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Lysine

Common Name(s): 2,6-diaminohexanoic acid, Alpha-epsilon-diaminocaproic acid, Lysine

Clinical Overview

Use

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, improving glucose metabolism and associated toxic glycated byproducts, 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 pain disorders. However, limited clinical trials exist to support lysine use for any of these conditions.

Dosing

In clinical trials, lysine 312 mg to 4 g daily has been used to prevent or treat herpes simplex infections, with higher dosages reserved for breakouts. In addition to amounts consumed in the average American diet, L-lysine doses in this range appear to be safe for use in adults and 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 considered, consultation with a health care provider is recommended.

Pregnancy/Lactation

Early data demonstrate that lysine supplementation in combination with vitamins and iron supplementation increase hemoglobin levels in pregnant women compared with controls.

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.

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 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 patients were not associated with adverse effects.

Source

Lysine can be found in foods such as legumes, cheese, yogurt, meat, milk, brewer's yeast, wheat germ, and other animal proteins.Gaby 2006, L-Lysine 2007, Tomblin 2001 Proteins derived from grains such as wheat and corn tend to be low in lysine content.L-Lysine 2007 The bioavailability of lysine is reduced with food preparation methods, such as heating in the presence of a reducing sugar (ie, fructose or glucose); heating in the presence of sucrose or yeast; and cooking at high temperatures in the absence of moisture. The average 70 kg human requires 800 to 3,000 mg of lysine daily.Gaby 2006

History

Lysine is an essential amino acid in human nutrition that can only be obtained through diet or supplementation.Budvari 1989 Lysine was first isolated from casein (a milk phosphoprotein) in 1889 by the German dentist Heinrich Drechsel.Dorland 1965 It was first introduced in the US market as lysine hydrochloride in 1955.Flodin 1997 Historically, there was an interest in fortifying bread with lysine to target populations with lysine-poor diets; however, the US Food and Drug Administration would not modify the Standards of Identity for white bread.Flodin 1997, L-Lysine 2007 Since 1970, lysine has been commonly added to animal feed.L-Lysine 2007

Chemistry

Lysine, (S)-2,6,-diaminohexanoic acid, is a hydrolytic cleavage product of protein, cleaved either by digestion or by boiling with hydrochloric acid.Budvari 1989, L-Lysine 2007 Many salt 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.Aarons 1989, Budvari 1989, Hill 1990, Sinzinger 1984, Vescovi 1984

Lysine residue contains a positive charge at physiologic pH and possesses metal-chelating properties.Flodin 1997

Uses and Pharmacology

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

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.Flodin 1997, L-Lysine 2007 Lysine is rapidly transported to muscle tissue, and within 5 to 7 hours following ingestion is highly concentrated in the muscle.Tomblin 2001

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

Anxiety and schizophrenic effects

Lysine is believed to exert anxiolytic effects by acting as a partial serotonin receptor 4 antagonist and as a partial benzodiazepine agonist.Smriga 2007

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 compared with the L-glutamine group; this effect was not observed in the L-lysine only group. Combination therapy also slightly reduced plasma corticosterone levels following stress induction.Smriga 2003

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 observed in pigs receiving a diet supplemented with L-lysine and L-arginine compared with pigs not receiving the supplementation. Supplementation with L-lysine and L-arginine also blocked the effects of stress on locomotion and immobility.Srinongkote 2003

Clinical data

In a randomized, double-blind, placebo-controlled study in 108 healthy subjects, the impact of L-lysine and L-arginine on trait and stress-induced state anxiety and basal levels of stress hormones was assessed. Patients were randomized to receive L-lysine (2.64 g/day) and L-arginine (2.64 g/day) combination or placebo for 1 week. Treatment with L-lysine and L-arginine decreased trait anxiety as well as blunted the increase in state anxiety induced by a stress battery. Salivary cortisol and chromogranin-A levels decreased in men only.Smriga 2007

