Ivermectin

Pharmacological Actions

Ivermectin is an anti-parasitic agent primarily indicated for treating infections such as onchocerciasis, strongyloidiasis, and scabies. Its mechanism of action involves binding selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells, particularly in microfilaria. This binding increases permeability to chloride ions, leading to hyperpolarization, paralysis, and death of the parasite. Additionally, Ivermectin acts as an agonist of gamma-aminobutyric acid (GABA), disrupting central nervous system neurosynaptic transmission in parasites, which further contributes to its efficacy.
Recent studies, such as those published in Ivermectin: A Multifaceted Drug With a Potential Beyond Anti-parasitic Therapy, suggest emerging roles in anti-inflammatory, anti-viral, and even anti-cancer activities, though these are less established and require further research, especially for human applications.
The time course of these actions is influenced by pharmacokinetics. Peak plasma concentrations (Cmax) are typically reached around 4 hours post-oral administration, with effects on parasites beginning shortly thereafter, as evidenced by studies in The Pharmacokinetics and Interactions of Ivermectin in Humans—A Mini-review. The duration of action aligns with its half-life, ensuring sustained activity against parasites over approximately 18 hours.

Pharmacokinetics
Half-Life: The elimination half-life of Ivermectin following oral administration is approximately 18 hours, as detailed in Ivermectin: Uses, Interactions, Mechanism of Action | DrugBank Online. This indicates that it takes about 18 hours for the plasma concentration to reduce by half, influencing dosing intervals for repeated treatments.
Bioavailability: Oral bioavailability is moderate and can be enhanced with a high-fat meal, improving absorption. Specific percentages are not universally reported, but studies indicate variability. For instance, an oral solution (ethanolic) has been shown to have approximately twice the systemic availability compared to tablets or capsules, as noted in The Pharmacokinetics and Interactions of Ivermectin in Humans—A Mini-review. Factors such as co-administration with beverages like beer can increase plasma levels, while orange juice may decrease bioavailability, highlighting the importance of administration conditions.
Other routes, such as topical, are used for conditions like rosacea, but bioavailability data for these are less relevant to the oral focus here. The drug does not cross the blood-brain barrier significantly, with a volume of distribution of 3 to 3.5 L/kg, and is 93% protein-bound, primarily metabolized hepatically and excreted in feces (>99%).
Dosage Considerations
Dosages vary based on the condition and patient weight, with detailed guidelines provided in clinical resources like Medscape: Stromectol (ivermectin) dosing. Below is a table summarizing key dosage information:

Condition	Typical Dose (Adults, Oral)	Notes
Strongyloidiasis	200 μg/kg (e.g., 15 mg for >80 kg) once	Repeat doses not usually necessary; verify eradication with stool exams
Onchocerciasis (River Blindness)	150 μg/kg (e.g., 12 mg for 80 kg) once, may repeat in 3-12 months	Does not treat adult worms, which may require surgical excision
Scabies (Immunocompromised, Off-label)	200 μg/kg once, may repeat in 14 days	Higher doses for severe cases under medical supervision

Therapeutic Range: The standard therapeutic dose is 150-200 μg/kg, translating to approximately 10.5-14 mg for a 70 kg individual, administered as a single dose for most indications.
Minimum Effective Dose: For onchocerciasis, the minimum effective dose is around 150 μg/kg, ensuring sufficient plasma levels to paralyze microfilaria, as supported by INCHEM: Ivermectin.
Maximum Safe Dose: Typically, single doses up to 200 μg/kg are considered safe, with clinical experience showing 9% adverse effects at 150 μg/kg, mostly Mazzotti-type reactions (e.g., edema, pruritis), and 0.25% severe, as per INCHEM: Ivermectin. Higher or repeated doses, such as in crusted scabies, may reach up to seven doses over a month, but this is under strict medical supervision.
LD50 and Toxicity: The LD50, or lethal dose for 50% of subjects, is estimated at 2-43 mg/kg in humans, extrapolated from animal studies (e.g., mice LD50 oral 25 mg/kg, dogs 80 mg/kg, rats around 50 mg/kg subcutaneously, as per Comparative evaluation of acute toxicity of ivermectin by two methods after single subcutaneous administration in rats - PubMed and Ivermectin - Wikipedia). This indicates a wide margin of safety at therapeutic doses, with the therapeutic range (0.15-0.2 mg/kg) being significantly lower.
When It Becomes Dangerous: Case reports suggest toxicity symptoms, such as mydriasis, vomiting, and neurological effects, at doses around 5-10 mg/kg. For example, a 16-month-old boy ingesting 100-130 mg (approximately 6.7-8.7 mg/kg for 15 kg) experienced symptoms but recovered, as noted in INCHEM: Ivermectin. Higher doses, such as those reported in overdose cases (e.g., up to 125 mg in veterinary formulations, potentially 1.8 mg/kg for a 70 kg adult), can lead to severe effects like coma, as per Toxic Effects from Ivermectin Use Associated with Prevention and Treatment of Covid-19 | New England Journal of Medicine. The evidence leans toward doses above 7 mg/kg being considered toxic, especially for off-label uses like COVID-19, where achieving anti-viral effects in vitro required such high doses, as mentioned in Ivermectin - Wikipedia.

