The veterinary deworming drug ivermectin has become the new hydroxychloroquine in that it is being promoted as a highly effective treatment against COVID-19—and by many of the same people who previously promoted HCQ—despite evidence that is, at best very weak and at worst completely negative. Unfortunately, with the publication of two new and biased reviews, the “HCQ vibe” about ivermectin is stronger than ever. I must admit that I approached this topic initially with a distinct lack of enthusiasm. The reason is quite simple: Been there, done that. The topic is ivermectin, the new-old wonder drug to treat COVID-19 that evidence can’t seem to kill, and I’m definitely getting flashbacks to a year ago when the first “miracle drug” for COVID-19 was being widely touted, used, and studied. That drug was hydroxychloroquine, and ivermectin is basically the new hydroxychloroquine. So why write about ivermectin again now? For one thing, it’s still being touted, despite an evidence base that can be described most charitably as weak. Second, two new new review articles were recently published and are being touted by ivermectin fans as significant evidence that we should take the drug seriously as a treatment for COVID-19. Hint: They’re not. To see why I’m getting a strong “hydroxychloroquine” vibe from ivermectin, let’s briefly review what happened with hydroxychloroquine early in the pandemic. After that, I’ll discuss the narrative about the drug being promoted by quacks like Joe Mercola. Finally, I’ll address the evidence for ivermectin in COVID-19, including the two papers cited above. CONCLUSION Ivermectin is the new hydroxychloroquine Ivermectin advocates hate it when we say this, but it’s true. Ivermectin is the new hydroxychloroquine. It’s been promoted the same way and by the same people. The same conspiracy theories have sprung up around it as the scientific evidence supporting its use is weak at best, negative at worst. That’s why I’m going to go back to what I once wrote about hydroxychloroquine: Because I’m dedicated to evidence and science when it comes to medical decision making, I always concede that it is still possible that hydroxychloroquine might still be found to have some anti-COVID-19 activity, although it’s becoming increasingly clear that, if there is any activity it will likely be very modest and require large clinical trials to detect, to the point where it’ll probably be clinically insignificant. That being said, it’s amazing how much believers in acupuncture, vitamin C to treat cancer, and hydroxychloroquine to treat COVID-19 have in common. It’s also distressing how much like the villain in a slasher flick the drug is. No matter how many times it appears to have died, it always comes back. Substitute the word “ivermectin” for every instance of “hydroxychloroquine,” and the paragraph above is still accurate. Again, I concede that it is possible that ivermectin has clinically relevant in vivo antiviral activity against SARS-CoV-2. Based on current evidence, however, it seems unlikely that it does, when pharmacokinetics considerations are taken into account. As I routinely used to say when discussing hydroxychloroquine, I’d be happy to change my mind if compelling scientific evidence for ivermectin were published. It’s just that neither of these reviews qualify, nor do any of the clinical trials I’ve seen thus far. That’s why I agree that ivermectin shouldn’t be used to treat COVID-19 outside of the context of a well-designed clinical trial with a strong scientific rationale. Certainly, the conspiracy mongering by Bret Weinstein, Pierre Kory, and their fans are not leading me to reconsider that opinion. ------------------------------------------ Analysis Hydroxychloroquine: A brief history When the COVID-19 pandemic first hit early in 2020, it was a truly frightening time, particularly in hospitals in the hardest-hit areas, which were deluged with incredibly sick patients and no treatments other than supportive ones. Faced with dying patients for whom they couldn’t do a lot, doctors felt desperate and started trying something—anything—to save their patients’ live. They thus often threw “everything but the kitchen sink” at the disease, which, again, was understandable early on, when there was no evidence, but is less so now. In that time of desperation, one drug was more popular than any other. It was an antimalarial drug, hydroxychloroquine (HCQ), which had been repurposed to treat COVID-19 based on in vitro observations of antiviral activity, its known mild immunosuppressive effect that had led it to become a mainstay of the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosis, and observations in Wuhan, China during the first epidemic that ultimately led to the pandemic. How did hydroxychloroquine become the first “miracle drug” for COVID-19? In brief, Chinese researchers reported that none of their 80 patients with lupus erythematosus who were taking hydroxychloroquine went on to become infected with SARS-CoV-2. As a result of that and old evidence of antiviral activity for the drugs, they became interested in using these antimalarial drugs to treat COVID-19. (Never mind that immunosuppressed patients are exactly the patients most likely to assiduously follow the recommendations of public health authorities during a pandemic.) A number of clinical trials were registered, and, based on anecdotal