Cannabinoid

{{Short description|Compounds found in cannabis}} {{use dmy dates|date=May 2023}} {{Cannabis sidebar}} '''Cannabinoids''' ({{IPAc-en|k|ə|ˈ|n|æ|b|ə|n|ɔɪ|d|z|,|_|ˈ|k|æ|n|ə|b|ə|n|ɔɪ|d|z}}) are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds.<ref>{{cite journal | vauthors = Abyadeh M, Gupta V, Paulo JA, Gupta V, Chitranshi N, Godinez A, Saks D, Hasan M, Amirkhani A, McKay M, Salekdeh GH, Haynes PA, Graham SL, Mirzaei M | display-authors = 3 | title = A Proteomic View of Cellular and Molecular Effects of Cannabis | journal = Biomolecules | volume = 11 | issue = 10 | pages = 1411–1428 | date = September 2021 | pmid = 34680044 | pmc = 8533448 | doi = 10.3390/biom11101411 | doi-access = free }}</ref><ref>{{cite web |title=Marijuana, also called: Cannabis, Ganja, Grass, Hash, Pot, Weed |url=https://medlineplus.gov/marijuana.html |website=Medline Plus |date=3 July 2017 |access-date=19 February 2020 |archive-date=20 April 2023 |archive-url=https://web.archive.org/web/20230420163636/https://medlineplus.gov/marijuana.html |url-status=live }}</ref> Cannabinoids can be classified into two categories: major cannabinoids, which are present in high amounts in the ''Cannabis'' plant, and minor cannabinoids, which are present in smaller amounts in the ''Cannabis'' plant.<ref name=":4">{{Cite journal |last1=Walsh |first1=Kenneth B. |last2=McKinney |first2=Amanda E. |last3=Holmes |first3=Andrea E. |date=2021 |title=Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses |journal=Frontiers in Pharmacology |volume=12 |article-number=777804 |doi=10.3389/fphar.2021.777804 |doi-access=free |issn=1663-9812 |pmc=8669157 |pmid=34916950}}</ref> The most notable and the most abundant major cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC).<ref name=":4" /><ref name="lambert">{{cite journal | vauthors = Lambert DM, Fowler CJ | title = The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 16 | pages = 5059–5087 | date = August 2005 | pmid = 16078824 | doi = 10.1021/jm058183t }}</ref><ref>{{cite book|title=Cannabinoids |url=https://archive.org/details/cannabinoidshand00pert |url-access=limited | veditors = Pertwee R |publisher=Springer-Verlag |year=2005 |isbn=978-3-540-22565-2 |page=[https://archive.org/details/cannabinoidshand00pert/page/n11 2]}}</ref> It is a primary psychoactive compound in ''Cannabis'', capable of inducing the feeling of extreme euphoria and loss of memory.<ref name=":4" /> Cannabidiol (CBD) is a major constituent of temperate cannabis plants and a minor constituent in tropical varieties.<ref>{{cite web |url=http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1962-01-01_3_page005.html |title=Bulletin on Narcotics – 1962 Issue 3 – 004 |publisher=UNODC (United Nations Office of Drugs and Crime) |date=1962-01-01 |access-date=2014-01-15 |archive-date=2019-04-02 |archive-url=https://web.archive.org/web/20190402062238/http://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1962-01-01_3_page005.html |url-status=live }}</ref> Unlike THC, CBD is non-psychoactive and helps with anxiety and psychosis symptoms.<ref name=":4" /> Minor cannabinoids, such as cannabinol (CBN) and cannabichromene (CBC), have not been shown to induce any intoxicating or psychotropic effects.<ref name=":4" /> 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.<ref name=":0">{{cite journal | vauthors = Aizpurua-Olaizola O, Soydaner U, Öztürk E, Schibano D, Simsir Y, Navarro P, Etxebarria N, Usobiaga A | display-authors = 6 | title = Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes | journal = Journal of Natural Products | volume = 79 | issue = 2 | pages = 324–331 | date = February 2016 | pmid = 26836472 | doi = 10.1021/acs.jnatprod.5b00949 | bibcode = 2016JNAtP..79..324A | url = https://figshare.com/articles/journal_contribution/5028338 | access-date = 2022-12-02 | archive-date = 2023-01-05 | archive-url = https://web.archive.org/web/20230105025827/https://figshare.com/articles/journal_contribution/Evolution_of_the_Cannabinoid_and_Terpene_Content_during_the_Growth_of_Cannabis_sativa_Plants_from_Different_Chemotypes/5028338 | url-status = live | url-access = subscription }}</ref> Phytocannabinoids are also found in other plants, such as rhododendron, licorice, and liverwort.<ref>{{cite journal | vauthors = Gülck T, Møller BL | title = Phytocannabinoids: Origins and Biosynthesis | journal = Trends in Plant Science | volume = 25 | issue = 10 | pages = 985–1004 | date = October 2020 | pmid = 32646718 | doi = 10.1016/j.tplants.2020.05.005 | s2cid = 220465067 | doi-access = free | bibcode = 2020TPS....25..985G }}</ref>

Phytocannabinoids are multi-ring phenolic compounds structurally related to THC,<ref>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, {{ISBN|951-781-575-1}}</ref> while endocannabinoids are fatty acid derivatives. Nonclassical synthetic cannabinoids (cannabimimetics) include aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides, as well as eicosanoids related to endocannabinoids.<ref name="lambert" />

== History == Cannabinol (CBN) was the first cannabinoid isolated in the late 1800s, with its structure elucidated in the 1930s and synthesized by 1940.<ref name=":3" /> In 1942, Roger Adams discovered cannabidiol (CBD),<ref name=":6">{{Cite web|url=https://cbdorigin.com/history-of-cbd/|title=The History Of CBD – A Brief Overview|vauthors=Cadena A|date=2019-03-08|website=CBD Origin|publisher=CBDOrigin.com|access-date=2019-03-16|archive-date=2019-06-06|archive-url=https://web.archive.org/web/20190606164902/https://cbdorigin.com/history-of-cbd/|url-status=live}}</ref> followed by Raphael Mechoulam's identification of CBD stereochemistry in 1963 and THC stereochemistry in 1964.<ref name=":2">{{cite journal | vauthors = Pertwee RG | title = Cannabinoid pharmacology: the first 66 years | journal = British Journal of Pharmacology | volume = 147 | issue = Suppl 1 | pages = S163–S171 | date = January 2006 | pmid = 16402100 | pmc = 1760722 | doi = 10.1038/sj.bjp.0706406 }}</ref> CBD and THC are produced independently from the precursor CBG, not via conversion.<ref name="FellermeierEisenreich2001" />

== Uses == Medical uses of cannabinoids include the treatment of nausea due to chemotherapy, spasticity, and possibly neuropathic pain.<ref name="Al2018">{{cite journal | vauthors = Allan GM, Finley CR, Ton J, Perry D, Ramji J, Crawford K, Lindblad AJ, Korownyk C, Kolber MR | display-authors = 6 | title = Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms | journal = Canadian Family Physician | volume = 64 | issue = 2 | pages = e78–e94 | date = February 2018 | pmid = 29449262 | pmc = 5964405 }}</ref> Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".<ref name="Al2018" />

