Jump to content

Cannabinoid

From Wikipedia, the free encyclopedia

Cannabinoids(/kəˈnæbənɔɪdzˌˈkænəbənɔɪdz/) are several structural classes of compounds found in thecannabisplant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds.[1][2]The most notable cannabinoid is thephytocannabinoidtetrahydrocannabinol(THC) (delta-9-THC), the primary psychoactive compound incannabis.[3][4]Cannabidiol(CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties.[5]At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four (i.e., THCA, CBDA, CBCA and their common precursor CBGA) have been demonstrated to have a biogenetic origin.[6]It was reported in 2020 that phytocannabinoids can be found in other plants such asrhododendron,licoriceandliverwort,[7]and earlier inEchinacea.

Phytocannabinoids are multi-ring phenolic compounds structurally related to THC,[8]but endocannabinoids are fatty acid derivatives. Nonclassical synthetic cannabinoids (cannabimimetics) includeaminoalkylindoles,1,5-diarylpyrazoles,quinolines,and arylsulfonamides as well aseicosanoidsrelated to endocannabinoids.[3]

Uses

[edit]

Medical uses include the treatment ofnauseadue tochemotherapy,spasticity,and possiblyneuropathic pain.[9]Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".[9]

Cannabinoid receptors

[edit]

Before the 1980s, cannabinoids were speculated to produce theirphysiologicaland behavioral effects via nonspecific interaction withcell membranes,instead of interacting with specificmembrane-boundreceptors.The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate.[10]These receptors are common in animals. Two known cannabinoid receptors are termedCB1andCB2,[11]with mounting evidence of more.[12]The human brain has more cannabinoid receptors than any otherG protein-coupled receptor(GPCR) type.[13]

TheEndocannabinoid System(ECS) regulates many functions of the human body. The ECS plays an important role in multiple aspects ofneuralfunctions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.[14]

Cannabinoid receptor type 1

[edit]

CB1receptors are found primarily in thebrain,more specifically in thebasal gangliaand in thelimbic system,including thehippocampus[11]and thestriatum.They are also found in thecerebellumand in both male and femalereproductive systems.CB1receptors are absent in themedulla oblongata,the part of thebrain stemresponsible for respiratory and cardiovascular functions. CB1 is also found in the human anterior eye and retina.[15]

Cannabinoid receptor type 2

[edit]

CB2receptors are predominantly found in theimmune system,or immune-derived cells[16][17][18][19]with varying expression patterns. While found only in the peripheral nervous system, a report does indicate that CB2is expressed by a subpopulation ofmicrogliain the humancerebellum.[20]CB2receptors appear to be responsible for immunomodulatory[19]and possibly other therapeutic effects of cannabinoid as seen in vitro and in animal models.[18]

Phytocannabinoids

[edit]
The bracts surrounding a cluster ofCannabis sativaflowers are coated with cannabinoid-ladentrichomes.
Cannabis indicaplant

The classical cannabinoids are concentrated in a viscousresinproduced in structures known as glandulartrichomes.At least 113 different cannabinoids have been isolated from theCannabisplant.[6]

All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized.[21]The classical cannabinoids are derived from their respective 2-carboxylic acids(2-COOH) bydecarboxylation(catalyzed by heat, light, oralkalineconditions).[22]

Well known cannabinoids

[edit]

The best studied cannabinoids includetetrahydrocannabinol(THC),cannabidiol(CBD) andcannabinol(CBN).

Tetrahydrocannabinol

[edit]

Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant.Delta-9-tetrahydrocannabinol9-THC, THC) anddelta-8-tetrahydrocannabinol8-THC), through intracellular CB1activation, induceanandamideand2-arachidonoylglycerolsynthesis produced naturally in the body and brain[citation needed][dubiousdiscuss].These cannabinoids produce the effects associated withcannabisby binding to the CB1cannabinoid receptors in the brain.[23]

Cannabidiol

[edit]

Cannabidiol (CBD) is mildlypsychotropic.Evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis.[24]Cannabidiol has little affinity forCB1andCB2receptors but acts as an indirect antagonist of cannabinoid agonists.[25]It was found to be an antagonist at the putative new cannabinoid receptor,GPR55,aGPCRexpressed in thecaudate nucleusandputamen.[26]Cannabidiol has also been shown to act as a5-HT1Areceptoragonist.[27]CBD can interfere with the uptake ofadenosine,which plays an important role in biochemical processes, such as energy transfer. It may play a role in promoting sleep and suppressing arousal.[28]

CBD shares aprecursorwith THC and is the main cannabinoid in CBD-dominantCannabisstrains. CBD has been shown to play a role in preventingthe short-term memory loss associated with THC.[29]

There is tentative evidence that CBD has an anti-psychotic effect, but research in this area is limited.[30][24]

Cannabinol

[edit]

Cannabinol (CBN) is a mildlypsychoactivecannabinoid that acts as a low affinitypartial agonistat both CB1 and CB2 receptors.[31][32][33]Through its mechanism of partial agonism at the CB1R, CBN is thought to interact with other kinds ofneurotransmission(e.g., dopaminergic, serotonergic, cholinergic, and noradrenergic).

