What symptoms and lab findings distinguish ivermectin overdose from other neurotoxic or cholinergic poisonings?
Executive summary
Ivermectin overdose typically produces a predominately neurologic syndrome characterized by CNS depression (drowsiness, disorientation, stupor/coma), ataxia, tremor or seizures, and gastrointestinal upset, arising when P‑glycoprotein exclusion of the brain is overwhelmed or inhibited — but there is no single laboratory test diagnostic for ivermectin toxicity and diagnosis remains clinical [1] [2] [3]. Distinguishing ivermectin from classical cholinergic poisonings or other neurotoxic syndromes depends on a combination of the pattern of neurologic signs, the presence or absence of hallmark autonomic-muscarinic and nicotinic features, exposure history (veterinary formulations/high-dose use), and limited ancillary testing or toxicology where available [2] [4] [3].
1. Classical clinical signature of ivermectin overdose: GABAergic‑predominant CNS depression
Ivermectin's human toxicity presents chiefly as progressive CNS depression — lethargy, decreased consciousness, ataxia, inability to stand, tremor, hallucinations, seizures and in severe cases coma and respiratory depression — reflecting excessive central GABAergic and related effects once blood‑brain barrier exclusion is lost [1] [3] [2]. Reports from poison centers and case series during the COVID period emphasize neurologic effects after large single or repeated supratherapeutic doses, especially with veterinary formulations or when P‑glycoprotein function is impaired [2] [4].
2. Cholinergic toxidrome — what it looks like and why it’s different
Acute cholinergic poisoning (organophosphates, carbamates) produces a clustered syndrome of muscarinic signs — salivation, lacrimation, urination, defecation, gastrointestinal cramping, miosis and bronchorrhea — together with nicotinic features such as muscle weakness, fasciculations and potentially paralysis, plus bradycardia and hypotension; mental status changes vary from agitation to coma depending on severity (classic “SLUDGE/BBB” picture) — these focused autonomic and neuromuscular findings contrast with ivermectin’s predominant sedating, ataxic and seizure-prone picture rather than the marked secretory and fasciculating pattern of cholinergics (note: some overlap in GI upset can occur) (none of the provided sources focus exclusively on classic organophosphate signs, so comparison relies on the described ivermectin features above and the cholinergic characterization present in animal studies showing cholinergic involvement) [5] [6].
3. Overlap, confounders and key bedside discriminators
Overlap exists: ivermectin can cause gastrointestinal symptoms, mydriasis or altered reflexes, and animal studies show cholinergic-system involvement, so a patient with nausea, vomiting, altered consciousness and abnormal pupils could be either; discriminators favoring ivermectin include striking CNS depression out of proportion to secretory signs, history of taking veterinary or very high doses, presence of tremor/seizures with progressive obtundation, and absence of prominent salivation/bronchorrhea and copious lacrimation that typify cholinergic poisonings [5] [2] [7].
4. Laboratory and toxicologic testing — limited, nonspecific, and often clinical
There is no routinely available, validated blood biomarker that reliably confirms ivermectin poisoning in clinical practice and published reports emphasize diagnosis by exposure history and clinical features; measured ivermectin concentrations exist in case reports but are rare and not standardized, and routine labs (electrolytes, glucose, blood gases) are used to assess complications rather than to diagnose ivermectin specifically [4] [2] [8]. By contrast, cholinergic poisoning can be supported by markedly depressed plasma cholinesterase/pseudocholinesterase or red‑blood‑cell acetylcholinesterase activity, which — when low — points strongly toward organophosphate/carbamate exposure and away from ivermectin (animal/rats data suggest ivermectin may alter AChE activity but human data are inconsistent) [6] [8].
5. Therapeutic and forensic implications that help distinguish causes
Ivermectin toxicity is managed supportively (airway/ventilation, seizure control) and may respond to measures reported in animal studies (e.g., anti‑GABAergic agents, experimental adjuncts like flumazenil in animals) but lacks a specific antidote widely accepted in humans; cholinergic poisoning has a specific, mechanism‑directed antidotal therapy (atropine and oximes for many organophosphates) — a clear clinical response to atropine/oxime would therefore support cholinergic toxicity rather than ivermectin as the primary cause [9] [3] [8].
6. Limitations of existing evidence and practical summary for clinicians and investigators
The literature is dominated by case reports, poison center series and animal studies; gaps include few standardized human concentration‑response data and rare documented blood ivermectin levels, so reliance on exposure history, pattern of autonomic versus CNS findings, cholinesterase assays when organophosphate exposure is suspected, and supportive toxicology remain the practical path to distinguishing ivermectin from cholinergic or other neurotoxic poisonings [4] [2] [8].