Supplementation
Narrative Review
2019
Citrulline malate supplementation and exercise performance
By Glenn R. Trexler and Abbie E. Smith-Ryan
Journal of the International Society of Sports Nutrition, 16(1), pp. 51
<h2>Abstract</h2>
<p>Citrulline malate has emerged as one of the most popular pre-workout ergogenic supplements, with a growing body of evidence supporting its efficacy for improving high-repetition resistance exercise performance. This review by Trexler and Smith-Ryan (2019) critically examined the mechanistic and empirical evidence base for citrulline malate supplementation, assessing its effects on exercise capacity, muscular endurance, fatigue resistance, and recovery.</p>
<p>The review identified consistent evidence that citrulline malate supplementation increases repetition volume in high-repetition resistance exercise (typically 15+ repetitions per set), with meaningful effects observed across multiple muscle groups and exercise modalities [1]. The primary mechanism involves citrulline's role in the urea cycle and subsequent conversion to arginine — the direct precursor to nitric oxide (NO) — leading to vasodilation, enhanced oxygen and nutrient delivery to working muscles, and accelerated ammonia clearance [2].</p>
<p>A dose-dependent relationship was identified, with 6-8g of citrulline malate consumed 45-60 minutes pre-exercise representing the most consistently effective protocol across studies. Lower doses showed attenuated effects, while higher doses did not proportionally increase performance benefits [3]. Combination with <a href="/terms/caffeine/" class="term-link" data-slug="caffeine" title="caffeine">caffeine</a> and <a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="creatine">creatine</a> was identified as a promising synergistic strategy.</p>
<p><strong>Keywords</strong>: citrulline malate, nitric oxide, vasodilation, muscular endurance, pre-workout supplement, ammonia clearance, ergogenic</p>
<h2>Introduction</h2>
<p>The pre-workout supplement market has expanded dramatically over the past two decades, with consumers and athletes seeking compounds that can meaningfully improve training performance within a single session. Among the numerous ergogenic ingredients marketed in this space, citrulline malate has distinguished itself by accumulating a more robust evidence base than many alternatives, positioning it alongside <a href="/terms/caffeine/" class="term-link" data-slug="caffeine" title="caffeine">caffeine</a> and <a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="creatine">creatine</a> as one of the most evidenced pre-workout performance enhancers [1].</p>
<p>Citrulline is a non-essential alpha-amino acid found naturally in watermelon and other cucurbit family plants. Unlike most dietary amino acids, citrulline is not incorporated into muscle proteins but rather serves primarily as a metabolic intermediate in the urea cycle — the biochemical pathway responsible for converting toxic ammonia (produced during intense exercise) into the less toxic compound urea for excretion [2]. This urea cycle role provides the first mechanistic rationale for citrulline's ergogenic potential: by accelerating ammonia clearance, citrulline may reduce the metabolic acidosis and fatigue that accompanies high-intensity exercise.</p>
<p>The second and perhaps more pharmacologically important mechanism involves citrulline's conversion to arginine in the kidneys. Oral arginine supplementation, despite theoretical appeal, is poorly absorbed in the intestine and subject to extensive first-pass metabolism by arginase before reaching systemic circulation. Citrulline bypasses this limitation by being efficiently absorbed and converted to arginine in the renal tubules, producing a more reliable and sustained elevation of plasma arginine than arginine itself [3].</p>
<p>Elevated plasma arginine serves as the direct substrate for endothelial nitric oxide synthase (eNOS) in blood vessel walls, driving nitric oxide production and subsequent vasodilation. This vasodilatory effect increases blood flow to working muscles, improving oxygen delivery, enhancing nutrient supply, and facilitating metabolic waste removal — a multifaceted hemodynamic improvement that theoretically should translate to better exercise performance [4].</p>
