Alpha-GPC

Last Updated: September 28 2022

Alpha-glycerophosphocholine (alpha-GPC or α-GPC) is a cholinergic compound that is used for cognitive-enhancement, and to increase power output in athletes. It appears to also support cellular membranes, and may help prevent cognitive decline.

Alpha-GPC is most often used for.

1.

Sources and Structure

1.1

Sources

L-alpha-glycerylphosphorylcholine (shortened to Alpha-GPC usually, also known as choline alphoscerate or glycerophosphocholine) is a choline containing phospholipid[16] and an intermediate of lecithin metabolism or simply a lecithin molecule with two less fatty acids.[17] It is a choline pro-drug, and is known to be a precursor to acetylcholine and phosphatidylcholine in the body following ingestion.[18][19]

Alpha-GPC is found as a naturally occurring constituent of red meat products[20] and organ tissue[21] but for the most part is scarce in appreciable amounts in naturally occurring sources.[19] Most supplements containing Alpha-GPC are made synthetically, where it can be enzymatically created from egg[22] or soy lecithin.[19] Due to this synthesis and the source, it is sometimes referred to as a semisynthetic derivative of lecithin.[23]

Alpha-GPC is a choline containing phospholipid, and is used as a precursor for both acetylcholine synthesis and phospholipid synthesis in the brain. It is essentially a prodrug for both choline and glycerophosphate

Some food sources and their contents include:

  • Toasted wheat germ (33.78mg/100g), wheat crackers (10.94mg/100g), and wheat bread (4.93mg/100g)[24]
  • Oat bran (33.25mg/100g)[24]
  • 2% Milk (9.98mg/100g) and skim milk (9.70mg/100g)[24]
  • Cheese (2.30mg/100g), Cottage cheese (8.39mg/100g), Cream cheese (9.26mg/100g)[24]
  • Yogurt (7.79-9.10mg/100g)[24]
  • Eggs (0.60mg/100g)[24]
  • Chicken breast (1.12-1.20mg/100g) and liver (8.80mg/100g)[24]
  • Pork sausage (7.41mg/100g), cooked pork loin (22.51mg/100g)[24]
  • Beef liver (77.93mg/100g)[24]
  • Atlantic cod (30.04mg/100g), Salmon (5.89mg/100g)[24]
  • Bananas (5.60mg/100g), blueberries (0.61mg/100g), avocado (0.73mg/100g), grapefruit (1.16mg/100g), cantelope (0.71mg/100g), oranges (1.10mg/100g), and strawberries (0.86mg/100g)[24]
  • Broccoli (1.32mg/100g), cabbage (3.47mg/100g), cucumber (0.48mg/100g), spinach (0.21mg/100g), onions (0.57mg/100g), sauerkraut (0.94mg/100g), sweet potatoes (1.97mg/100g), brussel sprouts (3.18mg/100g), and raw mushrooms (5.11mg/100g)[24]
  • Beer (light at 2.98mg/100g, regular at 5.06mg/100g) and coffee (0.67mg/100g)

Although the concentrations in food are well below that which is achieved with supplementation, Alpha-GPC appears to be fairly widespread in food sources with the only appreciable food sources being dairy and meat products (with an emphasis on organ meats) and wheat germ

1.2

Structure and Properties

Structurally speaking, Alpha-GPC is a choline molecule bound to a glycerol molecule via a phosphate group. It is phosphatidylcholine (a lecithin molecule) without its two fatty acids.

image

The molar mass of Alpha-GPC is 257.221g, and is 40% choline by weight (ie. 1,000mg Alpha-GPC confers 400mg free choline).

Alpha-GPC is a lecithin molecule (phosphatidylcholine in particular) without the two additional fatty acids

1.3

Comparisons to other choline sources

When controlling for the amount of choline in each supplement, Alpha-GPC requires 46% the dose of CDP-choline[16] and due to being relatively higher in choline on a weight basis, administration of the same doses of either agent result in the group given Alpha-GPC experiencing a greater serum increase in choline.[25] Alpha-GPC is considered to be a more effective (assessed by potency on a weight basis) cholinergic than both choline and CDP-choline when looking at serum values or benefit from clinical interventions.[26][27]

Alpha-GPC has also been found to potentiate the effects of the acetylcholinesterase inhibitor rivastigmine in a dose-dependent manner whereas choline per se was ineffective,[28] and this interaction has resulted in synergistic neuroprotection elsewhere in rats[29] and interim results so far support the idea of pairing Alpha-GPC with an acetylcholinesterase inhibitor for the treatment of Alzheimer's.[30]

Alpha-GPC appears to be the best currently known cholinergic in increasing plasma and brain choline levels, as it has better transportation into the brain than does choline (somewhat similar to CDP-choline) but since it is a greater percentage choline by weight (relative to CDP-choline) taking X dose of either drug gives more choline when using Alpha-GPC

2.

