Cannabidiol
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Cannabidiol (CBD) is a non-intoxicating cannabinoid and the main cannabinoid of fibre-type cannabis.[1][2] Like tetrahydrocannabinol (THC), whose isomer it is, it is made in the plant as an acid, cannabidiolic acid (CBDA). It appears in quantity only when the acid loses carbon dioxide, a reaction that needs no enzyme and is speeded by heat.[1][3]
The enzymes that make the two acids compete for the same precursor.[4] The balance a plant strikes between them sets its chemotype. Some landraces grown for resin, including the wide-leaflet hashish landraces and the kif of Morocco, carry CBD alongside THC.[5][6] In cannabis seized in the United States, CBD fell while THC rose up to 2014, which the analysts attributed to breeding for THC. Recent demand for CBD has favoured cultivars that carry a hemp synthase gene in a largely drug-type genome.[7][4]
CBD binds the cannabinoid receptors only weakly.[2] It is approved as a prescription medicine and is also sold over the counter in food supplements, cosmetics and electronic-cigarette liquids.[8]
Formation in the plant
CBDA and THCA are both made from cannabigerolic acid (CBGA), the product of the early steps of cannabinoid biosynthesis.[9]: 14 Futoshi Taura, Satoshi Morimoto and Yukihiro Shoyama identified and purified the enzyme of the CBD branch, CBDA synthase, in 1996 from the rapidly expanding leaves of a CBDA-rich strain; those leaves held more CBDA than mature ones. The older schemes of the pathway had assumed that CBDA forms from CBGA through a hydroxylated intermediate and that THCA forms from CBDA by ring closure. The enzyme converts CBGA to CBDA directly.[10]
The gene was cloned in 2007 from a fibre-type plant, the second gene of the cannabinoid pathway to be isolated after that of THCA synthase. Its protein is 83.9 per cent identical to THCA synthase; its discoverers suggested that the two enzymes descend from a common ancestor. Like THCA synthase it is a flavin-containing oxidase that needs molecular oxygen and releases hydrogen peroxide, which revised the 1996 finding that the enzyme needed no cofactor or oxygen. The two enzymes differ at one step: CBDA synthase removes a proton from a terminal methyl group of CBGA where THCA synthase removes one from a hydroxyl group. The ring then closes to give CBDA or THCA. Two further gene copies found in the same plant's DNA made no active enzyme.[1]
In the genome the CBDA and THCA synthase genes lie at separate, closely linked loci in a region rich in retrotransposons in which recombination is rare.[11] In a map of a cross between the drug strain Purple Kush and the hemp variety Finola, the drug parent carried a copy of the CBDA synthase gene that is probably non-functional, with a gypsy retrotransposon inserted in its middle.[11] A later assembly placed the synthase genes and their copies in tandem arrays within long terminal repeat retrotransposons on chromosome 7.[4]
Structure and stability
CBD has the formula C21H30O2 and a molecular weight of 314.46, the same as THC. Unlike THC, which is a viscous oil, it is a solid melting at 66–67 °C. It is insoluble in water and soluble in ethanol, chloroform and hexane.[9]: 21–22 CBD has two rings where THC has three: with cannabigerol and cannabichromene it belongs to the bicyclic cannabinoids, while THC and cannabinol are tricyclic.[8] The plant makes the (−)-enantiomer.[12]
Fresh plants hold far more of the acid than of the neutral compound.[1] In laboratory heating of cannabis extracts at 80 to 145 °C, CBDA lost its carboxyl group at about half the rate of THCA. Unlike THCA, it did not convert cleanly: some of the starting acid or of the product went missing in ways the authors could not explain.[3]
Acids can close the open ring of CBD. In the early 1940s Roger Adams and his colleagues reported that acid treatment turned CBD into a psychotropic product, which they took to be Δ9- or Δ8-THC. Y. Gaoni and Raphael Mechoulam later confirmed that hydrochloric acid gives mainly Δ9-THC, while p-toluenesulfonic acid gives Δ8-THC instead. A 2020 review of the literature found that most animal studies detected no THC or THC metabolites after CBD was given. None of the human studies of CBD taken by mouth detected any. The review also concluded that CBD does break down to psychotropic products in acidic conditions, so that the stability of CBD products in storage needs attention.[8]
Variation between plants
Chemotype and inheritance