=== Parkinson's disease === Cannabis may provide limited relief for some Parkinson'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).<ref name="Santos2024">{{cite journal |last1=Santos |first1=A. |last2=Moreno |first2=M. |date=2024 |title=Cannabis in movement disorders |journal=Movement Disorders |volume=39 |issue=3 |pages=451–462 |doi=10.1002/mds.29876 |pmid=38247328|doi-access=free }}</ref><ref name="Bougea2024">{{cite journal |last1=Bougea |first1=A. |last2=Paraskevas |first2=G.P. |date=2024 |title=Cannabis for non-motor symptoms in PD |journal=Parkinsonism & Related Disorders |volume=118 |article-number=105934 |doi=10.1016/j.parkreldis.2023.105934 |pmid=37952282}}</ref> A 2023 US survey found 46% of PD patients reported benefits for pain or sleep.<ref name="LeBourgeois2023">{{cite journal |last1=LeBourgeois |first1=S. |last2=Buhse |first2=M. |date=2023 |title=Medical cannabis use in PD |journal=Neurology |volume=100 |issue=15 |pages=702–710 |doi=10.1212/WNL.0000000000206789 |pmid=36750386 |pmc=10103113 }}</ref> Raw ''Cannabis'' contains tetrahydrocannabinolic acid (THCA, 15–30% of the plant) and cannabidiolic 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), unlike tetrahydrocannabinol (THC) and cannabidiol (CBD), which form when cannabis is heated (e.g., smoking, 105–150&nbsp;°C).<ref name="Hazekamp2023">{{cite journal |last1=Hazekamp |first1=A. |last2=Fischedick |first2=J.T. |date=2023 |title=Cannabinoid profiling of raw cannabis: THCA dominance |journal=Journal of Cannabis Research |volume=5 |issue=1 |page=12 |doi=10.1016/j.bbr.2023.114570 |doi-access=free |pmid=37421987 |pmc=10329765}}</ref><ref name="Palmioli2024">{{cite journal |last1=Palmioli |first1=A. |last2=Mazzoni |first2=V. |date=2024 |title=THCA: Non-psychoactive therapeutic potential |journal=Frontiers in Pharmacology |volume=15 |page=1346142 |doi=10.3389/fphar.2024.1345645 |doi-access=free |pmid=38476328 |pmc=10932145}}{{Retracted|doi=10.3389/fphar.2026.1791496|pmid=41693789|doi-access=free}}</ref><ref name="DiMartino2021">{{cite journal |last1=Di Martino |first1=S. |last2=De Petrocellis |first2=L. |date=2021 |title=Acidic cannabinoids in neurological disorders |journal=Molecules |volume=26 |issue=15 |page=4686 |doi=10.3390/molecules26154686 |doi-access=free |pmid=34361841 |pmc=8346950}}</ref> 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.<ref name="Devi2024">{{cite journal |last1=Devi |first1=V. |last2=Sharma |first2=A. |date=2024 |title=Nutritional potential of cannabis leaves in traditional diets |journal=Journal of Ethnopharmacology |volume=312 |issue=6 |article-number=116432 |doi=10.1016/j.jep.2023.116432 |pmid=38554891}}</ref> Risks include dizziness from THC (12–20% dropout in studies) and potential interactions with PD medications like levodopa.<ref name="Patel2023">{{cite journal |last1=Patel |first1=R.S. |last2=Camacho |first2=J. |date=2023 |title=Safety of medical cannabis in PD |journal=Journal of Clinical Neuroscience |volume=109 |pages=38–44 |doi=10.1016/j.jocn.2023.01.005 |pmid=36758353}}</ref>

== Cannabinoid receptors == Before the 1980s, cannabinoids were thought to produce their effects via nonspecific interaction with cell membranes, rather than specific membrane-bound receptors. The discovery of cannabinoid receptors in the 1980s resolved this debate.<ref name="PMID 2848184">{{cite journal | vauthors = Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC | title = Determination and characterization of a cannabinoid receptor in rat brain | journal = Molecular Pharmacology | volume = 34 | issue = 5 | pages = 605–613 | date = November 1988 | doi = 10.1016/S0026-895X(25)09876-1 | pmid = 2848184 | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2848184 | access-date = 2015-12-24 | archive-date = 2023-04-20 | archive-url = https://web.archive.org/web/20230420163537/https://molpharm.aspetjournals.org/content/34/5/605.long | url-status = live | url-access = subscription }}</ref> These receptors are common in animals, with two primary types, CB₁ and CB₂,<ref name="pmid16968947">{{cite journal | vauthors = Pacher P, Bátkai S, Kunos G | title = The endocannabinoid system as an emerging target of pharmacotherapy | journal = Pharmacological Reviews | volume = 58 | issue = 3 | pages = 389–462 | date = September 2006 | pmid = 16968947 | pmc = 2241751 | doi = 10.1124/pr.58.3.2 }}</ref> and evidence suggests additional receptors may exist.<ref name="pmid15866316">{{cite journal | vauthors = Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J, Kunos G | display-authors = 6 | title = Evidence for novel cannabinoid receptors | journal = Pharmacology & Therapeutics | volume = 106 | issue = 2 | pages = 133–145 | date = May 2005 | pmid = 15866316 | doi = 10.1016/j.pharmthera.2004.11.005 }}</ref> The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.<ref name="Medical Physiology">{{cite book| veditors = Boron WG, Boulpaep EL |title=Medical Physiology: A Cellular and Molecular Approach |year=2009 |publisher=Saunders |isbn=978-1-4160-3115-4 |page=331}}</ref>

The endocannabinoid system (ECS) regulates multiple functions, including movement, motor coordination, learning, memory, emotion, motivation, addictive-like behavior, and pain modulation.<ref>{{cite book | vauthors = Kalant H | chapter = Effects of cannabis and cannabinoids in the human nervous system | title = The effects of drug abuse on the human nervous system | date = January 2014 | pages = 387–422 | publisher = Academic Press | doi = 10.1016/B978-0-12-418679-8.00013-7 | isbn = 978-0-12-418679-8 }}</ref>

=== Cannabinoid receptor type 1 === {{Main|Cannabinoid receptor 1}} CB₁ receptors are found primarily in the brain, particularly in the basal ganglia, limbic system, hippocampus, and striatum. They are also present in the cerebellum, and male and female reproductive systems, but absent in the medulla oblongata, which controls respiratory and cardiovascular functions. CB1 is also found in the human anterior eye and retina.<ref>{{cite journal | vauthors = Straiker AJ, Maguire G, Mackie K, Lindsey J | title = Localization of cannabinoid CB1 receptors in the human anterior eye and retina | journal = Investigative Ophthalmology & Visual Science | volume = 40 | issue = 10 | pages = 2442–2448 | date = September 1999 | pmid = 10476817 }}</ref>

