Category:Cannabinoids: Difference between revisions

Cannabis is among the oldest plants used by humans as a medicine. Archaeological evidence places its use for intoxication at least 2,500 years ago — residue analysis of wooden braziers from the Jirzankal cemetery in the Pamir Mountains of western China, dated to around 500 BCE, found chemical traces consistent with the deliberate use of high-potency cannabis.<ref name="ren2019">Ren M, Tang Z, Wu X, et al. The origins of cannabis smoking: chemical residue evidence from the first millennium BCE in the Pamirs. ''Sci Adv.'' 2019;5(6):eaaw1391. PMID 31206023.</ref> Written records of its medicinal use appear earlier still, in ancient China, Egypt, and Greece, and later across the Roman world.<ref name="crocq2020">Crocq MA. History of cannabis and the endocannabinoid system. ''Dialogues Clin Neurosci.'' 2020;22(3):223–228. PMID 33162765.</ref>

In the nineteenth century, Western physicians in contact with Indian and Middle Eastern medicine — among them the Irish doctor William Brooke O'Shaughnessy — introduced cannabis preparations into European medical practice.<ref name="crocq2020"/> But the chemistry of the plant remained obscure for more than a century afterward, because its active constituents had never been isolated in pure form.

'''Cannabinoids''' are the family of compounds — found in the cannabis plant, produced naturally in the body, or made synthetically — that act on the body's cannabinoid signalling system. The term covers three overlapping groups: the '''phytocannabinoids''' of the plant (such as [[THC]] and [[CBD]]), the '''endocannabinoids''' produced within the body, and a range of '''synthetic cannabinoids'''.

The modern science of cannabinoids is usually dated to 1964, when Raphael Mechoulam and Yechiel Gaoni, then at the Weizmann Institute of Science in Rehovot, Israel, first isolated delta-9-tetrahydrocannabinol (THC) in pure form and determined its structure, identifying it as the principal psychoactive constituent of cannabis.<ref name="gaoni1964">Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. ''J Am Chem Soc.'' 1964;86(8):1646–1647.</ref><ref name="mechoulam2023">Mechoulam R. A delightful trip along the pathway of cannabinoid and endocannabinoid chemistry and pharmacology. ''Annu Rev Pharmacol Toxicol.'' 2023;63:1–13. PMID 35850522.</ref> The related compound cannabidiol (CBD) had been described earlier, and its structure was also established by Mechoulam's group in the early 1960s. This work opened cannabis to systematic pharmacological study; more than a hundred phytocannabinoids have since been identified, though only some are psychoactive.<ref name="pertwee2006">Pertwee RG. Cannabinoid pharmacology: the first 66 years. ''Br J Pharmacol.'' 2006;147(Suppl 1):S163–S171. PMID 16402100.</ref>

A second major chapter opened in the late 1980s and 1990s. In 1988, Allyn Howlett and William Devane identified specific binding sites for THC in rat brain tissue. The first cannabinoid receptor, CB1, was cloned in 1990 by Lisa Matsuda and colleagues at the U.S. National Institute of Mental Health, and a second, CB2, was cloned in 1993 by Sean Munro's group in Cambridge.<ref name="crocq2020"/>

Cannabinoids bind cannabinoid receptors — chiefly CB1 and CB2. CB1 is found at high density in the nervous system, and CB2 mainly in immune and peripheral tissues; THC binds both, and its binding at CB1 is widely associated with the intoxicating effects of cannabis.<ref name="pertwee2006"/> Beyond this, the relationship between cannabinoid receptor binding and the many effects attributed to cannabinoids is an area of active research and should not be regarded as fully established: that a compound binds a receptor is one kind of finding; that this binding produces a particular clinical or behavioral effect is a separate inference. CBD is a case in point — it has little affinity for CB1, and the purported mechanisms behind its reported effects remain under investigation.<ref name="pertwee2006"/>

Interest in the medical use of cannabinoids has grown substantially since the endocannabinoid system was described. Some cannabinoid medicines have received regulatory approval for specific uses — for example in certain forms of childhood epilepsy, and for nausea and appetite loss — while many other proposed uses remain under study.<ref name="crocq2020"/> The legal status of cannabis and cannabinoids varies widely between jurisdictions and has been changing rapidly in many countries.

Reported adverse effects vary by compound, dose, and route, and figures in the literature are population estimates that differ between studies. THC is associated with acute effects including anxiety, impaired short-term memory, and impaired coordination, and heavy or early use has been associated in observational research with mental-health risks, though the nature of that association continues to be debated. Synthetic cannabinoids — chemically varied and often far more potent at CB1 than THC — have been associated with a considerably higher rate of serious adverse effects. CBD is generally reported to be well tolerated. Individual response is reported to vary considerably between people.