The COVID A-to-Z Study: Let’s take a closer look

As many of you know, I am a huge fan of Vitamin C and Zinc for immune support during the pandemic. I teach about these supplements and more in my online course, Integrative and Functional Medicine Strategies for the Pandemic, and I have helped 100s of families successfully manage COVID-19 quickly and effectively without longhaul complications. 

So, when the COVID A to Z study was recently published concluding that high-dose zinc and ascorbic acid (Vitamin C) are NOT effective at reducing the duration of COVID-19 symptoms, many of you asked how to make sense of these new findings. Upon careful analysis, I found that the conclusions are significantly flawed. Let’s take a closer look.

The COVID A to Z Study enrolled 214 participants from April through October 2020, with an unmet goal of 520 participants. The participants were split into 4 different treatment groups. Treatment was started after receiving a positive SARS-CoV-2 PCR test and continued for 10 days. The treatment arms were as follows:

  • Zinc gluconate 50mg at bedtime
  • Ascorbic acid 8000mg divided 2-3 times per day with meals
  • Zinc gluconate 50mg + ascorbic acid 8000mg
  • “Usual care” without supplementation. (“Usual care” was not defined.)

These 2 supplements, zinc and ascorbic acid, were chosen because of their theoretical benefits for COVID-19 infection. As I’ve outlined in my article, A Pediatrician’s Pandemic Immune Support Plan, zinc increases our white blood cell’s ability to fight infections and may inhibit SARS-CoV-2 from replicating. Vitamin C is one of our most important antioxidants, protects our lungs from pneumonia and may reduce the risk of sepsis. 

Because of slower than expected enrollment, an interim analysis was performed in October with only 214 participants. The primary endpoint evaluated was days to 50% reduction in COVID-19 symptoms. The findings were:

  • Usual care without supplementation: 6.7 days
  • Ascorbic acid group: 5.5 days
  • Zinc gluconate group: 5.9 days
  • Ascorbic acid + Zinc gluconate group: 5.5 days

The study was stopped early “for futility” as these numbers were not considered statistically significant. 

The conclusion was made that high-dose zinc and ascorbic acid are not effective for COVID-19. 

But, not so fast there.

Let’s take a closer look at the study. Below are the several flaws I noted on closer inspection. (There may be more). 

Flaw 1: The definition of success

The supplement groups had a reduction in number of days to 50% symptoms compared to the usual care group by 0.8 – 1.2 days. The researchers did not consider this reduction in symptom days a “success” It’s not clear to me why a reduction in symptoms by 1 day is considered a failure when when Tamiflu is touted a “success” in trials because it reduces influenza symptoms by a whopping 25 hours.

Flaw 2: The amount of zinc administered was NOT actually “high-dose”

Participants received 50mg of zinc gluconate daily. This in no way would be considered a “high-dose” by most conventional and integrative practitioners. Zinc gluconate contains approximately 14.3% of elemental zinc which means that 50mg of zinc gluconate contains about 7mg of elemental zinc. The Recommended Dietary Intake (RDI) for most kids and adults is OVER 7mg daily (see chart below). The high dose needed to treat COVID-19 would therefore be expected to be much higher than the 50mg of zinc gluconate that was used in the study. 

Flaw 3: A zinc ionophore was not given with zinc

This study does not supplement zinc with an ionophore like quercetin. A zinc ionophore, like quercetin, is important to help zinc enter cells where it can do its job of inhibiting viral replication. The authors even comment “the biologic activity of zinc against viruses may require ionophores, such as pyrithione, to block viral replication.” To conclude that zinc does not work against SAS-CoV-2, without simultaneously giving it with a zinc ionophore, is faulty study design at best.

Flaw 4: Not blinded or placebo-controlled

The gold standard study is a randomized, blinded, placebo-controlled trial. In this study, participants and investigators knew which treatment arm each participant was in. Expectations of how effective supplements would be may have skewed participant’s reporting of their symptoms. 

Flaw 5: Supplements were taken for 10 days after a positive PCR test result – NOT at the start of symptoms

When using natural therapeutics for any condition, treatment is generally much more effective when started at the very onset of symptoms. There was no standardization of when in the course of illness participants began their 10 days of supplementation. As anyone who has had a PCR test knows, once you get the test, it can take days to get results, and if you don’t go in for a test until you’ve had symptoms for a few days, that could be a good week or more into your illness. The more the disease progresses, the higher the infectious and inflammatory burden, and the less likely any treatment intervention is to make a significant difference. 

Flaw 6:  Supplement brands were not disclosed

The quality of supplements can vary widely depending on the manufacturer. The study should have disclosed which supplement brands were used for zinc and ascorbic acid, and an independent assay should have been performed to ensure that the supplements given to participants contained the exact amount of each nutrient desired. 

Flaw 7: The study does not have statistical “power”

The study required 520 participants in order for the results to have “power,” or enough statistical sensitivity to detect a difference in the treatment arms. With any fewer than 520, the power is not great enough to make valid conclusions from the results. Due to slow enrollment, the study only included 214 subjects. Instead of concluding that zinc and ascorbic acid are not effective, the researchers should have stated that NO definitive conclusions can be made. Period. 

Flaw 8: Conflict of interest

One of the authors of the study, Dr. Carla McWilliams, receives consulting fees from Gilead Sciences, the maker of none other than Veklury (aka remdesivir) which was approved by the FDA in October 2020 for treatment of COVID-19. This seems like a fairly HUGE conflict of interest. What incentive would this researcher have to find 2 very inexpensive and easily accessible supplements actually effective against COVID-19 when a much more expensive and exclusive treatment is available from a drug company that pays her? I hate to be cynical, but…

Flaw 9: The study was not designed by integrative and functional medicine experts

None of the researchers is an integrative or functional medicine expert. The study design should have been developed with the assistance of functional medicine physicians who have experience in managing patients with COVID-19 and can best determine potential supplement dosages and combinations to be studied.

