Do you have joint pain? Have you tried going gluten-free but still get bloated? Do you suffer from candida, inflammation, colds or allergies? Do you suffer from shingles or cold sores? Are you low in calcium and iron? Do you have high blood pressure or high blood sugar? Are you experiencing hair loss? Do you have anxiety, depression or low energy? Are you inattentive or suffering from poor short-term memory? A diet that is low in the amino acid lysine and high in the amino acid arginine can lead to all these problems—and more.
Many amino acids, including arginine, are “nonessential,” meaning they are not diet-dependent but are made in the body out of other amino acids. Lysine, on the other hand, is an “essential” amino acid—we must get it from our diet. Notably, lysine is one of only two amino acids (the other being leucine) that breaks down into ketones rather than glucose, whereas arginine converts to glucose. Dietary arginine competes with lysine for absorption; thus, it interferes with the actions of lysine. Lysine and arginine also have different effects on the digestive system, weight and blood sugar control.
In this article, I explain why lysine is so important for good health and why too much dietary or supplemental arginine is problematic. Traditional diets that emphasize meat, fish, dairy and eggs are higher in lysine than arginine, while the standard American diet not only tends to be deficient in lysine but oversupplies arginine. Unfortunately, toxins worsen the problem by depleting lysine (see “Toxins and Lysine Impairment”).
BENEFITS OF A HIGH-LYSINE/LOW-ARGININE DIET
Adequate lysine is so fundamental to health that one 2016 study had as its title, “Why always lysine?”12 Lysine is important for absorption of important minerals (calcium, iron and zinc), digestive health,13,14 hormone production, growth and development, healthy sexual development, fertility (see “Lysine and Fertility”), organ health and immune health. The body also needs lysine for the production of strong and stable collagen, antioxidant activity, methylation and detoxification, and pain relief. Given these many functions, it is not surprising that lysine is “the most well conserved” amino acid in the body—meaning the last to be broken down.15
We need enough essential amino acids—including enough lysine in the diet—to make proteins such as enzymes, receptors, hormones, antibodies and neurotransmitters. However, the actions of many of these other proteins vary depending on how the lysine contained in them is acted upon. Because of this, researchers argue, lysine “may be the major means by which signalling pathways modify protein behaviour.”12
Whereas a high-lysine diet is protective, lysine deficiency is linked to a wide variety of serious health problems. These range from asthma, kidney stone formation and low thyroid hormone production to abnormal growth and development and some disorders of the reproductive system. Lysine deficiency can also cause nausea, fatigue, dizziness and loss of appetite. A low iron level (anemia)—and the fatigue that it causes—can be a marker of lysine deficiency due to lysine’s role in iron absorption.
Excessive arginine, for its part, provides a “terrain” that supports pathogens as well as cancer. Arginine releases nitric oxide (NO) into the blood, and in an inflammatory situation, excessive arginine increases inflammatory NO. NO (composed of one nitrogen atom and one oxygen atom) plays many important functions in the body, but inflammatory NO, with its harmful and reactive free radical peroxynitrite (including in the brain), can cause kidney damage, high homocysteine, low glutathione and even death.16
MY “HEALTHY” VEGETARIAN DIET
I was a vegetarian for thirty-five years, and at the time, I assumed I was eating a healthy diet. I ate organically grown peanut butter, sprouted my almonds, soaked my oatmeal, ate only whole-grain sprouted bread and cooked chickpeas for hours to make hummus. I also faithfully followed the recommendation to have one to two ounces of 80 percent cacao per day, even carrying a large bar in my purse.
Despite this diet, I seemed to have no energy, had bad dental health, was depressed and had trouble sleeping. Going through a stressful time certainly contributed to these problems, but stress can’t be avoided. At a certain point, I got compression fractures in my spine while doing normal movements and was diagnosed with adrenal fatigue and osteoporosis. At times, I even fainted and often woke up with a rapid heartbeat. Finally, I developed hip, back, shoulder and neck pain to the point of being disabled. I literally felt like I was falling apart.
Though a staunch vegetarian, I tried adding fish to my diet, but that step alone did not seem to lead to any improvement. Next, I looked into ways to increase calcium for the osteoporosis. Calcium is needed for tooth enameling, too, so I figured more would also help with my dental health. I learned that lysine increases calcium absorption and decreases calcium loss in urine, meaning that it might help both prevent and treat osteoporosis.22 Lysine also helps with problems of excessive calcification, such as a torn rotator cuff, calcified arteries and kidney calcium-oxalate crystals,23,24 by dissolving oxalate crystals and preventing their formation.25 Oxalate crystals in muscles and joints cause pain. I had been eating a lot of the foods that are highest in oxalates, such as spinach, almonds and sweet potatoes, as well as green tea.26
One way lysine regulates calcium is through the cholesterol transporter NPC1, which also is needed for autophagy—the clearing away of damaged cells to be replaced with new cells.27 I knew I needed that! However, uncontrolled autophagy causes continual breakdown, such as the muscle atrophy I was experiencing; lysine is needed to terminate autophagy and begin the regeneration process.