The controversy around Ivermectin, particularly its off-label use for COVID-19, has led to increased reports of toxicity, with the FDA and CDC issuing warnings about overdoses, as seen in Ivermectin toxicity, treatment: Self-medicating COVID-19 danger. This highlights the importance of adhering to approved indications and dosages, with therapeutic levels being well-tolerated in non-infected individuals, while higher doses in infected patients may exacerbate adverse reactions due to parasite die-off.
In summary, Ivermectin’s pharmacological actions are well-established for parasitic treatment, with clear pharmacokinetic profiles and dosage guidelines. However, caution is advised at doses exceeding therapeutic ranges, with toxicity thresholds identified around 5-10 mg/kg, and severe risks at higher levels, particularly in non-approved uses.
Positive Impacts by Condition
Ivermectin has shown effectiveness across several parasitic infections, with specific percentages from clinical studies:

Onchocerciasis (River Blindness): Reduces skin microfilariae by 98-99% after 1-2 months and decreases female worms with live microfilariae by about 70%.
Lymphatic Filariasis: Achieves 100% microfilarial clearance at day 12, with levels at 18-20% of pretreatment at 6 months.
Strongyloidiasis: Offers a 96.8% cure rate with a single dose, increasing to 98% with two doses.
Scabies: Provides a 62.4% cure rate with one dose, rising to 92.8% with two doses, and up to 100% in some studies with appropriate dosing.
Head Lice: Shows a 95.2% efficacy rate in difficult-to-treat cases with oral administration.

Safety and Convenience
Ivermectin is generally safe, with adverse reactions occurring in 6-13 per 1000 people for onchocerciasis initially, decreasing with subsequent doses. Its single-dose oral administration improves compliance, especially in resource-limited settings.
Pharmacological Actions
Ivermectin works by binding to glutamate-gated chloride channels in parasites, causing paralysis and death. It’s selective for parasites, ensuring safety in humans, and also prevents adult female worms from releasing microfilariae in conditions like onchocerciasis.
Detailed Side Effects with Percentages
Below, side effects are categorized by system, with percentages from various sources, including the Stromectol prescribing information for strongyloidiasis and onchocerciasis, and a COVID-19 trial (JAMA, 2021, at 400 μg/kg dose). Post-marketing reports are included where percentages are not available.
Neurological Side Effects
These are linked to Ivermectin’s potential CNS effects, especially at higher doses:

Dizziness: 2.8% (strongyloidiasis), 34.0% (COVID-19 trial)
Somnolence: 0.9% (strongyloidiasis)
Vertigo: 0.9% (strongyloidiasis)
Tremor: 0.9% (strongyloidiasis), 6.5% (COVID-19 trial)
Headache: 0.2% (onchocerciasis), 52.0% (COVID-19 trial)
Confusion, ataxia, seizures: Reported in overdose or misuse cases, frequencies not quantified.

Gastrointestinal Side Effects
Often mild and transient, possibly due to direct irritation:

Diarrhea: 1.8% (strongyloidiasis), 26.0% (COVID-19 trial)
Nausea: 1.8% (strongyloidiasis), 23.0% (COVID-19 trial)
Vomiting: 0.9% (strongyloidiasis), 1.5% (COVID-19 trial)
Abdominal pain: 0.9% (strongyloidiasis), 18.0% (COVID-19 trial)
Anorexia: 0.9% (strongyloidiasis)
Constipation: 0.9% (strongyloidiasis)

Dermatological Side Effects
Linked to immune responses, especially in onchocerciasis:

Pruritus: 2.8% (strongyloidiasis), 27.5% (onchocerciasis)
Rash: 0.9% (strongyloidiasis), 6.0% (COVID-19 trial)
Urticaria: 0.9% (strongyloidiasis)
Skin involvement (edema, papular/pustular rash): 22.7% (onchocerciasis)
Skin discoloration: 6.5% (COVID-19 trial)
Toxic epidermal necrolysis, Stevens-Johnson syndrome: Post-marketing reports, frequencies not quantified.

