Glycine

Glycine is an amino acid and neurtotransmitter. It can play both stimulatory and depressant roles in the brain. Supplementation can improve sleep quality.

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The lowest active dose of glycine supplementation in humans tends to be the 1-3g dosage range, although doses of up to 45g have been used without apparent side-effects.


The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Glycine has in your body, and how strong these effects are.
GradeLevel of Evidence
ARobust research conducted with repeated double blind clinical trials
BMultiple studies where at least two are double-blind and placebo controlled
CSingle double blind study or multiple cohort studies
DUncontrolled or observational studies only
Level of Evidence
EffectChange
Magnitude of Effect Size
Scientific ConsensusComments
CSymptoms of Schizophrenia

Minor

Is able to decrease symptoms of schizophrenia similar to both D-serine and sarcosine, but this occurs at an impractically high dose (minimum effective dose being around... show

CCognition

Minor

There are improvements in cognition due to glycine being able to treat schizophrenia and due to glycine being able to improve sleep; two states of impaired cognition.

CSleep Quality

Minor

In persons undergoing mild sleep deprivation, 3g of glycine an hour prior to sleep is able to increase sleep quality and improve self-reports of fatigue and well being... show

CFatigue

Minor

The reduction in fatigue may solely be secondary to how Glycine supplementation can improve sleep quality


Disagree? Join the Glycine Discussion

Table of Contents:


Edit1. Sources and Structure

1.1. Sources

Glycine is a dietary amino acid that serves as both a constitutional amino acid (used to create protein structures such as enzymes) and as a neurotransmitter/neuromodulator.

1.2. Structure

Glycine is known to be the smallest amino acid with a molar mass of 75.07g,[1] beating out alanine (89.09g).

1.3. Comparisons to other Glycinergics

D-Serine is an amino acid that is mechanistically similar to glycine in the sense that it can act on the glycine binding sites of NMDA receptors with similar potency[2][3][4] but differs as it cannot be transported by glycine transporters due to differences in size.[5] Possibly due to differences in transportation, D-serine is more effective at enhancing glutaminergic signalling through NMDA receptors as 1μM causes a 52+/-16% increase (further increases at 10-30μM) while 100μM of glycine is required for approximately 40% (further increases at 300-1,000μM).[6]

D-Serine is another molecule that acts on the same receptor classes that glycine can, but appears to be practically more potent since it is cleared from the receptors at a lower rate


Edit2. Neurology

2.1. Kinetics

Glycine can be taken into cells via the glycine transporter-1 (GlyT1) which appears to have a role in determinining synaptic concentrations of glycine and serine[7][8] as its inhibition can potentiate NDMA signalling (by increasing synaptic levels of glycine)[9] and may also be taken up by a second transporter known as GlyT2.[8] The alanine–serine–cysteine transporter-1 (AscT1) may also play a role in regulating synaptic concentrations of glycine and serine by modifying uptake into glial cells.[10][11]

There are a few transporters that draw glycine into cells, and they appear to have a regulatory role in controlling levels of synaptic glycine

2.2. Glycinergic Neurotransmission

Glycine itself is a neurotransmitter with its own signalling system (similar to GABA or Agmatine).[12] This system is inhibitory and works alongside the GABAergic system, although in the auditory brainstem[13][14] and hypoglossal nucleus[15] there appears to be a developmental shift towards favoring glycinergic inhibition, and glycinergic neurotransmission has been shown to have relevance in the thalamus,[16] cerebellum,[17] and hippocampus.[18][19] This system and its receptors are blocked by the research drug Strychnine[20] and when glycine activates its receptors the resulting influx of chloride (Cl-) ions causes an inhibitory effect secondary to making actions potentials more difficult.[21][8]

