Canna·wiki : The cannabinoid encyclopaedia

The word has two uses. In pharmacology, a cannabinoid is a molecule that acts on the cannabinoid receptors, chiefly CB1 and CB2, two G protein-coupled receptors, whatever its structure and origin. In plant chemistry, it also designates compounds related to THC and CBD, even when they act only weakly on these receptors, as CBD itself does.^{[1] (reference 1)} The chemical boundary of the group remains debated, the reference inventory proposing a biogenetic rather than a purely structural definition.^{[1] (reference 1)}

Phytocannabinoids are produced by Cannabis sativa, which accumulates them mainly in the trichomes of the flower heads. The structure of Δ⁹-tetrahydrocannabinol (THC), the main psychotropic compound, was elucidated in 1964 by Yehiel Gaoni and Raphael Mechoulam at the Weizmann Institute; that of cannabidiol (CBD) had been established the year before by Raphael Mechoulam and Yuval Shvo.^{[2] (reference 2)[3] (reference 3)} Depending on the counting criteria, 125 or more than 150 have been recorded, at very unequal concentrations: THC or CBD dominates in most varieties, the others often being present only in trace amounts.^{[4] (reference 4)[5] (reference 5)}

The plant does not synthesise THC or CBD directly. It first produces a common precursor, cannabigerolic acid (CBGA), often called the "mother molecule". Three synthases (THCA-, CBDA- and CBCA-synthase) convert it into THCA, CBDA and CBCA acids respectively, the forms actually present in the fresh plant.^{[1] (reference 1)} These acid forms are almost inactive at CB1. It is decarboxylation, the loss of a carboxyl group (−CO₂) under heat (slow drying, combustion, cooking), that turns THCA into THC and CBDA into CBD. CBN is not synthesised by the plant: it results from the slow oxidation of THC, which makes it a marker of ageing.

If the plant acts on humans, it is because the body already carries the system. The CB1 receptor was cloned in 1990; it is densely expressed in the central nervous system, where it modulates neurotransmitter release.^{[6] (reference 6)} The CB2 receptor, identified in 1993, is carried above all by immune cells and peripheral tissues.^{[7] (reference 7)}

The endogenous ligands of these receptors are the endocannabinoids. Anandamide (AEA), the first to be identified, was isolated in 1992 from pig brain; its name comes from the Sanskrit ananda, "bliss".^{[8] (reference 8)} The second, 2-arachidonoylglycerol (2-AG), was described in 1995.^{[9] (reference 9)} These lipids are not stored but synthesised on demand, then rapidly degraded: FAAH hydrolyses anandamide, MAGL hydrolyses 2-AG.

At the synapse they operate by retrograde signalling: released by the post-synaptic neuron, they travel back to the pre-synaptic neuron to curb neurotransmitter release there.^{[10] (reference 10)} The system thus takes part in the modulation of pain, mood, appetite, memory, sleep and inflammation. Anandamide also activates the TRPV1 receptor, which places it at the boundary between endocannabinoids and endovanilloids.

Synthetic cannabinoids are agonists designed in the laboratory (the JWH series of the chemist John W. Huffman, the HU series of the Hebrew University of Jerusalem, or CP), originally as pharmacological tools for mapping the receptors. Diverted into herbal smoking mixtures ("Spice", "K2"), they show an affinity that is often far higher than that of THC and a distinct toxicological profile, and have caused poisonings that are sometimes severe.

Semi-synthetic cannabinoids, for their part, are obtained by chemical modification of a plant cannabinoid, most often CBD extracted from hemp and first converted into THC: hydrogenating that THC gives hexahydrocannabinol (HHC), acetylating it gives THC-O. Recent arrivals on the market, several have since been the subject of scheduling measures (see Legal status).