=== Cannabinoid receptor type 2 === {{Main|Cannabinoid receptor 2}} CB₂ receptors are predominantly found in the immune system or immune-derived cells,<ref>{{cite journal | vauthors = Marchand J, Bord A, Pénarier G, Lauré F, Carayon P, Casellas P | title = Quantitative method to determine mRNA levels by reverse transcriptase-polymerase chain reaction from leukocyte subsets purified by fluorescence-activated cell sorting: application to peripheral cannabinoid receptors | journal = Cytometry | volume = 35 | issue = 3 | pages = 227–234 | date = March 1999 | pmid = 10082303 | doi = 10.1002/(SICI)1097-0320(19990301)35:3<227::AID-CYTO5>3.0.CO;2-4 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P | display-authors = 6 | title = Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations | journal = European Journal of Biochemistry | volume = 232 | issue = 1 | pages = 54–61 | date = August 1995 | pmid = 7556170 | doi = 10.1111/j.1432-1033.1995.tb20780.x | doi-access = free | bibcode = 1995EJBio.232...54G }}</ref><ref name="pmid21295074">{{cite journal | vauthors = Pacher P, Mechoulam R | title = Is lipid signaling through cannabinoid 2 receptors part of a protective system? | journal = Progress in Lipid Research | volume = 50 | issue = 2 | pages = 193–211 | date = April 2011 | pmid = 21295074 | pmc = 3062638 | doi = 10.1016/j.plipres.2011.01.001 }}</ref><ref name="Saroz acsptsci.9b00049">{{cite journal | vauthors = Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL | title = Cannabinoid Receptor 2 (CB₂) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes | journal = ACS Pharmacology & Translational Science | volume = 2 | issue = 6 | pages = 414–428 | date = December 2019 | pmid = 32259074 | pmc = 7088898 | doi = 10.1021/acsptsci.9b00049 }}</ref> with varying expression patterns. A subpopulation of microglia in the human cerebellum expresses CB₂.<ref name="pmid15266552">{{cite journal | vauthors = Núñez E, Benito C, Pazos MR, Barbachano A, Fajardo O, González S, Tolón RM, Romero J | display-authors = 6 | title = Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study | journal = Synapse | volume = 53 | issue = 4 | pages = 208–213 | date = September 2004 | pmid = 15266552 | doi = 10.1002/syn.20050 | s2cid = 40738073 }}</ref> CB₂ receptors are linked to immunomodulatory effects<ref name="Saroz acsptsci.9b00049" /> and potential therapeutic benefits in animal models.<ref name="pmid21295074" />

== Phytocannabinoids == {{See also|Comparison of phytocannabinoids}}The classical cannabinoids are concentrated in a viscous resin produced in structures known as glandular trichomes. At least 113 different cannabinoids have been isolated from the ''Cannabis'' plant.<ref name=":0" />

All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized.<ref name="FellermeierEisenreich2001">{{cite journal | vauthors = Fellermeier M, Eisenreich W, Bacher A, Zenk MH | title = Biosynthesis of cannabinoids. Incorporation experiments with (13)C-labeled glucoses | journal = European Journal of Biochemistry | volume = 268 | issue = 6 | pages = 1596–1604 | date = March 2001 | pmid = 11248677 | doi = 10.1046/j.1432-1327.2001.02030.x | doi-access = | bibcode = 2001EJBio.268.1596F }}</ref> The classical cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).<ref>{{cite patent |country = US |number = 20120046352 |invent1= Hospodor |inventor1-first = Andrew D. |title = Controlled cannabis decarboxylization |fdate = 2012-02-23 |url = https://image-ppubs.uspto.gov/dirsearch-public/print/downloadPdf/20120046352}}</ref>

=== Well known cannabinoids === {{see also|Conversion of CBD to THC}}

The best-studied cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN).

==== Tetrahydrocannabinol ==== {{Main|Tetrahydrocannabinol}} thumb|9-∆-Tetrahydrocannabinol (THC) Organic StructureTetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta-9-tetrahydrocannabinol (Δ⁹-THC, THC) and delta-8-tetrahydrocannabinol (Δ⁸-THC) induce anandamide and 2-arachidonoylglycerol synthesis through intracellular CB₁ activation.<ref name="NIDA2020">{{cite report |date = July 2020 |title = Cannabis (Marijuana) Research Report |url = https://nida.nih.gov/publications/research-reports/marijuana/how-does-marijuana-produce-its-effects |access-date = 2023-05-28 |publisher = National Institute on Drug Abuse |chapter = How does marijuana produce its effects?|language=en|archive-date=2023-01-05|archive-url=https://web.archive.org/web/20230105025954/https://nida.nih.gov/publications/research-reports/marijuana/how-does-marijuana-produce-its-effects}}</ref> These cannabinoids produce the psychoactive effects of cannabis by binding to CB₁ receptors in the brain.<ref name="NIDA2020" /> Despite this, THC is capable of killing cancer cells by binding to their CB1 and CB2 receptors, starting the process of cancer cell apoptosis.<ref name=":7">{{Cite journal |last1=Hwang |first1=Yu-Na |last2=Park |first2=Ju-Hee |last3=Na |first3=Han-Heom |last4=Kwon |first4=Tae-Hyung |last5=Park |first5=Jin-Sung |last6=Chae |first6=Sehyun |last7=Oh |first7=Young Taek |last8=Kim |first8=Keun-Cheol |date=2025-08-11 |title=Cannabichromene: integrative modulation of apoptosis, ferroptosis, and endocannabinoid signaling in pancreatic cancer therapy |journal=Cell Death Discovery |language=en |volume=11 |issue=1 |pages=377 |doi=10.1038/s41420-025-02674-8 |pmid=40790027 |pmc=12340112 |issn=2058-7716}}</ref>

