Supplements 101: Lipoic Acid

Alpha-lipoic acid (ALA), or sometimes simply lipoic acid, is an important molecule essential for various aspects of metabolism (breakdown of foods into useful energy molecules). The primary site where ALA goes to work is at the cellular energy machine—the mitochondria. ALA is a crucial helper to mitochondrial function. It acts as a coenzyme, assisting in mitochondrial energy (ATP) production. It is necessary to help the mitochondria use fats, sugars, and proteins to make ATP.

ALA’s function at the mitochondria is so important, that the mitochondria itself can synthesize ALA. The effectiveness of this synthesis declines with age. In addition to metabolism, it functions to recycle cellular antioxidants, including coenzyme Q (CoQ), vitamin C and E, and glutathione (GSH) to protect the delicate mitochondria membranes. It also works itself as an antioxidant—quenching free radicals.

Alpha-Lipoic Acid Cleans Up

Outside of the mitochondria energy producing machinery, ALA can bind to excess metals like iron or copper, which helps to chelate them for removal. It also stimulates the all-important Nrf2 pathway—a vital pathway that protects DNA from damage and stimulates liver detoxification pathways.

Food Sources of ALA

Lipoic acid found in natural foods is in a bound form of lipoyllysine, making it less available to the body. Food sources include red meat, kidney, liver, and heart. While in plants, it is found abundantly in spinach, tomatoes, broccoli, brussels sprouts, garden peas, potatoes, and rice bran. However, food forms of lipoic acid do not seem to have any effect on free form ALA. Also consider that food content is probably 1/1000th of what is found in supplements. So it is unlikely that high intake of these foods will provide benefits akin to supplemental ALA.

A Better Form

Ingested supplement forms of ALA have poor bioavailability. Only 30-40% of the compound is absorbed through the intestine. If taken with food, absorption is even less. Liquid formulations provide better results. All the same, ALA readily crosses the blood-brain barrier so it has the potential to exert effects at the level of the brain.

Another major problem with ALA is that once it is inside the cell it is reduced (to DHLA) and then rapidly transported out of the cell. Essentially chewed up and spat out. That won’t give it much time to have any benefit for mitochondrial function. Newer formulations of the supplement may help prevent this ejection to allow the molecule to stick around and have longer-lasting effects. One such formula, LA-Plus, provides a lipoic acid with a positive charge which helps trap it inside the cell. In vitro studies show this formulation is better able to be retained in the cell and has more potent anti-oxidant effects.

ALA is Very Effective for Neuropathy

Here in Germany, ALA is approved and readily prescribed as a treatment option for peripheral neuropathy. A meta-analysis of randomized controlled trials determined that IV infusion of 300-600 mg/day of lipoic acid for 2-4 weeks significantly reduced the symptoms of diabetic neuropathy. Are oral varieties also effective?

Yes. Clinical trials of 600mg or oral ALA for up to 5 weeks also show improvements in neuropathy. Even better, a 4-year-long study of more than 400 neuropathy patients taking 600mg ALA showed improvement in symptoms. Another randomized, double-blind, placebo-controlled trial in 181 patients showed that 600mg per day was just as effective as higher doses to reduce neuropathy symptoms.

What is most interesting about these studies, is that only subjective improvements were seen. That means objective measures like nerve conduction when tested before and after ALA supplementation had no effect. That’s interesting because of small fiber neuropathy…

Small Fiber Neuropathy

If ALA is effective for relieving symptoms of peripheral neuropathy, can it also benefit Fibromyalgia patients with small fiber neuropathy? Very, likely yes.

Small fiber neuropathy (SFN) is of growing interest surrounding fibromyalgia researchers. Instead of large fiber neuropathy commonly seen in diabetics, SFN results in damage to the minute nerve fibers. Often this occurs as a precursor to large fiber neuropathy. These tiny nerve fibers are responsible for sensing information related to somatic (body sense) and autonomic (automatic body processes) functions.

Symptoms of both large fiber and SFN can overlap. Both present with pins and needles sensations, abnormal sensations to temperature, heightened pain sensation, or allodynia—discomfort from otherwise non-painful stimuli such as a shower or clothing. Unlike large fiber neuropathy, SFN can also cause abnormal sweat patterns, restless legs, dry eyes and mouth, gut and bladder symptoms, or cardiac symptoms like palpitations. Symptoms of SFN can be worse at night or during periods of immobility.