Pharmacology

2.1

Absorption

Lecithin is metabolized when lysolecithin (from metabolism of lecithin by pancreatic phospholipase[17][31]) is subject to phospholipase B to form glycerophosphorylcholine (synonymous with Alpha-GPC),[32][33][34] which is then readily hydrolyzed by intestinal mucosal cells to form free choline and glycerophosphate (via glycerylphosphorylcholine diesterase[35][17]); this step can potentially be circumvented when lecithin is subject to Phospholipase D in the brain, which directly converts lecithin into glycerophosphate and choline (KM of 0.83).[36][17]

Alpha-GPC can also be formed as a byprodut when two molecules of lysolecithin reconfigure into a molecule of lecithin[17][37] (via an acetylation that is active when high concentrations of lysolecithin are present, with a KM of 3.6mM[38]).

Alpha-GPC is an intermediate in lecithin metabolism, and thus uses some of the same enzymes for its metabolism and absorption

2.2

Serum

Oral ingestion of Alpha-GPC does appear to increase plasma choline concentrations, with one study reporting an increase in plasma choline with 1,000mg Alpha-GPC in otherwise healthy young men from 8.1+/-1.4μmol/L up to 12.1+/-1.9μmol/L (49% at 60 minutes) and 11.4+/-1.7μmol/L (41% at 120 minutes).[39]

2.3

Neurological Kinetics

Phosphocholine (200-300nmol/g) and glycerophosphocholine (500-600nmol/g) concentrations in neural tissue are relatively higher than that of free choline or acetylcholine itself (less than 30nmol/g collectively),[40][41][42]

Free choline and acetylcholine are relatively low in neural tissue, whereas concentrations of storage forms of choline (phosphocholine and Alpha-GPC) are relatively higher

It has been noted that the concentrations of glycerophosphocholine found in the brain is comparable or slightly lesser than that found in the blood, suggesting fairly easy passage via the blood brain barrier.[43]

Alpha-GPC has been noted to be incorporated into brain phospholipids within 24 hours of ingestion in rats,[43] and brain concentrations are increased by either oral ingestion or intravenous injections.[44]

However, at least one study has noted that (using radiolabelled choline from Alpha-GPC) that the ability of excised neuronal tissue to release acetylcholine in response to stimulation peaked when the tissue was excised 1-3 hours after oral ingestion, and was not different than control at 8 hours.[45] When measured after 24 hours, there was still some radiolabelled choline being synthesized into acetylcholine.[45]

Can be taken up into the brain when orally ingested, and while a single large dose appears to consistently influence the brain over the course of 24 hours it may have a relative spike 1-3 hours post ingestion

3.

Neurology

3.1

Mechanisms

One study has noted that repeated, but not single, injections of Alpha-GPC has resulted in a greater neuronal accumulation of inositol phosphate. This was not blocked by atropine (antagonist of muscarinic cholinergic receptors), and was hypothesized to be due to an increase in phospholipid synthesis.[46] Along these lines, Alpha-GPC has been found to potentiate potassium-invoked calcium release in the hippocampus and receptor-mediated production of inositol phosphate,[47] which is a similar phenomena as seen with uridine (which is thought to act via support phospholipids).

Possible improvement in phospholipid biosynthesis associated with Alpha-GPC, and events which are seen with Alpha-GPC but are not readily replicated with choline are thought to be due to interactions with phospholipid metabolism

3.2

Dopaminergic Neurotransmission

It has been noted that Alpha-GPC (150mg/kg) is able to increase dopamine concentrations in the frontal cortex and cerebellum of rats following ingestion which was not seen with an equal dose of choline from CDP-choline[16] and the dopamine metabolite DOPAC has been noted to be increased in the striatum.[44] Alpha-GPC has also been noted to enhance potassium-invoked dopamine release from neurons,[44] which is thought to be due to interactions at the cellular membrane.

