GBB (Gamma-Butyrobetaine Ethyl Ester): Super Carnitine That Makes You Sweat?!

The story on GBB really starts with the end-goal: more L-carnitine.

Carnitine is a low molecular weight, water-soluble, bioactive amino acid whose L-isomer (L-carnitine) has long been known to participate in the process of lipid metabolism.^[3] Its many benefits are covered later in this article, but needless to say, it’s conditionally essential — while the body can generate some of its own, most needs to come from diet or it will not function properly.^[4]

The Carnitine Biosynthesis Pathway.^[5] GBB, or γBB, is circled in red.

Gamma-butyrobetaine (GBB) is a carnitine precursor that eventually gets converted into L-carnitine. GBB is converted to L-carnitine through an enzyme named Gamma-butyrobetaine dioxygenase (also known as BBD or BBOX).^[5-7] “GB dioxygenase”, as the name implies, is an oxidoreductase enzyme,^[8] and these enzymes facilitate conversions through electron movement. This is the final step in endogenous carnitine biosynthesis.

Supporting endogenous carnitine production

Researchers generally claim that 75% of L-carnitine comes from the diet, while the other 25% is synthesized endogenously^[9] (this statistic may change based upon diet and we are still working to confirm it). The last step in the endogenous production is conversion from GBB, thanks to support from essential amino acids like lysine and methionine in the brain, kidneys, and liver.^[10]

It’s that endogenous 25% we’re trying to support here. By supplementing with GBB, you provide a “push” for the body to produce more L-carnitine, without forcing customers to eat more red meat, which by far is the best natural source of carnitine.

The rate-limiting precursor?

Research shows that GBB availability in liver and kidneys is arguably the rate-limiting precursor for human carnitine biosynthesis.^[1] This is sometimes debated,^[7] but the point is that it — and the BBD/BBOX enzyme — are at least major limiting factors in endogenous carnitine deficiency. This is much like beta-alanine being the rate-limiting precursor to carnosine production for muscular endurance supplements. It thus makes sense to supplement some, even if carnitine is more orally bioavailable than carnosine, which necessitates precursors to a greater extent.

Utilizing Iron-dependent enzymes

It’s worth noting, however, that BBOX and other enzymes in the carnitine biosynthesis pathway are iron-dependent,^[6,11] so if GBB is being used as a “red meat workaround” for vegans, it may not work if they are iron-deficient due to not eating enough red meat.

To understand why it pushes the body to produce more L-carnitine, we require some basic general chemistry. Chemical reactions tend to behave according to Le Chatelier’s principle. Le Chatelier’s principle is a law of equilibrium^[12] — the body wants to maintain balance.

The GBB / L-Carnitine Equilibrium

When you add more GBB to the system, you get more carnitine until the levels of both product and reagent balance out. Likewise, if we have more product, enzymes can either downregulate to stop the production of more product, or even facilitate the breakdown of product into its constituent parts: more reagents. This allows the body to do its best to never have too much of any one thing. While it is never quite this simple in nature, it’s the easiest way to think of such reactions.

GBB gets converted to carnitine, and vice-versa, until the two compounds reach chemical equilibrium. Excess GBB gets turned into excess carnitine – excess carnitine can potentially get turned back towards GBB.

The pathway images in this article are more detailed than the above simple graphic, but the point is that your body will do its best to maintain homeostasis and that this reaction can go in both directions.

GBB supplementation works based on these principles. We add so much material to the left that the reaction goes to the right. It creates more carnitine to balance out the ratio of GBB and l-carnitine in the body. Tyrosine supplementation also works by helping conversion reactions move to the product side. This is why it’s easier to refer to GBB as a “pro-carnitine” ingredient.

“L-carnitine function. l-carnitine shuttles long-chain fatty acids inside the mitochondria by forming a long chain acetylcarnitine ester. The complex is then transported into the mitochondrial matrix by carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II). The fatty acids are then broken down through the process of β-oxidation to deliver the 2-carbon molecules to the Krebs cycle, leading to the generation of energy under the form of adenosine triphosphate (ATP). In addition, by binding an acetyl group, l-carnitine can maintain the levels of Acetyl-CoA and coenzyme A, playing its buffering role.”^[13]

The enzyme for GBB conversion to carnitine is commonly found in the kidney, liver, and the brain,^[14-16] with significantly more activity in the kidney.^[16] Given the roles of the kidney and liver in fat metabolism, having GBB dioxygenase in these organs makes sense. Carnitine serves an essential role in fat metabolism that will be discussed more below.

