A bio-SPME-LC-MS/MS method for the quantitative determination of cannabinoids in plasma samples: analytical strategy...

Cannabis sp. has been widely used for both medicinal and recreational purposes globally. Analyzing cannabinoids and their metabolites in human plasma samples is crucial for managing acute intoxications and for therapeutic monitoring in patients. This study describes the optimization and validation of an innovative, sensitive, simple, and environmentally friendly biocompatible solid-phase microextraction (bio-SPME) method using a hydrophilic-lipophilic balance (HLB)/polyacrylonitrile (PAN)-thin film for the quantification of cannabinoids (cannabidiol, tetrahydrocannabinol, and cannabinol) and their main metabolites (11-hydroxy-Δ9-tetrahydrocannabinol and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol acid) in human plasma samples. Extraction efficiency was compared between two geometry SPME devices (e.g., thin film and fiber geometry), showing that the use of the thin film microextraction (TFME) device improved extraction performance. Matrix modification was optimized using a central composite design to determine the optimal combination of sample dilution, organic modifier addition, and salt usage. The most effective matrix modification was achieved with 380 µL of phosphate-buffered saline solution containing 0.015 mol L^-1 sodium chloride and 57% acetonitrile added to 200 µL of human plasma. The extraction equilibrium time was established as 30 min, and the desorption step required only 20 min in 200 µL of desorption solvent. The method demonstrated linearity, high sensitivity, precision, and good accuracy, with no significant carryover between samples. When compared with recent methods, this approach scored higher in terms of "greenness" according to the AGREEprep metric, making it an environmentally sustainable option.