Something else that increases calcium absorption is vitamin D3, but I discovered that D3 needs to be activated by lysine in the vitamin D receptor. (Other co-factors for D3 are vitamins A and K2.) Is inadequate lysine one reason why people seem to need so much D3 these days? In addition, bone marrow cells that differentiate into bone, cartilage and elastin can also differentiate into fat cells—and people with osteoporosis have more fat cells in their bones.28 This differentiation into fat cells occurs with induction of a receptor called PPAR gamma, which regulates fatty acid storage and glucose metabolism. Insulin (from carbohydrates), linoleic acid, flaxseed oil, olive oil and pigments in fruits and vegetables called anthocyanins (which pretty much describes my diet at the time) all induce PPAR gamma. In contrast, ketogenesis—as induced by lysine via another receptor called PPAR alpha—prevents differentiation into fat, thus increasing bone mass.29,30
Following my initial investigation into lysine, I gave it a try one night. After having gotten progressively worse for years, I noticed a very slight positive effect—the next morning, I felt a little more “together.” This prompted me to dive into further research about lysine. The first thing I discovered was that the foods highest in lysine are meat, fish, dairy and eggs (see Table 1, opposite page). Not only were most of the foods that I was eating very poor sources of lysine, but they were high in arginine. I remembered that several of my grandparents and great-grandparents had lived long, healthy and active lives eating high-lysine animal foods. After a great deal of research, I was convinced. I completely changed my diet to a high-lysine diet—substituting meat for peanut butter and nuts and cutting way back on legumes and bread—and I’m happy to say that I’ve recovered from most of my health problems.
Lysine’s role in building stable and strong collagen and flexible but strong elastin powerfully illustrates its relative importance in the diet compared to arginine.31 As components of skin, joints (cartilage), tendons, bone, hair, nails, muscles, the heart and the lining of the cardiovascular system (endothelium), collagen and elastin heal the body and literally hold the body together.32 The eyes, ears, gums, stomach lining and lungs also need collagen and elastin. However, when there is more arginine than lysine in the diet, arginine can use the lysine transporter if it is unoccupied by lysine. As a result, the cell wall will no longer have lysine’s stabilizing function; it will become thin and “dramatically” deformed due to the “special role played by [arginine] as an amino acid to bind to, disrupt and permeabilize lipid membranes.”33 These facts could explain why I had the distinct feeling of “falling apart” on a low-lysine, high-arginine diet!
ARGININE IS HIGH-NITROGEN
Arginine’s “special role” in disrupting cell membranes is due to its high nitrogen content. Whereas most amino acids have only one molecule of nitrogen and lysine has two, arginine has four. The high nitrogen content is what gives arginine the bitterness that we taste in unroasted nuts, seeds, chocolate and grains. Importantly, the body identifies bitterness as poison—perhaps our taste buds can sense that too much arginine relative to lysine is a problem. Lysine, on the other hand, tastes slightly sweet.
When lysine is adequate in the diet, the high amount of nitrogen in arginine is beneficial rather than harmful. For example, it facilitates proper blood flow (via endothelial NO), including to the brain (via neuronal NO). Endothelial NO is one of the most important molecules for blood vessel health, causing healthy relaxation of arteries and preventing blood clots.
Nitrogen is also a powerful growth factor, so the arginine that we make is used for growth hormone—especially needed for development. Premature infants, who cannot synthesize arginine, need slightly more arginine than lysine in order to produce growth hormone, whereas full-term infants need more lysine (mother’s milk is higher in lysine than arginine). In one study, lysine improved appetite in infants who were failing to thrive.34
Most of the arginine present in the body is produced in the body (endogenous arginine)— with the help of lysine. Lysine provides healthful blood flow from endogenous arginine, as well as a strong immune response when needed. Lysine recycles arginine’s nitrogen by blocking the enzyme arginase, redirecting endogenous arginine to healthful constitutive NO and the amino acid citrulline—which then becomes arginine again (see Figure 1, next page). Arginine is produced from citrulline directly in the arteries and capillaries, which then produces the low level of NO needed for proper blood flow.
If lysine is unavailable to block arginase and maintain endothelial function—when, for example, toxins bind to lysine—the inflammatory peptide bradykinin induces inflammatory NO. Dietary arginine also increases inflammatory NO.
AMMONIA AND THE UREA CYCLE
Excess nitrogen from other amino acids and from the breakdown of bodily proteins produces ammonia. Arginine is involved in the urea cycle (see Figure 2, next page), the series of biochemical reactions that help the body detoxify ammonia, converting it into urea, which is excreted in the urine after filtering by the kidneys. In the final step of the urea cycle, arginase catalyzes the formation of urea and ornithine from arginine.
When the urea cycle isn’t functioning properly, ammonia builds up in the muscles and brain. Elevated blood ammonia is found with smoking, high blood sugar, heavy exercise and stress (raised cortisol). Elevated ammonia leads to a wide range of mental and physical symptoms, including insomnia, headaches, confusion, inability to concentrate, low body temperature, drowsiness, lack of coordination, shortness of breath, combativeness, muscle weakness and stiffness, lethargy, low serotonin, enlarged liver, tremor and blurry vision.35 High ammonia levels also are characteristic of alcoholism, Alzheimer’s, amyotrophic lateral sclerosis (ALS), anorexia, attention-deficit/hyperactivity disorder (ADHD), autism, congestive heart failure, diabetes, Lyme disease, multiple sclerosis, obsessive-compulsive disorder (OCD), Parkinson’s disease, poorly functioning liver, rheumatoid arthritis and schizophrenia.
During the inf lammatory immune response, excess ammonia increases production of inflammatory NO by contributing more nitrogen.36 This is illustrated in the example of rheumatoid arthritis, in which arginase is overactive.37 Arginase breaks down both endogenous and dietary arginine, causing low constitutive NO, but at the same time, inflammatory NO and bradykinin are high, creating a favorable situation for severe inflammatory diseases.38,39
Although it’s often claimed that dietary arginine is necessary for detoxifying ammonia, researchers in 2008 found that ammonia was adequately detoxified with endogenous arginine and without any dietary arginine.40 In fact, studies with healthy adults have revealed that production of arginine in the body remains unchanged even if arginine and arginine precursors like glutamate are eliminated from the diet.41 Importantly, the 2008 study showed that in the absence of dietary arginine, degradation of arginine and oxidation of arginine to potentially harmful inflammatory NO were “markedly reduced.”40 Dietary arginine actually adds disproportionately to the amount of nitrogen needing detoxification.