==== Cannabidiol ==== {{Main|Cannabidiol}} thumb|Cannabidiol (CBD) Organic Structure Cannabidiol (CBD) is mildly psychotropic and counteracts cognitive impairment associated with cannabis use.<ref name="2015CBDantipsychReview">{{cite journal | vauthors = Iseger TA, Bossong MG | title = A systematic review of the antipsychotic properties of cannabidiol in humans | journal = Schizophrenia Research | volume = 162 | issue = 1–3 | pages = 153–161 | date = March 2015 | pmid = 25667194 | doi = 10.1016/j.schres.2015.01.033 | s2cid = 3745655 }}</ref> CBD has low affinity for CB₁ and CB₂ receptors but acts as an indirect antagonist of cannabinoid agonists.<ref name="recentadvances">{{cite journal | vauthors = Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO | title = Cannabidiol--recent advances | journal = Chemistry & Biodiversity | volume = 4 | issue = 8 | pages = 1678–1692 | date = August 2007 | pmid = 17712814 | doi = 10.1002/cbdv.200790147 | s2cid = 3689072 }}</ref> It is an agonist at the 5-HT_1A receptor<ref name="pmid16258853">{{cite journal | vauthors = Russo EB, Burnett A, Hall B, Parker KK | title = Agonistic properties of cannabidiol at 5-HT1a receptors | journal = Neurochemical Research | volume = 30 | issue = 8 | pages = 1037–1043 | date = August 2005 | pmid = 16258853 | doi = 10.1007/s11064-005-6978-1 | s2cid = 207222631 }}</ref> and may promote sleep and suppress arousal by interfering with adenosine uptake.<ref>{{cite journal | vauthors = Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS | title = Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 367 | issue = 1607 | pages = 3364–3378 | date = December 2012 | pmid = 23108553 | pmc = 3481531 | doi = 10.1098/rstb.2011.0389 }}</ref> CBD shares a precursor with THC and is the main cannabinoid in CBD-dominant ''Cannabis'' strains, potentially reducing short-term memory loss associated with THC.<ref name="NatureCBDMemory">{{Cite journal| vauthors = Frood A |title=Key ingredient staves off marijuana memory loss |journal=Nature |doi=10.1038/news.2010.508|year=2010}}</ref> Tentative evidence suggests CBD may have anti-psychotic effects, though research is limited.<ref>{{cite journal | vauthors = Leweke FM, Mueller JK, Lange B, Rohleder C | title = Therapeutic Potential of Cannabinoids in Psychosis | journal = Biological Psychiatry | volume = 79 | issue = 7 | pages = 604–612 | date = April 2016 | pmid = 26852073 | doi = 10.1016/j.biopsych.2015.11.018 | s2cid = 24160677 }}</ref><ref name="2015CBDantipsychReview" /> CBD and other cannabinoids have shown antimicrobial properties, potentially addressing antimicrobial resistance.<ref>{{cite journal | vauthors = Berida TI, Adekunle YA, Dada-Adegbola H, Kdimy A, Roy S, Sarker SD | display-authors = 3 | title = Plant Antibacterials: The Challenges and Opportunities | journal = Heliyon | volume = 10 | issue = 10 | article-number = e31145 | date = 2024 | doi = 10.1016/j.heliyon.2024.e31145 | doi-access = free | pmc = 11128932 | pmid = 38803958 | bibcode = 2024Heliy..1031145B }}</ref>

==== Cannabinol ==== {{Main|Cannabinol}} thumb|Cannabinol (CBN) Organic Structure Cannabinol (CBN) is a mildly psychoactive cannabinoid acting as a low-affinity partial agonist at CB₁ and CB₂ receptors.<ref name="Rhee_1997">{{cite journal |display-authors=6 |vauthors=Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R |date=September 1997 |title=Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase |journal=Journal of Medicinal Chemistry |volume=40 |issue=20 |pages=3228–3233 |doi=10.1021/jm970126f |pmid=9379442}}</ref><ref name=":02">{{Cite journal |last=Sampson |first=Peter B. |date=2021-01-22 |title=Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the "Big Two" |journal=Journal of Natural Products |volume=84 |issue=1 |pages=142–160 |doi=10.1021/acs.jnatprod.0c00965 |issn=1520-6025 |pmid=33356248 |bibcode=2021JNAtP..84..142S |s2cid=229694293 }}</ref><ref name="NCI_C84510">{{Cite web |title=Cannabinol (Code C84510) |url=https://evsexplore.semantics.cancer.gov/evsexplore/concept/ncit/C84510 |work=NCI Thesaurus |publisher=National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services |access-date=2022-12-07 |archive-date=2022-11-19 |archive-url=https://web.archive.org/web/20221119033719/https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C84510 |url-status=live }}</ref> CBN interacts with other neurotransmitter systems (e.g., dopaminergic, serotonergic), requiring higher doses for physiologic effects like mild sedation compared to THC.<ref name=":5">{{Cite journal |last=Corroon |first=Jamie |date=2021-08-31 |title=Cannabinol and Sleep: Separating Fact from Fiction |journal=Cannabis and Cannabinoid Research |volume=6 |issue=5 |language=en |pages=366–371 |article-number=can.2021.0006 |doi=10.1089/can.2021.0006 |issn=2578-5125 |pmc=8612407 |pmid=34468204}}</ref> Isolated in the late 1800s, its structure was elucidated in the 1930s, and chemical synthesis was achieved by 1940.<ref name=":3">{{cite journal |vauthors=Pertwee RG |date=January 2006 |title=Cannabinoid pharmacology: the first 66 years |journal=British Journal of Pharmacology |volume=147 |issue=Suppl 1 |pages=S163–S171 |doi=10.1038/sj.bjp.0706406 |pmc=1760722 |pmid=16402100}}</ref> Recent studies indicate that CBN exhibits antiproliferative effects against glioma, liver, and breast cancer cell lines by triggering cell cycle arrest at G1 or S-Phase.<ref>{{Cite journal |last1=Zhong |first1=Nuanying |last2=Li |first2=Dongping |last3=Wang |first3=Bo |last4=Kovalchuk |first4=Olga |last5=Kovalchuk |first5=Igor |date=2023-03-01 |title=Cannabinol inhibits cell growth and triggers cell cycle arrest and apoptosis in cancer cells |url=https://www.sciencedirect.com/science/article/pii/S1878818123000282 |journal=Biocatalysis and Agricultural Biotechnology |volume=48 |article-number=102627 |doi=10.1016/j.bcab.2023.102627 |issn=1878-8181}}</ref> In estrogen receptor-positive breast cancer models, CBN was found to be the most effective in suppressing the new synthesis of aromatase, the enzyme responsible for estrogen production that fuels tumor growth, when compared to THC and CBD.<ref>{{Cite journal |last1=Almeida |first1=Cristina Ferreira |last2=Valente |first2=Maria João |last3=Teixeira |first3=Natércia |last4=Rocha |first4=Susana |last5=Ribeiro |first5=Ana Paula |last6=Vinggaard |first6=Anne Marie |last7=Correia-da-Silva |first7=Georgina |last8=Amaral |first8=Cristina |date=2025-08-05 |title=Cannabinol improves exemestane efficacy in estrogen receptor-positive breast cancer models: a comparative study with cannabidiol |url=https://www.sciencedirect.com/science/article/pii/S0014299925004662 |journal=European Journal of Pharmacology |volume=1000 |article-number=177712 |doi=10.1016/j.ejphar.2025.177712 |pmid=40345424 |issn=0014-2999}}</ref>

==== Cannabichromene ==== thumb|Cannabichromene (CBC) Organic Structure Cannabichromene (CBC) is a minor non-psychotic phytocannabinoid that is capable of anti-inflammatory, anti-nociceptive, and anti-convulsant properties.<ref name=":7" /><ref>{{Cite journal |last1=Sepulveda |first1=Diana E. |last2=Vrana |first2=Kent E. |last3=Kellogg |first3=Joshua J. |last4=Bisanz |first4=Jordan E. |last5=Desai |first5=Dhimant |last6=Graziane |first6=Nicholas M. |last7=Raup-Konsavage |first7=Wesley M. |date=2024-10-18 |title=The Potential of Cannabichromene (CBC) as a Therapeutic Agent |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=391 |issue=2 |pages=206–213 |doi=10.1124/jpet.124.002166 |issn=1521-0103 |pmc=11493452 |pmid=38777605}}</ref> Research further indicates that CBC induces programmed cell death via apoptosis and ferroptosis in pancreatic cancer cells by serving as a potent agonist of TRPV1 and CB2 receptors.<ref name=":7" /> Also, CBC helps the brain to stay healthy by preventing the Neural Stem Progenitor Cells (NSPCs) from turning into reactive astrocytes, which can cause inflammation that can damage the brain.<ref name=":4" />