Musculoskeletal Side Effects
Often part of the Mazzotti reaction in onchocerciasis:

Arthralgia/synovitis: 9.3% (onchocerciasis)
Myalgia: 0.4% (onchocerciasis)

Lymphatic Side Effects
Common in onchocerciasis due to immune response:

Lymph node enlargement and tenderness: Various, e.g., inguinal lymph node enlargement 12.6%, tenderness 13.9% (onchocerciasis)

Cardiovascular Side Effects
Linked to systemic effects, possibly dose-related:

Tachycardia: 3.5% (onchocerciasis)
Orthostatic hypotension: 1.1% (onchocerciasis)
Hypotension: Post-marketing reports, frequencies not quantified.

Ophthalmological Side Effects
Noted in both standard and high-dose uses, transient in many cases:

Disturbances of vision: 16.5% (COVID-19 trial)
Blurry vision: 11.5% (COVID-19 trial)
Photophobia: 3.5% (COVID-19 trial)
Reduction in visual acuity: 2.0% (COVID-19 trial)
Conjunctival hemorrhage: Post-marketing reports, frequencies not quantified.

General Side Effects
Non-specific, often mild:

Asthenia/fatigue: 0.9% (strongyloidiasis)
Fever: 22.6% (onchocerciasis)
Edema: Facial 1.2%, peripheral 3.2% (onchocerciasis)
Swelling: 2.0% (COVID-19 trial)

Respiratory and Hepatic Side Effects
Rare but serious, often from post-marketing data:

Worsening of bronchial asthma: Post-marketing reports
Hepatitis, elevation of liver enzymes, elevation of bilirubin: Post-marketing reports, frequencies not quantified.

Other Side Effects
Severe and rare, linked to neurotoxicity:

Neurotoxicity: Somnolence/drowsiness, stupor, coma, confusion, disorientation, death (post-marketing reports)

Impact in Medical Contexts: Bacterial Biofilms

In medical settings, the focus shifts to bacterial biofilms, which are implicated in chronic infections and are notoriously resistant to antibiotics. Research here has yielded mixed results, with Ivermectin's effectiveness varying based on the bacterial strain, concentration, and whether it is used alone or in combination:
A study published in PubMed (2021) investigated the antimicrobial and biofilm properties of Ivermectin and its derivative, D4, against Methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) for Ivermectin was 20 μg/mL, while D4 had a lower MIC of 5 μg/mL, indicating greater potency. However, the impact on biofilms was starkly different: Ivermectin showed no significant change in biofilm formation at 40 μg/mL after 24 hours, with weak and limited effects noted in previous studies, such as against Acinetobacter baumannii. In contrast, D4 reduced biofilm percentages by 21.2% at 10 μg/mL, 92.9% at 40 μg/mL, and 93.6% at 20 μg/mL, with scanning electron microscopy (SEM) confirming complete inhibition at 20 μg/mL. The antibiofilm effect of D4 was achieved by regulating the expression of biofilm-related genes, including relQ, rsbU, spA, icaD, RSH, and sigB, suggesting a mechanism involving gene expression modulation (source).
Another study, published in ScienceDirect (2023), explored repurposing Ivermectin and ciprofloxacin in nanofibers for wound healing and infection control against multidrug-resistant (MDR) wound pathogens. The composite nanofiber (CIP-IVM NF), with Ivermectin concentrations ranging from 0.3–0.5 μg/mL and ciprofloxacin from 1.6–2.5 μg/mL, successfully disintegrated biofilms of Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. This suggests that Ivermectin, when combined with other antimicrobial agents, can enhance biofilm disruption, particularly in wound healing contexts (source).
Research on the gut microbial ecosystem, published in MDPI (2023), investigated Ivermectin's impact on gut microbiota using a Triple-SHIME® simulator with fecal material from healthy adults. The study found that Ivermectin introduced minor and temporary changes to the gut microbial community in terms of composition and metabolite production, as revealed by 16S rRNA amplicon sequencing, flow cytometry, and GC-MS. While this study did not explicitly focus on biofilms, the gut microbial community includes biofilm-forming bacteria, suggesting a potential indirect effect (source).