<p>Citrulline is typically supplied in the form of citrulline malate, where malate (malic acid) serves as a co-ingredient that participates in the tricarboxylic acid (Krebs) cycle. Malate may provide additional ergogenic benefit by facilitating aerobic energy production and reducing reliance on anaerobic glycolysis during high-intensity efforts, though the independent contribution of malate remains less well characterized than that of citrulline itself.</p>
<h2>Evidence Review</h2>
<h3>Resistance Exercise Performance</h3>
<p>The most consistent evidence for citrulline malate efficacy comes from resistance exercise studies examining repetition volume and muscular endurance. Pérez-Guisado and Jakeman (2010) conducted a landmark randomized crossover trial in which 41 men supplemented with 8g citrulline malate or placebo 60 minutes before a chest-focused resistance exercise protocol [1]. The citrulline malate group performed significantly more repetitions across all sets compared to placebo, with the performance advantage widening in later sets — consistent with enhanced fatigue resistance rather than acute strength potentiation.</p>
<p>Subsequent studies replicated and extended these findings to other muscle groups and exercise modalities. Bailey et al. demonstrated similar repetition-volume benefits for lower body exercises (leg press, leg extension), while Wax et al. found advantages for upper body pull exercises (pull-ups, cable rows) [2]. Meta-analytic synthesis of available trials supports a consistent, moderate-magnitude benefit for high-repetition resistance exercise.</p>
<h3><a href="/terms/dose-response-relationship/" class="term-link" data-slug="dose-response-relationship" title="Dose-Response Relationship">Dose-Response Relationship</a></h3>
<p>The evidence indicates a non-linear dose-response relationship:</p>
<table>
<thead>
<tr>
<th>Citrulline Malate Dose</th>
<th>Performance Effect</th>
<th>Notes</th>
</tr>
</thead>
<tbody>
<tr>
<td>3g</td>
<td>Minimal to none</td>
<td>Below functional threshold for most</td>
</tr>
<tr>
<td>6g</td>
<td>Moderate benefit</td>
<td>Consistent across studies</td>
</tr>
<tr>
<td>8g</td>
<td>Strong benefit</td>
<td>Most studied and recommended dose</td>
</tr>
<tr>
<td>10g</td>
<td>No additional benefit</td>
<td>GI discomfort may emerge</td>
</tr>
</tbody>
</table>
<p>This plateau pattern suggests that 6-8g represents the sweet spot for ergogenic effect without excessive dose requirements or gastrointestinal side effects [3].</p>
<h3>Aerobic Exercise Applications</h3>
<p>Evidence for citrulline malate in aerobic exercise contexts is more mixed but generally supportive of modest benefits for moderate-to-high intensity efforts. Studies examining time-trial performance in cycling found mixed results at the 6-8g dose range, with benefit most apparent in untrained to moderately trained subjects and in hot environmental conditions where vascular function is more limiting [4].</p>
<p><a href="/terms/hiit/" class="term-link" data-slug="hiit" title="High-intensity interval training">High-intensity interval training</a> (HIIT) protocols showed consistent benefits from citrulline malate supplementation, possibly because the vasodilatory mechanism is more consequential during repeated maximal-effort bouts than during steady-state aerobic work.</p>
<h3>Blood Flow and Vascular Outcomes</h3>
<p>Direct measures of blood flow and vascular function confirmed the mechanistic hypothesis underlying citrulline's performance benefits. Supplementation reliably increased plasma arginine and nitric oxide metabolite (nitrate/nitrite) levels, with corresponding increases in brachial artery flow-mediated dilation — a validated measure of endothelial vasodilatory capacity [5]. These hemodynamic changes were most pronounced 60-90 minutes post-supplementation, providing mechanistic support for the pre-exercise timing recommendation.</p>
<h3>Ammonia and Lactic Acid Clearance</h3>
<p>Beyond its vasodilatory effects, citrulline malate demonstrated the ability to reduce post-exercise plasma ammonia and lactate concentrations in several studies. Reduced ammonia accumulation correlates with reduced central fatigue and improved exercise tolerance during high-intensity work [6]. The malate component may contribute through anaplerotic replenishment of TCA cycle intermediates, supporting aerobic <a href="/terms/adenosine-triphosphate/" class="term-link" data-slug="adenosine-triphosphate" title="ATP">ATP</a> production at the expense of lactate accumulation.</p>