A single-blind, placebo-controlled, crossover pilot study (N=10) evaluated L-lysine 6 g/day for 4 weeks in outpatient schizophrenic adults who had been episode free for 2 months and on a stable medication regimen for 3 months prior to study initiation. There was a significant reduction in symptoms (P<0.001), and 3 patients self-reported symptom improvement. The investigators wrote that further study of L-lysine therapy for this indication is needed.Wass 2011

Calcium absorption and osteoporosis

Lysine has been investigated for use in osteoporosis. Specifically, lysine increases intestinal absorption and reduces renal elimination of calcium.Civitelli 1992, Fini 2001, Tomblin 2001 Additionally, lysine plays a role in the cross-linking process of bone collagen.Fini 2001

Animal and in vitro data

Osteoblasts were isolated from distal femurs of healthy and osteopenic rats and divided into 4 treatment groups: control; lysine 0.587 mg/mL/day; arginine 0.625 mg/mL/day; and lysine 0.587 mg/mL/day plus arginine 0.625 mg/mL/day. In healthy osteoblasts treated with combination therapy, a 10.4% increase (0.49 mcM change) in nitric oxide production (P=0.002 vs control) 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 parameters for the healthy osteoblasts. Osteopenic bone–derived osteoblasts showed 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, but were not statistically significant.Fini 2001

Clinical data

Findings from 2 small studies regarding the effects of 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 intestinal absorption of calcium while the other 2 amino acids did not appear to have an effect.Civitelli 1992 Similar results in calcium absorption were observed in a double-blind, randomized, placebo-controlled crossover study (N=14) when premenopausal women 18 to 28 years of age were given a low-protein diet supplemented with L-lysine and another dibasic amino acid (L-arginine). In contrast, no changes in calcium absorption were seen when the diet was supplemented with L-tryptophan, L-phenylalanine, and L-histidine.Bihuniak 2014

Cardiovascular effects

Lysine may exert positive cardiovascular effects by blocking a lysine-binding domain on lipoprotein(a). Additionally, lysine can cause vasodilation. Limited data suggest lysine may exert beneficial effects on blood pressure and the incidence of stroke.Flodin 1997

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 per 100 g of ration) for 30 days. The total cholesterol level was 90±12.4 mg/dL compared with 127±5.2 mg/dL in 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.Jarowski 1975

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). The inhibitory effect reached 85% at a concentration of 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, with 35% inhibition occurring at 50 mcg/mL and 94% inhibition occurring 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.Ivanov 2007

Two case reports reflected amelioration of angina by lysine supplementation.McBeath 1993, Pauling 1998

Culinary uses

Lysine has been incorporated in the culinary processes of caramelizing or browning foods such as pastries and desserts. Lysine links with a reducing sugar such as fructose or glucose when heated, a process that reduces the ability of lysine to be absorbed.L-lysine 2007 L-lysine monohydrochloride has a salty flavor and has been incorporated into salt substitutes. One example product is marketed under the name Pansalt, which contains 57% NaCl, 28% KCl, 12% MgSO4 7H2O, 2% l-lysine monohydrochloride, and 1% anticaking agents. Lysine was possibly incorporated to mask the taste of magnesium sulfate and potassium chloride.Flodin 1997

GI effects

Clinical data

As a follow up to studies in rats, a small randomized, double-blind, crossover study was conducted in 6 healthy volunteers to identify the dose-dependent effects of L-lysine on GI function. Single doses of 0.5 g, 1.2 g, 3 g, and 7.5 g of L-lysine were administered in test meals. L-lysine 3 g and 7.5 g significantly delayed gastric emptying (P=0.01) and increased intestinal fluid volume (P<0.0001) in a dose- and time-dependent manner, with the highest dose resulting in self-limiting diarrhea within 1 to 6 hours after administration.Baruffol 2014

Growth effects

Clinical data

Lysine supplementation has been shown to improve appetite and growth rate in poorly thriving infants.Flodin 1997

Glucose effects

When given IV in large doses, lysine may exert insulin secretagogue properties.Kalogeropoulou 2009

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 decreased serum glucose while causing an increase in insulin and glucagon concentrations. 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.Kalogeropoulou 2009