Both Alpha-GPC (150mg/kg and CDP-Choline are able to increase the dopamine transporter in these brain regions.[16]

Limited evidence suggests that oral ingestion of Alpha-GPC can be dopaminergic, by both increasing dopamine release during neuronal action potentials and possibly by stimulating the expression of receptors

3.3

Serotonergic Neurotransmission

It has been noted that Alpha-GPC (150mg/kg) is able to increase serotonin concentrations in the frontal cortex and cerebellum of rats following ingestion, which was not seen with CDP-choline.[16]

The serotonin transporter (SERT) does not appear to have its expression altered with oral Alpha-GPC.[16]

Has at least once been implicated in increasing brain serotonin concentrations following oral administration

3.4

Cholinergic Neurotransmission

Oral ingestion of 300-600mg/kg Alpha-GPC to rats has been found to not inherently modify brain acetylcholine concentrations (relative to control), although the reduction of acetylcholine concentrations seen with scopolamine are partially reversed.[48][45] Another study has found an increase in acetylcholine concentrations only in the frontal cortex, with no significant influence on the cerebellum and striatum.[49]

In the striatum and cortex the protein content of the vesicular acetylcholine transporter appears to be increased and while this applied to both CDP-choline and Alpha-GPC, the increase in the transporter with Alpha-GPC appeared to apply to all tested brain regions.[49][50] This implicates the glycerophosphate moiety, as the dosages (325mg/kg CDP-choline and 100mg/kg Alpha-GPC) were matched for choline content.[49]

Can possibly increase brain acetylcholine levels, although this may be localized to the frontal cortex. It is more reliable in preserving acetylcholine concentrations during stressors (such as anticholinergics) and Alpha-GPC is also implicated in increasing expression of the vesicular acetylcholine transporter

Alpha-GPC has been shown to not enhance high-affinity choline uptake into the hippocampus.[45]

Administration of Alpha-GPC prior to scopolamine (cholinergic toxin) administration is able to attenuate the performence impairment from scopolamine when taken three hours prior to the test (single dose, scopolamine given 30 minutes before testing)[48][45] with maximal benefit seen at either 600mg/kg[48] or 300mg/kg.[45] This has been confirmed in a pilot study in otherwise healthy humans where the amnesiac effects of scopolamine were ablated, and appeared to be due to the cholinergic properties as amnesia via benzodiazepines was not affected.[51] Comparatively speaking, this anti-amnesiac effect is more potent than both idebenone (synthetic analogue of CoQ10) and aniracetam (mentioned via this review,[18] primary study not available online).

Appears to be protective against cholinergic toxins

3.5

Glutaminergic Neurotransmission

It has been noted[18] that due to the ability of Alpha-GPC to increase cholinergic activity in the brain, that activation of nicotinic acetylcholine receptors (and subsequent activation of PI3K) could confer protection against glutamate-induced neurotoxicity.

No evidence directly assessing the interactions of Alpha-GPC and glutaminergic neurotransmission, but theoretically it can be neuroprotective (a trait common to choline containing compounds)

3.6

GABAergic Neurotransmission

Alpha-GPC has been implicated in GABA release via the noradrenergic system.[52] 30-300mg/kg intraperitoneal injections has been noted to increase GABA release with peak efficacy after 150 minutes (130% of baseline) and potentiated by atropine but not mecamylamine (reaching nearly 160% in half the time) while it was abolished by the alpha-1 adrenergic receptor antagonist prazosin and slightly hindered by physostigmine.[52] The Alpha-1 adrenergic receptor is known to facilitate GABA release.[53][54]

In vitro, 1.2mM but not 0.12mM was effective in increasing spontaneous GABA release from neurons and was again inhibited by prazosin.[52]

Alpha-GPC appears to increase GABA release secondary to acting through Alpha-1 adrenergic receptors. It is not yet clear whether Alpha-GPC is acting as a ligand at these receptors (similar to agmatine), whether it merely potentiates the signalling of other ligands, or whether this is just due to an increase in noradrenaline release

3.7

Attention

One study using Alpha-GPC alongside both caffeine and phosphatidylserine has found increased attention and reaction time in persons undergoing acute stress.[55]