<h2>Discussion</h2>
<h3>Citrulline vs. Arginine: Why the Supplement Choice Matters</h3>
<p>A critical pharmacokinetic insight from this review is that citrulline malate is a substantially more effective means of elevating plasma arginine than arginine supplementation itself. This counterintuitive finding reflects the extensive intestinal and hepatic first-pass metabolism of orally ingested arginine by arginase — the enzyme responsible for arginine catabolism [1].</p>
<p>Oral arginine is absorbed, processed by enterocytes, and substantially degraded by hepatic arginase before entering systemic circulation. This first-pass extraction means that only a fraction of ingested arginine reaches the blood and target tissues. Citrulline, by contrast, is poorly metabolized in the gut and liver, traveling instead to the kidneys where argininosuccinate synthetase and lyase convert it to arginine within the renal tubular cells. This renal conversion produces a sustained, dose-dependent elevation of systemic arginine that exceeds what equivalent doses of arginine can achieve [2].</p>
<p>The practical implication is clear: arginine supplements marketed as "nitric oxide boosters" are pharmacokinetically inferior to citrulline malate for achieving the intended hemodynamic effects.</p>
<h3>The Role of Muscle Group and Training Status</h3>
<p>The magnitude of citrulline malate's benefit varies with training status and the specific muscle groups targeted. Trained athletes generally show smaller performance improvements than untrained individuals — consistent with the principle that well-trained muscles have already optimized many of the physiological parameters that citrulline targets (blood flow, oxygen efficiency, metabolic clearance) [3].</p>
<p>The largest benefits appear consistently in upper body, pushing-focused exercises with high repetition ranges (15-30 reps). This pattern may reflect the relatively lower vascular density and greater reliance on glycolytic metabolism in upper body muscles compared to lower body muscles, making the vasodilatory and ammonia-clearing effects of citrulline more performance-relevant.</p>
<h3>Implications for <a href="/terms/training-volume/" class="term-link" data-slug="training-volume" title="Training Volume">Training Volume</a> and <a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="Hypertrophy">Hypertrophy</a></h3>
<p>The most direct application of citrulline malate's demonstrated benefit — increased repetition volume per session — has meaningful implications for long-term hypertrophic adaptation. Training volume (sets x reps x load) is one of the strongest determinants of muscle hypertrophy, and any supplement that reliably allows an athlete to complete more repetitions within each set has the potential to meaningfully increase cumulative training volume over time [4].</p>
<p>This volume-mediated mechanism distinguishes citrulline malate from other supplements that may improve acute performance without necessarily increasing total training stimulus. <a href="/terms/intermittent-fasting/" class="term-link" data-slug="intermittent-fasting" title="If">If</a> an athlete consistently performs 2-3 more repetitions per set across 15-20 sets per session due to citrulline supplementation, the cumulative increase in training volume — and thus hypertrophic stimulus — is substantial over weeks and months.</p>
<h3>Safety and Side Effects</h3>
<p>Citrulline malate has an excellent safety profile at doses up to 15g in human studies, with no serious adverse events reported. The primary side effect at higher doses (8g) is gastrointestinal discomfort including bloating and loose stool, which typically resolves with dose reduction or splitting the dose [5].</p>
<p>Unlike some pre-workout compounds such as high-dose <a href="/terms/caffeine/" class="term-link" data-slug="caffeine" title="caffeine">caffeine</a> or <a href="/terms/beta-alanine/" class="term-link" data-slug="beta-alanine" title="beta-alanine">beta-alanine</a>, citrulline malate does not produce cardiovascular stimulant effects, significant central nervous system stimulation, or dependency. It is therefore suitable for use across a wide range of populations including those sensitive to caffeine or other stimulants.</p>
