I started writing about the drug ivermectin over 36 years ago. Back then it had the brand name Mectizan. Merck was giving it away in Africa to combat river blindness (onchocerciasis). We also gave it to our dog Rick once a month to prevent the heartworm parasite from causing heart failure and lung disease. When we heard that ivermectin might be helpful against COVID-19 in the spring of 2020 (Antiviral Research, April 3, 2020) we were excited. The most recent research has just been published (JAMA, Feb. 20, 2023). What does it reveal about ivermectin?
Why Was I So Hopeful About Ivermectin?
I had high hopes for this wonder drug! First, it has saved the eyesight of millions of people in Africa and Latin America.
I was teaching pharmacology to second year medical students at the Escuela de Medicina of the Universidad Autónoma Benito Juárez de Oaxaca in 1973 and 1974. While I was teaching, Terry was doing research on health and nutrition for a PhD in medical anthropology in Oaxaca, Mexico.
When we walked around the city square (the Zócolo) we would occasionally see and hear an amazing street musician. His name was Alfonso Cruz Jimenez. His young children would lead him from cafe to cafe where he would sing and play the guitar.
They had to lead him because he was blind due to onchocerciasis. His music was haunting and you can listen to it at this link. If ivermectin had been available sooner, he might not have become blind. It brings tears to my eyes to listen to his music today and marvel at his joy for life.
I was wishing that ivermectin would be a miracle for COVID patients…that it would shorten the duration and lessen the severity of this horrible infection. Better yet, I was hoping it would keep people out of the hospital and save lives.
Wishful Thinking vs. Actual Data on Ivermectin?
It has been more than three years since COVID-19 showed up. Like nearly everything else associated with the pandemic, views on ivermectin quickly became polarized. Many people wanted to believe that this fascinating medication was going to be the cure for COVID-19.
The latest study has just been published in JAMA, Feb. 20, 2023. What did the data reveal about ivermectin?
Here is the executive summary:
In a word, the results were disappointing.
Subjects were recruited from 93 sites between June, 2021 and July, 2022. Participants were outpatients with mild to moderate symptoms of test-verified COVID-19. 1,206 participants were randomized to receive high-dose ivermectin or placebo.
The median time to a sustained recovery was 11 days in the ivermectin group and 11 days in the placebo group. There was no difference between the two treatments. There was also no statistical difference in complications, hospitalizations or death. The authors conclude that:
“These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.”
Why Is There So Much Pushback About Ivermectin Research?
I will not speculate on why so many visitors to this website believe that ivermectin is a miracle against COVID-19. No matter how many studies are published, I am severely spanked for reporting the data.
For example, there was a prior study published in JAMA on October 25, 2022. Nearly 1,600 American adults participated in this double-blinded, randomized, placebo-controlled trial.
All patients tested positive for COVID-19 with mild to moderate symptoms. The median time to recovery was 12 days for those taking ivermectin and 13 days taking placebo. This was not statistically significant.
Drilling Down on Ivermectin:
The authors of this research provide some historical perspective:
“Numerous ivermectin studies have been completed across the spectrum of COVID-19 disease severity. While early studies, particularly in the inpatient setting, suggested potential treatment effect, variability in dosing and overall study quality, followed by multiple article retractions, has resulted in controversy. The largest randomized outpatient trial to date, TOGETHER, enrolled patients in Brazil with symptomatic mild to moderate COVID-19. No clinical benefit of ivermectin (400 μg/kg daily for 3 days) was observed for preventing disease progression.”
Let’s cut to the chase. What was the bottom line on ivermectin?
“Among outpatients with mild to moderate COVID-19, treatment with ivermectin, 400 μg/kg, daily for 3 days, compared with placebo, did not significantly improve time to recovery in this large trial that enrolled more than 1500 participants in the US. A lack of treatment effect was also seen for secondary clinical outcomes including hospitalization, death, or acute care visits. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.”
Why Did Readers Doubt the Research on Ivermectin?
Many people told us that the JAMA study from October, 25, 2022, was bogus. Why?
Readers Were Confused! What Was the Dose of Ivermectin?
Lots of people complained about this research because they did not comprehend the dosing schedule.
Marny did not understand that when a dose is based on weight, it is adjusted for each person individually. The dose in this study was 400 μg/kg/day.
Here is Marny’s complaint:
“The clinical trial conducted by Vanderbilt and Duke University used 400 ug/kg of ivermectin which translates into 0.4 mg. The usual dose used to treat COVID is approx 12 mg (determined by body weight). Using a fraction of the dose no doubt had little effect. Please do your homework!