CBN was the first cannabis compound to be isolated fromcannabisextract in the late 1800s. Its structure and chemical synthesis were achieved by 1940[34],followed by some of the first pre-clinical research studies to determine the effects of individual cannabis-derived compoundsin vivo.[35]Although CBN shares the samemechanism of actionas other more well-knownphytocannabinoids(e.g., delta-9tetrahydrocannabinolor D9THC), it has a loweraffinityfor 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.[36][35]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.[36]

Biosynthesis

[edit]

Cannabinoid production starts when anenzymecausesgeranyl pyrophosphateandolivetolic acidto combine and formCBGA.Next, CBGA is independently converted to eitherCBG,THCA,CBDAorCBCAby four separatesynthase,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

[edit]

In addition, each of the compounds above may be in different forms depending on the position of the double bond in thealicycliccarbon 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 Δ9-THC, while the minor form is called Δ8-THC. Under the alternateterpenenumbering system, these same compounds are called Δ1-THC and Δ6-THC, respectively.

Length

[edit]

Most classical cannabinoids are 21-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of theside-chainattached to thearomaticring. 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 suffixvarinand are designated THCV, CBDV, or CBNV, while those with the heptyl side chain are named using the suffixphoroland are designated THCP and CBDP.

Cannabinoids in other plants

[edit]

Phytocannabinoids are known to occur in several plant species besides cannabis. These includeEchinacea purpurea,Echinacea angustifolia,Acmella oleracea,Helichrysum umbraculigerum,andRadula marginata.[37]The best-known cannabinoids that are not derived from Cannabis are the lipophilic alkamides (alkylamides) fromEchinaceaspecies, most notably the cis/transisomersdodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamide.[37]At least 25 differentalkylamideshave been identified, and some of them have shown affinities to the CB2-receptor.[38][39]In someEchinaceaspecies, cannabinoids are found throughout the plant structure, but are most concentrated in the roots and flowers.[40][41]Yangoninfound in thekavaplant has significant affinity to the CB1 receptor.[42]Tea (Camellia sinensis)catechinshave an affinity for human cannabinoid receptors.[43]A widespread dietary terpene,beta-caryophyllene,a component from theessential oil of cannabisand other medicinal plants, has also been identified as a selective agonist of peripheral CB2-receptors,in vivo.[44]Black trufflescontain anandamide.[45]Perrottetinene,a moderately psychoactive cannabinoid,[46]has been isolated from differentRadulavarieties.Machaeriol Aand related compounds are found in plants from theMachaeriumfamily.[47]

Most of the phytocannabinoids are nearly insoluble in water but are soluble inlipids,alcohols,and other non-polarorganic solvents.

Cannabis plant profile

[edit]

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 breedinghas been used to control the genetics of plants and modify the cannabinoid profile. For example, strains that are used as fiber (commonly calledhemp) 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 forrecreationalpurposes are usually bred for high THC content or for a specific chemical balance.

Quantitative analysisof a plant's cannabinoid profile is often determined bygas chromatography(GC), or more reliably by gas chromatography combined withmass 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

[edit]

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 theliver,especially bycytochrome P450mixed-function oxidases, mainlyCYP 2C9.[48]Thus supplementing with CYP 2C9inhibitorsleads to extended intoxication.[48]

Some is also stored infatin addition to being metabolized in the liver. Δ9-THC is metabolized to11-hydroxy-Δ9-THC,which is then metabolized to9-carboxy-THC.[49]Some cannabismetabolitescan 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 instantaneousblood alcohol levels), but an integration of past consumption over an approximately month-long window. This is because they are fat-soluble,lipophilicmolecules that accumulate in fatty tissues.[50]

Research shows the effect of cannabinoids might be modulated by aromatic compounds produced by the cannabis plant, calledterpenes.This interaction would lead to theentourage effect.[51]

Modulation of mitochondrial activity

[edit]

Recent 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.[52]

Cannabinoid-based pharmaceuticals

[edit]

Nabiximols(brand name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC.[53]Also included are minor cannabinoids andterpenoids,ethanolandpropylene glycolexcipients,and peppermint flavoring.[54]The drug, made byGW Pharmaceuticals,was first approved by Canadian authorities in 2005 to alleviate pain associated withmultiple sclerosis,making it the first cannabis-based medicine. It is marketed by Bayer in Canada.[55]Sativex has been approved in 25 countries; clinical trials are underway in the United States to gain FDA approval.[56]In 2007, it was approved for treatment of cancer pain.[54]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.[57]

Dronabinol(brand names Marinol and Syndros) is a delta-9-THC containing drug for treatingHIV/AIDS-inducedanorexiaandchemotherapy-induced nausea and vomiting.[58]

TheCBDdrug Epidiolex has been approved by theFood and Drug Administrationfor treatment of two rare and severe forms ofepilepsy,[59]DravetandLennox-Gastautsyndromes.[60]

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.[58]

Separation

[edit]

Cannabinoids can be separated from the plant byextractionwith organicsolvents.Hydrocarbonsandalcoholsare often used as solvents. However, these solvents are flammable and many are toxic.[61]Butane may be used, which evaporates extremely quickly. Supercritical solvent extraction withcarbon dioxideis an alternative technique. Once extracted, isolated components can be separated using wiped film vacuum distillation or otherdistillationtechniques.[62]Also, techniques such as SPE or SPME are found useful in the extraction of these compounds.[63]

History

[edit]

The first discovery of an individual cannabinoid was made, when British chemistRobert S. Cahnreported the partial structure of Cannabinol (CBN), which he later identified as fully formed in 1940.