Flaw 10: Good effort, but possibly more harm than good …

I applaud the efforts of the researchers in investigating the role of natural treatments and supplements in combating the SARS-CoV-2 pandemic. These studies are long overdue and SO needed when 100s of thousands of people around the world continue to experience significant morbidity and mortality from COVID-19 and need access to effective and affordable treatments NOW. Unfortunately, this study, by inaccurately portraying its results, and the media now running to share these mistruths, may do more harm than good by removing zinc and vitamin C from the list of those potentially effective, affordable and accessible treatments. 

Knowledge is Power. And we need good knowledge … now.

xo Holistic mama doc – Elisa Song, MD

  1. Thank you so so much for breaking this down for us. I would not have found these flaws, so I’m very grateful for your work. I’ll continue to regard zinc and vitamin c in my treatment plan if I should need it.

    • Yes! Zinc and C are still in our family’s immune support list.

  2. Question: do you recommend any particular supplements leading up to the 2nd shot of the vaccine to hopefully reduce any possible side effects? I have been eating more greens and vegetables, taking a probiotic, and am trying to get my Vit D levels up (I usually test low at about 17). I would love to set myself up so I am least likely to experience the side effects some have.

    • stay tuned as I’ll be offering a masterclass on this subject…

      • I look forward to hearing about this! Thanks for sharing your knowledge

    • Great question. I’m curious as well.

  3. YOU ARE THE BEST DR. SONG!! Cheers from Maine

  4. kudos to you, you’re our local superhero! mainstream media’s efforts to discredit natural remedies and supplementation are shameful and suspect. thank goodness for wonderful doctors like you who challenge the “party line” by close analysis and critical thinking.

  5. Is Ivermectin a zinc ionophore?

    • No, hydroxychloroquine is…

    • Thank you, Dr. Song! Some sites were saying it was and others said it was not–very confusing. I have a prescription for use either as a prophylactic or as a treatment for early stage COVID. I won’t use it prophylactically–I’m afraid of everything!–but I was thinking about using it with zinc if I get COVID. I think I’m going to look into quercitin instead.

  6. Thank you Dr. Song! I can always count on you to be thorough and logical in your analysis!

  7. Wow yes huge conflict of interest there! Thanks so much for shedding light and truth behind this!

  8. Which particular type of zinc is best absorbed by the body and doesn’t cause stomach upset?
    I currently use Zinc Monomethionine for myself & my kids,is that effective?

    • Zinc piccolinate may have the best absorption, but monomethionine, citrate, and sulfate are good as well. They all can cause stomach upset so I would take with food. I’ll be writing a blogpost on zinc and kids soon!

      • Hi! Thank you so much for all you do. I recently purchased Pure encapsulations liquid zinc (which is zinc gluconate) based on your recommendation on your website. Is this not a good one anymore bc of the type of zinc and gluconate being not great absorption?

        • The Pure Encapsulations liquid zinc is a good zinc for kids who can’t swallow and still has relatively good absorption!

  9. Thank you Dr Song for all the time you put into your work. I really appreciate your perspective on things! There is a lot of push back in mainstream medicine in regards to covid and anyone who thinks outside the box. Do you have any thoughts on covid vaccine for children? Originally, the vaccines were touted to reduce severe disease and they seem to be working. However, we are also told that severe disease in children is rare. Now, the media, local and medical, is starting to focus on long covid in children. Which yes, can occur. I do not know if this is fear mongering or if there is a legitimate concern. We do not know the true seroprevalence of covid in the population (could be alot higher according to the MMWR report out of Mississippi-granted, there are limitations to it based on the population sampling) so a case report here and there may be the exception and not the norm. At one point I was pondering whether it would be best to have kids develop natural immunity over time if sarscov2 becomes endemic, therefore developing robust immunity by the time they get older and possibly more susceptible to severe disease. However, if repeated exposure to the virus causes more complications that would not be the best course of action. Any thoughts? (yes, this is way-off topic)

    • You raise so many good points, that we just don’t know a clear answer to, yet. I am watching these issues very closely for kids and adults. I will be teaching a masterclass, An Integrative & Functional Medicine Approach to the Current Vaccines, soon so be on the lookout for it! 🙂

  10. Dr Song, As always, you are an angel to the world. This is awesome what you share, thank you! My children are grown. I’m 71 now.

    Are the doses and supplements in your ‘strategies for pandemic course’ suitable for us adults as well?

    I’m like 120 pounds.(sometimes less. hard to keep my weight up) Also my grandson and granddaughter (13 and 17) are all bigger and weigh more than me. Thanks, Donna

    • Thank you so much! And yes – I discuss pediatric and adult suggested dosages in my online course. Take care!

  11. You are AMAZING! Thank you so much for going through this study for us and for truly EVERYTHING that you do. I echo Faith’s comment above – YOU ARE THE BEST! I come back to your website over and over again for trustworthy and clear information. You are a real blessing for this world.

    • Thank you so much for your kind words! I so appreciate them!

  12. This is such an incredible analysis on the paper. Thank you for the analysis. You have exposed the bias in this paper. Truly appreciate your work.

  13. What a great article, Dr Elisa. I would love to know your dosage recommendations for zinc and quercetin in treatment of Covid or other viral illnesses?

    • If you look at my article, A Pediatrician’s Immune Support Plan, I do have suggested dosages there!

Leave a Reply