According to the European Society for Sexual Medicine in Hamburg, Germany, about 30–40% of erectile dysfunction (ED) patients are non-responders to phosphodiesterase type-5 (PDE-5) inhibitor monotherapy.1 That means that single ED drugs such as sildenafil (Viagra®), tadalafil (Cialis®), vardenafil (Levitra®), lodenafil (Helleva®), and udenafil (Zydena®) do not work for as many as 2 out of 5 users overall. And failure may be higher for particular PDE-5 inhibitors. Is there any hope for those who do not respond, or for those who, because of actual or believed side effects, choose not to go the drug route?

In a new study published in Urology, researchers set out to test the efficacy and safety of oral citrulline supplementation in improving erection hardness in patients with mild ED.2 Penile erection hardness has been determined to be one of the key factors for successful sexual intercourse, as well as an important index in the diagnosis and treatment of ED.

A Matter of EDucation

It has been known for some time that arginine supplementation enhances the production of nitric oxide (NO), which in turn mediates vasodilation and endothelial function. In fact, a Nobel Prize was given for this and other discoveries about NO. Yet oral administration of arginine is hampered by extensive presystemic metabolism, which tends to eliminate it due to intestinal arginase activity. While citrulline is a semiessential amino acid that’s not found in the diet, it is synthesized in the body via a mechanism called the urea cycle. In this metabolic pathway, arginine is catalyzed by the enzyme arginase to urea and ornithine. Then, ornithine is converted to citrulline, which is converted to argininosuccinate, which is converted to arginine, and that completes the cycle. However, there are at least six different metabolic pathways that arginine can take.

The NO Pathway

One of these is a pathway that produces NO, and in that reaction, arginine is again converted to citrulline but by an entirely different mechanism that does not involve ornithine. Once citrulline is produced by anymechanism, it has only one place to go, metabolically speaking, and that’s back to arginine.

Thus, citrulline appears to escape any significant level of presystemic metabolism, and oral supplementation with citrulline consequently behaves directly as a donor for the arginine/NO pathway which leads to penile erection.

Erection: Trapping Blood within the Penis

NO acts both as a neurotransmitter in penile nerve fibers and as a vasodilator of smooth muscle cells of the penile arteries, as well as blood sinusoids, and the trabeculae, the internal surface of the fibrous envelope of the corpus cavernosum. The corpus cavernosum is one of a pair of sponge-like regions of erectile tissue which contains most of the blood in the penis during penile erection.

NO is essential to penile erection because it creates cyclic guanosine monophosphate(cGMP), a cyclic nucleotide which acts as a second messenger causing penile smooth muscle relaxation. Erection occurs when the small blood vessels known as sinusoids are engorged with blood, thereby compressing the emissary veins to closure, and thus trapping blood within the penis. The erection eventually subsides when cGMP has been hydrolyzed to inactive GMP by PDE-5.

PDE-5 inhibitors such as sildenafil, which increase penile smooth muscle relaxation by preventing cGMP hydrolysis, are drugs which are generally safe and effective oral treatments for ED. However, their cost, contraindications, and the fear of side effects have limited their use. Nutrients acting as NO donors would therefore represent an attractive alternative to the use of PDE-5 inhibitors.

The Limitations of Arginine, Given by Itself

The NO donor arginine is a semiessential amino acid present in dietary proteins and produced in the body from citrulline, another semiessential amino acid. As mentioned previously, citrulline is synthesized in the intestinal tract from glutamine. NO synthase isoforms convert arginine to NO, which activates the cGMP pathway. Then citrulline, which can be reconverted by the kidneys into arginine, restarts a NO-producing cycle. Thus, arginine causes in vitro relaxation of isolated corpus cavernosum tissue.

In a double-blind placebo-controlled study testing arginine versus placebo in 50 men with ED, subjective improvement was reported by 31% of men taking arginine (as L-arginine) at 5 g/day and 12% of men taking placebo.3 No side effects were reported. However, high oral administration of arginine in doses exceeding 30 g/day has been known to produce minor side effects, such as nausea and diarrhea, owing to intestinal and hepatic conversion of arginine to ornithine and urea.

