# Cannabinoid
A cannabinoid is a compound that acts on cannabinoid receptors or belongs to the class of meroterpenoid (hybrid natural product from terpene plus polyketide parts) secondary metabolites characteristic of *Cannabis sativa*; the term covers three chemically distinct groups, the plant-derived phytocannabinoids, the body's own endocannabinoids, and synthetic or semi-synthetic cannabinomimetics.[1](https://cdn.who.int/media/docs/default-source/controlled-substances/cannabis-and-cannabis-resin.pdf) • [2](https://connectsci.au/ch/article/74/6/369/89650/The-Chemistry-of-Cannabis-and-Cannabinoids) About 120 phytocannabinoids have been recorded for *C. sativa* in one regulatory review, while a 2025 analytical survey counts more than 177 identified, and a critical chemistry inventory places the figure at almost 200 known cannabinoids.[1](https://cdn.who.int/media/docs/default-source/controlled-substances/cannabis-and-cannabis-resin.pdf) • [3](https://www.mdpi.com/1420-3049/30/3/490) • [4](https://pubs.rsc.org/np/article/33/12/1357/528294/Phytocannabinoids-a-unified-critical-inventory)
| Key fact | Detail |
|---|---|
| Class definition | Phytocannabinoids are meroterpenoids with a resorcinyl core bearing a side chain of one (orcinoids), three (varinoids) or five (olivetoids) carbons[5](https://www.cell.com/trends/plant-science/fulltext/S1360-1385(20)30187-4) |
| Common precursor | CBGA, made by geranylpyrophosphate:olivetolic acid geranyltransferase, diverges into THCA, CBDA and CBCA[2](https://connectsci.au/ch/article/74/6/369/89650/The-Chemistry-of-Cannabis-and-Cannabinoids) |
| Plant form | About 95% of phytocannabinoids such as Δ9-THC, CBD and CBC exist as their acid precursors in the plant; heat decarboxylates them[3](https://www.mdpi.com/1420-3049/30/3/490) • [1](https://cdn.who.int/media/docs/default-source/controlled-substances/cannabis-and-cannabis-resin.pdf) |
| Receptor-active members | Of the almost 200 known cannabinoids, Δ9-THC, its isomer Δ8-THC, cannabinol (CBN), and Δ9-Tetrahydrocannabivarin (THCV) are among the phytocannabinoids that bind the CB1/CB2 ligand site with significant affinity[4](https://pubs.rsc.org/np/article/33/12/1357/528294/Phytocannabinoids-a-unified-critical-inventory) • [17](https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2024.1322434/full) |
| Endocannabinoids | Anandamide (AEA, identified 1992) is a partial agonist with high CB1 affinity; 2-AG (1995) is a lower-affinity full agonist[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/) |
| Smoking pharmacokinetics | Inhaled Δ9-THC bioavailability is about 10–35%, plasma peaks within about 10 minutes, and metabolites are detectable for up to 7 days[2](https://connectsci.au/ch/article/74/6/369/89650/The-Chemistry-of-Cannabis-and-Cannabinoids) |
| Approved drugs | The FDA has approved one cannabis-derived drug (Epidiolex, cannabidiol) and three synthetic cannabis-related drugs (Marinol, Syndros, Cesamet)[7](https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process) |
| Post-2023 development | HHC, a semi-synthetic cannabinoid made from hemp-derived cannabidiol, appeared on the drug market in 2021 and is a partial agonist at human CB1 and CB2[8](https://assets.publishing.service.gov.uk/media/682f3f03c054883884bff465/ACMD%2BReport%2B-%2BSemi-synthetic%2BCannabinoids%2BCannabinoids%2Brelated%2Bto%2Btetrahydro-cannabinol%2Band%2Bcannabidiol%2Bredacted%2BFINAL2.pdf) |
## Definition and classes
The word has two meanings that have drifted apart. Originally "cannabinoid" named a structurally homogeneous class of meroterpenoids typical of *Cannabis sativa* L.; it has since acquired a pharmacological meaning tied to affinity for the CB1 and CB2 receptors.[4](https://pubs.rsc.org/np/article/33/12/1357/528294/Phytocannabinoids-a-unified-critical-inventory) A chemistry-based grouping classifies cannabinoids as phytocannabinoids, endocannabinoids, and synthetic cannabinomimetics by their association with the mammalian cannabinoid receptors.[2](https://connectsci.au/ch/article/74/6/369/89650/The-Chemistry-of-Cannabis-and-Cannabinoids) Structurally, phytocannabinoids are terpenophenolic secondary metabolites more characteristic of cannabis than of any other plant, built from a phenolic (resorcinyl) core joined to a terpenoid fragment.[1](https://cdn.who.int/media/docs/default-source/controlled-substances/cannabis-and-cannabis-resin.pdf) • [5](https://www.cell.com/trends/plant-science/fulltext/S1360-1385(20)30187-4)
