Lysine

Scientific Name(s): 2,6-diaminohexanoic acid , alpha-epsilon-diaminocaproic acid

Common Name(s): Lysine

Uses

Lysine has been studied for the prevention and treatment of herpes infections and cold sores. It also increases the intestinal absorption of calcium and eliminates its renal excretion, suggesting a potential role in the management of osteoporosis. Lysine has been investigated for its effects on increasing muscle mass, lowering glucose, and improving anxiety. Case reports suggest lysine may ameliorate angina pectoris. Lysine acetylsalicylate has been used to treat pain and to detoxify the body after heroin use. Lysine clonixinate has been used for its analgesic properties for the treatment of migraine headaches and other painful conditions. However, limited clinical trials exist for these conditions.

Dosing

Lysine may be dosed from 1 to 3 g daily to prevent or treat herpes simplex infections, reserving the higher dosages for breakouts. In addition to the average American diet, L-lysine given at doses in this range appears to be safe for use in adults and prepubertal children.

Contraindications

Lysine supplementation is contraindicated in patients with hyperlysinemia/hyperlysinuria. Patients with hepatic and renal impairment should avoid supplementation with lysine. If use is warranted, patients should consult a health care provider. 1

Pregnancy/Lactation

Early data demonstrated that lysine supplementation in combination with vitamins and iron supplementation increased hemoglobin levels in pregnant women compared with control patients.

Interactions

Concomitant use of calcium supplements with lysine may be associated with increased absorption and reduced elimination of calcium. Aminoglycoside toxicity may be enhanced in patients taking lysine supplementation.

Adverse Reactions

GI adverse reactions, such as diarrhea, nausea, and abdominal pain, have been reported with lysine ingestion. A case report described the development of Fanconi syndrome and tubulointerstitial nephritis associated with lysine supplementation taken over a 5-year period.

Toxicology

High oral doses of lysine are likely to be safe due to slow entry into circulation, accelerated induction of hepatic lysine-ketoglutarate reductase activity, and increased time for urinary excretion of lysine. Doses of 100 mg/kg given to 2 Parkinson disease patients were not associated with adverse effects.

Lysine can be found in foods such as legumes, cheese, yogurt, meat, milk, brewer's yeast, wheat germ, and other animal proteins. 1 , 2 , 3 Proteins derived from grains such as wheat and corn tend to be low in lysine content. 1 The bioavailability of lysine is reduced with food preparation methods, such as heating foods in the presence of a reducing sugar (ie, fructose or glucose); heating foods in the presence of sucrose or yeast; and cooking in the absence of moisture at high temperatures. The average 70 kg human requires 800 to 3,000 mg of lysine daily. 3

History

Lysine is an essential amino acid in human nutrition, meaning the body cannot produce it; therefore, it must be obtained through diet or supplementation. 4 Lysine was first isolated from casein (a milk phosphoprotein) in 1889 by the German dentist Heinrich Drechsel. 5 It was first introduced in the US market as lysine hydrochloride in 1955. 6 There was an interest in fortifying bread with lysine to target populations with lysine-poor diets. However, the US Food and Drug Administration refused to modify the standards of identity for white bread. 1 , 6 Since 1970, lysine has been commonly added to animal feed. 1

Chemistry

Lysine, ( S )-2,6,-diaminohexanoic acid, is a hydrolytic cleavage product of protein, cleaved either by digestion or by boiling with hydrochloric acid. 1 , 4 Many forms of lysine exist, including L-lysine dihydrochloride, L-lysine monohydrochloride, calcium lysinate, lysortine (L-lysine monoorotate), L-lysine succinate, lysine clonixinate, and the lysine salt of aspirin, lysine acetylsalicylate. 4 , 7 , 8 , 9 , 10

Lysine residue contains a positive charge at physiologic pH. It possesses metal-chelating properties. 6

Uses and Pharmacology

Amino acids are fundamental constituents of all proteins. They promote protein production, reduce catabolism, promote wound healing, and act as buffers in extracellular and intracellular fluids. 11

Upon digestion from dietary proteins, lysine is transported to the liver from the gut via portal circulation. Its metabolism involves protein synthesis and oxidative catabolism. Lysine catabolism occurs almost exclusively in the liver. It does not undergo transamination. 1 , 6 Lysine is rapidly transported to muscle tissue, and within 5 to 7 hours following ingestion, is highly concentrated in the muscle. 2

Lysine improves calcium assimilation. However, most clinical data are available on its use in the treatment of herpes infection.