A high-arginine diet may interfere with the kidneys’ disposal of uric acid in the urea cycle. Long-term supplementation with arginine increases a protein called mTOR (which regulates cell growth and aging); increased mTOR ages the kidney and causes functional decline.42 Research shows that arginine supplementation also causes kidney fibrosis (which occurs with end-stage kidney disease) and shortens life span in mice with lupus.43
LYSINE AND IMMUNE FUNCTION
A high-lysine diet is important for immune function. Lysine increases natural killer (NK) cell activity and regulates the inflammatory immune response. It is needed, for example, to inhibit inflammatory tumor necrosis factor (TNF) and interferon.
Studies have found that pretty much all pathogens are dependent on arginine because pathogens degrade arginine into polyamines and also convert arginine into growth hormone. The excessive polyamines from a high-arginine diet serve as building blocks for cancer cells—in fact, “arginine is the most consumed amino acid in the inner necrotic core of tumor mass, indicating its high demand for the survival of tumor cells”44—and for the brain parasite Toxoplasma gondii,45 which has been linked to mental and neurological disorders, vision problems, rheumatoid arthritis, cancer, diabetes and more. Pneumonia-causing streptococcus, too, is arginine-dependent.46 I used to get bad colds several times a year and had pneumonia twice—conditions in which Streptococcus pneumoniae bacteria are abundant.
Excessive dietary arginine encourages herpes.47 The foods that have the highest arginine-to-lysine ratio—chocolate, peanut butter, nuts, seeds and coconut—often trigger cold sores.48 Two people who did not even know that they had herpes told me that they took arginine supplements one night, and woke up the next morning with cold sores! Researchers advise that “patients prone to herpetic lesions” abstain from “arginine excess” and consider adding supplemental lysine to their diet,49 “particularly during periods of stress.”47
One of lysine’s critical immune functions is its inhibition of the enzyme arginase (see “Lysine’s Inhibition of Arginase”). H. pylori, associated with diseases such as gastritis, ulcers and gastric cancer, furnishes an illustration of the problem of excess dietary arginine without lysine to inhibit arginase. As one study explains, arginine metabolism—through “polyamine-mediated oxidative stress and impairment of antimicrobial NO synthesis”—“leads to H. pylori-induced DNA damage and immune dysregulation.”50 Notably, the old-fashioned remedy for an ulcer was to drink milk (high in lysine).
Histamine is particularly high in nitrogen. Normally, histamine induces NO for a very short while, but NO can become excessive, causing symptoms such as breathing difficulties, anaphylaxis, hives, angioedema, eczema, sinus congestion and headache.52 Medications given to relieve allergy symptoms (such as epinephrine, Benadryl and corticosteroids) either increase endothelial NO or inhibit nitric oxide synthase (NOS), both of which lower inflammatory NO.53-55 Lysine, too, increases healthful NO as well as lowering adrenal stress hormones, which in turn lowers histamine release.56 Interestingly, I used to get eczema on my hands every time I had cow’s milk in any form, but after several years on a high-lysine ketogenic diet plus lysine supplementation (as well as elimination of sugar), the eczema disappeared.
Metabolic health is our ability to convert food into energy, including our ability to make ketones for heart energy. Insulin resistance, which lowers the ability to make energy, is an important cause of metabolic syndrome. The major manifestation of metabolic syndrome is coronary artery disease,57 but it also includes diabetes, fatty liver, kidney disease and often hypothyroidism.58 Lysine deficiency is characteristic with metabolic syndrome.
As previously mentioned, lysine is one of only two amino acids that are degraded exclusively into ketones instead of glucose. In addition, lysine is the catalytic amino acid for activating PPAR alpha, which induces ketogenesis. When supplemented, lysine rapidly turns into carnitine, a potent inducer of ketosis, which is important for maintaining a healthy weight. In contrast, because arginine becomes glucose rather than ketones, it raises insulin (which signals for fat storage) more than other amino acids. As a result, arginine decreases satiety, thus increasing meal frequency.59 On my ketogenic diet, I often eat a Wasa cracker covered with two tablespoons of butter two hours before a meal, along with a ketogenic tea, producing increased ketones that give me plenty of energy until the meal. As an experiment, I tried instead eating a high-arginine “fat bomb” of MCT oil, peanuts and chocolate totaling six grams of fat. Not only did my ketone level not budge, but I was hungry in forty-five minutes!
