I am returning to my blog series on a comprehensive update on SARS-CoV-2 and COVID-19 after a brief interruption caused by urgent developments relating to avian influenza outbreaks on U.S. dairy farms.

Even so, I wasn’t planning to cover treatments for COVID-19 just yet, but I am addressing this now, because like the vampire Dracula, the hype around ivermectin and hydroxychloroquine just won’t keep reappearing in the darkness of night. The Tennessee state legislature and governor made ivermectin available over the counter without a prescription a couple of years ago, a number of states are pushing similar legislation, there have been anti-science legislators in some states trying to protect doctors who prescribe ivermectin inappropriately from discipline by state medical boards, there have been misrepresentations and misunderstandings about the outcome of a lawsuit against the FDA over ivermectin, and some of the doctors who have been repeatedly wrong on the science have been doubling down on ivermectin as a preventative or treatment for COVID-19 in public forums lately.

Ivermectin was an interesting and theoretically possible candidate medication for use against the SARS-CoV-2 virus based upon in vitro (i.e., in the lab, in test tubes, but not in animals or humans) tests. While some doctors jumped on this and promoted it as an effective treatment, most of us realized that many times medications may appear to have benefit in the laboratory, but fail to show benefit in real life, and in some cases may even prove harmful in humans, and so we held out hope while we awaited results from well-designed and peer-reviewed clinical trials. Personally, my objection was not so much that some doctors were prescribing this medication, but rather they were promoting it while discouraging people from taking preventive measures and treatments proven to be effective.

So, we will review here some of the best designed and controlled studies that now conclusively show that ivermectin is not effective in preventing or treating COVID-19 to anyone who is objective and knows how to interpret the scientific literature.

But first, to quote the song lyrics from a big hit by The Who (the musical group, not the World Health Organization): “Then I’ll get on my knees and pray we don’t get fooled again,” I just want to offer some thoughts to people who might have been duped by those touting ivermectin as a cure-all, but don’t want to get duped again in the future.

I don’t know if I will be around for the next pandemic, although it looks increasingly likely that I will given how quickly new threats are emerging, so I will share with you how I could easily spot these physicians and not fall for their disinformation so that you can as well:

1. Always right about everything, even when proven wrong. Anyone who listened to me for the past four years knows that there were times that I admitted that I got something wrong about the virus, was wrong in my predictions about what was unfolding, or admitted that things happened that I simply could not explain. So, too, all of the scientists and physicians that I respect have admitted they have been wrong at times during the past four years, something that should be expected with a novel virus acting very differently from past viruses over such a protracted period of time. On the other hand, I have never heard one of the disinformation purveyors admit to being mistaken about anything, even when confronted with the evidence that they were wrong. Beware of people who are never wrong and never in doubt.

2. Reliance on anecdotal evidence. It was very common to hear statements to the effect of “Every patient I treated did well,” or “I treated [fill in the blank] patients and no one got sick.” First of all, in some of these cases, the doctor who was touting this essentially 100 percent success became ill with COVID-19 themselves, so that undermines the argument a bit, I would think. Second, ask any experienced, reputable doctor you know and ask them if any preventative or treatment they have prescribed has worked for every patient. I can’t think of one right off the top of my head.

It didn’t come out until later in many cases, that some of these doctors did not have practices where they actually followed patients over time. They may have conducted a telehealth visit, may have seen the patient in an urgent care setting, but then didn’t provide follow-up to these patients, so they often were not in a position to know whether those patients did well. In one case where the physician did not see patients in person or in an office setting and had no hospital practice, the physician was touting his essentially 100 percent success to the public, while emergency room physicians and critical care doctors were informing me and others that some of that physician’s patients were turning up in the hospital very sick from COVID-19, and in some cases, sadly died.

Further, if you have a disease for which most people recover and do not require hospitalization, especially young people without underlying medical conditions, it takes large numbers of patients treated compared to a similar number of controls and over a longer period of time to evaluate whether a medication intervention truly made any difference. Let’s take an example to make this point clear. Let’s say that early on in the pandemic, I provided advice to 100 people who are in their 30s and 40s, in great health, and able to work from home and home school their kids. They decided that for a month or two, they could avoid most public gatherings and were willing to wear N95 respirators when out in public. Now, I told them that the key is for them to eat one handful of M&Ms each day. They all happily agree to do so and none of them gets COVID-19 and none of them gets hospitalized for COVID-19. Success! No, these are people at low risk who are implementing public health measures known to protect them from infection and it would not be expected that many of them would get infected and not expected that any would get seriously ill if they did. You can imagine that if I had a control group of people the same age, the same good underlying health and the same willingness to comply with these public health measures, but I told them that it is imperative that they never eat a single M&M during the period of the study, they too would still have the same outcomes. So, the M&Ms did not have some amazing antiviral properties (darn it!) in humans based on that anecdotal experience. These folks were just at low risk and willing to avoid exposure-prone settings.