In another study of 30 college-aged men, the effects of arginine and lysine supplementation on glucose tolerance was assessed. Patients received either arginine/lysine supplementation (66 mg/kg fat-free body weight of each amino acid) 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.Gater 1992

A randomized trial following in vitro experiments investigated the effect of lysine supplementation on fasting blood glucose and lysozyme levels and activity, as well as on advanced glycation end products (AGEs) and fructosamine levels in 50 patients with type 2 diabetes. All patients received standard therapy with metformin and glibenclamide for 3 months, with the test group also receiving lysine 1.5 g twice daily. Statistically significant improvements were observed in all 5 parameters compared with baseline, suggesting a beneficial effect of lysine in preventing formation of damaging AGEs. No data were provided regarding comparisons with controls.Mirmiranpour 2016 This study built upon earlier in vitro and in vivo studies demonstrating lysine to be an effective chemical chaperone and chemical decoy for reducing sugars and, in a hyperglycemic environment, for possibly rectifying conformational changes of glycated fibrinogen.Mirmiranpour 2012 In contrast, a double-blind, randomized trial in under- and well-nourished young men in India did not demonstrate changes in fasting blood glucose or insulin sensitivity with 8-week supplementation of various doses of lysine (25 to 80 mg/kg/day).Unni 2012 In another study in healthy adults, intragastric infusions of lysine only slightly reduced glucose levels at 60 minutes, with a 20% decrease in insulin. Lysine did not affect insulin and glucose response at the earlier time point (15 minutes) and did not affect insulin or glucose area under the curve (AUC0-60 min). No changes in gastric emptying were noted.Ullrich 2017

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 break down arginine, and competing for transport into cells.Gaby 2006 Lysine supplementation may enhance protein nutrition to boost the immune response.Flodin 1997 Thus, to prevent and treat herpes simplex infections, increasing the intake of lysine and/or lysine-to-arginine may be beneficial.Gaby 2006

Animal data

In a study of cats inoculated with feline herpes virus type 1, L-lysine 400 mg once daily delayed the onset of clinical signs of infection by an average of 7 days. This was not statistically significant when compared with controls. Additionally, supplementation reduced viral shedding following changes in housing but not following administration of methylprednisolone for the induction of viral reactivation.Maggs 2003

Clinical data

One report describes a relationship between lysine and herpes simplex virus in which lysine administered as prophylaxis was 100% effective in preventing herpetic labialis in patients with frequent lesion occurrence. Treatment for recurrent aphthous ulcers was also evaluated in this study. Lysine dosing was 500 mg/day for prevention and 1,000 mg every 6 hours upon development of prodrome. Only 1 of 28 patients did not benefit from lysine therapy.Wright 1994

In an epidemiological survey (subjective response questionnaire), 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.Walsh 1983 An earlier report in 45 patients taking lysine 312 to 1,200 mg/day demonstrated beneficial effects (ie, acceleration of herpes simplex infection recovery and suppression of recurrence). Tissue culture studies indicate that viral replication is suppressed as the lysine-to-arginine ratio increases.Griffith 1978

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, with a subsequent crossover to the alternate 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 over from treatment to placebo (P<0.05). Those who switched from 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 lysine concentration was below 165 nmol/mL.Thein 1984

In contrast, at least 2 other studies reported a lack of benefit with lysine for treatment of herpes. Lysine 500 mg twice daily had no effect on 251 episodes of recurrent herpes simplex labialis in 119 patients.Milman 1978 Lysine hydrochloride 750 mg/day administered to 31 patients with herpes simplex labialis or genitalis showed no reduction in the number of episodes; in another study, only a higher dosage of 1,000 mg/day dose showed a significant reduction of 47%.Simon 1985

Hyperargininemia

Clinical data

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.Kang 1983

Hypertriglyceridemia

Clinical data

In a randomized, single-blind, placebo-controlled 12-week trial in adult men (N=85) with serum triglyceride levels higher than 150 mg/dL. Compared with placebo, no benefit was observed with administration of lysine 1 g/day nor with the combination of lysine at the same dose with vitamin B6 50 mg/day in terms of triglyceride reduction.Hlais 2012

