By Robert Schinetsky

Alpha-Glycerylphosphorylcholine (Alpha GPC) is a popular nootropic supplement that we’ve discussed previously. A bioavailable source of choline (an important brain nutrient) as well as a formidable nootropic, Alpha-GPC has been steadily gaining traction over the years in sports nutrition and productivity/gaming supplements. A handful of small studies (funded by a company who sells Alpha GPC) suggested that supplementation with Alpha GPC prior to exercise improved performance and growth hormone levels.[1,2,3,4]

While this doesn’t automatically invalidate the findings of the study, it is something to keep in mind.

Now, anything that may potentially increase performance, boost focus, and/or give individuals an edge in the gym, on the field, or in business is certainly enticing…but is it safe?

Not necessarily.

We’ve previously discussed a 10-year cohort study in which Alpha-GPC supplementation was significantly associated with a 10-year incident stroke risk in a dose-responsive manner. To be more precise, individuals supplementing with α-GPC vs not supplementing with it had a 46% higher risk of stroke.[5]

A new review published in Frontiers in Endocrinology highlights some potential benefits but also details some reasons that Alpha GPC may not be an ideal supplement.[6]

Previous Alpha GPC Research Findings

Alpha GPC is metabolized into phosphatidylcholine (the active form of choline) that can be used by the body to synthesize acetylcholine (the “learning neurotransmitter”) as well as ramp up production of brain-derived neurotrophic factor (BDNF -- an important brain protein that impacts the growth, development, and maintenance of neurons).

Human clinical trials investigating the potential benefits of Alpha-GPC have used a wide range of doses from as low as 150mg up to 1,000mg per day.[6]

For instance, Alpha GPC benefits was found to improve bench press performance, but did not enhance strength or power.[1] Other studies note ~3% increase in strength of the thigh muscles following 6 days of consuming 600mg of Alpha GPC compared to placebo, but there was no improvement noted in upper body exercise.[2,7]

A similar study using smaller doses (250 and 500mg Alpha GPC) given to participants for seven days noted a significant improvement in maximal power performance during countermovement jump for the group receiving 250mg, but not those receiving 500mg.[4] Other studies indicate that 300mg and 150mg were able to improve vertical jump power as well as reaction time.[8]

Other research indicates that taking 1000mg of Alpha GPC may increase growth hormone and hepatic fat oxidation, in addition to plasma choline levels.[9] Recently, 800mg alpha GPC was indicated to improve listening comprehension in older adults using hearing aids.[10]

Potential Risks of Alpha GPC Supplementation

May Increase Risk of Cardiovascular Disease

As mentioned above, a 10-year cohort study noted that alpha-GPC was associated with a 46% higher risk of stroke compared to individuals not using the nootropic. Researchers believe this may be linked to how Alpha-GPC is metabolized in the gut.

Trimethylamine N-oxide (TMAO) is a metabolite generated from the breakdown of certain nutrients, including choline and carnitine. Under certain conditions (such as osmotic or hydrostatic pressure stress), TMAO can be used by cells to maintain cell volume.

However, TMAO can activate various inflammatory molecules, including the proinflammatory cytokines IL1-β and IL-18 as well as vascular endothelial cell MAPK and NFκB signaling. A growing body of research also finds an association between TMAO and risk of cardiovascular disease and stroke.[11] A newly published review in the February 2023 issue of Frontiers in Endocrinology noted that TMAO may also directly contribute to platelet hyperreactivity and enhanced thrombosis as well as cholesterol accumulation and endothelial dysfunction.[12] Another new review appearing in Frontiers in Cardiovascular Medicine also noted a causal relationship between elevated levels of choline and valvular disease (damage to any heart valve). Researchers also reported that higher choline levels were linked to higher risk of myocardial infarction as were increased levels of carnitine.[13]

Researchers have stated that while the development of stroke was associated with the duration of Alpha-GPC use, some of the individuals included in the cohort did have hypertension, which is a known comorbidity and contributing factor to cardiovascular disease.

