Sources and Structure
Lysine initially saw usage not as a dietary supplement but, rather, a food additive. Vegetarian diets high in grains but low in legumes (a source of methionine) may run the risk of having suboptimal lysine intake and as such it was explored as a food additive for cereal grains as well as usage in farm animal feed.
Lysine is an essential amino acid that serves as a building block for proteins in the body; as lysine cannot be synthesized in the body it must be consumed through the diet or supplementation. It is considered a dibasic amino acid alongside amino acids such as arginine, cysteine, and ornithine due to having a second basic group.
According to a joint report from the World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO), and United Nations University (UNU) the basic level of lysine required for human health is 30mg/kg bodyweight; or approximately 2.1 grams for a 70kg individual.
Formulations and Variants
Lysine monohydrochloride is a form of lysine that is sometimes used as a food additive in snacks as the addition of either lysine or Cysteine can reduce acrylamide formation during heating.
Lysine is known to bind to some minerals such as Copper allowing easier transport into intestinal cells, as evidenced by a study using copper sulphate and finding presence of copper-lysine conjugates and allowing transport via amino acid transporters in vitro; that being said, efflux from the intestinal cells back into the gut was also noted to a high degree.
When tested in rats, supplementation of lysine (1.5% of rat feed) does not appear to interfere with the absorption of either copper or iron when at normal dietary levels in one study where overall protein content was average (20% of rat feed) despite a previous study noting an inhibitory effect of lysine on absorption of these two minerals in rats fed half the protein. Zinc appeared to not be affected by lysine under the conditions where it affected copper and iron.
Studies comparing the bioavailability of copper using either a lysine conjugate (copper-lysine) versus a more basic form (copper sulphate) have mixed effects in various tested animal species as to whether lysine aids in the absorption or if the two are equally effective, potentially related to how copper-lysine seems to form passively in intestinal cells from free copper.
While Lysine appears to interact with some trace minerals to allow them easier access into intestinal cells, it does not appear to have consistent evidence as to whether the inclusion of lysine with these minerals (ex. copper or iron) increases their absorption or if there is no effect
Lysine appears to be transported across the blood brain barrier by cationic amino acid transporters (system y+) with a KM of 470 +/- 106μM in a manner that is voltage dependent but not sodium dependent. Lysine seems to use this transporter almost exclusively since uptake is blocked with this transporter and b0,+ seems to play no role.  This transporter is also used by the other cationic amino acids, arginine and ornithine, and in the presence of sodium chloride both alanine and serine. It is the major transporter for lysine and arginine.
While at normal physiological concentrations competition between amino acids seems unlikely, saturating the transporter with lysine an inhibit the uptake of arginine subsequently reducing nitric oxide production; this was hypothesized to be a potential mechanism for how lysine supplementation could affect neurological function.
Lysine is taken up into the brain by the same transporter that takes arginine into the brain, and it is thought that high doses of lysine could hinder the ability of arginine to produce nitric oxide in this tissue and thus indirectly influence cognition
Interactions with Glucose Metabolism
When 0.1% lysine is added to the drinking water of diabetic rats, it failed to influence insulin concentrations despite affecting other parameters of glucose metabolism.
In a metabolic ward study comparing a low lysine diet, defined as between 25-40mg/kg bodyweight (similar to the 30mg/kg requirement from the World Health Organization) versus a high lysine diet of 80mg/kg in adult males, it was found that the addition of extra lysine to the diet did not further increase insulin sensitivity when compared to the low lysine diet despite having a small positive effect on skeletal muscle tissue function.
Glycation (non-enzymatic glycosylation) refers to the process of adding a sugar molecule onto a protein or lipid. This process can modify the function of proteins and is relevant to conditions with high blood sugar such as diabetes as it contributes to numerous complications. Lysine is investigated for its role in glycation as it is claimed to be a molecular chaperone, a group of molecules with various actions of which include stabilizing proteins. Numerous small amino acids, methylamines, and sugars may have these properties secondary to being osmolytes.
When testing lysine, the enzyme known as lysozyme experiences less glycation when incubated in the presence of lysine and the glycation of albumin appeared to be reduced in diabetic rats given 0.1% lysine in their drinking water.
Lysine shows preliminary promising in limiting glycation seen during states of high blood glucose, but the precise mechanism and potency relative to other options is unknown
Type II Diabetes
When supplementation of lysine (1.5g twice daily) was given to type II diabetic patients who were also given Metformin and glibenclamide over three months it was found that the addition of lysine to these two drugs showed benefit in reducing fructosamine, AGEs, and fasting blood sugar while improving the content and activity of lysozyme slightly.