2.3. Glutaminergic Neurotransmission

Glycine has a role in glutaminergic neurotransmission as the NMDA receptors (a subset of glutamate receptors) tend to be tetramers composed of two glycine-binding units (the GluN1 subunits) and glutamate-binding units (GluN2)[22][23][24][25] with the GluN1 subunit having eight splice variants.[26] On the GluN1 receptors both glycine (D-serine may be used as well) and glutamate are required to induce signalling, which causes these glutamate receptors to be known as 'glycine dependent' and glycine as a 'coagonist'.[27][28]

100μM or higher (30μM ineffective) appears to potentiate NDMA signalling and appears to be concentration-dependently increased up until 1,000μM,[6] which is thought to be due to how glycine binding sites are unsaturated[29] due to efficient buffering systems.[30]

2.4. Memory and Learning

The hippocampus appears to express functional glycine receptors (glycinergic system) with inhibitory effects on neuronal excitation[31][32] and are mostly located extrasynaptically[33] yet colocalized with synapsin.[34] Hippocampal cells can also release glycine upon neuronal activation[35][36][19] and glycine appears to be stored in the presynapse of these neurons alongside glutamate,[18] most glycine (according to immunohistology) appears to be stored presynaptically and most clusters of glycine observed (84.3+/-2.8%) were facing NMDA glutaminergic receptors.[18]

Glycine is involved in signalling through the hippocampus, and it seems that both the glycinergic and the glutaminergic systems can be involved here

2.5. Bioenergetics

Intracerebroventricular injections of glycine to rats are able to induce bioenergetic dysfunction[37][38] secondary to acting through the NDMA receptors and causing oxidative changes[37] which then negatively influence various enzymes such as citrate synthase and Na+/K+ ATP synthase as well as impairing the electron transport chain at multiple complexes.[37][38] Similar observations have been found with injections if D-serine[39] and isovaleric acid[40] which are protected against by glutamine receptor antagonists,[37] antioxidants,[37] or Creatine.[40]

2.6. Schizophrenia

800mg/kg of glycine daily for six weeks in persons with schizophrenia on stable antipsychotic therapy noted that supplementation was associated with a 23+/-8% reduction in negative symptoms and a lesser but also therapeutic effect on cognitive and positive symptoms.[41]

2.7. Obsession

A case study exists where an individual with both OCD and body dysmorphic disorder that, over the course of five years, had a significant reduction in symptoms when taking 800mg/kg glycine daily[42] which is the dose used in schizophrenia trials; the authors hypothesized that his symptoms were related to insufficient NDMA receptor signalling, and benefits manifested within 34 days.[42]

2.8. Sleep and Sedation

In female participants given 3g of glycine an hour prior to sleep, supplementation appears to reduce fatigue in the morning and improve self-reported sleep quality more than placebo.[43] Later, 3g of glycine was tested in otherwise healthy persons reporting dissatisfaction with their sleep who were then subject to an EEG via polysomnography; it was reported that glycine improved subjective sleep quality associated with shortened sleep latency and time to reach slow wave sleep (REM sleep and overall sleep architecture not affected).[44] This latter study also confirmed improved cognitive day-time performance associated with better self-reported sleep[44] and has been replicated where 3g of glycine taken an hour before sleep (in persons with mildly impaired sleep) was able to reduce fatigue the next day but that after three days this was no longer significant, whereas performance tasks (psychomotor vigilence) were consistently improved.[45]

Low doses of glycine supplementation appear to benefit the subjective sensation of a good night's sleep associated with reduced sleep latency (time taken to fall alseep) and improved performance the next day, and the subjective sensation lasts for only about one day whereas performance benefits persist


Edit3. Interactions with Organ Systems

3.1. Pancreas

Glycine has its glycinergic receptors expressed on pancreatic α-cells (those that mediate some endocrine responses such as glucagon regulation[46]), and appears to stimulate glucagon release when it acts upon these cells with a threshold of 300-400μM and maximal stimulation at 1.2mM reaching four-fold secretion.[47]

Glycine does not interact with insulin secretion in vitro.[47]