The complete cannabinoid biosynthesis pathway has been reconstituted in the yeast Saccharomyces cerevisiae: from a simple sugar (galactose), modified strains produce CBGA, then THCA, CBDA and their short-chain homologues (THCVA, CBDVA), as well as analogues that do not exist in nature when the yeast is fed other fatty acids.^{[11] (reference 11)} The authors present it as a platform for producing natural and unnatural cannabinoids, with no plant growing and no extraction.

Under French law, CBD is not a narcotic. On 29 December 2022 the Conseil d'État annulled the provision of the order of 30 December 2021 which banned the sale to consumers of raw cannabis flowers and leaves low in THC, holding that this general and absolute ban was disproportionate.^{[12] (reference 12)} The same order authorises the cultivation, import, export and industrial and commercial use only of varieties listed in a French or European catalogue whose Δ⁹-THC content does not exceed 0.3%; extracts are subject to the same ceiling. This threshold, the Conseil d'État specified, is not a safety threshold: it serves to distinguish these varieties from narcotic ones.^{[12] (reference 12)}

The framework nevertheless changes molecule by molecule. The ANSM classified HHC, HHC-O and HHC-P as narcotics by a decision of 12 June 2023, then, with effect from 3 June 2024, H4-CBD, H2-CBD and a family of benzo[c]chromene derivatives, from which CBN is excluded.^{[13] (reference 13)[14] (reference 14)} A cannabinoid that is legal today may therefore be scheduled tomorrow: the status is always read compound by compound.

1. 1.Hanuš L. O., Meyer S. M., Muñoz E., Taglialatela-Scafati O., Appendino G. « Phytocannabinoids: a unified critical inventory. » Natural Product Reports 33, 1357–1392 (2016).
2. 2.Gaoni Y., Mechoulam R. « Isolation, structure, and partial synthesis of an active constituent of hashish. » Journal of the American Chemical Society 86, 1646–1647 (1964).
3. 3.Mechoulam R., Shvo Y. « Hashish. I. The structure of cannabidiol. » Tetrahedron 19, 2073–2078 (1963).
4. 4.Radwan M. M., Chandra S., Gul S., ElSohly M. A. « Cannabinoids, Phenolics, Terpenes and Alkaloids of Cannabis. » Molecules 26, 2774 (2021).
5. 5.Maioli C., Mattoteia D., Amin H. I. M., Minassi A., Caprioglio D. « Cannabinol: History, Syntheses, and Biological Profile of the Greatest “Minor” Cannabinoid. » Plants 11, 2896 (2022).
6. 6.Matsuda L. A. et al. « Structure of a cannabinoid receptor and functional expression of the cloned cDNA. » Nature 346, 561–564 (1990).
7. 7.Munro S., Thomas K. L., Abu-Shaar M. « Molecular characterization of a peripheral receptor for cannabinoids. » Nature 365, 61–65 (1993).
8. 8.Devane W. A. et al. « Isolation and structure of a brain constituent that binds to the cannabinoid receptor. » Science 258, 1946–1949 (1992).
9. 9.Mechoulam R. et al. « Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. » Biochemical Pharmacology 50, 83–90 (1995).
10. 10.Wilson R. I., Nicoll R. A. « Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. » Nature 410, 588–592 (2001).
11. 11.Luo X. et al. « Complete biosynthesis of cannabinoids and their unnatural analogues in yeast. » Nature 567, 123–126 (2019).
12. 12.Conseil d’État, 1ère–4ème ch. réunies, 29 décembre 2022, n° 444887, annulation de l’arrêté du 30 décembre 2021.
13. 13.ANSM. « L’ANSM classe l’hexahydrocannabinol (HHC) et deux de ses dérivés sur la liste des stupéfiants » : HHC, HHC-O et HHC-P, décision du 12 juin 2023.
14. 14.ANSM. « L’ANSM inscrit de nouveaux cannabinoïdes sur la liste des stupéfiants » (24 mai 2024) : H4-CBD, H2-CBD et dérivés du benzo[c]chromène, CBN exclu, à compter du 3 juin 2024.