3.8

Memory and Cognition

Protein Kinase C (PKC) is an intracellular intemediate that appears to be associated with memory formation when activated[56][57] and is involved in long term potentiation as well.[58] This activation of PKC is present at a concentration of 50nM[59][60] and may be related to the phospholipid component as a related structure, diacylglyceride, is a known PKC activator.[61]

Administration of Alpha-GPC to rats has been noted to promote PKC translocation in the rat cortex at an oral dose of 600mg/kg[59] peaking at one hour after oral administration[60][62] and either normalizing or dipping below control 5 hours after ingestion.[62] The potency of 600mg/kg Alpha-GPC in activating PKC is similar to 100mg/kg oxiracetam and 30mg/kg Aniracetam (higher doses being ineffective).[60]

Alpha-GPC does not appear to influence forskolin or noradrenaline-induced adenyl cyclase activity.[47]

Alpha-GPC appears to activate PKC in the hippocampus of rats following the standard supplemental dosages

When given to young rats without cognitive impairment, intraperitoneal injections of 100-200mg/kg daily (but not 25-50mg/kg) for 21 days two hours prior to training was associated with improved learning in both active and passive avoidance learning tasks.[47]

Appears to have some evidence for efficacy in otherwise cognitively healthy young rats

3.9

Alzheimer's Disease

It has been noted that Alzheimer's Disease (postmortem evaluation) is associated with an increased rate of phospholipid degradation[63] which is hypothesized to be due to an increased requirement of choline (and thus, degrading choline containing phospholipids)[40] as it is well established that acetylcholine can be derived from choline-containing phospholipids (phosphatidylcholine) by a process sometimes referred to as autocannabilism.[64][65]

In this sense, glycerophosphocholine is a biomarker as despite its enzyme of catabolism (GPC-cholinephosphodiesterase) being unaltered, it itself bioaccumulates indicating a breakdown of the lipid membrane.[63][66] This is thought to be a part of pathology since the traditional biomarker of Alzheimer's disease, β-amyloid proteins, can activate phospholipase A2 in neurons[67] and accelerate phospholipid degradation due to this.[68][69]

Choline metabolism is known to be upregulated in Alzheimer's disease, and secondary to this increased requirement for choline there appears to be damage to the cellular membrane consisting of choline-containing phospholipids. Alpha-GPC is implicated here, but its role in treatment of membranes is uncertain

400mg thrice daily (1,200mg daily) over 180 days in persons with mild to moderate Alzheimer's noted that the Alpha-GPC group had a decrease in ADAS-Cog scores (indicating cognitive improvement) despite placebo having mild worsening. Other parameters measured (MMSE, GDS, ADAS-Behav, ADAS-Total, and CGI) had similar results, and while benefits were noted at 90 days there appeared to be further benefits at the end of the 180 day trial.[70]

1,000mg Alpha-GPC has elsewhere been shown (intramuscular injections) to have benefit in vascular dementia over 90 days in regards to behavioural, memory, and verbal symptoms. It generally outperforms the same dosage of CDP-choline.[71][27]

A review on the topic investigating 17 studies noted that the general usage of Alpha-GPC against cognitive disorders of degenerative or vascular origin (Alzheimer's, dementia, stroke, transitory ischemic attack) noted fairly consistent improvements on MMSE scores in the range of 10-26% (degenerative disorder origin) and 8-30% (vascular origin).[72] While Alpha-GPC at the therapeutic dosage (1200mg daily) was more effective in the one trial where it was compared against ALCAR (a variant of L-Carnitine),[73] it seems to be either more potent or equally effective to oxiracetam.[72]

When using the standard therapeutic dosage of 1,200mg Alpha-GPC taken in three divided dosages (400mg thrice a day), there appears to be improvement on cognitive and affective symptoms in persons with cognitive decline and Alzheimer's over prolonged periods

3.10

Ischemia and Stroke

A review (no meta-analysis conducted) looking at three uncontrolled trials of 2484 patients with either transitory ischemic attack or stroke noted that one month of intramuscular administration (1,000mg) followed up by five months of oral therapy (1,200mg) noted consistent improvement in function as assessed by CGRS (19-21% improvement), MMSE (12-15% improvement), and GDS (20% improvement) relative to control.[72] Of these trials, the largest can be located online.[74]

When given immediately following a stroke or ischemia attack, appears to be neuroprotective. Due to the human trials starting treatment with intramuscular injections and then following up with oral maintenance, it is not sure how doing solely oral therapy works

4.

