L-citrulline is often combined with malate, an intermediary of the Krebs cycle. In theory, supplementing with malate could increase ATP production, potentiating L-citrulline's ergogenic effects.^[6] Although there has been some promising research showing that citrulline malate can improve exercise performance^[3], it’s unclear whether citrulline malate is superior to citrulline, as there is currently no research directly comparing the two.

Citrulline is highest in watermelon (where it derives its name, as watermelons are known as Citrullus vulgaris^[7]), which contains an average of 2.1 milligrams of citrulline per gram of wet weight (although absolute numbers vary).^[8] Consuming watermelon has been noted to acutely increase both plasma arginine and citrulline (3.3 kilograms of watermelon is equivalent to 10 grams of supplemental L-arginine)^[9][10] and to increase fasting arginine and ornithine in the range of 12%–22% following consumption of 780–1560 grams daily.^[11]

Other food sources of citrulline include muskmelons (cantelope), bitter melons, squashes, gourds, cucumbers, and pumpkins.^[7]

Citrulline has been touted as an ergogenic aid due to its promotion of vasodilation and blood flow by indirectly increasing nitric oxide synthesis. However, research on citrulline suggests that its effect on exercise performance is not as substantial as some claim.

For instance, 2 meta-analyses found that citrulline supplementation did not improve strength^[12] or measures of aerobic exercise performance,^[13] whereas other meta-analyses found that supplementation with citrulline reduced rating of perceived exertion (a subjective measure of the difficulty of an exercise), decreased muscle soreness, and increased power output and total repetitions performed in resistance training.^[1][2][3]

It’s important to note that these mixed findings may be related to variations in study populations, doses, formulations, or lengths. Although certain studies found that supplemental citrulline does not improve some aspects of exercise performance, the totality of the evidence shows that it may be mildly helpful for some aspects of resistance training. Further research is needed to see whether changing these variables (e.g., higher doses) can improve exercise performance.

Citrulline supplementation has been presented as a way of lowering blood pressure due to its capacity to boost nitric oxide production, a vasodilator. One meta-analysis does suggest that supplementation with citrulline can mildly decrease blood pressure, but because the participants were limited to healthy individuals, more research is needed to see whether this decrease applies to people with high blood pressure.^[4] It’s also unclear whether certain forms (e.g., L-citrulline, citrulline malate, or citrulline from watermelon juice), higher doses (ranging from 2 to 8 grams in many studies), or increased lengths of supplementation reduce blood pressure further.

Citrulline is thought to be a proerectile agent because it is a precursor for arginine, and arginine is the substrate from which nitric oxide is produced and then can induce cGMP (via the NO/cGMP/VEGF pathway);^[32] an increase in cGMP is also the ultimate effect of PDE5 inhibitors such as sildenafil (also known as Viagra) or icariin from horny goat weed.^[33]

In men with erectile dysfunction (as assessed by weak erections and erectile hardness score^[34]) who were given 1,500 mg of citrulline daily (two doses of 750 mg) for one month, half of the 24 participants reported a benefit (as assessed by “very satisfied” with treatment), whereas there was an 8.3% improvement in the placebo group.^[5]

Citrulline appears to have proerectile properties that occur vicariously through arginine. It is likely more potent than arginine due to greater bodily exposure to arginine, but the preliminary evidence does not suggest that it is more potent than the reference drug sildenafil.

In humans, a 15-gram dose of citrulline taken acutely (in the short term) does not appear to cause diarrhea or intestinal upset.^[31] In this respect, citrulline is notably different from both ornithine and arginine, which may cause diarrhea at 10-gram doses when taken in boluses^[35][36] due to limited absorption of these amino acids, which then proceed to the colon to cause osmotic diarrhea.^[35]

Citrulline is created in the body by one of two pathways, either recycled from arginine (the conversion of arginine into nitric oxide leaves citrulline as a byproduct)^[14][15] or produced from the nitrogen (and some carbon) contained in L-glutamine,^[16] a process in which the enzyme ornithine transcarbamylase uses both ornithine and carbamoyl phosphate (which requires glutamine) to produce citrulline in enterocytes.^[17][18]

It appears that the arginine pathway accounts for about 10% of circulating citrulline and the glutamine pathway accounts for 90%;^[14] reducing plasma glutamine levels can reduce plasma citrulline.^[19]

The majority of citrulline either floats in the blood passively or is transported to the kidneys for conversion into arginine. Therefore, most bioactivities of citrulline are secondary to arginine ingestion.

Approximately 83% of orally ingested citrulline appears to be taken up by the kidneys,^[20][21][22] where it is converted into L-arginine in the proximal tubules (via the enzymes arginosuccinate synthase and arginosuccinate lyase^[23]); this conversion of citrulline into arginine (either from supplemental citrulline or that produced as a byproduct of arginine creation of nitric oxide) accounts for 5%–15% of circulating arginine but 60% of total arginine (the difference being due to the ability of arginine to be incorporated into proteins).^[19][24]

Although citrulline does not appear to be an activator of mTOR, like leucine, (mTOR activation, via S6K, induces muscle protein synthesis), citrulline does appear to restore muscle protein synthesis rates^[25][26] and muscular function after food restriction,^[27] and this positive effect on muscle protein synthesis is abolished by rapamycin and is thus mediated by the mTORc1 pathway.^[28][29]

Citrulline does not activate the p44/42 MAPK pathway or the ERK1/2 pathway in skeletal muscle,^[25] whereas leucine itself can activate ERK1/2 and induce 4E-BP1 (downstream of mTOR) to a much larger degree than citrulline.^[25]

Citrulline positively influences the mTOR pathway but does not appear to occur through direct activation, as with leucine. At minimum, citrulline normalizes suppressed mTOR signaling.

