Editing Cannabinoid (section)

== Phytocannabinoids ==
{{See also|Comparison of phytocannabinoids}}

[[File:Kolkata-Kut.jpg|thumb|right|The bracts surrounding a cluster of ''[[Cannabis sativa]]'' flowers are coated with cannabinoid-laden [[Trichomes#Plant trichomes|trichomes]].]]
[[File:Cannabis indica.jpg|thumb|right|''[[Cannabis indica]]'' plant]]
The classical cannabinoids are concentrated in a viscous [[resin]] produced in structures known as glandular [[trichome]]s. 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 =  }}</ref> The classical cannabinoids are derived from their respective 2-[[carboxylic acid]]s (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 ===
{{also|Conversion of CBD to THC}}

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

==== Tetrahydrocannabinol ====
{{Main|Tetrahydrocannabinol}}
Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. ''Delta''-9-[[tetrahydrocannabinol]] (Δ<sup>9</sup>-THC, THC) and [[delta-8-tetrahydrocannabinol]] (Δ<sup>8</sup>-THC), through intracellular CB<sub>1</sub> activation, induce [[anandamide]] and [[2-arachidonoylglycerol]] synthesis produced naturally in the body and brain{{citation needed|date=February 2019}}{{dubious|date=July 2019}}. These cannabinoids produce the effects associated with [[Cannabis (drug)|cannabis]] by binding to the CB<sub>1</sub> cannabinoid receptors in the brain.<ref>{{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|url-status=live}}</ref>

==== Cannabidiol ====
{{Main|Cannabidiol}}
Cannabidiol (CBD) is mildly [[psychotropic]]. Evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis.<ref name=2015CBDantipsychReview /> Cannabidiol has little affinity for [[Cannabinoid receptor#CB1|CB<sub>1</sub>]] and [[Cannabinoid receptor#CB2|CB<sub>2</sub>]] 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 was found to be an antagonist at the putative new cannabinoid receptor, [[GPR55]], a [[GPCR]] expressed in the [[caudate nucleus]] and [[putamen]].<ref>{{cite journal | vauthors = Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ | display-authors = 6 | title = The orphan receptor GPR55 is a novel cannabinoid receptor | journal = British Journal of Pharmacology | volume = 152 | issue = 7 | pages = 1092–1101 | date = December 2007 | pmid = 17876302 | pmc = 2095107 | doi = 10.1038/sj.bjp.0707460 }}</ref> Cannabidiol has also been shown to act as a [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] agonist.<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> CBD can interfere with the uptake of [[adenosine]], which plays an important role in biochemical processes, such as energy transfer. It may play a role in promoting sleep and suppressing arousal.<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 [[wikt:Precursor|precursor]] with THC and is the main cannabinoid in CBD-dominant ''Cannabis'' strains. CBD has been shown to play a role in preventing [[cannabis and memory|the 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>

There is tentative evidence that CBD has an anti-psychotic effect, but research in this area 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">{{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 }}<!--|access-date=9 October 2015--></ref>

==== Cannabinol ====
{{Main|Cannabinol}}
Cannabinol (CBN) is a mildly [[Psychoactive drug|psychoactive]] cannabinoid that acts as a low affinity [[partial agonist]] at both 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" |url=https://pubmed.ncbi.nlm.nih.gov/33356248 |journal=Journal of Natural Products |volume=84 |issue=1 |pages=142–160 |doi=10.1021/acs.jnatprod.0c00965 |issn=1520-6025 |pmid=33356248 |s2cid=229694293 |access-date=2022-12-07 |archive-date=2022-11-19 |archive-url=https://web.archive.org/web/20221119033717/https://pubmed.ncbi.nlm.nih.gov/33356248/ |url-status=live }}</ref>'''<ref name="NCI_C84510">{{Cite web |title=Cannabinol (Code C84510) |url=https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=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>''' Through its mechanism of partial agonism at the CB1R, CBN is thought to interact with other kinds of [[neurotransmission]] (e.g., dopaminergic, serotonergic, cholinergic, and noradrenergic).