Lysine has shown promise as a therapy for diabetes (see “Wonder Drug or Wonder Lysine?”). One study found that lysine increased diabetics’ insulin receptor enzyme activity, which lowered their blood sugar by 27 percent.60 Another group of researchers discovered that when healthy volunteers ingested lysine along with glucose, the lysine “dramatically attenuated the glucose-stimulated glucose response.”61
Hemoglobin detoxifies inflammatory NO, but when it isn’t detoxified quickly enough due to inadequate functional hemoglobin, the free radical peroxynitrite is formed.62 With both type 1 and type 2 diabetes, this causes considerable damage, leading to complications for 50 percent of diabetics.63 One problem with diabetes is that hemoglobin becomes glycated (covered with sugar from high blood sugar). Lysine maintains functional hemoglobin by preventing hemoglobin glycation (high HbA1c). (Interestingly, an elevated HbA1c score and hypertension are two of the highest risk factors for Covid-19 severity64—see “Covid-19 and Bradykinin.”) In one study with type 2 diabetics, three grams of lysine per day inhibited hemoglobin glycation, improved glycemic control and increased antioxidant markers.65 Lysine also appears beneficial for numerous other complications of diabetes, including fatty liver,66 cataracts (and potentially diabetic retinopathy)67,68 and diabetic neuropathy.69
LYSINE AND HEART HEALTH
Ketones are the primary energy source for the heart. In one study, researchers gave heart patients (fifty-eight years old on average) lysine, carnitine and other supplements to treat arrhythmia by generating ketones; after six months, 70 percent experienced some improvement, including 43 percent who became entirely free of arrhythmia episodes.80
Lysine is needed for the longevity protein SIRT1, which is low in both obesity and heart disease;81 increasing SIRT1 by a high-lysine ketogenic diet is a tool used for managing both metabolic syndrome and heart disease.82
Adrenal stress hormones raise blood pressure, and lysine is needed to keep these hormones at a healthy level. In 2017, French researchers reported that lysine normalized blood pressure (as increased by the adrenal hormone aldosterone),83 while researchers in Ghana described how just one gram of lysine per day normalized blood pressure in men and women who had a “suboptimal lysine intake” due to a high-grain diet—a diet possibly similar to that of many U.S. residents.84 Vegetarians eating a high-arginine, low-lysine diet are often deficient in heart-protective carnitine (abundant in animal foods and also endogenously synthesized from lysine and methionine), increasing their risk of stroke.85 In contrast, lysine decreases risk for stroke.
Lysine also plays a heart-protective role where LDL cholesterol is concerned. “Sticky” lipoprotein(a), or Lp(a), is considered “an independent risk factor for cardiovascular disease”— elevating risk by 70 percent86—but when lysine is absorbed into Lp(a)’s lysine-binding site, it becomes normal LDL. Furthermore, lysine converts cholesterol into bile, thus controlling LDL cholesterol and preventing fatty liver.22
Lysine, as noted, is essential for endothelial function and, therefore, cardiovascular health. Endothelial permeability and dysfunction represent early markers for heart disease and causes of blood clots, hypertension and angina.87,88 The recommendation to take lysine supplements for heart disease dates as far back as the 1970s; Linus Pauling found, for example, that taking six grams of lysine with three to eighteen grams of vitamin C gave quick relief from angina.89 In a study that gave people with heart failure a multinutrient treatment that included lysine, participants experienced improvement in symptoms of fatigue, shortness of breath collagen-making role as crucial for the protection of the endothelium of the artery walls.90 Loss of elastin in arteries increases risk for hypertension, heart attack, heart failure and stroke.
In a contrasting study, researchers tested whether nine grams of arginine per day would help people who had already had a heart attack. The premise that taking arginine could prevent another heart attack seemed to make sense because blood pressure is elevated during a heart attack, and supplemental arginine lowers blood pressure by dilating blood vessels.91 Uncontrolled high blood pressure also causes heart attacks. However, this study ended tragically because six people in the arginine group (and none in the placebo group) had another heart attack and died!92 (The study closed enrollment after this finding.)
There are several factors that could explain the study’s unexpectedly fatal outcomes. First, the blood-pressure-lowering effect of supplemental arginine is brought about via bradykinin and inflammatory NO, when healthful NO is low. Bradykinin stimulates a “rapid increase in L-arginine uptake and NO release,”93 which would explain the subsequent heart attacks since inflammatory NO in that context “is obligatory for local and systemic inflammatory activation and cardiac remodeling.”94 Stated another way, inflammatory NO lowers blood pressure in a destructive way—by causing blood vessels and capillaries to become permeable.76,93 This causes veins to constrict and capillaries to leak, and leaky capillaries can cause swelling. Edema is a known side effect of arginine supplementation.95,96
Another possible effect of supplementary arginine is an increase in the action of the “antidiuretic hormone” arginine vasopressin (AVP), which raises blood pressure by retaining water. Diuretics are often recommended to lower blood pressure, so perhaps excessive arginine could have opposite and excessive antidiuretic effects. In fact, people who are already taking diuretics or blood-pressure-lowering medications that increase bradykinin—such as ACE inhibitors, losartan or the diabetes medication metformin—are warned against taking arginine.97
A third factor has to do with the difference in how dietary arginine and endogenous arginine produce NO—which is so confusing that it’s been labeled the “arginine paradox.” The paradox is that when someone is healthy, taking supplemental arginine doesn’t increase the steady-state, constitutive NO supplied by arginine made in the body (which is what body builders look for when taking arginine). Supplemental arginine does increase it in unhealthy people—which is why the researchers did the study—but it helps only on a short-term basis, whereas, as shown in this longer study of six months, it also increases inflammatory NO via bradykinin.
THE CANCER CONNECTION
Methylation of lysine activates the major cancer-fighting protein p53, which some creative writers have dubbed the “Guardian of the Genome.”98 P53 blocks inflammatory NO and its mitochondrial and DNA damage.99 Lysine in p53 also stabilizes DNA for correct reading, silences cancer genes and repairs DNA, preventing development of cancer.100,101
As discussed, lysine is needed for ketogenesis (as induced by carnitine), and ketogenesis fights cancer in many ways,102 including through “inhibition of [cell] proliferation, induction of cell differentiation and induction or repression of gene expression.”103 Lysine is the active site for the cholesterol transporter NPC1, which regulates the mTOR protein. Unregulated or dysregulated mTOR is found with cancer as well as many other diseases104—and arginine induces mTOR!105
As the site for NPC1, lysine is needed both to activate and terminate the clearing away of dysfunctional cells like cancer cells (autophagy). As I noted earlier, this process needs to be regulated so that it won’t break down the body excessively. Without adequate lysine, autophagy is uncontrolled, causing atrophy and “many disease states.”106 Lysine marks cancer and other dysfunctional cells for destruction—and then terminates autophagy—by binding to a protein called ubiquitin (a name derived from its ubiquitous presence in the body and more support for the question, “why always lysine?”). This function of lysine is critically important; faulty ubiquination is linked to the development of “cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infection and muscle dystrophies.”107 With many chemicals binding to lysine residues and thereby limiting their availability, extra lysine is likely needed for these diseases.
