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Alpha-Lipoic Acid and Peripheral Neuropathy


Author: John A. Senneff
Source: Nutrients for Neuropathy, Volume 3 in the Numb Toes Series

There are probably more studies attesting to the benefits of alpha-lipoic acid (ALA), also known as lipoic acid or thioctic acid, for dealing with peripheral neuropathy than studies for any other nutrient. ALA is a sulfur containing fatty acid found inside every cell of the body, where it helps generate the energy that keeps us alive and functioning. This nutrient is a key part of the metabolic machinery that turns glucose (blood sugar) into energy for the body's needs.

Dr. Lester Packer, who heads the Department of Molecular & Cell Biology at the University of California, Berkley, calls ALA a "universal antioxidant." In addition to its remarkable abilities as a natural antioxidant, protecting nerves from oxidative damage and inflammation, it has great facility for raising levels of the enzyme glutathione, itself a powerful antioxidant.1 Some research also suggests that the nutrient may be able to do the work of other antioxidants when the body is deficient in them. As a corollary, it has been demonstrated that ALA can regenerate other antioxidants such as vitamins A and C as well as coenzyme Q10.

ALA offers dual antioxidant protection because it is both fat and water soluble. Water solubility means that it works inside the nerve cell. Its fat solubility permits it to work outside the cell, at the membrane level. This double action on both sides of nerve cell walls is said to result in a stronger defense against damaging free radicals. (As mentioned before, we encounter these harmful molecular fragments every day through exposure to the sun's rays, automobile exhaust, smoke from various sources, and air pollution in general.)

The classic early study on the efficacy of alpha-lipoic acid for peripheral neuropathy, referred to as the ALADIN study (Alpha-Lipoic Acid in Diabetic Neuropathy), was performed in Dusseldorf, Germany, in 1995. The effects of ALA were studied in a 3-week multi-center, randomized, double-blind placebo-controlled trial, in 328 non-insulin-dependent diabetic patients with symptomatic peripheral neuropathy. These patients were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid at three dose levels (1200, 600, or 100 mg), or placebo. Neuropathic symptoms (pain, burning, paresthesia, and numbness) were scored at baseline and at each visit. Based on the study results the investigators said that using intravenous treatment at a dose level of 600 mg daily was effective in reducing symptoms of peripheral neuropathy without causing significant adverse reactions.2

Clinical evidence from various parts of the world continues to support the use of ALA for diabetic and other peripheral neuropathies. A randomized, double-blind study at the University of Zagreb in Croatia in 1999, concluded that after the daily administration of 600 mg of ALA to one group of diabetic patients and 1200 mg to another for a period of two years (65 patients in all), ALA "appeared to have a beneficial effect on several attributes of nerve conduction."3 (The investigators did qualify their opinion by saying that although neuropathic symptoms seemed to have improved over the 24 month study period, the "long-term response remains to be established.")

A three-week study performed in Dusseldorf, Germany, reached a similar conclusion. The patients with diabetic neuropathy enrolled there were given 600 mg of ALA three times daily. Researchers made the point that not only were neuropathy pain symptoms lessened but the nutrient was well tolerated.4

Russian investigators also found symptomatic improvement in a group of 29 patients with diabetic neuropathy after 14 days of ALA.5

Similarly, American investigators at the Mayo Clinic in Rochester, Minnesota, found that after the administration of ALA, peripheral nerve function improved in rats in which diabetic neuropathy had previously been induced.6

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A more recent study delved into the nitty-gritty of the way ALA offers antioxidant protection.7 Researchers in Germany investigated the effects of the nutrient on the body's microcirculation system for carrying oxygen to nerve cells. (This system consists of blood vessels such as capillaries with a diameter of less than 300 micrometers. Peripheral neuropathy is sometimes associated with a lack of blood circulation to the nerve cells.) The investigators concluded that microcirculation was benefited by the administration of either 600 mg or 1200 mg daily over a six-week period. In technical terms they found that there was a decrease in the "time to peak capillary blood cell velocity,"--a marker in determining oxygen transport benefit. 8

A study performed at the University of Texas Southwestern Medical Center at Dallas also examined the manner in which ALA functions as an antioxidant, concluding it does so because "it decreases plasma- and LDL oxidation."9

Finally a meta analysis in Germany (which pre-dated the Texas study) examined the results of 15 clinical trials.10 The conclusion, based on all 15, was that short-term (three weeks) treatment of diabetic neuropathy, using 600 mg per day of ALA, "appeared to reduce the chief symptoms" of neuropathy. Moreover, the preliminary data indicated to the investigators the "possible long-term improvement in motor and sensory nerve conduction in the lower limbs." The investigators emphasized that these 15 trials revealed a "highly favorable safety profile" for ALA.11

A more recent paper, also from Germany and mentioned in the discussion of GLA, again acknowledged the benefits of ALA for the treatment of diabetic neuropathy: "Symptomatic therapy includes alpha-lipoic acid treatment, as the antioxidant seems to improve neuropathic symptoms."12 (It should be noted that ALA is specifically approved for the treatment of diabetic neuropathy in Germany.)