Herpes infections/cold sores

Replication of the herpes simplex virus requires arginine, and the proteins it produces are higher in arginine content than lysine. Lysine exerts antagonistic actions against arginine via several proposed mechanisms: serving as an antimetabolite of arginine, enhancing the excretion of arginine by competing for reabsorption at the renal tubule, competing for intestinal absorption, inducing arginase to breakdown arginine, and competing for transport into cells. 3 Lysine supplementation may enhance protein nutrition to boost the immune response. 6 Thus, to prevent and treat herpes simplex infections, increasing the intake of lysine and/or lysine-to-arginine may be beneficial. 3

Animal data

In a study of cats inoculated with feline herpes virus type 1, L-lysine 400 mg once daily was found to delay the onset of clinical signs of infection by an average of 7 days. This is not statistically significant when compared with controls. Additionally, supplementation was found to reduce viral shedding following changes in housing but not following administration of methylprednisolone for the induction of viral reactivation. 12

Clinical data

One report describes a relationship between lysine and herpes simplex virus. Lysine prophylaxis was 100% effective in preventing herpetic labialis in patients suffering from frequent lesion occurrence. Treatment for recurrent aphthous ulcers was also evaluated in this study. Only 1 of 28 patients did not benefit from lysine therapy. Dosing was lysine 500 mg/day for prevention and 1,000 mg every 6 hours upon development of prodrome in both treatments. 13

An epidemiological survey (subjective response questionnaire) found that 92% of patients with cold sores, 87% of those with canker sores, and 81% with genital herpes stated lysine supplementation was effective. Twelve percent reported no effect of lysine against herpes attacks. Others reported shortened healing time and less severe symptoms with supplementation. 14 An earlier report in 45 patients taking 312 to lysine 1,200 mg/day demonstrated beneficial effects from treatment in the form of accelerating herpes simplex infection recovery and suppressing recurrence. Tissue culture studies indicate that viral replication is suppressed as the lysine-to-arginine ratio increases. 15

In a double-blind, crossover study, 26 patients with recurrent herpes simplex labialis (4 to 16 recurrences per year) were given either lysine 1,000 mg daily or placebo for a 6-month period and with a subsequent crossover to the other group for an additional 6-month period. After the first 6 months of treatment, there were no differences in the frequency of lesions between those receiving lysine and those receiving placebo. Those who crossed over from placebo to lysine during the second 6-month period experienced significantly fewer lesions compared with those who crossed from treatment to placebo ( P < 0.05). Those who came off of lysine treatment experienced an increase in frequency of lesions ( P < 0.01). A student's t-test found that lysine concentrations greater than 165 nmol/mL were associated with a reduction in recurrent lesions ( P < 0.05). Conversely, an increase in lesion frequency occurred when the lysine concentration was below 165 nmol/mL. 16

The efficacy of a topical preparation containing L-lysine; zinc; lithium carbonate 3X; extracts of propolis and calendula flower, echinacea flower, goldenseal; and vitamins A, D, and E was assessed in 30 patients with oral herpes. Patients were instructed to apply the product every 2 hours during waking hours until the sore crusted or disappeared. Lesions were cured in 40% of the patients (n = 12) by day 3 of treatment, and this increased to 87% (n = 26) by day 6. By day 11, all patients reported a cure. No adverse effects were noted with treatment. In general, the average oral herpes infection lasts 7 to 10 days and is completely healed within 21 days without treatment. 17

In contrast, at least 2 other studies report failure of lysine in herpes treatment. Lysine 500 mg twice daily had no effect on 251 treated episodes of recurrent herpes simplex labialis in 119 patients. 18 Lysine hydrochloride 750 mg/day, administered to 31 patients with herpes simplex labialis or genitalis patients showed no reduction in the number of episodes; however, the 1 g dose showed a 47% reduction. 19