This is the problem with these doctors’ anecdotes: we don’t know the age range and health status of the people they treated, there was no comparison group and people at low risk continue to be at low risk even if you offer them medicine. And, if you treat people, but don’t follow them up, and don’t know that they showed up to an emergency room or were hospitalized, then you don’t really know that your treatment was effective.

3. Another big clue is when the company that makes the medication that would greatly benefit from increased sales of the medicine puts out a public statement that its own scientists find no evidence to support the use of the medication. This is one of the principles we use in law when we assess the veracity of witness statements. When the witness admits to something that is against their own interests, then it has a greater likelihood of being a truthful statement. Discouraging use of their medication as a preventative or treatment for COVID-19 is actually against their best interests in terms of sales and stock price.

4. On the other side, you may have to do some digging, but you can often find ways that intentionally deceiving people is benefiting the person promoting the disinformation. They may be getting large numbers of followers on social media and as a consequence advertising revenue. Some of these doctors began selling their own vitamins or supplements to help protect people who were wanting to avoid becoming ill or to treat the illness, even as those doctors were discouraging people from using proven methods. Some were getting lots more attention than they had before getting opportunities by elected leaders to talk at legislative hearings, committees or other gatherings, and to have pictures taken with elected leaders or sound bites in clips that they could share on their social media sites. Some got government positions themselves. Many began travelling and speaking at conferences all over the world and on cable news shows that further increased their social media presence.

5. Often, if you do follow their social media or listen to their presentations, it won’t take long until they say things that are demonstrably false about another issue besides ivermectin that should then cause you to doubt whether you can trust what they are saying about the drug they are promoting, and even more often, you will soon see that their talking points and social media posts take on a definite ideological bent and political bent, rather than being scientifically objective.

6. I have not seen any situations where these doctors have been willing to disclose their potential financial conflicts of interest. Very early on, I explained very clearly and in depth about any potential financial conflicts of interest that might apply to me. To my knowledge, these doctors have not disclosed their advertising revenue, speaker’s fees, who pays for their travel, revenues from selling supplements, etc.

7. There often are some other clues. Readers of my blog know that I often cite to the scientific studies that I explain to readers so that you can read the articles for yourself. Purveyors of disinformation often will not tell you what study or studies they are relying on, or when they do, they tend to refer you to some website that has an overwhelming list of studies of poor quality and they will not tell you which specific one you can look to in support of the assertion they are making, counting on the fact that few people have the time or expertise to sit down and read through a hundred articles that are often exhausting to read because they have so many flaws. Many of these articles appear in what we call “low impact” journals, in other words, not the journals that scientists most rely on for their information. Many times, articles they reference were submitted, but then later retracted. In one case, where I will give the person credit that he would at least provide us with the article he was mischaracterizing, I could usually find on short order where he was completely misstating what the authors of the paper stated. I think he just counted on the fact that most people would only read what he wrote and not take the time to read the paper, and in fact those same readers were likely to give his words greater weight because he also attached a reference paper, counting on the fact that most people would not read the publication for themselves.

8. These doctors also tended to use hyperbole and exaggeration, and an often-tell-tale clue is their use of emotional and inflammatory rhetoric. I have had discussions with anti-vaxxers and anti-maskers that have been quite civil. I enjoy learning how others are looking at the world and making decisions. I almost always learn something from talking to them. I had an anti-vaxxer who was raised by antivax parents recently tell me that because I did not demean people who were antivax or vaccine hesitant, and because I acknowledged that there were legitimate reasons for people to have concerns, but nevertheless presented the data and helped explain that all of these decisions are ones of weighing risks, because there are risks to not being vaccinated, that not only did she get vaccinated, but she has gotten her children caught up with their vaccines. There really is no need to vilify either doctors or parents who are trying to do the right thing and make the best decisions they can.

I consider that when I offer medical, legal or public health advice, that is all it is – advice. It is fine with me when people decide not to take my advice. I have relatives who have decided not to take my advice, and that is fine because they should be making their own decisions. I have enough decisions that I have to make in my own life; I certainly don’t need to be controlling anyone else’s. But, when people spreading misinformation for personal gain are challenged by experts or people express disagreements, you often see these exchanges become very emotional, nasty, mean-spirited, or result to insults, likely because they don’t have the facts on their side and they see the threat to whatever the personal gain is they are getting from their deception if they are exposed for what they are.

