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More people are poisoning themselves with horse-deworming drug to thwart COVID [arstechnica.com]:

Amid the current delta-fueled wave of COVID-19, officials have noted a dangerous surge in the misuse of a deworming drug routinely used in livestock. The result is an uptick in calls to poison control centers, empty shelves in farming supply stores, and pleas from regulators.

In an attention-grabbing tweet [twitter.com] over the weekend, the Food and Drug Administration wrote bluntly: "You are not a horse. You are not a cow. Seriously, y'all. Stop it."

The agency stressed that the drug, ivermectin, is not FDA-approved to treat or prevent COVID-19 and, so far, there is no evidence that it does either of those things. However, it can cause serious side effects and overdoses, which can be life-threatening, the agency warned. Overdoses can result in nausea, vomiting, diarrhea, hypotension (low blood pressure), allergic reactions (itching and hives), dizziness, ataxia (problems with balance), seizures, coma, and even death.

Meet ivermectin

Prior to the pandemic, ivermectin had been used for decades to prevent and treat parasitic infections in people and animals [nih.gov]. At low concentrations, the drug interferes with specific ion channels that are found in parasitic nematode worms, but not in people or animals. The ion channel disruption in nematodes results in paralysis and keeps the worms from feeding and reproducing. As such, ivermectin is routinely used in small animals, such as dogs and cats, to prevent heartworm infections. In large livestock animals—including cattle, horses, pigs, and sheep—it's used as a deworming drug.

In humans, the FDA has approved ivermectin tablets to treat conditions caused by parasitic intestinal worms as well as topical formulations for some external parasites, like head lice. But it's critical to note that the ivermectin drugs available to people involve relatively small doses and are in formulations known to be safe for human use. The over-the-counter livestock drugs, on the other hand, are not formulated for human use and have much larger doses for the animals' much larger bodies. At higher concentrations, ivermectin begins to interfere with not just nematode ion channels, but other types of critical channels in humans and animals, like neurotransmitter channels. This can be extremely dangerous.

Amid the pandemic, researchers highlighted data suggesting that ivermectin might also have antiviral activity. And preliminary data suggested that the drug could thwart the pandemic coronavirus, SARS-CoV-2—at least in petri dishes. Specifically, ivermectin appeared to block critical intracellular transport proteins that SARS-CoV-2 uses to invade human cells. The drug may also interfere with the virus' ability to latch onto human cells with its spike protein.

COVID concerns

But the petri dish data has yet to translate into any convincing clinical data that the drug is actually useful against COVID-19 in whole people. Studies in humans have been small and produced inconsistent results. Meta-analyses [oup.com] aimed at weeding out potential clinical benefits have struggled with faulty data [researchsquare.com], and some have been retracted. [twitter.com]

Additionally, researchers have reason to doubt that further research will prove ivermectin is effective against COVID-19. As the National Institutes of Health notes in its clinical guidance [nih.gov], drug studies suggest that getting blood concentrations of ivermectin high enough to replicate the SARS-CoV-2-thwarting effects seen in petri dishes would "require administration of doses up to 100-fold higher than those approved for use in humans."

All of this hasn't stopped COVID misinformation mills on the Internet from promoting the drug—and people from buying into it. The FDA has been warning of misuse for months [fda.gov]. But amid the surge in the delta coronavirus variant, ivermectin misuse has escalated to alarming levels.

Dangerous drug use

In a health alert Thursday [cdc.gov], the Centers for Disease Control and Prevention warned that prescriptions for ivermectin have skyrocketed this month. And people unable to get a prescription for the drug have resorted to buying the over-the-counter livestock drugs, clearing out supplies in farming stores. In turn, poison control centers have seen a spike in ivermectin-related calls in recent weeks, and reports of serious illnesses from overdoses have also increased.

According to a recent analysis, the average rate of ivermectin prescriptions per week went from 3,600 prepandemic to a peak of 39,000 prescriptions in the week ending on January 8 of this year, when COVID-19 cases surged. Since early July, ivermectin dispensing has again surged along with COVID-19 cases, reaching more than 88,000 prescriptions in the week ending August 13, the CDC noted. That translates to a 24-fold increase from the prepandemic baseline.

With the drug booms came booms in poisonings. In January, poison control centers across the US received three times the number of ivermectin-related calls compared with the prepandemic baseline, the CDC reported. In July, ivermectin calls have continued to increase sharply, reaching a fivefold increase from baseline. The calls have also been linked to a rise in ivermectin-related emergency department and hospital visits.

