WHAT IS ALPHA LIPOIC ACID?
Alpha lipoic acid (ALA) is a naturally occurring fat- and water-soluble antioxidant. ALA is found naturally occurring in certain foods such as red meat, spinach, broccoli, yam, carrot, beets, potato and yeast. As a supplement, ALA can be taken orally, or administered intravenously in doses up to 600mg at a time.
WHAT DOES ALPHA LIPOIC ACID DO IN THE BODY?
ALA plays a significant role in several biological processes in the body. It is considered the “universal antioxidant” since it demonstrates such diverse physiological activity.
Free radical scavenger: ALA is a potent anti-oxidant, quenching DNA- and cell-damaging oxidants, such as free radicals (1,2). Free radicals are produced when the body is under significant amounts of physical stress (such as the disease state) and to varying degrees with certain medications (such as chemotherapy and radiation). Free radicals can also cause disease, by damaging healthy cells and genetic material, especially in the face of antioxidant deficiency. Moreover, free radicals can accelerate the aging process.
Enzyme co-factor: ALA is required for healthy cell metabolism – specifically in the mitochondria (aka the “power house”) of our cells – thereby playing a critical role in energy production to fuel other activities in the body (3).
Potentiates other antioxidants: ALA helps regenerate glutathione – another major antioxidant in the body (4). Glutathione is critical to healthy aging and disease prevention, found in highest concentration in the heart, lungs, kidneys and liver. Without sufficient glutathione, these organs are particularly at high risk of disease. Furthermore, ALA augments the function of other key antioxidants such as vitamin E and vitamin C (1,3). Taken together, the synergy of antioxidants reduces the oxidative stress in the body, preventing and reversing tissue damage and initiating cell repair to help reduce tissue inflammation and promote recovery from illness.
WHAT DISEASES CAN BE PREVENTED & TREATED WITH ALPHA LIPOIC ACID?
Since ALA is required to slow the aging process, any disease of aging (such as cancer, cardiovascular disease, dementia) can be prevented and treated by ALA. Based on the evidence, ALA can be used to treat the following conditions:
TYPE I AND II DIABETES OR INSULIN RESISTANCE:
Since ALA plays a critical role in energy production, ALA as a supplement has been demonstrated to improve glycemic control, thereby slowing the progression of diabetes and preventing common illnesses that result as a consequence of poorly managed diabetes, including: peripheral neuropathy, retinopathy, cardiovascular disease, kidney disease, erectile dysfunction and cancer (5-9). Overtime, ALA may reverse insulin resistance or borderline diabetes, when combined with appropriate lifestyle and dietary interventions. Interestingly, oxidative-stress related hyperglycemia is now considered to be significant contributor to the development of hyperglycemia (high blood sugar) and its related complications (10).
In terms of treating diabetes-related chronic complications (such as retinopathy), well-designed studies have shown ALA in combination with other anti-oxidants can help reverse many of these complications (11).
WEIGHT LOSS & DYSLIPIDEMIA:
ALA has many actions that may result in weight loss and improved cholesterol levels, by improving glucose control, inhibiting formation of fat cells, reducing inflammation associated with fatty tissue, increasing HDL-cholesterol (“good” cholesterol) and reducing LDL-cholesterol (“bad” cholesterol) (12).
For weight loss, studies have used doses of ALA ranging from 1-1.8 grams for up to 20weeks in obese individuals, resulting in a weight loss of 3 kg (13). Based on study findings, it appears weight loss is more pronounced when ALA is combined with other nutritional agents, such as omega-3 fatty acids (14).
CANCER & PRE-CANCEROUS CONDITIONS:
Oxidative stress plays an important role in the development of cancer. Although investigation of ALA for role in the treatment and prevention of cancer is mainly limited to preclinical studies, there are a few randomized and non-randomized trials and case studies that support the use of ALA in combination with other therapies for cancer.