Inflammation and Immunology
Lysine is protective against the symptoms of the herpes simplex (HSV) due to being an analogue of Arginine. Arginine is considered a nutrient to HSV and promotes replication while the presence of lysine works in the opposite manner and can prevent replication by preventing the virus from using arginine.
Lysine has been tested a few times as an oral supplement in subjects with recurrent herpes simplex (without any other major immunological conditions) with both failures and success in reducing the frequency and intensity of flare-ups; potentially a dose-related issue as one study finding success with 1,248mg of lysine monohydrochloride failed to find benefits with half the dose while the other successful study used 3,000mg daily. Two studies on recurrent herpes labialis both using 1,000mg found a success and a failure with secondary analysis finding less recurrences in some patients. This effect does not appear to be curative as, when benefits are noted, these benefits dissipate within a week or two of stopping the lysine supplementation.
One study did note that recurrence rates of symptoms appeared to be related to the amount of lysine in serum, with those above the predetermined threshold (165μM/L) having less recurrence than those below this threshold.
Lysine appears to have a relation to recurrence, severity, healing time when it comes to herpes flare-ups. This appears to be somewhat related to the amount of lysine in your body and supplementation exceeding 2g a day seems to be associated with benefits. Increasing lysine in the diet also appears effective but requires Arginine to be limited
Other Medical Conditions
One study assessing the effects of lysine supplementation in schizophrenia found that supplementation of 6g lysine daily for four weeks alongside their prescribed medication resulted in a reduction in positive symptoms (assessed by PANSS, particularly the subscales for delusions and suspiciousness) with no significant effect on negative symptoms; there also appeared to be a benefit to problem solving skills and cognitive flexibility according to WCST compared to placebo.
L-arginine is an essential amino acid, and appears to be synergistic with L-lysine for increasing growth hormone.
1200mg of lysine (as hydrochloride) paired with 1200mg arginine (as 2-pyrrolidone-5-carboxylate) was able to increase secretion of insulin and somatotropin which promoted growth hormone secretion (peak value was 90 minute after ingestion and reached 7.94-fold baseline levels; there was no placebo for comparison), it was said to be synergistic as either agent alone at the same dose failed to promote growth hormone secretion, and measurements lasted 120 minutes.
A later study using 3g of L-arginine paired with 3g L-lysine twice daily (12g total) for 12 days in both youth and elderly men has failed to find appreciable increases in 24 hour AUC measurements of growth hormone and this failure has been replicated in a study using 2g of the three amino acids L-Arginine, L-Ornithine, and L-Lysine in weight trained men.
Although technically they appear to be synergistic (based on one study without a placebo control, so it has its flaws), this synergism is only acute and has failed to manifest in day-long GH measurements. Despite the synergism, the combination still may not be an appreciable way to increase growth hormone.
Lysine is thought to increase calcium absorption in humans. While some amino acids are capable of doing this through the calcium-sensing receptor (CASR) which can be acted upon by the likes of tryptophan, phenylalanine, and histidine (thought to partially explain why dietary protein improves calcium absorption) lysine itself does not appear overly effective in this manner. Lysine may be more effective practically, as one study supplementing a low protein diet (0.7g/kg) with a large amount of the dibasic amino acids lysine and arginine was able to increase calcium absorption and elimination to a greater degree than a diet with mixed amino acids or the aforementioned three that act on CASR.
Studies assessing the effects of lysine find that adding 400mg of lysine to 3g calcium chloride in both healthy and osteoporotic women increased calcium absorption and decreased the rate of exxretion.
Safety and Toxicology
Supplementation of 25-40g lysine (as monohydrochloride) over 3-5 days, in studies using the supplement with mercurial diuretics, has found no major side-effects with only mild diarrhea and cramping being reported; these symptoms dissipated when the dosage was lowered and likely due to most lysine not being absorbed from the intestines.
While fatty liver has been noted in rats fed 5% lysine in the diet it has been noted that this equates to 90-100 times greater than combined normal supplementary doses (assumed 2g) and human diet. An LD50 value could not be reached after oral ingestion although an LD50 of 4mg/kg has been found to intravenous injection.
Overall, oral supplementation of lysine appears to be highly safe. Large doses (25 grams or more over the course of a day) may cause intestinal distress and diarrhea which is alleviated by lowering the dose