Male enhancement, which includes penis enlargement and improvement of penile function during sexual intercourse, is among the most popular internet topics today. The subject gained additional visibility when a U.S. presidential candidate recently felt obliged to defend the size of his during a national debate.
So-called penis “enhancers” fall into one of two categories: synthetic/ pharmaceuticals or natural enhancers. Those in the pharmaceutical category are usually developed and prescribed by doctors to treat the condition known as erectile dysfunction (E.D.), a complaint more common among seniors than younger men. Younger men frequently obtain the identical products online without prescription and use them for “enhancement” purposes, although it’s illegal to do so in the United States. E.D. products include the so-called P.D.E.5 inhibitors which work by inhibiting breakdown of “messenger” nucleotide cGMP. (cGMP signals to relax the vascular smooth muscles inside the penis which cause erection.) Popular P.D.E.5 inhibitors include: sildenafil (Viagra brand name), tadalafil (Cialis brand name), and vardenafil (Levitra brand name). Viagra is a drug which, after a sizable financial investment on the part of its maker Pfizer, failed clinical trials for its originally intended purpose in treating angina caused by reduced blood flow to the heart . Pfizer subsequently marketed Viagra for treating erectile dysfunction after observing that it induced erection in trial subjects.
Legitimate concerns regarding adverse side effects of these drugs, including vision and hearing loss, have caused male consumers to search for safer natural alternatives. Among them are: the herb ginseng, grape seed extract, horny goat weed (epimedium), muira puama (“potency wood” bark extract) and ginko biloba (“silver fruit”). In addition, penile enhancement properties have been reported with supplements containing the non-essential amino acid L-arginine, and its biological precursor citrulline. Non-essential amino acids, you will recall, are those protein “building blocks” which the human body is capable of making itself; therefore, their use as supplements is much less likely to carry adverse side effects than pharmaceutical products. ( In fact, a natural source of citrulline is watermelon, whose flesh contains approximately 250 mg. per cup.!) Moreover, a wide range of additional health benefits are attributed to them, so that it really makes sense to use them in lieu of pharmacy products, provided efficacy claims are valid. Added direct benefits include an increase in both aerobic and anaerobic athletic performance with resulting indirect health benefits.
In our current segment, Spanking FIT examines carefully L-arginine/ citrulline health benefit claims by evaluating the results of available relevant clinical trials; but, first we present the biological theory behind the L-arginine/ citrulline enhancement hypothesis:
How might L-arginine/ citrulline enhance penile size and performance?
In “Role of nitric oxide in the physiology of erection” published in Biological Reproduction, 1995 March 52(3), 485-9, researchers A. Burnett et al. summarize acquired evidence that nitric oxide (NO) gas mediates physiologic penile erection by inducing relaxation of corpus cavernosal smooth muscle leading to engorgement of the penis with blood. The corpus cavernosa are a pair of sponge-like regions of erectile tissue which contain most of the blood in the erect penis.
Since the amino acid L-arginine increases internal nitric oxide production, it is theoretically plausible that dietary supplementation with it may enhance blood flow in the penis with resulting enlargement and functional improvement. Many nutritionists, however, maintain that dietary supplementation with the L-arginine precursor citrulline is more effective at achieving required L-arginine plasma concentration improvements, than supplementation with L-arginine itself. For example, in “Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine, etc.” published in British Journal of Clinical Pharmacology, 2008, 65(1) 51-9, researchers E. Schwedhelm et al. maintain that treatment with L-arginine is “hampered by extensive pre-system elimination due to intestinal arginase activity”. Arginase is an enzyme which breaks arginine down into ornithine (another amino acid) and urea. Citrulline, on the other hand, is more readily absorbed and partially converted to l-arginine in the kidneys. It’s unfortunate that the attempts made by these researchers to experimentally validate their theory suffered from a prevalent problem in biomedical research: the use of inappropriate parametric statistical tests (in this case “t-test for paired data“) with small sample sizes. I realize that most readers are not statisticians, so let me simply state that it is highly advisable to at least try non-parametric tests such as Wilcoxon in the case of small samples. (Parametric tests are less convincing with small samples because they require that assumptions be made regarding the shape of the population data when it is graphically plotted- usually that it is “normal” or “bell shaped”. While it is true that many biological populations appear “normal”, exceptions frequently can and do occur!) The same problem existed with all other studies Spanking FIT reviewed pertaining to the l-arginine/ citrulline hypothesis including: “Oral l-citrulline supplementation enhances cycling time trial performance in healthy trained men, etc.” by T. Suzuki, et al. and which was published in Journal of International Society of Sports Nutrition ,Feb 19, 2016. Consequently, Spanking FIT withholds judgement regarding which is the most desired method of obtaining the heightened plasma arginine levels necessary for satisfactory increases in NO production.
Evidence supporting claim that L-arginine/ citrulline are “male enhancers”
Among the more than fifty studies which Spanking FIT reviewed is “Involvement of L-arginine/ NO pathway at the paraventricular nucleus of hypothalamus in central neural regulation of penile erection, etc.” by K.K. Chen et al. which was published in the International Journal of Impotence Research, 2002, 14, 139-145. It stood out for it scientific precision and clarity.