Citrulline escapes significant levels of 
presystemic metabolism, and thus oral 
supplementation with citrulline 
behaves directly as a donor for the 
arginine/NO pathway which 
leads to penile erection.

On the other hand, citrulline escapes intestinal or liver metabolism, enters the kidneys, and is rapidly converted into arginine. Moreover, it has recently been shown that oral citrulline supplementation increases the plasma arginine concentration and augments NO-dependent signaling in a dose-dependent manner.4 This provides the rationale for using oral citrulline supplementation as a donor for the arginine/NO pathway in those with ED. The present Urology placebo-controlled pilot trial aimed to determine whether oral citrulline supplementation improved erection hardness in patients with mild ED.

The Benefits of Citrulline, Given by Itself

In the Urology study, 24 men with mild ED (erection hardness score of 3) received a placebo for 1 month, followed by citrulline, at 1.5 g/day split into two doses, for another month. With a mean age of 56.5 ± 9.8 years, the men in the study reported no adverse events. The researchers chose to concentrate on subjects reporting a mild to moderate reduction of penile rigidity, yet who were still able to achieve vaginal penetration but not satisfactory penetration and/or completion of successful intercourse. This situation has been well depicted by an erection hardness score (EHS) of 3. Consequently, the inclusion criteria were an EHS of 3 at the time of the screening and the enrollment visit, a stable heterosexual relationship, and an interest in improving sexual function by entering the study protocol and adhering to the scheduled follow-up visits.

The exclusion criteria were severe cardiovascular disease, recent cerebrovascular accidents, renal or hepatic insufficiency, psychiatric or severe neurologic disorders, untreated endocrine disease, previous radical prostatectomy, significant penile deformity, and previous or current treatment of ED. Just so you don’t imagine that the patients were mistreated or subject to some kind of unethical treatment (just joking), the study was performed in accordance with the standards of Helsinki Declaration. That also includes compliance with the local ethical committee which approved the study. Furthermore, all patients provided written informed consent. At the end of the study, the erection hardness score, number of intercourses per month, treatment satisfaction, and adverse events were recorded.

Completely Hard and Fully Rigid

The improvement in the EHS from 3 (mild ED) to 4 (normal erectile function) occurred in 2 (8.3%) of the 24 men when taking placebo during the first half of the study. But when the subjects were switched to citrulline, 12 (50%) of the 24 men reported achieving an EHS of 4. An EHS of 3 is considered “hard enough for penetration but not completely hard,” while an EHS 4 is “completely hard and fully rigid.” Citrulline increased hardness by 50%.

At the same time, the mean number of intercourses per month increased from 1.37 at baseline to 1.53 at the end of the placebo phase (about 12% greater frequency) and 2.3 at the end of the treatment phase (about a 68% increase) for citrulline. Citrulline increases successful intercourse connects by 56% more than placebo, and here’s an important factor: All patients reporting an EHS improvement from 3 to 4 reported being very satisfied.

Nutrients acting as NO donors 
therefore represent an attractive 
alternative to the use of 
PDE-5 inhibitors.

Although less effective than PDE-5 enzyme inhibitors, at least in the short term (few truly long-term studies have been done), citrulline supplementation has been proved to be safe and psychologically well accepted by patients. Its role as an alternative treatment for mild to moderate ED, particularly in patients who are psychologically afraid of the drugs, deserves further research.

At the month 2 visit, the researchers informed the patients were informed they had received a commercially available nutrient and given the possibility to continue it, if interested, or to receive a prescription for a PDE-5 inhibitor. It is an important finding that all subjects reporting improvement in their EHS elected to continue with citrulline treatment, but the others, reporting no improvement and thus scoring not satisfied, asked for a PDE-5 inhibitor prescription. This was probably because citrulline supplementation had no side effects and was psychologically well accepted, and because it was perceived by patients as a nutrient and not a drug. Moreover, this finding has further confirmed the importance of the EHS as a measure of both treatment efficacy and patient satisfaction.

