5-HTPvsL-Theanine

5-HTP readily crosses the blood-brain barrier via the large neutral amino acid transporter (LAT1/SLC7A5), unlike serotonin itself which cannot. Once in the brain, aromatic L-amino acid decarboxylase (AADC, also called DOPA decarboxylase) converts 5-HTP to serotonin (5-hydroxytryptamine) using pyridoxal-5-phosphate (active vitamin B6) as a cofactor. This completely bypasses tryptophan hydroxylase (TPH2), the rate-limiting enzyme in the normal serotonin synthesis pathway from dietary L-tryptophan. The result is a reliable, dose-dependent increase in serotonin across multiple brain regions including the dorsal raphe nucleus, hippocampus, and prefrontal cortex. Elevated serotonin activates 5-HT1A autoreceptors (calming), 5-HT2A/2C postsynaptic receptors (mood modulation), and 5-HT3 receptors (gut-brain signaling). In the pineal gland, serotonin is converted by arylalkylamine N-acetyltransferase (AANAT) to N-acetylserotonin, then by hydroxyindole O-methyltransferase (HIOMT) to melatonin — explaining the sleep-promoting effects.

L-Theanine (gamma-glutamylethylamide) crosses the blood-brain barrier via the large neutral amino acid transporter (LAT1/SLC7A5) and exerts anxiolytic effects through multiple pathways. It increases GABA synthesis by serving as a substrate for glutamate decarboxylase (GAD), elevating inhibitory tone without directly binding GABA-A receptors — avoiding sedation. It modulates serotonin by increasing tryptophan hydroxylase (TPH2) activity and raises dopamine levels in the prefrontal cortex via inhibition of dopamine reuptake. L-Theanine antagonizes glutamate binding at AMPA and kainate receptor subtypes (GluA1-4, GluK1-5), reducing excitatory neurotransmission and excitotoxicity risk. This glutamate antagonism, combined with increased GABA, drives the characteristic increase in alpha brain wave power (8-14 Hz) in the posterior parietal and occipital cortex — the EEG signature of relaxed alertness. When co-administered with caffeine, L-theanine attenuates caffeine-induced increases in blood pressure and anxiety by modulating sympathetic nervous system activation through alpha-2 adrenergic receptor pathways, while caffeine's dopaminergic and adenosine-blocking effects on focus and attention are preserved.