In it, L-arginine was administered into the paraventricular nucleus of the hypothalamus (P.V.N.) of five adult male rats The P.V.N. is a neuronal nucleus of the hypothalamus. It is believed that L-arginine is converted to nitric oxide synase (NOS) there. NOS is an enzyme that produces NO in the endothelial tissue lining blood vessel walls that is required for penile erection. Researchers collected data on changes in intra-cavernous pressure in rat corpus cavernosum by inserting a 26-gauge needle connected to a pressure transducer. They correctly employed the appropriate non-parametric Wilcoxon signed ranks test in performing data analysis, and reported a statistically significant erection response in the rats treated with l-arginine. Although the researchers are to be commended for using the correct test for small sample size, detailed statistical comparisons between results with l-arginine and other categories, including placebo, were not and could not be made because the samples collected were too small. In other words, results need to be duplicated with more rats.
Human studies which support the L-arginine/citrulline penis improvement theory have made use of subjects who experience “erectile dysfunction” (E.D.). One frequently cited by the supplement supporters is: “Effect of oral administration of high-dose nitric oxide donor L-arginine in men, etc.” by J. Chen et al. which was published in British Journal of Urology International, 1999; 83, 269-273. In it, 50 men diagnosed with organic E.D. were randomly assigned to either l-arginine or a placebo after a two week “run-in” period with only placebo. Organic E.D. causes included those diabetic, arteriogenic, and neurogenic in nature. Treatment consisted of 5 grams per day for six weeks of l-arginine. Each participant kept a written diary for recording sexual performance throughout the study period. Researchers observed that at end of six weeks, 9/ 29 (31%) of the l-arginine treated subjects reported improvement in contrast to only 2/ 17 ( 12%) in the placebo group. The study was double-blinded meaning that neither experimenters nor subjects knew who was receiving the treatment. Although the investigators reported the above as “significant” findings, the fact is that they are not. It is easy to demonstrate with a statistical Fisher exact test that their findings are not statistically significant, meaning that the probability is unacceptably high that the observed differences were due to chance fluctuation only.
Researchers also reported a significant increase in urinary NO levels of approximately 45% in the l-arginine treated subjects . This increase was reported to be even greater (112%) in those men who were treatment “responders” according to sex diary results. (As previously noted, evidence exists that NO plays a critical role in the penile erection process.) Unfortunately, their analysis contained the common previously explained flaw of using parametric statistical methods with the small sample sizes which they collected.
Finally, Spanking FIT uncovered “A randomized, double blind, crossover, placebo-controlled comparative clinical trial of arginine asparate and adenosine monophosphate, etc.” by Y. Neuzillet, et al. and published in Andrology 2013, March,1 (2),m223-8. The study employed 26 men (average age about 56) involved in a “stable” relationship, and who had experienced E.D. for at least three months. E.D. patients appear to include both organic and non-organic cases. As characteristic of a “cross-over”design, subjects were randomized to one of two study arms- either arm A: subjects who received the treatment and then after a two week “washout period” received placebo; or arm B: subjects who received placebo first, and then after same two week washout, received treatment. The purpose of such a cross-over design is (1) to minimize differences in the physical characteristics of subjects who received treatment versus those who do not, and (2) to reduce potential time period effects. In this study, treatment consisted of 8 gms. of L-arginine aspartate combined with 200 mg. of adenosine monophosphate (A.M.P.) taken 1-2 hrs. before intercourse, but not more than once a day. Researchers reported statistically significantly superior results in erectile function, as well as intercourse satisfaction, for the treatment group as measured using the International Index of Erectile Function (I.I.E.F.) questionnaire that was completed before and after treatment by each patient.
From a statistical perspective, this study contained flaws similar to those in previous studies: use of parametric matched pair t-tests in lieu of preferable non-parametric ones such as Wilcoxon. However, researchers redeemed themselves by analyzing both urologist and patient opinion surveys in an appropriate non-parametric manner by using McNemar tests. The results are definitely in favor of the L-arginine treatment.
This particular experiment combined L-arginine with the nucleotide adenosine monophosphate (AMP). (Nucleotides form the basic structural unit of nucleic acids such as DNA.) Their decision to do so was based on research they cited suggesting that adenosine acts as a neurotransmitter during the penile erection process. However, since AMP is a normal by-product of muscle stimulation, those who are physically active and who supplement their diets with Ubiquinol or Coenzyme 10 may already possess adequate AMP levels, and may not need further AMP supplementation. (See:”Does CoQ10 Enhance Athletic Performance?“, Spanking FIT, Sept. 2015)
Can L-arginine/ citrulline supplementation enhance athletic performance?