There is a case report of lysine supplementation for hyperargininemia in an 11-year-old girl. Lysine 250 mg/kg/day with ornithine produced a marked reduction of plasma ammonia and urinary orotic acid during 6 months of therapy. 20

Cardiovascular effects

Lysine may exert positive cardiovascular effects by blocking a lysine-binding domain on lipoprotein(a). Additionally, lysine can cause vasodilation. 6

Animal data

A study was conducted to assess the impact of lysine on cholesterol levels in female Sprague-Dawley rats fed a lysine-supplemented ration (0.114 g/100 g of ration) for 30 days. The total cholesterol level was 90 ± 12.4 mg/dL compared with 127 ± 5.2 in those rats that did not receive supplementation ( P < 0.001). Additionally, total cholesterol levels rose to 119 ± 7.9 mg/dL in rats receiving supplementation for 30 days followed by 11 days of no supplementation. This suggests that lysine improves the biological value and utilization of protein. 21

Clinical data

The hydroxylation of lysine and proline residues in collagen molecules is reduced by prolonged vitamin C deficiency. This weakens the vascular wall and may accelerate atherosclerosis development. Thus, supplementation of vitamin C and lysine has been assessed. The stimulation of human aortic smooth muscle cell growth by fetal bovine serum was inhibited by the addition of a nutrient mixture containing ascorbic acid, lysine, proline, arginine, N-acetyl cysteine, and epigallocatechin gallate from green tea extract. This occurred in a dose-dependent fashion ( P = 0.0023). This inhibitory effect reached 85% at 100 mcg/mL of the nutrient mixture ( P < 0.0001). Additionally, penetration and migration of these cells through Matrigel occurred with the nutrient mixture in a dose-dependent manner. Thirty-five percent inhibition occurred at 50 mcg/mL and 94% at 100 mcg/mL ( P < 0.0001). The nutrient mixture at a concentration of 100 mcg/mL decreased the secretion of interleukin-6 secretion by 46% ( P = 0.0002). A mixture containing the previously mentioned nutrients has the potential to block the development of atherosclerotic lesions by mediating the atherogenic responses of human aortic smooth muscle cells to pathologic stimuli. 22

Two case reports reflected amelioration of angina by lysine supplementation. 23 , 24

Pain management

Lysine clonixinate, a derivative of nicotinic acid, inhibits cyclooxygenase, serving as an anti-inflammatory agent with a low incidence of adverse events. Specifically, it has demonstrated oral analgesic activity that is 5 times more potent than that of aspirin. 25 , 26 Thus, lysine clonixinate has been investigated for its use in pain management. Additionally, the analgesic properties of lysine acetylsalicylate, the lysine salt of aspirin, have been studied for pain disorders.

Animal data

In rat lung preparations incubated with 14 C-arachidonic acid, lysine clonixinate at a concentration of 6.8 × 10 −5 M significantly inhibited the production of prostaglandin E 2 formed by cyclooxygenase-2, with 48.5% inhibition ( P < 0.001). 27

Clinical data

The efficacy of lysine clonixinate was compared with paracetamol/codeine in 131 primiparous women for the management of moderate to severe postepisiotomy pain. Patients were randomized in a double-blind, double-dummy fashion to receive lysine clonixinate 125 mg or paracetamol 500 mg/codeine 30 mg every 6 hours for 24 hours. The intensity of spontaneous pain was reduced after 24 hours of therapy from 4.28 ± 2.11 to 1.73 ± 1.46 ( P < 0.0001 compared with baseline) in the lysine clonixinate group and from 4.78 ± 2.08 to 1.90 ± 1.72 in the paracematol/codeine group ( P < 0.0001 compared with baseline). No significant differences were noted between the 2 treatment groups. The onset of analgesia was noted after 30 minutes in 54% of patients receiving lysine clonixinate and 55% receiving paracetamol/codeine. Total or partial relief of pain was noted in 95% of patients treated with lysine clonixinate and 96% treated with paracetamol/codeine. It was concluded that these 2 treatment options were equally effective. 25

