Hi, thanks for tuning in again!
It has been a while since the last blog post and I thought it was about time to bring them back! I apologise for the long radio silence but I hope to have some interesting for you again.
In this article, we’ll explore a popularised supplement called Alpha-GPC, which is short for Alpha glyceryl-phosphorylcholine (from now on, aGPC). The supplement has been growing in popularity through various brain-hacking channels and nootropic channels, so this article aims to dissect what we really know so far and see if those glorified articles and health claims are actually based on any reliable human data.
I will only include human studies here as I’m not particularly interested in lab animal or in-vitro studies as those do not always translate to human outcomes and mislead people into the realm of mechanistic speculation and lots of marketing claims.
With that out of the way, let's hit it!
What is Alpha GPC
aGPC is a potential precursor (building block) to a neurotransmitter called acetylcholine. aGPC may donate a molecule of choline (you’ve probably heard about the “choline and eggs” connection) so that acetylcholine can be produced. Acetylcholine, as a neurotransmitter, is released in the nervous system and it is what gets our muscles activated, and it allows sending down of an electrical signal that stimulates the muscles to work. Literally, every single time you move any part of your body, acetylcholine has to be released.
Acetylcholine appears to also play an essential role in the central nervous system (brain & spinal cord) by being a neuromodulator and having a potential role in neuroplasticity, memory and cognitive performance.
In addition, choline itself has many important physiological functions in the human cell structure, the nervous system, the kidneys and the liver and it seems extremely important, especially in the developing human brain of the foetus and newborn babies.
And so because aGPC is a precursor to acetylcholine and a choline donor, the theory was that by flooding the body with more choline containing product, we could strengthen the neuromuscular activation and potentially enhance the muscular performance in athletes as well as enhance cognitive performance, especially in people with dementia but perhaps even in those who do a lot of intellectually demanding work.
The first study which created the hype
The very first human trial that included aGPC was done in 1991 in Italy (Perri et al.)
Here researchers onboarded 120 patients diagnosed with vascular dementia (a type of dementia characterised by gradually obstructed blood flow into the brain due to progressive narrowing of the blood vessels ).
In this study, researchers randomly split the participants into two groups and on a daily basis for 90-days straight, injected them with either 1gram of aGPC or 1 gram of cytidine phosphocholine (CP). CP, being a medical drug back then has now been approved by FDA to be sold as a supplement in the US under the name Citicoline.
After 90 days of injecting the patients with one thing or the other, researchers saw dramatic improvements across the board in the areas of mood, cognition, behaviour, relationships, verbal fluency, memory, life satisfaction and happiness. Literally, every single marker that could have been increased was increased in both groups but way more in aGPC than in the CP group. There were nearly no side effects of the experimental treatment.
Despite the impressive results, there were a few things about the 1991 study that beg further update
Firstly, it would be interesting to have a similar study to be compared to the treatment used today, which consists of various medications aimed at improving the blood flow into the brain and reducing blood pressure and cholesterol rather than just manipulating choline in the brain. Due to advancements in medicine, it is possible that if compared to more modern protocols, aGPC would not be as drastically effective as it was back then.
Secondly, this was a pretty radical trial where people were injected every day for 90 days in a row. For some, this might potentially be unacceptable, and there is also the possibility that injecting aGPC is way more effective than oral one ingestion, which was how all the other studies were conducted.
Thirdly, people in the study were elderly living in hospitals long-term. You can probably imagine that living in a hospital setting for a long time will have a pretty negative effect on the person’s cognitive and mental well-being, and it is possible that the results would have been less profound if done on younger and healthier subjects.
And lastly, some of the methods used to assess cognitive function back then are now possibly outdated and replaced by better and more accurate assessments.
All this means is that despite the trial being very impressive, we need an updated study looking at non-hospitalised patients and comparing aGPC to a more modern medical treatment to see the range of effects in comparison.
Now let’s take a look at what else do we have on alpha-GPC besides this one trial
Athletic performance and aGPC
There are exactly 3 human trials looking at some form of muscular performance or endurance in relationship to aGPC. Rather than going in-depth on each one, I’ll just do a 30-second summary of the results and design of each:
Study one (Bellar et al. 2015)
3 young, healthy males split tested for the upper body and lower body & core strength tests called isometric Mid-Tight Pull Test & Upper Body Isometric Test. The group was divided into 600mg aGPC vs placebo.