To be clear, I have no problem with competent adults who want to be deceived being deceived. This can be an important psychological defense for some people. I don’t think it is a healthy defense, but if they think that is the best route for them personally, then fine with me. But, for those who are trying not to be deceived, other clues are when the medical schools the doctor has attended disavow themselves of the doctor’s statements, state medical boards have taken disciplinary action, national specialty boards have revoked their board certification, hospitals have removed the physicians from their medical staffs, or you begin seeing any number of reliable fact-checking sites identifying the doctor’s statements as false.

Now, let’s get into some of the evidence that ivermectin was not effective to prevent or treat COVID-19.

1. Reis, G., Silva E., Silva D., et al. “Effect of Early Treatment with Ivermectin Among Patients with COVID-19.” New England Journal of Medicine 386, no. 18 (2022): 1721 – 31. https://www.nejm.org/doi/full/10.1056/NEJMoa2115869.

This was a double-blind, randomized, placebo-controlled study involving symptomatic SARS-CoV-2–positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of COVID-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days or placebo.

The primary outcome was worsening of their COVID-19 reflected by the need for an emergency department visit or the development of severe disease reflected by the need for hospitalization occurring within 28 days after their randomization to receive ivermectin or placebo.

There were 679 patients randomized to receive ivermectin and 679 who were randomized to receive a placebo (a pill that would look identical to the ivermectin, but have no medication in it). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event (ER visit or hospitalization), as compared with 111 (16.3%) in the placebo group. Of the 211 patients that worsened, 171 (81%) required hospitalization.

The outcomes in these two groups were not statistically different (i.e., not any different than what might occur by chance), meaning that in this study, the recipients of ivermectin did not benefit from ivermectin treatment.

2. Lim, S., Hor C., Tay, K. et al. “Efficacy of Ivermectin Treatment on Disease Progression Among Adults with Mild to Moderate COVID-19 and Comorbidities: The I-Tech Randomized Clinical Trial.” Journal of the American Medical Association Internal Medicine no. 4 (2022): 426 – 35.https://pubmed.ncbi.nlm.nih.gov/35179551/.

This study was designed to determine whether Ivermectin could prevent progression to severe disease in high-risk patients with acute SARS-CoV-2 infections. It was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients’ symptom onset, the study enrolled patients 50 years and older with laboratory-confirmed COVID-19, comorbidities that placed them at high risk, and current evidence of mild to moderate disease.

Patients were randomized in a 1:1 ratio to receive either oral ivermectin, 0.4 mg/kg body weight daily for 5 days, plus standard of care (n = 241) or standard of care alone (n = 249). The standard of care consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging.

The primary outcome for this study was the proportion of patients who progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation at 95% or higher. Secondary outcomes of the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day in-hospital mortality, and adverse events.

52 of the 241 patients that received ivermectin (21.6%) and 43 of the 249 patients in the control group (17.3%) progressed to develop severe disease. With respect to secondary outcomes, mechanical ventilation occurred in 4 (1.7%) vs 10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17), intensive care unit admission in 6 (2.4%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79), and 28-day in-hospital death in 3 (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09).  Most readers are probably unfamiliar with these statistical measures, but generally they are providing us with the relative risk, the 95% confidence interval and the probability value that the results were not achieved simply by chance. What this study shows is that ivermectin had no statistically significant benefit in preventing progression of mild-to-moderate COVID-19 to severe disease, or preventing the need for an ICU admission or ventilator for breathing support, or death.

3. Naggie, S., Boulware, C., Lindsell C., et al. “Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients with COVID-19.” Journal of the American Medical Association 329, no. 11 (2023): 888 – 97. https://pubmed.ncbi.nlm.nih.gov/36807465/.

The investigators in this study evaluated the effectiveness of ivermectin at a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19.

A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022. Patients were randomized to receive high-dose ivermectin (602 patients) or placebo (604 patients) for six days.

The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28 after randomization.

The median time to sustained recovery was 11 days in the ivermectin group and 11 days in the placebo group. HR 1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. These statistical measures indicate that ivermectin provided no statistically valid improvement in time to recovery from onset of illness, nor did it reduce the risk of progression to severe disease.

Without making this blog post excessively long because there are many other well designed, well conducted studies that fail to show a benefit from ivermectin in the treatment of COVID-19, I am just going to list some more studies along with the authors’ conclusions, and then you may read any that pique your interest:

4. “Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial” https://pubmed.ncbi.nlm.nih.gov/34215210/. “Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19.” 

5.       “Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial” https://pubmed.ncbi.nlm.nih.gov/33662102/. “Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms.”

6.       “High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial.” https://pubmed.ncbi.nlm.nih.gov/34999239/. “High-dose ivermectin was safe but did not show efficacy to reduce viral load.”