5-HTPvsSAMe

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.

SAMe serves as the principal methyl donor in over 100 transmethylation reactions catalyzed by SAM-dependent methyltransferases. In the brain, it donates methyl groups to phosphatidylethanolamine N-methyltransferase (PEMT), converting PE to phosphatidylcholine and maintaining neuronal membrane fluidity critical for receptor function. It methylates DNA via DNMT enzymes, modulating gene expression epigenetically. SAMe is essential for catechol-O-methyltransferase (COMT) activity, which metabolizes dopamine and norepinephrine, and for phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine. It feeds the transsulfuration pathway, producing cysteine via cystathionine beta-synthase (CBS) and cystathionine gamma-lyase, ultimately supporting glutathione synthesis for antioxidant defense. SAMe also donates methyl groups for myelin basic protein methylation, essential for myelin sheath integrity and nerve conduction velocity.