In stark contrast, polyamines from excessive dietary arginine feed cancer cells, promote cancer cell proliferation and enhance tumor growth.108,109 Nitrosamines—strong carcinogens formed specifically from arginine—have been linked to cancers in a variety of organs and tissues.110 Most cancer cells can’t reproduce without dietary arginine. Healthy cells are able to get the arginine they need for normal growth by converting arginine precursors like glutamine (the most abundant amino acid in the body) into arginine, but cancer cells aren’t able to do this. As a result, investigators are interested in arginine deprivation as a strategy for shrinking tumors because it decreases inflammatory NO, insulin-like growth factor 1 (IGF-1) and mTOR.44
The process of making ornithine from endogenous arginine also makes creatine for muscles, but this uses up 70 percent of the body’s methyl groups. Methylation is extremely important for cancer prevention and numerous other functions. Even though dietary arginine doesn’t increase creatine, a 2009 study found that nine grams of arginine per day lowered methyl groups, impairing vital methylation.111 The researchers concluded, “L-arginine has the potential to paradoxically impair endothelial function.” Lowering methyl groups may thus relate to arginine’s role in cancer.
The arginine dose in the 2009 study also affected the “homocysteine cycle,” which produces the powerful antioxidant glutathione (far more necessary than the highly praised antioxidants in nuts and chocolate) that is critical for detoxification. Vegans’ high-arginine diet may partly explain why they often have low glutathione.112,113 Notably, glutathione recycles the antioxidant vitamin C, which is needed to detoxify peroxynitrite and form collagen. Furthermore, lysine is needed to activate the critical antioxidant of our mitochondria.114 Lysine also forms glycine when it is converted to carnitine, and glycine plays major roles in the entire homocysteine cycle that has glutathione as a major end product.115
MENTAL HEALTH AND NEUROLOGICAL DISORDERS
Inflammatory NO is a major factor with mental illnesses and neurological disorders.116 Its involvement in neuroinflammation is thought to be “due to its free radical properties, which compromise cellular integrity and viability via mitochondrial damage.”117 One problem is that it prevents adequate blood flow, with its vital supply of oxygen, to the brain. Excess arginine is also converted into glutamate, and excessive glutamate is neurotoxic.
In contrast, by controlling arginine actions, lysine protects the brain and nervous system, preventing neuronal NO from “uncoupling” and becoming inflammatory. It also prevents seizures by a “barbiturate-like” action.118 Notably, lysine (as acetyl coenzyme A) is a component of acetylcholine, the primary neurotransmitter of the normal, steady-state nervous system. Acetylcholine induces the “in-the-flow” alpha state of the brain needed for memory and learning as well as proper vasodilation in the circulatory system. In people with anxiety who are low in lysine, lysine has calming effects and regulates the adrenal stress hormones.13 In a study of people in Syria who ate mainly wheat,119 lysine fortification of flour lowered the cortisol response to stress and reduced chronic anxiety; in a related study in rats, lysine alleviated stress-induced anxiety and diarrhea-type intestinal dysfunctions.120,121
The arginine hormone AVP (arginine vasopressin) stimulates release of cortisol.122 This is probably because AVP stimulates the amygdala—the fear center of the brain. In contrast, oxytocin, which is the calming lysine counterpart to AVP, inhibits neurons in the amygdala.123 Oxytocin and AVP have the same structure, except that AVP has two additional amino acids—one of which is arginine. Males have more AVP receptors, and AVP is needed for male sexual arousal and long-term memory. Interestingly, caffeine, alcohol, marijuana and lithium all inhibit AVP.
Lysine is also needed for the calming neurotransmitter GABA, which is made from glutamate. In schizophrenia, GABA is low, while arginase activity is increased. The lysine enzyme OAT, which prevents production of polyamines, is also deficient. As a result, polyamine production is increased with schizophrenia as well as mood disorders, anxiety, suicidality, depression and bipolar disorder. As previously mentioned, polyamines feed the brain parasite Toxoplasma gondii, which is linked to all of these disorders.124 Lysine has been shown to improve schizophrenia symptoms through maintenance of proper levels of serotonin.125
Lysine is needed to activate myelin repair, and impaired myelin is found with both mental and neurological disorders. When given to mice, lysine has been shown to reduce multiple sclerosis symptoms and suppress disease progression.126,127 Debris is a basic driver of autoimmune diseases and with multiple sclerosis, substantial inflammatory NO blocks debris clean-up by M2 macrophages. Lysine’s role in lowering inflammatory NO thus helps there as well.