**Beyond cannabis.** Endocannabinoids are amide and ester derivatives of ω-6 arachidonic acid made in animal tissues: anandamide (AEA), identified from brain tissue in 1992, is an amide, and 2-arachidonoylglycerol (2-AG), identified from peripheral tissue in 1995, is an ester.[9](https://link.springer.com/article/10.1007/s12210-020-00957-z) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/) Synthetic cannabinomimetics include both the pharmaceuticals (dronabinol, nabilone) and the abused "Spice"-type agonists, while semi-synthetics such as Δ8-THC and HHC are made by chemically modifying natural phytocannabinoids.[7](https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process) • [8](https://assets.publishing.service.gov.uk/media/682f3f03c054883884bff465/ACMD%2BReport%2B-%2BSemi-synthetic%2BCannabinoids%2BCannabinoids%2Brelated%2Bto%2Btetrahydro-cannabinol%2Band%2Bcannabidiol%2Bredacted%2BFINAL2.pdf)
## History of cannabinoid science
Cannabinol (CBN) was the first phytocannabinoid isolated, at the end of the 19th century; R. S. Cahn elucidated its structure in the early 1930s, and R. Adams and [Lord Todd](https://www.edgepedia.org/lord-todd) achieved its first synthesis in 1940, the year cannabidiol (CBD) was first obtained.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC1760722/) The structures of CBD and of Δ9-THC were elucidated in Raphael Mechoulam's laboratory in 1963 and 1964, with total syntheses in 1965.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC1760722/) Receptor biology followed: the first cannabinoid receptor, CB1, was cloned after Pfizer developed a non-classical cannabinoid, and CB2 was cloned in 1993, followed by the isolation of the endogenous ligands AEA and 2-AG.[11](https://www.nature.com/articles/nrd1495)
## Chemistry and major compounds
The major phytocannabinoids differ in ring closure and oxidation state on a shared resorcinyl-terpene skeleton. The acidic forms dominate in the living plant: about 95% of Δ9-THC, CBD and CBC are stored as their carboxylic acid precursors (THCA, CBDA, CBCA), and the neutral forms arise mainly by decarboxylation.[3](https://www.mdpi.com/1420-3049/30/3/490) THCA itself is devoid of intoxicating properties and is not a scheduled substance; the cannabis plant does not enzymatically synthesize THC, and heating converts THCA to THC.[1](https://cdn.who.int/media/docs/default-source/controlled-substances/cannabis-and-cannabis-resin.pdf)
**Receptor-active versus inactive.** Of the almost 200 known cannabinoids, only Δ9-THC, Δ8-THC and, to a lesser extent, CBN bind with significant affinity to the ligand-recognizing site of CB1 and CB2.[4](https://pubs.rsc.org/np/article/33/12/1357/528294/Phytocannabinoids-a-unified-critical-inventory) CBD does not compete at the same site; it acts at CB1 as a negative allosteric modulator, decreasing the efficacy and potency of THC and 2-AG, and as an inverse agonist/antagonist at CB2, though a plant-science review instead describes it as a high-potency antagonist at CB1 and CB2, a characterization that other binding work does not uniformly support.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/) • [5](https://www.cell.com/trends/plant-science/fulltext/S1360-1385(20)30187-4) CBG has roughly 500-fold lower affinity for CB1 and CB2 than Δ9-THC but agonizes the TRPV1 and TRPA1 ion channels.[5](https://www.cell.com/trends/plant-science/fulltext/S1360-1385(20)30187-4)
## Biosynthesis in plants
Cannabinoids are made mainly in the stalked glandular trichomes.[3](https://www.mdpi.com/1420-3049/30/3/490) The terpenophenolic pathway combines a polyketide-derived phenolic acid with a terpenoid unit:
