A Critical Review of the Interactions Between Δ9-THC and Other Naturally Occurring Phytochemical Constituents of Cannabis sativa.

Elder H.; Jenkins B.; Zamarripa C.; Spindle T.; Vandrey R. · Current neuropharmacology · 2026

**Background & Methods** This is a narrative review that systematically examines empirical evidence for interactions between delta-9-tetrahydrocannabinol (Δ9-THC) and other phytochemical constituents of Cannabis sativa. A systematic PubMed literature search was conducted to identify controlled clinical and preclinical studies evaluating modulation of THC's effects by individual phytochemicals, including phytocannabinoids (CBD, CBN, THCV, CBG, CBC) and terpenes (α-pinene, d-limonene, β-myrcene, linalool, α-humulene, β-caryophyllene, bisabolol, terpinene, and terpineol). **Key Findings** - Cannabidiol (CBD) and THC interactions show route-dependent effects: oral coadministration significantly exacerbates THC effects, while inhaled coadministration does not demonstrate this interaction. - Tetrahydrocannabivarin (THCV) may reduce certain subjective and cognitive effects of THC, and some terpenes like limonene can selectively modulate adverse effects associated with high THC doses in humans. - Evidence supporting meaningful modulation of THC's effects by minor phytocannabinoids and terpenes in humans remains exceptionally limited, with mixed results and frequent failure to translate preclinical findings into measurable clinical outcomes. **Dosage & Administration** Not reported. The review synthesizes data across multiple studies with varied methodologies and dosing protocols without specifying standardized doses or administration routes. **Safety & Adverse Effects** The review notes that certain terpenes such as limonene can selectively modulate adverse effects associated with high THC doses in humans, but does not provide specific adverse effect profiles or safety data. Preclinical studies suggesting interactive effects were often not confirmed in clinical populations. **Evidence Quality** This narrative review has significant limitations. Clinical studies examining THC interactions beyond CBD remain comparatively limited, and most research focuses on preclinical animal models that frequently fail to translate into measurable human outcomes. The authors emphasize that varied study methods and results complicate interpretation, and that well-designed, controlled clinical studies of individual phytochemical interactions remain necessary. Many bioactive terpenes and trace cannabinoids have not yet been evaluated in human studies. The overall evidence quality for entourage effects in humans is characterized as exceptionally limited, highlighting the complexity of phytochemical interactions and challenges in translating preclinical findings.

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