A plant's chemotype is defined by its ratio of THC to CBD. CBD-dominant plants, chemotype III, are the low-ratio class; in the plants measured by Karl W. Hillig and Paul Mahlberg they made about 5 per cent as much THC as CBD. The minor cannabinoid cannabichromene rises and falls with CBD in chemotype II and III plants, at about 6 per cent of the CBD level.[5] The ratio behaves in crosses almost as a single gene. Hillig and Mahlberg worked with the model of Etienne de Meijer and colleagues, in which the CBD allele BD and the THC allele BT are alternatives at one locus; the genome map of 2019 found the two synthase genes at separate but closely linked loci.[5][11] In a cultivar with an intermediate ratio both synthase genes are expressed; in CBD-type plants only the CBDA synthase gene is.[4]
Hemp and the landraces
Of the 157 populations that Hillig and Mahlberg grew together, 26 per cent consisted entirely of plants with two copies of the CBD allele. In the groups they assigned to Cannabis sativa (the hemp of Europe, Asia Minor and Central Asia and the feral populations of eastern Europe) and in the ruderal accessions from Central Asia, they estimated that THC-dominant plants made up no more than about 1 per cent. The hemp landraces of southern and eastern Asia, which they assigned to Cannabis indica, were mostly THC-dominant, though lower in THC than the drug landraces.[5]
Among the drug landraces, Hillig and Mahlberg found the wide-leaflet drug landraces, traditionally grown for hashish, higher in combined CBD and THC than the narrow-leaflet drug landraces grown for their flowers, which carried significantly less CBD. They expected growers raising flowers for smoking, where each plant's harvest is used on its own, to favour THC-dominant plants as seed sources, while hashish is pooled from many plants whose chemotypes the grower usually does not know.[5] John McPartland and Ernest Small use the ratio, with terpene profiles and plant form, to separate the two domesticated drug varieties of Cannabis sativa subsp. indica: a THC to CBD ratio of 7 or more in the South Asian domesticate and below 7 in the Central Asian one.[13]: 81
Traditional resin production often uses a mix of THC-dominant, CBD-dominant and intermediate plants from landrace crops such as Moroccan kif, which gives modest THC with roughly equal CBD. Herbal cannabis typically lacks CBD. Tom Freeman and his colleagues link the rise of THC in European resin to the replacement of kif in Morocco by THC-dominant strains.[6]
Breeding away from CBD and back
In illicit cannabis seized in the United States and analysed at the University of Mississippi, CBD fell from about 0.28 per cent in 2001 to under 0.15 per cent in 2014, while the ratio of THC to CBD rose from about 14 to about 80. Mahmoud A. ElSohly and his colleagues took the ratio as a sign that producers were breeding for THC. Their data did not support the idea that users preferred material with high CBD.[7]
Demand for CBD has favoured cultivars that produce it in unprecedented quantities. A genome assembly of one of them, CBDRx, published in 2021, showed it to be mostly of marijuana ancestry, with a CBDA synthase gene introgressed from hemp and no complete THCA synthase gene. CBDRx and the cultivar First Light are related to the "Cherry" cultivars from Colorado, among them Cannatonic, Charlotte's Web and ACDC.[4] A cannabis pangenome published in 2025 traces high-CBD hemp lines such as CBDRx to this introgression of the CBDA synthase locus into drug-type genetics.[14] Such cultivars, often sold as hemp, can exceed the 0.3 per cent THC limit of statutory definitions of industrial hemp when grown to maturity.[4] Chemotype III plants also make some THC: about a fifth of the CBD-dominant plants that Hillig and Mahlberg measured exceeded 0.3 per cent.[5]
Isolation and structure
CBD was first obtained from cannabis in 1940 by Roger Adams and his colleagues, probably together with its acid.[12] The title of their first paper on its structure calls CBD "a product isolated from the marihuana extract of Minnesota wild hemp", from plants in Minnesota.[15] The structure and stereochemistry of CBD were worked out in Mechoulam's laboratory in 1963, a year before those of THC. The racemic compound was first synthesised there in 1965.[12]
Pharmacology
Unlike THC, CBD has no detectable psychoactivity. It displaces other ligands from the CB1 and CB2 cannabinoid receptors only at micromolar concentrations, so much of the research on it has looked for actions that do not go through those receptors. At much lower, nanomolar concentrations it can still block the effects of CB1 and CB2 agonists. It can also act as an inverse agonist at CB1. It blocks the orphan receptor GPR55, which THC activates. Its listed actions also include activation of the TRPV1 and 5-HT1A receptors.[2]
See also
References
- ↑ 1.0 1.1 1.2 1.3 Taura, F.; Sirikantaramas, S.; Shoyama, Y.; Yoshikai, K.; Shoyama, Y.; Morimoto, S. (2007). "Cannabidiolic-acid synthase, the chemotype-determining enzyme in the fiber-type Cannabis sativa". FEBS Letters. 581 (16): 2929–2934. doi:10.1016/j.febslet.2007.05.043.
