Back in April 2020, after evaluating a number of diverse data sources including bench studies, clinical trials, and epidemiologic investigations pertaining to the effects of nitric oxide (NO) upon coronaviruses, I appealed to the medical literature and research community to investigate the potential utility of arginine (ARG) supplementation in the prevention of severe COVID-19. At that point, the available evidence, while convergent, was fairly limited to the original SARS virus of course -- even then though, the clues seemed overwhelmingly positive.
There's not a lot of money to be made in studying dietary supplements, and my hat is off to the physicians and scientists who conducted the first randomized, double-blinded prospective in hospitalized COVID-19 patients in Italy (with collaboration from the Albert Einstein College of Medicine). Near as I can gather, they received no funding for their efforts, which are groundbreaking and deserving of international recognition and gratitude.
Study Findings
Let's start with the exciting stuff: the trial showed a statistically significant difference in secondary endpoint comprising hospital length of stay (LOS). Median LOS was 25 days in the ARG group compared to 46 days in the placebo group (P<0.0001). The primary endpoint was designed as reduction of respiratory support, which was also statistically significantly improved among the ARG group at day 10 (with an odds ratio of 6.6, P=0.01), but lost significance at day 20. Having said that, the authors note that this apparent attrition of benefit may actually reveal attrition of illness: a very large number of the ARG group had already healed/been discharged, enriching the proportion of the sickest in that arm.
Now let's analyze the study a little more. In all fairness, the treatment group showed significantly lower age -- 7.5 years lower. Multivariate modeling however still showed tremendous attributable influence of ARG, and furthermore, distribution of comorbidities did not vary. Interestingly, what did vary significantly was initial severity quotient of respiratory support between the two groups. Far more people in the ARG arm started out on non-invasive ventilation and CPAP. In other words, the treatment arm started with more severe respiratory disease. One could argue that the deck was stacked in favor of the ARG group in terms of primary endpoint (more room for improvement!), but there's no way to nay-say the stunning difference seen in terms of hospital discharge.
The other subtle finding (too small by the numbers to make it into any kind of analysis) was that three patients in the placebo arm died after day 20...compared to zero in the ARG arm.
The most important point of carefully controlled trials (and regulatory agencies) echoes the introduction to the physician's oath: primum non nocere (first, do no harm). Let's ensure safety. The big theoretical concern from ARG supplementation is the potential for increased systemic inflammatory response and cytokine storm. What if increasing NO is akin to throwing gasoline on the coals?
To address that hypothetical, let's look at the study results: no harms were seen in the treatment group.
Well, we've all been fooled by the results of one study before. Let's consider plausibility based upon other lines of evidence. What have we learned lately about the incredibly complex biology of NO?
The "NO" Technical Manual
It's certainly more complicated than we've grasped so far, but basically, there are two functional versions of nitric oxide synthase (NOS), the enzyme that makes NO from ARG: constitutive NOS or cNOS (always working) and inducible NOS or iNOS (works when called upon). cNOS furthermore has two types, for the hardcore among you: a neuronal version and an endothelial version called eNOS.
We'll start with iNOS. This "PRN" isoform seems to function primarily within the immune system, rendering potent NO-mediated antimicrobial activities by various leukocytes. We won't go into all these mechanisms (many of which are more directed toward bacteria), but rather focus on proposed anti-SARS-CoV-2 mechanisms. In vitro studies have shown that increased NO activity inhibits the ability of the virus to both bind the ACE2 receptor with its spike protein and to replicate. Conversely, more than one study has now shown that ARG levels are deficient in people with severe COVID-19 and leukocyte depletion/dysfunction (particularly CD8 T-cells), and demonstrated in vitro rescue of said T-cell function with an ARG-enriched environment.
Excess (iNOS-generated) NO however has been implicated in the development of pulmonary vascular toxicity, likely contributory to the ARDS state, and possibly the "cytokine storm" of systemic inflammatory response syndrome seen in severe infection.
Well what about eNOS? This constitutive version is (under normal circumstances) always at work generating NO for the endothelium of blood vessels, dilating them, protecting them from platelet and leukocyte aggregation, and atherogenesis. In pathologic states however (especially those associated with tetrahydrobiopterin deficiency, such as diabetes or simply old age) eNOS can generate reactive oxygen species rather than NO, leading to vascular damage. Interestingly, this so-called eNOS "uncoupling" has also been shown to occur in ARG-deficiency.
It's difficult to piece together for sure, but what we think we're seeing here is that ARG deficiency leads to a double whammy of enhanced vulnerability to viral entry and replication, and vasculopathy.
One final thing to consider here is the potential role for citrulline (CIT), an amino acid that is generated from ARG but also serves as a reservoir for reverse synthesis of ARG. It turns out the cNOS family primarily generates its NO from a specific compartment of ARG that is generated from this reverse CIT metabolism. iNOS on the other hand doesn't seem to use that stash, but rather, an intake-dependent pool of ARG. In this case, supplementation with CIT may actually make as much or more sense.
Toward Future Research
I can't think of a better way to both honor the work of these researchers and highlight the need for further trials (ideally comparing ARG and CIT to placebo) than to quote their conclusion:
"...our results may have important clinical implications for COVID-19 treatment especially in low-resource environments [where] vaccination is not widely available given the safety and the affordability of oral L-arginine."
Bravissimo.
This does not constitute medical advice. What it does constitute, as communicated last year, is an appeal for urgent research into a dirt-cheap potentially life-saving measure with no demonstrated risk.
is a board-certified anesthesiologist, pain physician, and addictionologist practicing in Alaska (the military sent him there and he decided to stay). If he wasn't trying to guide people in improving their own lives, teaching medical students to do the same, or writing about it, he'd probably be outdoors right now slogging up a mountain with a good friend or two.