Two years later, in 1942,[64]American chemist,Roger Adams,made history when he discovered Cannabidiol (CBD).[65]Progressing from Adams research, in 1963[66]Israeli professor Raphael Mechoulam[67]later identified thestereochemistryof CBD. The following year, in 1964,[66]Mechoulam and his team identified the stereochemistry of Tetrahydrocannabinol (THC).[citation needed]

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]

Emergence of derived psychoactive cannabis products

[edit]

TheAgriculture Improvement Act of 2018has been interpreted as allowing any hemp-derived product not exceeding 0.3%Δ9-THCto be sold legally in the US. Because the law limited only Δ9-THC levels, many other cannabinoids are generally considered legal to sell and are widely available in stores and online, includingΔ8-THC,Δ10-THC,HHC,andTHCP,[68][69]but have not had the same in-depth research that the Δ9isomer has on the human body; carrying potential risks in the short- or long-term. Other concerns include difficulties fordrug testingdue to novelmetabolites,or high potency/binding affinityof isomers forcannabinoid receptorsshowing potential forabuse(i.e., THCP, which has 33× the binding affinity of Δ9-THC)[70][71]From 2021 to 2023, the Δ8-THC market generated US$2 billion in revenue.[72]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.[73]

A 2023 paper seeking the regulation of cannabinoidterminologycoined the term "derived psychoactive cannabis products" to accurately and usefully distinguish said products whilst excluding unrelated substances.[74]

Endocannabinoids

[edit]
Anandamide,an endogenousligandof CB1and CB2

Endocannabinoids are substances produced from within the body that activatecannabinoid receptors.After the discovery of the first cannabinoid receptor in 1988, scientists began searching for endogenousligandsfor the receptors.[10][75]

Types of endocannabinoid ligands

[edit]

Arachidonoylethanolamine (Anandamide or AEA)

[edit]

Anandamidewas the first such compound identified asarachidonoylethanolamine. The name is derived fromananda,theSanskritword for bliss. It has a pharmacology similar toTHC,although its structure is quite different. Anandamide binds to the central (CB1) and, to a lesser extent, peripheral (CB2) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1receptor.[76]Anandamide is found in nearly all tissues in a wide range of animals.[77]Anandamide has also been found in plants, including small amounts in chocolate.[78]

Two analogs of anandamide,7,10,13,16-docosatetraenoylethanolamideandhomo-γ-linolenoylethanolamine, have similarpharmacology.All of these compounds are members of a family of signalling lipids calledN-acylethanolamines,which also includes the noncannabimimeticpalmitoylethanolamideandoleoylethanolamide,which possessanti-inflammatoryandanorexigeniceffects, respectively. ManyN-acylethanolamines have also been identified in plant seeds[79]and in molluscs.[80]

2-Arachidonoylglycerol (2-AG)

[edit]

Another endocannabinoid, 2-arachidonoylglycerol, binds to both the CB1and CB2receptors with similar affinity, acting as a full agonist at both.[76]2-AG is present at significantly higher concentrations in the brain than anandamide,[81]and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signallingin vivo.[11]In particular, onein vitrostudy suggests that 2-AG is capable of stimulating higherG-proteinactivation than anandamide, although the physiological implications of this finding are not yet known.[82]

2-Arachidonyl glyceryl ether (noladin ether)

[edit]

In 2001, a third,ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated fromporcinebrain.[83]Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at "any appreciable amount" in the brains of several different mammalian species.[84]It binds to the CB1cannabinoid receptor (Ki= 21.2nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1receptor, and only weakly to the CB2receptor.[76]

N-Arachidonoyl dopamine (NADA)

[edit]

Discovered in 2000, NADA preferentially binds to the CB1receptor.[85]Like anandamide, NADA is also an agonist for thevanilloid receptor subtype 1(TRPV1), a member of thevanilloidreceptor family.[86][87]

Virodhamine (OAE)

[edit]

A fifth endocannabinoid, virodhamine, orO-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a fullagonistat CB2and a partial agonist at CB1,it behaves as a CB1antagonistin vivo.In rats, virodhamine was found to be present at comparable or slightly lower concentrations thananandamidein thebrain,but 2- to 9-fold higher concentrations peripherally.[88]

Lysophosphatidylinositol (LPI)

[edit]

Lysophosphatidylinositolis the endogenous ligand to novel endocannabinoid receptorGPR55,making it a strong contender as the sixth endocannabinoid.[89]

Function

[edit]

Endocannabinoids serve asintercellular'lipid messengers',[90]signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-knownmonoamineneurotransmitterssuch asdopamine,endocannabinoids differ in numerous ways from them. For instance, they are used inretrograde signalingbetween neurons.[91]Furthermore, endocannabinoids arelipophilicmolecules that are not very soluble in water. They are not stored in vesicles and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use.

Ashydrophobicmolecules, endocannabinoids cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than dohormones,which can affect cells throughout the body.

The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.