CBN was the first cannabis compound to be isolated from [[cannabis]] extract in the late 1800s. Its structure and chemical synthesis were 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 |quote=Cannabinol (CBN; Figure 1), much of which is thought to be formed from THC during the storage of harvested cannabis, was the first of the plant cannabinoids (phytocannabinoids) to be isolated, from a red oil extract of cannabis, at the end of the 19th century. Its structure was elucidated in the early 1930s by R.S. Cahn, and its chemical synthesis first achieved in 1940 in the laboratories of R. Adams in the U.S.A. and Lord Todd in the U.K.}}</ref>''', followed by some of the first pre-clinical research studies to determine the effects of individual cannabis-derived compounds [[in vivo]].<ref name=":4">{{Cite journal |last=Pertwee |first=Roger G |date=2006 |title=Cannabinoid pharmacology: the first 66 years: Cannabinoid pharmacology |journal=British Journal of Pharmacology |language=en |volume=147 |issue=S1 |pages=S163–S171 |doi=10.1038/sj.bjp.0706406 |pmc=1760722 |pmid=16402100}}</ref> Although CBN shares the same [[mechanism of action]] as other more well-known [[phytocannabinoids]] (e.g., delta-9 [[tetrahydrocannabinol]] or D9THC), it has a lower [[Affinity (pharmacology)|affinity]] for CB1 receptors, meaning that much higher doses of CBN are required in order to experience physiologic effects (e.g., mild sedation) associated with CB1R agonism.<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 |doi=10.1089/can.2021.0006 |issn=2578-5125 |pmc=8612407 |pmid=34468204}}</ref><ref name=":4" /> Although scientific reports are conflicting, the majority of findings suggest that CBN has a slightly higher affinity for CB2 as compared to CB1. Although CBN has been marketed as a sleep aid in recent years, there is a lack of scientific evidence to support these claims, warranting skepticism on the part of consumers.<ref name=":5" />

=== Biosynthesis ===
Cannabinoid production starts when an [[enzyme]] causes [[geranyl pyrophosphate]] and [[olivetolic acid]] to combine and form [[CBGA (cannabinoid)|CBGA]]. Next, CBGA is independently converted to either [[Cannabigerol|CBG]], [[Tetrahydrocannabinolic acid|THCA]], [[CBDA]] or [[CBCA (cannabinoid)|CBCA]] by four separate [[synthase]], FAD-dependent dehydrogenase enzymes. There is no evidence for enzymatic conversion of CBDA or CBD to THCA or THC. For the propyl homologues (THCVA, CBDVA and CBCVA), there is an analogous pathway that is based on CBGVA from divarinolic acid instead of olivetolic acid.

=== Double bond position ===
In addition, each of the compounds above may be in different forms depending on the position of the double bond in the [[alicyclic compound|alicyclic]] carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called Δ<sup>9</sup>-THC, while the minor form is called Δ<sup>8</sup>-THC. Under the alternate [[terpene]] numbering system, these same compounds are called Δ<sup>1</sup>-THC and Δ<sup>6</sup>-THC, respectively.

=== Length ===
Most classical cannabinoids are 21-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the [[Side chain|side-chain]] attached to the [[aromatic hydrocarbon|aromatic]] ring. In THC, CBD, and CBN, this side-chain is a pentyl (5-carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3-carbon) chain. Cannabinoids with the propyl side chain are named using the suffix ''varin'' and are designated THCV, CBDV, or CBNV, while those with the heptyl side chain are named using the suffix ''phorol'' and are designated THCP and CBDP.

=== Cannabinoids in other plants ===

Phytocannabinoids are known to occur in several plant species besides cannabis. These include ''[[Echinacea purpurea]]'', ''[[Echinacea angustifolia]]'', ''[[Acmella oleracea]]'', [[Helichrysum|''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> The best-known cannabinoids that are not derived from Cannabis are the [[Anandamide]]-like alkylamides from ''[[Echinacea]]'' species, most notably the cis/trans [[isomers]] of dodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamide.<ref name="Woelkart-2008" /> At least 25 different [[alkylamide]]s have been identified, and some of them have shown affinities to the CB<sub>2</sub>-receptor.<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 | 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>  In some ''Echinacea'' species, cannabinoids are found throughout the plant structure, but are most concentrated in the 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 | 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]] found in the [[kava]] plant has significant affinity to the CB1 receptor.<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]] have an 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> A widespread dietary terpene, [[beta-caryophyllene]], a component from the [[Cannabis flower essential oil|essential oil of cannabis]] and other medicinal plants, has also been identified as a selective agonist of peripheral CB<sub>2</sub>-receptors, ''[[in vivo]]''.<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,<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 | pages = eaat2166 | date = October 2018 | pmid = 30397641 | pmc = 6200358 | doi = 10.1126/sciadv.aat2166 | bibcode = 2018SciA....4.2166C }}</ref> has been isolated from different ''[[Radula (plant)|Radula]]'' varieties. [[Machaeriol A]] and related compounds are found in plants from the ''[[Machaerium (plant)|Machaerium]]'' family.<ref>Muhammad I, Li XC, Jacob MR, Tekwani BL, Dunbar DC, Ferreira D. Antimicrobial and antiparasitic (+)-trans-hexahydrodibenzopyrans and analogues from Machaerium multiflorum. ''J Nat Prod''. 2003 Jun;66(6):804-9. {{doi|10.1021/np030045o}} {{PMID|12828466}}</ref>

Most of the phytocannabinoids are nearly insoluble in water but are soluble in [[lipid]]s, [[Alcohol (chemistry)|alcohols]], and other non-polar [[organic solvent]]s.