Inflammatory NO is found with many other mental and neurological disorders: ALS, Alzheimer’s, autism spectrum disorders, bipolar disorders, OCD, Parkinson’s, schizophrenia, suicidality, and traumatic brain injury.117,128 In animal models of traumatic brain injury, inflammatory NO blockers have been shown to improve cortical thickness needed for memory, attention, speech and learning.116
BEWARE ARGININE SUPPLEMENTATION
In the recent past, supplemental arginine was heavily promoted as a “fountain of youth” for older people—with claims that its effects on growth hormone could help extend life and increase bone density and muscle mass. However, studies have found that arginine supplements raise growth hormone only in young people. Another unsupported premise, as we have seen, is the claim that supplemental arginine improves cardiovascular health. A 2014 study reported that taking arginine on a long-term basis actually caused “endothelial senescence,” meaning age-related deterioration!129
For many years, arginine was highly recommended for increased athletic performance because of arginine’s role in making creatine. However, it’s now known that only endogenous arginine—and not dietary arginine—is involved in making creatine. Athletes also supposed that arginine supplementation would produce more endothelial NO, but “numerous studies have shown that orally supplemented l-arginine
. . . even when dosed as high as 6g/day, has no benefit on nitric oxide production or athletic performance.”130
As we have seen, endogenous arginine converts to citrulline plus healthful NO. Citrulline supplements actually increase arginine in the blood more than arginine itself, although this does not appear to increase NO production in healthy people with low but normal NO.131
There is a more solid rationale for recommending lysine for “peak performance.”132 Notably, carnitine from lysine improves exercise performance, even in healthy people, and there is a rapid conversion of lysine to carnitine. Carnitine is a form of the ketone beta-hydroxybutyrate, and ketones power not only the heart but the muscles. The lysine-to-carnitine conversion also yields glycine, which is needed for collagen and muscle. Researchers report that supplemental lysine “is rapidly transported into muscle tissue and that lysine concentrations in muscle exceed those of other amino acids, especially at five to seven hours after ingestion.”133
Two case reports describe body builders who developed pancreatitis from taking arginine.134,135 Chronic pancreatitis damages insulin-producing beta cells, so it can lead to diabetes. Arginine is even given to mice to study necrotizing pancreatitis, and in one study, they cured the mice with lysine!136 In that study, lysine also increased glutathione as well as catalase (low catalase causes grey hair) and the vital antioxidant superoxide dismutase. This suggests that lysine is important for the most important antioxidants—those made in the body.
Arginine is still recommended for erectile dysfunction and for increasing testosterone. However, while it does cause erections, it doesn’t increase testosterone in the long term.137 Moreover, arginine increases and sustains high IGF-1, which is linked to development of prostate cancer.138 On the other hand, studies have found that inhibiting inflammatory NO—which is what lysine does, whereas arginine supplements counterproductively increase it—improves erectile dysfunction.139
Despite the clearly negative long-term results regarding arginine, erectile dysfunction and prostate health, arginine and high-arginine nuts and seeds are still promoted as “superfoods” for both. Based on one 2016 study, nuts are even recommended for prostate cancer survival. However, funding for the study came from the International Tree Nut Council Nutrition Research & Education Foundation, and one of its lead investigators was avid vegan and nut promoter Walter Willett, so the diagnostics may be questionable.140
In addition to the side effects already mentioned, arginine supplementation is associated with a wide range of other unpleasant symptoms: heart palpitations, dizziness, light-headedness, irritability, depression, anxiety, dehydration, headache, restless legs, indigestion, swollen legs, chest pain, low blood sugar, lower back pain, blood abnormalities, breathing problems, worsened asthma, elevated homocysteine and worsened kidney disease and sickle cell disease. The aggravation of allergies and asthma linked to arginine supplementation comes from increased histamine release from mast cells, with its accompanying NO.141,142 Of note, some of the biggest triggers of anaphylaxis in the U.S. and other countries are peanuts, tree nuts, sesame seeds and chickpeas—which just happen to have the highest arginine content of all the foods that are higher in arginine than lysine.
When I was eating my high-arginine diet, I suffered from many of these side effects and experienced a lot of pain. In fact, though arginine supplements are said to help with the extreme pain called “complex regional pain syndrome,” excessive arginine (as a precursor to inflammatory NO) is known to aggravate pain in a number of ways. For example, the formation of the free radical peroxynitrite from inflammatory NO activates pain receptors and is responsible for the delayed muscle soreness that follows exercise.143 Mouse studies indicate that sensitivity to pain is blocked by inhibiting NO formation.144 Such studies have found that inhibitors of inflammatory NO help with pain ranging from arthritis to nerve pain; however, no NO inhibitor has been developed for humans.145 The complex involvement of NO “and its derivatives” in the experience of pain is thought to contribute to the functional disability of osteoarthritis.146
TRADITIONAL DIET = HIGH-LYSINE
Because lysine is readily available in meat, fish and dairy products, it may seem easy to get enough. Yet for a number of reasons, a person may still not be consuming adequate lysine— defined as twelve (or even thirty) milligrams per kilogram of body weight daily for people aged thirteen years and above.19 Given the many toxins that bind to lysine, even thirty milligrams per kilogram of body weight may be too low.
Dairy products and fish are the foods highest in lysine, but both foods are eaten far more in Europe than in the U.S. In Japan, where they eat little dairy but a lot of grains, fish consumption is three times higher than in the U.S. In recent times, with the American dietary establishment’s emphasis on whole grains, legumes, nuts, seeds, peanut butter and dark chocolate—and its concurrent advice to cut back on meat and dairy products—many Americans are eating far more high-arginine foods and fewer high-lysine foods than in the past.
Some legumes—such as red, black and white beans—are higher in lysine than arginine, and lentils are about even. Fermentation of high-arginine grains also increases lysine in the diet (see Figure 3, opposite page). Traditionally, wheat, rye, millet, rice and quinoa were ground to a flour and then fermented for many hours, resulting in items like sourdough bread, South Indian rice pancakes and African teff or millet breads. In modern times, however, the wheat and other grains used to make bread, crackers, pizza, pasta and desserts undergo little or no fermentation.
