Cannabinoid

Template:Short description Template:Use dmy dates Template:Cannabis sidebar Cannabinoids (Template:IPAc-en) are several structural classes of compounds found primarily in the Cannabis plant or as synthetic compounds.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref> The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis.<ref name="lambert">Template:Cite journal</ref><ref>Template:Cite book</ref> Cannabidiol (CBD) is a major constituent of temperate cannabis plants and a minor constituent in tropical varieties.<ref>Template:Cite web</ref> At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four (THCA, CBDA, CBCA, and their common precursor CBGA) have a confirmed biogenetic origin.<ref name=":0">Template:Cite journal</ref> Phytocannabinoids are also found in other plants, such as rhododendron, licorice, and liverwort.<ref>Template:Cite journal</ref>

Phytocannabinoids are multi-ring phenolic compounds structurally related to THC,<ref>Pate, DW (1999). Anandamide structure-activity relationships and mechanisms of action on intraocular pressure in the normotensive rabbit model. Kuopio University Publications A. Pharmaceutical Sciences Dissertation 37, Template:ISBN</ref> while endocannabinoids are fatty acid derivatives. Nonclassical synthetic cannabinoids (cannabimimetics) include aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides, as well as eicosanoids related to endocannabinoids.<ref name="lambert" />

Uses

Medical uses of cannabinoids include the treatment of nausea due to chemotherapy, spasticity, and possibly neuropathic pain.<ref name=Al2018>Template:Cite journal</ref> Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".<ref name=Al2018 />

Parkinson's Disease

Cannabis may provide limited relief for some Parkinson's disease (PD) symptoms, such as pain, sleep issues, or anxiety, based on small human studies (2023–2024, 10–50 participants), but it does not improve motor symptoms like tremors or stiffness (no significant change in Unified Parkinson's Disease Rating Scale scores).<ref name="Santos2024">Template:Cite journal</ref><ref name="Bougea2024">Template:Cite journal</ref> A 2023 US survey found 46% of PD patients reported benefits for pain or sleep.<ref name="LeBourgeois2023">Template:Cite journal</ref> Raw Cannabis contains tetrahydrocannabinolic acid (THCA, 15–30% of the plant) and cannabidiolic acid (CBDA), which are non-psychoactive. Animal studies (2021–2024) suggest THCA and CBDA may reduce inflammation and protect brain cells in PD models, acting on CB2 receptors and other pathways (e.g., TRP channels, PPARγ), unlike tetrahydrocannabinol (THC) and cannabidiol (CBD), which form when cannabis is heated (e.g., smoking, 105–150°C).<ref name="Hazekamp2023">Template:Cite journal</ref><ref name="Palmioli2024">Template:Cite journal</ref><ref name="DiMartino2021">Template:Cite journal</ref> No human studies have tested THCA or CBDA for PD as of 2025. In regions like India, raw cannabis is used traditionally for tremors, but scientific evidence is lacking.<ref name="Devi2024">Template:Cite journal</ref> Risks include dizziness from THC (12–20% dropout in studies) and potential interactions with PD medications like levodopa.<ref name="Patel2023">Template:Cite journal</ref>

Cannabinoid receptors

Before the 1980s, cannabinoids were thought to produce their effects via nonspecific interaction with cell membranes, rather than specific membrane-bound receptors. The discovery of cannabinoid receptors in the 1980s resolved this debate.<ref name="PMID 2848184">Template:Cite journal</ref> These receptors are common in animals, with two primary types, CB₁ and CB₂,<ref name="pmid16968947">Template:Cite journal</ref> and evidence suggests additional receptors may exist.<ref name="pmid15866316">Template:Cite journal</ref> The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.<ref name="Medical Physiology">Template:Cite book</ref>

The endocannabinoid system (ECS) regulates multiple functions, including movement, motor coordination, learning, memory, emotion, motivation, addictive-like behavior, and pain modulation.<ref>Template:Cite book</ref>

Cannabinoid receptor type 1

Template:Main CB₁ receptors are found primarily in the brain, particularly in the basal ganglia, limbic system, hippocampus, and striatum. They are also present in the cerebellum, and male and female reproductive systems, but absent in the medulla oblongata, which controls respiratory and cardiovascular functions. CB1 is also found in the human anterior eye and retina.<ref>Template:Cite journal</ref>