In a study of 125 women with primary dysmenorrhea, patients were randomized to receive either lysine clonixinate 125 mg plus propinox 10 mg, paracetamol 500 mg plus hyoscine N-butylbromide 10 mg, or placebo to be taken every 6 hours beginning 3 days before the onset of menses and continued for 5 days thereafter. Patients recorded the intensity of menstrual pain in a diary. At day 5, both active treatment groups experienced a reduction in pain compared with placebo and baseline; however, a statistically significant difference was noted in only the lysine clonixinate/propinox groups by days 3 and 4 of treatment. 28

Lysine clonixinate was compared with naproxen sodium for the short-term treatment of 2 migraine headaches in a double-blind, crossover study. Seventy patients were randomized to receive either lysine clonixinate 250 mg for the first migraine and naproxen sodium 550 mg for the second headache or vice versa. Sixty patients completed the study. Of these patients, 14% of the attacks treated with lysine clonixinate compared with 12% treated with naproxen sodium were pain free at 1 hour postdosing ( P < 0.0001 compared with baseline for both drugs). The percentage of patients pain free at 2 hours who were treated with lysine clonixinate was 36% compared with 35% receiving naproxen sodium ( P < 0.0001 compared with baseline for both drugs). Statistical significance was not reached between treatment groups for these measures. Both treatments reduced nausea compared with baseline measures; however, compared with naproxen sodium, lysine clonixinate was associated with significantly more attacks that were nausea free at 1 hour ( P < 0.0005) but not after 2 hours. Photophobia was reduced more at 1 hour with lysine clonixinate compared with naproxen sodium ( P < 0.016); however, both groups experienced improvements in photophobia after 2 hours. It was concluded that lysine clonixinate and sodium naproxen demonstrate similar efficacy for the short-term treatment of migraines. However, the study findings are limited without the inclusion of a placebo group. 29

Lysine clonixinate was also compared with placebo for the management of short-term migraines in a double-blind study. Sixty-four patients with migraines were randomized to receive either lysine clonixinate 250 mg or placebo. Lysine clonixinate was found to significantly improve moderate attacks 1, 2, and 4 hours after administration compared with placebo. However, no differences were noted with severe attacks. Additionally, lysine clonixinate was associated with much less rescue medication use (6%) after 4 hours compared with placebo (68%, P < 0.0001). 26

Intravenous (IV) administration of lysine clonixinate (4 mL of 200 mg plus 21 mL of saline 0.9%) effectively treated severe migraine attacks. Twenty-nine patients completed the study, 17 receiving lysine clonixinate and 12 receiving placebo. At 30 minutes, 30% of patients in the lysine clonixinate group were pain free. Following 60 and 90 minutes, respectively, 71% and 82% of patients in the lysine clonixinate group were pain free compared with 25% and 42% of patients in the placebo group ( P = 0.021, P = 0.028 between groups, respectively). Adverse effects reported in the lysine clonixinate group included burning pain at the injection site, heartburn, and dizziness/malaise. 30

The efficacy of repeated doses of a combined treatment of oral lysine acetylsalicylate (1,620 mg, equivalent to aspirin 900 mg) and metoclopramide (10 mg) was assessed in patients suffering from migraine headaches. Patients were asked to administer a second dose 2 hours after the first dose once they determined the first dose was ineffective. A third dose or rescue medicine was allowed 2 hours after the second dose if determined ineffective. Two-hundred ninety-two patients were included, of which 262 patients treated 517 migraine attacks. Relief of headache was achieved in 55% of the attacks after 1 dose with disappearance occurring in 26% of the attacks. Following the second dose, 48% of the attacks improved, and following the third dose, 40% of the attacks improved. Ninety-two percent of the patients judged the tolerance as “good.” 31

Another report describes findings from 2 randomized, double-blind, clinical trials involving lysine acetylsalicylate 1,620 mg plus metoclopramide 10 mg as compared with placebo and oral sumatriptan 100 mg for the treatment of short-term migraine attacks. Combination therapy was found to be more effective as compared with placebo in providing relief for the first and second attacks considered separately (59% vs 29%, P < 0.001 for the first attack and 53% vs 26%, P < 0.001 for the second attack) and together (56% vs 28%, P < 0.001). Overall, based on the relief provided for the first migraine attack, the therapeutic gain associated with combination therapy was 30% (95% confidence interval, 18% to 48%). There were no differences between lysine and metoclopramide when compared with sumatriptan with both groups being more effective compared with placebo. However, combination therapy was found to be better at treating nausea compared with sumatriptan. The study concluded that combination with lysine acetylsalicylate and metoclopramide was roughly equivalent to treatment with oral sumatriptan, with combination therapy having more of an effect on nausea. 32