=== Cannabis plant profile ===
Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant's cannabinoid profile. [[Selective breeding]] has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains that are used as fiber (commonly called [[hemp]]) are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for [[recreational drug use|recreational]] purposes are usually bred for high THC content or for a specific chemical balance.

[[Quantitative analysis (chemistry)|Quantitative analysis]] of a plant's cannabinoid profile is often determined by [[gas chromatography]] (GC), or more reliably by gas chromatography combined with [[mass spectrometry]] (GC/MS). [[Liquid chromatography]] (LC) techniques are also possible and, unlike GC methods, can differentiate between the acid and neutral forms of the cannabinoids. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.

=== Pharmacology ===
Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the [[liver]], especially by [[cytochrome P450]] mixed-function oxidases, 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> Thus supplementing with CYP 2C9 [[Enzyme inhibitor|inhibitors]] leads to extended intoxication.<ref name=":1" />

Some is also stored in [[adipose|fat]] in addition to being metabolized in the liver. Δ<sup>9</sup>-THC is metabolized to [[11-Hydroxy-THC|11-hydroxy-Δ<sup>9</sup>-THC]], which is then metabolized to [[11-nor-9-Carboxy-THC|9-carboxy-THC]].<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> Some cannabis [[metabolite]]s can be detected in the body several weeks after administration. These metabolites are the chemicals recognized by common antibody-based "drug tests"; in the case of THC or others, these loads do not represent intoxication (compare to ethanol breath tests that measure instantaneous [[blood alcohol level]]s), but an integration of past consumption over an approximately month-long window. This is because they are fat-soluble, [[lipophilic]] molecules that accumulate in fatty tissues.<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 | quote = Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4-5 days. They are then slowly released back into other body compartments, including the brain. They are then slowly released back into other body compartments, including the brain. Because of the sequestration in fat, the tissue elimination half-life of THC is about 7 days, and complete elimination of a single dose may take up to 30 days. | doi-access = free }}</ref>

Research shows the effect of cannabinoids might be modulated by aromatic compounds produced by the cannabis plant, called [[terpenes]]. This interaction would lead to the [[entourage effect]].<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 ====
Evidence has shown that cannabinoids play a role in the modulation of various mitochondrial processes, including intracellular calcium regulation, activation of apoptosis, impairment of electron transport chain activity, disruption of mitochondrial respiration and ATP production, and regulation of mitochondrial dynamics. These processes contribute to various aspects of cellular biology and can be modified in response to external stimuli. The interaction between cannabinoids and mitochondria is complex, and various molecular mechanisms have been proposed, including direct effects on mitochondrial membranes and receptor-mediated effects. However, an integrated hypothesis of cannabinoids' actions on these processes has yet to be formulated due to conflicting data and the complexity of the pathways involved.<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 |language=en |volume=187 |pages=106603 |doi=10.1016/j.phrs.2022.106603 |pmid=36516885 |s2cid=254581177 |doi-access=free }}</ref>