The CDC alert highlighted two cases, one in which an adult drank an injectable ivermectin formulation intended for use in cattle in an attempt to prevent COVID-19 infection. The person experienced confusion, drowsiness, visual hallucinations, and tremors and spent nine days in the hospital. Another adult was hospitalized after taking ivermectin tablets of unknown strength that were bought off the Internet. The person took five pills a day for five days and developed an "altered mental status," in which they were disoriented and unable to answer questions or follow commands.

State-level concerns

In a report Wednesday [usatoday.com], USA Today noted state-level trends in poison control center calls. In Florida, for instance, there were 27 ivermectin-related calls to the poison control center in August, up from 11 in July. From January to June, there were only six calls total. Likewise, in Texas, the state's poison control center fielded 150 calls about ivermectin this year, with 55 of them just in August. In Georgia, the poison control center typically sees about one ivermectin-related call per month. This month, it has logged around 15 so far.

In Arkansas, officials also noted an increase in ivermectin-related calls to the state's poison control center. One official in Arkansas' Washington County was particularly alarmed to learn that the medical provider for a county detention center has been prescribing ivermectin to inmates and county employees [washingtonpost.com]. Since the start of the pandemic, over 500 inmates at the center have tested positive for COVID and an unknown number of them received the drug.

Dr. Rob Karas, the medical provider for the center, told a local CBS affiliate [5newsonline.com] that he had taken ivermectin himself and given it to many of his family members. The Arkansas Medical Board has since opened an investigation into the case [5newsonline.com].

Still, some state leaders continue to send dangerous messages about the drug. In a Thursday tweet related to Karas' case [twitter.com], Arkansas State Rep. Robin Lundstrum wrote: "Doc saves 500 inmates lives, taxpayers money & saves hospital bed space! Let's stone Doc & Sherriff instead of thanking them!"

Likewise in Alaska, Kenai Peninsula Borough Mayor Charlie Pierce continued to promote and defend ivermectin use [go.com], saying in a radio interview: “Let the doctors experiment with perhaps some things that haven’t been signed off by the Food and Drug Administration.”

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Ivermectin and COVID-19: Why poison centers are getting calls about this controversial drug [cnet.com]:

Since the start of the COVID-19 [cnet.com] pandemic, some medical professionals have reviewed already available drugs to see if they could be used as effective treatments. Ivermectin, an anti-parasitic, was administered to some patients across the globe, with seemingly positive effects. However, more studies show it has little to no effect when it comes to treating COVID-19. There's also been an increase in calls to poison centers [ms.gov] by people who are taking ivermectin intended for animals.

On one side, there are doctors who say ivermectin could help end the pandemic if used globally. On the other are public health officials who have reviewed the data and say the drug's effectiveness against COVID-19 isn't conclusive.

Get the CNET Culture newsletter Explore movies, games, superheroes and more with CNET Culture. Delivered Tuesdays and Fridays.

Here's everything you need to know about ivermectin and its use for COVID-19.

What is ivermectin?

Ivermectin is an anti-parasitic medicine "that works by altering cellular channels," said Dr. Soumi Eachempati, CEO of Cleared4 [cleared4.org] and former professor of surgery and public health at Weill Cornell Medical College. The drug inhibits some viruses from infecting cells, thus preventing the virus from spreading. Ivermectin is usually given to treat parasitic infections like lice and Strongyloides, according to Eachempati.

Scientists at pharmaceuticals giant Merck discovered ivermectin in 1975 and began to use it to treat scabies, river blindness and other parasitic diseases carried by worms and lice starting in 1981. It's on the World Health Organization's list of essential medicines [who.int] for a basic health care system. More than 250 million people take the drug [nature.com] across the globe each year, and it's effective for animals as well.

The drug is considered safe when taken in appropriate dosages. Side effects for the ivermectin [medicalnewstoday.com] vary depending on whether it's taken orally to treat intestinal infections or topically for skin infections. Oral tablets can cause drowsiness, nausea, vomiting and, in very rare cases, an increase in heart rate and seizures. Side effects for the topical ivermectin can include skin rash and irritation, while dry skin and stinging pain are severe and rare.

Can ivermectin be used to cure COVID-19?

