Cannabinoids (/kəˈnæbənɔɪdzˌˈkænəbənɔɪdz/) are several structural classes of compounds found primarily in theCannabis plant or as synthetic compounds.[1][2] The most notable cannabinoid is thephytocannabinoidtetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound incannabis.[3][4]Cannabidiol (CBD) is a major constituent of temperate cannabis plants and a minor constituent in tropical varieties.[5] At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four (THCA, CBDA, CBCA, and their common precursor CBGA) have a confirmed biogenetic origin.[6] Phytocannabinoids are also found in other plants, such asrhododendron,licorice, andliverwort.[7]
Phytocannabinoids are multi-ring phenolic compounds structurally related to THC,[8] while endocannabinoids are fatty acid derivatives. Nonclassical synthetic cannabinoids (cannabimimetics) includeaminoalkylindoles, 1,5-diarylpyrazoles,quinolines, and arylsulfonamides, as well aseicosanoids related to endocannabinoids.[3]
Medical uses of cannabinoids include the treatment ofnausea due tochemotherapy,spasticity, and possiblyneuropathic pain.[9] Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".[9]
Cannabis may provide limited relief for someParkinson's disease (PD) symptoms, such as pain, sleep issues, or anxiety, based on small human studies (2023–2024, 10–50 participants), but it does not improve motor symptoms like tremors or stiffness (no significant change in Unified Parkinson's Disease Rating Scale scores).[10][11] A 2023 US survey found 46% of PD patients reported benefits for pain or sleep.[12] RawCannabis containstetrahydrocannabinolic acid (THCA, 15–30% of the plant) andcannabidiolic acid (CBDA), which are non-psychoactive. Animal studies (2021–2024) suggest THCA and CBDA may reduce inflammation and protect brain cells in PD models, acting on CB2 receptors and other pathways (e.g., TRP channels, PPARγ), unliketetrahydrocannabinol (THC) andcannabidiol (CBD), which form when cannabis is heated (e.g., smoking, 105–150°C).[13][14][15] No human studies have tested THCA or CBDA for PD as of 2025. In regions like India, raw cannabis is used traditionally for tremors, but scientific evidence is lacking.[16] Risks include dizziness from THC (12–20% dropout in studies) and potential interactions with PD medications like levodopa.[17]
Before the 1980s, cannabinoids were thought to produce their effects via nonspecific interaction withcell membranes, rather than specificmembrane-boundreceptors. The discovery of cannabinoid receptors in the 1980s resolved this debate.[18] These receptors are common in animals, with two primary types,CB1 andCB2,[19] and evidence suggests additional receptors may exist.[20] The human brain has more cannabinoid receptors than any otherG protein-coupled receptor (GPCR) type.[21]
Theendocannabinoid system (ECS) regulates multiple functions, including movement, motor coordination, learning, memory, emotion, motivation, addictive-like behavior, and pain modulation.[22]
CB2 receptors are predominantly found in theimmune system or immune-derived cells,[24][25][26][27] with varying expression patterns. A subpopulation ofmicroglia in the humancerebellum expresses CB2.[28] CB2 receptors are linked to immunomodulatory effects[27] and potential therapeutic benefits in animal models.[26]
The classical cannabinoids are concentrated in a viscousresin produced in structures known as glandulartrichomes. At least 113 different cannabinoids have been isolated from theCannabis plant.[6]
All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized.[29] The classical cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) bydecarboxylation (catalyzed by heat, light, oralkaline conditions).[30]
Cannabidiol (CBD) is mildlypsychotropic and counteracts cognitive impairment associated with cannabis use.[32] CBD has low affinity forCB1 andCB2 receptors but acts as an indirect antagonist of cannabinoid agonists.[33] It is an agonist at the5-HT1A receptor[34] and may promote sleep and suppress arousal by interfering withadenosine uptake.[35] CBD shares a precursor with THC and is the main cannabinoid in CBD-dominantCannabis strains, potentially reducingshort-term memory loss associated with THC.[36] Tentative evidence suggests CBD may have anti-psychotic effects, though research is limited.[37][32] CBD and other cannabinoids have shown antimicrobial properties, potentially addressing antimicrobial resistance.[38]
