The two cases presented highlight the importance of considering Cannabis intoxication in the differential diagnosis of infants presenting with unexplained neurological symptoms, particularly in the absence of fever or signs of infection. As Cannabis use becomes increasingly widespread and accidental pediatric exposures rise, emergency physicians and pediatricians must remain vigilant in recognizing the potential for THC intoxication in young children.

Both infants in our cases exhibited central nervous system depression, a hallmark feature of Cannabis intoxication, yet their initial workups included considerations of infectious and metabolic causes. This underscores a critical issue: the potential for unnecessary and invasive investigations, such as lumbar punctures, CT scans, or empirical antiviral and antibiotic therapies, when a toxicological cause is overlooked. These interventions not only increase healthcare costs and resource utilization but also expose pediatric patients to unnecessary risks, including radiation exposure and medication side effects.

Routine toxicology screening should be strongly considered in infants and young children presenting with altered mental status, hypotonia, or excessive sleepiness in the absence of fever or other clear signs of infection, as it can prevent unnecessary interventions and facilitate timely and appropriate clinical management.

Rapid urine drug screening represents a non-invasive, cost-effective, and timely diagnostic tool that can prevent unnecessary investigations and accelerate appropriate clinical management. A positive toxicology result facilitates early diagnosis, supports the prompt initiation of supportive care, and provides reassurance to families. It also enables the activation of targeted social interventions to prevent future exposures.

Importantly, a positive screening result should be viewed as a clinical “red flag” warranting more specific and accurate confirmatory testing, such as second-tier toxicological analysis and, when available, therapeutic drug monitoring (TDM) using LC-MS/MS. This stepwise diagnostic strategy ensures precise identification of the substance involved, more accurate assessment of the degree of exposure, and ultimately more informed and effective clinical decision-making.

In our two pediatric intoxication cases, the observed plasma peak concentrations (45 μg/L and 54.7 μg/L, respectively) were markedly higher than the mean Cmax values previously reported in pediatric patients treated with standardized cannabis preparations for refractory epilepsy, analyzed using the same LC–MS/MS methodology (Gherzi et al., 2020). In that cohort, administered THC doses ranged from 6.6 mg to 33.0 mg, yielding proportionally lower plasma concentrations. A comparable dose–Cmax relationship has been reported in adults by Pellesi et al. (2018), who observed mean Cmax values of approximately 3 μg/L following ingestion of 50 mg THC edibles, consistent with the findings of Vandrey et al. (2017).

Conversely, the peak THC concentrations observed in our two cases are consistent with those described by Guidet et al. (2020), who reported plasma THC levels ranging from 4.4 to 127 ng/mL in 10 infants admitted for accidental cannabis intoxication. These similarities further support the clinical plausibility of our toxicokinetic findings and underline the marked variability in systemic THC exposure following unintentional ingestion in young children.

With regard to elimination kinetics, the estimated half-lives (52.5 h and 21.7 h) indicate markedly prolonged THC persistence compared with adult data, where half-lives typically range from 20 to 30 h. When compared with both our pediatric reference data and available adult studies, this prolongation may suggest a dose-dependent kinetic behavior in acute intoxication settings.

Due to limited information on the time interval between ingestion and blood collection, it was not possible to reliably assess the relationship between plasma THC concentrations and the severity of clinical manifestations. However, all subsequent blood samples were collected at defined intervals relative to the patients’ arrival at the hospital, providing a consistent temporal framework for toxicokinetic interpretation.

It should be noted that urine THC concentrations primarily reflect prior exposure and do not predict current impairment (Fitzgerald et al., 2023). Similarly, while the toxicokinetic data obtained in these pediatric cases provide valuable information on the timing and extent of exposure, they cannot be directly translated into an assessment of functional impairment. The toxicokinetic evaluation is further limited by the small number of samples (four per patient) and the inclusion of only two cases, which precludes broader generalization of the findings.

In addition to clinical and toxicokinetic considerations, preventive measures such as caregiver education and safer drug packaging may contribute to reducing the risk of accidental intoxications and to guiding appropriate social and child protection interventions (Amirshahi et al., 2019; Zwiebel et al., 2025). In conclusion, THC intoxication should be included in the differential diagnosis of any infant presenting with unexplained neurological symptoms, particularly in afebrile cases. Implementing early toxicological screening in such scenarios can prevent unnecessary invasive procedures, reduce the misuse of antimicrobials, and improve patient outcomes through appropriate and timely diagnosis.