Inversely, giving a BBD/BBOX inhibitor will reduce carnitine levels in cells, and by as much as 70%!^[6] Here, we’re obviously trying to avoid that, but it goes to show how critical this pathway is.

This article assumes you already understand carnitine’s benefits. If you don’t, you can skip down to the carnitine section, but for everyone else, let’s continue to the GBB research:

The leading GBB researcher is Charles J Rebouche, of the Neuromuscular Research Laboratory and Department of Neurology, Mayo Foundation, Rochester, MN. The primary research was conducted in his lab after his team showed that GBB successfully increased L-carnitine concentrations in rodents.^[17] But it’s the human study where things get wild:

• A sweaty situation!

  The reason many readers are here is because GBB makes most athletes sweat far more than normal. This is often the main selling point, as some of us love to sweat when training.

  The most commonly-cited research study about the usage of GBB was published in 1989, where 16 participants were given various carnitine precursors for 10 days, after being given a lower-carnitine (no red meat) diet for 10 days beforehand.^[1]

  The carnitine precursors given were one of the following:

  • L-methionine + L-lysine (6 participants, 75mg/kg each)
  • ε-N-trimethyllysine (TML) (5 participants, 75mg/kg)
  • GBB (75mg/kg, reduced down to 36.5mg/kg)

  Right off the bat, we know that the GBB group got a ridiculously high dose! We generally max out at 50 milligrams — a standard 175lb man would have received a 6 gram dose, which was then reduced to 3 grams.^[1] That starting dose is over 100x what we normally see in the dietary supplement world!

  Why did they reduce the dosage? You can only guess:

  Participant 12 received 75mg γ-butyrobetaine/(kg body wt-d). The solid inner salt was dissolved in fruit juice or carbonated beverage and consumed in two equal amounts daily at breakfast and dinner.

  Because participant 12 complained of excessive sweating and salivation 1-3 h after ingestion of the γ-butyrobetaine supplement, the dosage was reduced to 37.5 mg/(kg body wt-d) for participants 13-16. Only one of these subjects reported any unusual effects (mild increase in sweating on d 11-13) with that dosage of the supplement.^[1]

  Those are some wild doses, but they did lead to incredibly increased serum carnitine concentrations: a 60-78% lift!^[1] This was by far more than any other carnitine precursor.

  

  Another look at how good GBB is at increasing plasma L-carnitine levels.^[1]

  This study also showed that the BBD/BBOX enzyme is likely not the rate-limiter — the enzyme works plenty fine, so long as there’s enough GBB to satisfy it.

  With regards to the sweating, however, the scientists don’t dig any deeper and fail to suggest a reason why that may have happened. We’ve seen no explanation why this sweating effect occurs, but it’s certainly incredibly effective at doing so. You can also rest assured that no dietary supplement is going anywhere near what those subjects were taking in the above study.

  

  While the carnitine levels doubled from GBB, the excretion was 30x higher, meaning there’s all kinds of carnitine turnover with GBB!^[1]

  One postulation of ours is that the chemical reaction to get from GBB to Carnitine is exothermic (releases heat), and by triggering the reaction en masse via supplementation, it theoretically outputs the heat. Alternatively, we’ve wondered if this is a chemically-induced version of the “meat sweats”, for those of you who’ve had such an experience (which is normally blamed on the higher thermic effect of protein).

  If we stumble upon an explanation that’s based in actual science, we’ll update this article.

  So if that’s not enough for the more conservative-minded folks who need to know every mechanism about every ingredient they take, then they may need to wait until more research is done.

• GBB leads to nitric oxide enhancement

  Another unique aspect of GBB is its consistent impact on nitric oxide levels.^[18] At least a few studies have shown GBB to be a potent vasodilator, but it may require higher doses than most individuals are willing to take.