Whereas large fiber neuropathy can easily be detected with electrodiagnostic testing, SFN can only be determined by tissue biopsy. The research now suggests that up to 50% of fibromyalgia patients also have SFN. This is substantial when one considers that just 16-20% of diabetics have SFN. Viruses like EBV, infections like Lyme, and nutritional deficiencies can all cause SFN.

Remember how ALA supplementation has no effect on nerve conduction? SFN is not detectable with this type of testing. So how are patients experiencing improvement in neuropathy symptoms in all of those impressive clinical trials? It is quite likely that the ALA preferentially acts on the small nerve fibers and has no effect on large fibers. If this is the case, ALA seems like a first choice for a large percentage of fibromyalgia patients. It may even have more profound effect than in diabetic neuropathy. We will learn more about this soon enough.

ALA in Neurodegenerative Disease

ALA is one of the most studied supplements in cellular and animal models related to brain aging and neurodegeneration. In mice models of multiple sclerosis, supplementation with ALA prevented development of the condition! It is thought that the neuroprotective effects seen here are due to ALA’s ability to stabilize the blood-brain barrier.

Speaking of the blood-brain barrier….

A small trial of 30 MS patients took 1200 or 2400mg of ALA per day for 2 weeks. Those with the highest serum lipoic acid had the lowest serum concentrations of MMP-9 — a marker of inflammation and blood-brain barrier function. A higher MMP-9 is associated with a “leakier” blood-brain barrier.

Another randomized, placebo-controlled study in 52 MS subjects found an increase in blood total antioxidant capacity following supplementation at 1,200 mg/day for 12 weeks, but no effect on glutathione enzymes.

One more study.

A 2-year trial of 1200mg ALA in secondary progressive MS, the most severe form of the condition showed promise. Here there was a significant reduction of whole-brain atrophy and a trend toward improvement in walking speed. More long-term MS studies are ongoing.

Side Effects of Lipoic Acid

Like many other supplements, side effects with supplementation of ALA are rare. Caution is suggested for those who are diabetics as ALA can interact with diabetes medications and cause blood sugar swings.

Bottom Line

In general, ALA has poor bioavailability and any effect it may exert is very short-lived (~1 hour). Despite these clear factors, clinical trials are still mostly positive. Deficiency is not possible to define (except for rare genetic mutation of metabolism) and is highly unlikely since mitochondria synthesize their own ALA. Food sources of lipoic acid will not provide the therapeutic benefit of supplements.

For those with neuropathy (diabetic or SFN), ALA is a wise choice. If you have fibromyalgia, there is also a strong possibility for positive benefits due to its effects on the small nerve fibers. Choose a liquid form to improve bioavailability. If you’re targeting SFN, dose at least 600mg per day. For more potent effects aimed at fatigue and brain effects, dose at least 1200mg per day which is in line with clinical trials. Do not take it with meals. Better yet, opt for a new-to-market novel form like LA-Plus or ask your doctor for IV administration.

References

Image courtesy of AB Electrical & Communications Ltd.

Park S. et al (2004) Physiological effect and therapeutic application of alpha lipoic acid. Curr Med Chem. 21(32):3636-45.

M Swiecka. (2018) Small fiber neuropathy as a part of fibromyalgia or a separate diagnosis. Int. J. Clin. Rheumatol. 13(6), 353-359.

McIlduff CE & Rutkove SB. (2011) Critical appraisal of the use of alpha lipoic acid (thioctic acid) in the treatment of symptomatic diabetic polyneuropathy. Ther Clin Risk Manag. 7: 377–385.

Sen, C. K., Tirosh, O., Roy, S., Kobayashi, M. S., & Packer, L. (1998). A Positively Charged α-Lipoic Acid Analogue with Increased Cellular Uptake and More Potent Immunomodulatory Activity. Biochemical and Biophysical Research Communications, 247(2), 223–228.

Liu J. (2008) The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 33(1):194-203.

Waslo, C., Bourdette, D., Gray, N., Wright, K., & Spain, R. (2019). Lipoic Acid and Other Antioxidants as Therapies for Multiple Sclerosis. Current Treatment Options in Neurology, 21(6).