Evidence Trace, complete trial record
In plain terms
In plain terms: L-Citrulline shows early signals in human research but the evidence is limited -- small trials, surrogate endpoints, or not yet independently replicated. It is an emerging area, not yet a proven one.
L-Citrulline
C
Limited: small, mixed or unreplicated trials
The endpoint this grade is based on: Surrogate biomarker endpoint, Blood pressure, where one pooled analysis found systolic pressure 4.1 mmHg lower with a borderline interval and diastolic pressure lower only at 6 g/day or more, and another pooled analysis found no effect on brachial or aortic pressure. Exercise performance is not supported for free L-citrulline: pooled analyses of aerobic and endurance performance are null, and the small strength and repetition effects rest largely on citrulline malate, a different form.
The evidence as the record states it
Blood pressure: Barkhidarian et al. (Avicenna J Phytomed, 2019; PMID 30788274): meta-analysis of small trials (12 to 34 subjects each), 3 to 9 g/day for 1 to 17 weeks; systolic pressure 4.10 mmHg lower (95% CI -7.94 to -0.26), diastolic not significant overall (-2.08, -4.32 to 0.16) and lower only at 6 g/day or more. Mirenayat et al. (Curr Hypertens Rep, 2018; PMID 30284051): meta-analysis of five trials; no effect on brachial systolic (0.28 mmHg) or diastolic pressure, or on aortic pressure. Gonzales et al. (Exp Physiol, 2017; PMID 28940638): randomized crossover, 25 older adults, 6 g/day for 14 days; femoral blood flow during calf exercise 11 percent higher in men only, not significant after adjusting for baseline diastolic pressure, and no change in women; a vascular surrogate study, not a performance trial. Performance: Viribay et al. (Nutrients, 2022; PMID 36079738): meta-analysis of 10 trials; no effect on aerobic performance, perceived exertion, VO2 kinetics or lactate. Harnden et al. (J Int Soc Sports Nutr, 2023; PMID 37155582): meta-analysis of 9 trials in young healthy adults; no effect on time to exhaustion or time to completion. Trexler et al. (Sports Med, 2019; PMID 30895562): meta-analysis of 12 trials, 198 participants; small benefit on strength and power (SMD 0.20), mixing citrulline and citrulline malate. Wang et al. (Nutrients, 2026; PMID 42356270): three-level meta-analysis of 30 trials of citrulline malate; small overall performance effect (g 0.16), GRADE low to very low; a different form. Grade C: small and inconsistent blood pressure effects on a surrogate; performance not supported for free L-citrulline.
PMID 30788274 PMID 30284051 PMID 28940638 PMID 36079738 PMID 37155582 PMID 30895562 PMID 42356270
Evidence by specific use
Blood pressure in adults
Grade C
Pooled analyses disagree. Barkhidarian et al. (Avicenna J Phytomed, 2019; PMID 30788274): small trials, 3 to 9 g/day; systolic pressure 4.10 mmHg lower (95% CI -7.94 to -0.26), diastolic not significant overall and lower only at 6 g/day or more. Mirenayat et al. (Curr Hypertens Rep, 2018; PMID 30284051): five trials; no effect on brachial systolic (0.28 mmHg) or diastolic pressure, or on aortic pressure. One borderline positive pooling and one null pooling of small trials: C.
PMID 30788274 PMID 30284051
Aerobic and endurance exercise performance, free L-citrulline
Grade D
Viribay et al. (Nutrients, 2022; PMID 36079738): meta-analysis of 10 trials; no effect on aerobic performance, perceived exertion, VO2 kinetics or lactate. Harnden et al. (J Int Soc Sports Nutr, 2023; PMID 37155582): meta-analysis of 9 trials in young healthy adults; no effect on time to exhaustion or time to completion. Two pooled nulls: D on Route 2. The small strength and power effects in Trexler et al. (Sports Med, 2019; PMID 30895562) and Wang et al. (Nutrients, 2026; PMID 42356270) rest largely or entirely on citrulline malate, a different form, and do not grade free L-citrulline.
PMID 36079738 PMID 37155582 PMID 30895562 PMID 42356270
Why Grade C and not Grade B
Grade C reflects early or limited human evidence -- small trials, surrogate endpoints, or preliminary findings not yet independently replicated. The evidence points in a promising direction but does not yet meet the standard for Grade B. A single well-powered, independently replicated trial with a meaningful endpoint would move this to Grade B or higher.
What this grade covers and what it does not
Grade C, the record's best use: blood pressure, where two pooled analyses of small randomized trials disagree, Barkhidarian et al. (Avicenna J Phytomed, 2019; PMID 30788274) finding systolic pressure 4.1 mmHg lower with a confidence interval that nearly touches zero and Mirenayat et al. (Curr Hypertens Rep, 2018; PMID 30284051) finding no effect on brachial or aortic pressure. A borderline positive pooling beside a null one is mixed randomized evidence on a surrogate: C. THE PERFORMANCE USE CARRIES D ON ROUTE 2, because two pooled analyses of free L-citrulline found no effect on aerobic or endurance performance (Viribay et al., 2022; PMID 36079738; Harnden et al., 2023; PMID 37155582). The small strength and power effects reported in pooled analyses that mix in citrulline malate (Trexler et al., 2019; PMID 30895562; Wang et al., 2026; PMID 42356270) belong to a different form. The record was divided into two uses in October 2026 by the written rule. WHAT THIS GRADE DOES NOT COVER: citrulline malate, a different form with its own literature; blood flow during exercise, where one crossover study (Gonzales et al., 2017; PMID 28940638) found a sex-specific signal that did not survive adjustment; and erectile function or any clinical outcome, where no trial on this record applies.
What would move this grade
A well-powered randomized trial with an objective, clinically meaningful primary endpoint and at least one independent replication would support Grade B or higher.
How to track whether this is working
Systolic and diastolic blood pressure at baseline and 8 weeks for cardiovascular applications. For exercise performance, measure peak power output or time-to-exhaustion at baseline and 4 weeks. Blood pressure response is the most practical clinical endpoint given the nitric oxide mechanism.