Lysinuric protein intolerance

Clinical data

Lysine supplementation has been investigated in treatment of lysinuric protein intolerance (LPI), an autosomal recessive transport disorder of lysine, arginine, and ornithine. Specifically, 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 (5 of whom were younger than 11 years of age [3, 4.5, 5, 8, and 10.5 years]), 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 patients (P<0.014).Tanner 2007

Muscle mass effects

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.Baier 2009, Flakoll 2004

Animal data

Sixteen horses were studied in a 2x2 factorial design of treatments, with 2 age groups (up to 10 years or 20 years of age and older) and 2 diet groups (supplementation with 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 via 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). Throughout the study, body condition scores were lower for the older versus younger horses (P=0.001) as well as for the supplemented versus unsupplemented group of horses (P=0.026).Graham-Thiers 2005

Clinical data

A double-blind, randomized trial in under- and well-nourished young men in India showed significant changes in muscle function without an associated change in muscle girth with 8-week supplementation of high-dose lysine (80 mg/kg/day). Instead, a positive correlation was found between muscle function and percent change in appendicular lean soft tissue (both fat and muscle) (P=0.001).Unni 2012

Pain management

Lysine clonixinate, a derivative of nicotinic acid, serves as an anti-inflammatory agent through inhibition of cyclooxygenase, with a low incidence of adverse events. Specifically, it has demonstrated oral analgesic activity 5 times more potent than that of aspirin.De los Santos 1998, Krymchantowski 2001 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 and in vitro data

In rat lung preparations incubated with 14C-arachidonic acid, lysine clonixinate at a concentration of 6.8×10−5 M significantly inhibited the production of prostaglandin E2 formed by cyclooxygenase-2, with 48.5% inhibition (P<0.001).Franchi 1998

Clinical data

The efficacy of lysine clonixinate was compared with acetaminophen/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 based on visual analog scale score 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 1.9±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 in 55% receiving paracetamol/codeine. Total or partial relief of pain was noted in 95% of patients treated with lysine clonixinate and in 96% treated with acetaminophen/codeine. It was concluded that the 2 treatment options were equally effective.De los Santos 1998

In a study of 125 women with primary dysmenorrhea, patients were randomized to receive lysine clonixinate 125 mg plus propinox 10 mg (antimuscarinic), acetaminophen 500 mg plus hyoscine N-butylbromide 10 mg, or placebo 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 only in the lysine clonixinate/propinox group by days 3 and 4 of treatment.de los Santos 2001

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, in whom 14% of the attacks treated with lysine clonixinate compared with 12% treated with naproxen sodium were pain free at 1 hour postdose (P<0.0001 compared with baseline for both drugs). The percentage of patients who were pain free at 2 hours was 36% with lysine clonixinate compared with 35% with naproxen sodium (P<0.0001 compared with baseline for both drugs). Statistical significance between treatment groups was not reached 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 inclusion of a placebo group.Krymchantowski 2005

Lysine clonixinate was also compared with placebo for the short-term management of migraines in a double-blind study. Sixty-four patients with migraines were randomized to receive either lysine clonixinate 250 mg or placebo. Lysine clonixinate significantly improved moderate attacks 1, 2, and 4 hours after administration compared with placebo. However, no between-group differences were noted for severe attacks. Additionally, lysine clonixinate was associated with much less rescue medication use (6%) after 4 hours compared with placebo (68%) (P<0.0001).Krymchantowski 2001

Intravenous (IV) administration of lysine clonixinate (4 mL of lysine clonixinate 200 mg plus 21 mL of saline 0.9%) was effective in treating 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, 71% and 82% of patients, respectively, in the lysine clonixinate group were pain free compared with 25% and 42% of patients in the placebo group (P=0.021 and P=0.028 between groups at 60 and 90 minutes, respectively). Adverse effects reported in the lysine clonixinate group included burning pain at the injection site, heartburn, dizziness, and malaise.Krymchantowski 2003

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 a study of 292 patients with 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. Of the 292 patients included, 262 patients self-treated 517 migraine attacks. Headache relief was achieved in 55% of the attacks after 1 dose, with headache 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 patients judged the tolerance as "good."Hugues 1997

