Semi-Synthetic Cannabinoids in Forensic Toxicology and Public Health: Analytical Challenges, Emerging Detection Strategies, and Regulatory Implications

Semi-synthetic cannabinoids (SSCs) are chemically modified derivatives of naturally occurring phytocannabinoids that have rapidly emerged in commercial cannabis and hemp-derived products, including vape cartridges, edibles, infused oils, and concentrated extracts. Increasing availability of compounds such as hexahydrocannabinol (HHC), HHC analogues, and Δ8-tetrahydrocannabinol (Δ8-THC) has created significant challenges for forensic toxicology, analytical detection, public health surveillance, and regulatory control. This structured narrative review evaluated current evidence on the forensic, toxicological, pharmacological, and analytical implications of SSCs. The literature published between January 2019 and May 2026 was identified through searches of PubMed, Scopus, and Web of Science using predefined search terms related to SSCs, forensic toxicology, analytical detection, intoxication, metabolism, and public health. Recent evidence demonstrates that HHC-related compounds currently dominate the SSC market and scientific literature. Available studies indicate that SSCs undergo extensive Phase I and Phase II metabolism, producing hydroxylated, oxidized, and glucuronidated metabolites that frequently predominate over parent compounds in biological matrices. This metabolic complexity complicates forensic interpretation, particularly in postmortem investigations and impairment assessments where toxicological reference ranges remain poorly established. Emerging intoxication reports describe prolonged sedation, neuropsychiatric manifestations, cognitive impairment, and severe poisoning associated with HHC analogues, although much of the current evidence remains limited to case reports and small observational studies. From an analytical perspective, conventional toxicology screening methods may fail to detect SSC exposure, necessitating advanced analytical approaches such as liquid chromatography–tandem mass spectrometry (LC–MS/MS), high-resolution mass spectrometry (HRMS), and chiral chromatographic techniques for metabolite identification and epimer differentiation. However, limited reference standards, evolving structural diversity, and regulatory variability across jurisdictions continue to hinder standardized detection and interpretation. Overall, SSCs represent a rapidly evolving class of psychoactive compounds requiring coordinated advancements in forensic toxicology, analytical surveillance, pharmacological characterization, and public health monitoring to improve detection reliability, risk assessment, and regulatory response.