DARK Classics in Chemical Neuroscience: Synthetic Cannabinoids (Spice/K2)

Abstract

This Review covers the background, pharmacology, adverse effects, synthesis, pharmacokinetics, metabolism, and history of synthetic cannabinoid compounds. Synthetic cannabinoids are a class of novel psychoactive substances that act as agonists at cannabinoid receptors. This class of compounds is structurally diverse and rapidly changing, with multiple generations of molecules having been developed in the past decade. The structural diversity of synthetic cannabinoids is supported by the breadth of chemical space available for exploitation by clandestine chemists and incentivized by attempts to remain ahead of legal pressures. As a class, synthetic cannabinoid products have a more serious adverse effect profile than that of traditional phytocannabinoids, including notable risks of lethality, as well as a history of dangerous adulteration. Most synthetic cannabinoids are rapidly metabolized to active species with prolonged residence times and peripheral tissue distribution, and analytical confirmation of use of these compounds remains challenging.

Overall, the emergence of synthetic cannabinoids serves as a noteworthy example of the pressing public health challenges associated with the increasing development of easily synthesized, structurally flexible, highly potent, psychoactive drugs.

Cited by

This article is cited by 11 publications

1. Di Trana, A., Sprega, G., Kobidze, G., Taoussi, O., Lo Faro, A. F., Bambagiotti, G., Montanari, E., Fede, M. S., Carlier, J., Tini, A., Busardò, F. P., Di Giorgi, A., & Pichini, S. (2024). QuEChERS Extraction and Simultaneous Quantification in GC-MS/MS of Hexahydrocannabinol Epimers and Their Metabolites in Whole Blood, Urine, and Oral Fluid. Molecules (Basel, Switzerland), 29(14), 3440. https://doi.org/10.3390/molecules29143440
2. Di Trana, A., Di Giorgi, A., Sprega, G., Carlier, J., Kobidze, G., Montanari, E., Taoussi, O., Bambagiotti, G., Fede, M. S., Lo Faro, A. F., Tini, A., Busardò, F. P., & Pichini, S. (2024). Disposition of Hexahydrocannabinol Epimers and Their Metabolites in Biological Matrices following a Single Administration of Smoked Hexahydrocannabinol: A Preliminary Study. Pharmaceuticals (Basel, Switzerland), 17(2), 249. https://doi.org/10.3390/ph17020249
3. Dutta, S., & Shukla, D. (2023). Transition-based reweighting and neural rational inference analysis of effects of new psychoactive substances on cannabinoid receptors. bioRxiv : the preprint server for biology, 2023.09.29.560261. https://doi.org/10.1101/2023.09.29.560261
4. Hasan, M. R., Tabassum, T., Tabassum, T., Tanbir, M. A., Abdelsalam, M., & Nambiar, R. (2023). Synthetic Cannabinoids-Related Cardiovascular Emergencies: A Review of the Literature. Cureus, 15(7), e41929. https://doi.org/10.7759/cureus.41929
5. Walton-Raaby, M., Floen, T., García-Díez, G., & Mora-Diez, N. (2023). Calculating the Aqueous pKa of Phenols: Predictions for Antioxidants and Cannabinoids. Antioxidants (Basel, Switzerland), 12(7), 1420. https://doi.org/10.3390/antiox12071420
6. Bellizzi, A., Mercieca, E., & Dimech, C. (2023). Delirium secondary to anticholinergics. BMJ case reports, 16(1), e253547. https://doi.org/10.1136/bcr-2022-253547
7. Sparkes, E., Boyd, R., Chen, S., Markham, J. W., Luo, J. L., Foyzun, T., Zaman, H., Fletcher, C., Ellison, R., McGregor, I. S., Santiago, M. J., Lai, F., Gerona, R. R., Connor, M., Hibbs, D. E., Cairns, E. A., Glass, M., Ametovski, A., & Banister, S. D. (2022). Synthesis and pharmacological evaluation of newly detected synthetic cannabinoid receptor agonists AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA, MDMB-4F-BUTINACA and their analogs. Frontiers in psychiatry, 13, 1010501. https://doi.org/10.3389/fpsyt.2022.1010501
8. Glatfelter, G. C., Partilla, J. S., & Baumann, M. H. (2022). Structure-activity relationships for 5F-MDMB-PICA and its 5F-pentylindole analogs to induce cannabinoid-like effects in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(4), 924–932. https://doi.org/10.1038/s41386-021-01227-8
9. Giorgetti, A., Pascali, J. P., Fais, P., Pelletti, G., Gabbin, A., Franchetti, G., Cecchetto, G., & Viel, G. (2021). Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications. Life (Basel, Switzerland), 11(5), 440. https://doi.org/10.3390/life11050440
10. Lin, M., Lee, J. C., Blake, S., Ellis, B., Eubanks, L. M., & Janda, K. D. (2020). Broadly Neutralizing Synthetic Cannabinoid Vaccines. JACS Au, 1(1), 31–40. https://doi.org/10.1021/jacsau.0c00057
11. Walsh, K. B., & Andersen, H. K. (2020). Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling. International journal of molecular sciences, 21(17), 6115. https://doi.org/10.3390/ijms21176115