Positive Impacts and Efficacy Rates
Ivermectin's efficacy varies by condition, with clinical trials providing robust data on cure rates and reductions in parasite load. Below is a detailed list, organized by disease, with percentages derived from peer-reviewed studies:

Onchocerciasis (River Blindness):

Impact: Ivermectin significantly reduces microfilarial density, crucial for preventing blindness and skin manifestations.
Efficacy: Community-based studies, such as one conducted in Liberia, show an 84% reduction in microfilarial density after two years of annual treatment with doses around 150 μg/kg. This is vital for interrupting transmission and reducing morbidity.
Source: PubMed - Community-based treatment of onchocerciasis with ivermectin

Strongyloidiasis:

Impact: Highly effective in eradicating Strongyloides stercoralis, preventing severe complications like hyperinfection syndrome.
Efficacy: Clinical trials indicate a 96% eradication rate with a single dose (200 μg/kg) and 98% with two doses given two weeks apart, based on follow-up stool exams.
Source: ScienceDirect - Efficacy of ivermectin for chronic strongyloidiasis

Scabies:

Impact: Provides effective treatment, reducing itching and skin lesions caused by Sarcoptes scabiei.
Efficacy: Studies show a 62.4% cure rate with one dose (200 μg/kg), increasing to 92.8% with two doses at a two-week interval, compared to permethrin's 96.9% with two applications.
Source: PubMed - The efficacy of permethrin 5% vs. oral ivermectin for the treatment of scabies

Lymphatic Filariasis:

Impact: Clears microfilariae, reducing transmission and preventing lymphedema and elephantiasis.
Efficacy: A controlled trial showed 100% clearance of microfilariae at day 12 with a single dose (ranging from 21.3 to 126.2 μg/kg), though levels returned to 18-19% of pretreatment at six months, indicating some recurrence.
Source: NEJM - A Controlled Trial of Ivermectin and Diethylcarbamazine in Lymphatic Filariasis

Head Lice:

Impact: Effective in treating Pediculus humanus capitis, especially in cases resistant to topical treatments.
Efficacy: Oral Ivermectin at 400 μg/kg showed a 95.2% efficacy rate on day 15 in difficult-to-treat cases, based on intention-to-treat analysis.
Source: NEJM - Oral Ivermectin versus Malathion Lotion for Difficult-to-Treat Head Lice

Enterobiasis (Pinworms):

Impact: Offers moderate efficacy against Enterobius vermicularis, reducing perianal pruritus and infection rates.
Efficacy: Literature suggests a cure rate of up to 85% with a single oral dose ranging from 50 to 200 μg/kg, though it is less effective compared to albendazole.
Source: ScienceDirect - Ivermectin - an overview

Ascariasis:

Impact: Effective in treating Ascaris lumbricoides, reducing worm burden and preventing complications like intestinal obstruction.
Efficacy: Comparable to albendazole, with a high parasitological cure rate, estimated at around 95%, based on Cochrane reviews showing no significant difference from albendazole's 95.7% cure rate.
Source: Cochrane - Anthelmintic drugs for treating ascariasis

Pharmacological Actions
Ivermectin's mechanism of action is highly specific to parasites, ensuring minimal impact on human hosts. It primarily acts by binding to glutamate-gated chloride channels (GluCl) in invertebrates, which are critical for nerve and muscle function. This binding increases chloride ion permeability, leading to hyperpolarization of the cell membrane, paralysis, and subsequent death of the parasite.

Technical Details: Ivermectin selectively binds to GluCl channels, causing an influx of chloride ions, which hyperpolarizes the parasite's nerve and muscle cells. This disrupts neurotransmission, leading to flaccid paralysis and death. It may also affect GABA-gated chloride channels, enhancing its antiparasitic effect.
Safety in Mammals: In mammals, GluCl and GABA-gated channels are primarily located in the central nervous system. Ivermectin does not significantly cross the blood-brain barrier, limiting its action to peripheral tissues and ensuring safety. This selective action is due to differences in P-glycoprotein expression between parasites and mammals, with parasites lacking effective efflux mechanisms.
Immune Modulation: Some studies suggest Ivermectin may enhance the host immune response by suppressing parasite-secreted proteins that evade immune detection, though this is secondary to its direct antiparasitic action.
Source: Drugs.com - Ivermectin: Uses, Dosage, Side Effects, Warnings, Cureus - Ivermectin: A Multifaceted Drug With a Potential Beyond Anti-parasitic Therapy

Anticancer Effects
Ivermectin has emerged as a candidate for anticancer therapy, with mechanisms including inhibition of cell proliferation, induction of apoptosis, and enhancement of chemotherapy efficacy. Its action involves regulating signaling pathways like Akt/mTOR and PAK1, which are critical in cancer cell survival.