The physical tests were administered several times. First time at the very beginning of the study. Afterwards, subjects were given the first dose of aGPC or placebo, and 1 hour later, they were retested. Then they were sent home to take the supplements for six consecutive days and then tested again. And afterwards, the groups were shifted, and both of them repeated the same exact process (from the very beginning) one more time but this time taking the other capsule. So in the end, both groups tried both placebo and aGPC, but neither group knew when they were taking which.
RESULTS: There was no difference in the first test (the 1-hour after); however, when they looked at the 6-day post results, they saw significant improvement on the Isometric Mid-Tight Pull exercise in the groups taking aGPC. This exercise indicates the strength of lifting and bearing heavy weights in the semi-standing postures, a type of strength required in powerlifting, wrestling, judo and other sports where a raw force of being able to lift heavy is valued.
Study two (Marcus, et al 2017)
48 healthy males split into 4 groups receiving one of the following (200 mg caffeine, 250mg aGPC, 500mg aGPC or placebo) for 7 days. Tests undergone: a psychomotor test and vertical jump test, as well as the two strength tests mentioned in the previous study before & after the 7-day supplementation. Results were compared between all 4 groups.
RESULTS: mostly no difference among the groups when the baseline and day 7 performance was put next to each other. The only difference was that the group taking 250mg aGPC had increased mechanical force during a vertical jump test.
Study three (Bunn, et al. 2018)
20 men who regularly exercised were tested for bench press strength, vertical jump test as well as a cognitive performance test. They received either a placebo or a capsule containing a blend of 500mg aGPC, 250 mg uridine-5’-monophosphate, and 1500 mg DHA). 90 minutes after taking the capsules, they took the 3 tests. 2 days later, the groups switched to the other capsule and 90-minutes later, they repeated the test.
RESULTS – no statistical difference in any of the tests between the placebo and the experimental group.
Source: Bunn et al. 2018.
In summary, based on the 3 trials on athletic performance, it is too early to say whether aGPC has any significant impact on athletic performance. The only potential effects observed here were an increase of mechanical force during a vertical jump as well as Mid-Tigh Pull Tests. This means that short term supplementation of 250mg aGPC may theoretically help improve strength in sports that require lifting or working with heavyweights such as powerlifting, wrestling, judo and similar. Equally the positive results in vertical jumps may make it interesting for athletes competing in basketball, volleyball or other sports requiring high vertical jumps. But we require more and larger studies to confirm even these results.
GPC in Motivation & Mood
A recent study from Japan (Tamura et al. 2021) has assessed the effect of aGPC supplementation compared to placebo on anxiety & relief and, motivation & lethargy.
For 2 weeks, participants either took two capsules of 200mg aGPC or 2 capsules of placebo and after 2 weeks. Both groups were also asked to self-assess levels of their mood and motivation on a digital scale called Kokoro (a unique program designed to assess & track changes in anxiety & motivation).
What happened in the end?
Neither group felt more or less anxiety and their values were comparable. In terms of motivation, it appears to the aGPC group felt more motivated, especially during the evening time.
Source: (Tamura et al. 2021)
Is that it?
Yes, that’s indeed it. As of today, the amount of human trials that had some degree of control from which we can extrapolate real-life results is still very little. Perhaps in time, we will have more information. But for now, we’ll have to make do with the data we have
Should you take a-GPC & is it safe long-term?
There is one concern with supplementing any high doses of choline-containing supplements. The risk is called TMAO (Trimethylamine n-oxide). TMAO is formed in the body when we ingest choline & carnitine containing foods such as red meat, eggs and fish. Excessive choline & carnitine in the body, especially the choline that was not absorbed in small intestines, gets turned by the intestinal bacteria into something called Trimethylamine (TMA) which then gets transported into the liver and converted to Trimethylamine-N-oxide. And while short bursts of TMAO are not problematic and the body can deal with it, chronically elevated TMAO levels can become problematic.
Chronic TMAO elevation has been associated with cardiovascular disease in another research (not correlated – which means TMAO does not cause heart disease but people with heart disease often have increased levels of TMAO in the blood compared to people without). People with long-term TMAO elevation are at increased risk of dying from all causes (all-cause mortality). This risk is strongly dose-dependent meaning the higher the levels the higher the risk.
