How does ivermectin cross the blood–brain barrier and under what conditions (dose, drug interactions, genetic variants like ABCB1/MDR1) does it cause neurological harm?
Executive summary
Ivermectin normally does not cross the human blood–brain barrier (BBB) because P‑glycoprotein (ABCB1/MDR1) at the BBB effluxes the drug; knockout or defective ABCB1 leads to brain levels tens of times higher and clear neurotoxicity in animals and susceptible dogs (up to ~70–100× increase in mice when Abcb1 is absent) [1] [2] [3]. Human neurotoxicity is rare at standard antiparasitic doses (0.2–0.3 mg/kg), but reported after massive overdoses, veterinary (parenteral) formulations, or where ABCB1 function is impaired by genetics, disease, or interacting drugs [4] [5] [6] [7].
1. How ivermectin is excluded from the brain — the P‑glycoprotein gatekeeper
Ivermectin is lipophilic and could diffuse across brain endothelium, but endothelial P‑glycoprotein (product of ABCB1/MDR1) actively pumps it back into the bloodstream; that efflux is the principal reason ivermectin shows poor CNS penetration in vertebrates under normal conditions [1] [8] [9]. Multiple pharmacology and animal studies demonstrate ivermectin is a model substrate for ABCB1 and that loss of this transporter dramatically raises brain concentrations [2] [10].
2. What changes the gate — genetic loss of ABCB1 and animal models
Complete or function‑reducing loss of ABCB1 produces dramatic effects: Abcb1 knockout mice show 70– to 100‑fold increases in brain exposure and much greater neurotoxicity, and herding‑breed dogs with ABCB1 (MDR1) deletion develop severe neurologic signs at doses that are otherwise safe [1] [11] [12]. A documented human case associated nonsense mutations in ABCB1 with severe neurologic effects after a standard single oral dose (0.23 mg/kg) of ivermectin, illustrating that human ABCB1 loss‑of‑function can be clinically relevant [7].
3. When dose matters — therapeutic vs supratherapeutic and veterinary exposures
Approved human antiparasitic regimens are generally 0.2–0.3 mg/kg (some trials tested 400–600 µg/kg for off‑label uses), and at those standard doses ivermectin is usually safe because of ABCB1 efflux [4] [13]. Neurotoxicity clusters in reports where people ingested veterinary formulations, received parenteral veterinary ivermectin, or took massive oral overdoses; clinical series link higher, acute doses to rapid onset CNS symptoms and hospitalizations (toxic serum levels reported in one IV case ~187.7 ng/mL) [5] [14] [15].
4. Drug interactions and physiological 'leaks' that lower the barrier
Co‑administered drugs that inhibit or saturate ABCB1—or drugs that change ivermectin metabolism via CYPs (CYP3A4 implicated in ivermectin clearance)—can raise circulating or brain exposure; animal and in vitro data show coadministration of ABCB1‑interacting agents alters ivermectin CNS levels [8] [2] [16]. Severe systemic illness, sepsis, or CNS inflammation can impair BBB function and have been implicated as confounders in case series of neurologic events after ivermectin [1].
5. The mechanisms of harm inside the brain
Once ivermectin reaches sufficient brain concentrations it acts on vertebrate ligand‑gated chloride channels (GABA(A), glycine receptors) and can produce CNS depression, ataxia, tremor, seizures, visual changes, and coma; animal electrophysiology and toxicity studies document these effects and link them to concentrations achievable only with overdose or BBB failure [17] [3] [18].
6. Human epidemiology and recurring uncertainties
Large pharmacovigilance and case series show serious encephalopathy is rare but trackable: early outbreaks of severe encephalopathy occurred in people heavily infected with Loa loa after mass ivermectin campaigns, and post‑marketing databases list scattered serious neurologic ADRs outside onchocerciasis settings [6] [19]. Available sources highlight rarity but call for investigation of individual risk factors (co‑infection, genetics, drug interactions) and note limitations of passive reporting systems [19] [6].
7. Practical implications and unresolved questions
Clinically, standard antiparasitic doses remain safe for most people because ABCB1 protects the CNS [4] [8]. Significant risks arise when doses are markedly higher (veterinary formulations, parenteral use), when ABCB1 function is lost or inhibited, or when the BBB is compromised [5] [12] [1]. Available sources do not mention population‑level frequencies of human ABCB1 loss‑of‑function variants causing ivermectin toxicity, and they call for more data on how common clinically relevant ABCB1 polymorphisms are in humans and how specific drug–drug interactions alter brain exposure [20] [7].
Limitations: this summary relies on the supplied literature only; mechanistic animal and in vitro findings are robust, but extrapolation to every human scenario requires more epidemiologic and genotypic data [16] [6].