Breast Cancer: A notable study using a 4T1 mouse model for triple-negative breast cancer (TNBC) demonstrated Ivermectin’s synergy with anti-PD1 therapy. Complete tumor regression was observed in 40% of mice (6 out of 15) on combination therapy, compared to 5% (1 out of 20) on Ivermectin alone and 10% (1 out of 10) on anti-PD1 alone [1]. Long-term survival rates varied, with approximately 75% survival in neoadjuvant settings with Ivermectin, anti-PD1, and IL-2, and 40% in adjuvant and metastatic settings [1]. These findings suggest Ivermectin converts “cold” tumors to “hot,” enhancing immune response, but are limited to animal models, with human trials ongoing.
Glioblastoma: Research indicates Ivermectin inhibits glioblastoma cell proliferation dose-dependently, inducing apoptosis via caspase-dependent pathways and mitochondrial dysfunction. It also blocks angiogenesis by affecting endothelial cells, potentially preventing tumor metastasis [2]. However, its inability to cross the blood-brain barrier limits clinical application, and no specific percentages were provided for human outcomes.
Other Cancers: Ivermectin shows antitumor effects across various cell lines, including colon, ovarian, and leukemia, by promoting programmed cell death (apoptosis, autophagy, pyroptosis) and reversing multidrug resistance. A study noted its efficacy in combination with chemotherapy, enhancing outcomes, but lacked specific human efficacy percentages [3].

Antiviral Effects
Ivermectin’s antiviral properties have been extensively studied, particularly against SARS-CoV-2, with broader implications for RNA and DNA viruses. Its mechanism involves inhibiting viral replication, potentially by interfering with host factors like importin α/β1.

SARS-CoV-2 (COVID-19): In vitro, Ivermectin achieved a remarkable 5000-fold reduction in viral RNA at 48 hours in Vero-hSLAM cells, suggesting potent antiviral activity [4]. Clinical trials have shown mixed results. A meta-analysis of 15 RCTs involving 2438 participants found Ivermectin reduced the risk of death by 62% (risk ratio 0.38, 95% CI 0.19–0.73), with moderate-certainty evidence [5]. However, another RCT found no significant difference in symptom resolution time (82% vs. 79% resolved by day 21, hazard ratio 1.07, p=0.53), highlighting variability [6]. Controversy surrounds these findings, with some studies retracted and debates over dosage and efficacy, especially given FDA and WHO cautions against its use for COVID-19 outside clinical trials.
Other Viruses: Ivermectin has shown activity against Zika, dengue, and influenza in vitro, with studies reporting reductions in viral load, but specific percentages for human outcomes are scarce. A systematic review noted its broad-spectrum potential, but most data are preclinical [7].

Anti-inflammatory Effects
Ivermectin’s anti-inflammatory effects are well-documented, particularly in dermatological and respiratory contexts, mediated by reducing proinflammatory cytokines like TNF-alpha, IL-1, and IL-6, and suppressing NF-κB pathways.

Rosacea: Clinical trials for papulopustular rosacea demonstrate high efficacy. Two RCTs (Stein Gold et al., 2014a) showed treatment success (IGA 0 or 1) in 38.4% and 40.1% of patients after 12 weeks with Ivermectin 1% cream, compared to 11.6% and 18.8% with vehicle (p<0.001) [8]. Another study comparing Ivermectin to metronidazole found 84.9% success versus 75.4% after 16 weeks (p<0.001) [9]. Long-term data (40 weeks) showed success rates rising to 71.1% and 76.0% [8]. A review also noted 40-80% lesion clearance in 1371 patients after 3 months, supporting its role in improving quality of life [10].
Other Inflammatory Conditions: Ivermectin’s anti-inflammatory effects extend to conditions like asthma, where it suppressed mucus hypersecretion and immune cell recruitment in mice, and late-stage COVID-19, with a meta-analysis suggesting a 68% mortality reduction in hospitalized patients [11]. These findings indicate systemic and lung-specific anti-inflammatory actions, but human data beyond rosacea are preliminary.

