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The Therapeutic Effects of Acetyl-L-Carnitine on Peripheral Neuropathy: A Review of the Literature

Peripheral neuropathy is nerve conduction disruption that occurs outside of the central nervous system.
By Tina Kaczor, ND, FABNO
About The Author
Tina Kaczor, ND, FABNO, is senior medical editor of the Natural Medicine Journal and is also a naturopathic physician, board certified in naturopathic oncology. She received her naturopathic doctorate from National College of Natural Medicine, and completed her residency in naturopathic oncology at Cancer Treatment Centers of America in Tulsa, Okla. Dr. Kaczor received undergraduate degrees from the State University of New York at Buffalo. She is the current treasurer of the Oncology Association of Naturopathic Physicians and secretary of the American Board of Naturopathic Oncology. She has been published in several peer-reviewed journals.


Peripheral neuropathy is nerve conduction disruption that occurs outside of the central nervous system. It usually presents with sensory derangements, the most debilitating of which is pain in the extremities. Conventional therapies have limited success in preventing or reversing symptoms of neuropathic pain and numbness. In the past decade there has been a surge in publications suggesting acetyl-L-carnitine (ALC) may be an effective neuroprotectant and antinociceptive for peripheral neuropathy. This review highlights the uses, doses, and proposed mechanisms of action for the therapeutic effects of ALC in patients with peripheral neuropathy.


Peripheral neuropathy (PN) can be a debilitating condition, and the cause is not always understood. Presenting symptoms often are sensory derangements, including numbness (paresthesia), hypersensitivity to mild painful stimuli (hyperesthesia), pain on light touch (allodynia), electric shock sensations (dysesthesias), and spontaneous pain without stimulus.1 In more severe peripheral neuropathy, motor function impairments may present with lack of coordination, weakness, or paralysis. The autonomic nervous system may also be involved in peripheral neuropathies, and when affected, end organ function can be impaired. The causes of PN are diverse and are generally deduced through knowledge of the patient’s medical history. Some of the most common causes include diabetes, alcoholism, nutrient deficiencies (eg, vitamin B12, vitamin E, vitamin B6), exposure to toxic substances such as solvents or toxic metals (e.g., lead, arsenic), autoimmune conditions, infections (e.g., Lyme disease, syphilis), and PN secondary to drug use (e.g., chemotherapeutics, antiretroviral drugs).2 Of these, diabetic, drug-induced, and compressioninduced PN will be reviewed more closely in this paper.

The treatment of PN presents a challenge to the clinician. Opiods, anticonvulsants, antidepressants, nonsteroidal antiinflammatory drugs, and topical agents have been used with only limited success in mitigating symptoms.3,4 There is a great need for effective agents to prevent and treat PN, as the prevalence of the disease increases significantly with age. In one study, 26% of people over 65 and 54% of people over 85 had sensory
signs or symptoms of the disease.5

Acetyl-L-carnitine (ALC), a naturally occurring amino acid, may be an ideal therapeutic agent to address this otherwise recalcitrant condition. ALC is potentially effective at preventing peripheral neuropathy as well as lessening neuropathic symptoms once they have developed. Both animal and human data consistently demonstrate the neuroprotective and antinociceptive effects of ALC. In addition, ALC is well tolerated without significant risk of side effects or drug-nutrient interactions. ALC is the ester acetylated form of carnitine, a well characterized amino acid involved in fatty acid beta-oxidation in mitochondria. The final step in the synthesis of ALC takes place in the mitochondrial matrix by the enzyme acetyl-L-transferase, which uses the substrates carnitine and acetyl CoA. ALC’s normal physiological roles in the mitochondria include aiding in the export of acetyl moieties (through acetylation of various compounds) and ensuring the availability of acetyl-CoA through reversal of the enzymatic synthesis reaction.6 As an integral compound in mitochondrial function, ALC is widely distributed throughout tissues, with the highest concentrations in cardiac and skeletal muscle. The brain also has high levels, and ALC has been shown to influence neurotransmitters (NTs), including acetylcholine and dopamine.7,8,9 ALC may also prevent neural degeneration related to aging in the brain through the preservation of the neurotrophin, nerve growth factor (NGF).10,11 These actions of ALC have been known for decades and account for the popular use of ALC as an antiaging or memory-supportive nutrient.

In the early 1990s this influence on NTs was proposed as the mechanism of ALC’s antinociceptive effects. While ALC may influence pain perception through NT modulation, it is now thought that ALC’s antinociceptive effects involve direct actions at the ganglia root or peripheral axonal synapses. In addition to reducing the perception of pain, there is also evidence suggesting that ALC acts as a neuroprotectant and neuroregenerative agent. This dual action of both blocking pain perception and protecting the nerve from further damage suggests ALC is an ideal candidate to include in the treatment of peripheral neuropathy.

Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. The classic presentation is numbness in the toes and/or fingers bilaterally, which progresses in a “stocking pattern” up the limb. Of clinical relevance, peripheral neuropathy can be asymptomatic in this patient population. Further, there may be a trend in diabetic patients toward ALC deficiency, which would contribute to neuronal degeneration.28 The prevalence of DPN is estimated to be 43% for all diabetics, with a higher prevalence in type 2 diabetes (50.8%) versus type I (25.1%).29

While the molecular mechanisms of DPN vary between type 1 and type 2 diabetes, they both result in axonal degeneration, which is prevented with ALC.30 This has been demonstrated in diabetic rat models, where axonal degeneration is associated with reduced nerve conduction velocity. Many rodent studies have shown that ALC prevents the diabetic-induced disruption in nerve transmission specifically.31,32,33, 34

There are also clinical data corroborating ALC’s role as a neuroprotectant in DN. In a double-blind, multicenter trial of 333 patients with established DPN, ALC significantly reduced both objective and subjective measures of neuropathy. Intervention consisted of 10 days of intramuscular injections (1,000 mg/day) of ALC, followed by a daily oral administration of 2,000 mg ALC for 12 months. Measurements of nerve conduction velocity (NCV) and amplitude were established at baseline. 294 of the participants had measurably impaired NCV and amplitude. At 12 months, there was a statistically significant improvement in average NCV in the intervention group versus the placebo group (P=0.01). Pain perception was also assessed using a visual analogue scale (VAS). After 12 months, mean VAS scores of the intervention group were 49% lower than their baseline average, while the placebo group had a reduction of only 8% (P=0.01). The authors concluded that ALC may be a “promising treatment option for patients with diabetic neuropathy.”35

An analysis of 2 randomized, placebo-controlled multicenter prospective studies of type 1 and type 2 diabetic patients with DPN (San Antonio criteria) was undertaken using frozen data points. The 2 studies that were pooled for analysis included 1 study across 28 centers in the United States and Canada (U.S.-Canada Study [UCS]) and 34 U.S., Canadian, and European centers (UCES). A total of 1,257 participants were considered in the analysis. ALC orally (500 mg or 1,000 mg 3 times per day) or placebo was used in both the UCS and the UCES studies. Overall compliance by study participants is not stated and is presumed to be less than complete given the yearlong duration of the data. End points of nerve conduction velocity, vibration perception, and a VAS for pain were used to assess neuropathic signs/symptoms. In addition, at baseline and at the study’s conclusion, 245 participants underwent nerve fiber biopsy. While nerve conduction velocities and amplitudes did not improve, there was improvement in vibration perception and pain in the cohort taking 1,000 mg 3 times per day. Nerve fiber numbers and regenerating nerve fiber clusters were significantly improved in the group receiving 500 mg ALC 3 times per day (P=0.049 and P=0.033, respectively). In the arm that was taking 1,000 mg ALC 3 times per day, there was a trend toward nerve improvement, but it was not statistically significant. Of note in this analysis, ALC alleviated neuropathic pain most effectively in patients with type 2 diabetes, and this effect was inversely correlated with the duration of DPN.36

In addition to the antinociceptive effects of ALC in sensory neuropathies, there may be a therapeutic benefit to the autonomic nerves as well. In a rodent study using steptozocin-induced diabetic rats, both sympathetic and parasympathetic cardiac tone was intentionally reduced in the rodents. ALC was able to reverse both bradycardia and rhythm disturbance compared to placebo.31 This is in keeping with earlier animal studies that suggested the protective effects of ALC on autonomic nerve damage involving the gastrointestinal tract.37


Acetyl-L-carnitine (ALC) is a naturally occurring amino acid derivative that has both neuroprotective and antinociceptive effects. The mechanisms of action of ALC are not clear and are likely to be multifactorial, with effects on circulating neurotrophins, mitochondrial function (including anti-apoptotic effects), and synaptic transmission influencing both nerve structure/ function and patient perception of neuropathic symptoms. Clinical trials of several prominent causes of peripheral neuropathy suggest oral doses from 1,000 mg daily to 3,000 mg daily are effective for symptom relief in a majority of patients. Electrophysiological testing and skin biopsies substantiate the regenerative capacity of ALC on nerve innervation. Some studies suggest that the regenerative capacity of ALC continues for up to 24 months after beginning therapy. Tolerance to ALC appears to be excellent with mild, infrequent side effects, including insomnia and gastric irritation. Given the level of evidence of ALC’s therapeutic effects on various types of PN combined with its lack of toxicity, ALC has the potential to dramatically affect the quality of life of patients with PN.


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