Edit4. Nutrient-Nutrient Interactions

4.1. Minerals

Glycine is sometimes bound to minerals such as Zinc or Magnesium as a 'diglycinate' chelation, which enables the minerals to be absorbed via peptide transporters in an intact form[48][49] which tends to lead to enhanced absorption relative to the free form of the mineral in the upper intestine.[50] Although absorption via peptide transporters can extend to most amino acids, diglycine tends to be absorbed rather than hydrolyzed[51] which makes it an efficient carrier. Triglycine works as well, although four glycine molecules gets hydrolyzed into two diglycine molecules.[52]

Additionally, due to glycine being the smallest amino acid the overall molecular weight of supplements is lower when glycine is used as a chelation relative to heavier amino acids.[1]

Two glycine molecules in a dipeptide form (Diglycinate) are sometimes used as a way to enhance the absorption of mineral supplementation since, only when bound to a dipeptide, can be absorbed through a different set of transporters

References

  1. Versiane O, et al. Synthesis, molecular structure and vibrational spectra of a dimeric complex formed by cobalt and glycine. Spectrochim Acta A Mol Biomol Spectrosc. (2006)
  2. Monahan JB, et al. Characterization of a {3H}glycine recognition site as a modulatory site of the N-methyl-D-aspartate receptor complex. J Neurochem. (1989)
  3. D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release
  4. Watson GB, et al. D-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed in Xenopus oocytes. Brain Res. (1990)
  5. Supplisson S, Bergman C. Control of NMDA receptor activation by a glycine transporter co-expressed in Xenopus oocytes. J Neurosci. (1997)
  6. Berger AJ, Dieudonné S, Ascher P. Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Neurophysiol. (1998)
  7. Aragón C, López-Corcuera B. Glycine transporters: crucial roles of pharmacological interest revealed by gene deletion. Trends Pharmacol Sci. (2005)
  8. Betz H, et al. Glycine transporters: essential regulators of synaptic transmission. Biochem Soc Trans. (2006)
  9. D'Souza DC, et al. Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence. Neuropsychopharmacology. (2012)
  10. Ribeiro CS, et al. Glial transport of the neuromodulator D-serine. Brain Res. (2002)
  11. Hayashi F, Takahashi K, Nishikawa T. Uptake of D- and L-serine in C6 glioma cells. Neurosci Lett. (1997)
  12. The glycinergic inhibitory synapse
  13. Corelease of Two Fast Neurotransmitters at a Central Synapse
  14. O'Brien JA, Berger AJ. Cotransmission of GABA and glycine to brain stem motoneurons. J Neurophysiol. (1999)
  15. Muller E, et al. Developmental dissociation of presynaptic inhibitory neurotransmitter and postsynaptic receptor clustering in the hypoglossal nucleus. Mol Cell Neurosci. (2006)
  16. Ghavanini AA, et al. Distinctive glycinergic currents with fast and slow kinetics in thalamus. J Neurophysiol. (2006)
  17. Dumoulin A, Triller A, Dieudonné S. IPSC kinetics at identified GABAergic and mixed GABAergic and glycinergic synapses onto cerebellar Golgi cells. J Neurosci. (2001)
  18. Muller E, et al. Vesicular storage of glycine in glutamatergic terminals in mouse hippocampus. Neuroscience. (2013)
  19. Luccini E, Romei C, Raiteri L. Glycinergic nerve endings in hippocampus and spinal cord release glycine by different mechanisms in response to identical depolarizing stimuli. J Neurochem. (2008)
  20. Young AB, Snyder SH. Strychnine binding associated with glycine receptors of the central nervous system. Proc Natl Acad Sci U S A. (1973)
  21. Laube B, et al. Modulation of glycine receptor function: a novel approach for therapeutic intervention at inhibitory synapses. Trends Pharmacol Sci. (2002)
  22. Monyer H, et al. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. (1994)