The endocannabinoid2-AGhas been found inbovineand human maternal milk.[92]

A review by Matties et al. (1994) summed up the phenomenon of gustatory enhancement by certain cannabinoids.[93]The sweet receptor (Tlc1) is stimulated by indirectly increasing its expression and suppressing the activity of leptin, the Tlc1 antagonist. It is proposed that the competition of leptin and cannabinoids for Tlc1 is implicated in energy homeostasis.[94]

Retrograde signal

[edit]

Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids, on the other hand, are described asretrograde transmittersbecause they most commonly travel ‘backward’ against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid-mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitterGABAis reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitterglutamateis reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.[95][citation needed]

"Runner's high"

[edit]

Therunner's high,the feeling of euphoria that sometimes accompanies aerobic exercise, has often been attributed to the release ofendorphins,but newer research suggests that it might be due to endocannabinoids instead.[96]

Synthetic cannabinoids

[edit]

Historically, laboratory synthesis of cannabinoids was often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led byRoger Adamsas early as 1941 and later in a group led byRaphael Mechoulam.[97]Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.[98]

Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.[99]

When synthetic cannabinoids are used recreationally, they present significant health dangers to users.[100]In the period of 2012 through 2014, over 10,000 contacts topoison control centersin the United States were related to use of synthetic cannabinoids.[100]

Medications containing natural or synthetic cannabinoids or cannabinoid analogs:

Other notable synthetic cannabinoids include:

Recently, the term "neocannabinoid" has been introduced to distinguish thesedesigner drugsfromsynthetic phytocannabinoids(obtained by chemical synthesis) orsynthetic endocannabinoids.[103]

See also

[edit]