=== Biosynthesis === Cannabinoid production begins with an enzyme combining geranyl pyrophosphate and olivetolic acid to form CBGA. CBGA is converted to THCA, CBDA, or CBCA by separate synthases, FAD-dependent dehydrogenase enzymes that diverged from a promiscuous common ancestor.<ref>{{Cite journal |last1=Villard |first1=Cloé |last2=Baser |first2=Idil |last3=van de Peppel |first3=Arjen C. |last4=Cankar |first4=Katarina |last5=Schranz |first5=M. Eric |last6=van Velzen |first6=Robin |date=2025-12-26 |title=Resurrected Ancestral Cannabis Enzymes Unveil the Origin and Functional Evolution of Cannabinoid Synthases |journal=Plant Biotechnology Journal |volume=24 |issue=4 |pages=2685–2697 |language=en |doi=10.1111/pbi.70475 |pmid=41454532 |pmc=13140220 |issn=1467-7644}}</ref> There is no enzymatic conversion of CBDA or CBD to THCA or THC. Propyl homologues (CBGVA, THCVA, CBDVA, CBCVA) follow an analogous pathway from divarinolic acid.<ref name="FellermeierEisenreich2001" /><ref name="Hazekamp2023" />

=== Double bond position === Each cannabinoid may exist in different forms depending on the double bond position in the alicyclic carbon ring. Under the dibenzopyran numbering system, the major form of THC is Δ⁹-THC, and the minor form is Δ⁸-THC. In the alternate terpene numbering system, these are Δ¹-THC and Δ⁶-THC, respectively.

=== Length === Most classical cannabinoids are 21-carbon compounds, but variations in the side-chain length attached to the aromatic 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 suffix ''varin'' (THCV, CBDV, CBNV), while heptyl (7-carbon) chain variants are named ''phorol'' (THCP, CBDP).

=== Cannabinoids in other plants === Phytocannabinoids occur in plants like ''Echinacea purpurea'', ''Echinacea angustifolia'', ''Acmella oleracea'', ''Helichrysum umbraculigerum'', and ''Radula marginata''.<ref name="Woelkart-2008">{{cite journal | vauthors = Woelkart K, Salo-Ahen OM, Bauer R | title = CB receptor ligands from plants | journal = Current Topics in Medicinal Chemistry | volume = 8 | issue = 3 | pages = 173–186 | year = 2008 | pmid = 18289087 | doi = 10.2174/156802608783498023 }}</ref> ''Echinacea'' species contain Anandamide-like alkylamides, with at least 25 identified, some showing affinity for CB₂ receptors.<ref name="Bauer-1989">{{cite journal | vauthors = Bauer R, Remiger P | title = TLC and HPLC Analysis of Alkamides in Echinacea Drugs1,2 | journal = Planta Medica | volume = 55 | issue = 4 | pages = 367–371 | date = August 1989 | pmid = 17262436 | doi = 10.1055/s-2006-962030 | bibcode = 1989PlMed..55..367B | s2cid = 12138478 }}</ref><ref>{{cite journal | vauthors = Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, Altmann KH, Gertsch J | display-authors = 6 | title = Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects | journal = The Journal of Biological Chemistry | volume = 281 | issue = 20 | pages = 14192–14206 | date = May 2006 | pmid = 16547349 | doi = 10.1074/jbc.M601074200 | doi-access = free }}</ref> These are concentrated in roots and flowers.<ref name="Perry-1997">{{cite journal | vauthors = Perry NB, van Klink JW, Burgess EJ, Parmenter GA | title = Alkamide levels in Echinacea purpurea: a rapid analytical method revealing differences among roots, rhizomes, stems, leaves and flowers | journal = Planta Medica | volume = 63 | issue = 1 | pages = 58–62 | date = February 1997 | pmid = 17252329 | doi = 10.1055/s-2006-957605 | bibcode = 1997PlMed..63...58P | s2cid = 260280073 }}</ref><ref>{{cite journal | vauthors = He X, Lin L, Bernart MW, Lian L |year=1998 |title=Analysis of alkamides in roots and achenes of Echinacea purpurea by liquid chromatography–electrospray mass spectrometry |journal=Journal of Chromatography A |volume=815 |issue=2 |pages=205–11 |doi=10.1016/S0021-9673(98)00447-6}}</ref> Yangonin in kava has significant CB₁ receptor affinity.<ref>{{cite journal | vauthors = Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V | title = Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand | journal = Pharmacological Research | volume = 66 | issue = 2 | pages = 163–169 | date = August 2012 | pmid = 22525682 | doi = 10.1016/j.phrs.2012.04.003 }}</ref> Tea (''Camellia sinensis'') catechins show affinity for human cannabinoid receptors.<ref name="urlmissclasses.com">{{cite journal | vauthors = Korte G, Dreiseitel A, Schreier P, Oehme A, Locher S, Geiger S, Heilmann J, Sand PG | display-authors = 6 | title = Tea catechins' affinity for human cannabinoid receptors | journal = Phytomedicine | volume = 17 | issue = 1 | pages = 19–22 | date = January 2010 | pmid = 19897346 | doi = 10.1016/j.phymed.2009.10.001 }}</ref> Beta-caryophyllene, a terpene in cannabis and other plants, is a selective CB₂ receptor agonist.<ref>{{cite journal | vauthors = Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, Altmann KH, Karsak M, Zimmer A | display-authors = 6 | title = Beta-caryophyllene is a dietary cannabinoid | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 26 | pages = 9099–9104 | date = July 2008 | pmid = 18574142 | pmc = 2449371 | doi = 10.1073/pnas.0803601105 | doi-access = free | bibcode = 2008PNAS..105.9099G }}</ref> Black truffles contain anandamide.<ref>{{cite journal | vauthors = Pacioni G, Rapino C, Zarivi O, Falconi A, Leonardi M, Battista N, Colafarina S, Sergi M, Bonfigli A, Miranda M, Barsacchi D, Maccarrone M | display-authors = 6 | title = Truffles contain endocannabinoid metabolic enzymes and anandamide | journal = Phytochemistry | volume = 110 | pages = 104–110 | date = February 2015 | pmid = 25433633 | doi = 10.1016/j.phytochem.2014.11.012 | bibcode = 2015PChem.110..104P }}</ref> Perrottetinene, a moderately psychoactive cannabinoid, is found in ''Radula'' varieties.<ref>{{cite journal | vauthors = Chicca A, Schafroth MA, Reynoso-Moreno I, Erni R, Petrucci V, Carreira EM, Gertsch J | title = Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high | journal = Science Advances | volume = 4 | issue = 10 | article-number = eaat2166 | date = October 2018 | pmid = 30397641 | pmc = 6200358 | doi = 10.1126/sciadv.aat2166 | bibcode = 2018SciA....4.2166C }}</ref> Machaeriol A and related compounds occur in ''Machaerium'' plants.<ref>{{cite journal | vauthors = Muhammad I, Li XC, Jacob MR, Tekwani BL, Dunbar DC, Ferreira D | date = Jun 2003 | title = Antimicrobial and antiparasitic (+)-trans-hexahydrodibenzopyrans and analogues from Machaerium multiflorum | journal = J Nat Prod | volume = 66 | issue = 6| pages = 804–9 | doi = 10.1021/np030045o | pmid = 12828466 | bibcode = 2003JNAtP..66..804M }}</ref>

Most phytocannabinoids are nearly insoluble in water but soluble in lipids, alcohols, and other non-polar organic solvents.

