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BHuman cohort / observational

Citrulline Malate

L-Citrulline

Citrulline malate is a dietary supplement pairing the non-essential amino acid L-citrulline with malic acid, marketed to lifters and endurance athletes as a "pump"/ergogenic aid. L-citrulline is a food-derived amino acid (notably from watermelon) that raises plasma arginine and nitric-oxide precursor availability more effectively than oral arginine itself. It is one of the more benign compounds in this reference set: human loading studies up to 15 g report no serious toxicity and it is generally well tolerated, with the main complaint being mild gastrointestinal discomfort at higher single doses. The main cautions are not organ toxicity but rather: (1) its blood-pressure-lowering effect can stack with antihypertensives, nitrates, PDE5 inhibitors (e.g. sildenafil), and other vasodilators to cause hypotension; (2) the performance evidence is genuinely mixed — a single-dose resistance study is positive, but multiple meta-analyses find no meaningful effect on endurance/aerobic performance; and (3) supplement products are unregulated and may be mislabeled or adulterated. It is not a hormone, is not hepatotoxic, and has no known effect on the hypothalamic-pituitary-gonadal axis.

Clinical readoutAncillary · ergogenic
Hepatic strainLow
CardiovascularLow
HPTA suppressionNone
Half-life
1 h
Route
Oral
Evidence
B
Active
Plasma arginine/ornithi…
1 h2 h3 h4 h5 h
Illustrative single-compartment washout · each mark = one half-life · t½ ≈ Short. Intravenous citrulline pharmacokinetic study in children estimated an elimination half-life of ~60 minutes (clearance ~0.6 L/h/kg, volume of distribution ~0.9 L/kg) (Barr 2007). Oral plasma half-life is not precisely defined in adults but is similarly short.
Pharmacology

Mechanism of action

L-citrulline is absorbed and largely bypasses hepatic first-pass metabolism, then is converted in the kidney to L-arginine, raising systemic arginine more efficiently (roughly twice as potently) than an equivalent oral arginine dose. Increased arginine substrate can support endothelial nitric oxide synthase (eNOS)-mediated nitric oxide production and vasodilation, though the "L-arginine paradox" means plasma arginine already exceeds eNOS Km, so the mechanism is incompletely understood. Citrulline also participates in the urea cycle and may enhance ammonia handling. Malate is a tricarboxylic-acid-cycle intermediate proposed (mechanistically, not proven in humans) to aid aerobic ATP production; the malate contribution to any ergogenic effect is not separately established. Reported outcomes (blood pressure reduction, endothelial function, possible reduction in muscle soreness) are attributed primarily to the citrulline-to-arginine-to-nitric-oxide pathway.
Kinetics

Pharmacokinetics

Half-life

Short. Intravenous citrulline pharmacokinetic study in children estimated an elimination half-life of ~60 minutes (clearance ~0.6 L/h/kg, volume of distribution ~0.9 L/kg) (Barr 2007). Oral plasma half-life is not precisely defined in adults but is similarly short.

Active duration

Plasma arginine/ornithine rise within ~1-2 h of an oral dose and return toward baseline over several hours; a single dose is a transient, hours-long exposure. For monitoring/washout purposes, systemic effect is effectively cleared within roughly a day.

Route

Oral (powder/capsule). Intravenous citrulline exists only in clinical research settings, not consumer use.

Metabolism & clearance

Absorbed intestinally with minimal hepatic first-pass metabolism; converted to arginine primarily in the kidney. Urinary excretion of unchanged citrulline is low (<5% even at high oral doses); at high doses (e.g., 15 g) citrulline accumulates in plasma while the arginine rise plateaus, consistent with saturation of renal citrulline-to-arginine conversion (Moinard 2007). Not known to require dose adjustment beyond caution in renal impairment (see contraindications).

For monitoring and washout planning, not drug-test evasion.