  

  GBB elevates nitric oxide levels, but researchers don’t understand the entire pathway yet!^[18]

  The sports supplement industry is loaded full of nitric oxide supplements that improve blood flow and workout capacity, and this is another ingredient worth exploring for the right situation. By improving blood flow through increased vasodilation, GBB may help get nutrients to damaged muscle and joint tissues at a more rapid rate. It may even help keep blood pressure down. GBB has been more consistent in terms of vasodilation than other forms of carnitine.^[18]

• Poor carnitine precursor availability leads to lower carnitine concentrations

  Research on pregnant women has repeatedly shown that carnitine concentrations decrease during gestation, even when dietary intake of carnitine increases. This was not understood until researchers began studying precursors, and they found that low plasma concentrations of GBB were related to the lower plasma concentrations of carnitine.^[19]

  While we never recommend dietary supplement experimentation in pregnant women, and always recommend speaking to a doctor before beginning any new diet or supplementation program, this is very strong evidence that GBB is critically important to overall carnitine levels in normal adults.

• Reduces fatty liver in mice

  A very promising study published in 2010 showed that high intravenous 50 mg/kg doses of GBB (γ-butyrobetaine) reduced liver concentrations of free fatty acids in mice with juvenile visceral steatosis.^[20]

  What really impressed the researchers is that GBB can be taken up into the liver and transformed into L-carnitine,^[20] and in cases where carnitine transporters are defective, this can make a massive difference!

  

  Intravenous GBB Reduces Free Fatty Acids in Mice with Fatty Liver^[20]

  They conclude with the following:

  Consequently, administration of γ-butyrobetaine may be more useful than that of L-carnitine itself for treatment of primary deficiency of carnitine due to a functional defect of the carnitine transporter.^[20]

  Even though it’s an animal model with intravenous use, that’s still a powerful conclusion, and worth considering for the appropriate user.

• Reduced in people with mood disorders

  

  After reading a new review based upon 100 citations,^[13] we are finding fewer and fewer reasons not to take ~2g L-Carnitine each day.

  There’s a well-studied connection between the progression of mood disorders and the severity of carnitine deficiency.^[21] There’s additionally a lot of research showing various forms of L-carnitine supporting these mood disorders.^[22]

  Unsurprisingly, GBB levels are also lower in patients with depressive disorders.^[23] There isn’t much to infer from this knowledge — it’s unclear if mood disorders deplete GBB, or if low GBB causes lower mood, or if it’s a random association with no real connection.

  With that said, it’s still worth knowing about this potential connection. If one’s mood is low, a first line of defense is to dramatically increase red meat consumption and find ways to boost carnitine stores — the best studies seem to use the acetyl L-carnitine form.^[22] Can GBB help? We’d love to find out – we don’t think it’s a terrible idea to try.

Whenever a new supplement storms onto the scene, we go directly to studies that advocate for its safety. In this matter, we won’t lie — GBB took us by surprise. They studied GBB in human infants and determined GBB to be safe to take.^[2]

Given that infants may be the most sensitive test subjects around, we can logically say GBB supplementation is probably safe for adults,^[2] although we’d always welcome more toxicology research.

This study found freakin D-Carnitine heavily dosed in one supplement. Whose was it? We’ll probably never know. But it could be avoided with third-party lab testing, simply eating more meat, or having your body create the carnitine itself… with GBB.

In fact, some GBB manufacturers claim that GBB is safer than many carnitine supplements! While that must be taken with a grain of salt, they argue that there’s a problem with carnitine suppliers providing carnitine that may contain the D-carnitine enantiomer of L-carnitine.^[24] D-carnitine is toxic in humans and mammals,^[25] as it may reduce your body’s stores of carnitine and induce a deficiency!^[17,26]

GBB can claim superiority in a few other realms beyond safety. Science has associated L-carnitine supplementation with gastric distress in high doses.^[27-29] Anecdotal reviews concur. Since the dose of GBB is often much lower than other forms, it likely can circumvent this unfortunate side effect. Carnitine suffers from a poor bioavailability as the body may use only 18% of the dose.^[30] While we have seen little data on the bioavailability of oral GBB, we’re hoping it’s better than 18%!

Despite what the researchers put those poor subjects through in 1989 with massive doses, the standard reasonable dosage is roughly 10-25mg twice daily, or 25-50mg in one shot. Lower doses will likely still yield benefits, they just may not be “felt”, while higher doses may work but may induce too much thermogenesis for some individuals.