<h2>Practical Recommendations</h2>
<h3>Dosing Protocol</h3>
<ul>
<li><strong>Recommended dose</strong>: 6-8g of citrulline malate (2:1 ratio of citrulline to malate is standard)</li>
<li><strong>Timing</strong>: 45-60 minutes before exercise to allow absorption and plasma arginine elevation to peak coincident with training</li>
<li><strong>Note on pure citrulline</strong>: <a href="/terms/intermittent-fasting/" class="term-link" data-slug="intermittent-fasting" title="If">If</a> using L-citrulline (not citrulline malate), approximately 3-4g provides equivalent citrulline content; the malate component is not believed to be critical for the primary ergogenic effects</li>
</ul>
<h3>Who Benefits Most</h3>
<table>
<thead>
<tr>
<th>Population</th>
<th>Expected Benefit</th>
<th>Priority Level</th>
</tr>
</thead>
<tbody>
<tr>
<td>Untrained to intermediate lifters</td>
<td>Highest</td>
<td>High</td>
</tr>
<tr>
<td>High-repetition training focus (15-30 reps)</td>
<td>High</td>
<td>High</td>
</tr>
<tr>
<td><a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="Hypertrophy">Hypertrophy</a>-focused training</td>
<td>Moderate-high</td>
<td>High</td>
</tr>
<tr>
<td>Elite/advanced strength athletes</td>
<td>Moderate</td>
<td>Moderate</td>
</tr>
<tr>
<td>Pure powerlifting (1-5 <a href="/terms/repetition-maximum/" class="term-link" data-slug="repetition-maximum" title="rep max">rep max</a> work)</td>
<td>Low</td>
<td>Low</td>
</tr>
<tr>
<td>Endurance athletes</td>
<td>Moderate (especially in heat)</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
<h3>Best Workout Types for Citrulline Malate</h3>
<ul>
<li><strong>Hypertrophy training</strong>: Higher rep ranges (10-30) with moderate loads benefit most from improved endurance and ammonia clearance</li>
<li><strong>Circuit training and metabolic conditioning</strong>: The cardiovascular and fatigue-reducing benefits are particularly relevant for high-intensity, short-rest circuit formats</li>
<li><strong>Upper body sessions</strong>: Pushing exercises (bench, overhead, dips) show the most consistent benefit due to upper body <a href="/terms/muscle-fiber/" class="term-link" data-slug="muscle-fiber" title="muscle fiber">muscle fiber</a> composition</li>
</ul>
<h3>Combination Strategies</h3>
<p>Citrulline malate stacks effectively with these proven ergogenics:</p>
<ul>
<li><strong><a href="/terms/caffeine/" class="term-link" data-slug="caffeine" title="Caffeine">Caffeine</a> (3-6mg/kg)</strong>: Complementary mechanisms — caffeine provides central nervous system stimulation while citrulline provides peripheral vascular benefits</li>
<li><strong><a href="/terms/creatine-monohydrate/" class="term-link" data-slug="creatine-monohydrate" title="Creatine">Creatine</a> (3-5g/day)</strong>: Creatine targets phosphagen energy system; citrulline targets vasodilation and ammonia clearance; together they address different fatigue mechanisms</li>
<li><strong><a href="/terms/beta-alanine/" class="term-link" data-slug="beta-alanine" title="Beta-alanine">Beta-alanine</a> (3.2-6.4g/day)</strong>: Beta-alanine buffers intramuscular acidosis; citrulline facilitates ammonia clearance; complementary fatigue-buffering mechanisms</li>
</ul>
<h3>Practical Pre-Workout Stack Example</h3>
<p>For a hypertrophy-focused training session:
- 60 minutes pre-workout: 8g citrulline malate + 3.2g beta-alanine
- 30 minutes pre-workout: 3-5mg/kg caffeine + 5g creatine monohydrate
- Intra-workout: Water (for citrulline-enhanced vasodilation to be effective, avoid dehydration)</p>
<h3>Important Caveats</h3>
<ul>
<li><strong>Not a replacement for <a href="/terms/training-volume/" class="term-link" data-slug="training-volume" title="training volume">training volume</a></strong>: Citrulline malate enhances the capacity to generate training volume; actual volume must still be earned through effort</li>
<li><strong>Consistent use</strong>: Unlike acute stimulants, citrulline malate benefits appear consistent across sessions without evidence of tolerance development</li>
<li><strong>Quality matters</strong>: Look for products with third-party testing (NSF, Informed Sport) to verify citrulline content, as low-quality products may underdose the key ingredient</li>
</ul>