  23. Kuner T, Schoepfer R. Multiple structural elements determine subunit specificity of Mg2+ block in NMDA receptor channels. J Neurosci. (1996)
  24. Functional and Pharmacological Differences Between RecombinantN-Methyl-D-Aspartate Receptors
  25. Traynelis SF, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. (2010)
  26. Hollmann M, et al. Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor. Neuron. (1993)
  27. Thomson AM. Glycine is a coagonist at the NMDA receptor/channel complex. Prog Neurobiol. (1990)
  28. Dingledine R, Kleckner NW, McBain CJ. The glycine coagonist site of the NMDA receptor. Adv Exp Med Biol. (1990)
  29. Javitt DC, Heresco-Levy U. Are glycine sites saturated in vivo. Arch Gen Psychiatry. (2000)
  30. Glycine and N-Methyl-D-Aspartate Receptors: Physiological Significance and Possible Therapeutic Applications
  31. Chattipakorn SC, McMahon LL. Strychnine-sensitive glycine receptors depress hyperexcitability in rat dentate gyrus. J Neurophysiol. (2003)
  32. Song W, Chattipakorn SC, McMahon LL. Glycine-gated chloride channels depress synaptic transmission in rat hippocampus. J Neurophysiol. (2006)
  33. Danglot L, et al. Morphologically identified glycinergic synapses in the hippocampus. Mol Cell Neurosci. (2004)
  34. Brackmann M, et al. Cellular and subcellular localization of the inhibitory glycine receptor in hippocampal neurons. Biochem Biophys Res Commun. (2004)
  35. Galli A, et al. Sodium-dependent release of exogenous glycine from preloaded rat hippocampal synaptosomes. J Neural Transm Gen Sect. (1993)
  36. Fatima-Shad K, Barry PH. Morphological and electrical characteristics of postnatal hippocampal neurons in culture: the presence of bicuculline- and strychnine-sensitive IPSPs. Tissue Cell. (1998)
  37. Moura AP, et al. Glycine Intracerebroventricular Administration Disrupts Mitochondrial Energy Homeostasis in Cerebral Cortex and Striatum of Young Rats. Neurotox Res. (2013)
  38. Busanello EN, et al. Neurochemical evidence that glycine induces bioenergetical dysfunction. Neurochem Int. (2010)
  39. Zanatta A, et al. In vitro evidence that D-serine disturbs the citric acid cycle through inhibition of citrate synthase activity in rat cerebral cortex. Brain Res. (2009)
  40. Ribeiro CA, et al. Creatine administration prevents Na+,K+-ATPase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats. Brain Res. (2009)
  41. Heresco-Levy U, et al. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry. (2004)
  42. High-Dose Glycine Treatment of Refractory Obsessive-Compulsive Disorder and Body Dysmorphic Disorder in a 5-Year Period
  43. Subjective effects of glycine ingestion before bedtime on sleep quality
  44. Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes
  45. Bannai M, et al. The effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers. Front Neurol. (2012)
  46. Gromada J, Franklin I, Wollheim CB. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev. (2007)
  47. Li C, et al. Regulation of glucagon secretion in normal and diabetic human islets by γ-hydroxybutyrate and glycine. J Biol Chem. (2013)
  48. Wapnir RA, et al. Absorption of zinc by the rat ileum: effects of histidine and other low-molecular-weight ligands. J Nutr. (1983)
  49. The role of protein breakdown products in the absorption of essential trace elements
  50. Schuette SA, Lashner BA, Janghorbani M. Bioavailability of magnesium diglycinate vs magnesium oxide in patients with ileal resection. JPEN J Parenter Enteral Nutr. (1994)
  51. Intestinal transport of dipeptides in man: relative importance of hydrolysis and intact absorption
  52. Adibi SA, Morse EL. The number of glycine residues which limits intact absorption of glycine oligopeptides in human jejunum. J Clin Invest. (1977)

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