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Health Benefits of Leucine + Side Effects

Written by Puya Yazdi, MD | Last updated:
Medically reviewed by
Evguenia Alechine, PhD (Biochemistry), Jonathan Ritter, PharmD, PhD (Pharmacology) | Written by Puya Yazdi, MD | Last updated:

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Autophagy Benefits Muscles

Leucine is an amino acid that is used by the body mainly for building muscle and providing energy. Despite a lack of research, people use it to improve strength during exercise and muscle recovery times. This makes it a popular supplement among athletes and gym members. However, leucine supplementation carries certain risks. Keep reading to learn about the purported benefits and side effects of leucine.

What Is Leucine?

Leucine is a branched-chain amino acid that is sold as a supplement. The other two BCAAs are valine and isoleucine but leucine is the most popular of the three as a bodybuilding supplement.

Leucine supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.

Leucine is an essential amino acid, meaning that it cannot be produced in the body and needs to be taken in through diet. It increases energy and protein (therefore, muscle) production [1, 2].

Similarly to many other amino acids, leucine is found in many foods that are high in protein. Examples include meats (such as fish, chicken, and turkey), dairy products (such as yogurt and cheese), and soybeans. Other foods like eggs, nuts, seeds, and fruit also contain leucine, but to a lesser extent.

Leucine can be classified as:

  • L-leucine is the natural version of the amino acid, is found in the proteins of the body and is the main form used as a supplement.
  • D-leucine is the mirror image of L-leucine, which is created in the laboratory and is also used as a supplement.

Despite the popularity of leucine among gym enthusiasts, the science to back up most of its uses is weak.

Purported Health Benefits of Leucine

Possibly Effective for:

Brain Function in Liver Disease

Oral branched-chain amino acids likely improve symptoms and liver function in people with poor brain function caused by liver disease (hepatic encephalopathy) [3, 4, 5].

Some evidence suggests that branched-chain amino acids may also improve cognition in people with declining brain function due to liver disease. However, not all studies had positive findings. Additionally, branched-chain amino acids likely don’t reduce the chance of death in people with this condition [6].

Post-Exercise Muscle Recovery

Solid evidence supports the use of branched-chain amino acids (including leucine) for reducing fatigue and exertion after prolonged or intense exercise [7].

Exercise leads to branched-chain amino acid (BCAA) breakdown, especially in the muscles [8].

Scientists believe that BCAAs help protein synthesis and prevent protein degradation, which in turn helps prevent muscle fatigue and soreness [9].

In a study of 30 healthy adults, squat exercises caused muscle fatigue and soreness. Those that received BCAA supplementation had less soreness in the following days, while those that did not receive supplementation showed prolonged periods of soreness [8].

Muscle fatigue after exercise also decreased with BCAA supplementation [8].

Additional research on individual BCAAs should be done to see if these amino acids can produce the desired effects individually (such as leucine).

Also, scientists found that leucine increased two muscle-building pathways in rats (AKT by 98% and mTOR by 49%) and decreased muscle protein breakdown. Clinical trials on leucine are needed [10].

Tardive Dyskinesia (A Movement Disorder)

Oral branched-chain amino acids likely reduce symptoms of tardive dyskinesia, according to several clinical trials [5, 11, 12].

Tardive dyskinesia is a movement disorder that results in involuntary movement. It is most commonly caused by the long-term use of antipsychotic medication in people with schizophrenia or bipolar disorder [13].

Likely Ineffective for:

Liver Cancer

Branched-chain amino acids like leucine do not improve liver cancer outcomes, according to several meta-analyses [14, 15].

However, limited early evidence suggests that branched-chain amino acids may improve survival and prevents cancer recurrence in people with liver cancer who have not had surgery. We can’t draw any conclusions from this study due to its small sample size and other study design issues [16].

Exercise Performance

Evidence about the effectiveness of branched-chain amino acids for athletic performance is contradictory. The products used in the studies varied as did the end measures and control groups. In most studies, oral branched-chain amino acids did not enhance exercise or athletic performance [7].

In one study, short-term amino acid supplementation (mostly L-leucine, but mixed with 13 other amino acids) showed no effect on 100km ultra-runners. Muscle soreness and race completion times did not improve with the supplementation [17].

Insufficient Evidence for:

No valid clinical evidence supports the use of leucine (or BCAAs) for any of the conditions listed in this section.

Mania

In one small clinical study of 25 people, a tyrosine-free amino acid drink containing leucine, isoleucine, and valine, reduced acute manic symptoms within 6 hours compared with placebo. When taken daily for 7 days, it continued to improve symptoms over 2 weeks. Large-scale studies are needed [18].

