Tetrahydrocannabinol (THC) is the active component of cannabis and hashish that was first isolated from the Indian hemp plant (Cannabis sativa) and synthesized in 1965. The discovery of THC was made by Israeli chemist Raphael Mechoulam in Israel in 1964, and since then, more than 100 cannabinoids have been catalogued. THC acts on the hypothalamus to lower body temperature, and is thought to cause the marijuana “high”; several variations of the CNR1 gene are associated with marijuana dependence. The mechanism of this activity became clear 3 decades later, when it was discovered that cannabidiol (CBD), but not THC or cannabinol (CBN), is a powerful inhibitor of several classes of liver microsomes. Experiments conducted during the 1970s indicated that tolerance to many of the effects of cannabis and Δ9-THC can be developed, and that it is essentially pharmacodynamic in nature and is not largely dependent on changes in disposition or cannabinoid metabolism.
When psychoactive cannabinoids other than Δ9-THC were developed, it became clear that they can also induce tolerance. However, it was necessary to wait for the discovery of cannabinoid receptors for a more complete clarification of the mechanisms underlying the development of this tolerance. It was then possible to establish, at least for the CB1 receptor-mediated effects of cannabinoids, that the internalization of these receptors with or without their subsequent degradation, the decrease in the synthesis of the CB1 receptor protein and the reductions in the efficiency of CB1 receptor signaling (desensitization) can all contribute to the development of tolerance to the agonists of these receptors. Interestingly, the extent to which any of these mechanisms participate in the production of this tolerance appears to depend on the brain area and also to be influenced by agonist efficacy.
Not much is currently known about tolerance to the CB2 receptor-mediated effects of cannabinoids. The amount of THC in marijuana has increased dramatically in recent decades, and burned cannabis seeds have been found in graves dating back to 500 BC. Cannabis evolved about 28 million years ago on the eastern plateau of Tibet, according to a pollen study published in May. The plant is still growing wild in Central Asia, and more than 4000 years ago Chinese farmers began to cultivate it for oil and fiber to make ropes, clothes and paper. We review studies on cannabinoids prior to the identification of Δ9-THC as the intoxicating components of recreational cannabis by Raphael Mechoulam in 1964, critically analyzing the controversies and errors that have characterized early research in this area.
The results obtained indicated that the psychotropic effects of cannabis could essentially be attributed only to Δ9-THC.