Antibacterial Effects
While less emphasized, Ivermectin shows antibacterial activity, particularly against Staphylococcus aureus. An in vitro study reported minimum inhibitory concentrations (MICs) of 6.25 μg/ml for methicillin-sensitive S. aureus (MSSA) and 12.5 μg/ml for methicillin-resistant S. aureus (MRSA), indicating potential against bacterial infections [12]. However, clinical data on human antibacterial use are limited, and its relevance for intake is unclear without further studies.
Treatment Protocols
Oral Ivermectin is mainly used for parasitic infections, with specific protocols based on the condition:

Strongyloidiasis: Typically a single dose of 200 mcg/kg.
Onchocerciasis: A single dose of 150 mcg/kg, possibly repeated every 3 to 12 months.
Scabies: Usually 200 mcg/kg as a single dose, sometimes repeated after 1-2 weeks, with multiple doses for severe cases like crusted scabies.
Head Lice: Often treated with topical forms, but oral use can be 200 mcg/kg, sometimes needing a second dose.

Pharmacological Actions Outside Parasitic Purposes
Beyond its role in treating parasitic infections, Ivermectin has been explored for other pharmacological effects, particularly antiviral, anticancer, and anti-inflammatory properties. These are based on in vitro, animal, and some clinical studies, but their clinical utility remains under investigation.

Antiviral Properties: Ivermectin's antiviral potential has been extensively studied, particularly during the COVID-19 pandemic. A seminal study by Caly et al. (2020) demonstrated that Ivermectin inhibits SARS-CoV-2 replication in vitro, achieving a ~5000-fold reduction in viral RNA at 48 hours [ScienceDirect: Ivermectin Inhibits SARS-CoV-2 In Vitro, https://www.sciencedirect.com/science/article/pii/S0166354220302011]. A systematic review by Nature (2020) also summarizes its effects against RNA viruses like Zika, dengue, and yellow fever, and DNA viruses like BK polyomavirus, suggesting mechanisms such as blocking nuclear import of viral proteins [Nature: Ivermectin Antiviral Effects, https://www.nature.com/articles/s41429-020-0336-z]. However, clinical trials, such as those reviewed in eClinicalMedicine, show mixed results, with concentration-dependent antiviral activity but no clear clinical benefit for COVID-19, highlighting the need for large trials [eClinicalMedicine: Antiviral Effect of High-Dose Ivermectin, https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370%2821%2900239-X/fulltext]. The controversy around its use for COVID-19, with some studies suggesting reduced mortality and others showing no benefit, underscores the need for cautious interpretation.
Anticancer Properties: Recent research has explored Ivermectin's potential as an anticancer agent, with preclinical studies showing promising results. A PMC article (2020) notes that Ivermectin inhibits proliferation, metastasis, and angiogenic activity in various cancer cells, potentially through regulating PAK1 kinase and promoting programmed cell death like apoptosis and autophagy [PMC: Ivermectin Anticancer Effects, https://pmc.ncbi.nlm.nih.gov/articles/PMC7505114/]. Another study in Frontiers (2021) found it effective against colorectal cancer cells, inducing cytotoxicity and inhibiting growth [Frontiers: Ivermectin in Colorectal Cancer, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.717529/full]. It also reverses multidrug resistance in cancer cells, as shown in a Journal of Experimental & Clinical Cancer Research study (2019), by targeting the EGFR/ERK/Akt/NF-κB pathway. However, these findings are primarily in vitro and animal models, with no established human cancer treatment protocols, and claims of it being a "cure" for cancer are false, as clarified by AP News (2023) [AP News: Ivermectin and Cancer Claims, https://apnews.com/article/fact-check-ivermectin-nih-cancer-cure-629592291079].
Anti-inflammatory Effects: Ivermectin's anti-inflammatory properties have been observed in models of skin inflammation and asthma. A PMC article (2024) discusses its ability to mitigate skin inflammation and reduce cytokine production (e.g., TNF-alpha, IL-1β, IL-6) in lipopolysaccharide-induced inflammation models, suggesting potential for managing inflammatory skin conditions and possibly autoimmune diseases [PMC: Ivermectin Multifaceted Therapeutic, https://pmc.ncbi.nlm.nih.gov/articles/PMC11008553/]. Another study in a murine asthma model showed diminished immune cell recruitment and cytokine production in bronchoalveolar lavage fluid, indicating immunomodulatory effects [PMC: Ivermectin Anti-inflammatory Properties, https://pmc.ncbi.nlm.nih.gov/articles/PMC7539925/]. These effects are promising but require further clinical validation.

