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Long-term use of supplemental lysine--is it safe?

Abstract

The amino acids lysine and arginine have been shown to respectively inhibit and stimulate herpes simplex virus (HSV) replication. Lysine supplements have been used over the last three decades to inhibit viral replication, shorten the duration of herpetic blisters and help prevent recurrence. However arginine has many physiological roles in the body and as it uses the same intracellular transport routes as lysine there is the potential for adverse effects due to a relative arginine deficiency. There is also the potential for adverse effects on renal function due to increased amino acid intake.

Background

In 1977 Griffith, Norms and Kagan (1, 2) discovered that if arginine was added to isolated HSV in a petri dish, the virus would multiply. However, when lysine was added the virus's ability to multiply was inhibited. In 1983 they ran a small study on 45 human subjects "V which supported their hypothesis that lysine would inhibit the HSV in vivo. A subsequent study in 1983 expanded the research to 1543 participants which again supported the therapeutic application of lysine.

Clinical and anecdotal evidence suggests that the benefits of lysine supplements are obtained with doses from 394mg to 3000mg, and ranging up to 9000mg. In one double blind study using a dose of 1000mg t.d.s, after six months lysine was rated as effective or very effective by 74% as opposed to 28% on placebo, with the conclusion that L-lysine is an effective agent for reduced occurrence, severity and healing time for recurrent HSV infection. (3)

Studies have yielded mixed results; For example, a 1984 study by DiGiovanna and Harvey found no benefit. (4) But this may have been due to factors such as the dose tested being too low for therapeutic benefit, the severity of the outbreak, the large number of dropouts in the placebo group and whether the supplement was used prophylactically or post-outbreak. Some studies have also used synthetic non-biologically active d-lysine.

The most common side effects reported from acute usage are nausea, diarrhoea and weakness. Side effects appear to be minimised if doses are divided into smaller ones and ingested with foods containing protein.

Arginine

Arginine is a conditionally essential amino acid as it can be obtained from the diet and is synthesised endogenously from the amino acid citrulline and sourced from the breakdown of proteins in the body. Arginine synthesis from citrulline occurs primarily in the small intestine and the renal tubules in the kidney. (5, 6, 8)

Infants and people with kidney or small intestine damage require exogenous sources due to the reduced ability to synthesise arginine. Arginine becomes essential in pathological states such as sepsis, burns, trauma or surgery. (6, 8) Low plasma arginine levels are a hallmark of sepsis. (8) Arginine deficiency is also a feature of sickle cell disease. (9)

Arginine is important for the transport, storage and removal of excess nitrogen and ammonia. (7) In one patient with small intestine and kidney damage an arginine deficiency led to hyperammonemia and resultant disturbed consciousness, which were corrected with supplemental arginine. (10)

Arginine is converted to ornithine by arginase. Ornithine is converted to polyamines necessary for cell growth and differentiation and to proline which is important for collagen synthesis and wound healing. (5, 7, 8) Supplementation with arginine has been shown to directly support collagen synthesis and wound healing. (11)

Arginine is an important amino acid which is an essential precursor for the synthesis of molecules with wide ranging metabolic roles, including nitric oxide. (5, 6, 7)

Nitric oxide

Nitric oxide has many physiological roles in the body, including vasodilation which affects cardiovascular health, free radical scavenging and neurotransmission. Nitric oxide released by vascular endothelium is vasoprotective and anti-atherosclerotic. (6, 7, 8) Endothelial dysfunction is associated with atherosclerosis and cardiovascular disease. Arginine administration has been shown to improve endothelial function in animals and humans with hypercholesterolemia and atherosclerosis. (12)

Defective gallbladder motility is implicated in cholesterol gallbladder disease. Nitric oxide plays an important role in gallbladder motility by triggering relaxation of the gallbladder and allowing emptying, thereby reducing the build-up of gallstones. (13, 14) Supplemental lysine has been linked to hypercholesterolemia and gallstone formation in animal studies. (15, 16)