“I love People’s Pharmacy, and you usually do well at presenting both sides of an issue.”
The total dose was not 0.4 mg! It was determined by body weight. If a patient weighed 84 kg (185 pounds), that would equal 34 mg per day. Our hypothetical patient would take five 7 mg tablets a day to reach a total dose of 35 mg.
Linda didn’t even bother to consider the dose:
“Usually love reading your articles but, this one disappointed me. I thought you looked at things from a ‘real’ perspective and did not side with the propaganda machines. After reading this, I am considering discontinuing my account.”
Cathy did not understand the conversion from micrograms to milligrams:
“I am really surprised and disappointed that you clearly have not read the study reviews which point out the extremely low dose given for only 3 days, and started days after symptoms. 400 mcg = .004 mg/kg. So the dose for me would be less than 1 mg. That’s ridiculous. You need to follow studies by those not funded in any way by the drug industries.”
400 micrograms equals 0.4 mg. The authors describe the intervention:
“A central pharmacy supplied ivermectin or placebo to participants via direct home delivery. Ivermectin was supplied as a bottle of 15 7-mg tablets. Participants were instructed to take a prespecified number of tablets for 3 consecutive days based on their weight for a daily dose of approximately 400 μg/kg.”
Let’s do some basic math. If a patient received 15 tablets and each tablet was 7 mg and they were supposed to take those tablets over three days, the average daily dose would have been 35 mg. That is about the dose calculated above for a man weighing 185 pounds (84 kg).
As for funding by “the drug industries,” that is not likely. Ivermectin has been available since 1987. It is no longer under patent as a human medication. That means that the big brand name pharmaceutical companies are not very interested in funding studies for a medicine that they cannot patent and that is available generically.
Fast Forward to JAMA, Feb. 20, 2023:
Let’s assume for a moment that Marny, Cathy and many other visitors to this website were correct that the dose of ivermectin reported in the Oct. 25, 2022 JAMA research paper was too low to do anything meaningful. Let’s fast forward to this week and the Feb. 20, 2023 JAMA article. It was titled:
“Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19”
The COVID patients who participated in this study were randomized to receive either placebo or 600 μg/kg daily for 6 days. So, higher dose for twice as long:
Do you remember the results of ivermectin in this trial?
“…the median time to sustained recovery was 11 days in the ivermectin group and 11 days in the placebo group.”
COVID-19 vs. Ivermectin?
I have lost count of the number of messages we have received insisting that ivermectin is an absolute cure for COVID. Here are just a couple:
Linda has no doubt that ivermectin cured her:
“If COVID cases start to rise again, I will not change anything. I will not get boosted. Nor will I wear a mask or stay home. I contracted COVID late Feb 2022, took ivermectin early in the course of the virus and in 12 hours had no symptoms. I’ll take ivermectin again if I catch COVID again.”
Michael asserts:
“Early treatment [with ivermectin] would have saved hundreds of thousands of lives.”
D0n offers his friends as proof of ivermectin’s effectiveness:
“I have several friends who were doing poorly with COVID, until they took Ivermectin. All have fully recovered.”
Charlotte is adamant about ivermectin:
“I always knew ivermectin worked.
“In Australia, U.S., and South Africa, compassionate use of Ivermectin (obtained after families applied to courts for it to be used) has amazingly reversed the illness. In one case a dying woman came off a ventilator and was much better the next day.
“Surely when people are dying from this terrible virus, Ivermectin use is justified.
“There shouldn’t be ‘clinical trials’ when drugs have been in use for over 50 years.
Surely the outcome is an ALIVE PATIENT?“Denying a patient who has severe COVID that drug (or hydroxychloroquine for that matter) in my opinion, is criminal and borders on the psychopathic.”
Why Wait for RCTs of Ivermectin?
The course of illness with COVID-19 is highly variable. Some people remain asymptomatic even though they test positive. Others have mild symptoms, barely worse than a “common” cold. Many people become very sick with a fever, chills, cough, fatigue and serious breathing problems. Some end up in the hospital while others die. At last count, hundreds are still dying daily from complications of COVID.
The anecdotes that people share on our website are not scientific. They may be interesting, but they do not tell the whole story. Both Linda and Don may believe that ivermectin is effective against COVID, but that is not enough to endorse the treatment. Some people take a turn for the better without any treatment. Some people take a turn for the worse with treatment.