Another report describes findings from 2 randomized, double-blind, clinical trials comparing lysine acetylsalicylate 1,620 mg plus metoclopramide 10 mg with placebo or oral sumatriptan 100 mg for the treatment of short-term migraine attacks. Combination therapy was more effective than 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 relief provided for the first migraine attack, the therapeutic gain associated with combination therapy was 30% (95% confidence interval [CI], 18% to 48%). There were no differences between lysine plus metoclopramide and treatment with sumatriptan, with both groups being more effective compared with placebo. However, combination therapy was better for treating nausea compared with sumatriptan.Tfelt-Hansen 2000

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. Both treatment groups experienced reduced pain at 24 and 48 hours after administration compared with baseline.Martí 1993

Renal uptake with radiolabeled somatostatin analogs

Animal data

IV (400 mg/kg) and oral (400 to 800 mg/kg) administration of D-lysine reduced 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 also positively charged radiolabeled somatostatin analogs.Verwijnen 2005

Dosing

In clinical trials, lysine 312 mg to 4 g daily has been used to prevent or treat herpes simplex infections, reserving higher dosages for breakouts.Griffith 1978, Milman 1978, Simon 1985, Thein 1984, Wright 1994 A small, short-term pilot study used 6 g/day for schizophrenia.Wass 2011 In addition to amounts consumed in the average American diet, L-lysine doses in this range appear to be safe for use in adults and prepubertal children.Flodin 1997

Pregnancy / Lactation

Early data demonstrated that lysine supplementation in combination with vitamins and iron supplementation increased hemoglobin levels in pregnant women compared with controls; levels were maintained throughout pregnancy and for 3 days postpartum. No cases of preeclampsia were reported with lysine supplementation compared with 6 reports in the control group. Lysine may enhance iron absorption by chelation.Flodin 1997, Terry 1957 A pregnant woman with familial hyperlysinemia, a genetic disorder in which lysine levels are 5 to 10 times higher than normal, 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, although the group receiving 500% excess was associated with less maternal weight gain and smaller fetuses.Flodin 1997

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.Tomblin 2001

Adverse Reactions

GI adverse reactions, such as diarrhea, nausea, and abdominal pain, have been reported with lysine ingestion.Kalogeropoulou 2009, L-Lysine 2007, Tanner 2007, Wass 2011

A case report describes the development of Fanconi syndrome and tubulointerstitial nephritis associated with lysine supplementation. A 44-year-old female entered 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, and a urinalysis demonstrated proteinuria and hematuria. This azotemia continued to progress over 4 months, with serum creatinine fluctuating between 1.8 and 3.3 mg/dL. A renal biopsy revealed long-term vascular injury with marked interstitial fibrosis and tubular atrophy, as well as a prominence of lysosomes in the proximal tubules. The patient then mentioned that she had been taking lysine 3 g daily for the last 5 years for the prevention of herpes labialis, also noting an improvement in her energy level upon discontinuation of supplementation. However, her serum creatinine increased to 6.7 mg/dL with a BUN level of 57 mg/dL and she progressed to end-stage renal failure within 5 months of the biopsy, necessitating initiation of peritoneal dialysis. Discussion exists about the association of amino acid infusions with short-term renal failure, especially in patients experiencing ischemia or those receiving aminoglycosides. Specifically, lysine may have a direct nephrotoxic effect.Lo 1996

Toxicology

High oral doses of lysine are likely safe due to slow entry into circulation, accelerated induction of hepatic lysine-ketoglutarate reductase activity, and increased time for urinary excretion of lysine.Flodin 1997

In a study of rats, the short-term toxic IV dose was determined to be 4 g/kg body weight.Flodin 1997 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.Dubroff 1979 In a clinical study of 2 patients with Parkinson disease receiving lysine supplementation in doses of 100 mg/kg body weight, there were no adverse reactions or changes in levodopa blood levels.Flodin 1997, Nutt 1984 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. High-dose IV L-lysine was associated with almost complete inhibition of renal tubular protein reabsorption.Flodin 1997

References

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