Despite the theoretical arguments that L-arginine/ citrulline supplementation may act as an ergogenic aid by increasing circulation in muscles, very few controlled clinical trials or even observational studies have been conducted to test them out. Spanking FIT uncovered two relevant scientific studies: one that indicates aerobic enhancement, and another anaerobic enhancement. Let’s begin with the L-arginine/ citrulline aerobic enhancement study:
“Oral l-citrulline supplementation enhances cycling time trial performance in healthy trained men, etc.” by T. Suzuki and published in Journal of International Society of Sports Nutrition, 2016, Feb. 19. In this study, 22 trained males who were 20-39 years old, were randomly assigned to either a placebo or 2.4 gm. per day of l-citrulline for a period of seven days. On day eight, they were then given either the placebo or 2.4 gm of l-citrulline an hour prior to performing a four kilometer timed cycling trial. Following a three week “washout period”, the procedure was repeated with “crossover”. In other words, the athletes who originally received l-citrulline were given placebo, and those who originally received placebo crossed over to l-citrulline. Researchers reported : (1) statistically significant increases in plasma l-arginine levels for the l-citrulline treated athletes, (2) a statistically significant reduction of 1.5 % in required time to complete the test for those treated, and (3) a statistically significant 2% increase in power output in those treated. They also reported a marginally significant increase in PO/ VO2 ratio for certain elapsed distances among the treated athletes. (Increased PO/ VO2 ratios are indicative of superior physical performance.)
From a statistical perspective, researchers used a matched pair t-test in performing analysis, whereas independent sample t-tests are generally preferable in this situation. In any event, given the relatively small sample employed in the experiment (n=22), a non-parametric test should have been used instead of the parametric one. In addition, it was disclosed in the publication that at least three of the investigators were employed by Kyowa Hakko Bio Co. Ltd., which Spanking FIT confirmed to be a citrulline maker. Consequently, an appearance of conflict of interest exists. Now for the anaerobic study:
“Citrulline malate enhances enhances athletic performance and relieves muscle soreness” by J. Perez-Guisado published in Journal of Strength Conditioning Research, 2010, May 24 (5): 1215-22. This was another randomized double-blind placebo controlled experiment that also used a two period crossover design. In it, 41 men having an average age of about 30 and who were currently weight training, were randomly assigned to either placebo or to receipt of 8 gms. of citrulline malate, one hour before their barbell workout. The specific workout included both flat and inclined barbell bench presses. Crossover was executed following a one week “washout period”. Using both parametric and non-parametric tests, researchers reported statistically significant performance improvements of about one to two additional bench press reps for the citrulline users. That translated into about a 10-50% improvement in athletic performance depending on the specific exercise set or test performed. Also, significantly less muscle soreness after 24 and 48 hrs. of testing was reported in the citrulline group. Study authors postulate that citrulline facilitates clearance of the ammonia which causes “deviation of energy metabolism towards formation of lactate”. Lactate accumulation is considered a major factor in muscular fatigue. It is believed that addition of malate to the formula further limits lactic acid accumulation. As previously explained, citrulline is converted to arginine in the body and results in heightened NO production. In addition to improving circulation and blood flow, NO is theorized to also participate in the muscle repair process.
Most men are understandably “put off” by the idea of using pharmaceuticals that have been developed primarily to treat Erectile Dysfunction (E.D.) for purposes of enhancing penile performance. These products also carry with them serious risk of men experiencing adverse side effects. Consequently, they are drawn to natural alternatives such as dietary supplementation with substances such as L-arginine and citrulline. These amino acids are produced naturally in the body, and are also found in common fruits such as watermelon. Solid biochemical principles support their usage. Nevertheless, attempts to experimentally validate theory suffer from common flaws in biomedical research including the use of inappropriate statistical techniques on the part of researchers in analyzing data. (Such flawed analyses do not refute theory, but simply yield them less convincing.) Researchers need to either use the appropriate methods or to slow down and collect more data on fewer parameters. Moreover, given the profound implications of these preliminary findings to the field of cardio-vascular medicine, large scale clinical trials should immediately commence testing the effects of L-arginine/ citrulline supplementation on all aspects of human health for both women and men.
Specifically for older men who are suffering from E.D., L-arginine and citrulline therapy looks promising. However, prevention is always the best medicine. This includes a lifetime of proper nutrition, vigorous exercise, and rest. For younger men seeking heightened sexual enjoyment, L-arginine/ citrulline dietary supplementation appears a much safer alternative to experimenting with drugs. Case example evidence also exists that it may be possible for men to achieve prolonged orgasmic plateaus, in lieu of the standard male peaks, using L-arginine/ citrulline. This effect has been reported anecdotally by many users. Finally, there also exists preliminary scientific evidence that L-arginine/ citrulline will enhance aerobic and anaerobic athletic performance.
As I explained in the Spanking FIT “ABOUT US” section, bio-individuality factors make it difficult to predict the outcome of a specific therapy on any individual. Therefore, if you are interested in further exploring amino acids and amino acid derivatives for improving sexual and athletic performance, please also read: “Does L-Carnitine Enhance Sexual Performance & more?” Spanking FIT, August, 2016. Thank you, again. As usual, I look forward to your valuable feedback. Doctor Garrett