Source: Giacamo Schiattarella, et al. 2017
In a meta-analysis of 15,662 patient data (Giacamo Schiattarella, et al. 2017). It was found that the relative risk of all causes of mortality was increased by 7.6% for every 10nmol/L serum TMAO (in-blood). In a simple language, it means, that the higher TMAO levels people have the higher the odds of dying prematurely regardless of whether they have chronic kidney disease or not although patients with a degree of CKD are at a higher risk.
There was one study that tested how much TMAO increases upon supplementing choline from different sources (including aGPC) and how quickly did it go down to baseline after supplements were stopped. It took about 24 hours for it to go back after they discontinued the supplements. As shown on the chart below, aGPC produced a short-term increase of TMAO, which was less profound than other choline supplements and eventually all returned to zero.
But the question is:
Is long-term supplementation of choline (> 3 months) safe and are we sure that TMAO levels can’t get too high?
Is aGPC safe for people who are at increased risk of cardiovascular disease and may already have chronically elevated levels of TMAO?
The answer to both questions is that we probably still don’t know. We don’t have the long term data on human subjects and aGPC supplementation. The formation of TMAO from choline also depends on the individual microbiota profile and in different people, the body reacts in a different way. We, however, have a very convincing data from a study that accumulated details from over 15,000 people and this study clearly shows that chronically elevated levels of TMAO are risk factors for cardiovascular disease and for all-cause of mortality. They also show that for people with ongoing CKD this problem is even more significant.
Dosing and who should be careful?
Oral supplementation of 200mg up to 500mg has been tested and well tolerated although none of the studies lasted even a month so the absence of long-term safety data is something to keep in mind.
Intramuscular injection of 1g for 90 days has been done in one study however this was a hospital environment under the careful observation of a medical team so I would not suggest following this protocol (not even orally) without consulting your doctor.
Due to potential TMAO accumulation, people with a history of cardiovascular incidence, who have elevated blood pressure, high cholesterol, coagulation problems or are taking any medication aimed at reducing the risk of heart disease as well as people with diagnosed chronic kidney disease should probably not supplement aGPC, at least not without the prior consent of their doctor.
Summary & Final thoughts
In summary, I would say that as of today we simply do not have enough human research to prove that an aGPC really stands to a lot of its health claims. But for enthusiasts willing to experiment, short term supplementation with aGPC appears to be safe in people who are not at risk of cardiovascular disease or who do not have a degree of chronic kidney disease. Long term supplementation would probably not be advised at least not until we have more information.
According to the available data, aGPC may potentially be useful for improvement of motivation and reduction of lethargy as well as for people who compete professionally in sports such as basketball, volleyball, wrestling, powerlifting or other sports where either the force of a jump or a raw lifting force are valued and beneficial. In terms of recommending aGPC to patients with vascular dementia, I would still err on the side of the caution before recommending it to a patient even alongside a medical treatment. Best discuss this step with doctor because it is not a condition to be taken lightly.
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References
Bellar, D. LeBlanc, N. Campbell, B. (2015). ‘The effects of 6 days of alpha glyceryl phosphorylcholine on isometric strength ’, Journal of the International Society of Sports Nutrition, 17, pp.42
Bockmann, K. Franz, A.R. Minarski, M. et al. (2022). ‘Differential metabolism of choline supplements in adult volunteers’, European Journal of Nutrition, 61, pp.219-230.
Bunn, J.A. Crossley, A. Timiney, M.D. (2018) ‘Acute ingestion of neuromuscular enhancement supplements do not improve power output, work capacity, and cognition’, Journal of the International Society of Sports Nutrition, 58 (7-8), pp.974-979.
Giacomo Schiattarella, G. Sannino, A. Toscano, E. et al. (2017). ‘Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis’, European heart journal, 38 (39), pp.2948-2956.
Marcus, L. Soileau, J. Judge, L.W. et al. (2017). ‘Evaluation of the effects of two doses of alpha glycerylphosphorylcholine on physical and psychomotor performance’, Journal of the International Society of Sports Nutrition,14, pp.39.
Perri, A.D. Coppola, G. Ambrosio, L.A. et al. (1991). ‘A multicentre trial to evaluate the efficacy and tolerability of alpha-glycerylphosphorylcholine versus cytosine phosphocholine in patients with vascular dementia’, Journal of international medical research, 19 (4), pp.330-341.
Tamura, Y. Takata, K. Matsubara, et al. (2021). ‘Alpha-Glyceryl phosphorylcholine Increases Motivation in Healthy Volunteers: A Single-Blind, Randomized, Placebo-Controlled Human Study’, Nutrients, 13 (6), pp.2091.