Carnitine: a controversial view and why it can actually be bad for you

Carnitine could be more harmful than good for you.

I’m going against the grain here to bring to light that carnitine might not be as good as you think it is.

What inspired me to write this article

I had a conversation with someone the other day. I told him that carnitine isn’t really effective for fat loss because fat oxidation does not equal fat loss. He then said: “Yes, carnitine is ineffective because its absorption is very bad. Its molecular size is too big and digestion will just break it down similar to collagen and glutathione.” (As if that’s the reason why it’s not effective). None of these statements are true and I’ll explain why.

But first, if you believe that fat oxidation equals fat loss, I implore you to read two of my previous articles on this subject.

>Myth: Burn fat to lose fat. Busted!
>Myth: Fasted cardio for better fat loss. Busted!

Carnitine is most famous for its transport of fatty acid into cells to be converted into energy. From this fallacious assumption, it’s touted to improve fat loss, improve exercise performance, enhance mental focus, improve insulin sensitivity, etc.

 

Carnitine fatty acid oxidation MenElite

 

As you can see from the diagram above, CPT1 combines an acyl-CoA (fatty acid combined with a coenzyme A (CoA)) with free carnitine to create acylcarnitine, which can then be transported across the cell membrane.

Once inside the cell, acylcarnitine is reconverted to acyl-CoA and carnitine by CPT2.

Once the fat has arrived in the mitochondria, the beta-oxidation complex gets a hold of it and chops it up 2 carbons at a time, generating NADH, FADH2 and acetyl coenzyme A (acetyl-CoA) in the process. 

Pyruvate dehydrogenase carnitine acetyl-CoA MenElite

An excess of acetyl-CoA can inhibit pyruvate dehydrogenase (PDH), the key rate-limited step for glucose oxidation. Carnitine can bind to the acetyl-CoA in the mitochondria and transport it out. This allows the PDH to be uninhibited by the increased fat oxidation.

However, several studies have demonstrated the accumulation of acylcarnitines in ischemic myocardium, which leads to harmful effects on mitochondrial function and heart survival. Furthermore, some evidence suggests that the detrimental effects of acylcarnitines might be related to their pro-inflammatory action.

More carnitine, more acylcarnitines, more possible inflammation.

 

The good about carnitine

#1 Carnitine can buffer the excess acetyl-CoA in the mitochondria, thus lowering it and this promotes pyruvate dehydrogenase (PDH) activity. More PDH activity, faster glucose oxidation, less lactate production and more ATP and CO2 production.

#2 It might slightly aid in fat loss (not all studies agree on this). 

Results from meta-analysis of eligible trials revealed that subjects who received carnitine lost significantly more weight (MD: -1.33 kg; 95% CI: -2.09 to -0.57) and showed a decrease in body mass index (MD: -0.47 kg m(-2) ; 95% CI: -0.88 to -0.05) compared with the control group.” (R)

However, the magnitude of weight loss resulted from carnitine supplementation significantly decreased over time. If your goal is to lose 10kg, carnitine might boost that to 11.33kg under all optimistic conditions, if the reduced returns don’t kick in first. Is an extra 1.33kg really worth all that carnitine supplemental money to you?

#3 Treatment with L-carnitine was shown to protect against ischemia-reperfusion injury, but L-carnitine can actually worsen ischemic injury under conditions where L-carnitine
does not facilitate glucose metabolism (R).

#4 Acetyl-L-carnitine might have anti-anxiety properties by inhibiting glutamate release through upregulating the glutamate autoreceptor, Glut2, expression (R).

#5 Acetyl-L-carnitine has been found to reduce neuropathic pain, but not carnitine itself, which points to the importance of the acetyl moiety.

#6 L-carnitine-L-tartrate has been shown to increase androgen receptors.

It seems to me that the main benefit of carnitine is actually to promote glucose oxidation. Which in my opinion is quite paradoxical, because people take it to boost fat oxidation, but instead, it improves their glucose oxidation. They then go on to praise the wonders of fat oxidation.

 

The bad of carnitine

#1 Carnitine promotes fat oxidation.

But wait isn’t that good? Although CPT1 is the rate-limited step to fat oxidation, boosting it doesn’t mean anything. If beta-oxidation is dysfunction, forcing more fats down its guzzle is like blowing up a bubblegum bubble and waiting for it to explode.

Research shows that dysfunctional beta-oxidation drives diabetes. Giving more carnitine does not improve beta-oxidation. Doing things like calorie restriction and cardio to increase lipolysis and fat oxidation just increase incomplete mitochondrial fatty acid oxidation (R). This leads to insulin resistance, lipid buildup and a subsequent increase in reactive oxygen species (ROS) generation, oxidative stress and inflammation.

