Early phytocannabinoid chemistry to endocannabinoids and beyond, Raphael Mechoulam et al, 2014

Early phytocannabinoid chemistry to endocannabinoids and beyond

Raphael Mechoulam, Lumír O. Hanuš, Roger Pertwee and Allyn C. Howlett


Doi : 10.1038/nrm3811



Isolation and structure elucidation of most of the major cannabinoid constituents — including Δ9-tetrahydrocannabinol (Δ9-THC), which is the principal psychoactive molecule in Cannabis sativa — was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.


The plant Cannabis sativa and its many preparations (for example, marijuana, hashish, bhang and ganja) have been used for millennia for recreation (and at times for the achievement of religious ecstasy) as well as in medicine. In ancient China, cannabis was prescribed (together with other plants, as is customary in Chinese medicine) for numerous diseases, but it was noted that when taken in excess it could lead to ‘seeing devils’. In Assyria (about 800 bc), it was named both gan‑zi‑gun‑nu (‘the drug that takes away the mind’) and azallu (when used as a therapeutic). In India, ancient Persia and medieval Arab societies, cannabis use proceeded along these two divergent routes1. In many countries, hemp — a strain of Cannabis sativa that does not cause psychoactivity — was grown for its durable fibres. Our present-day society follows a long tradition of recreational, industrial and medical cannabis use.

Cannabinoid discovery — early history

The behavioural effects of cannabis, in several animal species as well as in humans, were observed in the mid-nineteenth century2 (FIG. 1). These experimental observations led to the first attempts to isolate the active constituents of the plant, as had already been done with other plants that had known neuro-pharmacological activity — for example, the isolation of morphine. A prize was even awarded in 1855 for the ‘successful’ accomplishment of this project. However, the first isolation of a plant cannabinoid — named cannabinol (CBN) — was not achieved until the end of the nineteenth century. Its structure was elucidated much later, in the 1930s, by the groups of Cahn and Todd in the United Kingdom and by Adams in the United States, when a further component, cannabidiol (CBD), was isolated; however, its structure could not be elucidated at that time. Although considerable effort was invested on the isolation and the elucidation of the structure of the main psychoactive constituents of cannabis, this goal was not reached at that time. A synthetic compound, Δ6a,10a‑ tetrahydrocannabinol (Δ6a,10a-THC), showed pharmacological activity that paralleled the activity of cannabis extracts. Therefore, it was assumed that Δ6a,10a-THC was chemically related to the active compounds of the plant (FIG. 2). Much of the early research in this area was done using synthetic Δ6a,10a-THC, which is now known to be considerably less potent than the actual natural product. The chemical and pharmacological work that was carried out until the mid 1940s has been reviewed elsewhere3–5. Some Δ6a,10a-THC analogues were even tested in humans. In light of recent media reports about the action of cannabinoids in paediatric epilepsy, it is of interest to note that a derivative of synthetic Δ6a,10a-THC (at doses of 1.2–1.8 mg daily) was administered to a small number of children with epilepsy and showed positive results. Historical cannabis use in medicine over the ages and early chemical investigations are reviewed in REF. 1.

The reasons for the lack of progress were mostly technical. We now know that cannabinoids are present in cannabis as a mixture of many closely related constituents — over 100 — which were difficult to separate using the methods that were available in the nineteenth and early twentieth centuries. As the active constituents of cannabis were not available in pure form, there was very little biological or clinical work done in this area from the late 1940s until the mid 1960s.

By the 1960s, chromatography methods were well developed for the isolation of pure compounds from mixtures and the availability of novel spectrometric methods meant that the elucidation of the structure of these compounds was possible. Indeed, many cannabinoids were isolated, including Δ9-THC, which was reported by Gaoni and Mechoulam in 1964 (REF. 6) (FIG. 2). Their structures were mainly elucidated using NMR, which was a modern method at the time. Several total syntheses of these compounds have been reported and most cannabinoids are now available as both natural and synthetic products.The chemical work until the mid 1970s is reviewed in REF. 7.

The next step in cannabinoid research was the elucidation of the metabolism of Δ9-THC and later of CBD. The major metabolic pathway of Δ9-THC is hydroxylation, which leads to the formation of an active metabolite, followed by its further oxidation to an inactive acid, which then binds to a sugar molecule. These acid-derived metabolites are stored in fatty tissues and are slowly released8. Indeed, the major final Δ9-THC metabolite (a carboxylic acid that is present as a glucuronide) can be detected in human urine for several weeks after cannabis use (FIG. 2).