Glycine

Cheapest amino acid supplement on the shelf with two real but limited use cases: (1) 3 g pre-bed for subjectively better sleep — evidence is two small Ajinomoto-funded RCTs (Yamadera 2007, Bannai 2012) with no independent replication, mechanism is core-body-temperature drop via peripheral vasodilation, and (2) NMDA co-agonist substrate — relevant in schizophrenia adjunct trials (10-60 g/day) but generic and likely non-rate-limiting in healthy adults. For Dylan: PHASING-OUT. The V5 plan correctly swaps glycine 3 g for l-tryptophan 1 g pre-bed because l-tryptophan has A-tier evidence + actually feeds the melatonin pathway a late-chronotype is trying to advance. Net cost difference is trivial; net evidence quality is meaningfully better.

Glycine is the smallest amino acid (just NH₂–CH₂–COOH, no side chain) and the most chemically simple. Three distinct mechanisms matter for nootropic/sleep use:

1. Inhibitory neurotransmitter at the glycine receptor (GlyR)

The strychnine-sensitive glycine receptor is a pentameric ligand-gated chloride channel, structurally related to GABA-A. It is the dominant inhibitory transmitter in spinal cord and brainstem (GABA dominates forebrain inhibition; glycine dominates caudal inhibition). Activation opens chloride channels → hyperpolarization → reduced neuronal excitability. This is why strychnine — a glycine receptor antagonist — causes spinal hyperexcitability and tetanic convulsions. GlyR is also expressed at lower density in retina, hippocampus, and some cortical regions.

For oral glycine supplementation, this mechanism is nearly irrelevant because glycine crosses the BBB poorly compared to its endogenous synthesis, and CNS glycine is tightly regulated by glycine transporters GlyT1 and GlyT2. The acute "calming" effect from 3 g oral glycine is not primarily GlyR-mediated.

2. NMDA receptor glycine-site co-agonist (forebrain)

Glycine (and D-serine) is an obligatory co-agonist at the NMDA glutamate receptor — both glutamate AND a glycine-site agonist must bind for the channel to open. The glycine-binding site is on the GluN1 subunit; glutamate binds GluN2. In healthy adults, this site is approximately saturated under normal physiological conditions (synaptic glycine + D-serine are sufficient), which is why oral glycine supplementation does not produce striking cognitive effects in healthy people.

In schizophrenia, the NMDA-hypofunction hypothesis posits that NMDA signaling is impaired (consistent with PCP/ketamine inducing schizophrenia-like symptoms via NMDA antagonism). Adjunct glycine-site agonists have been trialed: glycine itself (10-60 g/day), D-serine, D-cycloserine, and sarcosine (an N-methylglycine that is a GlyT1 inhibitor, raising synaptic glycine indirectly). Results are mixed but suggest modest benefit for negative symptoms in some patients (see Evidence section).

This is the mechanism most often cited when biohackers describe glycine as "cognitive-enhancing" — but the dose required for measurable NMDA-site effect in healthy adults is far above the 3 g pre-bed sleep dose, and the cognitive evidence in healthy populations is essentially absent.

3. Thermoregulation via peripheral vasodilation (the actual sleep mechanism)

This is the best-evidenced mechanism for glycine's sleep effect. Pre-bed glycine (3 g) produces peripheral vasodilation (likely via NMDA-modulated suprachiasmatic nucleus → autonomic outflow), which dissipates core body heat through skin/extremities and accelerates the nocturnal core body temperature drop that is a normal precursor to sleep onset. Bannai et al. (2012, animal models + human PSG correlation) showed that pre-bed glycine reduced core body temperature faster than placebo and shortened polysomnographically-measured sleep onset latency. This is a thermoregulatory effect, not a GABAergic or NMDA effect in any direct neurotransmitter sense.

Practical implication: glycine's sleep effect should stack additively with cold-room/cool-shower behavioral protocols and is theoretically blunted in hot bedrooms.

4. Other roles (relevant context, not primary for Dylan)

• Glutathione synthesis substrate. Glutathione (GSH) is glycine + cysteine + glutamate. Glycine availability becomes rate-limiting for GSH synthesis under oxidative stress, in older adults, and possibly during heavy training — but cysteine availability is the more common bottleneck (which is why NAC supplementation — already in V4 — does more for GSH than glycine alone).
• Creatine biosynthesis substrate. Glycine + arginine + methionine → creatine. Dylan supplements creatine directly; the synthesis pathway is not load-bearing.
• Heme biosynthesis substrate. Glycine + succinyl-CoA → δ-aminolevulinic acid (ALA), the first step in porphyrin/heme synthesis. Not nootropic-relevant.
• Bile acid conjugation. In humans, glycine-conjugated bile acids (glycocholate, glycochenodeoxycholate) outnumber taurine-conjugated ~3:1. Not relevant to oral supplementation effect.
• Collagen synthesis substrate. Glycine is ~33% of collagen by residue (every third residue in the Gly-X-Y triplet). Probably the most-quoted "glycine for skin/joints" claim — but oral glycine is not rate-limiting for collagen synthesis at typical Western dietary intakes.