We generally don’t go for doses over 50mg per day right now… we know that more is safer, but the effect is quite pronounced for us at that point. Everyone’s experiences var.

Note, however, that the infant study used “500 µM γ-butyrobetaine”,^[2] with 500 micromolar = 0.0005 moles, and GBB’s molar mass is 146.2074 g/mol. This then equates to 73 milligrams of GBB on the infants! Obviously we don’t suggest this, but we do acknowledge that adults can definitely handle more than 50 milligrams.

In the other study, this happened at very high doses:

Participant 12 received 75 mg “y-butyrobetaine/(kg body wt-d). The solid inner salt was dissolved in fruit juice or carbonated beverage and consumed in two equal amounts daily at breakfast and dinner. Because participant 12 complained of excessive sweating and salivation 1-3 h after ingestion of the -y-butyrobetaine supplement, the dosage was reduced to 37.5 mg/(kg body wt-d) for participants 13-16. Only one of these subjects reported any unusual effects (mild increase in sweating on d 11-13) with that dosage of the supplement.^[1]

It goes without saying that we don’t suggest such astronomical doses (37.5mg/kg is nearly a 3g dose), but it’s interesting to see that the researchers even bring up the excessive sweat and salivation!

Carnitine is the molecule that facilitates movements of fatty acids during beta-oxidation, the process that lets us get energy from fats.^[7] It’s easy to visualize carnitine as a “fatty acid taxi cab” that takes the fatty acids to different spots within the mitochondria (the powerhouse of the cell).^[31] Once the fatty acids are dropped off by carnitine, they are converted into ATP through beta-oxidation. This process is going on constantly throughout the day but elevates during intensive exercise as fatty acids are burned for fuel.

Carnitine’s Function in Intracellular Transport.^[5] Note how important this molecule is if you plan on delivering fatty acids to cells. You can ignore the bottom yeast section.

Thus, it may make sense to take some before a workout: more taxis going to the destination means more guests will arrive, correct?

This is where GBB should also kick in, beyond its thermogenic effects. By providing enough GBB, we allow the body to “push” the conversion reaction and get more carnitine in serum. If we have more carnitine, we can transport more fatty acids into the mitochondria to burn as fuel.

What does having more carnitine do?

Let’s finally get to the crux of our pursuit: does carnitine supplementation really do anything? The short answer is that carnitine has several benefits it can impart through proper supplementation, especially in those that are deficient. Carnitine is likely best known for improving brain health, as it improves focus, memory formation, and even the ability of the brain to resist disease or degradation.^[32-34]

Vegan? Vegetarian? Aging? Then read up

Carnitine really shines for fat loss in those that are deficient. Vegans, vegetarians, and boomers should all consider giving carnitine a shot as supplementation is associated with improved fat oxidation (through its natural mechanism) and even enhanced intra-set recovery.^[35] It may even help the deficient hold on to muscle mass more efficiently as these demographics age.^[36,37]

Any form of carnitine is a good idea for vegans

General health, fertility, and more

In terms of general health, more carnitine is quite often a very good thing. Carnitine has been long-used to improve sperm quality,^[38] and since first publishing this article, more data has come out demonstrating how powerful carnitine is for fertility in both men and women.^[39] Additionally, it functions as a potent antioxidant.^[40]

It contributes to metabolic flexibility,^[41] and helps keep glucose levels down in the body while improving insulin sensitivity.^[42] It may even be worth trying when treating symptoms of autism and ADHD!^[43,44]

The carnitine deficiency downfall

The above benefits are only the most clear. There’s an uncountable number of things that can go wrong when the body can’t mobilize fat due to a carnitine deficiency, so there’s nearly as many things that it may improve in some form when you correct such a deficiency. Because of this, it’s tough to make claims about how it will specifically help you, but we can confidently say that “being carnitine deficient is a decidedly bad thing”.

So yes, GBB will probably do something by virtue of improving carnitine levels in the blood. Carnitine itself is a very well studied compound — the biggest differences with GBB are the method of increment, the dose, and the thermogenic effect. While we lose out on the versatility of other forms of carnitine, like acetyl l-carnitine’s ability to cross the blood-brain barrier, we make up for it with a lower and more tolerable dose with some additional “fringe” benefits.