The first synthetic cannabinoids were synthesized by Roger Adams in the early 1940s. Early cannabinoid research concentrated on tetrahydrocannabinol or "THC" as the main psychoactive compound found in the cannabis plant. Other natural cannabinoids such as cannabidiol or "CBD" are less well studied, and not illegal in most jurisdictions. Most synthetic cannabinoids are analogs of THC.
The first generation of THC analogs (synhexyl, nabilone, nabitan, nantradol) featured slight variations of the THC molecule, such as esterifying the phenolic hydroxy group, extending and branching of the pentyl side chain, or substituting nitrogen for oxygen in the benzopyran ring. These analogs can be grouped into classical (HU-210), bicyclic (CP-55,940), and tricyclic (CP-55,244). Tritium-labelled cannabinoids such as [³H]CP-55,940 were instrumental in discovering the cannabinoid receptors in the early 1990s.
Nabilone entered the clinic in 1981 as an antiemetic. Synthetic THC (marinol, dronabinol) entered the clinic in 1985 as an antiemetic and again in 1991 as an appetite stimulant.
The second generation of THC analogs features compounds derived from anandamide (metanandamide), aminoalkylindole (WIN 55,212-2), pyrrole, pyrazole (SR-141716A), and indene (BAY 38-7271).