The Validity of Measuring Erection Hardness Score

It is interesting to note that there are quite a few methods for measuring penile hardness.5 Among these are those for objective indexes, such as Rigiscan, axial buckling test and color Doppler ultrasonography, and those for subjective indexes of ED subjects, such as IIEF, the Erectile Function Domain of IIEF (IIEF-EF), and Erection Hardness Score (EHS), which the Urology study used.

The EHS was developed in 1998 as a simple (one-item) method to quantify erection outcome data. Although it is intuitive that erection hardness and successful sexual intercourse (SSI) are related, the link had not been directly established. To evaluate the relationship between EHS and SSI, in order to establish EHS as a clinically useful tool was undertaken recently at San Diego Sexual Medicine, Alvarado Hospital, University of California, San Diego.6

Estimating the Odds Ratio of Sexual Satisfaction to Hardness

Using 307 subjects, the researchers conducted a multinational, double-blind, placebo-controlled trial (with open-label extension) using the PDE-5 inhibitor sildenafil in men with erectile dysfunction. The study used an event-based model and recorded every intercourse attempt and the EHS to estimate the odds ratio of SSI between adjacent EHS categories.

Nutrients acting as NO donors 
therefore represent an attractive 
alternative to the use of 
PDE-5 inhibitors.

Mean-based modeling recorded EHS per patient to determine its relationship to percentage of SSI. Mediation-based modeling used mean EHS and mean percentage of SSI over the double-blind phase to estimate the direct effect of sildenafil treatment on SSI and the indirect effect of sildenafil treatment on SSI via erection hardness.

Hardness Matters

The odds of SSI for EHS 3 (hard enough for penetration but not completely hard) were 41.9 times that for EHS 2 (hard but not hard enough for penetration). However, the odds of SSI for EHS 4 (completely hard and fully rigid) were 23.7 times that for EHS 3. The percentage of SSI increased approximately curvilinearly with the increase in mean EHS, from almost 60% at EHS 3 to 78.5% at EHS 3.5 and to 93.1% at EHS 4. The indirect effect of sildenafil treatment on SSI via erection hardness accounted for almost 90% of the total effect on SSI. Bringing this finding home, the harder the better for sexual satisfaction, and these findings support the broader use of the EHS, as an easily recognizable, valid, reliable, and responsive measure for clinical practice.

The Benefits of Arginine and Citrulline, Together

Because it is widely found in the diet, arginine at high levels is considered safer than Citrulline at high levels, which is not found in the diet. Life extension researchers Durk Pearson & Sandy Shaw have written about the cardiovascular benefits of using both amino acids, along with antioxidants.

It’s Good to be Hard and Hard to be Good

Let’s remember that the focus of this article is to home in on the use of an easy to take supplement, citrulline, which can match up in many ways and even exceed the benefits of drugs such as the PDE-5 inhibitors. And it can do that by itself, although its power is enhanced when taken along with arginine and other nutrients. And remember: the prosexual benefits are especially likely to be true in those for whom the drugs do not work, for those concerned about side effects, and for those who prefer the natural route to sexual fulfillment. The cardiovascular benefits are available to all.


  1. Porst H. The future of erectile dysfunction (ED). Arch Esp Urol 2010 Oct;63(8):740-7.
  2. Cormio L, De Siati M, Lorusso F, Selvaggio O, Mirabella L, Sanguedolce F, Carrieri G. Oral citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology 2011 Jan;77(1):119-22.
  3. Chen J, Wollman Y, Chernichovsky T, et al. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study. BJU Int1999;83:269-73.
  4. Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol 2008;65:51-9.
  5. Yuan YM, Zhou S, Zhang K. Methods for evaluation of penile erection hardness. Zhonghua Nan Ke Xue 2010 Jul;16(7):642-5.
  6. Goldstein I, Mulhall JP, Bushmakin AG, Cappelleri JC, Hvidsten K, Symonds T. The erection hardness score and its relationship to successful sexual intercourse. J Sex Med 2008 Oct;5(10):2374-80.