A small case-control study in 2010 found ALA in combination with conventional therapy was effective in managing the oral submucous fibrosis (OSF), a chronic irreversible condition of the mouth with proven malignant (cancerous) potential (15). The ALA group exhibited better relief of symptoms such as burning sensation of the mucosa and mouth opening and demonstrated greater reversal of higher clinical stages to lower ones, as compared to the control group.
Besides its antioxidant activity impacting the transformation of healthy cells to cancer cells, ALA was recently demonstrated to induce apoptosis (cancer cell death) in lung cancer cells. It is believed the mechanism of apoptosis induction is via activation of capsases – enzymes that induce cell apoptosis (16,17). ALA has also been shown to prevent degradation of a tumor suppressor gene (p53) in colon cancer cells (18).
Furthermore, ALA is cofactor of pyruvate dehydrogenase, an enzyme that converts pyruvate to acetyl-CoA, which reduces the formation of lactate. Lactate is produced from glucose in excessive amounts by cancer cells, as a result of altered cell metabolism (a phenomenon known as the Warburg effect). ALA reduces the amount of lactate produced by cancer cells, slowing their growth rate (19,20). In this way, ALA is synergistic with DCA (dichloroacetate) in its ability to alter cancer cell metabolism.
Another anti-cancer mechanism of ALA is its ability to inhibit a signaling pathway responsible for cell growth and insulin secretion, known as the mTOR (mammalian target of rapamycin) pathway (21). mTOR inhibitors (such as Afinitor or everolimus) are presently used in the treatment of certain cancers, to reduce cancer growth. Thus, ALA is considered a natural mTOR inhibitor.
There are several published case reports documenting improved symptoms and survival time following treatment with ALA with or without low-dose naltrexone (LDN)(22-24).
For decades, Dr. Berkson, MD, PhD has successfully treated a variety of liver disorders – such as hepatitis – using intravenous ALA (25). Studies have shown that therapeutic doses of IV ALA can remarkably help regenerate the liver, but excessively high doses (greater than 600mg IV ALA) can cause liver necrosis (26).
Non-alcoholic fatty liver disease (NAFLD) is a condition often associated with diabetes or insulin resistance and high cholesterol. Mitochondrial dysfunction, oxidative stress and inflammation play a key role in the development of NAFLD and other fatty liver diseases. Animal studies have demonstrated some promise for the use of ALA in the treatment of fatty liver disease (12).
Due to its lipophilic (fat soluble) nature, ALA can enter cells and cross the blood-brain barrier to treat neurological conditions such as dementia, Alzheimer’s disease or multiple sclerosis and possibly aid in the treatment of malignancies (cancer) in neurological tissue such as gliomas, malignant nerve sheath tumors and other cancers (27,28). Recently, animal studies demonstrate promise in ALA’s ability to promote functional recovery after stroke (29). ALA (IV and oral) is a frequent component of integrative cancer protocols, as well as treatment protocols for diseases such as MS and dementia, Alzheimer’s disease and to aid recovery from traumatic and ischemic brain injury such as concussion and stroke.
PERIPHERAL NEUROPATHY (PN):
A common feature of progressive diabetes and a frequent side effect of certain chemotherapies (also known as “diabetic neuropathy” and “chemo-induced peripheral neuropathy”, respectively), PN can be a debilitating condition with significant impact on quality of life. ALA can help treat PN, especially when used a multi-modal treatment approach, but it is most effective when used prophylactically to prevent PN (30-33). Often IV and oral forms of ALA are used to help prevent neuropathy associated with chemotherapy treatment and to prevent neuropathy that can be associated with DCA treatment.
ARE THERE SAFETY OR EFFICACY CONSIDERATIONS WITH ALPHA LIPOIC ACID?
It is important to know that many well-designed studies and recent meta-analyses have demonstrated greater efficacy with intravenous ALA compared to oral ALA (34). Therefore, outcomes with ALA are dependent on several factors, especially the route of administration.