Cannabinol (CBN) is a mildlypsychoactive cannabinoid acting as a low-affinitypartial agonist at CB1 and CB2 receptors.[39][40][41] CBN interacts with other neurotransmitter systems (e.g., dopaminergic, serotonergic), requiring higher doses for physiologic effects like mild sedation compared to THC.[42] Isolated in the late 1800s, its structure was elucidated in the 1930s, and chemical synthesis was achieved by 1940.[43]
Cannabinoid production begins with anenzyme combininggeranyl pyrophosphate andolivetolic acid to formCBGA. CBGA is converted toCBG,THCA,CBDA, orCBCA by four separatesynthase, FAD-dependent dehydrogenase enzymes. There is no enzymatic conversion of CBDA or CBD to THCA or THC. Propyl homologues (THCVA, CBDVA, CBCVA) follow an analogous pathway from divarinolic acid.[29][13]
Each cannabinoid may exist in different forms depending on the double bond position in thealicyclic carbon ring. Under the dibenzopyran numbering system, the major form of THC is Δ9-THC, and the minor form is Δ8-THC. In the alternateterpene numbering system, these are Δ1-THC and Δ6-THC, respectively.
Most classical cannabinoids are 21-carbon compounds, but variations in theside-chain length attached to thearomatic ring exist. In THC, CBD, and CBN, the side-chain is a pentyl (5-carbon) chain. Propyl (3-carbon) chain variants are named with the suffixvarin (THCV, CBDV, CBNV), while heptyl (7-carbon) chain variants are namedphorol (THCP, CBDP).
Cannabis plants vary widely in their cannabinoid profiles due toselective breeding.Hemp strains are bred for low THC content, often for fiber, while medical strains may prioritize high CBD, and recreational strains target high THC or specific balances.[13]Quantitative analysis usesgas chromatography (GC), or GC combined withmass spectrometry (GC/MS), to measure cannabinoid content.Liquid chromatography (LC) can differentiate acid (e.g., THCA, CBDA) and neutral (e.g., THC, CBD) forms.[6] Legal restrictions in many countries hinder consistent monitoring of cannabinoid profiles.
Cannabinoids are administered via smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Most are metabolized in theliver bycytochrome P450 enzymes, mainlyCYP 2C9.[55]Inhibiting CYP 2C9 can extend intoxication.[55] Δ9-THC is metabolized to11-hydroxy-Δ9-THC and then9-carboxy-THC, detectable in the body for weeks due to theirlipophilic nature and storage infat.[56][57] Theentourage effect suggests thatterpenes modulate cannabinoid effects.[58]
Cannabinoids influence mitochondrial processes, including calcium regulation, apoptosis, electron transport chain activity, mitochondrial respiration and ATP production. Mitochondrial dynamics—encompassing the processes of fusion and fission, as well as alterations in morphology and organelle mobility, are also affected by cannabinoid exposure.[59] In addition, cannabinoids have been shown to modulate mitochondrial biogenesis through the dysregulation of PGC-1α levels.[60] These effects are complex, involving direct membrane interactions and receptor-mediated pathways, but a unified hypothesis is lacking due to conflicting data.[61]
Cannabinoids are extracted using organicsolvents likehydrocarbons oralcohols, which are flammable or toxic, or supercriticalcarbon dioxide, a safer alternative.[65] Isolated components are separated using wiped film vacuum distillation or otherdistillation techniques.[66]
Cannabinol (CBN) was the first cannabinoid isolated in the late 1800s, with its structure elucidated in the 1930s and synthesized by 1940.[43] In 1942,Roger Adams discoveredCannabidiol (CBD),[67] followed byRaphael Mechoulam's identification of CBD stereochemistry in 1963 and THC stereochemistry in 1964.[68] CBD and THC are produced independently from the precursor CBG, not via conversion.[29]
Emergence of derived psychoactive cannabis products