References

[edit]
  1. ^Abyadeh M, Gupta V, Paulo JA, et al. (September 2021)."A Proteomic View of Cellular and Molecular Effects of Cannabis".Biomolecules.11(10): 1411–1428.doi:10.3390/biom11101411.PMC8533448.PMID34680044.
  2. ^"Marijuana, also called: Cannabis, Ganja, Grass, Hash, Pot, Weed".Medline Plus.3 July 2017.Archivedfrom the original on 20 April 2023.Retrieved19 February2020.
  3. ^abLambert DM, Fowler CJ (August 2005). "The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications".Journal of Medicinal Chemistry.48(16): 5059–5087.doi:10.1021/jm058183t.PMID16078824.
  4. ^Pertwee R, ed. (2005).Cannabinoids.Springer-Verlag. p.2.ISBN978-3-540-22565-2.
  5. ^"Bulletin on Narcotics – 1962 Issue 3 – 004".UNODC (United Nations Office of Drugs and Crime). 1 January 1962.Archivedfrom the original on 2 April 2019.Retrieved15 January2014.
  6. ^abAizpurua-Olaizola O, Soydaner U, Öztürk E, Schibano D, Simsir Y, Navarro P, et al. (February 2016)."Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes".Journal of Natural Products.79(2): 324–331.doi:10.1021/acs.jnatprod.5b00949.PMID26836472.Archivedfrom the original on 5 January 2023.Retrieved2 December2022.
  7. ^Gülck T, Møller BL (October 2020)."Phytocannabinoids: Origins and Biosynthesis".Trends in Plant Science.25(10): 985–1004.doi:10.1016/j.tplants.2020.05.005.PMID32646718.S2CID220465067.
  8. ^Pate, DW (1999). Anandamide structure-activity relationships and mechanisms of action on intraocular pressure in the normotensive rabbit model. Kuopio University Publications A. Pharmaceutical Sciences Dissertation 37,ISBN951-781-575-1
  9. ^abAllan GM, Finley CR, Ton J, Perry D, Ramji J, Crawford K, et al. (February 2018)."Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms".Canadian Family Physician.64(2): e78–e94.PMC5964405.PMID29449262.
  10. ^abDevane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC (November 1988)."Determination and characterization of a cannabinoid receptor in rat brain".Molecular Pharmacology.34(5): 605–613.PMID2848184.Archivedfrom the original on 20 April 2023.Retrieved24 December2015.
  11. ^abcPacher P, Bátkai S, Kunos G (September 2006)."The endocannabinoid system as an emerging target of pharmacotherapy".Pharmacological Reviews.58(3): 389–462.doi:10.1124/pr.58.3.2.PMC2241751.PMID16968947.
  12. ^Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, et al. (May 2005). "Evidence for novel cannabinoid receptors".Pharmacology & Therapeutics.106(2): 133–145.doi:10.1016/j.pharmthera.2004.11.005.PMID15866316.
  13. ^Boron WG, Boulpaep EL, eds. (2009).Medical Physiology: A Cellular and Molecular Approach.Saunders. p. 331.ISBN978-1-4160-3115-4.
  14. ^Kalant H (January 2014). "Effects of cannabis and cannabinoids in the human nervous system.".The effects of drug abuse on the human nervous system.Academic Press. pp. 387–422.doi:10.1016/B978-0-12-418679-8.00013-7.ISBN978-0-12-418679-8.
  15. ^Straiker AJ, Maguire G, Mackie K, Lindsey J (September 1999). "Localization of cannabinoid CB1 receptors in the human anterior eye and retina".Investigative Ophthalmology & Visual Science.40(10): 2442–2448.PMID10476817.
  16. ^Marchand J, Bord A, Pénarier G, Lauré F, Carayon P, Casellas P (March 1999)."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".Cytometry.35(3): 227–234.doi:10.1002/(SICI)1097-0320(19990301)35:3<227::AID-CYTO5>3.0.CO;2-4.PMID10082303.
  17. ^Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, et al. (August 1995)."Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations".European Journal of Biochemistry.232(1): 54–61.doi:10.1111/j.1432-1033.1995.tb20780.x.PMID7556170.
  18. ^abPacher P, Mechoulam R (April 2011)."Is lipid signaling through cannabinoid 2 receptors part of a protective system?".Progress in Lipid Research.50(2): 193–211.doi:10.1016/j.plipres.2011.01.001.PMC3062638.PMID21295074.
  19. ^abSaroz Y, Kho DT, Glass M, Graham ES, Grimsey NL (December 2019)."Cannabinoid Receptor 2 (CB2) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes ".ACS Pharmacology & Translational Science.2(6): 414–428.doi:10.1021/acsptsci.9b00049.PMC7088898.PMID32259074.
  20. ^Núñez E, Benito C, Pazos MR, Barbachano A, Fajardo O, González S, et al. (September 2004). "Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study".Synapse.53(4): 208–213.doi:10.1002/syn.20050.PMID15266552.S2CID40738073.
  21. ^Fellermeier M, Eisenreich W, Bacher A, Zenk MH (March 2001). "Biosynthesis of cannabinoids. Incorporation experiments with (13)C-labeled glucoses".European Journal of Biochemistry.268(6): 1596–1604.doi:10.1046/j.1432-1327.2001.02030.x.PMID11248677.
  22. ^US 20120046352,Hospodor, Andrew D., "Controlled cannabis decarboxylization"
  23. ^"How does marijuana produce its effects?".Cannabis (Marijuana) Research Report(Report).National Institute on Drug Abuse.July 2020.Archivedfrom the original on 5 January 2023.Retrieved28 May2023.
  24. ^abIseger TA, Bossong MG (March 2015). "A systematic review of the antipsychotic properties of cannabidiol in humans".Schizophrenia Research.162(1–3): 153–161.doi:10.1016/j.schres.2015.01.033.PMID25667194.S2CID3745655.
  25. ^Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (August 2007). "Cannabidiol--recent advances".Chemistry & Biodiversity.4(8): 1678–1692.doi:10.1002/cbdv.200790147.PMID17712814.S2CID3689072.
  26. ^Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, et al. (December 2007)."The orphan receptor GPR55 is a novel cannabinoid receptor".British Journal of Pharmacology.152(7): 1092–1101.doi:10.1038/sj.bjp.0707460.PMC2095107.PMID17876302.