Furthermore, oral ALA can have adverse effects – predominately in the gastrointestinal tract (nausea, vomiting, acid reflux, indigestion and abdominal pain or discomfort). Hypoglycemia (lowering of blood sugar) is a common effect (often therapeutic) of ALA, but may be amplified in patients taking blood-sugar lowering medications (35). Therefore, caution should be exercised in using ALA for those taking medications that lower blood glucose levels.
Taking oral ALA with food minimizes the tendency for GI-related side effects and hypoglycemia, but compromises absorption of ALA. Since ALA is most beneficial when a bolus dose is administered, it is best to take oral ALA on an empty stomach, in 1-2 doses per day rather than several doses throughout the day. Alternately, an intravenous dose of ALA (not exceeding 600mg or 10mg/kg) is not likely to result in any adverse effects and demonstrates better clinical efficacy than oral ALA.
1. Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. General pharmacology. 1997;29(3):315-31.
2. Packer L. Alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Drug metabolism reviews. 1998;30(2):245-75. Epub 1998/06/02.
3. Goraca A, Huk-Kolega H, Piechota A, Kleniewska P, Ciejka E, Skibska B. Lipoic acid – biological activity and therapeutic potential. Pharmacological reports: PR. 2011;63(4):849-58. Epub 2011/10/18.
4. Mantovani G, Maccio A, Madeddu C, Mura L, Massa E, Gramignano G, et al. Reactive oxygen species, antioxidant mechanisms, and serum cytokine levels in cancer patients: impact of an antioxidant treatment. J Environ Pathol Toxicol Oncol. 2003;22(1):17-28.
5. Ibrahimpasic K. Alpha lipoic acid and glycaemic control in diabetic neuropathies at type 2 diabetes treatment. Med Arch. 2013; 67(1):7-9.
6. Melhem MF, Craven PA, Derubertis FR. Effects of dietary supplementation of alpha-lipoic acid on early glomerular injury in diabetes mellitus. J Am Soc Nephrol. 2001;12:124-133.
7. Melhem MF, Craven PA, Liachenko J, et al. Alpha-lipoic acid attenuates hyperglycemia and prevents glomerular mesangial matrix expansion in diabetes. J Am Soc Nephrol. 2002;13:108-116.
8. Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 2001, 414:813–820.
9. Mitkov MD, Aleksandrova IY, Orbetzova MM. Effect of transdermal testosterone or alpha-lipoic acid on erectile dysfunction and quality of life in patients with type 2 diabetes mellitus. Folia Med (Plovdiv). 2013; 55(1):55-63.
10. Packer L, Kraemer K, Rimbach G. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition. 2001;17(10):888-895.
11. Nebbioso M, Federici M, Rusciano D, Evangelista M, Pescosolido N: Oxidative stress in preretinopathic diabetes subjects and antioxidants. Diabetes Technol Ther. 2012, 14(3):257–263.
12. Gomes M, Negrato C. Alpha-lipoic acid as a pleiotropic compound with other potential therapeutic use in diabetes and other chronic diseases. Diabetology & Metabolic Syndrome. 2014, 6:80.
13. Koh EH, Lee WJ, Lee SA, Kim EH, Cho EH, Jeong E, Kim DW, Kim MS, Park JY,
Park KG, Lee HJ, Lee IK, Lim S, Jang HC, Lee KH, Lee KU: Effects of alpha-lipoic acid on body weight in obese subjects. Am J Med. 2011, 124:85.e1–85.e8.
14. Udupa AS, Nahar PS, Shah SH, Kshirsagar MJ, Ghongane BB. Study of comparative effects of antioxidants on insulin sensitivity in type 2 diabetes mellitus. J Clin Diagn Res. 2012, 6(9):1469–1473.
15. Rao PK. Efficacy of alpha lipoic acid in adjunct with intralesional steroids and hyaluronidase in the management of oral submucous fibrosis. Journal of cancer research and therapeutics. 2010;6(4):508-10. Epub 2011/03/02.