Cannabinoid receptor type 2

Template:Main CB₂ receptors are predominantly found in the immune system or immune-derived cells,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="pmid21295074">Template:Cite journal</ref><ref name="Saroz acsptsci.9b00049">Template:Cite journal</ref> with varying expression patterns. A subpopulation of microglia in the human cerebellum expresses CB₂.<ref name="pmid15266552">Template:Cite journal</ref> CB₂ receptors are linked to immunomodulatory effects<ref name="Saroz acsptsci.9b00049" /> and potential therapeutic benefits in animal models.<ref name="pmid21295074" />

Phytocannabinoids

The bracts surrounding a cluster of Cannabis sativa flowers are coated with cannabinoid-laden 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.<ref name=":0" />

All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized.<ref name="FellermeierEisenreich2001">Template:Cite journal</ref> The classical cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).<ref>Template:Cite patent</ref>

Well known cannabinoids

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

Tetrahydrocannabinol

Template:Main Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta-9-tetrahydrocannabinol (Δ⁹-THC, THC) and delta-8-tetrahydrocannabinol (Δ⁸-THC) induce anandamide and 2-arachidonoylglycerol synthesis through intracellular CB₁ activation.<ref name="NIDA2020">Template:Cite report</ref> These cannabinoids produce the psychoactive effects of cannabis by binding to CB₁ receptors in the brain.<ref name="NIDA2020" />

Cannabidiol

Template:Main Cannabidiol (CBD) is mildly psychotropic and counteracts cognitive impairment associated with cannabis use.<ref name="2015CBDantipsychReview">Template:Cite journal</ref> CBD has low affinity for CB₁ and CB₂ receptors but acts as an indirect antagonist of cannabinoid agonists.<ref name="recentadvances">Template:Cite journal</ref> It is an agonist at the 5-HT_1A receptor<ref name="pmid16258853">Template:Cite journal</ref> and may promote sleep and suppress arousal by interfering with adenosine uptake.<ref>Template:Cite journal</ref> CBD shares a precursor with THC and is the main cannabinoid in CBD-dominant Cannabis strains, potentially reducing short-term memory loss associated with THC.<ref name="NatureCBDMemory">Template:Cite journal</ref> Tentative evidence suggests CBD may have anti-psychotic effects, though research is limited.<ref>Template:Cite journal</ref><ref name="2015CBDantipsychReview" /> CBD and other cannabinoids have shown antimicrobial properties, potentially addressing antimicrobial resistance.<ref>Template:Cite journal</ref>

Cannabinol

Template:Main Cannabinol (CBN) is a mildly psychoactive cannabinoid acting as a low-affinity partial agonist at CB1 and CB2 receptors.<ref name="Rhee_1997">Template:Cite journal</ref><ref name=":02">Template:Cite journal</ref><ref name="NCI_C84510">Template:Cite web</ref> CBN interacts with other neurotransmitter systems (e.g., dopaminergic, serotonergic), requiring higher doses for physiologic effects like mild sedation compared to THC.<ref name=":5">Template:Cite journal</ref> Isolated in the late 1800s, its structure was elucidated in the 1930s, and chemical synthesis was achieved by 1940.<ref name=":3">Template:Cite journal</ref>

Biosynthesis

Cannabinoid production begins with an enzyme combining geranyl pyrophosphate and olivetolic acid to form CBGA. CBGA is converted to CBG, THCA, CBDA, or CBCA by four separate synthase, FAD-dependent dehydrogenase enzymes. There is no enzymatic conversion of CBDA or CBD to THCA or THC. Propyl homologues (THCVA, CBDVA, CBCVA) follow an analogous pathway from divarinolic acid.<ref name="FellermeierEisenreich2001" /><ref name="Hazekamp2023" />

Double bond position

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

Length

Most classical cannabinoids are 21-carbon compounds, but variations in the side-chain length attached to the aromatic ring exist. In THC, CBD, and CBN, the side-chain is a pentyl (5-carbon) chain. Propyl (3-carbon) chain variants are named with the suffix varin (THCV, CBDV, CBNV), while heptyl (7-carbon) chain variants are named phorol (THCP, CBDP).