  27. ^Russo EB, Burnett A, Hall B, Parker KK (August 2005). "Agonistic properties of cannabidiol at 5-HT1a receptors".Neurochemical Research.30(8): 1037–1043.doi:10.1007/s11064-005-6978-1.PMID16258853.S2CID207222631.
  28. ^Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (December 2012)."Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders".Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.367(1607): 3364–3378.doi:10.1098/rstb.2011.0389.PMC3481531.PMID23108553.
  29. ^Frood A (2010). "Key ingredient staves off marijuana memory loss".Nature.doi:10.1038/news.2010.508.
  30. ^Leweke FM, Mueller JK, Lange B, Rohleder C (April 2016). "Therapeutic Potential of Cannabinoids in Psychosis".Biological Psychiatry.79(7): 604–612.doi:10.1016/j.biopsych.2015.11.018.PMID26852073.S2CID24160677.
  31. ^Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, et al. (September 1997). "Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase".Journal of Medicinal Chemistry.40(20): 3228–3233.doi:10.1021/jm970126f.PMID9379442.
  32. ^Sampson, Peter B. (22 January 2021)."Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the" Big Two "".Journal of Natural Products.84(1): 142–160.doi:10.1021/acs.jnatprod.0c00965.ISSN1520-6025.PMID33356248.S2CID229694293.Archivedfrom the original on 19 November 2022.Retrieved7 December2022.
  33. ^"Cannabinol (Code C84510)".NCI Thesaurus.National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services.Archivedfrom the original on 19 November 2022.Retrieved7 December2022.
  34. ^Pertwee RG (January 2006)."Cannabinoid pharmacology: the first 66 years".British Journal of Pharmacology.147(Suppl 1): S163–S171.doi:10.1038/sj.bjp.0706406.PMC1760722.PMID16402100.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.
  35. ^abPertwee, Roger G (2006)."Cannabinoid pharmacology: the first 66 years: Cannabinoid pharmacology".British Journal of Pharmacology.147(S1): S163–S171.doi:10.1038/sj.bjp.0706406.PMC1760722.PMID16402100.
  36. ^abCorroon, Jamie (31 August 2021)."Cannabinol and Sleep: Separating Fact from Fiction".Cannabis and Cannabinoid Research.6(5): 366–371.doi:10.1089/can.2021.0006.ISSN2578-5125.PMC8612407.PMID34468204.
  37. ^abWoelkart K, Salo-Ahen OM, Bauer R (2008). "CB receptor ligands from plants".Current Topics in Medicinal Chemistry.8(3): 173–186.doi:10.2174/156802608783498023.PMID18289087.
  38. ^Bauer R, Remiger P (August 1989). "TLC and HPLC Analysis of Alkamides in Echinacea Drugs1,2".Planta Medica.55(4): 367–371.doi:10.1055/s-2006-962030.PMID17262436.S2CID12138478.
  39. ^Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, et al. (May 2006)."Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects".The Journal of Biological Chemistry.281(20): 14192–14206.doi:10.1074/jbc.M601074200.PMID16547349.
  40. ^Perry NB, van Klink JW, Burgess EJ, Parmenter GA (February 1997). "Alkamide levels in Echinacea purpurea: a rapid analytical method revealing differences among roots, rhizomes, stems, leaves and flowers".Planta Medica.63(1): 58–62.doi:10.1055/s-2006-957605.PMID17252329.S2CID260280073.
  41. ^He X, Lin L, Bernart MW, Lian L (1998). "Analysis of alkamides in roots and achenes of Echinacea purpurea by liquid chromatography–electrospray mass spectrometry".Journal of Chromatography A.815(2): 205–11.doi:10.1016/S0021-9673(98)00447-6.
  42. ^Ligresti A, Villano R, Allarà M, Ujváry I, Di Marzo V (August 2012). "Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand".Pharmacological Research.66(2): 163–169.doi:10.1016/j.phrs.2012.04.003.PMID22525682.
  43. ^Korte G, Dreiseitel A, Schreier P, Oehme A, Locher S, Geiger S, et al. (January 2010). "Tea catechins' affinity for human cannabinoid receptors".Phytomedicine.17(1): 19–22.doi:10.1016/j.phymed.2009.10.001.PMID19897346.
  44. ^Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, et al. (July 2008)."Beta-caryophyllene is a dietary cannabinoid".Proceedings of the National Academy of Sciences of the United States of America.105(26): 9099–9104.Bibcode:2008PNAS..105.9099G.doi:10.1073/pnas.0803601105.PMC2449371.PMID18574142.
  45. ^Pacioni G, Rapino C, Zarivi O, Falconi A, Leonardi M, Battista N, et al. (February 2015). "Truffles contain endocannabinoid metabolic enzymes and anandamide".Phytochemistry.110:104–110.Bibcode:2015PChem.110..104P.doi:10.1016/j.phytochem.2014.11.012.PMID25433633.
  46. ^Chicca A, Schafroth MA, Reynoso-Moreno I, Erni R, Petrucci V, Carreira EM, Gertsch J (October 2018)."Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high".Science Advances.4(10): eaat2166.Bibcode:2018SciA....4.2166C.doi:10.1126/sciadv.aat2166.PMC6200358.PMID30397641.
  47. ^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/np030045oPMID12828466
  48. ^abStout SM, Cimino NM (February 2014)."Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review".Drug Metabolism Reviews.46(1): 86–95.doi:10.3109/03602532.2013.849268.PMID24160757.S2CID29133059.Archivedfrom the original on 6 October 2022.Retrieved7 December2017.
  49. ^Aizpurua-Olaizola O, Zarandona I, Ortiz L, Navarro P, Etxebarria N, Usobiaga A (April 2017)."Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis".Drug Testing and Analysis.9(4): 626–633.doi:10.1002/dta.1998.PMID27341312.S2CID27488987.Archivedfrom the original on 5 January 2023.Retrieved2 December2022.
  50. ^Ashton CH (February 2001)."Pharmacology and effects of cannabis: a brief review".The British Journal of Psychiatry.178(2): 101–106.doi:10.1192/bjp.178.2.101.PMID11157422.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.
  51. ^Russo EB (August 2011)."Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects".British Journal of Pharmacology.163(7): 1344–1364.doi:10.1111/j.1476-5381.2011.01238.x.PMC3165946.PMID21749363.