Does Science Matter?
The only way to truly assess the effectiveness of ivermectin (or any drug, for that matter) is to perform large, randomized controlled trials (RCTs). Neither the patients nor the investigators know who gets what. Such RCTs are not perfect, but they are the best tool we have because they do away with politics and preconceptions that might influence the outcome.
There will always be disagreements about the timing of the treatment, the dose of ivermectin, the duration of treatment, and goodness knows what else. For me, though, if ivermectin were a magic bullet, we should have seen something in the latest clinical trial.
Patients who got this drug should have fared much better than those on placebo. That did not happen. Here are key metrics: emergency care, hospitalizations and deaths!
The latest study reports:
“Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo. 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.”
Believe me when I tell you that I would love for ivermectin to work against COVID, even if the benefit is modest. That’s because I love this drug.
Other Studies of Ivermectin?
Lest you think that there are only two randomized controlled trials of ivermectin that produced disappointing results, let me quote from the Editor’s Note in JAMA, Feb. 20, 2023.
“A Cochrane meta-analysis of 11 eligible trials examining the efficacy of ivermectin for the treatment of COVID-19 published through April 2022 concluded that ivermectin has no beneficial effect for people with COVID-19. Since May 2022, an additional 3 large randomized clinical trials including several thousand participants have been published, each reaching a similar conclusion.
“Today JAMA publishes a new trial of ivermectin treatment for mild to moderate COVID-19 that addresses the possibility that the existing literature may have missed the efficacy of ivermectin because the previously tested dose (approximately 400 μg/kg daily for 3 days) was insufficient. At a higher treatment dose (600 μg/kg daily) and longer treatment duration (6 days), Naggie and colleagues again conclude that ivermectin is not beneficial for the treatment of COVID-19.”
Please remember that I love ivermectin. I wanted this drug to work for COVID. Perhaps you will find its history as fascinating as I have.
Where Did This Amazing Drug for Parasites Come from?
Please indulge me for a quick minute. In case you have not read anything about this fascinating medicine, here is a quick historical overview:
Fifty years ago a Japanese microbiologist tested some dirt from a golf course near Honshu. He and his colleague William Campbell at Merck discovered that unique bacteria in that soil had anti-parasitic activity against roundworms in mice. Their research led to a Nobel Prize in Physiology or Medicine in 2015.
Merck introduced ivermectin for treating parasites in animals in 1981. Many dog lovers still administer a monthly dose of ivermectin (Heartgard) to their canine companions to prevent heartworm.
Then the company discovered that ivermectin could also fight off the parasite Onchocerca volvulus that causes “river blindness” in humans. Infected Simulium black flies carry the larvae of this worm. It causes untold misery in Africa and Latin America.
Symptoms include skin rashes, nodules and horrific itching. Inflammation in the eye can lead to clouding of the cornea, optic nerve damage and ultimately blindness. Public health agencies approved ivermectin to treat people with river blindness in 1987. The brand name was Mectizan. It has saved the sight of millions of people in Africa and Latin America. Some experts consider it a wonder drug on a par with aspirin and penicillin.
Lice and Scabies: Ivermectin? Really!
In addition, ivermectin can help treat conditions beyond river blindness and heartworm disease. Although most of these are in the form of filaria, tiny thread-like worms, it is also effective against lice and scabies.
A review in the Journal of Drugs in Dermatology (March, 2016) states:
“Numerous studies report low rates of adverse events, as an oral treatment for parasitic infections, scabies and head lice. Ivermectin has been used off-label to treat diseases associated with Demodex mites, such as blepharitis and demodicidosis. New evidence has linked Demodex mites to rosacea, a chronic inflammatory disease. Ivermectin has recently received FDA and EU approval for the treatment of adult patients with inflammatory lesions of rosacea, a disease in which this agent has been shown to be well tolerated.”
None of this got anyone particularly excited. But then COVID-19 hit.
The Coronavirus and Ivermectin?
There have been dozens of publications about ivermectin vs. COVID-19. There are enthusiasts and critics. Like just about everything related to this virus, there are strong emotions. We don’t understand why this amazing drug has been caught in the crossfire, but it has.
A Drug for Parasites Has Antiviral Activity:
It may seem surprising that a drug for parasites would knock out viruses. However, scientists have previously found that it can slow proliferation of the virus that causes dengue fever.