reports and small clinical trials (nearly all of which are as yet unpublished), in February 2020 the Chinese government published an expert consensus recommending CQ or HCQ for patients with COVID-19. Soon after, a number of nations followed suit. From there, a French “brave maverick scientist” named Didier Raoult latched onto the drug as the “answer” to the COVID-19 pandemic, publishing risibly bad studies claiming to show its efficacy. Tech bros such as Elon Musk discovered the claims about hydroxychloroquine and Raoult’s bad science, leading to Donald Trump Tweeting favorably about his study and, ultimately, to the FDA issuing an emergency use authorization for the drug to treat COVID-19. Unfortunately, it was not long before a drip-drip-drip of negative studies started to cast doubt on whether hydroxychloroquine had any activity against COVID-19, and by summer’s end last year it was pretty obvious that there was no “there” there with hydroxychloroquine, that it didn’t work. Even so, the drug continued to be promoted with enthusiasm ranging from just suggesting that it could prevent COVID-19 after exposure to the virus to full-blown “miracle drug” claims. I once referred to hydroxychloroquine as the “Black Knight” of COVID-19 treatments, a reference to the scene in Monty Python and the Holy Grail in which the Black Knight refuses to admit defeat even as Arthur lopped off limb after limb because evidence just couldn’t seem to kill it. The saga of hydroxychloroquine demonstrated the importance of randomized clinical trials, even in a pandemic, and the price of abandoning science- and evidence-based medicine in the face of hucksters and astroturf groups promoting the drug with bad science and “miracle cure” testimonials the drug and physicians making an honest effort to try something—anything—to save their patients. As it became clear from more and more evidence that hydroxychloroquine doesn’t work against COVID-19, the narrative started to—shall we say?—evolve? For instance, Dr. Vladimir Zelenko claimed that you had to use zinc with hydroxychloroquine. Others started coming up with cocktails of drugs, vitamins and supplements willy-nilly, with no evidence for efficacy of any of the individual components except the steroids sometimes included in the mix, with grand claims that the cocktail was the miracle cure. Truly, 2020 was a year of physicians behaving badly. In the midst of this massive shifting of goalposts came ivermectin, which many have dubbed “the new hydroxychloroquine.” Enter ivermectin, the new hydroxychloroquine Just as hydroxychloroquine was repurposed based on in vitro (cell culture and biochemical) studies showing antiviral activity that didn’t translate to in vivo (in experimental animals or humans) activity, it was proposed to repurpose ivermectin based on in vitro observations of antiviral activity. Just as hydroxychloroquine was widely used despite a marked lack of evidence, so, too, in many parts of the world ivermectin is being used to treat COVID-19 patients despite a marked lack of evidence. Just as an astroturf effort to promote hydroxychloroquine as an effective treatment for COVID-19 popped up, so, too, an astroturf campaign, complete with conspiracy theories about ivermectin—like hydroxychloroquine!—being an inexpensive drug that “they” don’t want you to know about because its wide use would harm big pharma profits and the sales of COVID-19 vaccines, has emerged. As we’ve seen, hydroxychloroquine is an antimalaria drug that also has modest immunosuppressive effects sufficient to be useful for some autoimmune diseases, but what is ivermectin? Basically, as colleague and friend Scott Gavura described, ivermectin (Stromectol) is an antiparasitic drug used to treat intestinal strongyloidiasis (threadworm, caused by infection from Strongyloides stercoralis), onchocerciasis (river blindness, caused by the parasitic worm Onchocerca volvulus, and spread by the Simulium blackfly), and roundworm infestations. In veterinary medicine, ivermectin is commonly used to prevent heartworm in dogs and cats and is also used off-label to treat a number of other parasitic infections in animals, including mites in dogs (demodectic mange, scabies, and ear mites) and intestinal parasites (hookworms, roundworms), and Capillaria. In farming, the drug is also used as a deworming medicine in cattle, swine, sheep, goats, and horses. The interest in ivermectin appears to have originated in an Australian study published early in the pandemic that showed that high concentrations of ivermectin in vitro demonstrated antiviral activities. I’m not going to rehash that study in detail, as Scott has already discussed it, other than to repeat and emphasize that the concentrations used in the experiments published were not concentrations that were achievable in the plasma using standard dosages and to cite a short article from June 2020 that pointed out that pharmacokinetic considerations made ivermectin a poor candidate as an antiviral drug, regardless of how much antiviral activity it might have exhibited at high concentrations in vitro. Basically, the article pointed out that it is likely not possible to achieve the same concentrations of the drug in the plasma, because the drug itself is tightly bound to blood proteins and that even 8.5X the FDA-approved dose (1,700 μg/kg) resulted in blood concentrations far below the dose