  52. ^Malheiro, Rui Filipe; Carmo, Helena; Carvalho, Félix; Silva, João Pedro (January 2023)."Cannabinoid-mediated targeting of mitochondria on the modulation of mitochondrial function and dynamics".Pharmacological Research.187:106603.doi:10.1016/j.phrs.2022.106603.PMID36516885.S2CID254581177.
  53. ^Keating GM (April 2017). "Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity ".Drugs.77(5): 563–574.doi:10.1007/s40265-017-0720-6.PMID28293911.S2CID2884550.
  54. ^abRusso EB (February 2008)."Cannabinoids in the management of difficult to treat pain".Therapeutics and Clinical Risk Management.4(1): 245–259.doi:10.2147/TCRM.S1928.PMC2503660.PMID18728714.
  55. ^Cooper R (21 June 2010)."GW Pharmaceuticals launches world's first prescription cannabis drug in Britain".Archivedfrom the original on 30 November 2018.Retrieved29 November2018.
  56. ^"3 prescription drugs that come from marijuana".USA Today.Archivedfrom the original on 20 April 2023.Retrieved30 November2018.
  57. ^Schubert-Zsilavecz M, Wurglics M (2011–2012).Neue Arzneimittel(in German).
  58. ^ab"FDA and Cannabis: Research and Drug Approval Process".US Food and Drug Administration. 24 February 2023.Retrieved23 May2023.
  59. ^"FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy".US Food and Drug Administration. 25 June 2018.Archivedfrom the original on 23 April 2019.Retrieved25 June2018.
  60. ^Scutti S (25 June 2018)."FDA approves first cannabis-based drug".CNN.Archivedfrom the original on 2 December 2018.Retrieved1 December2018.
  61. ^Romano LL, Hazekamp A (2013)."Cannabis Oil: chemical evaluation of an upcoming cannabis-based medicine"(PDF).Cannabinoids.7(1): 1–11.Archived(PDF)from the original on 15 December 2017.Retrieved7 December2017.
  62. ^Rovetto LJ, Aieta NV (November 2017). "Supercritical carbon dioxide extraction of cannabinoids from Cannabis sativa L.".The Journal of Supercritical Fluids.129:16–27.doi:10.1016/j.supflu.2017.03.014.hdl:11336/43849.
  63. ^Jain R, Singh R (2016). "Microextraction techniques for analysis of cannabinoids".TrAC Trends in Analytical Chemistry.80:156–166.doi:10.1016/j.trac.2016.03.012.
  64. ^Weinberg B (Fall 2018)."U.S. Chemist Roger Adams Isolated CBD 75 Years Ago".Freedom Leaf(34 ed.).Archivedfrom the original on 6 April 2019.Retrieved16 March2019– via Issuu.com.
  65. ^Cadena A (8 March 2019)."The History Of CBD – A Brief Overview".CBD Origin.CBDOrigin.com.Archivedfrom the original on 6 June 2019.Retrieved16 March2019.
  66. ^abPertwee RG (January 2006)."Cannabinoid pharmacology: the first 66 years".British Journal of Pharmacology.147(Suppl 1): S163–S171.doi:10.1038/sj.bjp.0706406.PMC1760722.PMID16402100.
  67. ^Mechoulam R."Raphael Mechoulam Ph.D."cannabinoids.huji.ac.il(Biography). The Hebrew University of Jerusalem.Archivedfrom the original on 2 April 2019.Retrieved16 March2019.
  68. ^Florko N (23 February 2023)."How I found 'Trips Ahoy' and 'Blackberry Diesel' 'weed' vapes in a state where marijuana is very much illegal".statnews.com.Stat.Archivedfrom the original on 2 April 2023.Retrieved2 April2023.
  69. ^"Delta 8 THC: Everything You Need To Know".LA Weekly.9 July 2020.Archivedfrom the original on 10 July 2020.Retrieved14 July2020.
  70. ^"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".National Institute of Justice.USDOJ. 9 December 2021.Retrieved20 July2023.
  71. ^Nagarkatti, Prakash; Nagarkatti, Mitzi (28 April 2023)."Cannabis-derived products like delta-8 THC and delta-10 THC have flooded the US market".University of South Carolina.USC.Retrieved29 May2023.
  72. ^Sabaghi D."Delta-8 THC Generated $2 Billion In Revenue In Two Years, Report Finds".Forbes.Archivedfrom the original on 2 April 2023.Retrieved2 April2023.
  73. ^"WHO Expert Committee on Drug Dependence Critical Review"(PDF).p. 22.Archived(PDF)from the original on 2 June 2022.Retrieved5 March2023.
  74. ^Rossheim ME, LoParco CR, Henry D, Trangenstein PJ, Walters ST (March 2023). "Delta-8, Delta-10, HHC, THC-O, THCP, and THCV: What should we call these products?".Journal of Studies on Alcohol and Drugs.84(3): 357–360.doi:10.15288/jsad.23-00008.PMID36971760.S2CID257552536.
  75. ^Katona I, Freund TF (2012)."Multiple functions of endocannabinoid signaling in the brain".Annual Review of Neuroscience.35:529–558.doi:10.1146/annurev-neuro-062111-150420.PMC4273654.PMID22524785.
  76. ^abcGrotenhermen F (October 2005). "Cannabinoids".Current Drug Targets. CNS and Neurological Disorders.4(5): 507–530.doi:10.2174/156800705774322111.PMID16266285.
  77. ^Martin BR, Mechoulam R, Razdan RK (1999). "Discovery and characterization of endogenous cannabinoids".Life Sciences.65(6–7): 573–595.doi:10.1016/S0024-3205(99)00281-7.PMID10462059.
  78. ^di Tomaso E, Beltramo M, Piomelli D (August 1996)."Brain cannabinoids in chocolate".Nature(Submitted manuscript).382(6593): 677–678.Bibcode:1996Natur.382..677D.doi:10.1038/382677a0.PMID8751435.S2CID4325706.Archivedfrom the original on 2 October 2022.Retrieved2 October2022.
  79. ^Chapman KD, Venables B, Markovic R, Bettinger C (August 1999)."N-Acylethanolamines in seeds. Quantification Of molecular species and their degradation upon imbibition".Plant Physiology.120(4): 1157–1164.doi:10.1104/pp.120.4.1157.PMC59349.PMID10444099.
  80. ^Sepe N, De Petrocellis L, Montanaro F, Cimino G, Di Marzo V (January 1998). "Bioactive long chain N-acylethanolamines in five species of edible bivalve molluscs. Possible implications for mollusc physiology and sea food industry".Biochimica et Biophysica Acta.1389(2): 101–111.doi:10.1016/S0005-2760(97)00132-X.PMID9461251.