In a randomized, double-blind study, 200 patients with pain following minor dental surgery received 1 to 2 tablets of either lysine clonixinate 125 mg or paracetamol 500 mg every 8 hours for 48 hours or until pain relief was experienced. Both treatment groups experienced reduced pain at 24 and 48 hours after administration compared with baseline. 33

Calcium absorption and osteoporosis

Lysine has been investigated for use in osteoporosis. Specifically, lysine increases the intestinal absorption and reduces the renal elimination of calcium. 2 , 34 , 35 Additionally, lysine plays a role in the cross-linking process of bone collagen. 34

Animal data

Osteoblasts were isolated from distal femurs of healthy and osteopenic rats and were divided into 4 treatment groups: control, lysine 0.587 mg/mL/day, arginine 0.625 mg/mL/day, and lysine plus arginine 0.587 and 0.625 mg/mL/day. In healthy osteoblasts treated with combination therapy, an increase in 0.49 mcM nitric oxide production ( P = 0.002) occurred at day 7. Additionally, significant increases in type I collagen synthesis occurred in healthy osteoblasts treated with arginine and combination therapy (2.65%, P = 0.014 and 2.98%, P = 0.007, respectively). No changes were noted at 48 hours in any of the parameters for the healthy osteoblasts. Osteopenic bone-derived osteoblasts had significant differences in cell proliferation and cell count at 48 hours in the combination therapy group. The differences in these parameters were not noted at 7 days.

Increases in nitric oxide production and type I collagen synthesis were noted, though not statistically significant. 34

Clinical data

Findings from 2 small studies regarding the effects of dietary L-lysine on calcium metabolism in humans were reported. In the first study, oral calcium chloride 3 g with or without lysine hydrochloride 400 mg was given to 15 healthy women and 15 women with osteoporosis. Following administration, calcium concentrations increased in both groups of women. In the healthy women receiving lysine, calcium excretion was suppressed, but this was not clearly manifested in women with osteoporosis. In the second study, 45 patients with osteoporosis received 800 mg/day of either L-lysine, L-valine, or L-tryptophan for 3 days. Intestinal calcium absorption was assessed the day immediately following the last dose of the amino acid. L-lysine was associated with an increase in the intestinal absorption of calcium while the other 2 amino acids did not appear to have an effect. 35

Glucose effects

When given IV in large doses, lysine may exert insulin secretagogue properties. 36

Animal data

No animal data are available regarding the use of lysine for its glucose effects.

Clinical data

In 13 healthy volunteers, the effects of lysine ingestion on glucagon, insulin, glucose, and serum lysine levels were assessed. On 4 separate occasions following a 12-hour fast, participants were given water, glucose 25 g, lysine 1 mmol/kg lean body mass, or lysine plus glucose. A 2-fold increase in lysine concentration was noted at 30 minutes after ingestion and rose to a 2.9-fold increase by 150 minutes. The 2.5 hour glucose area response was reduced by 44% ( P < 0.02) upon receiving the combination of lysine and glucose. Lysine administration was associated with an increase in glucagon release ( P < 0.02). Overall, lysine was found to decrease serum glucose while causing an increase in the concentrations of insulin and glucagon. It was noted that the increase in the rate of insulin in the first 20 minutes following lysine and glucose ingestion was greater compared with glucose ingestion alone, suggesting lysine may have an effect on first-phase insulin secretion. 36

In another study of 30 college-aged men, the effects of arginine and lysine supplementation on glucose tolerance were assessed. Using a 2 × 2 factorial design, the patients received either arginine/lysine supplementation (66 mg of each amino acid/kg fat-free body weight) daily or placebo (cornstarch 132 mg/kg fat-free body weight) daily with or without resistance training for 10 weeks. Oral glucose tolerance parameters (ie, insulin, glucose, glucagon) were not different among treatment groups at the end of the study. 37

