Cannabinoid

Cannabinoids () are several structural classes of compounds found primarily in the Cannabis plant or as synthetic compounds. Cannabinoids can be classified into two categories: major cannabinoids, which are present in high amounts in the Cannabis plant, and minor cannabinoids, which are present in smaller amounts in the Cannabis plant. The most notable and the most abundant major cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC). It is a primary psychoactive compound in Cannabis, capable of inducing the feeling of extreme euphoria and loss of memory. Unlike THC, CBD is non-psychoactive and helps with anxiety and psychosis symptoms. Phytocannabinoids are also found in other plants, such as rhododendron, licorice, and liverwort.

Phytocannabinoids are multi-ring phenolic compounds structurally related to THC, 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. followed by Raphael Mechoulam's identification of CBD stereochemistry in 1963 and THC stereochemistry in 1964. CBD and THC are produced independently from the precursor CBG, not via conversion. Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high". A 2023 US survey found 46% of PD patients reported benefits for pain or sleep. 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). 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. Risks include dizziness from THC (12–20% dropout in studies) and potential interactions with PD medications like levodopa.

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. These receptors are common in animals, with two primary types, CB₁ and CB₂, and evidence suggests additional receptors may exist. The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.

The endocannabinoid system (ECS) regulates multiple functions, including movement, motor coordination, learning, memory, emotion, motivation, addictive-like behavior, and pain modulation.

Cannabinoid receptor type 1

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

Cannabinoid receptor type 2

CB₂ receptors are predominantly found in the immune system or immune-derived cells, with varying expression patterns. A subpopulation of microglia in the human cerebellum expresses CB₂. CB₂ receptors are linked to immunomodulatory effects The classical cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation (catalyzed by heat, light, or alkaline conditions).

Well known cannabinoids

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

Tetrahydrocannabinol

thumb|9-∆-Tetrahydrocannabinol (THC) Organic StructureTetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta-9-tetrahydrocannabinol (Δ⁹-THC, THC) and delta-8-tetrahydrocannabinol (Δ⁸-THC) induce anandamide and 2-arachidonoylglycerol synthesis through intracellular CB₁ activation. These cannabinoids produce the psychoactive effects of cannabis by binding to CB₁ receptors in the brain.

Cannabidiol

thumb|Cannabidiol (CBD) Organic Structure

Cannabidiol (CBD) is mildly psychotropic and counteracts cognitive impairment associated with cannabis use. CBD has low affinity for CB₁ and CB₂ receptors but acts as an indirect antagonist of cannabinoid agonists. It is an agonist at the 5-HT_1A receptor and may promote sleep and suppress arousal by interfering with adenosine uptake. 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. Tentative evidence suggests CBD may have anti-psychotic effects, though research is limited.

Cannabinol

thumb|Cannabinol (CBN) Organic Structure

Cannabinol (CBN) is a mildly psychoactive cannabinoid acting as a low-affinity partial agonist at CB₁ and CB₂ receptors. CBN interacts with other neurotransmitter systems (e.g., dopaminergic, serotonergic), requiring higher doses for physiologic effects like mild sedation compared to THC. Isolated in the late 1800s, its structure was elucidated in the 1930s, and chemical synthesis was achieved by 1940. Recent studies indicate that CBN exhibits antiproliferative effects against glioma, liver, and breast cancer cell lines by triggering cell cycle arrest at G1 or S-Phase. In estrogen receptor-positive breast cancer models, CBN was found to be the most effective in suppressing the new synthesis of aromatase, the enzyme responsible for estrogen production that fuels tumor growth, when compared to THC and CBD.

Cannabichromene

thumb|Cannabichromene (CBC) Organic Structure

Cannabichromene (CBC) is a minor non-psychotic phytocannabinoid that is capable of anti-inflammatory, anti-nociceptive, and anti-convulsant properties. Research further indicates that CBC induces programmed cell death via apoptosis and ferroptosis in pancreatic cancer cells by serving as a potent agonist of TRPV1 and CB2 receptors. There is no enzymatic conversion of CBDA or CBD to THCA or THC. Propyl homologues (CBGVA, THCVA, CBDVA, CBCVA) follow an analogous pathway from divarinolic acid. Echinacea species contain Anandamide-like alkylamides, with at least 25 identified, some showing affinity for CB₂ receptors. These are concentrated in roots and flowers. Yangonin in kava has significant CB₁ receptor affinity. Tea (Camellia sinensis) catechins show affinity for human cannabinoid receptors. Beta-caryophyllene, a terpene in cannabis and other plants, is a selective CB₂ receptor agonist. Black truffles contain anandamide. Perrottetinene, a moderately psychoactive cannabinoid, is found in Radula varieties. Machaeriol A and related compounds occur in Machaerium plants.

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

Cannabis plant profile

thumb|right|The bracts surrounding a cluster of [[Cannabis sativa flowers are coated with cannabinoid-laden trichomes.]]

thumb|right|[[Cannabis indica plant]]

Historically, cannabis was classified into two main species based on structural traits: Cannabis indica and Cannabis sativa. Cannabis indica is relatively short plant with broad leaves, while Cannabis sativa is a taller plant with thinner leaves. Inhibiting CYP 2C9 can extend intoxication. The entourage effect suggests that terpenes modulate cannabinoid effects.

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. In addition, cannabinoids have been shown to modulate mitochondrial biogenesis through the dysregulation of PGC-1α levels. These effects are complex, involving direct membrane interactions and receptor-mediated pathways, but a unified hypothesis is lacking due to conflicting data.

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. Dronabinol (Marinol, Syndros) and nabilone (Cesamet) are synthetic THC analogs for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting. CBD drug Epidiolex is approved for Dravet syndrome and Lennox–Gastaut syndrome.

Separation

Cannabinoids are extracted using organic solvents like hydrocarbons or alcohols, which are flammable or toxic, or supercritical carbon dioxide, a safer alternative. Isolated components are separated using wiped film vacuum distillation or other distillation techniques.

Emergence of derived psychoactive cannabis products

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. 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). A 2023 paper proposed the term "derived psychoactive cannabis products" to distinguish these substances.

Endocannabinoids

class=skin-invert-image|thumb|[[Anandamide, an endogenous ligand of CB₁ and CB₂]]

Endocannabinoids are substances produced within the body that activate cannabinoid receptors. After the discovery of the first cannabinoid receptor in 1988, researchers identified endogenous ligands.

Types of endocannabinoid ligands

Arachidonoylethanolamine (Anandamide or AEA)

Anandamide, derived from arachidonic acid, is a partial agonist at CB₁ and CB₂ receptors, with potency similar to THC at CB₁. Found in nearly all tissues and plants like chocolate, it also acts on vanilloid receptors.

2-Arachidonoylglycerol (2-AG)

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.

Other endocannabinoids

Other endocannabinoids include noladin ether, NADA, OAE, and LPI, each with varying receptor affinities and effects.

Function

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

Retrograde signal

Endocannabinoids are retrograde transmitters, released from postsynaptic cells to act on presynaptic cells, reducing conventional neurotransmitter release (e.g., GABA or glutamate).

"Runner's high"

Some studies suggest that the runner's high should be attributed to endocannabinoids rather than to endorphins.

Synthetic cannabinoids

Synthetic cannabinoids, historically based on herbal cannabinoids, have been developed since the 1940s. Modern compounds may not resemble natural cannabinoids but are designed to interact with cannabinoid receptors. They are used to study structure-activity relationships but pose health risks when used recreationally. Examples include dronabinol, nabilone, and rimonabant.