1. **Polyketide assembly.** Tetraketide synthase (TKS), a type III polyketide synthase, condenses hexanoyl-CoA sequentially with three molecules of malonyl-CoA to yield 3,5,7-trioxododecaneoyl-CoA.[12](https://link.springer.com/article/10.1186/s42238-021-00062-4)
2. **Cyclization.** Olivetolic acid cyclase (OAC) cyclizes this tetraketide to olivetolic acid, the five-carbon side-chain phenolic acid.[12](https://link.springer.com/article/10.1186/s42238-021-00062-4)
3. **Prenylation.** An aromatic prenyltransferase transfers geranyl pyrophosphate onto olivetolic acid, producing cannabigerolic acid (CBGA), the common precursor of the major cannabinoid families.[12](https://link.springer.com/article/10.1186/s42238-021-00062-4) • [2](https://connectsci.au/ch/article/74/6/369/89650/The-Chemistry-of-Cannabis-and-Cannabinoids)
4. **Divergence and decarboxylation.** Oxidocyclase enzymes convert CBGA into THCA, CBDA and CBCA; these acids then decarboxylate non-enzymatically to THC, CBD and CBC respectively.[12](https://link.springer.com/article/10.1186/s42238-021-00062-4)
A 2025 *Nature* pangenome study characterized the domesticated cannabinoid synthase genes that determine these chemotypes, classifying plants as, for example, Δ9-tetrahydrocannabinolic acid types, amid expanding legal medical or adult use.[13](https://www.nature.com/articles/s41586-025-09065-0)
## The endocannabinoid system
CB1 is the most abundant [G protein-coupled receptor](https://www.edgepedia.org/g-protein-coupled-receptor) in the central nervous system and is found predominantly at central and peripheral nerve terminals, where activation inhibits transmitter release; CB2 occurs mainly on immune cells and tissues, and is highly induced in microglia after injury or inflammation and expressed on macrophages, osteoclasts, osteoblasts, spleen, and thymus.[5](https://www.cell.com/trends/plant-science/fulltext/S1360-1385(20)30187-4) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC1760722/) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/) Both receptors signal through Gi/o proteins negatively coupled to adenylate cyclase.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC1760722/)
The endocannabinoids themselves are made and destroyed on demand. Anandamide is a partial agonist with high CB1 affinity, whereas 2-AG is a lower-affinity full agonist that elicits robust intracellular signaling; both are synthesized when needed and inactivated by the hydrolytic enzymes FAAH (for AEA) and MAGL (for 2-AG).[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC1760722/) Endocannabinoids, and cannabinoids generally, also act at non-CB1/CB2 targets including GPR55 (a putative third cannabinoid receptor), TRPV1 and other [TRP channels](https://www.edgepedia.org/trp-channels), and the nuclear PPARα, γ and δ receptors.[9](https://link.springer.com/article/10.1007/s12210-020-00957-z) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/)
## Pharmacology and pharmacokinetics
Inhaled Δ9-THC from a cannabis cigarette has a bioavailability of roughly 10 to 35%, with about 30% of the Δ9-THCA destroyed by burning; plasma THC peaks within about 10 minutes of inhalation, and the carboxylic acid metabolite is detectable in plasma for up to 7 days.[2](https://connectsci.au/ch/article/74/6/369/89650/The-Chemistry-of-Cannabis-and-Cannabinoids) Smoked CBD shows a bioavailability of 11–35% and a plasma half-life of 27 to 35 hours; THC metabolites persist because they are stored in adipose tissue.[2](https://connectsci.au/ch/article/74/6/369/89650/The-Chemistry-of-Cannabis-and-Cannabinoids)
