As a non-protein amino acid, L-theanine crosses the blood-brain barrier, exerting various neurophysiological and pharmacological effects including: anxiolytic and calming effects, due to inhibitory neurotransmitters and selective serotonin and dopamine modulation; cognitive improvements perhaps through decreased NMDA-dependent CA1 long-term potentiation (LTP) and increased NMDA-independent CA1-LTP; and improved selective attention during mental tasks likely due to changes in alpha brain wave activity ⁽²⁵⁾. Neuroprotective effects are also thought to be due to its selective binding to glutamate receptors ⁽²⁾.

In animal models, L-theanine appears to have a dose-dependent biphasic effect on NSAID-induced gastric ulcers, delaying healing at higher doses (40 mg/kg), but accelerating healing at lower doses (10 mg/kg) perhaps through the maintenance of glutathione levels thus protecting against oxidative damage ⁽²⁶⁾.

In human studies, L-theanine attenuated effects of caffeine on oxygenated hemoglobin, cognition, and mood, suggesting both independent and interactive effects between the two compounds ⁽²²⁾. Other studies suggest that combining caffeine and theanine intake causes their individual effects to counteract each other ^(30) (31). L-theanine also stabilizes glutamatergic concentrations in the brain, which may explain its therapeutic effect in patients with schizophrenia ⁽²¹⁾.

L-theanine was shown to increase the antitumor activity of chemotherapeutic drugs doxorubicin and idarubicin ^(5) (6). These agents normally bind the glutamate receptor and the complex is transported across the cell resulting in reduced concentrations, hence attenuating effects of these drugs. Consequent mechanistic studies revealed that L-theanine, a glutamate analogue, competes with glutamate to bind the glutamate receptor, resulting in suppression of chemotherapy efflux (extracellular transport), increasing their concentration ⁽²⁷⁾.

Interestingly, L-theanine also reduces the adverse effects of doxorubicin. The proposed mechanism is based on the variance of glutamate receptors expressed in normal and tumor cells. Whereas theanine binds the glutamate receptor in tumor cells, it is metabolized to glutamate in normal cells. This increase in glutamate likely results in increased efflux of doxorubicin from the cells, thereby decreasing toxicity ⁽²⁸⁾.

Animal models indicate the prevention of doxorubicin-induced acute hepatotoxicity occurs through suppression of intrinsic caspase-3-dependent apoptotic signaling ⁽²⁴⁾. L-theanine does not induce or inhibit cytochrome P450 enzymes ⁽⁹⁾.

Some novel theanine derivatives were found to inhibit lung tumor growth by targeting EGFR/VEGFR-Akt/NF-kappaB pathways ⁽²³⁾.