Acid-Catalyzed Conversion of Cannabidiol to Tetrahydrocannabinols: En Route to Demystifying Manufacturing Processes and Controlling the Reaction Outcomes.

Abstract

Background: Over the last decade, there has been a significant increase in the production of multiple tetrahydrocannabidiol (THC) related products via the acid catalysis of cannabidiol (CBD). The widespread availability of CBD and the unregulated or poorly regulated nature of its use have flooded the market with THC-containing products of unverifiable provenance and frequently contaminated by trace metals and residual solvents. Under non-optimized, poorly controlled, or harsh reaction conditions, these acid-catalyzed transformations yield multiple cannabinoids including Δ⁹-THC and Δ⁸-THC, along with numerous side products. These side products are rarely identified or quantified accurately, and their safety and pharmacology remain largely unknown. Aims: This review aims to present an up-to-date understanding of one of the fundamental transformations in cannabinoid chemistry: the cyclization of CBD to THC. This knowledge will facilitate the development of safer, cleaner, more affordable, and accessible cannabinoid products while guiding medical practitioners and regulators. Materials and Methods: We conducted a literature review of studies published over the last 5-6 years on the interconversion of CBD to THC. Our review focused on the following key aspects: (1) advances in understanding reaction mechanisms and optimizing desirable reaction outcomes; (2) development of new catalysts, including "green chemistry" approaches such as solid-supported acids; and (3) implementation of fit-for-purpose analytical methods to better characterize reaction outcomes and reassess the accuracy of cannabis and hemp product labeling. Results: Provided strict quality controls of materials, reaction conditions, and related isolation techniques, the latest research of the acid-catalyzed CBD cyclization shows that it is feasible to access products with elevated and consistently high quality, enriched with either CBD or THC fractions, in a cost-effective manner. Among a spectrum of possible products, easy access to low-potency THC compositions may be particularly relevant for serving the needs of medical patients consuming cannabis and hemp-derived cannabinoids including dose titration as well as to supporting safe and responsible use in recreational markets now saturated with overly potent products.