This is where things get complicated. Public health agencies, including the Federal Drug Administration, the National Institutes of Health and the World Health Organization, don't suggest ivermectin's use to treat COVID-19. They cite the lack of data from large, randomized trials confirming the drug's effectiveness to treat the disease.

Doctors who cited multiple smaller studies and firsthand experience say otherwise. They claim ivermectin does work to prevent people from developing symptoms from COVID-19 and can shorten recovery time for those already infected.

What do the public health agencies say about ivermectin use for COVID-19 treatment?

The FDA said in March it hasn't approved the use of ivermectin to treat COVID-19 [fda.gov]. It warned that large doses of the drug are "dangerous and can cause serious harm." The agency also advised against human use of ivermectin produced for animals, such as cows and horses, as the doses aren't the same and could contain ingredients intended only for animals.

A growing number of people have been taking ivermectin for animals [go.com] as word's spread on social media about its possible use against COVID-19. This has resulted in some people calling state poison centers [go.com] after taking the drug, since the medication is intended for animals. On Aug. 20, the Mississippi State Department of Health sent out an alert regarding the number of calls its poison center received, with 70% related to the "ingestion of livestock or animal formulations of ivermectin purchased at livestock supply centers [ms.gov]."

In April, the FDA reaffirmed in a post on its website that ivermectin isn't approved to treat COVID-19 nor has it been given emergency use authorization [fda.gov].

The NIH said in February there was insufficient data [nih.gov] to "recommend either for or against the use of ivermectin for the treatment of COVID-19." It did say lab tests found the drug stopped the reproduction of the SARS-CoV-2 virus that cause the disease. However, to be effective, the dosages would need to be "100-fold higher than those approved for use in humans."

While some clinical studies showed ivermectin to have no benefit, the NIH said others saw a lower mortality rate among patients. However, those studies were incomplete or had methodological limitations such as small sample sizes or patients receiving additional medicine along with ivermectin, according to the NIH.

The WHO said in March [who.int] the current evidence on the use of ivermectin for treatment of COVID-19 was "inconclusive."

Who says ivermectin is a treatment, and what information do they have?

Ivermectin's potential use as a COVID-19 therapeutic made headway last December during a Senate Homeland Security Committee meeting called Focus on Early Treatment of COVID-19. Dr. Pierre Kory, a pulmonary and critical care specialist, testified about the drug's usage for treatment of the disease.

"Ivermectin is highly safe, widely available, and low cost," Kory said in the Senate meeting [senate.gov]. "We now have data from over 20 well-designed clinical studies, 10 of them randomized, controlled trials, with every study consistently reporting large magnitude and statistically significant benefits in decreasing transmission rates, shortening recovery times, decreasing hospitalizations, or large reductions in deaths. These data show that ivermectin is effectively a 'miracle drug' against COVID-19."

During his testimony, Kory referred to a paper he authored -- Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19 [covid19criticalcare.com] -- that was published in the May edition of the American Journal of Therapeutics.

The paper was also included in the Frontiers of Pharmacology journal [frontiersin.org] in January but was then removed in March [frontiersin.org]. Dr. Frederick Fenter, chief executive editor of the journal, said the paper was removed due to "strong, unsupported claims based on studies with insufficient statistical significance, and at times, without the use of control groups." Fender also said the authors promoted their own specific ivermectin-based treatment, which goes against editorial policies.

A study listed in Kory's paper involved giving ivermectin to 234 uninfected health care workers in Argentina [clinicaltrials.gov] and found those who received the drug were far less likely to be diagnosed with COVID. For mildly ill patients, an Iraq study saw a quicker recovery time [medrxiv.org].

There are also studies that show otherwise. A clinical trial of 476 patients [jamanetwork.com] found ivermectin didn't improve the recovery time in patients who had COVID-19. A review of 10 random clinical trials [oup.com], with more than 1,000 participants, also didn't find improvements with ivermectin. One Egyptian study [researchsquare.com] claimed to show positive results, but it's since been redacted over ethical concerns [theguardian.com]. Another study, of 1,500 patients [latimes.com], found that ivermectin had "no effect whatsoever."

Merck, the company that discovered ivermectin, released a statement in February [merck.com] saying there was "no scientific basis for a potential therapeutic effect against COVID-19 from pre-clinical studies" and "no meaningful evidence for clinical activity or clinical efficacy in patients with COVID-19 disease." It also cited a lack of safety data from major studies.

Why is there controversy over ivermectin?

