Cannabinoid

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Cannabinoids (

liverwort,[7] and earlier in Echinacea
.

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

Uses

Medical uses include the treatment of nausea due to chemotherapy, spasticity, and possibly neuropathic pain.[9] Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".[9]

Cannabinoid receptors

Before the 1980s, cannabinoids were speculated to produce their

CB2,[11] with mounting evidence of more.[12] The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.[13]

The Endocannabinoid System (ECS) regulates many functions of the human body. The ECS plays an important role in multiple aspects of neural functions, 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

Main article:
Cannabinoid receptor type 1

CB1 receptors are found primarily in the

brain stem responsible for respiratory and cardiovascular functions. CB1 is also found in the human anterior eye and retina.[15]

Cannabinoid receptor type 2

Main article:
Cannabinoid receptor type 2

CB2 receptors are predominantly found in the immune 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 CB2 is expressed by a subpopulation of microglia in the human cerebellum.[20] CB2 receptors appear to be responsible for immunomodulatory[19] and possibly other therapeutic effects of cannabinoid as seen in vitro and in animal models.[18]

Phytocannabinoids

See also: Comparison of phytocannabinoids
trichomes
.
Cannabis indica plant

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.[6]

All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized.

alkaline conditions).[22]

Well known cannabinoids

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

Tetrahydrocannabinol

Main article: Tetrahydrocannabinol

Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta-9-

2-arachidonoylglycerol synthesis produced naturally in the body and brain[citation needed][dubious – discuss]. These cannabinoids produce the effects associated with cannabis by binding to the CB1 cannabinoid receptors in the brain.[23]

Cannabidiol

Main article: Cannabidiol

Cannabidiol (CBD) is mildly

GPCR expressed in the caudate nucleus and putamen.[26] Cannabidiol has also been shown to act as a 5-HT1A receptor agonist.[27] 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.[28]

CBD shares a

the 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

Main article: Cannabinol

Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at 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 of neurotransmission (e.g., dopaminergic, serotonergic, cholinergic, and noradrenergic).

CBN was the first cannabis compound to be isolated from

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.[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

Cannabinoid production starts when an

CBDA or 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 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 Δ9-THC, while the minor form is called Δ8-THC. Under the alternate terpene numbering system, these same compounds are called Δ1-THC and Δ6-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

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

Black truffles contain anandamide.[45] Perrottetinene, a moderately psychoactive cannabinoid,[46] has been isolated from different Radula varieties. Machaeriol A and related compounds are found in plants from the Machaerium family.[47]

Most of the phytocannabinoids are nearly insoluble in water but are soluble in

organic solvents
.

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 purposes are usually bred for high THC content or for a specific chemical balance.

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

CYP 2C9.[48] Thus supplementing with CYP 2C9 inhibitors leads to extended intoxication.[48]

Some is also stored in

lipophilic molecules that accumulate in fatty tissues.[50]

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.[51]

Modulation of mitochondrial activity

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

excipients, and peppermint flavoring.[54] 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.[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 treating HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting.[58]

The

Lennox-Gastaut syndromes.[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

Cannabinoids can be separated from the plant by

extraction with organic solvents. Hydrocarbons and alcohols are 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 with carbon dioxide is an alternative technique. Once extracted, isolated components can be separated using wiped film vacuum distillation or other distillation techniques.[62] Also, techniques such as SPE or SPME are found useful in the extraction of these compounds.[63]

History

The first discovery of an individual cannabinoid was made, when British chemist Robert S. Cahn reported 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 the stereochemistry of 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

Further information:
Delta-8-Tetrahydrocannabinol § Legality_in_the_United_States

The

binding affinity of isomers for cannabinoid receptors showing potential for abuse (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 cannabinoid terminology coined the term "derived psychoactive cannabis products" to accurately and usefully distinguish said products whilst excluding unrelated substances.[74]

Endocannabinoids

Further information on the functions and regulation of the endocannabinoids: Endocannabinoid system
Anandamide, an endogenous ligand of CB1 and CB2

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

Types of endocannabinoid ligands

Arachidonoylethanolamine (Anandamide or AEA)

Main article:
Arachidonoylethanolamine

Anandamide was the first such compound identified as arachidonoyl ethanolamine. The name is derived from ananda, the Sanskrit word for bliss. It has a pharmacology similar to THC, 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 CB1 receptor.[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,

anorexigenic effects, respectively. Many N-acylethanolamines have also been identified in plant seeds[79] and in molluscs.[80]

2-Arachidonoylglycerol (2-AG)

Main article: 2-Arachidonoylglycerol

Another endocannabinoid, 2-arachidonoylglycerol, binds to both the CB1 and CB2 receptors with similar affinity, acting as a full agonist at both.

G-protein activation than anandamide, although the physiological implications of this finding are not yet known.[82]

2-Arachidonyl glyceryl ether (noladin ether)

Main article: 2-Arachidonyl glyceryl ether

In 2001, a third,

nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1 receptor, and only weakly to the CB2 receptor.[76]

N-Arachidonoyl dopamine (NADA)

Main article: N-Arachidonoyl dopamine

Discovered in 2000, NADA preferentially binds to the CB1 receptor.[85] Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.[86][87]

Virodhamine (OAE)

Main article: Virodhamine

A fifth endocannabinoid, virodhamine, or O-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1, it behaves as a CB1 antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2- to 9-fold higher concentrations peripherally.[88]

Lysophosphatidylinositol (LPI)

Lysophosphatidylinositol is the endogenous ligand to novel endocannabinoid receptor GPR55, making it a strong contender as the sixth endocannabinoid.[89]

Function

Endocannabinoids serve as

lipophilic
molecules 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.

As

hydrophobic molecules, 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 do hormones
, 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 endocannabinoid

bovine and 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

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 as

GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.[95] [citation needed
]

"Runner's high"

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

Synthetic cannabinoids

Main article:
Synthetic cannabinoid

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 by Roger Adams as early as 1941 and later in a group led by Raphael 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 to poison control centers in 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 these

designer drugs from synthetic phytocannabinoids (obtained by chemical synthesis) or synthetic endocannabinoids.[103]

See also

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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Cannabinoid&oldid=1214942450"