Muscle Wasting

Research is exploring whether leucine reduces muscle wasting in ill patients. However, proper clinical evidence is currently lacking to support this use [19, 20].

In patients with either burns, trauma, or sepsis (infection in the tissues), branched-chain amino acid (BCAA) supplementation, which includes leucine and two other amino acids, decreased muscle wasting [19].

Additionally, when humans age, they undergo sarcopenia, a natural decline of muscle that leads to an increased risk of injury and disability [21].

In younger adults, both high and low dosages of leucine supplements were able to increase protein synthesis [22].

However, in elderly patients, only those given high-content supplements increased protein synthesis [23].

Scientists are looking at the effect of L-leucine supplementation on decreasing muscle degradation in animals (by the AMPK pathway) [10].

In studies on rats with cancer cachexia (a disease with heavy muscle wasting), leucine supplementation increased muscle mass (by 23% in the gastrocnemius, and by 22% in the tibialis anterior) [20].

Leucine also increased total amino acid concentration in blood in animals, which may be beneficial in creating more proteins and muscle [20].

Strength

A study performed on 26 men tested suggested that leucine supplementation may increase strength, measured through the maximum weight someone can lift five times. Those that received L-leucine supplements were able to lift heavier weights [24].

However, leucine supplementation did not lead to increased muscle mass. What’s more, these findings have not yet been replicated. Large trials are needed [24].

Liver Cirrhosis

It’s unclear how BCCAs affect liver cirrhosis. One study has shown that BCAA supplementation increased nutritional status and the quality of life (improved sleep and decreased fatigue) in patients with liver cirrhosis. Other studies had negative findings [25, 26].

Kidney Failure

There is not enough evidence to suggest that BCAA supplementation is beneficial for those with chronic kidney failure. In limited, small-scale studies, BCAA supplementation improved nutrition and appetite in patients undergoing dialysis [27, 28].

Lacking Evidence (Animal Research)

Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

Leucine (or BCAAs) should not be used for any of the conditions described below due to a complete lack of safety and efficacy data in humans.

Protein Synthesis

In studies on rat diaphragms, adding amino acids increased protein synthesis. Higher concentrations of amino acids produced greater effects [9].

However, these effects were solely due to the branch chained amino acids (BCAAs) and the other amino acids produced no effect on protein synthesis. Leucine, isoleucine, and valine are the three BCAAs [9].

When BCAAs were tested individually in rats, leucine was the most significant enhancer of protein synthesis. Valine by itself was unable to affect protein synthesis and isoleucine produced an inhibitory effect [2].

Excessive breakdown of these amino acids, which is common during fasting and in diabetic patients, leads to a limited supply of BCAAs, which in turn may decrease protein synthesis rates [9].

Proteins are the building blocks of muscles, so scientists believe that increasing protein synthesis may help build muscle in a similar way to how leucine supplementation may increase muscle recovery. However, clinical data are lacking [29].

Hardening of the Arteries (Atherosclerosis)

Hardening of the arteries (atherosclerosis) is linked to high levels of low-density lipoproteins (LDL), while high-density lipoproteins may (HDL) reduce the risk of atherosclerosis due to their role in reverse cholesterol transport (the process of returning cholesterol from the tissues to the liver) [30].

In rat studies, leucine supplementation decreased LDL by 41% and increased HDL by 40% [30].

Leucine supplementation also decreased atherosclerotic lesions (by 58%) in animals [30].

Obesity

The effects of leucine on obesity in experimental animals cannot be translated to humans.

Rats given leucine-rich diets gained 32% less weight and decreased obesity by 25% [31].

Leucine also decreased cholesterol levels by 27% and LDL or “bad” cholesterol levels by 53%, thus potentially reducing the risk of obesity [31].

Longevity

There’s no evidence to suggest that leucine has any effect on longevity.

The existing animal studies are limited to cells.

Many substances have anti-aging effects in cells but fail to pass further animal studies due to a lack of safety or efficacy. Quercetin is one good example that should remind us how cell culture work often doesn’t translate to living beings.

On the other hand, leucine may help scientists explore the possible pathways involved in aging.

For example, dairy-rich diets (which have a lot of amino acids such as leucine) increased the activation of the SIRT1 gene, which increased the number of mitochondria by 40% in muscle and fat cells. Some theories have linked an increase in mitochondria to cell longevity [32].

High-calcium diets by themselves didn’t improve lifespan in rats, so some scientists think leucine alone should be studied in animals [32, 33].