The debate about ivermectin's usage to treat COVID-19 has gone from the hospital to social media, exacerbating the discourse as well as the vitriol. While those in support of the drug appear to want an end to the pandemic, their arguments in favor of ivermectin have become fodder for anti-vaxxers and conspiracy theorists.

Groups that have spread misinformation about COVID-19 throughout the pandemic latched onto ivermectin's usage following Kory's Senate testimony. Anti-vax groups on Telegram share misinformation about the vaccine while asking where they can buy the drug. Rumble, an alternative video platform to YouTube, has pages of videos falsely saying vaccines are ineffective while advising people to also take ivermectin.

Anti-vax posts and videos can also be found on YouTube, Facebook and Twitter, although the companies are attempting to take these posts down or make them harder to find.

Kory was a guest on the Dark Horse Podcast [apple.com] hosted by Bret Weinstein, a former professor at Evergreen State College, on June 1 to talk about ivermectin. That video was eventually demonetized on YouTube and Weinstein's channel received a strike, which prevented him from posting content for one week and could lead to its removal if he receives two more strikes within 90 days.

YouTube says its actions on Weinstein's videos were part of its policies.

"While we welcome open discussions of potential treatments and clinical trials related to COVID-19 on YouTube, based on guidance from the CDC, FDA and other local health authorities, we don't currently allow content that recommends ivermectin as an effective treatment or prevention method for the virus," said Ivy Choi, a YouTube spokesperson. "We craft our policies [outlook.com] to prevent the risk of egregious real-world harm, and update them as official guidance evolves. We do allow exceptions [outlook.com] to our policy about ivermectin, including content that also gives viewers the full context of the FDA's current position [outlook.com]."

Because of YouTube's decision, the controversy over ivermectin grew and became tied to what some claim to be "big tech censorship."

What is required for ivermectin to get approved for COVID-19 treatment?

For the public health agencies, it's going to come down to the results of large clinical studies being conducted around the world.

"In the UK, it was announced that ivermectin will be added to the Principle Trial [principletrial.org], a large clinical study designed to assess potential COVID therapies for non-hospitalized therapies for patients at higher risk for severe disease," said Dr. David Shafran, head of pediatrics at telehealth app K Health [khealth.com]. "This should demonstrate more definitively the efficacy of ivermectin in early-stage COVID infections. Fingers crossed because it's a cheap medication with a good safety profile. It would be great to add this to the armament of medication to fight COVID."

The Oxford University Principle Trial has more than 5,000 participants and will give a three-day course of oral ivermectin treatment to individuals randomly and compare their results to individuals who will receive standard care.

In the US, the NIH is evaluating therapeutics for COVID-19 with its Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) [nih.gov] master protocol. ivermectin was added in phase three of ACTIV-6, which will test the effectiveness of repurposed drugs.

"The ACTIV prioritization group, trial team and trial oversight groups continuously track new data on any agent we are studying in our trials and evaluate that data for how it might influence our testing of that agent and the safety/well being of the participants in the trial," said Dr. Sarah Dunsmore, a program director at the National Center for Advancing Translational Sciences that is part of the NIH.

What's unclear is how long the whole process will take. The studies need time to be completed, and then the agencies will require additional time to come up with decisions based on the data.

Ivermectin As a COVID-19 Therapy [sciencemag.org]:

Clinical Trials

I last wrote about ivermectin here [sciencemag.org], but I’m getting so many question about it that I need to revisit the topic. Although (I’ve said this before), I believe that I will regret doing it, because I expect the signal/noise in the comments section to degenerate to mid-pandemic levels in response.

The mechanistic story here has always been confused, but to be honest, that doesn’t bother me too much. There are a lot of effective drugs whose exact mechanisms we’re unclear about. But keep in mind that if you argue in favor of ivermectin because of its antiviral activity in cell assays, that these levels are far off of what is reached in the reported clinical effects (when there are any – see below). You can’t have both of those arguments working at once: if you build your case on the in vitro results, then you need to regard most of the clinical data as having been dosed at far too low a level to be relevant. I’m not interested in fighting about the mechanism of action, though – the real question is, does it work? If it does, we can figure out how it happens later.

My current opinion is pretty much exactly that of the WHO guidance [magicapp.org]: I do not think that the current evidence is strong enough to say that ivermectin is a useful therapy for coronavirus patients. I know that there are quite a few studies out there in the literature, but they suffer from various combinations of small sample size, poor trial design, not enough data reported, and (in many cases) inconclusive statistics. I think that WHO page does a solid job of evaluating the literature to that point, and overall, the better the quality of the evidence, the more it tends to show little or no effect of ivermectin.

