The fight of innate immunity and abnormal cannabinoids against Candida infection.

Ofori P.; Zaffran I.; Levi Schaffer F. · British journal of pharmacology · 2026

**Background & Methods** This is a narrative review article synthesizing current knowledge on innate immune mechanisms against Candida species and the emerging pharmacology of abnormal cannabinoids (Abn-CBDs) as potential antifungal agents. The review integrates evidence on how innate immune cells coordinate antifungal defenses with the novel properties of structurally distinctive synthetic cannabinoids that function independently of classical CB1/CB2 receptor pathways. **Key Findings** • Candida species represent the most clinically significant fungal pathogens in humans, with invasive candidiasis demonstrating 30%-40% mortality in critically ill patients despite current antifungal therapy, highlighting the need for novel therapeutic approaches. • The innate immune system provides the primary defense against Candida through coordinated activities of multiple cell types including neutrophils, macrophages, natural killer cells, mast cells, and eosinophils; however, Candida possesses formidable evasion mechanisms that often overwhelm these defenses. • Abnormal cannabinoids (Abn-CBDs) represent a novel pharmacological class of non-psychoactive synthetic lipid compounds with distinctive regioisomeric configurations that exhibit both direct antifungal properties and immunomodulatory effects, functioning through receptor-independent mechanisms distinct from classical cannabinoid signaling. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This review article synthesizes existing literature rather than presenting original experimental data, representing a lower level of evidence (Level 4-5) compared to primary research studies. Key limitations include: (1) reliance on published studies with potential publication bias; (2) the emerging nature of abnormal cannabinoid research means the evidence base may be limited; (3) lack of clinical trial data in humans for Abn-CBDs; and (4) the complex tripartite interaction between innate immunity, Abn-CBDs, and Candida evasion strategies requires further mechanistic investigation. The authors critically address this complexity but acknowledge the need for rigorous in vitro and in vivo studies to validate therapeutic potential. Translation from bench research to clinical efficacy in invasive candidiasis remains experimental, and further investigation is required before clinical recommendations can be established.

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