Anxiolytic effects

Lysine is believed to exert anxiolytic effects by acting as a partial serotonin receptor 4 antagonist and as a partial benzodiazepine agonist. 38

Animal data

The efficacy of L-lysine alone and in combination with L-arginine on stress-induced anxiety in rats was assessed in a 5-day study. Rats were randomized to receive an infusion of L-lysine 200 mg/kg, L-lysine 200 mg/kg plus L-arginine 200 mg/kg, or L-glutamine (control) 200 mg/kg for 4 consecutive days. On day 5, the rats were subjected to 2 hours of restraint stress and were immediately placed on an elevated plus maze. Combination therapy with lysine and arginine was associated with increased exploration time spent in the open arms of the maze, but this did not happen with the L-lysine only group as compared with the L-glutamine group. Combination therapy was also found to slightly reduce plasma corticosterone levels following stress induction. 39

Similarly, the ability of L-lysine and L-arginine to impact anxiogenic responses in pigs being transported was assessed. Inhibitory effects on plasma cortisol levels were noticed in pigs receiving a diet supplemented with L-lysine and L-arginine compared with pigs not receiving the additional supplementation. Combination therapy was also found to block the effects of stress on locomotion and immobility. 40

Clinical data

In a randomized, double-blind, placebo-controlled study, the impact of L-lysine and L-arginine on trait and stress-induced state anxiety and basal levels of stress hormones was assessed. One hundred and eight healthy patients were randomized to receive either L-lysine (2.64 g/day) and L-arginine (2.64 g/day) or placebo for 1 week. Treatment with L-lysine and L-arginine was found to decrease trait anxiety as well as blunt the increase in state anxiety induced by a stress battery. Salivary cortisol and chromogranin-A levels were decreased in men only. 38

Effects on muscle mass

Muscle mass in humans begins to decline by about 8% per decade around 40 years of age with an acceleration in loss of 15% per decade after 70 years of age. This is likely due to motor unit remodeling, effects of disease states, and a decrease in hormonal activity. Thus, lysine in combination with other targeted nutritional supplements has been evaluated for its effects on age-associated changes in muscle mass, protein metabolism, and functionality in elderly patients. 41 , 42

Animal data

Sixteen horses were studied in a 2 x 2 factorial design based on age (up to 10 or 20 years of age and older) and treatment to receive lysine 20 g/day and threonine 15 g/day or no supplementation for 14 weeks. Light, routine exercise occurred for each horse throughout the study. Diet and age did not yield any differences in body weight; however, horses in the supplemented group tended to gain more weight while those receiving no supplementation tended to lose weight. Subjective muscle mass scores as measured with a Likert scale and based on before and after photographs of the horses' muscles were greater for the supplemented group (+ 1.02) compared with the horses not receiving supplementation (+ 0.52, P = 0.05). Body condition scores were lower for the older horses throughout the study as well as in the supplemented group of horses compared with the nonsupplemented group ( P = 0.026). 43

Clinical data

In double-blind studies conducted at 2 clinical sites, elderly women (65 to 90 years of age; mean, 76.7 years of age) were randomized to receive a daily cocktail containing beta-hydroxy-beta-methylbutyrate (HMB, 2 g), arginine (Arg, 5 g), lysine hydrochloride (Lys, 1.5 g), and ascorbic acid (0.5 g) or a placebo cocktail (study 1, maltodextrain and ascorbic acid 0.5 g; study 2, isocaloric isonitrogenous mixture [1.8 g of nitrogen] containing alanine 5.6 g, glutamic acid 0.9 g, glycine 3.1 g, serine 2.2 g, and ascorbic acid 0.5 g). After 12 weeks of treatment, patients in the HMB/Arg/Lys group experienced a 17% improvement in the get-up-and-go test that involved the patient starting off in the sitting position, standing, walking for 3 minutes, turning around, walking back to the chair, and sitting down. Specifically, the performance times improved by −2.3 ± 0.5 sec with treatment compared with placebo 0.0 ± 0.5 sec ( P = 0.002). Additionally, though not all statistically significant, improvements were noted in knee extensor force ( P = 0.1), knee flexor force ( P = 0.05), and handgrip strength ( P = 0.04) in patients receiving HMB/Arg/Lys treatment compared with the placebo group. Lastly, rates of whole body protein synthesis increased by 20% in patients receiving HMB/Arg/Lys compared with placebo ( P = 0.03). 41