**Metabolism.** Δ9-THC is metabolized primarily in the liver, where [CYP2C9](https://www.edgepedia.org/cyp2c9) enzymes hydroxylate it to the active metabolite 11-hydroxy-Δ9-THC; phase I metabolites are then glucuronidated and excreted.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC1760722/) • [9](https://link.springer.com/article/10.1007/s12210-020-00957-z) A key contrast with the endogenous system is degradability: endocannabinoid signaling is controlled by biosynthetic and hydrolytic enzymes (NAT, NAPE-PLD, DAGLs; FAAH, NAAA, MAGL), whereas phytocannabinoids are metabolized by other pathways and must be excreted after modification.[9](https://link.springer.com/article/10.1007/s12210-020-00957-z)
## Medical and recreational use
The FDA has not approved a marketing application for cannabis itself for any disease or condition, but has approved one cannabis-derived drug and three synthetic cannabis-related drugs, all prescription-only: Epidiolex (cannabidiol) for seizures associated with Lennox-Gastaut syndrome or [Dravet syndrome](https://www.edgepedia.org/dravet-syndrome); Marinol and Syndros (both dronabinol) for chemotherapy-associated nausea and AIDS-related anorexia; and Cesamet (nabilone) for chemotherapy-induced nausea.[7](https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process) On the pharmacology of CBD, one review reports no toxic effects in humans at doses between 10 and 700 mg, administered as the purified drug Epidiolex for treatment-resistant epilepsy.[5](https://www.cell.com/trends/plant-science/fulltext/S1360-1385(20)30187-4) CBD also decreases Δ9-THC-elicited psychotic symptoms, consistent with its modulatory action at CB1.[5](https://www.cell.com/trends/plant-science/fulltext/S1360-1385(20)30187-4) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/)
## What has changed since 2023: semi-synthetics and regulation
The semi-synthetic market has reshaped the regulatory picture. Acid treatment of CBD yields a mixture of natural Δ9-THC and semi-synthetic Δ8-THC, and hydrogenation of Δ9- or Δ8-THC provides hexahydrocannabinol (HHC) as a mixture of 9R and 9S isomers, with 9(R)-HHC showing higher affinity and potency; HHC is a partial agonist at human CB1 and CB2.[8](https://assets.publishing.service.gov.uk/media/682f3f03c054883884bff465/ACMD%2BReport%2B-%2BSemi-synthetic%2BCannabinoids%2BCannabinoids%2Brelated%2Bto%2Btetrahydro-cannabinol%2Band%2Bcannabidiol%2Bredacted%2BFINAL2.pdf) HHC appeared on the drug market in 2021, produced from hemp-derived cannabidiol.[14](https://aiche.onlinelibrary.wiley.com/doi/10.1002/dta.3519) The UK's Advisory Council on the Misuse of Drugs now defines semi-synthetic cannabinoids to cover both compounds synthesized from natural phytocannabinoids and close structural analogs made from other material, and notes they are structurally unrelated to Spice-type synthetic cannabinoid receptor agonists.[8](https://assets.publishing.service.gov.uk/media/682f3f03c054883884bff465/ACMD%2BReport%2B-%2BSemi-synthetic%2BCannabinoids%2BCannabinoids%2Brelated%2Bto%2Btetrahydro-cannabinol%2Band%2Bcannabidiol%2Bredacted%2BFINAL2.pdf) In the United States, a proposed legislative framework would apply a THC concentration threshold of not more than 0.3% and regulate hemp-derived cannabinoids including delta-8, delta-9 and delta-10 THC, covering all isomers, acids, acetates, salts, esters, ethers and derivatives thereof.[15](https://www.wyden.senate.gov/imo/media/doc/cannabinoid_safety_and_regulation_act_section-by-sectionpdf.pdf)
**Hazard contrast.** Spice-type synthetic cannabinoid receptor agonists differ from plant cannabinoids in efficacy, not merely in affinity: many are highly potent full agonists at CB1, which partly explains their significant toxicity and deaths compared with THC, a relatively innocuous partial agonist at CB1.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/)
## How cannabinoids compare with related compounds
Within secondary metabolism, cannabinoids belong to the terpenophenolic (meroterpenoid) group: like other such metabolites they join a phenolic core built from the polyketide pathway to a prenyl unit from the terpenoid pathway, here geranyl pyrophosphate fused to olivetolic acid to form CBGA.[5](https://www.cell.com/trends/plant-science/fulltext/S1360-1385(20)30187-4) • [12](https://link.springer.com/article/10.1186/s42238-021-00062-4) Their distinguishing feature is that a small family of plant enzymes at the CBGA branch point generates a large, structurally uniform class of compounds, over 150 of which are minor cannabinoids that together make up less than 1% of the dry mass of a cannabis bud.[16](https://www.sciencedirect.com/science/article/pii/S2589004220304880)