Cannabinoids in other plants

Phytocannabinoids occur in plants like Echinacea purpurea, Echinacea angustifolia, Acmella oleracea, Helichrysum umbraculigerum, and Radula marginata.<ref name="Woelkart-2008">Template:Cite journal</ref> Echinacea species contain Anandamide-like alkylamides, with at least 25 identified, some showing affinity for CB₂ receptors.<ref name="Bauer-1989">Template:Cite journal</ref><ref>Template:Cite journal</ref> These are concentrated in roots and flowers.<ref name="Perry-1997">Template:Cite journal</ref><ref>Template:Cite journal</ref> Yangonin in kava has significant CB1 receptor affinity.<ref>Template:Cite journal</ref> Tea (Camellia sinensis) catechins show affinity for human cannabinoid receptors.<ref name="urlmissclasses.com">Template:Cite journal</ref> Beta-caryophyllene, a terpene in cannabis and other plants, is a selective CB₂ receptor agonist.<ref>Template:Cite journal</ref> Black truffles contain anandamide.<ref>Template:Cite journal</ref> Perrottetinene, a moderately psychoactive cannabinoid, is found in Radula varieties.<ref>Template:Cite journal</ref> Machaeriol A and related compounds occur in Machaerium plants.<ref>Template:Cite journal</ref>

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

Cannabis plant profile

Cannabis plants vary widely in their cannabinoid profiles due to selective breeding. Hemp strains are bred for low THC content, often for fiber, while medical strains may prioritize high CBD, and recreational strains target high THC or specific balances.<ref name="Hazekamp2023" /> Quantitative analysis uses gas chromatography (GC), or GC combined with mass spectrometry (GC/MS), to measure cannabinoid content. Liquid chromatography (LC) can differentiate acid (e.g., THCA, CBDA) and neutral (e.g., THC, CBD) forms.<ref name=":0" /> Legal restrictions in many countries hinder consistent monitoring of cannabinoid profiles.

Pharmacology

Cannabinoids are administered via smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Most are metabolized in the liver by cytochrome P450 enzymes, mainly CYP 2C9.<ref name=":1">Template:Cite journal</ref> Inhibiting CYP 2C9 can extend intoxication.<ref name=":1" /> Δ⁹-THC is metabolized to 11-hydroxy-Δ⁹-THC and then 9-carboxy-THC, detectable in the body for weeks due to their lipophilic nature and storage in fat.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The entourage effect suggests that terpenes modulate cannabinoid effects.<ref name="PMCentourage2011">Template:Cite journal</ref>

Modulation of mitochondrial activity

Cannabinoids influence mitochondrial processes, including calcium regulation, apoptosis, electron transport chain activity, mitochondrial respiration and ATP production. Mitochondrial dynamics—encompassing the processes of fusion and fission, as well as alterations in morphology and organelle mobility, are also affected by cannabinoid exposure.<ref>Malheiro, R.F., Costa, A.C., Carmo, H. et al. The synthetic cannabinoid THJ-2201 modulates mitochondrial activity and enhances mitochondrial recruitment to newly-forming neurites during neurodifferentiation of NG108-15 cells. Arch Toxicol (2025). https://doi.org/10.1007/s00204-025-04217-7</ref> In addition, cannabinoids have been shown to modulate mitochondrial biogenesis through the dysregulation of PGC-1α levels.<ref>MALHEIRO, Rui Filipe et al. The synthetic cannabinoids ADB-FUBINACA and AMB-FUBINACA enhance in vitro neurodifferentiation of NG108-15 cells, along with PGC-1α dysregulation and mitochondrial dysfunction. Toxicology, p. 154213, 2025. https://doi.org/10.1016/j.tox.2025.154213</ref> These effects are complex, involving direct membrane interactions and receptor-mediated pathways, but a unified hypothesis is lacking due to conflicting data.<ref>Template:Cite journal</ref>

Cannabinoid-based pharmaceuticals

Nabiximols (Sativex) is an aerosolized mist with a near 1:1 ratio of CBD and THC, used for multiple sclerosis-related pain and spasticity.<ref>Template:Cite journal</ref> Dronabinol (Marinol, Syndros) and Nabilone (Cesamet) are synthetic THC analogs for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting.<ref name="fda">Template:Cite web</ref> CBD drug Epidiolex is approved for Dravet and Lennox–Gastaut syndromes.<ref name="fda18">Template:Cite web</ref>

Separation

Cannabinoids are extracted using organic solvents like hydrocarbons or alcohols, which are flammable or toxic, or supercritical carbon dioxide, a safer alternative.<ref>Template:Cite journal</ref> Isolated components are separated using wiped film vacuum distillation or other distillation techniques.<ref>Template:Cite journal</ref>