Australian researchers have found that ivermectin has strong antiviral activity in the lab (Antiviral Research, online, April 3, 2020):
“Taken together these results demonstrate that ivermectin has antiviral action against the SARS-CoV-2 clinical isolate in vitro, with a single dose able to control viral replication within 24–48 h in our system…Ultimately, development of an effective anti-viral for SARS-CoV-2, if given to patients early in infection, could help to limit the viral load, prevent severe disease progression and limit person-person transmission…This Brief Report raises the possibility that ivermectin could be a useful antiviral to limit SARS-CoV-2, in similar fashion to those already reported…”
A Randomized Controlled Trial of a Drug for Parasites:
Over two years ago we wrote:
“Unfortunately, this basic laboratory research is still far from uncovering clinical efficacy. Since ivermectin has been used in human medicine for decades, clinicians already know quite a bit about its side effects. However, as with most of the other drugs currently under study, we won’t know if it works against COVID-19 until clinical trials are conducted.”
A year later we had a sliver of clinical research to support ivermectin against COVID-19 (EClinicalMedicine, Jan. 19, 2021). Researchers treated 24 COVID patients in Pamplona, Spain. They randomly assigned half of the participants to take ivermectin. The others took placebo pills.
Patients who received ivermectin had substantially less viral load after four days. Seven days after treatment with the drug, the viral load was 18 times lower than in the placebo patients. The treated patients were half as likely to lose their sense of taste and smell and a third less likely to develop a cough.
Big Clinical Trial Results! What Happened to Ivermectin?
Let’s be honest. A clinical trial involving 24 COVID patients in Pamplona, Spain, is not enough to draw any meaningful conclusions. Other clinical trials followed but they produced mixed results and there were serious questions about methodology and interpretation.
One set of authors initially published a meta-analysis of research that supported the use of ivermectin against COVID (Open Forum Infectious Diseases, July 6, 2021).
They later retracted the article because:
“These instances suggest that the data available to support the use of ivermectin for COVID-19 is not reliable. In July 2021, after the potentially fraudulent studies were identified, we retracted our published meta-analysis and began working on an updated analysis, assessing the effects of stratifying by trial quality on the overall results.”
Once the authors eliminated the fraudulent or questionable research, they found that:
“…ivermectin results in a non-significant 4% increase in survival.”
They concluded:
“These observations demonstrate that the significant effect of ivermectin on survival was dependent on the inclusion of studies with a high risk of bias or potential medical fraud.”
What About Other Results with Ivermectin?
One of the biggest randomized clinical trials was published in the New England Journal of Medicine (March 30, 2022).
The researchers recruited “symptomatic SARS-CoV-2–positive adults recruited from 12 public health clinics in Brazil.”
“A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157).”
And the envelope please! The authors conclude:
“We did not find a significantly or clinically meaningful lower risk of medical admission to a hospital or prolonged emergency department observation (primary composite outcome) with ivermectin administered for 3 days at a dose of 400 μg per kilogram per day than with placebo. We found no important effects of treatment with ivermectin on the secondary outcomes.”
Other Studies of Ivermectin?
Another “controlled, clinical, randomized, double-blind trial that included hospitalized patients with COVID-19-induced pneumonia, without severe respiratory failure” was published in the journal Infectious Disease Reports (March 3, 2022).
The conclusion:
“In non-critical hospitalized patients with COVID-19 pneumonia, neither ivermectin nor hydroxychloroquine decreases the number of in-hospital days, respiratory deterioration, or deaths.”
But Wait…There’s More:
Investigators writing in JAMA Internal Medicine (Feb. 18, 2022) describe the reasoning behind their study:
“Importance: Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19. Evidence-based data to recommend either for or against the use of ivermectin are needed.
“Objective: To determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19.
“Conclusions and relevance: In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.”
Final Words:
Let me be perfectly clear. I think ivermectin is a fabulous drug! You can read why at this link. It works well against river blindness in people and heartworm disease in dogs. It also has utility against hard-to-treat lice and scabies and may be helpful topically against rosacea. But large, well-controlled trials demonstrate that ivermectin does not help people with COVID avoid hospitalization or death .
We received this message from Dr. E, a researcher at Merck, the company that originally developed ivermectin:
“I worked for Merck in the 1980’s and you’re right, ivermectin is a fantastic drug for certain conditions. Just not COVID. As always, you have written a well researched, well referenced & well written article on this topic. Thank you for being the ‘town crier’ of science and putting it all in perspective for all.”
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