Supplements 101: Carnitine
Acetyl-L-carnitine, or ALCAR, acts as a biological shuttle bus—moving big bulky fats into the mitochondria for breakdown to cellular energy, ATP. Yet, it does much more. It has been studied as a potential therapeutic nutrient for over 100 years since it was first isolated in 1905. Numerous clinical studies in humans demonstrate the positive effects of acetyl-L-carnitine on brain function, cognition, and memory. More recent studies suggest that it may slow or reverse mild cognitive impairment and the progression of dementia in Alzheimers disease. It has also been studied as a pain reliever in nerve injury.
But is ALCAR a good candidate supplement for MECFS? And Fibromyalgia? This post is part of a series on popular supplements in ME/CFS. You can read more from this series here.
L-Carnitine vs ALCAR vs Propionyl-L-Carnitine
Supplementing with carnitine incurs buyer options. L-carnitine is readily available. But the acetyl-L-carnitine form is better absorbed than traditional L-carnitine. The extra acetyl group also facilitates the molecule easily crossing the blood-brain barrier through a specialized transporter. Yet another option is propionyl-L-carnitine. This is often packaged in supplements as glycine-propionyl-L-carnitine (GPLC). This carnitine derivative seems to be more specific to muscle cells, where it improves uptake of fats to produce ATP. This form also allows for better mitochondrial function when oxygen is low (hypoxia), by providing another substrate for ATP production, propionate, which can be converted to energy. A word of caution regarding propionyl-L-carnitine: it is a vasodilator so may not be wise for those with very low blood pressure as it could lower it further.
ALCAR for Brain Health
ALCAR can be used as a precursor for neurotransmitters such as acetylcholine. In the brain, acetylcholine is vital for learning and memory as well as protecting the brain from inflammation. ALCAR can also be used to form glutamate, glutamine, and GABA. For these reasons, it has been of great interest as a potential anti-depressant. Also of note, the acetyl part of ALCAR can be incorporated into lipids for nerve myelination and cell growth.
ALCAR supplementation can increase glutathione in the brain. A study from 2003, in patients with multiple sclerosis showed that 6 months of supplementation with ALCAR increased glutathione in the cerebrospinal fluid and reduced markers of oxidative stress when compared to untreated MS controls.
L-Carnitine-Rich Foods
As the name implies (“carne”), all animal foods are rich sources of L-carnitine. This also includes fish and dairy products. Just 4 oz of beef, contains roughly 50-160mg of carnitine. Very small amounts of carnitine are found in vegetables and grains. Vegan or vegetarian diets may comprise just 10–12mg per day.
Even on a low or no animal food diet, carnitine can be synthesized by the body. The kidney and liver can synthesize the nutrients from the amino acids methionine and lysine. For this reason, deficiency is seldom seen. However, carnitine stores rapidly decline with age.
Drugs that Reduce Carnitine
It is worth mentioning here that certain medications can deplete ALCAR. A handful of anti-convulsant drugs, some of which are prescribed for fibromyalgia, deplete ALCAR and those on these medications should consider supplementing. This includes anticonvulsants valproic acid, phenobarbital (Lumenol), phenytoin (Dilantin), or carbamazepine (Tegretol).
The Elephant in the Room: Carnitine and TMAO
Several years ago, news headlines linked trimethylamine oxide (TMAO) from the L-carnitine in red meat to an increased risk of heart disease. This was based on the fact that L-carnitine from meat is metabolized by certain gut bacteria to form TMAO. They found that the higher the TMAO the more atherosclerotic lesions. The paper was high-impact in Nature, but was performed in MICE!
But guess what? The same group continued to test their hypothesis by looking at humans. Their 2013 paper concluded that the microbiota of humans also metabolizes L-carnitine to TMAO. When administered antibiotics, TMAO levels were dramatically cut in both mice and humans. This supports the hypothesis that gut bacteria are essential for the production of TMAO. This study also included an observational design in which they determined again high TMAO of meat eaten was associated with a greater risk of heart disease. The study design however was riddled with potential confounders like smoking and medication usage.
What’s more…. other studies have not supported the TMAO-heart disease hypothesis.
There is no clear pathophysiological mechanism linking TMAO directly to cardiovascular disease in any other studies. Numerous other foods generate TMAO in the gut. Carrots, cauliflower, peanuts, peas, potatoes, soybeans, and tomatoes produce more TMAO than red meat. Even chicken, bread, mushrooms, cheese, and eggs all produce more TMAO than red meat. Most surprisingly, seafood consumption is associated with very high TMAO, and yet seafood consumption is always associated with positive heart health.
The TMAO story is thoroughly muddied. It is not at all clear if it does in fact relate to cardiovascular disease risk and no mechanism is apparent to link these things together. So, have little worry that supplementing with ALCAR puts one at risk of cardiovascular disease. There are even several studies that suggest L-carnitine is cardioprotective as it reduces the oxidative stress of heart tissue. It has been used in clinical trials of angina, heart failure, and peripheral artery disease.
ALCAR in ME/CFS
In general, studies utilizing ALCAR in ME/CFS are few and poorly designed. No surprise there!
A very small study from 2002, of 8 ME/CFS patients showed low levels of ALCAR in the serum. This also correlated with the severity of fatigue—the lower the ALCAR in the blood, the more fatigue. The group then used brain imaging to test the effectiveness of ALCAR uptake in the brain. Here, those with MECFS had reduced ALCAR uptake in distinct brain regions when compared to controls. Since ALCAR can act as a precursor to neurotransmitters, this reduced uptake by the brain could result in overall reduced neurotransmitter synthesis.