Incidentally, in addition to painful sensory neuropathies, alpha-lipoic acid is useful with autonomic neuropathies. These disorders, which affect involuntary or semi-voluntary functions such as control of inner organs, are common among people with diabetes and have been reported to be present in up to 40% of Type 2 diabetic patients. Symptoms may include gastroparesis (a condition where the stomach is not emptying properly and characterized by nausea, vomiting, and abdominal distension), sexual dysfunction, low blood pressure when standing up (postural hypotension), and inability to sweat, as well as a variety of cardiac abnormalities.

An earlier German study showed that alpha-lipoic acid caused a significant improvement in irregular heart rate in subjects with autonomic neuropathy.13 (Richard N. Podell, M.D., who has studied ALA extensively, maintains that this study "provides the first clear evidence that nutritional treatment alone can reverse the course of autonomic neuropathy.")

There is no daily requirement established for ALA, presumably because a healthy body makes enough of it to supply daily energy requirements. However some practitioners recommend supplementation regularly because of its superior antioxidant capabilities; Lester Packer, Ph. D., considered an expert in this area, recommends daily dietary additions of 100 mg.

Many health care professionals recommend dosage levels of 400-600 mg of ALA daily for therapeutic purposes. In fact some go as high as 1200 mg per day. There reportedly have been no serious adverse effects from the use of ALA, even in quite high dosages (up to 1800 mg daily). Minor effects have been mainly allergic skin reactions.

If you are looking for natural sources of this nutrient, liver and yeast contain small amounts.

References:
1. Glutathione protects nerves and virtually all other tissues in the body from oxidative damage by free radicals. A study in the Journal of Trace Elements (2000; 13: 105-111), maintains that although dietary supplements of this enzyme are available, they are not well absorbed by the GI tract and are therefore ineffective. In the Journal article Dr. J. Aseth confirms that the antioxidant nutrients alpha-lipoic acid, vitamin C and vitamin E all help regenerate the body's glutathione.
2. Diabetoiogia (1995 Dec; 38 (12): 1425-33).
3. Free Radical Research (1999 Sep; 31(3): 171-79.
As previously noted, results from clinical studies sometimes are measured in terms of objective parameters such as vibration threshold and nerve conduction velocity.
4. Diabetic Medicine (1999 Dec; 16(12): 1040-43). To give perspective, I should report that another German study came to a different conclusion, finding "no effect on neuropathic symptoms distinguishable from placebo." They admitted, though, that their findings might have been off the mark because the various centers where the 509 patients in the study were examined were using different scoring methods [tschl] (Diabetes Care, 1999 Aug; 22 (8). 1296-1301). lnterestingly, two of the investigators in this study were investigators in both the Zagreb and Dusseldorf studies just mentioned.
5. Zb Nevrol Psikhiatr Im S S Korsakova (1999; 99(6): 18-22).
6. Diabetes (1999 Oct; 48 (10): 2045-51). Apparently, though, not all rats are the same. A study in the Netherlands found only minor beneficial effects from alpha-lipoic acid and that these effects were insufficient to improve nerve conduction deficits in their diabetic rats. European Journal of Clinical Investigation (2001 May; 31 (5): 417 24). Perhaps there is something different about rats bred in the Netherlands. Another study from that country in 2001 found that conjugate of GLA and ALA failed to reverse established deficits of nerve conduction velocity in their rats induced with diabetic neuropathy; the investigators acknowledged that there was a body of evidence establishing that GLA-ALA did improve early deficits in such conduction. Journal of the Neurological Sciences (2001 Jan 1; 182(199-106).
7. Experimental and Clinical Endocrinology and Diabetes (2000;1 (3): 168-74).
8. Free Radical Research (1999 Nov; 27 (9 -10): 1114-20). Another study at the University of Michigan, reported in Diabetes (2000 June 49(6): 1006-15), noted the "complex interrelationships among neuperfusion, energy metabolism, osmolyte content, conduction velocity, and oxidative stress that may reflect the heterogeneous and compartmentalized composition of peripheral nerve." In particular the researchers said the studies implicated oxidative stress as an important factor in diabetic neuropathy.
One study. in concluding alpha-lipoic therapy "improves and may prevent diabetic neuropathy," indicated that "oxidative stress appears to be primarily due to the processes of nerve ischemia [reduced blood flow] and hyperglycemia autooxidation." In Vivo (2000 Mar-Apr; 14 (2): 327-30). An interesting paper concerning impaired blood flow with restricted oxygen delivery to peripheral nerves, implicates the accumulation of heavily glycated proteins within the arterial walls, resulting in "chronic vasoconstriction." Free Radical Biology and Medicine (2000 Feb 15; 28 (4): 652-56).
9. Free Radical Biology and Medicine (1999 Nov; 27 (9-10): 1114¬21).
A Russian study determined that alpha-lipoic acid also had a therapeutic effect in the nitric oxide and stress protein systems in diabetic patients with polyneuropathy. Bulletin of Experimental Biology & Medicine (2000 Oct; 130 (10): 986-90).
10. In a meta analysis or study, the results from a number of selected trials are combined in order to come to general conclusions. It is often used when a number of small trials give conflicting or statistically insignificant results.
11. Experimental and Clinical Endocrinology and Diabetes (1999; 107(7):421-30).
12. Fortschritte der Neurologie-Psychiatrie (2000 Jun; 68 (6): 278-88).
13. Diabetes Care (1997; 20:369-73).

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