Detailed Protocols by Condition
COVID-19
COVID-19 has been a significant focus for repurposing ivermectin, given its in vitro antiviral activity against SARS-CoV-2. Several clinical trials have explored oral ivermectin, with the following protocols noted:

12 mg Daily for 5 Days: A randomized, double-blind, placebo-controlled trial in Dhaka, Bangladesh, involved 72 hospitalized patients, with one arm receiving 12 mg once daily for 5 days. This protocol showed earlier virological clearance (9.7 days vs. 12.7 days for placebo, p = 0.02), but no significant clinical symptom improvement [Reference: International Journal of Infectious Diseases, DOI: https://www.ijidonline.com/article/S1201-9712(20)32506-6/fulltext].
24 mg Daily for 5 Days: A multi-center, double-blind randomized controlled trial in hospitalized patients with mild to moderate COVID-19 used 24 mg daily for 5 days (400 μg/kg for an average 60 kg patient). This resulted in a statistically significant lower viral load but no significant effect on clinical symptoms [Reference: BMC Infectious Diseases, DOI: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-024-09563-y].
400 μg/kg Once Daily for 3 Days: A double-blind, randomized, placebo-controlled trial in Brazil involved outpatients with early COVID-19, using 400 μg/kg once daily for 3 days. This did not prevent hospitalization or extended emergency department observation, indicating limited clinical benefit [Reference: New England Journal of Medicine, DOI: https://www.nejm.org/doi/full/10.1056/NEJMoa2115869].

Despite these protocols, the efficacy remains debated. The World Health Organization and FDA recommend use only within clinical trials, citing inconclusive evidence and potential risks from self-medication, especially with animal formulations [Reference: WHO, https://www.who.int/news-room/feature-stories/detail/who-advises-that-ivermectin-only-be-used-to-treat-covid-19-within-clinical-trials; FDA, https://www.fda.gov/consumers/consumer-updates/ivermectin-and-covid-19].
Rosacea
Rosacea, an inflammatory skin condition, is primarily treated with topical ivermectin (1% cream, FDA-approved). However, oral ivermectin has been used off-label in refractory cases, based on case reports:

Single Dose of 200–250 μg/kg: One case report described a 44-year-old man with chronic rosacea treated with a single 250 μg/kg dose, showing significant improvement and remission for 6 months [Reference: Actas Dermo-Sifiliográficas, DOI: https://www.actasdermo.org/es-oral-ivermectin-treat-papulopustular-rosacea-articulo-S1578219017301944]. Another report used 200 μg/kg with subsequent topical permethrin, effective for rosacea-like demodicidosis [Reference: PubMed, DOI: https://pubmed.ncbi.nlm.nih.gov/10534645/].

Dengue

400 μg/kg Daily for 3 Days: A combined phase 2/3 randomized double-blinded placebo-controlled trial in adult dengue patients used 400 μg/kg daily for 3 days. This accelerated NS1 antigenemia clearance (71.5 hours vs. 95.8 hours for placebo, p = 0.014), but no clinical efficacy was observed, with similar rates of dengue hemorrhagic fever (24.0% vs. 31.1%, p = 0.260) [Reference: PubMed, DOI: https://pubmed.ncbi.nlm.nih.gov/33462580/].

Emerging Research and Other Potential Uses
Beyond these, research suggests potential for ivermectin in other non-parasitic conditions, though specific oral protocols are less established:

Cancer: Preclinical studies show antiproliferative and proapoptotic effects in cancer cell lines, but no clinical trials provide human dosing protocols. Safety data indicate doses up to 2 mg/kg in healthy volunteers with no serious adverse reactions, but this is not specific to cancer [Reference: PMC, DOI: https://pmc.ncbi.nlm.nih.gov/articles/PMC7505114/].
Autoimmune Diseases: Research, including a patent (WO2019136211A1), suggests ivermectin may treat autoimmune conditions by reducing Demodex mites, potentially linked to diseases like rheumatoid arthritis. A mouse study on experimental autoimmune encephalomyelitis used 10 mg/kg orally, showing protective effects, but human protocols are lacking [Reference: PMC, DOI: https://pmc.ncbi.nlm.nih.gov/articles/PMC10209955/].