Since that recommendation in March, nothing has appeared that changes my mind about that.  This study [wiley.com] from Egypt compared two groups of about 80 patients in an open-label design, which is certainly not ideal. But it failed to show any statistically significant differences between the treatment group and the controls. This study [mdpi.com] from Lebanon was more positive: it looked at fifty asymptomatic SARS-CoV-2 positive patients who received a single dose of ivermectin versus fifty asymptomatic age-matched positive controls. The treatment group showed a statistically significant change in cycle threshold when tested by PCR for viral load, indicating a lower viral load. But that goes against the earlier evidence (see the WHO page) that ivermectin treatment had either no effect on viral clearance or (in some cases) lengthened the time needed. This study [nih.gov] from Iran was double-blinded, but had only 35 patients in each group. The authors report a shorter duration of symptoms and shorter hospitalization in the ivermectin-treated group, but the statistics for the two groups still overlap, from what I can see.

Update: one of the more positive studies now appears to have fallen apart, and very badly [theguardian.com], with strong evidence of faked data and poor controls. It appears that if this one is taken out, that some meta-analyses of ivermectin trials that have pointed towards possible benefit may no longer even do so. . .

And this paper [jamanetwork.com], which appears to have come out in time to be included in the WHO guidance, is one of the larger studies. A team in Colombia looked at 200 ivermectin-treated patients and 200 controls with mild coronavirus infections, and found no statistical differences between the two. Objections [plos.org] have been raised to that trial’s use of an oral suspension formulation, I should note.

All in all, though, the most compelling reports of ivermectin’s effects seem to come from the smallest and least controlled samples (all the way down to anecdotal results) while the larger and more well-controlled trials tend to produce equivocal evidence at best. This very much reminds me of the hydroxychloroquine situation, which topic I have no desire whatsoever to revisit. A similar landscape of “the harder you look, the less you see” obtained there, too. And I have to say, there is a passionate constituency for ivermectin treatment, as there was for hydroxychloroquine. I hear from people who are convinced that this is the cure for the pandemic, and they are (variously) baffled that others don’t see it, zealous about spreading the word, or even ready to accuse the vaccine manufacturers and others of actively suppressing this treatment.

But as I said above, I look at the data and I’m not convinced, or certainly not yet (and neither are the WHO reviewers). The only way I can see the reaction of some of my correspondents is if they have been looking at all the most positive reports, accepting them completely and ignoring everything else, and that’s no way to treat the medical literature. This was the case for HCQ as well, I’m afraid. If you haven’t had to mess with drug discovery for a living, it’s understandable that you hear that Some Person Somewhere was very sick, took New Therapy X, and suddenly got better, and then assume that there it is, the cure has been found. But that’s not how it works. Real results stand up when you run larger, better-controlled trials, but most early results don’t turn out to be all that real. Even when this is your job, it’s frustrating to watch this happen, so I can only imagine how baffling it is if you haven’t seen this kind of evaporation before.

And as for the further bunch that are ready to go the conspiracy-theory route, well, as you’d imagine, I’m not having it. As usual, letting that stuff into your head simplifies everything enormously. Things get way too simple, actually. Everything bad is Their Fault, and you’re on the side of the good guys, the angels, struggling against the dark evil forces. It’s a bit like the pre-modern habit of thinking that made someone, every time they come down with some illness or problem, immediately wonder what witch or evil spirit did this to them. Someone has to be to blame, because nothing “just happens”. For the advanced conspiracy theorist, there are no accidents and there are no coincidences: things either directly support the all-encompassing theory, or they just show how the conspiracy is even bigger than it first appeared. It’s non-falsifiable – you can like your favorite conspiracy framework or you can love it, and those are your only choices.

So let me finish up by saying that my mind is not yet made up about ivermectin. I can be convinced by good data; if I couldn’t be, I shouldn’t be doing my day job at all. But I am not too optimistic – the data so far are consistent with a lot of other sorta-kinda-maybe-maybe not things I’ve seen over the years, where if you climb up on the right chair and hold your hand up to your face to block out the exact right stuff then things might look OK, but otherwise not so much. The good data that would dispel this are going to have to be really good, and the longer this goes on the less likely they seem.

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