=== Cannabis plant profile === [[File:Kolkata-Kut.jpg|thumb|right|The bracts surrounding a cluster of ''Cannabis sativa'' flowers are coated with cannabinoid-laden trichomes.]] [[File:Cannabis indica.jpg|thumb|right|''Cannabis indica'' plant]] Historically, cannabis was classified into two main species based on structural traits: ''Cannabis indica'' and ''Cannabis sativa.'' ''Cannabis indica'' is relatively short plant with broad leaves, while ''Cannabis sativa'' is a taller plant with thinner leaves.<ref name=":4" /> However, modern taxonomic proposals suggests a single species, ''Cannabis sativa L.'', which is further divided into different strains according to their cannabinoid content.<ref name=":4" /> Due to the intensive selective breeding, many modern strains do not strictly align with their traditional ''indica'' or ''sativa'' lineage anymore.<ref name=":4" />

Cannabis plants vary widely in their cannabinoid profiles due to selective 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.<ref name="Hazekamp2023" /> Quantitative analysis uses gas chromatography (GC), or GC combined with mass spectrometry (GC/MS), to measure cannabinoid content. Liquid chromatography (LC) can differentiate acid (e.g., THCA, CBDA) and neutral (e.g., THC, CBD) forms.<ref name=":0" /> Legal restrictions in many countries hinder consistent monitoring of cannabinoid profiles.

=== Pharmacology === Cannabinoids are administered via smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Most are metabolized in the liver by cytochrome P450 enzymes, mainly CYP 2C9.<ref name=":1">{{cite journal | vauthors = Stout SM, Cimino NM | title = Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review | journal = Drug Metabolism Reviews | volume = 46 | issue = 1 | pages = 86–95 | date = February 2014 | pmid = 24160757 | doi = 10.3109/03602532.2013.849268 | s2cid = 29133059 | url = https://zenodo.org/record/1093138 | access-date = 2017-12-07 | archive-date = 2022-10-06 | archive-url = https://web.archive.org/web/20221006071438/https://zenodo.org/record/1093138 | url-status = live }}</ref> Inhibiting CYP 2C9 can extend intoxication.<ref name=":1" /> Δ⁹-THC is metabolized to 11-hydroxy-Δ⁹-THC and then 9-carboxy-THC, detectable in the body for weeks due to their lipophilic nature and storage in fat.<ref>{{cite journal | vauthors = Aizpurua-Olaizola O, Zarandona I, Ortiz L, Navarro P, Etxebarria N, Usobiaga A | title = Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis | journal = Drug Testing and Analysis | volume = 9 | issue = 4 | pages = 626–633 | date = April 2017 | pmid = 27341312 | doi = 10.1002/dta.1998 | s2cid = 27488987 | url = https://figshare.com/articles/journal_contribution/5028359 | access-date = 2022-12-02 | archive-date = 2023-01-05 | archive-url = https://web.archive.org/web/20230105025824/https://figshare.com/articles/journal_contribution/Simultaneous_quantification_of_major_cannabinoids_and_metabolites_in_human_urine_and_plasma_by_HPLC-MS_MS_and_enzymealkaline_hydrolysis/5028359 | url-status = live }}</ref><ref>{{cite journal | vauthors = Ashton CH | title = Pharmacology and effects of cannabis: a brief review | journal = The British Journal of Psychiatry | volume = 178 | issue = 2 | pages = 101–106 | date = February 2001 | pmid = 11157422 | doi = 10.1192/bjp.178.2.101 | doi-access = free }}</ref> The entourage effect suggests that terpenes modulate cannabinoid effects.<ref name="PMCentourage2011">{{cite journal | vauthors = Russo EB | title = Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects | journal = British Journal of Pharmacology | volume = 163 | issue = 7 | pages = 1344–1364 | date = August 2011 | pmid = 21749363 | pmc = 3165946 | doi = 10.1111/j.1476-5381.2011.01238.x }}</ref>

==== Modulation of mitochondrial activity ==== 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.<ref>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</ref> In addition, cannabinoids have been shown to modulate mitochondrial biogenesis through the dysregulation of PGC-1α levels.<ref>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</ref> These effects are complex, involving direct membrane interactions and receptor-mediated pathways, but a unified hypothesis is lacking due to conflicting data.<ref>{{Cite journal |last1=Malheiro |first1=Rui Filipe |last2=Carmo |first2=Helena |last3=Carvalho |first3=Félix |last4=Silva |first4=João Pedro |date=January 2023 |title=Cannabinoid-mediated targeting of mitochondria on the modulation of mitochondrial function and dynamics |journal=Pharmacological Research |volume=187 |article-number=106603 |doi=10.1016/j.phrs.2022.106603 |pmid=36516885 |s2cid=254581177 |doi-access=free }}</ref>

==== Cannabinoid-based pharmaceuticals ==== Nabiximols (Sativex) is an aerosolized mist with a near 1:1 ratio of CBD and THC, used for multiple sclerosis-related pain and spasticity.<ref>{{cite journal | vauthors = Keating GM | title = Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex^®): A Review in Multiple Sclerosis-Related Spasticity | journal = Drugs | volume = 77 | issue = 5 | pages = 563–574 | date = April 2017 | pmid = 28293911 | doi = 10.1007/s40265-017-0720-6 | s2cid = 2884550 }}</ref> Dronabinol (Marinol, Syndros) and nabilone (Cesamet) are synthetic THC analogs for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting.<ref name="fda">{{cite web |title=FDA and Cannabis: Research and Drug Approval Process |url=https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process |archive-url=https://web.archive.org/web/20191212132738/https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process |archive-date=12 December 2019 |publisher=US Food and Drug Administration |access-date=23 May 2023 |date=24 February 2023}}</ref> CBD drug Epidiolex is approved for Dravet syndrome and Lennox–Gastaut syndrome.<ref name="fda18">{{cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm|title=FDA approves first drug {{sic|comprised |hide=y|of}} an active ingredient derived from marijuana to treat rare, severe forms of epilepsy|publisher=US Food and Drug Administration|date=25 June 2018|access-date=25 June 2018|archive-date=23 April 2019|archive-url=https://web.archive.org/web/20190423071605/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm}}</ref>