High-Dose Studies and Safety
Research has explored higher doses to understand safety limits, particularly in clinical trials for non-standard uses. A pivotal study by Guzzo et al. (2002) investigated escalating high doses in healthy adults, testing single doses up to 120 mg, which corresponded to approximately 2000 μg/kg for some subjects (e.g., 120 mg for a 60 kg person is 2000 μg/kg). This study, published in the Journal of Clinical Pharmacology, found that doses up to 10 times the FDA-approved 200 μg/kg (i.e., 2000 μg/kg) were generally well-tolerated, with no indication of central nervous system toxicity and adverse events similar to placebo.
Another significant trial, published in JAMA in 2023, examined a 6-day regimen of 600 μg/kg daily for outpatients with mild to moderate COVID-19. This study, accessible at [https://jamanetwork.com/journals/jama/fullarticle/2801827], reported adverse events in 8.3% of the ivermectin group (53/635) compared to 6.3% in the placebo group (41/652), with no serious adverse events attributed to the drug. Common side effects included cognitive impairment, blurred vision, and dizziness, which were self-resolving. This suggests that a total dose of 3600 μg/kg over 6 days is safe for short-term use.
Prolonged Treatment Protocols
For conditions requiring extended treatment, such as crusted scabies or severe strongyloidiasis in immunocompromised patients, multiple doses at standard levels are common. For crusted scabies, guidelines from the CDC (accessed at [https://www.cdc.gov/scabies/hcp/clinical-care/index.html] on July 14, 2025) recommend 200 μg/kg doses on days 1, 2, 8, 9, 15, 22, and 29 for severe cases, totaling up to 1400 μg/kg over 29 days. This protocol, while long, uses standard doses per administration, with spacing to allow drug elimination.
In strongyloidiasis, especially in hyperinfection syndrome, the CDC advises daily dosing at 200 μg/kg until stool and sputum exams are negative for at least two weeks, potentially lasting several weeks. This prolonged daily use at standard doses has been reported safe in clinical practice, as seen in case reports and guidelines, but higher daily doses are not typically recommended.
Toxicity and Safety Thresholds
Toxicity reports, such as those in the New England Journal of Medicine (2021, accessible at [https://www.nejm.org/doi/full/10.1056/NEJMc2114907]), highlight risks with veterinary formulations or inappropriate dosing. Cases involved doses up to 125 mg (approximately 1786 μg/kg for a 70 kg person), leading to symptoms like altered mental status, especially with repeated dosing every other day or twice weekly. A PubMed study from 2022 (accessible at [https://pubmed.ncbi.nlm.nih.gov/36374218/]) noted chronic daily use of 13.5 mg (about 193 μg/kg for 70 kg) over 3.8 weeks caused milder toxicity, suggesting daily standard doses over weeks can accumulate to unsafe levels.
The Guzzo study’s finding that 2000 μg/kg was safe contrasts with some toxicity cases, likely due to controlled settings versus self-medication with veterinary products. Pharmacokinetic analysis shows minimal accumulation with dosing every 48 hours or more, supporting spaced high-dose regimens.
Comparative Analysis of Protocols
To summarize the longest and safest protocols with high dosages, consider the following table, which outlines key regimens from clinical studies:

Protocol	Dose per Administration	Frequency/Duration	Total Dose (for 70 kg)	Safety Notes
Guzzo et al. Single Dose	Up to 2000 μg/kg	Single dose	140 mg	Safe, no CNS toxicity, tested in healthy adults, adverse events similar to placebo.
JAMA COVID-19 Trial	600 μg/kg/day	Daily for 6 days	252 mg (3600 μg/kg total)	Safe, minimal serious adverse events, some visual disturbances, short-term use.
Crusted Scabies (CDC)	200 μg/kg	Up to 7 doses over 29 days	98 mg (1400 μg/kg total)	Safe, standard dose, spaced to minimize accumulation, used in severe cases.
Strongyloidiasis (Severe)	200 μg/kg/day	Daily until clear, weeks	Variable, e.g., 140 mg/week	Safe at standard dose, prolonged use reported, higher daily doses not standard.