Legumes and grains contain trypsin inhibitors, which block absorption of lysine, and modern wheat has been bred to have even more trypsin inhibitors to protect against insects. Again, fermentation is the answer; trypsin inhibitors are broken down during traditional fermentation, making lysine more available for digestion. Fermenting bacteria also produce lysine, so lysine is increased over five-fold in oats when fermented at 98.6 degrees F! It’s no wonder that people traditionally have prepared their low-lysine foods in this way.
Danish foods provide a good illustration of traditional dietary practices with regard to lysine and arginine, also showing that a high-lysine diet is as delicious as it is nutritious. For example, because split peas are much higher in arginine than lysine, the Danes take three days to soak and cook their split pea soup! They cook the peas with a ham bone for some high-arginine collagen but then add plenty of ham for a beautifully balanced soup. For many Danes, it is also still a highly revered tradition to make sourdough rye bread at home—and rye has the best lysine-to-arginine ratio of any grain. The Danes ferment their bread for about twelve hours. They then slice it thin and spread it with enough butter to reveal your teeth marks (tandsmør) in it! This bread is the basis for open-face sandwiches, called smørrebrød, that are served with a large variety of high-lysine toppings like ham, shrimp, beef or their favorite—liver paté and beet pickles. More evidence for high-lysine Nordic diets with few plant foods comes from a paleolithic site in Sweden, which uncovered a diet of mainly fish with some meat; mushrooms, berries and nuts made up a “meagre” 3 percent of their intake.147
Given the importance of lysine, together with the potential harms of too much arginine, it makes sense to me that high-lysine protein foods, including potatoes, were the basic foods of my Northern European great-grandparents. Even the foods I grew up with—such as chicken soup, which is the national soup in many countries around the world—were either high in lysine or at least balanced equally. Chicken is high in lysine, while the gelatin in broth is high in arginine, making for a balanced dish. Notably, in countries like Russia and India, where they consume a lot of grains, they eat fermented dairy foods at every meal.
TURNING THE TIDE
Over the past century-plus, there has been a sea change in the American diet, which has shifted away from relying on high-lysine foods like seafood, meat soups and stews, potatoes, sourdough bread and dairy products to heavily emphasizing high-arginine foods like unfermented wheat, soybeans, peanuts, nuts, seeds (see “Eschew the Seeds”), chocolate and berries, along with added sugar. The high-arginine diet, together with widespread exposure to chemicals that bind to (and thus deplete) lysine—including toxins in livestock and fish fed cottonseed meal—has likely led to widespread lysine deficiency, contributing in important ways to the health problems that have plagued Americans since the early 1900s.
This dire situation can be helped by reverting to a high-lysine, low-arginine traditional diet consisting primarily of meat and milk products from pastured animals, wild-caught seafood, a small amount of fermented lower-arginine rye bread, low-carb roots and seasonal nuts and berries— along with careful avoidance of chemicals. For individuals who have been eating a high-arginine diet or who have any of the disorders described in this article, it may be a good idea also to ask one’s health care provider about possible L-lysine supplementation, including the appropriate dosage and duration of intake.
Nowadays, I avoid trendy “superfoods” and thank God that I was finally led to trust the wisdom of my ancestors, who over many centuries learned how to be strong, healthy and happy by eating a high-lysine diet. Although I made other changes to my diet as well, my experience of shifting from a high-arginine to a high-lysine diet, as well as supplementing lysine, illustrates the amazing power of this one amino acid. My disability seems like a long-ago dream or, I should say, nightmare. I have learned first-hand that the benefits of lysine are considerable!
TOXINS AND LYSINE IMPAIRMENT
Lysine is present at the catalytic (or regulating) site of many receptors, including nuclear receptors for the hormones that affect and manage hundreds of bodily processes. Unfortunately, many chemicals specifically bind to lysine in these receptors and cause problems, including pyrethroid insecticides,1 organophosphate pesticides (such as Roundup and its active ingredient glyphosate),2 bisphenol A (BPA)3 and the ubiquitous solvent trichloroethylene (present, for example, in degreasers and aerosol sprays used for crafts).4 Through their action on specific receptors, these chemicals have been linked to birth defects, cancer, diabetes, fatty liver, heart disease, kidney disease, mental illness, miscarriage and infertility, multiple sclerosis, obesity and Parkinson’s disease.5
When chemicals impair the catalytic lysine on the insulin receptor, for example, the impairment causes insulin resistance.6 Insulin resistance is the fundamental problem underlying metabolic syndrome, which includes hypertension, diabetes, heart disease, kidney disease and obesity.7 (For this reason, these chemicals are called “obesogens.”8) When estrogenic chemicals or endocrine disruptors bind to lysine on the estrogen receptor, they can cause breast cancer and infertility.9 The latter group of chemicals includes “compounds to which the human population is exposed in daily life through their use in pesticides/herbicides, industrial and household products, plastics, detergents, flame retardants and as ingredients in personal care products.”10
A poison in cottonseed oil, called gossypol, also depletes lysine; gossypol may be present in cheap hamburgers from industrial dairy cows and in farmed fish, as both are commonly fed cottonseed meal. This poison “has a strong tendency to accumulate in animal tissues and is not easily cleared from the animal body.”11 Gossypol binds to lysine in the cholesterol transporter, causing atherosclerosis, dementia, fatty liver and low hemoglobin.
LYSINE AND FERTILITY
Adequate lysine is required for synthesis and the actions of sex hormones. Lysine is so important for fertility that it was featured in the movie Jurassic Park—the dinosaurs were infertile without lysine. One way that lysine determines fertility is that, in females, lysine is a catalytic amino acid in the enzyme aromatase, which converts testosterone into estradiol.17 Low aromatase activity causes high testosterone in females, with androgen-related polycystic ovarian syndrome (PCOS) symptoms of infertility, insulin resistance, facial hair and increased muscle mass.18 Lysine helps with these symptoms, perhaps by regulating aromatase.
