Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) and are the best known and most extensively studied phytocannabinoids found in cannabis and cannabis-derived products. An increasing number of studies and trials have been carried out including one or both compounds, in order to investigate their therapeutic effects towards several pathological conditions such as paediatric epilepsy, anxiety disorders and chronic pain. Feasible and accurate monitoring of THC and CBD and their metabolites is essential for assessing treatment adherence, addressing public health issues, and to understand cannabinoid pharmacokinetics. There is a need for reliable, economically scalable, and fully validated bioanalytical methods for the comprehensive analysis of the main cannabinoid Phase I metabolites. Current methodologies rely on the use of macro-volumes of biological fluids, with inherent discomfort for the sampled subjects and logistical issues. The aim of this research was the development of an original approach for the simultaneous LC-MS/MS analysis of THC, CBD, and their metabolites 11-OH-THC, 11-COOH-THC, 6-OH-CBD, 7-OH-CBD and 7-COOH-CBD in whole blood microsamples collected by volumetric absorptive microsampling (VAMS) technology. VAMS allows the minimally-invasive collection of volumetrically accurate microvolumes as low as 10 μL of whole blood independently from its density. Once dried, VAMS samples are stored at room temperature without appreciable analyte losses and processed by an optimized, yet feasible and high-throughput pretreatment workflow prior to LC-MS/MS analysis. After obtaining satisfactory validation results in terms of precision (RSD &lt; 6.9%) and extraction yield (&gt; 84%) the method was applied to real whole blood sampled by VAMS from self-reported users of products containing either THC and/or CBD. The results of this promising proof of concept demonstrate how VAMS technology represent a valuable tool with immediate utility for the accurate assessment of cannabinoids and metabolites in whole blood miniaturised samples, with promising potential for the monitoring of subjects during cannabis-based administrations in clinical trials and for therapy personalisation. This could contribute to expanding knowledge about circulating cannabinoid levels and obtain useful correlations by exploiting a patient-friendly, miniaturised sampling tool.

Analysis of THC, CBD, and related metabolites in miniaturised whole blood samples

ACS Fall 2021

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