In brief
- Families
- 3endogenous, plant, synthetic
- Receptors
- CB1 · CB2G-protein coupled
- Phytocannabinoids recorded
- ≈ 150
- THC structure elucidated
- 1964Gaoni & Mechoulam
- Legal threshold in France
- < 0,3 %of Δ⁹-THC
Definition
A cannabinoid is a molecule able to activate the cannabinoid receptors, chiefly CB1 and CB2, two G protein-coupled receptors. The term gathers compounds of very different structures and origins, joined by this single pharmacological property: recognising the same target.[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)
Phytogenic cannabinoids
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; the same work also described cannabidiol (CBD).[2] (reference 2) Close to 150 phytocannabinoids have since been recorded, at very unequal concentrations. A few dominate the profile of a given chemotype: THC and CBD, but also CBG, CBN, CBC or THCV.[1] (reference 1)
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.
Endocannabinoid system
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.[3] (reference 3) The CB2 receptor, identified in 1993, is carried above all by immune cells and peripheral tissues.[4] (reference 4)
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".[5] (reference 5) The second, 2-arachidonoylglycerol (2-AG), was described in 1995.[6] (reference 6) 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.[7] (reference 7) 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.
“If the plant acts on us, it is because the body already carried the system.”
Synthetic & semi-synthetic
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.
“Often far greater affinity than THC, for a distinct toxicological profile.”
Semi-synthetic cannabinoids, for their part, are obtained by chemical modification of a plant cannabinoid: hydrogenation of THC for hexahydrocannabinol (HHC), acetylation for THC-O. Recent arrivals on the market, several have since been the subject of scheduling measures (see Legal status).
Production by genetic engineering
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.[8] (reference 8) The main technical obstacle, making the THCAS and CBDAS synthases work in yeast, was removed by addressing them to the vacuole of the cell. The benefit: controlled production, with no plant growing and no extraction.
Legal status (France · European Union)
Under French law, CBD is not a narcotic. On 29 December 2022 the Conseil d'État annulled the order of 30 December 2021 which banned the sale in raw form of cannabis flowers and leaves low in THC, holding that a general and absolute ban was disproportionate.[9] (reference 9) Products whose Δ⁹-THC content stays below 0.3% are deemed free of narcotic properties; only varieties listed in the European Catalogue may be grown.
The framework nevertheless changes molecule by molecule. Because of the risks they present, the ANSM added HHC and several semi-synthetic cannabinoids to the narcotics list with effect from 3 June 2024.[10] (reference 10) A cannabinoid that is legal today may therefore be scheduled tomorrow: the status is always read compound by compound.
References
- 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.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.Matsuda L. A. et al. « Structure of a cannabinoid receptor and functional expression of the cloned cDNA. » Nature 346, 561–564 (1990).
- 4.Munro S., Thomas K. L., Abu-Shaar M. « Molecular characterization of a peripheral receptor for cannabinoids. » Nature 365, 61–65 (1993).
- 5.Devane W. A. et al. « Isolation and structure of a brain constituent that binds to the cannabinoid receptor. » Science 258, 1946–1949 (1992).
- 6.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).
- 7.Wilson R. I., Nicoll R. A. « Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. » Nature 410, 588–592 (2001).
- 8.Luo X. et al. « Complete biosynthesis of cannabinoids and their unnatural analogues in yeast. » Nature 567, 123–126 (2019).
- 9.Conseil d’État, 1ère–4ème ch. réunies, 29 décembre 2022, n° 444887, annulation de l’arrêté du 30 décembre 2021.
- 10.ANSM. « L’ANSM inscrit de nouveaux cannabinoïdes sur la liste des stupéfiants » : HHC et dérivés semi-synthétiques, à compter du 3 juin 2024.