identified for antiviral effects. I’ll also point out that Scott nicely summarized earlier studies that failed to find a significant impact on the clinical course of COVID-19. Unfortunately, as was the case with hydroxychloroquine before, conspiracy theories have arisen around the supposed “suppression” of ivermectin. I hasten to point out that hydroxychloroquine hasn’t gone away. Indeed, it is still being touted in Brazil now, fed by the misinformation promoted by Brazilian President Jair Bolsonaro, even as Brazil’s death toll has hit 500,000 and looks likely to surpass that of the US, whose death toll recently hit 600,000 but is slowing down markedly as more and more people are vaccinated. Even so, ivermectin is the new hydroxychloroquine in much of the rest of the world, particularly in the antivaccine, COVID-19-minimizing conspiracy world. One example is how, a month ago, ivermectin was being offered to every citizen of India as the pandemic was killing thousands of people a day in that country, bizarrely leading to bogus claims that ivermectin had “crushed” COVID-19 in that country based on highly dubious “analyses” supposedly correlating ivermectin use with decreased numbers of deaths. Indeed, the Indian health ministry ditched ivermectin as a recommended treatment earlier this month. Let’s look at the narrative. COVID, ivermectin and the “crime of the century” A week and a half ago, über-quack Joe Mercola published an article entitled “COVID, Ivermectin and the Crime of the Century“, naming it after an episode of Bret Weinstein’s podcast. It features an interview with Dr. Pierre Kory, one of the most prominent proponents of ivermectin for COVID-19 by evolutionary biologist Bret Weinstein, who has become prominent as a COVID-19 contrarian and spreader of disinformation, particularly about the “lab leak theory” of SARS-CoV-2 origins. He now likes to Tweet about “persecution” by Twitter: It also turns out that Dr. Pierre Kory is president of the Frontline COVID-19 Critical Care Alliance (FLCCC) and has testified before Congress. During that testimony, Dr. Kory claimed that ivermectin, used with other medicines such as vitamin C, zinc and melatonin, could “save hundreds of thousands of people,” and cited more than 20 studies. The narrative of Mercola’s article is eerily similar to the narratives we heard about hydroxychloroquine a year ago, namely that ivermectin is a cheap, safe, and effective drug that “they” don’t want you to know about that could have saved hundreds of thousands of lives if not for doctors’ fetish for randomized clinical trials. For example: Yet, despite stellar credentials and being on the frontlines treating hundreds of COVID-19 patients, they have been dismissed as “kooks on the fringe, making wild-eyed claims,” Weinstein says. How can that be? Initially, the FLCCC insisted, based on the evidence, that COVID-19 was a corticosteroid-dependent disease and that corticosteroids were a crucial part of effective treatment. And: Since those early days, the FLCCC has been vindicated and corticosteroids, as well as blood thinners, are now part of the standard of care for COVID-19 in many places. The same cannot be said for the remainder of the protocols, however, including the use of ivermectin, which continues to be suppressed, despite robust clinical evidence supporting its use in all phases of COVID-19. I do like how the FLCCC claims the “brave maverick doctor” and “brave maverick scientist” role and assumes that, because Dr. Kory was on the right side of a couple of areas then he must be right about everything. I also can’t help but note that Dr. Kory, contrary to his “brave maverick” claims, was nowhere near the only one proposing the use of anticoagulants and steroids as part of the supportive treatment of severe COVID-19. These were being debated at my hospital in March 2020 (admittedly, along with hydroxychloroquine). And, of course, Dr. Kory pulls the favorite gambit of doctors promoting dubious treatments, the “we can’t do randomized clinical trials because it’s unethical” gambit: With regard to calls for randomized controlled trials, Kory points out that once you can see from clinical evidence that something really is working, then conducting controlled trials becomes more or less unethical, as you know you’re condemning the control group to poor outcomes or death. I suppose it’s the same reason that antivaxxers think a double-blind, randomized controlled trial of vaccinating versus not vaccinating children is ethical, because they falsely believe that vaccines cause harm. In this case, the ivermectin believers already fervently believe that ivermectin cures (or at least is a highly effective treatment for) COVID-19. And, of course, ivermectin is being “suppressed”: As noted by Weinstein, ivermectin appears to be intentionally suppressed. It’s simply not allowed to be a go-to remedy. The obvious question is why? Don’t they want to save lives? Isn’t that why we shut down the world?