16. Michikoshi H, Nakamura T, Sakai K, Suzuki Y, Adachi E, Matsugo S, Matsumoto
K: α-Lipoic acid-induced inhibition of proliferation and met phosphorylation
in human non-small cell lung cancer cells. Cancer Lett. 2013, 335(2):472–478.
17. Van de Mark K, Chen JS, Steliou K, Perrine SP, Faller DV. Alpha-lipoic acid induces p27Kip-dependent cell cycle arrest in non-transformed cell lines and apoptosis in tumor cell lines. J Cell Physiol. 2003; 194(3): 325–4.
18. Yoo TH, Lee JH, Chun HS, Chi SG. a-Lipoic acid prevents p53 degradation in colon cancer cells by blocking NF-kB induction of RPS6KA4. Anticancer Drugs. 2013; 24(6):555-65.
19. Feuerecker B, Pirsig S, Seidl C, Aichler M, Feuchtinger A, Bruchelt G,
Senekowitsch-Schmidtke R: Lipoic acid inhibits cell proliferation of tumor
cells in vitro and in vivo. Cancer Biol Ther 2012, 13(14):1425–1435.
20. Kim JI, Cho SR, Lee CM, Park ES, Kim KN, Kim HC, Lee HY: Induction of ER
stress-mediated apoptosis by α-Lipoic Acid in A549 cell lines. Korean J
Thorac Cardiovasc Surg 2012, 45(1):1–10.
21. Targonsky ED, Dai F, Koshkin V, Karaman GT, Gyulkhandanyan AV, Zhang Y, Chan CB, Wheeler MB: Alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells. Diabetologia 2006, 49(7):1587–1598.
22. Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integrative cancer therapies.
23. Berkson BM, Rubin DM, Berkson AJ. The long-term survival of a patient with pancreatic cancer with metastases to the liver after treatment with the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Integrative cancer therapies. 2006;5(1):83-9. Epub 2006/02/18.
24. Mantovani G, Maccio A, Madeddu C, et al. Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. J Mol Med. 2003; 81(10): 664–73.
25. Berkson BM. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. Med Klin. 1999;94 Suppl 3:84-89.
26. Vigil M, Berkson B, Garcia A. Adverse Effects of High Doses of Intravenous Alpha Lipoic Acid on Liver Mitochondria. Glob Adv Health Med. 2014 Jan; 3(1):25-27.
27. Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson DA, Munch G. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s Disease. Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1463-70.
28. Hager K, Kenklies M, McAfoose J, Engel J, Munch G. Alpha-lipoic acid as a new treatment option for Alzheimer’s Disease – a 48 months follow up analysis. J Neural Transm Suppl. 2007;(72):189-93.
29. Choi KH, Park MS< Kim HS, Kim KT, Kim JT, Kim MK, Park JT, Cho KH. Alpha-lipoic acid treatment is neurorestorative and promotes functional recovery after stroke in rats. Mol Brain. 2015 Feb 11;8:9.
30. Gedlicka C, Scheithauer W, Schull B, Kornek GV. Effective treatment of oxaliplatin-induced cumulative polyneuropathy with alpha-lipoic acid. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2002;20(15):3359-61. Epub 2002/08/01.
31. Gedlicka C, Kornek GV, Schmid K, Scheithauer W. Amelioration of docetaxel/cisplatin induced polyneuropathy by alpha-lipoic acid. Annals of Oncology: official journal of the European Society for Medical Oncology/ESMO. 2003;14(2):339-40. Epub 2003/02/04.
32. Han T, Bai J, Liu W, Hu Y. A systematic review and meta-analysis of alpha-lipoic acid in the treatment of diabetic peripheral neuropathy. European journal of endocrinology / European Federation of Endocrine Societies. 2012;167(4):465-71.
33. Ziegler D. Thioctic acid for patients with symptomatic diabetic polyneuropathy: a critical review. Treatments in endocrinology. 2004;3(3):173-89.
34. Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJ. Alpha lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. International journal of endocrinology. 2012;2012:456279.
35. Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schütte K, Kerum G, Malessa R: Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999, 22(8):1296–1301.