Do Choline Supplements like Alpha-GPC Increase the Risk of Stroke?

In this article, we are going to be investigating a topic that was brought to our attention by a customer who reached out to the Transparent Labs customer service team. The customer expressed concern about AlphaSize® alpha-GPC (glycerylphosphorylcholine) in Transparent Labs BULK pre-workout after reading an email from a self-appointed "nootropics expert" who seems to have egregiously misinterpreted the abstract of a recent study.

Naturally, we were curious whether this "expert's" claim that alpha-GPC increases the risk of having a stroke by 95% (yes, you read that right) has any validity. Here's what the data really suggests.

What Is Alpha-GPC?

Alpha-GPC is a popular nootropic supplement and source of bioavailable choline, an essential nutrient that plays an important role in cholinergic transmission and, by extension, cognitive function. Alpha-GPC is primarily found in the brain and is one of the two major storage forms of choline in the cytosol (interior space of cells), along with phosphocholine [1].

In recent years, alpha-GPC has been spotlighted as a natural treatment for Alzheimer's disease and dementia. Clinical trials demonstrate promising benefits of alpha-GPC use in elderly patients at risk for these neurodegenerative conditions [2]. Somewhat ironically, other research suggests that alpha-GPC is, in fact, a protective agent against cerebrovascular disease [3].

There's also evidence that alpha-GPC increases growth hormone production and fatty acid oxidation in athletes [4]; hence, alpha-GPC is a pertinent ingredient in pre-workout formulas.

Taking Alpha-GPC for Choline Deficiency

Choline supplements are commonly used to combat choline deficiency and consequent cognitive impairment. Choline intake in the diet is generally limited, so supplements like alpha-GPC, choline bitartrate, and cytidine diphosphate (CDP) choline, aka "citicoline," are abundant nowadays. CDP-choline and alpha-GPC are seemingly neck and neck in terms of prophylactic efficacy against cognitive impairment, with insufficient evidence that choline bitartrate is an effective cognitive enhancer [5].

Alpha GPC and Stroke Risk

Now, does the aforementioned "nootropics expert" have a case here by saying that alpha-GPC supplements increase the risk of stroke by 95%?

To start, let's identify where this 95% figure came from; it appears that this fellow "expert" read a recent study abstract and, for whatever reason, thought the 95% confidence interval reflected the effect size of the results. It's unclear if this was intentional misinformation or a laughable misapprehension of the study abstract.

Those who have taken a rudimentary statistics class should know that the confidence interval has virtually nothing to do with the effect size. Confidence intervals are more so a measure of data reliability (e.g. can we trust the findings are not due to random chance?).

The study reported that there was an average hazard ratio of 1.46 for stroke in people that were taking alpha-GPC as a prescription drug vs. those who weren't. What the hazard ratio means is subjects taking alpha-GPC were apparently 46% more likely to have a stroke during the 10-year study period than those who did not take alpha-GPC.

The way that reads suggests that long-term alpha-GPC users are 46% more likely to have a stroke, but that doesn't accurately reflect the findings when you look deeper at the study. The absolute risk increase of having a stroke for those taking alpha-GPC was about 0.9%. This is in addition to the baseline risk for stroke (i.e. risk without alpha-GPC), which was quite low -- 0.7% in the study cohort.

Absolute vs. Relative Changes

To help make sense of the study results and how they were reported in the abstract, consider this example:

You're running an 8-week study to investigate weight loss in subjects that take a fat burner supplement versus those that don't. By the end of the study period, you find that the control group — receiving a placebo sugar pill — lost half a pound of body fat. Those taking the fat burner lost one pound of body fat.

Here's how you can spin that data to make it seem extraordinary: subjects that took the fat burner supplement lost twice as much weight as the placebo group. Simple and compelling, right? Tons of people would jump on the bandwagon, "Wow, I can lose 30 pounds instead of 15 pounds in the same amount of time if I take that supplement." But then you look at the actual data and the absolute change is not convincing by any means — an extra half-pound of fat loss over eight weeks is unremarkable in the grand scheme of things.

That's just one example of how one can make absolutely insignificant changes between groups appear significant by highlighting the relative changes.

Is it Safe to Take a Choline Supplement for Cognitive Function?

To recap, the fellow "nootropics expert," is completely off base by saying alpha-GPC increases the risk of stroke by 95%. The study referenced herein actually showed that the absolute risk increase for stroke between alpha-GPC users and non-users was about 0.9%. This is an inconsequential effect size for a retrospective study of this nature.

As the authors of the study note, the results need to be replicated in future research; it's impossible to determine if the increased risk of stroke was due purely to choline supplements or other factors. There was no control for variables like exercise or diet. They also did not report any dosages for alpha-GPC. (It's likely the subjects were using much higher doses of alpha-GPC than you'll find in over-the-counter supplements.)

It's interesting that the present study proposes a mechanism involving dietary choline — from any source — and gut microbiota that use choline to produce trimethylamine n-oxide (TMAO), the same molecule responsible for the apparent health risks of excess red meat consumption. So, that means CDP-choline, which is another popular choline supplement, would also be a substrate for gut microbiota to produce TMAO.

CDP-choline is reportedly "less likely" to be used for TMAO synthesis than choline bitartrate and phosphatidylcholine, but it's unclear how it stacks up against alpha-GPC [6].

If the gut TMAO-mediated mechanism is valid, any dietary choline supplements would theoretically be a risk factor for a stroke. Again, that's assuming there is any connection, which is impertinent to conclude based on a single study.