Comparing the three classes at the receptor makes the pharmacological differences concrete. Endocannabinoids are short-lived lipid messengers, AEA a high-affinity partial agonist and 2-AG a full agonist, inactivated by FAAH and MAGL; Δ9-THC is a partial agonist that is enzymatically metabolized by the body, primarily through liver enzyme CYP2C9, with CYP3A4 also contributing; Spice-type synthetics are full agonists with correspondingly greater toxicity.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/) • [9](https://link.springer.com/article/10.1007/s12210-020-00957-z) • [18](https://pmc.ncbi.nlm.nih.gov/articles/PMC6374540/) • [19](https://pmc.ncbi.nlm.nih.gov/articles/PMC6708768/)
## References
1. [WHO Expert Committee on Drug Dependence: Cannabis and Cannabis Resin critical review](https://cdn.who.int/media/docs/default-source/controlled-substances/cannabis-and-cannabis-resin.pdf)
2. [The Chemistry of Cannabis and Cannabinoids, Australian Journal of Chemistry](https://connectsci.au/ch/article/74/6/369/89650/The-Chemistry-of-Cannabis-and-Cannabinoids)
3. [Chromatographic and Spectroscopic Analyses of Cannabinoids: A Narrative Review, Molecules (2025)](https://www.mdpi.com/1420-3049/30/3/490)
4. [Phytocannabinoids: a unified critical inventory, Natural Product Reports](https://pubs.rsc.org/np/article/33/12/1357/528294/Phytocannabinoids-a-unified-critical-inventory)
5. [Phytocannabinoids: Origins and Biosynthesis, Trends in Plant Science](https://www.cell.com/trends/plant-science/fulltext/S1360-1385(20)30187-4)
6. [The Basic Science of Cannabinoids](https://pmc.ncbi.nlm.nih.gov/articles/PMC10788142/)
7. [FDA and Cannabis: Research and Drug Approval Process](https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process)
8. [ACMD Report – Semi-synthetic Cannabinoids (UK Advisory Council on the Misuse of Drugs, 2025)](https://assets.publishing.service.gov.uk/media/682f3f03c054883884bff465/ACMD%2BReport%2B-%2BSemi-synthetic%2BCannabinoids%2BCannabinoids%2Brelated%2Bto%2Btetrahydro-cannabinol%2Band%2Bcannabidiol%2Bredacted%2BFINAL2.pdf)
9. [Phytocannabinoids and endocannabinoids: different in nature, Rendiconti Lincei](https://link.springer.com/article/10.1007/s12210-020-00957-z)
10. [Cannabinoid pharmacology: the first 66 years, British Journal of Pharmacology (Pertwee)](https://pmc.ncbi.nlm.nih.gov/articles/PMC1760722/)
11. [The endocannabinoid system and its therapeutic exploitation, Nature Reviews Drug Discovery](https://www.nature.com/articles/nrd1495)
12. [The biosynthesis of the cannabinoids, Journal of Cannabis Research](https://link.springer.com/article/10.1186/s42238-021-00062-4)
13. [Domesticated cannabinoid synthases amid a wild mosaic cannabis pangenome, Nature (2025)](https://www.nature.com/articles/s41586-025-09065-0)
14. [Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review, Drug Testing and Analysis (2024)](https://aiche.onlinelibrary.wiley.com/doi/10.1002/dta.3519)
15. [Cannabinoid Safety and Regulation Act – section-by-section, U.S. Senate](https://www.wyden.senate.gov/imo/media/doc/cannabinoid_safety_and_regulation_act_section-by-sectionpdf.pdf)
16. [Cannabinoids and Cannabinoid Receptors: The Story so Far, iScience](https://www.sciencedirect.com/science/article/pii/S2589004220304880)
17. [Frontiers, A critical assessment of the abuse, dependence and associated safety risks of naturally occurring and synthetic cannabinoids](https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2024.1322434/full)
18. [pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6374540/)
19. [pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6708768/)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Metabolism and metabolic pathways › Secondary and natural-product metabolism › Terpenoid and terpenophenolic metabolism › Terpenophenolic pathways*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license