Mitochondria are the main site of lipid oxidation which, in the heart (which burns mostly fat), supplies most of the energy required for its blood pumping function. Paradoxically, however, too much fat impairs mitochondrial function leading to metabolic syndrome, insulin resistance and diabetes (R).

Additionally, excess fats in the cell can uncouple mitochondrial respiration, reducing ATP production and triggering excess emission of oxidants while impairing antioxidant systems.

Research also shows that fatty acid oxidation is enhanced in cancer. 

The overexpression of CPT1A is often associated with tumor progression in several cancers such as breast, gastric, prostate, lymphoma, leukemia, ovarian, lung, and myeloma. Several studies reported that inhibition/depletion of CPT1 leads to apoptosis and suppression of cancer cell proliferation, chemoresistance, and neo-vascularization.

Carnitine can also reduce mitophagy and autophagy which disrupts the clearance of damaged mitochondria in the body. This leads to a loss of protection from increased reactive oxygen species (ROS) and reduced mitochondrial ATP supply (R). 

Cells that won’t die, which can be induced by carnitine, is a hallmark of cancer.

 

#2 Carnitine can drive reverse electron flow

As you can see from the diagram above, fatty acid oxidation (of saturated fat) generates about a ratio of 2:1 NADH to FADH2. The oxidation of unsaturated fat generates a little less FADH2 than the oxidation of saturated fat. Glucose oxidation generates a ratio of 5:1 NADH to FADH2. Based on that math, fat oxidation generates much more FADH2 than glucose.

NADH feeds into complex I and FADH2 into complex II, where they donate their electrons to CoQ10 (ubiquinone). In a theoretical scenario where the electrons flow like ducklings on a pond, one after the other, through complex I to complex II, then III and lastly IV, we have a problem. 

The problem is created by excess carnitine. Excess carnitine is pumping too much fat into the mitochondria (which is broken down by beta-oxidation) and keeps the acetyl-CoA:CoA ratio low, which allows PDH to speed up as well. Now your cells are burning both glucose and fats at the same time, creating heaps of NADH and FADH2.

The FADH2 is taking up all the free space in complex II. The electrons from complex I has to run past complex II, but it’s all jammed up with the electron from FADH2. Where do the electrons go? Out of the electron transport chain. This is called reverse electron flow and this leads to an increased generation of ROS. Leaked electrons react with oxygen to create superoxide. Superoxide is a highly reactive free radical.

A little ROS is good as it acts as a signal in the cell. Too much leads to oxidative stress, DNA damage, inflammation, etc.

Point being, excess carnitine can cause this. Too much ROS can oxidize the lipids and proteins in the cell, which will cause damage and reduce cellular function. Now the electron transport chain is even more dysfunction and more ROS is created. Superoxide can also react with nitric oxide and create the highly damaging peroxynitrite. Not a place you want to be.

Lastly, a buildup of NADH, due to electrons that can’t flow forward, in turn, inhibits PDH. So carnitine might help short term to boost PDH, but in the long term, it can lead to a buildup of NADH, which will block PDH again.

Moreover, l-carnitine accelerated reactive oxygen species production in serum and liver, thereby triggering hepatic NOD-like receptor 3 (NLRP3) inflammasome activation to elevate serum interleukin (IL)-1β and IL-18 levels in rats. Alteration of serum alkaline phosphatase levels further confirmed liver dysfunction in l-carnitine-fed rats. Additionally, l-carnitine may potentially disturb kidney function by altering renal protein levels of rat organic ion transporters.” (R)

 

#3 Carnitine is anti-thyroid

That’s right, carnitine inhibits thyroid function (R). It’s actually used to treat hyperthyroidism. What would happen if you took it and you had normal or already low thyroid hormone production? You’d get even lower thyroid hormone production.

Besides, carnitine production is under the control of the thyroid (R). Why try to bypass it. Instead of supplementing carnitine, optimize your thyroid hormones.

“BBH activity was decreased in the hypothyroid state and increased in hyperthyroid animals.

Thyroid hormones are known to interact with lipid metabolism, in particular by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria. Our study showed that thyroid hormones also increased carnitine bioavailability.”

 

#4 Carnitine is pro-cortisol

Carnitine has pro-cortisol effects as injections of acetyl-L-carnitine increases cortisol levels (R).

L-carnitine can also activate the cortisol receptor alpha (GRα). Through this mechanism it can regulate glucocorticoid-responsive genes, potentially sharing some of the biological properties of glucocorticoids (R).

