Phenolic Profiling and OECD-Guided Acute and Subacute Oral Toxicity Assessment of Cannabis sativa L. Seed Hydroethanolic Extract.

El-Mernissi R.; El Menyiy N.; Zouhri A.; El-Mernissi Y.; Nouioura G.; Bouhrim M.; Alqahtani M.; Alqahtani J.; Miantezila Basilua J.; Senhaji N. et al. · Molecules (Basel, Switzerland) · 2026

**Background & Methods** This study characterized the phenolic profile of Cannabis sativa L. seed hydroethanolic extract and evaluated its acute and 28-day repeated-dose oral toxicity in mice following OECD guidelines. Phenolic composition was analyzed via HPLC-DAD, acute toxicity was assessed at 5000 mg/kg body weight (OECD 423), and repeated-dose toxicity was evaluated at 500 and 1000 mg/kg/day for 28 days (OECD 407), with comprehensive monitoring of clinical signs, body weight, organ weights, hematological and biochemical parameters, and histopathological examinations. **Key Findings** - HPLC-DAD analysis identified seven major phenolic compounds in the extract: catechin, chlorogenic acid, caffeic acid, vanillin, p-coumaric acid, quercetin, and kaempferol. - No mortality, behavioral abnormalities, or treatment-related clinical signs were observed in either acute or repeated-dose studies; body weight gain, food and water consumption, relative organ weights, and liver and kidney histology were unaffected by treatment. - The extract demonstrated a favorable safety profile with an estimated LD50 greater than 5000 mg/kg; notably, treated animals exhibited significant reductions in serum total cholesterol and triglyceride levels, with reduced platelet counts observed only in female mice at the highest dose (1000 mg/kg/day). **Dosage & Administration** Acute toxicity: single oral administration of 5000 mg/kg body weight. Repeated-dose toxicity: 500 and 1000 mg/kg/day administered orally for 28 consecutive days. **Safety & Adverse Effects** No adverse effects were reported during acute or repeated-dose studies. The only notable finding was a significant reduction in platelet counts in female mice receiving 1000 mg/kg/day, which may warrant further investigation. Serum lipid reductions (total cholesterol and triglycerides) were observed but were not characterized as adverse effects. **Evidence Quality** This study represents moderate evidence quality due to rigorous adherence to OECD toxicological guidelines and comprehensive assessment parameters. However, limitations include animal-based findings (murine model) with unclear translatability to humans, relatively short subacute assessment period (28 days), and lack of chronic toxicity data. The study provides foundational safety evidence supporting traditional use but does not constitute definitive human safety documentation. Long-term studies and human clinical trials are needed to substantiate therapeutic applications.

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