In a double-blind, controlled study, elderly women and men (76 ± 1.6 years of age) were randomized to receive a daily cocktail containing HMB 2 or 3 g, L-arginine 5 or 7.5 g, L-lysine hydrochloride 1.5 or 2.25 g, and ascorbic acid 0.1 g, or a placebo cocktail similar to a previously reported study. 41 The dose of HMB/Arg/Lys was based on weight, with those weighing 68 kg or less receiving the lower dose and those weighing more than 68 kg receiving the higher dose. After 1 year of treatment, HMB/Arg/Lys was associated with an increase in fat-free mass and/or lean mass when compared with placebo. Body cell mass increased by 0.58 ± 0.19 kg in those receiving HMB/Arg/Lys compared with 0.02 ± 0.18 kg in those receiving placebo. Protein turnover was 20% greater in those receiving treatment compared with placebo at 3 and 12 months. Specifically, HMB/Arg/Lys increased protein turnover by 8% and 12% at 3 and 12 months, respectively, compared with a decrease in the rate in the placebo group by 11% and 9%, respectively ( P < 0.01). Handgrip and leg strength declined in both groups and the get-up-and-go tests were not different between the groups. 42

Other uses

Lysine acetylsalicylate has been used to treat rheumatoid arthritis and to detoxify the body after heroin use. 7 , 10

Limited data suggest lysine may exert beneficial effects on blood pressure and the incidence of stroke. 6

Lysine supplementation has been shown to improve appetite and growth rate in poorly thriving infants. 6

Lysine supplementation has been investigated in lysinuric protein intolerance (LPI), an autosomal recessive transport disorder of lysine, arginine, and ornithine. Specifically, these patients experience a decrease in GI absorption of these cations with enhanced urinary excretion. Signs and symptoms include postprandial vomiting, growth retardation, osteoporosis, hepatosplenomegaly, hyperammonemia, and muscle weakness. In 27 Finnish patients with LPI, L-lysine hydrochloride was provided in titrated doses of 8 to 46 mg/kg (average, 22.7 mg/kg) daily divided 3 to 4 times per day to avoid GI adverse reactions for a mean of 30 months (range, 6 to 60 months). Supplementation with lysine was associated with increases in plasma concentrations of lysine with no induction of hyperammonemia for a 12-month period. Specifically, the lower limit of the reference range was reached with 12 months of therapy in 55% of the patients ( P < 0.014); five of the patients were younger than 11 years of age (3, 4.5, 5, 5, 8, and 10.5 years of age). 44 IV (400 mg/kg) and oral (400 to 800 mg/kg) administration of D-lysine was shown to reduce the renal uptake of a radiolabeled somatostatin analog for tumor treatment in rats by approximately 40%, suggesting D-lysine may allow a higher dose of antitumor treatment with decreased renal adverse reactions. Because lysine is positively charged and binds proximal tubular cells that exert a negative charge, it is able to partially block the renal reabsorption of the also positively charged radiolabeled somatostatin analogs. 45

A nutrient mixture consisting of vitamin C 700 mg, L-lysine 1,000 mg, L-proline 750 mg, L-arginine 500 mg, N-acetyl cysteine 200 mg, and standardized green tea extract 1,000 mg was able to inhibit human bladder cancer T-24 cell secretion of matrix metalloproteinase (MMP)-2 and -9. Nearly total inhibition of MMP-2 occurred at 500 mcg/mL and of MMP-9 at 100 mcg/mL. Cell invasion through Matrigel was reduced with the nutrient mixture, with 95% inhibition at 500 mcg/mL and 100% at 1,000 mcg/mL ( P < 0.001). 46

Lysine has been incorporated in the culinary processes of caramelizing or browning of foods, such as pastries and desserts. Lysine links with a reducing sugar, such as fructose or glucose, when heated. Unfortunately, this process reduces the ability of lysine to be absorbed. 1

