Pharmacology of 30 semisynthetic cannabinoids – and why details matter when assessing the harm potential of seized drugs
Background: The introduction of the ‘Farm Bill’ (2018) in the US, differentiating hemp (£ 0.3% D9-THC, dry weight) from marihuana, created ‘a legal loophole’ in the cannabis industry. The cultivation of industrial low-THC hemp created an oversupply of CBD-rich products, which were then used to diversify the markets by producing ‘hemp-compliant’ THC analogs. These analogs include D8-THC, THC homologs, hexahydrocannabinol (HHC) and others, which all can be derived by chemical conversion of hemp products.
Methods: This study included a large panel (n=30) of THC isomers, homologs and analogs, that might possibly be derived via semisynthetic procedures. As a proxy for the abuse potential of these compounds, we assessed their potential to activate the CB1 cannabinoid receptor, which is responsible for the psychoactive effects of D9-THC, the primary psychoactive compound in cannabis. This was achieved using a cell-based NanoBiT® b-arrestin2 recruitment bioassay, assessing the compounds’ intrinsic CB1 activation potential, relative to D9-THC. In addition, evaluation of seized drug samples of HHC material (Belgium) with liquid chromatography coupled to tandem high resolution mass spectrometry (LC-MS/HRMS) showed the presence of different HHC epimer mixtures. These mixtures were subsequently artificially generated and also evaluated in the bioassay.
Results: THC homologs with longer alkyl chain lengths (THCH, hexyl-tail; THCP, heptyl-tail; THC-C8, octyl-tail), together with THC analogs HHC and hexahydrocannabiphorol (HHCP), were identified as compounds with a CB1 activation potential exceeding that of D9-THC, based on either potency (EC50) or efficacy (Emax). THC isomers show lesser potential for CB1 activation, which likely makes these compounds less prone to emerge as semisynthetic cannabinoids on the recreational drug market. In general, the pharmacology of stereoisomers (S versus R) was pronouncedly different, with one isomer showing higher CB1 activity than the other. This proved to be important in seized HHC drug products that showed various relative compositions of 9(S)-HHC (21-47%) and always contained more 9(R)-HHC, the epimer with the highest CB1 activation potential. This was confirmed by demonstrating that a decreased relative abundance of the 9(S)-epimer led to an increased potency, corresponding to a potentially more harmful product.
Conclusions: Multiple derivatives of THC were shown to have a higher intrinsic CB1 activation potential than D9-THC, the primary psychoactive constituent in cannabis. Some of these derivatives have already emerged on recreational drug markets (e.g. HHC, HHCP, THCP), others might be anticipated to share the same fate. Detailed characterization of products containing these semisynthetic cannabinoids is encouraged, given the widely differing CB1 activation potential, and the importance of the relative composition of different stereoisomers, which will impact the harm potential, relative to D9-THC-containing products.