Physical Performance and Skeletal Muscle

4.1

Power Output

Supplemental of Alpha-GPC given 600mg Alpha-GPC prior to a power test (bench throws) reported a 14% power output improvement relative to placebo when taken 45 minutes prior to activity; this was a pilot study.[75]

Preliminary evidence that Alpha-GPC can enhance power output

5.

Fat Mass and Obesity

5.1

Interventions

One study using Alpha-GPC at 1,000mg has reported that, in otherwise healthy men, an increase in plasma biomarker of lipolysis (the ketone bodies acetoacetate and 3-hydroxyacetate, as well as free fatty acids) was reported to occur 120 minutes after supplement ingestion; the study did not measure time points beyond 120 minutes.[39]

6.

Interactions with Hormones

6.1

Growth Hormone

Growth hormone secretion in response to stimulation (via GHRH) is amplified with administration of Alpha-GPC, and although it is effective in both youth and elderly it seems that elderly persons experience a greater relative increase (due to having less output initially).[76] This was attributed to the cholinergic properties of Alpha-GPC[76] and can occur without exogenous stimulation by GHRH.[39] One trial in otherwise healthy adults given 1,000mg Alpha-GPC noted that plasma choline increased 30-120 minutes postingestion (returning to baseline at 4 hours) and the spike in growth hormone was only reported at 60 minutes (from 1.4+/-1.6 to 4.5+/-2.7ng/mL; 221% increase) which normalized at 120 minutes.[39]

One other study has reported that 600mg Alpha-GPC taken 45 minutes prior to physical exercise is able to augment the exercise-induced growth hormone spike from 5.0+/-4.8ng/mL in placebo to 8.4+/-2.1 ng/mL with supplementation.[75] The increase appeared to be significantly more than placebo when measured immediately and up to 15 minutes after exercise cessation, normalizing at 60 minutes.[75]

Appears to increase growth hormone secretion following oral ingestion, but due to a rapid normalization of growth hormone concentrations within 2 hours it may not lead to practical benefits (see the Arginine page and its growth hormone subsection for more info on this topic)

7.

Nutrient-Nutrient Interactions

7.1

Uridine (and Uridine prodrugs)

Uridine is a nucleotide which is used supplementally to increase brain phospholipid synthesis, and some other supplements (Triacetyluridine or CDP-choline) are uridine prodrugs in the sense that they confer uridine to the body following their ingestion.

Supplementation of uridine (via either uridine itself or prodrugs) has been noted to increase concentrations of some brain phospholipids and namely phosphoethanolamine,[77][78] but the increase in glycerophosphocholine has not always been detected (a failure with 500mg uridine in youth for a week[77] but a 5.1% increase over 6 weeks in older adults given 500mg CDP-choline[78] although 500mg has elsewhere failed to significantly influence GPC levels[79]).

Supplemental Uridine and/or uridine prodrugs may increase brain glycerophosphocholine concentrations, but it seems quite unreliable

7.2

Iron

Alpha-GPC appears to be able to enhance the absorption of nonheme iron from food products similar to how vitamin C does when it is in a 2:1 ratio with iron,[20] and due to this Alpha-GPC is thought to be or at least contribute to the phenomena where meat products can enhance the absorption of nonheme iron.[80][81] This study used 46mg Alpha-GPC and it was of comparable potency to vitamin C,[20] but elsewhere there has been a failure reported with a doubling of this ratio (4:1) or 70mg Alpha-GPC.[82] Both studies used a mixed meal to deliver Alpha-GPC and nonheme iron, and it is unsure why the difference in results occurs.

There is mixed evidence for how Alpha-GPC can influence iron absorption, and it is not sure if it requires a lower dose or if it is only effective in experimental settings. More research is required on this topic

8.

Safety and Toxicology

8.1

General

The LD50 of orally ingested Alpha-GPC appears to be greater than 10,000mg/kg in rats and mice, and subchronic toxicity studies with 1,000mg/kg in rats leads to slight weight loss and reductions in food consumption.[23] It was said that the No Observed Adverse Effect Level (NOAEL) for humans was at least 150mg/kg over 26 weeks based on extrapolation from dogs.[23]

Alpha-GPC does not appear to possess mutagenic activity.[23]

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