  81. ^Stella N, Schweitzer P, Piomelli D (August 1997)."A second endogenous cannabinoid that modulates long-term potentiation".Nature(Submitted manuscript).388(6644): 773–778.Bibcode:1997Natur.388..773S.doi:10.1038/42015.PMID9285589.S2CID4422311.
  82. ^Savinainen JR, Järvinen T, Laine K, Laitinen JT (October 2001)."Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB(1) receptor-dependent G-protein activation in rat cerebellar membranes".British Journal of Pharmacology.134(3): 664–672.doi:10.1038/sj.bjp.0704297.PMC1572991.PMID11588122.
  83. ^Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, et al. (March 2001)."2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor".Proceedings of the National Academy of Sciences of the United States of America.98(7): 3662–3665.Bibcode:2001PNAS...98.3662H.doi:10.1073/pnas.061029898.PMC31108.PMID11259648.
  84. ^Oka S, Tsuchie A, Tokumura A, Muramatsu M, Suhara Y, Takayama H, et al. (June 2003)."Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species".Journal of Neurochemistry.85(6): 1374–1381.doi:10.1046/j.1471-4159.2003.01804.x.PMID12787057.S2CID39905742.
  85. ^Bisogno T, Melck D, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V (November 2000)."N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo".The Biochemical Journal.351 Pt 3 (3): 817–824.doi:10.1042/bj3510817.PMC1221424.PMID11042139.
  86. ^Bisogno T, Ligresti A, Di Marzo V (June 2005). "The endocannabinoid signalling system: biochemical aspects".Pharmacology, Biochemistry, and Behavior.81(2): 224–238.doi:10.1016/j.pbb.2005.01.027.PMID15935454.S2CID14186359.
  87. ^Ralevic V (July 2003). "Cannabinoid modulation of peripheral autonomic and sensory neurotransmission".European Journal of Pharmacology.472(1–2): 1–21.doi:10.1016/S0014-2999(03)01813-2.PMID12860468.
  88. ^Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J, et al. (June 2002)."Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor"(PDF).The Journal of Pharmacology and Experimental Therapeutics.301(3): 1020–1024.doi:10.1124/jpet.301.3.1020.PMID12023533.S2CID26156181.Archived fromthe original(PDF)on 3 March 2019.
  89. ^Piñeiro R, Falasca M (April 2012)."Lysophosphatidylinositol signalling: new wine from an old bottle".Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.1821(4): 694–705.doi:10.1016/j.bbalip.2012.01.009.PMID22285325.Archivedfrom the original on 11 February 2021.Retrieved13 September2019.
  90. ^"What to know about endocannabinoids and the endocannabinoid system".Medical news Today.27 February 2021.Archivedfrom the original on 4 August 2021.Retrieved4 August2021.
  91. ^Kano M, Ohno-Shosaku T, Maejima T (2002)."Retrograde signaling at central synapses via endogenous cannabinoids".Molecular Psychiatry.7(3): 234–235.doi:10.1038/sj.mp.4000999.PMID11920149.S2CID3200861.
  92. ^Fride E, Bregman T, Kirkham TC (April 2005). "Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood".Experimental Biology and Medicine.230(4): 225–234.doi:10.1177/153537020523000401.PMID15792943.S2CID25430588.
  93. ^Mattes RD, Shaw LM, Engelman K (April 1994). "Effects of cannabinoids (marijuana) on taste intensity and hedonic ratings and salivary flow of adults".Chemical Senses.19(2): 125–140.doi:10.1093/chemse/19.2.125.PMID8055263.
  94. ^Yoshida R, Ohkuri T, Jyotaki M, Yasuo T, Horio N, Yasumatsu K, et al. (January 2010)."Endocannabinoids selectively enhance sweet taste".Proceedings of the National Academy of Sciences of the United States of America.107(2): 935–939.Bibcode:2010PNAS..107..935Y.doi:10.1073/pnas.0912048107.PMC2818929.PMID20080779.
  95. ^Vaughan CW, Christie MJ (2005). "Retrograde signalling by endocannabinoids".Cannabinoids.Handbook of Experimental Pharmacology. Vol. 168. pp. 367–383.doi:10.1007/3-540-26573-2_12.ISBN3-540-22565-X.PMID16596781.
  96. ^Reynolds G (10 March 2021)."Getting to the Bottom of the Runner's High".The New York Times.ISSN0362-4331.Archivedfrom the original on 15 March 2021.Retrieved16 March2021.
  97. ^Mechoulam R, Lander N, Breuer A, Zahalka J (1990). "Synthesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative".Tetrahedron: Asymmetry.1(5): 315–318.doi:10.1016/S0957-4166(00)86322-3.
  98. ^Elsohly MA, Gul W, Wanas AS, Radwan MM (February 2014). "Synthetic cannabinoids: analysis and metabolites".Life Sciences.Special Issue: Emerging Trends in the Abuse of Designer Drugs and Their Catastrophic Health Effects: Update on Chemistry, Pharmacology, Toxicology and Addiction Potential.97(1): 78–90.doi:10.1016/j.lfs.2013.12.212.PMID24412391.
  99. ^Lauritsen KJ, Rosenberg H (July 2016). "Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana".The American Journal of Drug and Alcohol Abuse.42(4): 377–384.doi:10.3109/00952990.2015.1135158.PMID26910181.S2CID4389339.
  100. ^ab"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)"(PDF).Drug and Chemical Evaluation Section, Office of Diversion Control,Drug Enforcement Administration.December 2014. Archived fromthe original(PDF)on 27 September 2018.Retrieved9 January2015.
  101. ^"More medicinal uses for marijuana".Marijuana.org. 18 October 2005. Archived fromthe originalon 21 December 2005.Retrieved15 January2014.
  102. ^Rinaldi-Carmona M, Barth F, Millan J, Derocq JM, Casellas P, Congy C, et al. (February 1998). "SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor".The Journal of Pharmacology and Experimental Therapeutics.284(2): 644–650.PMID9454810.
  103. ^Riboulet-Zemouli K (2020)."'Cannabis' ontologies I: Conceptual issues with Cannabis and cannabinoids terminology ".Drug Science, Policy and Law.6:25–29.doi:10.1177/2050324520945797.ISSN2050-3245.S2CID234435350.
[edit]