- ↑ 2.0 2.1 2.2 Pertwee, R.G. (2008). "The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin". British Journal of Pharmacology. 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC 2219532.
- ↑ 3.0 3.1 Wang, M.; Wang, Y.-H.; Avula, B.; Radwan, M.M.; Wanas, A.S.; van Antwerp, J.; Parcher, J.F.; ElSohly, M.A.; Khan, I.A. (2016). "Decarboxylation study of acidic cannabinoids: a novel approach using ultra-high-performance supercritical fluid chromatography/photodiode array-mass spectrometry". Cannabis and Cannabinoid Research. 1 (1): 262–271. doi:10.1089/can.2016.0020. PMC 5549281.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Grassa, C.J.; Weiblen, G.D.; Wenger, J.P.; Dabney, C.; et al. (2021). "A new Cannabis genome assembly associates elevated cannabidiol (CBD) with hemp introgressed into marijuana". New Phytologist. 230 (4): 1665–1679. doi:10.1111/nph.17243. PMC 8248131.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Hillig, K.W.; Mahlberg, P.G. (2004). "A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae)". American Journal of Botany. 91 (6): 966–975. doi:10.3732/ajb.91.6.966.
- ↑ 6.0 6.1 Freeman, Tom P.; Groshkova, Teodora; Cunningham, Andrew; Sedefov, Roumen; Griffiths, Paul; Lynskey, Michael T. (2019). "Increasing potency and price of cannabis in Europe, 2006–16". Addiction. 114 (6): 1015–1023. doi:10.1111/add.14525. PMC 6590252.
- ↑ 7.0 7.1 ElSohly, Mahmoud A.; Mehmedic, Zlatko; Foster, Susan; Gon, Chandrani; Chandra, Suman; Church, James C. (April 2016). "Changes in cannabis potency over the last 2 decades (1995–2014): analysis of current data in the United States". Biological Psychiatry. 79 (7): 613–619. doi:10.1016/j.biopsych.2016.01.004. PMID 26903403.
- ↑ 8.0 8.1 8.2 Golombek, P.; Müller, M.; Barthlott, I.; Sproll, C.; Lachenmeier, D.W. (2020). "Conversion of cannabidiol (CBD) into psychotropic cannabinoids including tetrahydrocannabinol (THC): a controversy in the scientific literature". Toxics. 8 (2) 41. doi:10.3390/toxics8020041. PMC 7357058.
- ↑ 9.0 9.1 United Nations Office on Drugs and Crime (2009). Recommended Methods for the Identification and Analysis of Cannabis and Cannabis Products (PDF). Manual for use by national drug analysis laboratories (Revised and updated ed.). New York: United Nations. ISBN 978-92-1-148242-3. ST/NAR/40.
- ↑ Taura, F.; Morimoto, S.; Shoyama, Y. (1996). "Purification and characterization of cannabidiolic-acid synthase from Cannabis sativa L.: biochemical analysis of a novel enzyme that catalyzes the oxidocyclization of cannabigerolic acid to cannabidiolic acid". Journal of Biological Chemistry. 271 (29): 17411–17416. doi:10.1074/jbc.271.29.17411.
- ↑ 11.0 11.1 11.2 Laverty, K.U.; Stout, J.M.; Sullivan, M.J.; Shah, H.; Gill, N.; Holbrook, L.; Deikus, G.; Sebra, R.; Hughes, T.R.; Page, J.E.; van Bakel, H. (2019). "A physical and genetic map of Cannabis sativa identifies extensive rearrangements at the THC/CBD acid synthase loci". Genome Research. 29 (1): 146–156. doi:10.1101/gr.242594.118. PMC 6314170.
- ↑ 12.0 12.1 12.2 Pertwee, R.G. (2006). "Cannabinoid pharmacology: the first 66 years". British Journal of Pharmacology. 147 (S1): S163–S171. doi:10.1038/sj.bjp.0706406. PMC 1760722.
- ↑ McPartland, J.M.; Small, E. (2020). "A classification of endangered high-THC cannabis (Cannabis sativa subsp. indica) domesticates and their wild relatives". PhytoKeys. 144: 81–112. doi:10.3897/phytokeys.144.46700.
- ↑ Lynch, R.C.; Padgitt-Cobb, L.K.; Garfinkel, A.R.; Knaus, B.J.; Hartwick, N.T.; et al. (2025). "Domesticated cannabinoid synthases amid a wild mosaic cannabis pangenome". Nature. 643 (8073): 1001–1010. doi:10.1038/s41586-025-09065-0. PMC 12286863.
- ↑ Adams, R.; Hunt, M.; Clark, J.H. (1940). "Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. I". Journal of the American Chemical Society. 62 (1): 196–200. doi:10.1021/ja01858a058.