When it comes to human health, histidine is an essential amino acid that wears many hats. As a protein building block and a precursor for important biochemical products, it is involved in protecting the skin against UV radiation and reducing inflammation and oxidative stress. Read on to learn more about the importance of maintaining healthy levels.
What Is Histidine?
Histidine (L-histidine) is one of the 20 amino acids that make up the proteins in our body. These building blocks are generally classified as either nonessential or essential. Nonessential amino acids are those that the body can produce by itself, while essential amino acids must be acquired through diet because the body cannot make its own supply [1].
Histidine is an essential amino acid. A long-term study demonstrated that adults who consume a diet deficient in histidine over long periods of time may experience negative health effects such as reduced hemoglobin (the protein that carries oxygen in red blood cells) levels [2, 3, 4].
Histidine is produced by the liver in small quantities. Hence, it must be consumed in the diet to maintain necessary histidine levels in the body. Here, it is converted into a number of important substances such as histamine and carnosine [5, 6, 7].
Function
Histidine is required for the growth and repair of tissues, red blood cell production, and protecting tissues from damage from radiation and heavy metals. It is especially necessary for the formation of myelin sheaths, which are layers surrounding nerves that enables faster transmission of signals to the brain [1, 8].
In both human and animal studies, histidine functioned in maintaining normal levels of hemoglobin, the protein responsible for delivering oxygen from the lungs to the tissues of the body [9, 3].
Urocanic acid, produced through histidine, is a major absorber of ultraviolet (UV) radiation. This protects skin cells from damage [10, 1].
Additionally, it is converted to histamine, a messenger molecule involved in immunity, digestion, and sexual function [7, 1].
It is also a major component (along with β-alanine) of carnosine, an important antioxidant that slows the progression of multiple degenerative diseases and reduces plaque buildup in the arteries. It may also help improve muscle performance for high-intensity exercise [5, 6].
Snapshot
Proponents
- Essential amino acid
- HKT solution routinely used in surgical procedures
- Antioxidant and anti-inflammatory
- May protect the heart and lower blood pressure
- May lower blood sugar
- May help lose weight
- May help with brain function
- May protect the skin
- May reduce blood clots
Skeptics
- Very few clinical trials carried out so far
- High doses of histidine supplements may have some adverse effects
Health Benefits
Effective for:
Surgical Procedures
Bretschneider’s histidine-tryptophan-ketoglutarate solution (HTK) is a histidine-containing buffering solution routinely used to induce heart arrest during surgical procedures and protect the heart muscle from low blood supply.
Several clinical trials attest to its effectiveness to reduce damage due to low oxygen in not only the heart, but also the kidneys [11, 12, 13, 14, 15, 16].
The solution is also used to preserve donor organs [17, 18, 19, 20].
Insufficient Evidence for:
The following purported benefits are only supported by limited, low-quality clinical studies and some animal and cell-based research. There is insufficient evidence to support the use of histidine supplements for any of the below-listed uses until larger, more robust clinical trials are conducted. Remember to speak with a doctor before taking histidine supplements. They should never be used as a replacement for approved medical therapies.
1) Protecting the Heart
Mutations resulting in increased histidine levels were associated with lower incidence of coronary heart disease in an observational study on over 1,100 African Americans [21].
The histidine derivative carnosine improved exercise performance and quality of life in a clinical trial on 50 people with congestive heart failure [22].
Damaged rat hearts (due to restored blood supply after a heart stroke) treated with histidine showed better recovery. Histidine presumably reduced reactive oxidative species and helped preserve energy (ATP) [23].
In diabetic mice, supplementation with carnosine reduced blood fat levels and plaque build-up in the arteries [24].
2) Reducing Blood Pressure
Dietary histidine was associated with lower blood pressure, especially at higher doses, in a study on 92 people with heart disease [25].
In a study in rats with elevated blood pressure, oral histidine supplementation significantly reduced it. Similarly, carnosine reduced blood pressure in obese rats [26, 27].
3) Antioxidant
In a study involving 92 obese women with histidine deficiency, supplementing this amino acid over 12 weeks reduced oxidative stress [28].
Another study on over 400 women found an association between low histidine levels and oxidative stress. Additionally, obese women had worse antioxidant status, possibly due to their abnormal histidine and arginine metabolism [29].
4) Inflammation
In 2 studies on over 500 women, histidine supplementation led to reduced inflammation by blocking the production of inflammatory cytokines [29, 28].
5) Blood Sugar Levels
In a clinical trial on 92 obese women with metabolic syndrome, histidine supplementation (4 g/day for 12 weeks) significantly decreased insulin resistance.
An observational study on 88 obese people associated higher dietary histidine with lower fasting blood glucose levels and increased insulin sensitivity [30].
In mice, supplementation with histidine and carnosine helped prevent diabetic complications [31].
6) Brain Function
In a clinical trial on 20 people with chronic fatigue and sleep disturbances, supplementation with histidine for 2 weeks improved attention, memory, and clarity of thinking while reducing fatigue [32].
In another trial on 25 Gulf War I veterans, carnosine treatment improved cognitive function [33].
In rats, histidine supplementation improved short-term memory and protected the brain from the damage caused by reduced oxygen supply (cerebral ischemia) [34, 35].
7) Obesity
An observational study on 88 obese people associated higher dietary histidine with a reduced body mass index (BMI), waist circumference, and blood pressure [30].