Effects on Energy Production

Energy-Increasing Potential

Leucine breakdown produces two molecules that are used to obtain energy: acetyl-CoA and acetoacetate [1].

In rats, leucine also serves as a precursor to different fats (fatty acids, nonsaponifiable fats, and sterols) that are later broken down to produce energy [1].

Scientists think fasting may lead to increased levels of leucine in the blood and increased activity of enzymes that convert leucine into ketone bodies and used for energy [1].

Patients with deficiencies in the molecule that breaks down leucine into acetyl-CoA and acetoacetate (3-Hydroxy-3-methylglutaryl-CoA lyase) develop acidosis (low blood pH) and hypoglycemia (low blood glucose) [34].

On the other hand, in rats, leucine increases blood levels of insulin, which causes glucose uptake by the cells and ultimately energy production. Together, leucine and glucose-induced a 4.5-fold increase in insulin (compared to 2.4-fold by glucose alone). Therefore, leucine may play a key role in maintaining glucose levels and producing energy [35].

In tissue studies, leucine increases energy production over the first 45 minutes, but afterward, it produces a decrease in energy (most likely due to the restriction of pyruvate breakdown) [36].

Energy-Decreasing Potential

Even though leucine seems to increase insulin, which usually increases glucose uptake, leucine can also block glucose uptake.

Limited studies suggest that fasting increases blood levels of branched-chain amino acids (BCAAs) such as leucine. A study found that fasted animals with increased leucine concentrations did not uptake as much glucose as non-fasted animals thereby reducing energy production [37].

Leucine blocks pyruvate (a molecule that glucose is converted to produce energy) breakdown so that the glucose can’t be used for energy [37].

Some researchers suspect that this process of restricting pyruvate breakdown may explain why glucose uptake and energy production in the muscle of rats decreases after approximately 45 minutes [36, 37].

In people that fasted, leucine supplements also reduced energy production because it inhibited the insulin-mediated glucose uptake by the muscles [38].

Leucine decreased insulin-mediated glucose utilization by 50 to 83% in fasted rats [37, 38].

Some bodybuilders try to avoid this inhibitory effect of leucine on energy production by consuming a meal prior to workouts.

BCAA vs. Leucine Only

Many studies did not specifically test for leucine but for all the branch chained amino acids (BCAAs): leucine, isoleucine, and valine.

The efficacy and safety data on leucine is extremely limited. Clinical trials are lacking.

In rats, leucine increased protein synthesis, while isoleucine actually had an inhibitory effect. These effects have not been confirmed in humans [2].

Leucine Side Effects

Safety

Branched-chain amino acids like leucine are possibly safe when appropriately used as oral supplements.

Pregnant and breastfeeding women should avoid supplementing due to a lack of safety data.

Other Potential Side Effects

Theoretically, the blood-brain barrier competes for the absorption into the brain of branch-chained amino acids (BCAA) and aromatic amino acids (ArAA), which are the precursors of serotonin. This competition may, in theory, decrease serotonin production [39].

Leucine absorption into the brain may be influenced by diet; carbohydrate-rich, protein-poor diets increase BCAAs and decrease ArAAs in the brain, while a carbohydrate-poor, protein-rich diet may do the opposite [40].

The recommended dosage of leucine for everyday people is 50 mg/kgd, but the dosage should not go over 500 mg/kgd. Overdose can lead to increased blood ammonia levels; therefore, brain damage and liver disease [41].

Leucine Supplementation

Contraindications

Leucine supplementation lowers glucose levels, which can lead to unhealthy levels in people with:

  • Hypoglycemia (low blood sugar) [42]
  • Diabetes, in those who take blood sugar-lowering medication [38, 42]

Supplement Reviews

The opinions expressed in this section are solely those of the users who may or may not have medical or scientific training. Their reviews do not represent the opinions of SelfHacked. SelfHacked does not endorse any specific product, service, or treatment.

Do not consider user experiences as medical advice. Never delay or disregard seeking professional medical advice from your doctor or another qualified healthcare provider because of something you have read on SelfHacked. We understand that reading individual, real-life experiences can be a helpful resource, but it is never a substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.

Most users stated that the leucine was very helpful and that it was crucial to them in maintaining the muscles after workouts. One user stated that the supplement helps him feel “recharged after an intense workout”.

People also notice more muscle gain after leucine supplementation.

One note of caution is that almost every review bemoaned the taste of the leucine supplement. Many said that leucine was very bitter, but that it was worth it due to its positive effects.

Some users saw some different side effects like loud ringing in her ears and increased anger that disappeared only after she stopped taking the leucine supplements.

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About the Author

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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