Are “keto supplements” necessary?

Skeletal formula of beta-hydroxybutyric acid

A reader writes,

I searched the Science-Based Medicine website but can’t find an answer to this question that has been bugging me. As a primary care physician I am constantly asked about supplements, lately about “keto supplements” for weight loss. Those living the “keto lifestyle” monitor for ketosis via urine ketone test strips. One popular keto supplement is KetoCharge. Its active ingredient is 800mg of beta-hydroxybutyrate. Biochemistry was 20+ years ago, but my sense is that this is an unabashed scam. Sell people beta-hydroxybutyrate to ingest, then have them test their urine for … beta-hydroxybutyrate. The scam seems to be that people don’t realize the ketones showing up on their test strips are exogenous, not a result of any internal biochemical process other than excretion. Am I missing something, or is this just the supplement industry not even trying to be honest anymore?

What is a ketogenic diet aka going “keto”?

Normally, glucose is acquired through your diet by consuming carbohydrates, including sugars and starches. Once ingested, your body breaks down these carbohydrates into glucose, which serves as a source of energy. Surplus glucose is stored in the liver and is released when required. Carbohydrates are the usual base fuel for cells such as the brain and nervous system that depend on glucose.

A ketogenic diet is one that generally includes under 50 grams of carbohydrate. When carbohydrates are not available, the body begins to break down fat, putting your body in a state of “ketosis” and producing “ketones”.

Studies have indicated that ketosis may offer some health benefits. Some forms of epilepsy respond to keto diets. A more current reason for interest in the ketogenic diet is its potential for promoting weight loss. Being in ketosis seems to reduce appetite, potentially resulting in decreased food consumption. A “keto diet” is not inherently superior to other types of diet for weight loss, however. The benefit seems to be from the overall reduction in calories, rather than anything magical about ketosis itself. The jury is out on the long-term health effects of a keto diet.

Keto sounds straightforward! Why would I need a supplement?

Until this reader request, I had never heard of a keto supplement. Keto Charge is one of many supplements that contain beta-hydroxybutyrate (BHB).  Beta-hydroxybutyrate (BHB) is the primary ketone utilized by the body for energy when glucose availability is restricted. Normally, BHB levels in the blood are low, but during periods of fasting (or low/no carbohydrate ingestion), the liver converts fatty acids to ketone bodies like BHB, which can be utilized by other organs and tissues as energy. BHB is also a signaling molecule that can influence various cellular processes, including metabolism and gene expression. This has led to interest in studying the potential therapeutic effects of BHB, such as its impact on exercise performance, cognitive function, and certain health conditions. Some of the natural questions about BHB might include formulation (is it well absorbed?) and the effect on different paramaters, particularly in those that are on a keto diet (who are already using ketone body as a primary fuel) and those that are not on a keto diet, and primarily using glucose as a primary fuel.

Has beta hydroxybutyrate been studied in clinical trials?

Unlike many other supplements, the answer is yes…but there is some digging we need to do to determine the relevance of these trials.  Searching for BHB brings up pages of results, but when I searched for randomized controlled trials using BHB as a supplement, I found just nine results:

1. One trial looked at intravenous infusions of 3-hydroxybutyrate, so was irrelevant to a review of dietary supplements.
2. A 2021 trial randomized pre-diabetic adults to a BHB supplement to evaluate the effect on plasma glucose. It concluded “Ingestion of the KEβHB-supplemented drink acutely increased the blood βHB concentrations and lowered the plasma glucose concentrations in adults with prediabetes.”
3. A 2018 trial examined the effect of a BHB-containing beverage on cognition and anaerobic exercise performance measures, and found no effects.
4. A 2021 trial of BHB supplements on markers of iron metabolism in people with prediabetes. No meaningful effects (other than increased blood levels of BHB) were noted.
5. A 2019 trial of BHB supplementation to evaluate the effect on a regulator of inflammation.
6. A 2020 trial of a pre-workout supplement of BHB, caffeine and amino acids on high-intensity exercise, in people on ketosis diets and those that were on a non-keto diet. This was a non-blinded trial, and the supplement was found to benefit both groups.
7. A 2019 trial examining BHB supplementation (or placebo) on walking economy and measures of perceived exertion. It found no difference between groups.
8. A 2021 trial of 90 days of BHB supplementation in adolescents to evaluate safety, including ” fasting blood safety metrics, bone density, happiness, emotional intelligence, or blood pressure”. It concluded the supplement was safe and well tolerated. I am curious how this manufacturer-funded trial passed institutional review board review.
9. A 2019 evaluating ingestion of BHB on exercise in trained cyclists. It concluded “ingestion of βHB salts does not affect lactate appearance, perceived exertion, or muscular efficiency.”

I also found one paper in the Journal of Insulin Resistance which didn’t come up in a PubMed search because it seems that journal isn’t abstracted by the National Library of Medicine, which is a red flag for quality, but not a reason to ignore the findings. Regular readers may recall that Journal of Insulin Resistance is where Aseem Malhotra published two long articles filled with antivaccine misinformation – discussed at length by David Gorski in late 2022, an also by Health Feedback here. The journal seems to be erratically published (only six editions since 2016 and a two year gap from 2019-2022). While the main findings of that trial seemed uncontroversial (BHB supplementation raises BHB plasma levels), I’m not going to spend any further time on it.

So why take a BHB supplement?

Here’s what the manufacturer of one supplement says about the effect of supplementation:

I could find no credible published evidence to support any of these claims, with the possible exception of “instant ketones”, as there seems to be reasonable evidence that orally consumed BHB is absorbed. I could locate no published clinical trials to show that BHB consumption provides meaningful medical or health benefits to those in ketosis (on keto diets) or to those that are not in ketosis. If you’re “going keto” with the intent of burning ketones from fat, then I’m at a loss to understand why you would consume exogenous ketones, which simply provide a source of external fuel – like any other energy source. And measuring your urine for the presence of ketones when you deliberately consume BHB makes no sense to me whatsoever.

BHB looks like a supplement still in search of a purpose. Perhaps one will be identified someday. There is no convincing evidence to suggest that BHB supplementation is beneficial or necessary, regardless of your dietary choices.