==== Cannabinoid-based pharmaceuticals ====
[[Nabiximols]] (brand name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC.<ref>{{cite journal | vauthors = Keating GM | title = Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex<sup>®</sup>): 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> Also included are minor cannabinoids and [[terpenoids]], [[ethanol]] and [[propylene glycol]] [[excipients]], and peppermint flavoring.<ref name="ReferenceA">{{cite journal | vauthors = Russo EB | title = Cannabinoids in the management of difficult to treat pain | journal = Therapeutics and Clinical Risk Management | volume = 4 | issue = 1 | pages = 245–259 | date = February 2008 | pmid = 18728714 | pmc = 2503660 | doi = 10.2147/TCRM.S1928 | doi-access = free }}</ref> The drug, made by [[GW Pharmaceuticals]], was first approved by Canadian authorities in 2005 to alleviate pain associated with [[multiple sclerosis]], making it the first cannabis-based medicine. It is marketed by Bayer in Canada.<ref>{{cite news |vauthors=Cooper R |title=GW Pharmaceuticals launches world's first prescription cannabis drug in Britain |url=https://www.telegraph.co.uk/finance/newsbysector/pharmaceuticalsandchemicals/7842794/GW-Pharmaceuticals-launches-worlds-first-prescription-cannabis-drug-in-Britain.html |access-date=29 November 2018 |date=21 June 2010 |archive-date=30 November 2018 |archive-url=https://web.archive.org/web/20181130030419/https://www.telegraph.co.uk/finance/newsbysector/pharmaceuticalsandchemicals/7842794/GW-Pharmaceuticals-launches-worlds-first-prescription-cannabis-drug-in-Britain.html |url-status=live }}</ref> Sativex has been approved in 25 countries; clinical trials are underway in the United States to gain FDA approval.<ref name="USATodaySativex">{{cite web |title=3 prescription drugs that come from marijuana |url=https://www.usatoday.com/story/money/personalfinance/2014/03/17/three-drugs-that-come-from-marijuana/6531291/ |website=USA Today |access-date=30 November 2018 |archive-date=20 April 2023 |archive-url=https://web.archive.org/web/20230420163531/https://www.usatoday.com/story/money/personalfinance/2014/03/17/three-drugs-that-come-from-marijuana/6531291/ |url-status=live }}</ref> In 2007, it was approved for treatment of cancer pain.<ref name="ReferenceA" /> In Phase III trials, the most common adverse effects were dizziness, drowsiness and disorientation; 12% of subjects stopped taking the drug because of the side effects.<ref name="Schubert">{{cite book | vauthors = Schubert-Zsilavecz M, Wurglics M | title = Neue Arzneimittel | date = 2011–2012 | language = de }}</ref>

[[Dronabinol]] (brand names Marinol and Syndros) is a delta-9-THC containing drug for treating [[HIV/AIDS]]-induced [[anorexia (symptom)|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 |url-status=dead |archive-date=12 December 2019 |publisher=US Food and Drug Administration |access-date=23 May 2023 |date=24 February 2023}}</ref>

The [[Cannabidiol|CBD]] drug Epidiolex has been approved by the [[Food and Drug Administration]] for treatment of two rare and severe forms of [[epilepsy]],<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|url-status=dead}}</ref> [[Dravet syndrome|Dravet]] and [[Lennox-Gastaut syndrome|Lennox-Gastaut]] syndromes.<ref name="CNNDravet">{{cite web|vauthors=Scutti S|url=https://www.cnn.com/2018/06/25/health/fda-approves-first-cannabis-drug-bn/index.html|title=FDA approves first cannabis-based drug|website=CNN|date=25 June 2018|access-date=1 December 2018|archive-date=2 December 2018|archive-url=https://web.archive.org/web/20181202070652/https://www.cnn.com/2018/06/25/health/fda-approves-first-cannabis-drug-bn/index.html|url-status=live}}</ref>

[[Nabilone]] (Cesamet) is an FDA approved synthetic analog of THC, prescribed for the treatment of nausea and vomiting induced by chemotherapy treatment in people who have failed to respond adequately to conventional antiemetic treatments.<ref name=fda/>

=== Separation ===
Cannabinoids can be separated from the plant by [[solvent extraction|extraction]] with organic [[solvent]]s. [[Hydrocarbon]]s and [[Alcohol (chemistry)|alcohols]] are often used as solvents. However, these solvents are flammable and many are toxic.<ref>{{cite journal |vauthors=Romano LL, Hazekamp A |title=Cannabis Oil: chemical evaluation of an upcoming cannabis-based medicine |journal=Cannabinoids |date=2013 |volume=7 |issue=1 |pages=1–11 |url=http://www.cannabis-med.org/data/pdf/en_2013_01_1.pdf |access-date=2017-12-07 |archive-date=2017-12-15 |archive-url=https://web.archive.org/web/20171215093111/http://www.cannabis-med.org/data/pdf/en_2013_01_1.pdf |url-status=live }}</ref> Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction with [[carbon dioxide]] is an alternative technique. Once extracted, isolated components can be separated using wiped film vacuum distillation or other [[distillation]] techniques.<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> Also, techniques such as SPE or SPME are found useful in the extraction of these compounds.<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>

=== History ===
The first discovery of an individual cannabinoid was made, when British chemist [[Robert W. Cahn|Robert S. Cahn]] reported the partial structure of Cannabinol (CBN), which he later identified as fully formed in 1940.