History

Cannabinol (CBN) was the first cannabinoid isolated in the late 1800s, with its structure elucidated in the 1930s and synthesized by 1940.<ref name=":3" /> In 1942, Roger Adams discovered Cannabidiol (CBD),<ref>Template:Cite web</ref> followed by Raphael Mechoulam's identification of CBD stereochemistry in 1963 and THC stereochemistry in 1964.<ref name=":2">Template:Cite journal</ref> CBD and THC are produced independently from the precursor CBG, not via conversion.<ref name="FellermeierEisenreich2001" />

Emergence of derived psychoactive cannabis products

Template:Further The Agriculture Improvement Act of 2018 allows hemp-derived products with ≤0.3% Δ⁹-THC to be sold legally in the US, leading to widespread availability of cannabinoids like Δ⁸-THC, Δ¹⁰-THC, HHC, and THCP.<ref>Template:Cite web</ref> These compounds lack the extensive research of Δ⁹-THC, posing potential risks and challenges for drug testing due to novel metabolites and high potency (e.g., THCP's 33× binding affinity).<ref>Template:Cite web</ref><ref>Template:Cite web</ref> A 2023 paper proposed the term "derived psychoactive cannabis products" to distinguish these substances.<ref>Template:Cite journal</ref>

Endocannabinoids

Anandamide, an endogenous ligand of CB₁ and CB₂

Endocannabinoids are substances produced within the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, researchers identified endogenous ligands.<ref name="PMID 2848184" /><ref>Template:Cite journal</ref>

Types of endocannabinoid ligands

Arachidonoylethanolamine (Anandamide or AEA)

Template:Main Anandamide, derived from arachidonic acid, is a partial agonist at CB₁ and CB₂ receptors, with potency similar to THC at CB₁.<ref name="grotenhermen 2005">Template:Cite journal</ref> Found in nearly all tissues and plants like chocolate, it also acts on vanilloid receptors.<ref name="pmid10462059">Template:Cite journal</ref><ref name="pmid8751435">Template:Cite journal</ref>

2-Arachidonoylglycerol (2-AG)

Template:Main 2-AG, a full agonist at CB₁ and CB₂, is present at higher brain concentrations than anandamide, potentially playing a larger role in endocannabinoid signaling.<ref name="grotenhermen 2005" /><ref name="stella 1997">Template:Cite journal</ref>

Other endocannabinoids

Other endocannabinoids include noladin ether, NADA, OAE, and LPI, each with varying receptor affinities and effects.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Function

Endocannabinoids act as lipid messengers, released from one cell to activate cannabinoid receptors on nearby cells.<ref>Template:Cite web</ref> Unlike monoamine neurotransmitters, they are lipophilic, insoluble in water, and synthesized on-demand rather than stored.<ref>Template:Cite journal</ref> They act locally due to their hydrophobic nature, unlike hormones. The endocannabinoid 2-AG is found in bovine and human maternal milk.<ref>Template:Cite journal</ref> Cannabinoids enhance sweet taste by increasing Tlc1 receptor expression and suppressing leptin, impacting energy homeostasis.<ref>Template:Cite journal</ref>

Retrograde signal

Endocannabinoids are retrograde transmitters, released from postsynaptic cells to act on presynaptic cells, reducing conventional neurotransmitter release (e.g., GABA or glutamate).<ref>Template:Cite book</ref>

"Runner's high"

The runner's high may be attributed to endocannabinoids rather than endorphins.<ref>Template:Cite news</ref>

Synthetic cannabinoids

Template:Main Synthetic cannabinoids, historically based on herbal cannabinoids, have been developed since the 1940s.<ref>Template:Cite journal</ref> Modern compounds may not resemble natural cannabinoids but are designed to interact with cannabinoid receptors.<ref>Template:Cite journal</ref> They are used to study structure-activity relationships but pose health risks when used recreationally.<ref>Template:Cite web</ref> Examples include Dronabinol, Nabilone, and Rimonabant.<ref name="fda" />

See also

• List of cannabinoids
• List of hallucinogens
• Cancer and nausea § Cannabinoid
• Cannabinoid receptor antagonist
• Endocannabinoid enhancer
• Endocannabinoid reuptake inhibitor

External links

• Template:Commons category-inline