Histidine is converted to histamine in the brain. In rats, histidine supplementation reduced their feeding behavior through its conversion to histamine. In another study, histidine supplementation reduced not only feeding, but also fat accumulation [36, 37].
However, histidine was ineffective as an appetite suppressant in an old clinical trial [38].
8) Skin Protection
Histidine is a precursor of urocanic acid, a substance that builds up in human skin cells and absorbs UV radiation. By doing so, urocanic acid acts as a “natural sunscreen” that may protect DNA from sunlight [10].
In a clinical trial on 24 people with eczema, supplementation with histidine for 4 weeks significantly reduced disease severity and 39% of patients reported feeling “much better” [39].
Two studies in mice found increased urocanic acid levels on the skin after histidine supplementation, resulting in increased protection from UV-radiation [40, 41].
9) Preventing Blood Clots
In a clinical trial on 18 people with increased formation of blood clots (spontaneous platelet aggregation), supplementation with histidine for a week prevented blood clots. The effects were probably mediated by the action of arachidonic acid metabolites [42].
Possibly Ineffective for:
Cataracts
Eye drops with N-acetylcarnosine, a dipeptide composed of histidine and beta-alanine, are often advertised to improve cataracts without the need for surgery. However, a meta-analysis failed to find sufficient evidence to back this claim [43].
Histidine supplementation prevented the development of cataracts in salmons [44].
Animal and Cell Research (Lack of Evidence)
No clinical evidence supports the use of histidine supplements for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies should not be interpreted as supportive of any health benefit.
Wilson’s Disease
Wilson’s disease is a rare genetic disease that causes excessive copper buildup in the organs, particularly the liver. In a study in rats, a diet containing excess histidine flushed the excess of liver copper out with urine [45, 46].
Seizures
In rats, histidine injections reduced the severity of seizures. The authors believed that the effect was due to the role of histidine as a precursor to histamine, a seizure inhibitor [47, 48].
Limitations and Caveats
Very few clinical trials, many of them on small populations, have been carried out. Larger, more robust clinical trials are needed to confirm the potential health benefits of histidine supplementation for most conditions.
Additionally, several studies combined histidine with other substances, making the specific contribution of histidine to the effects observed difficult to estimate.
Symptoms of Deficiency
The symptoms we discuss here are commonly associated with histidine deficiency, but are insufficient for a diagnosis. Work with your doctor to discover what underlying condition might be causing your low levels of this amino acid and to develop an appropriate plan to improve your health.
Since histidine is an essential amino acid, its deficiency may cause several detrimental effects. The main symptoms include dry or scaly skin lesions, anemia, poor hearing, and general feelings of unwellness [49, 50, 51].
Inflammation and Oxidative Stress
In a study on 325 people with chronic kidney disease, low blood levels of histidine were associated with inflammation, oxidative stress, and increased mortality[52].
Two additional studies on over 300 obese women associated low histidine levels with obesity, increased inflammation, and oxidative stress [28, 29].
Anemia
Four healthy adults consumed a histidine-free diet for 48 days and their hemoglobin and other protein levels were monitored. An 11% decrease in hemoglobin levels, possibly leading to anemia, was observed overtime with histidine depletion [53].
Reduced Brain Function
A clinical trial on 17 people found that histidine depletion affected response processes [54].
Skin
In a study on 18 people with wounds, 16 had significantly lower histidine levels. A deficiency in histidine may weaken the skin, leading to larger wounds [55].
Anxiety
A deficiency of histidine in the diet of mice caused anxiety-like behavior, possibly due to the low histamine levels in their brains [56].
Side Effects
This list does not cover all possible side effects. Contact your doctor or pharmacist if you notice any other side effects.
Call your doctor for medical advice about side effects. In the US, you may report side effects to the FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch. In Canada, you may report side effects to Health Canada at 1-866-234-2345.
High amounts of histidine in the body may result in unwanted side effects. Excess histidine consumption (> 32g/day) has been reported to cause headaches, weakness, fatigue, nausea, anorexia, depression, and memory failure [57].
In a study on 11 people diagnosed with schizophrenia, the blood histidine levels were above the average. Although this is not necessarily a side effect, chronically high histidine levels (leading to high histamine levels) may have detrimental effects on the brain [58].
In rats, excess dietary histidine led to copper deficiency, high cholesterol, liver enlargement, and appetite suppression [36, 59].
Factors That Decrease Histidine
The main cause of histidine deficiency is not consuming enough histidine with the diet, since the body cannot produce enough levels of this amino acid.. Vitamin B9 (folate, folic acid) deficiency also causes the body to lose histidine through urination. Maintaining normal levels of folate in the body is important for preventing histidine deficiency [50].
Foods and Supplementation
There are a number of foods that contain high amounts of histidine and may help supplement low histidine levels. They include protein-based foods such as eggs, beef, chicken, pork, and fish. Additional histidine-rich foods include soybeans, beans, wheat, maize, quinoa, and rice [60].
Alternatively, histidine supplements are commercially available.
Dosage
The World Health Organization (WHO) estimated that the recommended intake of histidine is 8-12 mg/kg per day in adults [61].
Because histidine supplements are not approved by the FDA for any condition, there is no official dose. Users and supplement manufacturers have established unofficial doses based on trial and error. Discuss with your doctor if histidine supplementation may be useful as a complementary approach in your case and which dose you should take.
Doses of up to 4 g/day caused no adverse side effects in clinical trials [28, 29, 30].