L-lysine monohydrochloride has a salty flavor and has been incorporated into salt substitutes. One example is marketed under the name Pansalt that contains 57% NaCl, 28% KCl, 12% MgSO 4 7H 2 O, 2% l-lysine monohydrochloride, and 1% anticaking agents. Lysine was possibly incorporated to mask the taste of magnesium sulfate and potassium chloride. 6

Dosage

Lysine may be dosed from 500 mg to 3 g daily to prevent or treat herpes simplex infections, reserving the higher dosages for breakouts. 47 , 48 , 49 In addition to the average American diet, L-lysine given at doses in this range appears to be safe for use in adults and prepubertal children. 6

Pregnancy/Lactation

Early data demonstrated that lysine supplementation in combination with vitamins and iron supplementation increased hemoglobin levels in pregnant women compared with control patients. This was maintained throughout pregnancy and 3 days postpartum. No cases of pre-eclampsia were reported with lysine supplementation compared with 6 reports in the control group. Lysine may have enhanced iron absorption by chelation. 6 , 50 A pregnant woman with familial hyperlysinemia, a genetic disorder in which lysine levels are 5 to 10 times higher than usual, gave birth to a normal infant with no malformations. Additionally, no fetal malformations were noted in pregnant rats given 50%, 100%, or 500% excesses of lysine, though the group receiving 500% excess was associated with less maternal weight gain and small fetuses. 6

Interactions

Concomitant use of calcium supplements with lysine may be associated with increased absorption and reduced elimination of calcium. Additionally, increased toxicity may occur in patients taking lysine who are receiving aminoglycosides. 2

Adverse Reactions

GI adverse reactions, such as diarrhea, nausea, and abdominal pain, have been reported with lysine ingestion. 1 , 36 , 44

A case report describes the development of Fanconi syndrome and tubulointerstitial nephritis associated with lysine supplementation. A 44-year-old female presented to a nephrology clinic with symptoms of polyuria, polydipsia, and fatigue. Her laboratory findings included a serum creatinine of 1.8 mg/dL and serum urea nitrogen (BUN) of 18 mg/dL. A 24-hour urine collection revealed a creatinine clearance of 54 mL/min. A urinalysis demonstrated proteinuria and hematuria. This azotemia continued to progress over 4 months, and the serum creatinine fluctuated between 1.8 and 3.3 mg/dL. A renal biopsy was performed that demonstrated long-term vascular injury with marked interstitial fibrosis and tubular atrophy. There was a prominence of lysosomes in the proximal tubules. It was at this point the patient mentioned she had been taking lysine 3,000 mg daily for the last 5 years for the prevention of herpes labialis. The patient noted an improvement in her energy level upon discontinuation of lysine supplementation. However, her serum creatinine increased to 6.7 mg/dL with a BUN level of 57 mg/dL. She progressed to end-stage renal failure within 5 months of the biopsy, necessitating the initiation of peritoneal dialysis. There is a discussion about how amino acid infusions have been associated with short-term renal failure, especially in patients experiencing ischemia or those receiving aminoglycosides. Specifically, lysine may have a direct nephrotoxic effect. 51

Toxicology

High oral doses of lysine are likely to be safe due to a slow entry into circulation, accelerated induction of hepatic lysine-ketoglutarate reductase activity, and increased time for urinary excretion of lysine excretion. 6

Animal data

In a study of rats, the short-term toxic IV dose was determined to be 4 g/kg body weight. 6 Additionally, effects of dietary lysine on toxicity of barbiturates and ethanol in rats have been evaluated. An increase in onset of loss of righting reflex was observed. 52

Clinical data

In a study of 2 patients with Parkinson disease receiving lysine supplementation in doses of 100 mg/kg body weight, there were no adverse reactions or change in levodopa blood levels. 6 , 53 Additionally, doses as high as 15 to 40 g/day for the treatment of hypochloremic alkalosis in patients with heart disease with a few cases of liver impairment produced only abdominal pain and diarrhea, which dissipated with dosage reduction. There was no evidence of renal or hematopoietic toxicity. 6 High-dose IV L-lysine was associated with almost complete inhibition of renal tubular protein reabsorption. 6

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