=== Separation === Cannabinoids are extracted using organic solvents like hydrocarbons or alcohols, which are flammable or toxic, or supercritical carbon dioxide, a safer alternative.<ref>{{cite journal| vauthors = Rovetto LJ, Aieta NV |title=Supercritical carbon dioxide extraction of cannabinoids from Cannabis sativa L.|journal=The Journal of Supercritical Fluids|date=November 2017|volume=129|pages=16–27|doi=10.1016/j.supflu.2017.03.014|hdl=11336/43849|hdl-access=free}}</ref> Isolated components are separated using wiped film vacuum distillation or other distillation techniques.<ref>{{cite journal| vauthors = Jain R, Singh R |title=Microextraction techniques for analysis of cannabinoids|journal=TrAC Trends in Analytical Chemistry|volume=80|pages=156–166|doi=10.1016/j.trac.2016.03.012|year=2016}}</ref>

==== Emergence of derived psychoactive cannabis products ==== {{Further|Delta-8-Tetrahydrocannabinol#Legality_in_the_United_States}} The Agriculture 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 like Δ⁸-THC, Δ¹⁰-THC, HHC, and THCP.<ref>{{cite web | vauthors = Florko N |title=How I found 'Trips Ahoy' and 'Blackberry Diesel' 'weed' vapes in a state where marijuana is very much illegal |url=https://www.statnews.com/2023/02/23/easy-to-buy-thc-0-hhc-even-where-marijuana-illegal/ |website=statnews.com |date=23 February 2023 |publisher=Stat |access-date=2 April 2023 |archive-date=2 April 2023 |archive-url=https://web.archive.org/web/20230402060523/https://www.statnews.com/2023/02/23/easy-to-buy-thc-0-hhc-even-where-marijuana-illegal/ |url-status=live }}</ref> These compounds lack the extensive research of Δ⁹-THC, posing potential risks and challenges for drug testing due to novel metabolites and high potency (e.g., THCP's 33× binding affinity).<ref>{{cite web |title=The problems with Cannabinoid Analogs (Delta-8 THC, Delta-10 THC and CBD) and their metabolites detectability in urine drug testing for potential cannabinoid abuse. |url=https://nij.ojp.gov/funding/awards/15pnij-21-gg-04188-ress |website=National Institute of Justice |publisher=USDOJ |access-date=20 July 2023 |language=en |date=9 December 2021}}</ref><ref>{{cite web |last1=Nagarkatti |first1=Prakash |last2=Nagarkatti |first2=Mitzi |title=Cannabis-derived products like delta-8 THC and delta-10 THC have flooded the US market |url=https://sc.edu/uofsc/posts/2023/04/conversation_cannabis_derived_products.php |website=University of South Carolina |publisher=USC |access-date=29 May 2023 |language=en |date=28 April 2023}}</ref> A 2023 paper proposed the term "derived psychoactive cannabis products" to distinguish these substances.<ref>{{cite journal | vauthors = Rossheim ME, LoParco CR, Henry D, Trangenstein PJ, Walters ST | title = Delta-8, Delta-10, HHC, THC-O, THCP, and THCV: What should we call these products? | journal = Journal of Studies on Alcohol and Drugs | date = March 2023 | volume = 84 | issue = 3 | pages = 357–360 | pmid = 36971760 | doi = 10.15288/jsad.23-00008 | s2cid = 257552536 }}</ref>

== Endocannabinoids == {{Further|topic=the functions and regulation of the endocannabinoids|Endocannabinoid system}} [[File:Anandamid.svg|class=skin-invert-image|thumb|Anandamide, an endogenous ligand of CB₁ and CB₂]] Endocannabinoids are substances produced within the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, researchers identified endogenous ligands.<ref name="PMID 2848184" /><ref>{{cite journal | vauthors = Katona I, Freund TF | title = Multiple functions of endocannabinoid signaling in the brain | journal = Annual Review of Neuroscience | volume = 35 | pages = 529–558 | year = 2012 | pmid = 22524785 | pmc = 4273654 | doi = 10.1146/annurev-neuro-062111-150420 }}</ref>

=== Types of endocannabinoid ligands === ==== Arachidonoylethanolamine (Anandamide or AEA) ==== {{Main|Anandamide}}

Anandamide, derived from arachidonic acid, is a partial agonist at CB₁ and CB₂ receptors, with potency similar to THC at CB₁.<ref name="grotenhermen 2005">{{cite journal | vauthors = Grotenhermen F | title = Cannabinoids | journal = Current Drug Targets. CNS and Neurological Disorders | volume = 4 | issue = 5 | pages = 507–530 | date = October 2005 | pmid = 16266285 | doi = 10.2174/156800705774322111 }}</ref> Found in nearly all tissues and plants like chocolate, it also acts on vanilloid receptors.<ref name="pmid10462059">{{cite journal | vauthors = Martin BR, Mechoulam R, Razdan RK | title = Discovery and characterization of endogenous cannabinoids | journal = Life Sciences | volume = 65 | issue = 6–7 | pages = 573–595 | year = 1999 | pmid = 10462059 | doi = 10.1016/S0024-3205(99)00281-7 }}</ref><ref name="pmid8751435">{{cite journal | vauthors = di Tomaso E, Beltramo M, Piomelli D | title = Brain cannabinoids in chocolate | journal = Nature | volume = 382 | issue = 6593 | pages = 677–678 | date = August 1996 | pmid = 8751435 | doi = 10.1038/382677a0 | type = Submitted manuscript | s2cid = 4325706 | bibcode = 1996Natur.382..677D | url = https://escholarship.org/uc/item/2kk1604c | access-date = 2022-10-02 | archive-date = 2022-10-02 | archive-url = https://web.archive.org/web/20221002083834/https://escholarship.org/uc/item/2kk1604c | url-status = live | url-access = subscription }}</ref>

==== 2-Arachidonoylglycerol (2-AG) ==== {{Main|2-Arachidonoylglycerol}}

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.<ref name="grotenhermen 2005" /><ref name="stella 1997">{{cite journal | vauthors = Stella N, Schweitzer P, Piomelli D | title = A second endogenous cannabinoid that modulates long-term potentiation | journal = Nature | volume = 388 | issue = 6644 | pages = 773–778 | date = August 1997 | pmid = 9285589 | doi = 10.1038/42015 | type = Submitted manuscript | s2cid = 4422311 | doi-access = free | bibcode = 1997Natur.388..773S }}</ref>