Nitric oxide is also important for male reproduction due to effects on sperm production and for achieving and maintaining erections. (7, 8) Nitric oxide triggers the synthesis of cyclic GMP which causes calcium uptake leading to muscle cell relaxation, vasodilation and increased blood flow to the penis. As an example of the importance of this pathway for achieving and maintaining erections, the drug Sildenafil (Viagra) works by binding the enzyme PDE5 that degrades cyclic GMP. (17)

Asthma sufferers have been found to have lower circulating arginine levels than controls. The relative nitric oxide deficiency induces hyper-reactive airways which contributes to asthma symptoms. (9, 18)

Arginine is important for the thymus and lymphocyte count and nitric oxide is generated by phagocytes as part of the immune response. Nitric oxide is utilised by macrophages, neutrophils, mast cells, fibroblasts, hepatocytes, vascular endothelial cells, smooth muscles cells and cardiac myocytes. (7)

Nitric oxide has an indirect but important role in the repair and integrity of gastric mucosa. (7, 19) This in turn has an indirect effect on the immune system, which is supported by an intact gut lining and weakened by intestinal permeability.

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Lysine

Lysine is an essential amino acid; it is not synthesised in the body and must be obtained from the diet. Lysine excess can inhibit nitric oxide production via its competition with arginine for shared intracellular transport. Long term use of lysine therefore has the potential to hinder nitric oxide production with possible effects on immunity, collagen synthesis, wound healing, male sexual health and cardiovascular health. (8, 20)

Lysine may have a nephrotoxic effect and should not be taken with aminoglycoside antibiotics due to the increased risk of nephrotoxicity. (21, 22) The kidney has an important role in the metabolism of amino acids. Excess amino acid intake causes greater amounts of waste such as urea that must be eliminated. This can overload kidney function leading to progressive kidney impairment, particularly in people with existing kidney disease, hypertension, diabetes or aged over 65 years.

A case report from 1996 linked a daily intake of 3000mg lysine over five years to Fanconi syndrome which progressed to end stage renal failure. (23) The 44-yearold female presented to a nephrology clinic with polyuria, polydipsia and fatigue. Tests revealed proteinuria and abnormal creatinine clearance. After four months a biopsy showed long-term vascular injury with interstitial fibrosis and tubular atrophy. At this stage, the patient revealed she had been taking 3000mg of lysine a day for five years.

Lysine aids calcium absorption and therefore may be beneficial for those suffering from effects of calcium deficiency such as osteoporosis or osteopenia (24, 25) but may not be advisable for people with hypercalcaemia.

There is a potential for a rebound effect when ceasing lysine intake after chronic use. Anecdotal reports suggest HSV sufferers report lesion recurrence if they stop taking lysine. In an early small double cross-over study those allocated to six months on lysine who were then changed to the placebo group experienced an increase in herpetic lesion frequency. (26)

Table A shows that in the sample lysine supplements a prophylactic dose from 800 to 1000mg is recommended on an ongoing daily basis with various increases recommended during outbreaks. The safety advice varies but there doesn't appear to be any information relating to duration of use.

Discussion

Supplementation with lysine has shown benefit in the acute treatment of HSV

There is however, the potential for lysine to be counterproductive long term due to competition with arginine for shared transport and a proposed relative arginine deficiency.

Arginine is the precursor for many important molecules with influence in many pathways, but of particular concern in relation to HSV are the roles in the immune system, gut integrity and wound healing. Given the possibility of a rebound effect when ceasing supplementation, there is the possibility that people with HSV especially chronic sufferers, will continue to take lysine in order to prevent HSV outbreaks. In fact most lysine supplements recommend an ongoing prophylactic daily intake of 1000mg.

