Supplementation with L-citrulline + Glutathione may enhance blood flow during exercise: RCT

©  Rawpixel / Getty Images
© Rawpixel / Getty Images

Related tags Glutathione L-citrulline Blood flow exercise performance Sports nutrition

Eight days of supplementation with L-citrulline + Glutathione (GSH) may enhance blood flow and blood analytes during exercise, says a new study.

This randomized, double-blind, placebo-controlled crossover study, conducted at the University of North Carolina at Chapel Hill, enrolled twenty-five aerobically fit males randomly assigned to ingest six capsules of L-citrulline + GSH (Setria Performance Blend (SPB)) or placebo (PL) one hour prior to exercise for eight days.

Participants completed two separate exercise testing visits: one for the active treatment and one for the placebo.  Both exercise testing visits consisted of three treadmill runs to exhaustion (TTE) to determine blood flow, vessel diameter, and blood analytes.

Results of the study, published in the Journal of the International Society of Sports Nutrition​, showed significant increase in blood flow post exercise as well as increased plasma concentrations of L-citrulline and L-arginine, with SPB supplementation compared with PL.  There were no significant SPB treatment effects on vessel diameter and aerobic performance vs. PL.

Despite the data not supporting the hypothesis that SPB supplementation would improve aerobic performance and increase vessel diameter in aerobically trained individuals, previous research has demonstrated this in recreationally trained individuals (Hickner, 2006).

“Future research may benefit from evaluating the effects of L-citrulline between aerobic athletes and recreationally active individuals to assess the impact of training status on performance and blood analyte outcomes,” stated Cabre et al.


As the fastest-growing segment in consumer health, sports nutrition is drawing attention from supplement manufacturers.  Among the most popular sports nutrition ingredients includes amino acids.

L-citrulline is a nonessential amino acid, which is growing in popularity in the sports nutrition market.  It is among one of the most common ingredients found in commercially available pre-workout supplements, as 71% include L-citrulline (Jagim, 2019).

Approximately 83% of orally ingested L-citrulline is converted into L-arginine, via the citrulline-NO cycle (Kerksick, 2018).  L-arginine is the precursor for the synthesis of nitric oxide (NO).  NO is a gas that diffuses rapidly across cell membranes, promoting optimal physiological functioning (Gantner, 2020).

Over the past 20 years, NO has become a performance outcomes measure in athlete physiology studies (Onur, 2021).  The most known and remarkable function of NO is its role in controlling vasodilation, blood rate, and mitochondrial respiration, thus enhancing athletic performance (Onur, 2021).

As numerous studies demonstrated the ineffectiveness of L-arginine supplementation on increasing NO synthesis, researchers have begun to explore the potential therapeutic benefits of L-citrulline. 

Study details

Twenty-five aerobically fit males were recruited to participate in the study.  Half the participants were randomly assigned to the Setria Performance Blend [SPB; L-citrulline (2 g) + glutathione (200 mg); Kyowa Hakko Bio, Tokyo, Japan] and the other half a placebo (PL; 3.1 g cellulose).

Participants were instructed to ingest six capsules of the assigned treatment once per day one hour prior to exercise for seven days.  On day eight, participants were instructed to bring the treatment to the exercise visit where the eighth dose was consumed an hour before the exercise test.  This was followed by a 14-day washout period before the participants crossed over to the alternative treatment.

Participants completed two separate exercise testing visits: one for the active treatment and one for the placebo.  Both exercise testing visits consisted of three treadmill runs to volitional fatigue at 90%, 100%, and 110% of the peak treadmill speed that was determined by peak velocity (PV) from the maximal oxygen consumption (VO2max) test during visit one.  Time to exhaustion (TTE) was used to measure endurance for each run.

Brightness-mode ultrasound was used to assess vessel diameter and blood flow through the brachial artery.  Measurements were taken on visits 2 and 4 one hour prior to exercise (1hrPrEX), immediately after each run to exhaustion (90%, 110%, and 110%), and 30 minutes post-exercise (30minPEX).

Blood analytes of L-citrulline and L-arginine were drawn at visit one, prior to VO2max, midpoint of the study, and during visits two and four 1hrPrEX, immediately post exercise (immediate PEX), and 30minPEX.

Results of the study showed no significant treatment effects with SPB on TTE at 90%, 100%, or 110%; vessel diameter at 1hrPrEX, 90%, 100%, 110%, or at 30minPEX; or blood flow at 1hrPrEX, 90%, 100%, or 110%.  There was greater blood flow at 30minPEX with SPB treatment.

Supplementation with SPB showed no significant effects on L-citrulline plasma concentration at baseline visit one vs. visit three.  There was significant difference in L-arginine plasma concentration at baseline visit one vs. visit three with SPB supplementation.  Both blood analyte concentrations were significantly increased with SPB, immediately PEX and 30-min PEX.  There was no significant effect on plasma concentrations 1hrPrEX.

Although acute ingestion of SPB for eight days did not enhance aerobic performance, increased plasma concentration of L-citrulline and L-arginine may result in enhanced NO production, augmenting vasodilation and blood flow. 

“Although SPB supplementation did not translate to improved performance, there was a significant increase in blood flow at 30 minutes following exercise. Increased blood flow after exercise may promote exercise recovery due to augmented nutrient, hormone, and oxygen delivery,” stated Cabre et al.

“Further research is needed to elucidate potential mechanisms related to L-citrulline supplementation in other aspects of performance.”

Source: Journal of the International Society of Sports Nutrition          
Published online 2023 Apr. 26 doi:                                 
“The effects of L-Citrulline and Glutathione on Endurance performance in young adult trained males.”                                                                                                                                                 
Authors: Cabre et al.

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