Reported effects

Physiological & performance effects

  • Single 8 g citrulline malate dose before resistance exercise increased bench-press repetitions to fatigue (significant from the 3rd set, ~52.9% more reps in the final set) and reduced self-reported muscle soreness at 24 and 48 h by ~40% in one randomized crossover trial (Perez-Guisado 2010).
  • No ergogenic benefit on high-intensity cycling sprint or time-to-exhaustion performance from a single 12 g dose in well-trained men (Cunniffe 2016).
  • Meta-analyses find no significant benefit of citrulline supplementation on endurance/aerobic performance (time-to-exhaustion, time-to-completion, VO2 kinetics, RPE, lactate) (Harnden 2023; Viribay 2022; d'Unienville 2021).
  • Combined with structured exercise, citrulline supplementation was associated with modest improvements in 6-minute walk distance and lower-limb strength in overweight older adults (small meta-analysis; Xie 2023).
  • Raises plasma arginine and ornithine more effectively than oral arginine (Moinard 2007; Khalaf 2019).
  • Lowers blood pressure modestly and improves endothelial (flow-mediated dilation) function in some populations, e.g., a 4-week 10 g/day trial in hypertensive postmenopausal women reduced aortic diastolic BP and mean arterial pressure and improved FMD (Maharaj 2022); review estimates oral citrulline BP reduction on the order of ~4/2 to ~7.5/3.8 mmHg (Khalaf 2019).
Safety

Adverse effects by system

Cardiovascular

Blood-pressure lowering is an expected pharmacologic effect, not a toxicity, but can become adverse (symptomatic hypotension) when combined with antihypertensives, nitrates, PDE5 inhibitors, or other vasodilators. One cycling study noted higher exercise heart rate on citrulline malate versus placebo (Cunniffe 2016). No evidence of structural cardiotoxicity.

Hepatic

No evidence of hepatotoxicity. Citrulline is minimally metabolized by the liver (low first-pass) and is a normal endogenous amino acid; no signal of liver injury in human loading studies up to 15 g (Moinard 2007). No adequate long-term human liver-outcome data.

Endocrine / HPTA

No known effect on the hypothalamic-pituitary-gonadal axis. In a controlled loading study, citrulline did not significantly change plasma insulin or growth hormone (Moinard 2007). It is not a hormone or SERM and does not suppress or stimulate endogenous testosterone.

Reproductive

No adequate human data on fertility, pregnancy, or lactation outcomes; not studied for reproductive safety, so use is not advised in pregnancy/breastfeeding by default.

Neuropsychiatric

No known neuropsychiatric adverse effects reported in human trials. No adequate data on mood or cognition specific to citrulline.

Renal

Cleared and converted to arginine in the kidney; urinary citrulline excretion remains low and at high doses renal conversion saturates (Moinard 2007). No nephrotoxicity demonstrated in healthy subjects, but caution is warranted in renal impairment because the kidney is the primary conversion site and data in kidney disease are lacking.

Hematologic

No known hematologic toxicity. Citrulline malate raised plasma glutamine and ornithine without reported hematologic abnormalities (Cunniffe 2016; Moinard 2007). Because of nitric-oxide/vasodilatory activity, theoretical additive effect with other agents affecting bleeding/vascular tone is unquantified — no direct human evidence.

Dermatologic

No known dermatologic adverse effects reported. No adequate data.

Recovery

HPTA suppression & recovery

Suppression: None expected

Citrulline malate is not a hormone, androgen, or SERM and has no established effect on the hypothalamic-pituitary-gonadal axis; controlled dosing did not alter insulin or growth hormone (Moinard 2007), and no HPTA suppression is expected, so post-cycle recovery/SERM considerations do not apply. This monograph does not describe SERM or dual-SERM protocols. Any genuine concern about testosterone or HPTA function should be evaluated with bloodwork and managed by an endocrinologist rather than self-treated.

Bloodwork & vitals

Monitoring

Recommended labs & checks
Baseline and periodic blood pressure (home or clinic), especially if hypertensive or on cardiovascular/vasodilator medicationBasic metabolic panel including renal function (creatinine/eGFR) if there is any kidney disease or concernMedication review with a pharmacist or clinician for interactions with antihypertensives, nitrates, and PDE5 inhibitors

Cadence: Not a high-surveillance compound. Check blood pressure around initiation and if symptoms occur; reassess renal labs only if clinically indicated or if kidney disease is present. Re-evaluate with a clinician if combining with any cardiovascular medication.