TheAgriculture Improvement Act of 2018 allows hemp-derived products with ≤0.3% Δ9-THC to be sold legally in the US, leading to widespread availability of cannabinoids likeΔ8-THC,Δ10-THC,HHC, andTHCP.[69] These compounds lack the extensive research of Δ9-THC, posing potential risks and challenges fordrug testing due to novelmetabolites and high potency (e.g., THCP's 33× binding affinity).[70][71] A 2023 paper proposed the term "derived psychoactive cannabis products" to distinguish these substances.[72]
Endocannabinoids are substances produced within the body that activatecannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, researchers identified endogenousligands.[18][73]
2-AG, a full agonist at CB1 and CB2, is present at higher brain concentrations than anandamide, potentially playing a larger role in endocannabinoid signaling.[74][77]
Endocannabinoids act aslipid messengers, released from one cell to activate cannabinoid receptors on nearby cells.[82] Unlikemonoamineneurotransmitters, they arelipophilic, insoluble in water, and synthesized on-demand rather than stored.[83] They act locally due to their hydrophobic nature, unlike hormones. The endocannabinoid2-AG is found inbovine and human maternal milk.[84] Cannabinoids enhance sweet taste by increasing Tlc1 receptor expression and suppressing leptin, impacting energy homeostasis.[85]
Endocannabinoids areretrograde transmitters, released from postsynaptic cells to act on presynaptic cells, reducing conventional neurotransmitter release (e.g.,GABA orglutamate).[86]
Synthetic cannabinoids, historically based on herbal cannabinoids, have been developed since the 1940s.[88] Modern compounds may not resemble natural cannabinoids but are designed to interact with cannabinoid receptors.[89] They are used to study structure-activity relationships but pose health risks when used recreationally.[90] Examples includeDronabinol,Nabilone, andRimonabant.[63]
^abLambert DM, Fowler CJ (August 2005). "The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications".Journal of Medicinal Chemistry.48 (16):5059–5087.doi:10.1021/jm058183t.PMID16078824.
^Pate, DW (1999). Anandamide structure-activity relationships and mechanisms of action on intraocular pressure in the normotensive rabbit model. Kuopio University Publications A. Pharmaceutical Sciences Dissertation 37,ISBN951-781-575-1
^Devi, V.; Sharma, A. (2024). "Nutritional potential of cannabis leaves in traditional diets".Journal of Ethnopharmacology.312 (6) 116432.doi:10.1016/j.jep.2023.116432.PMID38554891.
^Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, et al. (May 2005). "Evidence for novel cannabinoid receptors".Pharmacology & Therapeutics.106 (2):133–145.doi:10.1016/j.pharmthera.2004.11.005.PMID15866316.
^Boron WG, Boulpaep EL, eds. (2009).Medical Physiology: A Cellular and Molecular Approach. Saunders. p. 331.ISBN978-1-4160-3115-4.
^Kalant H (January 2014). "Effects of cannabis and cannabinoids in the human nervous system".The effects of drug abuse on the human nervous system. Academic Press. pp. 387–422.doi:10.1016/B978-0-12-418679-8.00013-7.ISBN978-0-12-418679-8.
^Straiker AJ, Maguire G, Mackie K, Lindsey J (September 1999). "Localization of cannabinoid CB1 receptors in the human anterior eye and retina".Investigative Ophthalmology & Visual Science.40 (10):2442–2448.PMID10476817.
^Núñez E, Benito C, Pazos MR, Barbachano A, Fajardo O, González S, et al. (September 2004). "Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study".Synapse.53 (4):208–213.doi:10.1002/syn.20050.PMID15266552.S2CID40738073.
^abcFellermeier M, Eisenreich W, Bacher A, Zenk MH (March 2001). "Biosynthesis of cannabinoids. Incorporation experiments with (13)C-labeled glucoses".European Journal of Biochemistry.268 (6):1596–1604.doi:10.1046/j.1432-1327.2001.02030.x.PMID11248677.
^US 20120046352, Hospodor, Andrew D., "Controlled cannabis decarboxylization"
^Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, et al. (September 1997). "Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase".Journal of Medicinal Chemistry.40 (20):3228–3233.doi:10.1021/jm970126f.PMID9379442.
