The discovery of THC, the main psychoactive component of cannabis, is a story that dates back to the late 19th century. Israeli chemist Raphael Mechoulam was the first to isolate and identify THC in 1964. Since then, more than 100 cannabinoids have been catalogued and their structures and stereochemistry elucidated. The discovery of the cannabinoid receptors in the early 1990s provided a more complete understanding of the mechanisms that underlie the development of tolerance to the effects of cannabis and Δ9-THC. Cannabis has been used for centuries for its medicinal and recreational properties.
It evolved about 28 million years ago in the eastern Tibetan plateau and was first cultivated by Chinese farmers for oil and fiber around 4000 years ago. Burnt cannabis seeds have been found in the tombs of shamans in China and Siberia since 500 BC. In the early 1940s, CBD and THC were first extracted from cannabis, followed by their synthesis in 1965 in Mechoulam's laboratory. The experiments conducted during the 1970s indicated that tolerance can be developed to many of the effects of cannabis and Δ9-THC, that some effects are more easily and rapidly induced than others, and that it is essentially pharmacodynamic in nature and is not largely dependent on changes in the disposition or metabolism of cannabinoids.
It was then possible to establish, at least with regard to the effects mediated by CB1 cannabinoid receptors, that the internalization of these receptors with or without their subsequent degradation, the reduction of protein synthesis of the CB1 receptor and the reduction in the efficiency of CB1 receptor signaling (desensitization) can contribute to the development of tolerance to the agonists of these receptors. Currently, not much is known about tolerance to the CB2 receptor-mediated effects of cannabinoids. Tetrahydrocannabinol (THC) acts on the hypothalamus to lower body temperature. Recent scientific evidence provides an alternative explanation for this activity. It was also discovered that CBD, but not THC or CBN, is a powerful inhibitor of several classes of liver microsomes. The findings that cannabis is the single source of a set of at least 66 compounds that are now known as cannabinoids and that its psychotropic effects are mainly caused by (−) -trans-Δ9-tetrahydrocannabinol (Δ9-THC) are much more recent.
The extent to which any of these mechanisms are involved in producing this tolerance seems to depend on the brain area and is also influenced by agonistic efficacy. The discovery of THC has had a major impact on medical research and drug policy in Israel and other Western countries. Raphael Mechoulam is considered the father of modern cannabis studies for his pioneering work on THC and endocannabinoids.