Warning signs — seek care
  • Dizziness, lightheadedness, fainting, or unusually low blood pressure (possible additive hypotension)
  • Persistent or severe gastrointestinal discomfort, nausea, or diarrhea
  • Headache or flushing suggestive of excessive vasodilation, particularly if using nitrates or PDE5 inhibitors
  • Any allergic reaction (rash, swelling, difficulty breathing) — stop and seek care
Do not use if

Contraindications

  • Concurrent use of nitrates, PDE5 inhibitors (e.g., sildenafil, tadalafil), or other vasodilators — additive hypotension risk (mechanistic, based on nitric-oxide/BP-lowering activity; Khalaf 2019).
  • Existing hypotension or use of antihypertensive medication without clinician oversight — additive BP reduction (Maharaj 2022; Khalaf 2019).
  • Significant renal impairment — the kidney is the primary site of citrulline-to-arginine conversion and safety data in kidney disease are lacking (Moinard 2007).
  • Pregnancy and breastfeeding — no adequate human safety data.
  • Known hypersensitivity to the product; caution with any unregulated supplement due to possible mislabeling/adulteration.
  • Perioperative period — theoretical additive effect on blood pressure/vascular tone; disclose to anesthesiology and consider stopping before surgery.
Combinations

Interaction profile

  • ContraindicatedWith DNP: Additive cardiovascular strain

Check a specific combination in the interaction checker.

Harm reduction

Reducing harm & when to stop

  • Treat performance claims skeptically: the human evidence is mixed — one resistance study is positive but multiple meta-analyses show no endurance benefit, so do not assume efficacy.
  • If you take antihypertensives, nitrates, or PDE5 inhibitors (e.g., sildenafil/tadalafil), talk to a clinician or pharmacist before use because blood-pressure-lowering effects can stack and cause hypotension.
  • Start with a lower amount to assess GI tolerance; mild stomach discomfort is the most commonly reported effect at larger single doses.
  • Stop and seek medical care for dizziness, fainting, severe or persistent GI symptoms, or any allergic reaction.
  • Because supplements are unregulated, choose third-party-tested products to reduce risk of mislabeling or adulteration, and disclose all supplements to your clinician (including before surgery).
  • Avoid in pregnancy and breastfeeding, and use caution with kidney disease, due to lack of safety data.
  • This is general harm-reduction information, not medical advice or a recommendation to use; individualized decisions should involve a qualified clinician.
Evidence

Citations (10)

Every clinical claim above is tied to a primary source. Overall evidence grade B — graded to the best available evidence for its core claims.

  1. 01

    Single 8 g citrulline malate dose increased bench-press repetitions to fatigue (significant from set 3, ~52.9% more reps in final set) and reduced muscle soreness at 24/48 h by ~40%; ~14.6% of subjects reported stomach discomfort.

    RCTPMID 20386132 ↗

  2. 02

    A single 12 g citrulline malate dose produced no ergogenic benefit on high-intensity cycling sprint/time-to-exhaustion performance in well-trained men; no GI side effects; higher exercise heart rate observed.

    RCTPMID 26808848 ↗

  3. 03

    Meta-analysis found no significant benefit of acute citrulline supplementation on endurance performance (time-to-exhaustion, time-to-completion).

    Meta-analysisPMID 37155582 ↗

  4. 04

    Meta-analysis found no significant effect of citrulline supplementation on aerobic exercise performance, RPE, VO2 kinetics, or lactate.

    Meta-analysisPMID 36079738 ↗

  5. 05

    Meta-analysis of nitric-oxide-related foods found no effect of L-citrulline-rich food consumption on endurance performance.

    Meta-analysisPMID 34965876 ↗

  6. 06

    Combined exercise with citrulline supplementation modestly improved 6-minute walk distance and lower-limb strength in overweight older adults.

    Meta-analysisPMID 37711701 ↗

  7. 07

    Oral L-citrulline raises plasma arginine more effectively (~twice as potent) than oral arginine due to lower first-pass metabolism, and lowers blood pressure by roughly 4/2 to 7.5/3.8 mmHg; additive hypotension mechanism with vasodilators.

    ReviewPMID 31336573 ↗

  8. 08

    Four weeks of 10 g/day L-citrulline improved flow-mediated dilation and reduced aortic diastolic BP and mean arterial pressure in hypertensive postmenopausal women.

    RCTPMID 36297080 ↗

  9. 09

    Oral citrulline loading up to 15 g was safe and well tolerated with no side effects; raised plasma citrulline/ornithine/arginine; urinary citrulline excretion <5%; renal conversion saturates at high doses; no change in insulin or growth hormone.

    RCTPMID 17953788 ↗

  10. 10

    Intravenous citrulline pharmacokinetics: elimination half-life ~60 minutes, clearance ~0.6 L/h/kg, volume of distribution ~0.9 L/kg; safe and well tolerated in children.

    CohortPMID 17662768 ↗

Last reviewed 2026-07-06 · Verified against PubMed · Educational, not medical advice