tested in vitro

The acute oral LD₅₀ of theacrine to mice appears to be 810.6mg/kg (769.5–858.0mg/kg).^[8]

Theacrine has been noted to cause chromosomal abberations in plant cells, which is standard for methylated oxopurine compounds (including caffeine).^[5] Currently no genotoxicity studies in mammalian cells exist.

Possible genotoxicity of theacrine is unknown, but possibly comparable to caffeine