Two years later, in 1942,<ref>{{Cite web|url=https://issuu.com/freedomleaf/docs/freedomleafissue34issuu|title=U.S. Chemist Roger Adams Isolated CBD 75 Years Ago|vauthors=Weinberg B|date=Fall 2018|website=Freedom Leaf|via=Issuu.com|access-date=2019-03-16|edition=34|archive-date=2019-04-06|archive-url=https://web.archive.org/web/20190406122157/https://issuu.com/freedomleaf/docs/freedomleafissue34issuu|url-status=live}}</ref> American chemist, [[Roger Adams]], made history when he discovered Cannabidiol (CBD).<ref>{{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> Progressing from Adams research, in 1963<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> Israeli professor Raphael Mechoulam<ref>{{Cite web|url=https://cannabinoids.huji.ac.il/people/raphael-mechoulam|title=Raphael Mechoulam Ph.D.|vauthors=Mechoulam R|website=cannabinoids.huji.ac.il|publisher=The Hebrew University of Jerusalem|type=Biography|access-date=2019-03-16|archive-date=2019-04-02|archive-url=https://web.archive.org/web/20190402090908/https://cannabinoids.huji.ac.il/people/raphael-mechoulam|url-status=live}}</ref> later identified the [[stereochemistry]] of CBD. The following year, in 1964,<ref name=":2" /> Mechoulam and his team identified the stereochemistry of Tetrahydrocannabinol (THC).{{citation needed|date=December 2013}}

Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the Cannabis plant from the precursor CBG.{{citation needed|date=December 2013}}

==== Emergence of derived psychoactive cannabis products ====
{{Further|Delta-8-Tetrahydrocannabinol#Legality_in_the_United_States}}
The [[Agriculture Improvement Act of 2018]] has been interpreted as allowing any hemp-derived product not exceeding 0.3% '''Δ<sup>9</sup>-THC''' to be sold legally in the US. Because the law limited only Δ<sup>9</sup>-THC levels, many other cannabinoids are generally considered legal to sell and are widely available in stores and online, including [[Delta-8-Tetrahydrocannabinol|Δ<sup>8</sup>-THC]], [[Delta-10-Tetrahydrocannabinol|Δ<sup>10</sup>-THC]], [[Hexahydrocannabinol|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><ref>{{Cite web|date=2020-07-09|title=Delta 8 THC: Everything You Need To Know|url=https://www.laweekly.com/delta-8-thc-everything-you-need-to-know/|access-date=2020-07-14|website=LA Weekly|language=en-US|archive-date=2020-07-10|archive-url=https://web.archive.org/web/20200710111113/https://www.laweekly.com/delta-8-thc-everything-you-need-to-know/|url-status=live}}</ref> but have not had the same in-depth research that the Δ<sup>9</sup> isomer has on the human body; carrying potential risks in the short- or long-term. Other concerns include difficulties for [[drug testing]] due to novel [[metabolite]]s, or high potency/[[binding affinity]] of isomers for [[cannabinoid receptor]]s showing potential for [[Substance abuse|abuse]] (i.e., THCP, which has 33× the binding affinity of Δ<sup>9</sup>-THC)<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> From 2021 to 2023, the Δ<sup>8</sup>-THC market generated US$2 billion in revenue.<ref>{{cite web | vauthors = Sabaghi D |title=Delta-8 THC Generated $2 Billion In Revenue In Two Years, Report Finds |url=https://www.forbes.com/sites/dariosabaghi/2023/01/16/delta-8-thc-generated-2-billion-in-revenue-in-2-years-report-finds/?sh=6f49eca34a62 |work=Forbes |access-date=2 April 2023 |archive-date=2 April 2023 |archive-url=https://web.archive.org/web/20230402060526/https://www.forbes.com/sites/dariosabaghi/2023/01/16/delta-8-thc-generated-2-billion-in-revenue-in-2-years-report-finds/?sh=6f49eca34a62 |url-status=live }}</ref> Many substances are scheduled at the state level under various synonyms owing to the different dibenzopyran and monoterpenoid naming conventions. Delta-1, Delta-6, and Delta 3,4-Tetrahydrocannabinol are alternative names for Delta-9, Delta-8, and Delta-6a10a Tetrahydrocannabinol, respectively.<ref>{{Cite web |title=WHO Expert Committee on Drug Dependence Critical Review |url=https://cdn.who.int/media/docs/default-source/controlled-substances/isomersthc.pdf?sfvrsn=8d45f582_2&download=true |page=22 |access-date=2023-03-05 |archive-date=2022-06-02 |archive-url=https://web.archive.org/web/20220602175627/https://cdn.who.int/media/docs/default-source/controlled-substances/isomersthc.pdf?sfvrsn=8d45f582_2&download=true |url-status=live }}</ref>

A 2023 paper seeking the regulation of cannabinoid [[terminology]] coined the term "derived psychoactive cannabis products" to accurately and usefully distinguish said products whilst excluding unrelated 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>