There’s more though…

A follow-up review, published shortly after the JAMA review, on Alpha GPC supplementation concluded:

“our results show GPC promotes atherosclerosis through multiple mechanisms and that caution should be applied when using GPC as a nutritional supplement.”[14]

It should be noted that some researchers state that TMAO may not be a causative (or a protective) factor in regards to cardiovascular disease. It may simply be an indicator of “disrupted homeostasis.”[15]

TMAO Impairs Cognitive Function

A recently published study in Food & Function found that TMAO treatment caused both long-term memory (LTM) and short-term memory impairments, neuron loss, and synaptic plasticity impairments.[16] Keep in mind that this is an animal model and TMAO was administered in isolation, so the findings aren’t translatable on a 1-to-1 basis, but it does give insight into another possible mechanism by which excessive supplemental choline may not be benign.

Impacts the Gut Microbiome

Alpha GPC supplementation has been found to reduce the quantity of several good gut bacteria that are known to support gut barrier integrity.[14]

Supplementation with the popular nootropic also alters the composition of the gut microbiome, leading to a reduction in the prevalence of butyric acid-producing bacteria (such as akkermansia) and consequently butyric acid (aka butyrate). It’s also important to realize that decreased production of short-chain fatty acids like butyrate can result in elevated levels of pro-inflammatory cytokines and chemokines.

Animal models also suggest that reduced butyric acid levels may exacerbate the progression of atherosclerosis, and Alpha GPC administration can decrease the abundance of Lactobacillus in the mouse gut. Lactobacillus is one of the popular and widely-researched probiotics that has been shown to improve gut barrier integrity.

May Be Cytotoxic

Yet another potential concern to add to the list of reasons to be wary of alpha GPC supplementation is that animal models (cardiac myocytes in rats) suggest that Alpha GPC may be cytotoxic.[17]

Researchers noted that short-term use of Alpha GPC under normal (healthy) conditions) had conflicted effects on cardiac cells:

“It may be beneficial in short-term administration to maintain the physiological balance of ROS production under normoxic, healthy conditions and could be also protective in I/R conditions, but could, in fact, be cytotoxic if it surrounded the cells for long enough.”[17]

Still, previous studies have shown that GPC is able to prevent oxidative stress and decrease radical production in different models. Overall, the sub-chronic and chronic oral toxicity of GPC is considered to be very low.

So, Is Alpha GPC Safe?

Technically speaking, Alpha GPC is generally considered a safe and non-toxic compound. Furthermore, the compound is classified as GRAS (Generally recognized as safe) in the USA (GRN 000419).

It has been studied in individuals with neurological disorders (stroke, ischemic attack, etc.) and found to offer a therapeutic role as well as neuroprotective effects (using dosages between 400-1200mg per day).

In addition to its neuroprotective effects, GPC was documented to preserve mitochondrial respiration in liver mitochondria and to reduce oxidative stress and inflammation in rodent models of ischemia/reperfusion.

However, more research is being published that should give individuals (and supplement companies alike) pause when it comes to making Alpha GPC a “must have” inclusion in products.

For these reasons (and more), Advanced Molecular Labs Pre Workout and its nootropic/productivity supplements (Dopa Rush Cocktail, Dopa Rush Shots, etc.) do NOT contain Alpha GPC (or other choline donors), opting instead for ingredients that support dopamine -- a key neurotransmitter involved in motivation, mood, decision-making and motor control. Dopamine also plays an essential role in the regulation of heart rate, blood pressure, muscle tone, visual processing, and protein synthesis.[22]

Additional studies also note the essential role dopamine plays in exercise performance as well as brown fat thermogenesis (which may be of particular interest to those seeking weight loss and body recomposition).[20-26] Collectively, this makes dopamine-precursors, such as Tyrosine and velvet bean extract, the superior option.

What to Do?

If you’re considering supplementing with Alpha GPC, but you’re concerned about some of the potential risks, there are a couple of options: 

1. Get your choline from dietary sources like eggs, nuts, liver, etc.
2. Try CDP-Choline, which is noted to be less prone to conversion to TMA and TMAO than other forms of supplemental choline[18]
3. If using Alpha GPC, consider supplementing with Berberine, which has been found in some research to attenuate choline-induced atherosclerosis by modifying the gut microbiome such that less TMAO is produced.[21]
4. If consuming Alpha GPC, consider also supplementing with phloretin, a flavonoid extracted from apple leaves, that plays a protective role, and it improves vascular endothelial dysfunction and liver health.[27]

 ©Published by Advanced Research Media, Inc. 2023

©Reprinted with permission from Advanced Research Media, Inc.

References

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