^"Cannabinol (Code C84510)".NCI Thesaurus. National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services.Archived from the original on 19 November 2022. Retrieved7 December 2022.
^Woelkart K, Salo-Ahen OM, Bauer R (2008). "CB receptor ligands from plants".Current Topics in Medicinal Chemistry.8 (3):173–186.doi:10.2174/156802608783498023.PMID18289087.
^Perry NB, van Klink JW, Burgess EJ, Parmenter GA (February 1997). "Alkamide levels in Echinacea purpurea: a rapid analytical method revealing differences among roots, rhizomes, stems, leaves and flowers".Planta Medica.63 (1):58–62.Bibcode:1997PlMed..63...58P.doi:10.1055/s-2006-957605.PMID17252329.S2CID260280073.
^He X, Lin L, Bernart MW, Lian L (1998). "Analysis of alkamides in roots and achenes of Echinacea purpurea by liquid chromatography–electrospray mass spectrometry".Journal of Chromatography A.815 (2):205–11.doi:10.1016/S0021-9673(98)00447-6.
^Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V (August 2012). "Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand".Pharmacological Research.66 (2):163–169.doi:10.1016/j.phrs.2012.04.003.PMID22525682.
^Korte G, Dreiseitel A, Schreier P, Oehme A, Locher S, Geiger S, et al. (January 2010). "Tea catechins' affinity for human cannabinoid receptors".Phytomedicine.17 (1):19–22.doi:10.1016/j.phymed.2009.10.001.PMID19897346.
^Muhammad I, Li XC, Jacob MR, Tekwani BL, Dunbar DC, Ferreira D (June 2003). "Antimicrobial and antiparasitic (+)-trans-hexahydrodibenzopyrans and analogues from Machaerium multiflorum".J Nat Prod.66 (6):804–9.Bibcode:2003JNAtP..66..804M.doi:10.1021/np030045o.PMID12828466.
^Malheiro, R.F., Costa, A.C., Carmo, H. et al. The synthetic cannabinoid THJ-2201 modulates mitochondrial activity and enhances mitochondrial recruitment to newly-forming neurites during neurodifferentiation of NG108-15 cells. Arch Toxicol (2025).https://doi.org/10.1007/s00204-025-04217-7
^MALHEIRO, Rui Filipe et al. The synthetic cannabinoids ADB-FUBINACA and AMB-FUBINACA enhance in vitro neurodifferentiation of NG108-15 cells, along with PGC-1α dysregulation and mitochondrial dysfunction. Toxicology, p. 154213, 2025.https://doi.org/10.1016/j.tox.2025.154213
^Rovetto LJ, Aieta NV (November 2017). "Supercritical carbon dioxide extraction of cannabinoids from Cannabis sativa L.".The Journal of Supercritical Fluids.129:16–27.doi:10.1016/j.supflu.2017.03.014.hdl:11336/43849.
^Jain R, Singh R (2016). "Microextraction techniques for analysis of cannabinoids".TrAC Trends in Analytical Chemistry.80:156–166.doi:10.1016/j.trac.2016.03.012.
^Rossheim ME, LoParco CR, Henry D, Trangenstein PJ, Walters ST (March 2023). "Delta-8, Delta-10, HHC, THC-O, THCP, and THCV: What should we call these products?".Journal of Studies on Alcohol and Drugs.84 (3):357–360.doi:10.15288/jsad.23-00008.PMID36971760.S2CID257552536.
^Fride E, Bregman T, Kirkham TC (April 2005). "Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood".Experimental Biology and Medicine.230 (4):225–234.doi:10.1177/153537020523000401.PMID15792943.S2CID25430588.
^Mechoulam R, Lander N, Breuer A, Zahalka J (1990). "Synthesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative".Tetrahedron: Asymmetry.1 (5):315–318.doi:10.1016/S0957-4166(00)86322-3.
^Elsohly MA, Gul W, Wanas AS, Radwan MM (February 2014). "Synthetic cannabinoids: analysis and metabolites".Life Sciences.97 (1):78–90.doi:10.1016/j.lfs.2013.12.212.PMID24412391.
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