Chemistry and Pharmacology of Delta-8-Tetrahydrocannabinol

Cannabis sativa is one of the oldest plants utilized by humans for both economic and medical purposes. Although the use of cannabis started millennia ago in the Eastern hemisphere, its use has moved and flourished in the Western nations in more recent centuries. C. sativa is the source of psychoactive cannabinoids that are consumed as recreational drugs worldwide. The C21 aromatic hydrocarbons are restricted in their natural occurrence to cannabis (with a few exceptions). Delta-9-tetrahydrocannabinol (Δ⁹-THC) is the main psychoactive component in cannabis, with many pharmacological effects and various approved medical applications. However, a wide range of side effects are associated with the use of Δ⁹-THC, limiting its medical use. In 1966, another psychoactive cannabinoid, Delta-8-tetrahydrocannabinol (Δ⁸-THC) was isolated from marijuana grown in Maryland but in very low yield. Δ⁸-THC is gaining increased popularity due to its better stability and easier synthetic manufacturing procedures compared to Δ⁹-THC. The passing of the U.S. Farm Bill in 2018 led to an increase in the sale of Δ⁸-THC in the United States. The marketed products contain Δ⁸-THC from synthetic sources. In this review, methods of extraction, purification, and structure elucidation of Δ⁸-THC will be presented. The issue of whether Δ⁸-THC is a natural compound or an artifact will be discussed, and the different strategies for its chemical synthesis will be presented. Δ⁸-THC of synthetic origin is expected to contain some impurities due to residual amounts of starting materials and reagents, as well as side products of the reactions. The various methods of analysis and detection of impurities present in the marketed products will be discussed. The pharmacological effects of Δ⁸-THC, including its interaction with CB1 and CB2 cannabinoid receptors in comparison with Δ⁹-THC, will be reviewed.