Without appropriate safety advice, people may also take a larger prophylactic dose than recommended, as demonstrated by the case study linked to Fanconi syndrome. Excess protein or amino acid intake can lead to kidney damage. It is possible there are other cases where adverse effects have occurred due to excess or long term lysine ingestion without the cause being identified.

Conclusion

Short term use of lysine appears to be safe for the symptomatic treatment of F1SV in the general population, especially if taken in divided doses and ingested with meals containing protein. The available evidence on the safety of long term and/or high dose lysine supplementation for the general population is inconclusive; however doses at or above 3000mg should not be recommended for long term use due to the potential for kidney damage.

Lysine should not be recommended for infants or young children or for persons at risk of harm from a relative arginine deficiency such as, but not limited to, people suffering from asthma, sickle cell disease, kidney disease or small intestine complications such as short bowel syndrome, without appropriate medical advice. In addition, caution is warranted in relation to males with reproductive health concerns such as low sperm count or erectile dysfunction as well as persons with hypercalcemia, gallbladder disease or cardiovascular disease and also during pregnancy and breastfeeding.

Abbreviations

q.d = once a day; b.d = twice a day; t.d.s = three times a day

References

(1.) Griffith RS, Norins AL, Kagan C. A Multicentered Study of Lysine Therapy in Herpes simplex infection. Dermatology. 1978;156(5): 257-267

(2.) Griffith RS, Walsh DE, Behforooz A. Subjective Response to Lysine in the Therapy of Herpes Simplex. Oxford, Jnl of Antimicrobial Chemo. 1983; 12(16): 489-496

(3.) Griffiths RS et al. Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Dermatologica. 1987; 175(4): 183-90

(4.) DiGiovanna JJ, Blank H. Failure of Lysine in Frequently Recurrent Herpes Simplex Infection Treatment and Prophylaxis. Arch Dermatol. 1984:120(1):48-51

(5.) Morris S. Arginine Metabolism in Vascular Biology and Disease. Vase Med. 2005:10:S83

(6.) Flynn NE et al. The Metabolic Basis of Arginine Nutrition and Pharmacotherapy. Biomed Pharmacotherapy. 2002; 56(9):427-38

(7.) Duggan C, Gannon J, Walker WA. Protective Nutrients and Functional Foods for the Gastrointestinal Tract. AmJ Clin Nutr. 2002; 75(5): 789-808

(8.) Luiking YC, Deutz NEP. Biomarkers of Arginine and Lysine Excess. J. Nutr. 2007; 137(6): 1662S-1668S

(9.) Morris CR et al. Elevated Arginase and Limited Arginine Availability: a Common Feature in Asthma and Sickle Cell Disease. Nitric Oxide. 2004:11:112

(10.) Yokoyam Ket al. Hyperamnonemia in a Patient with Short Bowel Syndrome and Chronic Renal Failure. Nephron. 1996; 72(4):693-5

(11.) Barbul A. Proline Precursors to Sustain Mammalian Collagen Synthesis. J Nutr. 2008; 138(10): 2021S-2024S

(12.) Gornik HL, Creager MA. Arginine and Endothelial and Vascular Health. J Nutr. 2004;134(10 suppl):2880S-2887S

(13.) van Berge-Henegouwen GP et al. Drugs Affecting Biliary Secretion and Gallbladder Motility: Their Potential Role in Gallstone Treatment and Prevention. Current Drug Target--Imm, Endocr & Metab Disorders. 2005; 5(2):185-191

(14.) Poso MJ, Camello PJ, Mawe GM. Chemical Mediators of Gallbladder Dysmotility. Current MedChem. 2004:11(13):1801-1812

(15.) Klurfeld DM, Weber MM, Kritchevsky D. Dietary Protein Effects on Gallstone Formation. 1987; 64(8): 1193-1195

(16.) Antonio, J PhD et al. Essentials of Sports Nutrition and Supplements. Spring Sciences & Business Media LLC. Totowa USA: Humana Press; 2008.