In human studies, supplementation with 0.18 g/kg of citrulline per day for one week did not significantly modify leucine oxidation rates or whole-body protein synthesis,^[30] but elsewhere, at the same dosage, it has been noted to improve nitrogen balance in humans in the fed state.^[19] Oral doses of citrulline between 2 and15 grams do not appear to acutely affect urinary nitrogen in the fasted state.^[31]

Mixed evidence as to whether citrulline supplementation can help with muscle protein synthesis

Nutrient-Nutrient Interactions

Branched Chain Amino Acids (special reference to Leucine)

Branched-chain amino acids (BCAAs) are a group of three amino acids (leucine, isoleucine, and valine) that are involved in skeletal muscle synthesis and degradation. Of these three, leucine is commonly said to be the most “important” because it is the prime mediator of muscle protein synthesis (and appears to be the most common reason for supplementation with BCAAs).

When looking at citrulline ingestion at rest, a dose of 0.18 g/kg was found to improve nitrogen balance in one study when ingested in the fed state^[19] whereas another study noted a failure with the same dose; both whole-body protein synthesis and leucine oxidation rates were unaffected.^[30]

During exercise, 6 grams of citrulline taken by trained cyclists prior to a 137 km cycling test produced a reduction in plasma BCAAs relative to the control, and this effect was attributed to increased utilization of BCAAs for fuel.^[37]

Citrulline does appear to interact with BCAA metabolism in the body, although human studies have produced differing results based on the context of the study.

Similar to how citrulline is able to restore muscle protein synthesis rates^[25]PMD:16608884 and muscular function^[27] during aging and malnourishment in rats via mTORc1-dependent means,^[28][38] citrulline itself is a weak agonist (enough that it could be false positive from sensitizing mTORc1^[25]). Conversely, leucine itself is a potent activator of mTORc1 activity.

Citrulline may positively mediate leucine's signaling through mTOR, which theoretically suggests that they are synergistic. The application of this combination in weight lifters has not yet been investigated, so the synergism is currently just a hypothesis rather than a demonstrated fact.

Glutathione

Citrulline increases levels of nitric oxide (NO), a vasodilator. Although NO effects are potent, the extent of vasodilation is limited by the short half life of NO, which is broken down by oxidation soon after it is formed.^[39] One study found that taking reduced glutathione (GSH; a reducing agent) alongside citrulline may help to protect against the rapid oxidative destruction of NO. In vitro studies in human umbilical vein endothelial cells demonstrated that citrulline (0.3 mM) in combination with GSH (1 mM) resulted in significantly greater nitrite levels than vehicle-treated controls or citrulline alone. Similarly, 3-day treatment of rats with citrulline (500 mg/kg/day) and GSH (50 mg/kg/day) by oral gavage increased plasma nitric oxide levels more than a control or citrulline alone. The investigators also conducted a small human trial in which resistance-trained men were randomly assigned to orally ingest either a placebo or L-citrulline (2 g/day), GSH (1 g/day), or citrulline (2 g/day) in combination with GSH (200 mg/day) for 7 days, followed by a resistance exercise session. Consistent with in vitro and rat studies, participants who took GSH along with citrulline had significantly higher nitrite and nitric oxide levels at 30 minutes after exercise relative to placebo or citrulline alone.^[39]

Supplementing with reduced glutathione (GSH) alongside citrulline may extend the half life of nitric oxide, potentially resulting in greater vasodilation compared to L-citrulline alone.

Nitrate

Nitrate is a small nitric oxide donor that is the main bioactive of beetroot juice.

Serum nitrite (reduced form of nitrate) appears to be increased during exercise after consumption of 6 grams of citrulline malate, which is thought to be an indicator of increased nitric oxide production.^[40]

Sodium Bicarbonate

Sodium bicarbonate (baking soda) is an ergogenic supplement that is reported to increase physical performance, and although it is somewhat unreliable overall in doing so, it appears to be effective for short-duration activities characterized by metabolic acidosis ('the burn').

Citrulline administration appears to promote ureogenesis (production of urea) and secondarily promote the renal resorption of bicarbonate;^[41] it is thought that citrulline may promote a slight buffering effect by preserving bicarbonate.^[42]

A study assessing the synergism between citrulline and bicarbonate supplementation is currently not available.

Theoretically synergistic, but has not been directly investigated at this moment in time

Statins

One study in endothelial cells (in vitro) noted that the tested statin (simvastatin) was able to increase mRNA concentrations of eNOS (the enzyme in endothelial cells that produces nitric oxide from arginine) and thus was said to act synergistically with arginine and/or citrulline to improve blood pressure in participants with high cholesterol.^[43]

Because simvastatin,^[43] atorvastatin,^[44][45] and lovastatin^[46] (bioactive in red yeast rice) have all been noted to increase eNOS,^[44] iNOS,^[44][46] and nNOS^[45] it is thought that this is a mechanism common to statin drugs in general.

Statin drugs may be able to increase expression of the enzyme that mediates the conversion of arginine into nitric oxide, and there is possible synergism for other processes pertaining to nitric oxide. This hypothesis has not yet been tested in a living system.