“I would have these data arguments,” Kory says. “But it’s not about the data. There’s something else. There’s [something] out there that is just squashing, distorting, suppressing the efficacy of ivermectin, and its egregious.”Indeed, as noted by Weinstein, it’s not even difficult to prove that ivermectin is being suppressed and censored. Censorship of certain COVID-related information, such as ivermectin, is written into the community guidelines. You’re not allowed to talk about it. If you do, your post will be censored, shadow-banned or taken down. If you persist, your entire account will be taken down. Meanwhile, journalist Matt Taibbi, someone who really should know better but apparently does not, is promoting the conspiracy theory with an article on Substack entitled ‘Why Has “Ivermectin” Become a Dirty Word?’ Its subtitle? “At the worst moment, Internet censorship has driven scientific debate itself underground.” Ask yourself if this sounds familiar: A consequence is that issues like the ivermectin question have ended up in the same public bucket as debates over foreign misinformation, hate speech, and even incitement. The same Republican Senator YouTube suspended for making statements in support of ivermectin, Ron Johnson, has also been denounced in the press for failing to call the January 6th riots an insurrection, resulting in headlines that blend the two putative offenses. “You have these ideas about the need to censor hate speech, calls for violence, and falsity,” Kory says, “and they’ve put science on the same shelf.” Congratulations, Mr. Taibbi! You’ve used an argument identical to one that I’ve seen used by antivaxxers and quacks on many an occasion dating back 16 years, complete with a false characterization of quality control as “censorship.” Indeed, fans of cancer quack Stanislaw Burzynski loved to use similar arguments, claiming that their hero’s work was being “suppressed.” Taibbi even uncritically quotes ivermectin fans saying just that: Ivermectin may never be proven effective as a Covid-19 treatment, but its story has already appeared as a powerful metaphor of the Internet’s transformation. Once envisioned as a vast democratizing tool, which would massively raise global knowledge levels by allowing instant cross-global communication between all people, it’s morphed instead into a giant unaccountable bureaucracy for suppressing dialogue, run by people with an authoritarian vision for information flow. Many ivermectin advocates believe discussion of the the [sic] drug is being suppressed because of its status as a threat to a billion-dollar vaccine business, but it’s just as likely that its reputation worldwide as a “populist” treatment, a medicine taken by people not waiting for official validation, has made it a target of censors and pundits alike. “I think what happened is that at the outset of the pandemic, it was decided that all information must go in one direction, from the Gods of Science down,” says Kory. “But that’s not the way it works. Science happens on the ground. That’s where the little discoveries are made. They don’t happen at the top of the mountain.” As I said, Dr. Kory is pushing a classic conspiracy theory very much like the classic conspiracy theory about hydroxychloroquine last year, that ivermectin is a cure for COVID-19 that “they” don’t want you to know about. (And it’ll render vaccines unnecessary.) I see echoes of Kevin Trudeau. Who is this “Gorski” character, anyway? But what about the evidence? Mercola cites in the interview the various lines of evidence listed by Dr. Kory. It turns out that Scott already dealt with a number of those studies. I’m going to focus mainly on the two that I cited initially. Both are being touted on Twitter. Here’s the first: And here’s the second: Let’s dig in, starting with the “clinical review article.” Mechanisms of ivermectin against SARS-CoV-2? The first article is labeled a “clinical review article”. That immediately puzzled me, because it’s far more a basic science review article than it is a clinical review. The vast majority of the article is a rehash of in vitrostudies showing antiviral activity of the drug at high concentrations, as listed in Table 2. It is not really a systematic review, and it’s published in a relatively minor journal by two people who are part of a pro-ivermectin advocacy group, and people on Twitter also immediately saw a lot of issues with the studies cited, for example: https://twitter.com/GidMK/status/1405362898415718403 Basically, the authors cite a paper that found that ivermectin inhibits the activity of a protein, importin, that, according to them, “blocking the nuclear transport of viral proteins.” Given that the viruses replicate in the cytoplasm (the rest of the cell other than the nucleus), you can see why Ed was unimpressed. It is true that if even a part of the viral replication process takes place in the nucleus such inhibition might be useful, but even if that were the case, this is stretching. Also: https://twitter.com/ENirenberg/status/1405366854827323392 https://twitter.com/GidMK/status/1405367503174324231 Perusing the totality of the paper, I noted that the authors cite a lot of biochemical papers that purport to show that ivermectin interferes with various cellular processes relevant to the replication of SARS-CoV-2 in a sort of “shotgun” approach, all with a heaping dose of speculation. For instance, they cite computer modeling (in silico) work thusly: Another in-silico study by Swargiary et al. demonstrated the best binding interaction of −9.7 kcal/mol between Ivermectin and RdRp suggesting inhibition of viral replication [33]. The RdRP residing in nsp12 is the centerpiece of the coronavirus replication and transcription complex and has been suggested as a promising drug target as it is