The Dark Side of Cannabidiol: The Unanticipated Social and Clinical Implications of Synthetic Δ⁸-THC

Abstract

Introduction: The explosive growth of the cannabis industry in the United States over the past decade has spurred a multitude of products derived from phytocannabinoids produced by Cannabis sativa L. Decades of cannabis prohibition coupled with the more recent 2018 Farm Bill have lead to several unanticipated consequences and the widespread availability of synthetic cannabinoids derived from hemp CBD, including Δ 8 -THC, Δ 10 -THC and HHC. Methods: Herein, we review the available literature of the complexity of the chemistry of its current manufacture, namely, the acid-catalyzed ring closure of cannabidiol (ACRCC), the myriad of issues involving the unsolved technical problems with quality control of ACRCC-Δ 8 -THC and the multitude of isomerized byproducts, and the lack of consistent regulation regarding consumer safety and labeling. Results: We provide what we believe is the first comprehensive listing of all the documented ACRCC-Δ 8 -THC byproducts. Perhaps, most importantly, we highlight the growing concern that, other than Δ 8 -THC itself, the compounds in ACRCC-Δ 8 -THC product mixtures have not been subjected to any human toxicological evaluation. This is especially troubling as ACRCC-Δ 8 -THC products relate to vaping, and their contribution to a growing and lethal epidemic of electronic cigarette, or vaping, product use–associated lung injury (EVALI). Conclusions: Quality control is totally inadequate in the newly emerging Δ 8 -THC industry. American consumers are ingesting products that are mislabeled with many compounds that have never received any toxicological testing. EVALI cases continue to be reported with a fatality rate approaching 2% (in California).

Hexahydrocannabinol and closely related semi‐synthetic cannabinoids: A comprehensive review

“…The appearance in around 2019 on the drug market of semi-synthetic cannabinoids (SSCs) such as Δ 8 -tetrahydrocannabinol (Δ 8 -THC) ("Δ 8 -THC craze"), [22][23][24][25] and subsequently HHC, may be attributed to recent regulatory changes in the United States concerning the legal status of hemp, C. sativa. Therefore, a brief legal background for revitalization of hemp cultivation in the United States in recent years is given.…”

“…In the meantime, hemp producers diversified and devised new hemp‐based products manufactured by simple chemical transformations of CBD‐rich extracts to legal or quasi‐legal substances. The appearance in around 2019 on the drug market of semi‐synthetic cannabinoids (SSCs) such as Δ 8 ‐tetrahydrocannabinol (Δ 8 ‐THC) (“Δ 8 ‐THC craze”), 22–25 and subsequently HHC, may be attributed to recent regulatory changes in the United States concerning the legal status of hemp, C. sativa . Therefore, a brief legal background for revitalization of hemp cultivation in the United States in recent years is given.…”

Differentiation of Δ9-THC and CBD Using Silver-Ligand Ion Complexation and Electrospray Ionization Tandem Mass Spectrometry (ESI-MS/MS)

“…In addition, the impact of the ligand choice on cannabinoid binding and fragmentation highlights the potential for improved selectivity compared to Ag salts alone. When applied to authentic cannabis plant material samples, a 95% correct classification rate for the differentiation between Δ 9 -THC-rich and CBD-rich cannabis was obtained, with the lone misclassification belonging to a sample that contained elevated Δ 8 -THC relative to Δ 9 -THC, which is uncommon for natural cannabis plant material …”

Development and Validation of a GC-FID Method for the Quantitation of Δ 8-Tetrahydrocannabinol and Impurities Found in Synthetic Δ 8-Tetrahydrocannabinol and Vaping Products

“…Because the methods used to convert CBD to Δ 8 -THC are not specifically addressed in hemp laws, the legality of synthetic Δ 8 -THC stays unclear. This raises safety and product quality concerns for consumers given the unknown and untested nature of Δ 8 -THC, other synthetic analogs, and any other impurities present 24 , 25 , 26 .…”

“…Because the methods used to convert CBD to Δ 8 -THC are not specifically addressed in hemp laws, the legality of synthetic Δ 8 -THC stays unclear. This raises safety and product quality concerns for consum-ABBREVIATIONS 4,8-epoxy-iso-THC 4,8-epoxy-iso-tetrahydrocannabinol 8-OH-iso-THC United States Pharmacopeia Δ 4,8 -iso-THC Δ 4,8 -iso-tetrahydrocannabinol Δ 4 -iso-THC Δ 4 -iso-tetrahydrocannabinol Δ 8 -cis-iso-THC Δ 8 -cis-iso-tetrahydrocannabinol Δ 8 -iso-THC Δ 8 -iso-tetrahydrocannabinol Δ 8 -THC trans-Δ 8 -tetrahydrocannabinol Δ 9 -THC trans-Δ 9 -tetrahydrocannabinol ers given the unknown and untested nature of Δ 8 -THC, other synthetic analogs, and any other impurities present [24][25][26]. U. S. health officials are warning about the potential dangers of Δ 8 -THC following hospitalizations tied to the substance.…”