This research group found that carnitine injections (1g for 12 months) even led to an increase in fat mass and a decrease in lean mass, while increasing total and LDL cholesterol. There are limitations to the study, but the outcome is in line with a regression in thyroid function and an increase in cortisol (R). 

 

Conclusion & finishing thoughts

It might seem like I’m bashing carnitine, which I am, but I’m not pro-carnitine depletion. Yes if you have excess carnitine it might be an issue, but we still need carnitine to an extent. Unless you have an enzyme deficiency in synthesizing carnitine or have kidney damage, I would not supplement it.

What you want to do is provide the necessary building blocks for the body to synthesize its own carnitine, such as lysine and methionine. Ascorbic acid (vitamin C), iron, vitamin B6 and vitamin B3 are also necessary cofactors.

I would rather make sure that my thyroid is working optimally and then supply what is needed to make carnitine, such as methionine, lysine, vitamin C, B6, B3 and iron.

 

But what about diabetes?

“Recently, the average L-carnitine in the blood of control subjects was found not to differ among subgroups of patients with type 1 or type 2 diabetes” (R)

 

What about insulin sensitivity?

“In type 2 diabetic patients, L-carnitine improves insulin sensitivity and increases
the amount of whole-body glucose utilisation and glucose oxidation [36–38].” (R)

It’s to be expected from anything that can promote glucose oxidation. But given that carnitine can increase inflammatory acylcarnitines as well as cortisol levels, I don’t think this is the best thing to use to improve insulin sensitivity.

Besides, prolactin (PRL) increases the expression and the activity of CPT1A, which is involved in cancer progression (R).

 

What about exercise performance and recovery?

It does seem to boost physical performance and endurance slightly (although not all studies find a benefit), because it actually boosts glucose oxidation (R).

“However, in contrast to the idea that supplementation of carnitine can accelerate fatty acid oxidation, data from animal models demonstrated that carnitine supplementation during high-intensity exercise increases glucose oxidation at the expense of fatty acid oxidation []. The mechanism at the basis of this phenomenon is that, by decreasing the mitochondrial glycolytic acetyl-CoA by acetyl-carnitine synthesis, the pyruvate dehydrogenase enzyme can be activated, thus facilitating complete glucose utilization with a reduction in lactate accumulation. Therefore, the raised availability of carbohydrate during exercise increases glycolysis and pyruvate flux through the pyruvate dehydrogenase with a corresponding decrease in the rate of fat oxidation.” (R)

But a rather offputting quality of carnitine (L-carnitine-L-tartrate in this study) is that it reduced muscle oxygenation responses to resistance training (R). Creating a state of long term hypoxia is never good.

 

Cardiovascular risk?

Humans obtain carnitine mainly from the diet, predominantly from animal-based food products such as red meat, chicken, fish and dairy. About 25% of carnitine comes from endogenous synthesis.

Only about 5-18% of the supplemented carnitine is absorbed in the gut (up to 75% for dietary carnitine) and the rest that is not absorbed at the level of the small intestine is completely degraded by bacteria in the large intestine to produce trimethylamine (TMA) (R). TMA is then oxidized in the liver to form trimethylamine-N-oxide (TMAO). TMAO has been demonstrated to promote atherosclerosis and to increase cardiovascular risk in animals. In human studies, a significant positive correlation has been found between fasting plasma TMAO levels and major cardiovascular events (R).

 

Is the lack of effect not due to bad absorption?

Despite the low oral bioavailability of l-carnitine (and the rapid clearance thereof), the issue is not due to carnitine deficiency, since serum carnitine levels in patients receiving oral supplements were well above those of controls (R).

 

Why I would not use carnitine

Carnitine increases fatty acid oxidation and PDH (it possibly only boosts PDH in the short term) and this can lead to an increase in ATP.

But why is ATP production low in the first place? Most often due to elevated ROS coming from a dysfunction electron transport chain, excess fat oxidation and excess PUFAs. Fixing the root cause will be a much better approach than trying to stuff more fat into the mitochondria. If you can’t chew and swallow the marshmallows in your mouth, don’t try to put more marshmallows in your mouth! 

Lower the excess ROS, fix PDH (without supplemental carnitine) and the electron transport chain and then your body will automatically increase ATP production.

Plus, supplementing more carnitine might even do nothing. For example, giving vegans carnitine improved their carnitine levels but didn’t do much of anything else.

Oral L-carnitine supplementation normalizes the plasma carnitine stores and slightly increases the skeletal muscle carnitine content in vegetarians, but without affecting muscle function and energy metabolism.” (R)

 

As always, thanks so much for reading my article. Let me know if this article was helpful in the comments below.
If you found it helpful and insightful please like and share so others can also benefit from this information and feel free to leave a comment down below if you have any questions for me.

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