(17.) Pfizer Canada. Product monograph Viagra. Quebec Canada. Last reviewed August 2013. Available from www. pfizer.ca/en/our_products/products/ monograph/132

(18.) Morris, CR et al. Decreased Arginine Bioavailability and Increased Serum Arginase Activity in Asthma. Amer Jnl Resp & Crit Care Med. 2004; 170(2)

(19.) Kochar Nl, Chandewal AV, Bakal RL, Kochar PN. Nitric Oxide and the Gastrointestinal Tract. Int Jnl Pharm. 2011; 7(1): 31-39

(20.) Tong BC, Barbu I A. Cellular & Physiological Effect of Arginine. Mini Reviews in Medical Chemistry. 2004; 4(8): 823-832

(21.) L-Lysine (Internet) NYU Langone Medical Centre: Dept Otolaryngology [reviewed Aug 2013 EBSCO CAM Review board] Available from http://ent.med.nyu.edu/ content?ChunklID=21791

(22.) Ehrlich, SD. Lysine University of Maryland Medical Centre. Updated 2011. Available from: http://umm.edu/health/medical/altmed/supplement/lysine

(23.) Lo JC, Chertow GM, Rennke H, Seifter JL. Fanconi's Syndrome and Tubulointerstitial Nephritis in Association with L-lysine Ingestion. AmJ Kidney Dis, 1996; 28(4):614-7

(24.) Tanner LM, Nanto-Saionen K, Niinikoski H. Long-term Oral Lysine Supplementation in Lysinuric Protein Intolerance. Metabolism. 2007; 56(2): 185-189

(25.) Civitelli R et al. Dietary L-lysine and Calcium Metabolism in Humans. Nutrition. 1992; 8 (6):400-5

(26.) Thein DJ, Hurt WC. Lysine as a Prophylactic Agent in the Treatment of Recurrent Herpes Simplex Labialis. Oral Surg Oral Med Oral Path, 1984; 58(6):659-66

Lea Bumpstead | BHSx (Nut Med), Prof Ext Dip Herb Med, MEAA Safety Cons. Lea is currently working as a nutritionist in the Geelong area. Email: lea@walktohealth.com.au

TABLE A
A SELECTION OF LYSINE SUPPLEMENTS, RECOMMENDED DOSE AND ADVICE

BRAND                  LYSINE DOSE

Supermarket Brand A    Adults 500mg b.d
(contains other        1000mg b.d during outbreak
ingredients)           Children 6-12, 500mg q.d

Supermarket Brand B    500mg b.d with food

Health Store Brand C   Adults prevention 1000mg q.d
(contains other        Acute 1000mg t.d.s
ingredients)           Children <121 000mg q.d

Health store Brand D   500mg b.d 10OOmg b.d or t.d.s acute

Practitioner Brand E   1 x 800mg q.d
(contains other        2 x 800mg b.d
ingredients)

BRAND                  ADVICE/CONTRADICTIONS/CAUTIONS

Supermarket Brand A    Or as professionally prescribed
(contains other        Advice given on other ingredients
ingredients)

Supermarket Brand B    Or as recommended by a healthcare
                       practitioner

Health Store Brand C   Or as directed by a healthcare practitioner
(contains other
ingredients)

Health store Brand D   Consult a healthcare practitioner if you
                       have kidney or liver disease or during
                       pregnancy and breastfeeding

Practitioner Brand E   Not all contradictions and cautions are
(contains other        listed on the bottle.
ingredients)           A phone number is provided for further
                       information then: Not recommended for
                       persons with hypercalcaemia, kidney
                       disease, existing high blood levels of
                       lysine, pregnancy and lactation, plus other
                       advice related to other ingredients
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Author:Bumpstead, Lea
Publication:Journal of the Australian Traditional-Medicine Society
Article Type:Report
Geographic Code:8AUST
Date:Dec 1, 2013
Words:2403
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