Another of lysine’s roles in fertility is that it is the precursor to carnitine with its ketogenic effects,19 which has immense capabilities regarding fertility. Carnitine is low in male as well as female infertility and has been shown to help with both.20
Toxins that bind to lysine—including the cottonseed oil poison gossypol—cause infertility by inhibiting steroid synthesis.21 Farm animals are given lysine supplements to increase fertility, possibly needed because of the cottonseed meal they are fed. When given to cows, lysine also increases milk production, probably due to its role in producing oxytocin. Oxytocin is also needed for erections, orgasm and childbirth. Women have more oxytocin receptors than men. It seems likely that a high-lysine diet, especially as a ketogenic diet, would help humans with fertility problems and other male and female sexual disorders.
LYSINE’S INHIBITION OF ARGINASE
Lysine’s inhibition of the enzyme arginase serves a number of important purposes:
- Inhibiting arginase recycles the nitrogen in arginine to become healthful NO rather than being expelled and wasted as urine via arginase. As mentioned elsewhere, it also makes citrulline to form arginine again, which avoids formation of polyamines, cell proliferation and excessive glutamate via arginase.
- In the case of an infection, arginine becomes inflammatory NO to destroy the pathogen, rather than being degraded into polyamines, which feed the infection instead! As soon as the pathogen is destroyed, lysine signals for debris clean-up by macrophages via an enzyme called OAT (ornithine aminotransferase), which degrades arginine into ornithine. For wound healing and regeneration, lysine doesn’t inhibit arginase but instead uses ornithine to make proline for collagen, again via OAT.
- Lysine-generated inflammatory NO is controlled, whereas with excessive dietary arginine, inflammatory NO reacts with superoxide to form peroxynitrite, which interferes with energy generation, damages DNA and is found with many (if not all) serious diseases.51
- Recalling that lysine is a ketogenic amino acid, it is also noteworthy that one function of ketones is to inhibit arginase.
WONDER DRUG OR WONDER LYSINE?
Metformin is the most widely prescribed diabetic drug in the world—prescribed to more than one hundred fifty million people—and also the most-prescribed drug in the U.S. It is called a “wonder drug.”70 In addition to being the first-line medication for type 2 diabetes, it is also prescribed for prediabetes, PCOS and schizophrenia. It is also viewed as helpful for asthma, several cancers (breast, colon and prostate), dementia, psoriasis, stroke and life span. It’s even given to children as young as six years old!
Metformin does three major things—which lysine happens to do as well. First, it induces ketosis, which reduces the post-meal production of glucose and supplies the energy that diabetics can’t produce from glucose.71 Second, metformin blocks arginase, so it improves blood flow.72 Third, metformin blocks the enzyme that degrades dietary arginine into polyamines. Many pathogens also have this enzyme, so the reduction in polyamines lowers pathogen “load” and helps with cancer.72
Metformin has a major side effect—stomach upset—which often leads to poor compliance. Diabetics also commonly develop moderate chronic kidney disease, and the actions of metformin damage the kidneys further.73 This may be because, like arginine, metformin is very high in nitrogen. Another metformin side effect is increased nitrogen in urine; a high blood urea nitrogen (BUN) test normally indicates kidney damage. Lysine, on the other hand, “diminish[es] development of hypertension and kidney injury” in rats through protective mechanisms that include “diuresis, further acceleration of lysine conjugate formation, and inhibition of tubular albumin uptake.”74 Thus, even the reported benefits of the “wonder drug” metformin end up illustrating the wonders of lysine, especially as part of a high-lysine ketogenic diet—and lysine has only good side effects!
COVID-19 AND BRADYKININ
A confusing thing about Covid-19, according to Anthony Fauci, was that hypertension was by far the most common comorbidity in hospitalized Covid-19 patients, almost double that of patients with diabetes.75 According to Fauci, just having high blood pressure should not have increased risk for acute respiratory distress syndrome.
Inflammatory NO as caused by bradykinin offers an important clue. In individuals with Covid-19, the ACE2 enzyme is dysfunctional—and ACE2 is needed to degrade bradykinin and block the bradykinin inflammatory receptor (BK1) that produces inflammatory NO. If a person already had elevated bradykinin and developed Covid-19, blocking ACE2, this could lead to low arterial blood pressure, constricted veins and leaky capillaries in the lung, causing acute respiratory distress syndrome.76 The most prescribed medications for high blood pressure, ACE-inhibitors, do just that—they elevate bradykinin! In short, the reason Covid-19 is a problem for people with high blood pressure may be that many are taking ACE inhibitors77 and that the illness further elevates bradykinin and promotes inflammatory NO. Some, therefore, recommend lysine to both prevent and treat Covid-19 symptoms.78 (Editor’s note: See the article, “Questioning Covid” by Ilana Nurpi in the Summer 2021 issue of Wise Traditions for a fascinating discussion of Covid mortality and the role of ACE inhibitors and other medications inhibitory to the sympathetic nervous system.79)
ESCHEW THE SEEDS
Understanding the importance of lysine and the problems of arginine begs the question, are seeds a natural, healthy food for humans? Seeds of every sort are high in nitrogen. The only mammals who eat seeds in the wild are small rodents who have a very different digestive system, one equipped with extra gut bacteria to break down the seeds. Squirrels ferment their nuts in their cheeks and by hiding them over the winter. Birds—the other major consumers of seeds—have no ability even to make arginine! It may be best to leave the seeds to these creatures, at least for the most part, while we make sure that we as humans have a high-lysine diet.
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This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly journal of the Weston A. Price Foundation, Summer 2023🖨️ Print post