In a 2006 systematic review, there was just one single randomized-controlled trial with overall benefit using ALCAR at a dose of 2g/day. However, this trial failed to utilize a placebo control. In another study from 2008, after 6 months of acetyl-L-carnitine (500mg) in 96 aged subjects with MECFS there was benefit in reported physical and cognitive fatigue. However, this study focused on patients over the age of 70, so the effects may be more profound given that ALCAR diminishes significantly with age. Also, the design of this study is geared more toward factors unique to the elderly, not for MECFS specifically per se.
ALCAR Improves PDH Function
The enzyme pyruvate dehydrogenase (PDH) is vital for taking energy-rich molecules from the diet into the mitochondria to be converted to ATP. It is also an enzyme that has been implicated in the pathophysiology of ME/CFS. A metabolomics study of 200 ME/CFS patients meeting the Canadian Consensus Criteria and 102 controls found a pattern of amino acids that suggested functional impairment of the PDH enzyme. A study from 1994, demonstrated that supplementing with L-carnitine (4g/day) significantly increased the activity of the PDH enzyme as measured by muscle biopsies in adults.
ALCAR for Pain Relief
Supplementing with ALCAR seems to have a neuroprotective effect. Suggested mechanisms for these effects could stem from ALCAR’s ability to positively affect mitochondrial function, its antioxidant properties, and its ability to affect glutamate production, or something else entirely. Early animal study findings showing neuroprotection, sparked an interest in using ALCAR in those with nerve damage related to chemotherapy or from nerve damage that occurs with HIV drug treatment. In these trials, ALCAR supplementation showed positive benefits in relieving nerve pain (neuropathy) and even improving nerve function (conduction).
If ALCAR can relieve neuropathic pain, does it help with fibromyalgia pain? A 2007 study of over 100 fibro patients used ALCAR (1g/day) and some in the group also received ALCAR by injection for 8 weeks. After the trial there were reported reductions in pain and improvements in quality of life compared to controls.
In another fibromyalgia study, 65 fibro patients were given standard treatment of duloxetine of 60 mg/day or acetyl L-carnitine of 1500 mg/day. At four and 12 weeks, there were reported improvements in both groups regarding pain and quality of life.
More Clinical Trials of ALCAR
In a meta-analysis of double-blind, placebo-controlled clinical trials, supplements of acetyl-L-carnitine (doses between 1.5-3g/day) improved mental function and reduced cognitive deterioration in older adults with mild cognitive impairment and Alzheimer’s disease.
ALCAR is effective and routinely prescribed to remove ammonia in the body in those with liver disease or liver injury due to medications. As mentioned in another post, some may have bacterial overgrowth in the gut that contributes to excesses of ammonia.
A systematic review of 11 randomized placebo-controlled studies on ALCAR in patients diagnosed with dementia supported significant positive effects on memory and overall cognitive functioning when assessed at 12 and 24 weeks after starting treatment. Other studies have looked at the role of ALCAR in dementia, Alzheimers, traumatic brain injury, and mental illness.
While not all studies are positive, overall ALCAR appears to be promising when dosed properly and utilized for longer durations. Furthermore, there is little risk of side effects. Most commonly reported are nausea, diarrhea, headache, or vomiting, though all are relatively rare.
Bottom Line
ALCAR supplementation is a good idea for those with chronic fatigue syndrome due to its ability to increase the function of the PDH enzyme, improve mitochondrial function, and ability to increase important neurotransmitters. For those with fibromyalgia, ALCAR supplementation is also very promising to reduce pain given its protective effect on peripheral nerves and nerve function.
ALCAR supplementation is especially important for older patients. It should also be included for those who require the medications mentioned above, some of which may be prescribed for fibromyalgia or chronic pain. Finally, if there is evidence of elevations in ammonia from bacterial overgrowth, ALCAR is the first choice to sequester ammonia.
Based on clinical trials, dosing of at least 2g per day is recommended. If no effect is seen, dosing up to 4g per day is in line with available studies. Potential side effects are likely reduced by lowering the dose. ALCAR is preferred over L-carnitine for improved bioavailability and ensured potency. Glycine-propionyl-L-carnitine (GLPC) is not recommended for those with low blood pressure.
References
Rebouche, C. J. (2004). Kinetics, Pharmacokinetics, and Regulation of l-Carnitine and Acetyl-l-carnitine Metabolism. Annals of the New York Academy of Sciences, 1033(1), 30–41.
Ferreira GC & McKenna MC (2017) L-Carnitine and Acetyl-L-carnitine Roles and Neuroprotection in Developing Brain. Neurochem Res; 42(6):1661-1675. Neurochem Res. 28(9):1321-8.
Calabrese V. et al (2003) Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine.
Kuratsune H. et al (2002) Brain regions involved in fatigue sensation: reduced acetylcarnitine uptake into the brain. Neuroimage; 17(3):1256-65.
Vermeulen RC & Scholte HR. (2004) Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 66(2):276-82.
Montgomery SA, Thal LJ, Amrein R. (2003) Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol. 18:61-71.
Rossini, M. et al. (2007) Double-blind, multicenter trial comparing acetyl l-carnitine with placebo in the treatment of fibromyalgia patients. Clin Exp Rheumatol. 25(2):182-8.
Leombruni P et al. (2015) A randomised controlled trial comparing duloxetine and acetyl L-carnitine in fibromyalgic patients: preliminary data. Clin Exp Rheumatol. 33(1 Suppl 88):S82-5.
Malaguarnera M, Gargante MP, Cristaldi E, Colonna V, Messano M, Koverech A et al. (2008). Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue. Arch Gerontol Geriatr 46: 181–190.