a crucial enzyme in the virus life cycle both for replication of the viral genome but also for transcription of subgenomic mRNAs (sgRNAs) [34]. Ivermectin binds to the viral rdrp and disrupts it. The highly efficient binding of ivermectin to nsp14 confirms its role in inhibiting viral replication and assembly. It is well known that nsp14 is essential in transcription and replication. It acts as a proofreading exoribonuclease and plays a role in viral RNA capping by its methyltransferase activity [35]. Moreover, highly efficient binding of ivermectin to the viral N phosphoprotein and M protein is suggestive of its role in inhibiting viral replication and assembly [23]. This is a lot of handwaving and speculation. It might have value as pre-clinical evidence to support trying ivermectin in animal models of viral illnesses, but in and of itself, none of it is good evidence that ivermectin actually works in humans. Then there was this red flag: https://twitter.com/GidMK/status/1405362892845686785 That’s a world-record time for acceptance of a review article for publication! The only other instances that I can recall of such rapid acceptance have been by “pay-to-publish” predatory journals. Be that as it may, oddly enough, the only human evidence cited by the authors comes primarily from a pro-ivermectin website, Ivermectin for COVID-19: real-time meta analysis of 60 studies, whose abuse and misunderstanding of the use of p-values is epic: The probability that an ineffective treatment generated results as positive as the 60 studies to date is estimated to be 1 in 2 trillion (p = 0.00000000000045). I like how this was immediately mocked—and rightfully so: https://twitter.com/GidMK/status/1405362910298185731 I also can’t help but note that this ivmmeta.com website uses exactly the same dubious techniques as were used by another website, hcqmeta.com, to tout hydroxychloroquine. Indeed, it very much appears that the same people are behind the two websites, and it is rather clear to me that these websites represent an astroturf effort to promote unproven treatments for COVID-19. There’s a saying I invoke all the time for meta-analyses and systematic reviews: GIGO, or “garbage in, garbage out”. Neither ivmeta.com nor hcqmeta.com is a true meta-analysis, as neither properly takes into account the quality of the studies being pooled, as is pointed out here: https://twitter.com/GidMK/status/1405362920985292802 https://twitter.com/GidMK/status/1405362929143144453 To quote the WHO analysis: Compared with previous drugs evaluated as part of the WHO Living Guidelines for Therapeutics in COVID-19 (see below), currently there are far fewer RCT data available for ivermectin. The existing data on ivermectin also have a substantially higher degree of uncertainty, with included trials having enrolled substantially fewer patients with far fewer events. And: For most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalization and viral clearance, the panel considered the evidence of very low certainty. Evidence was rated as very low certainty primarily because of very serious imprecision for most outcomes: the aggregate data had wide confidence intervals and/or very few events. There were also serious concerns related to risk of bias for some outcomes, specifically lack of blinding, lack of trial pre-registration, and lack of outcome reporting for one trial that did not report mechanical ventilation despite pre-specifying it in their protocol (publication bias). I also can’t help but note that there are other astroturf-like websites promoting ivermectin too, such as c19ivermectin.com, which has identical formatting and methodologies to a previous website for hydroxychloroquine, c19hcq.com. We have been warned about them for a long time: Different websites (such as https://ivmmeta.com/, https://c19ivermectin.com/, https://tratamientotemprano.org/estudios-ivermectina/, among others) have conducted meta-analyses with ivermectin studies, showing unpublished colourful forest plots which rapidly gained public acknowledgement and were disseminated via social media, without following any methodological or report guidelines. These websites do not include protocol registration with methods, search strategies, inclusion criteria, quality assessment of the included studies nor the certainty of the evidence of the pooled estimates. Prospective registration of systematic reviews with or without meta-analysis protocols is a key feature for providing transparency in the review process and ensuring protection against reporting biases, by revealing differences between the methods or outcomes reported in the published review and those planned in the registered protocol. These websites show pooled estimates suggesting significant benefits with ivermectin, which has resulted in confusion for clinicians, patients and even decision-makers. This is usually a problem when performing meta-analyses which are not based in rigorous systematic reviews, often leading to spread spurious or fallacious findings. This is as good a point as any to move on to the meta-analysis being touted by Dr. Kory. It comes from the UK, specifically from authors associated with the BIRD Group, a pro-ivermectin advocacy group that appears to me to be very similar to the FLCCC. More analysis at https://respectfulinsolence.com/2021/06/28/ivermectin-is-the-new-hydroxychloroquine-for-covid-19/