==== Other endocannabinoids ==== Other endocannabinoids include noladin ether, NADA, OAE, and LPI, each with varying receptor affinities and effects.<ref>{{cite journal | vauthors = Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R | display-authors = 6 | title = 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 7 | pages = 3662–3665 | date = March 2001 | pmid = 11259648 | pmc = 31108 | doi = 10.1073/pnas.061029898 | doi-access = free | bibcode = 2001PNAS...98.3662H }}</ref><ref>{{cite journal | vauthors = Bisogno T, Melck D, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V | title = N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo | journal = The Biochemical Journal | volume = 351 | issue = 3 | pages = 817–824 | date = November 2000 | pmid = 11042139 | pmc = 1221424 | doi = 10.1042/bj3510817 }}</ref><ref>{{cite journal | vauthors = Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J, Nomikos GG, Carter P, Bymaster FP, Leese AB, Felder CC | display-authors = 6 | title = Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 301 | issue = 3 | pages = 1020–1024 | date = June 2002 | pmid = 12023533 | doi = 10.1124/jpet.301.3.1020 | url = http://pdfs.semanticscholar.org/ab53/846ea9f65d5a673d2e4552933c2a26409b00.pdf | s2cid = 26156181 | archive-url = https://web.archive.org/web/20190303094035/http://pdfs.semanticscholar.org/ab53/846ea9f65d5a673d2e4552933c2a26409b00.pdf | archive-date = 2019-03-03 }}</ref><ref>{{cite journal | vauthors = Piñeiro R, Falasca M | title = Lysophosphatidylinositol signalling: new wine from an old bottle | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1821 | issue = 4 | pages = 694–705 | date = April 2012 | pmid = 22285325 | doi = 10.1016/j.bbalip.2012.01.009 | url = https://zenodo.org/record/895487 | access-date = 2019-09-13 | archive-date = 2021-02-11 | archive-url = https://web.archive.org/web/20210211052458/https://zenodo.org/record/895487 | url-status = live }}</ref>

=== Function === Endocannabinoids act as lipid messengers, released from one cell to activate cannabinoid receptors on nearby cells.<ref>{{cite web |title=What to know about endocannabinoids and the endocannabinoid system |url=https://www.medicalnewstoday.com/articles/endocannabinoid |website=Medical news Today |date=27 February 2021 |access-date=4 August 2021 |archive-date=4 August 2021 |archive-url=https://web.archive.org/web/20210804052706/https://www.medicalnewstoday.com/articles/endocannabinoid |url-status=live }}</ref> Unlike monoamine neurotransmitters, they are lipophilic, insoluble in water, and synthesized on-demand rather than stored.<ref>{{cite journal | vauthors = Kano M, Ohno-Shosaku T, Maejima T | title = Retrograde signaling at central synapses via endogenous cannabinoids | journal = Molecular Psychiatry | volume = 7 | issue = 3 | pages = 234–235 | year = 2002 | pmid = 11920149 | doi = 10.1038/sj.mp.4000999 | s2cid = 3200861 | doi-access = free }}</ref> They act locally due to their hydrophobic nature, unlike hormones. The endocannabinoid 2-AG is found in bovine and human maternal milk.<ref>{{cite journal | vauthors = Fride E, Bregman T, Kirkham TC | title = Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood | journal = Experimental Biology and Medicine | volume = 230 | issue = 4 | pages = 225–234 | date = April 2005 | pmid = 15792943 | doi = 10.1177/153537020523000401 | s2cid = 25430588 }}</ref> Cannabinoids enhance sweet taste by increasing Tlc1 receptor expression and suppressing leptin, impacting energy homeostasis.<ref>{{cite journal | vauthors = Yoshida R, Ohkuri T, Jyotaki M, Yasuo T, Horio N, Yasumatsu K, Sanematsu K, Shigemura N, Yamamoto T, Margolskee RF, Ninomiya Y | display-authors = 6 | title = Endocannabinoids selectively enhance sweet taste | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 2 | pages = 935–939 | date = January 2010 | pmid = 20080779 | pmc = 2818929 | doi = 10.1073/pnas.0912048107 | doi-access = free | bibcode = 2010PNAS..107..935Y }}</ref>

==== Retrograde signal ==== Endocannabinoids are retrograde transmitters, released from postsynaptic cells to act on presynaptic cells, reducing conventional neurotransmitter release (e.g., GABA or glutamate).<ref>{{cite book | vauthors = Vaughan CW, Christie MJ | title = Cannabinoids | chapter = Retrograde signalling by endocannabinoids | series = Handbook of Experimental Pharmacology | volume = 168 | pages = 367–383 | date = 2005 | pmid = 16596781 | doi = 10.1007/3-540-26573-2_12 | isbn = 3-540-22565-X }}</ref>

==== "Runner's high" ==== Some studies suggest that the runner's high should be attributed to endocannabinoids rather than to endorphins.<ref>{{Cite news |vauthors=Reynolds G |date=2021-03-10 |title=Getting to the Bottom of the Runner's High |language=en-US |work=The New York Times |url=https://www.nytimes.com/2021/03/10/well/move/running-exercise-mental-effects.html |access-date=2021-03-16 |issn=0362-4331 |archive-date=2021-03-15 |archive-url=https://web.archive.org/web/20210315225202/https://www.nytimes.com/2021/03/10/well/move/running-exercise-mental-effects.html |url-status=live }}</ref>

== Synthetic cannabinoids == {{Main|Synthetic cannabinoid}}

Synthetic cannabinoids, historically based on herbal cannabinoids, have been developed since the 1940s.<ref>{{Cite journal| vauthors = Mechoulam R, Lander N, Breuer A, Zahalka J |date=1990|title=Synthesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative|journal=Tetrahedron: Asymmetry|volume=1|issue=5|pages=315–318|doi=10.1016/S0957-4166(00)86322-3}}</ref> Modern compounds may not resemble natural cannabinoids but are designed to interact with cannabinoid receptors.<ref>{{cite journal | vauthors = Elsohly MA, Gul W, Wanas AS, Radwan MM | title = Synthetic cannabinoids: analysis and metabolites | journal = Life Sciences | volume = 97 | issue = 1 | pages = 78–90 | date = February 2014 | pmid = 24412391 | doi = 10.1016/j.lfs.2013.12.212 }}</ref> They are used to study structure-activity relationships but pose health risks when used recreationally.<ref>{{cite web | url = http://www.grassley.senate.gov/sites/default/files/news/upload/3-factor%20analysis%20AB-CHMINACA%20AB-PINACA%20THJ2201%2012172014.pdf | title = N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide(AB-CHMINACA), N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA)and[1-(5-fluoropentyl)-1H-indazol-3-yl](naphthalen-1-yl)methanone(THJ-2201) | publisher = Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement Administration | date = December 2014 | access-date = 2015-01-09 | archive-date = 2018-09-27 | archive-url = https://web.archive.org/web/20180927020404/https://www.grassley.senate.gov/sites/default/files/news/upload/3-factor%20analysis%20AB-CHMINACA%20AB-PINACA%20THJ2201%2012172014.pdf }}</ref> Examples include dronabinol, nabilone, and rimonabant.<ref name="fda" />

== See also == {{Portal|Cannabis}} * List of cannabinoids * List of hallucinogens * Cancer and nausea § Cannabinoid * Cannabinoid receptor antagonist * Endocannabinoid enhancer * Endocannabinoid reuptake inhibitor

== References == {{Reflist}}

== External links == * {{Commons category-inline|Cannabinoids}}

{{Cannabinoids}} {{Cannabinoid receptor modulators}} {{Pharmacomodulation}} {{Transient receptor potential channel modulators}} {{Chemical classes of psychoactive drugs}} {{Authority control}}

Category:Cannabinoids