Semi-synthetic cannabinoids: Recent developments, analytical challenges and strategic responses

The emergence and proliferation of semi-synthetic cannabinoids (SSCs) represents a significant evolution in the European new psychoactive substances (NPS) landscape. SSCs, are substances that mimic the effects of delta-9 tetrahydrocannabinol (THC or delta-9-THC), the substance primarily responsible for the major psychoactive effects of cannabis. They are marketed as 'legal' replacements to cannabis and delta-9 THC and can be produced from cannabidiol (CBD) extracted from low-THC cannabis (hemp). Since the first detection of hexahydrocannabinol (HHC) in Europe in late 2022, the SSC market has rapidly expanded, with over 30 compounds now under monitoring by the European Union Drugs Agency (EUDA). These substances exhibit targeted chemical modifications to the structure of delta-9-THC, aimed at increasing potency, altering pharmacokinetics, or circumventing legislation. However, little is known about their pharmacological and toxicological profiles, metabolic pathways, or long-term health effects. SSCs are widely available in various consumer-friendly forms, including vapes, edibles, and herbal products. They are frequently mislabelled, can often contain undeclared substances or contaminants, and are marketed in ways that can appeal to younger or inexperienced users. These factors, combined with their unpredictable potency, have contributed to an increase in acute poisonings reported by several EU countries. Analytically, SSCs pose major challenges. The rapid pace of market innovation, issues with accessibility and affordability of certified reference materials, and the presence of isomeric compounds, for example, complicate detection and identification. Consumer product matrices-ranging from vape liquids to edibles-introduce additional variability and analytical interference. Forensic and toxicological laboratories involved in SSC analysis must navigate a challenging landscape, characterised by uncertainty and rapidly changing targets. To address these challenges and to ensure laboratories are best equipped to respond to emerging threats, such as SSCs, coordinated and collaborative efforts are needed. The sharing of information, best practices and analytical data, combined with investment in research, test-purchasing projects and pharmacological and toxicological studies are some key strategic responses. The EUDA coordinates some of these efforts and has implemented several strategic initiatives. These include the EU Early Warning System (EWS), the establishment of a dedicated Network of forensic and toxicological laboratories, and the development of the EUDA-JRC GC-MS library containing reference spectra for newly identified substances. Technical meetings and collaborative efforts have identified key priorities such as inter-laboratory harmonisation, increased data sharing, and targeted research into metabolism and toxicity.