Cannabinoids () are several structural classes of compounds found primarily in the Cannabis plant or as synthetic compounds.
Phytocannabinoids are multi-ring phenolic compounds structurally related to THC,[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, ] while endocannabinoids are fatty acid derivatives. Nonclassical synthetic cannabinoids (cannabimimetics) include , 1,5-diarylpyrazoles, , and arylsulfonamides, as well as related to endocannabinoids.
Uses
Medical uses of cannabinoids include the treatment of
nausea due to
chemotherapy,
spasticity, and possibly
neuropathic pain.
Common side effects include dizziness, sedation, confusion, dissociation, and "feeling high".
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).
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, CB
1 and CB
2,
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
CB
1 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
CB
2 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 CB
2.
CB
2 receptors are linked to immunomodulatory effects
and potential therapeutic benefits in animal models.
Phytocannabinoids
The classical cannabinoids are concentrated in a viscous
resin produced in structures known as glandular
. At least 113 different cannabinoids have been isolated from the
Cannabis plant.
All classes derive from cannabigerol-type (CBG) compounds and differ mainly in the way this precursor is cyclized.
Well known cannabinoids
The best-studied cannabinoids include tetrahydrocannabinol (THC),
cannabidiol (CBD), and
cannabinol (CBN).
Tetrahydrocannabinol
Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant.
Delta-9-tetrahydrocannabinol (Δ
9-THC, THC) and delta-8-tetrahydrocannabinol (Δ
8-THC) induce
anandamide and 2-arachidonoylglycerol synthesis through intracellular CB
1 activation.
These cannabinoids produce the psychoactive effects of cannabis by binding to CB
1 receptors in the brain.
Cannabidiol
Cannabidiol (CBD) is mildly
psychotropic and counteracts cognitive impairment associated with cannabis use.
CBD has low affinity for CB
1 and CB
2 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.
CBD and other cannabinoids have shown antimicrobial properties, potentially addressing antimicrobial resistance.
Cannabinol
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.
Biosynthesis
Cannabinoid production begins with an
enzyme combining geranyl pyrophosphate and
olivetolic acid to form CBGA. CBGA is converted to
Cannabigerol, 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.
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 Δ
9-THC, and the minor form is Δ
8-THC. In the alternate
terpene numbering system, these are Δ
1-THC and Δ
6-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, and
Radula marginata.
species contain
Anandamide-like alkylamides, with at least 25 identified, some showing affinity for CB
2 receptors.
These are concentrated in roots and flowers.
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 CB
2 receptor agonist.
contain anandamide.
, a moderately psychoactive cannabinoid, is found in
Radula varieties.
and related compounds occur in
Machaerium plants.
Most phytocannabinoids are nearly insoluble in water but soluble in , alcohols, and other non-polar .
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.
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.
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.
CYP 2C9 can extend intoxication.
Δ
9-THC is metabolized to 11-hydroxy-Δ
9-THC and then 9-carboxy-THC, detectable in the body for weeks due to their
lipophilic nature and storage in
adipose.
The
entourage effect suggests that
terpenes modulate cannabinoid effects.
Modulation of mitochondrial activity
/ref> 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.
(Marinol, Syndros) and
Nabilone (Cesamet) are synthetic THC analogs for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting.
drug Epidiolex is approved for
Dravet syndrome and Lennox–Gastaut syndromes.
Separation
Cannabinoids are extracted using organic
like
Hydrocarbon 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.
History
Cannabinol (CBN) was the first cannabinoid isolated in the late 1800s, with its structure elucidated in the 1930s and synthesized by 1940.
In 1942,
Roger Adams discovered
Cannabidiol (CBD),
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.
Emergence of derived psychoactive cannabis products
The Agriculture Improvement Act of 2018 allows hemp-derived products with ≤0.3% Δ
9-THC to be sold legally in the US, leading to widespread availability of cannabinoids like Δ
8-THC, Δ
10-THC, HHC, and
THCP.
These compounds lack the extensive research of Δ
9-THC, posing potential risks and challenges for
drug testing due to novel
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
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 CB
1 and CB
2 receptors, with potency similar to THC at CB
1.
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 CB
1 and CB
2, is present at higher brain concentrations than anandamide, potentially playing a larger role in endocannabinoid signaling.
Other endocannabinoids
Other endocannabinoids include noladin ether, NADA,
Virodhamine, and LPI, each with varying receptor affinities and effects.
Function
Endocannabinoids act as
lipid signaling, released from one cell to activate cannabinoid receptors on nearby cells.
Unlike
monoamine , 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).
(2025). 354022565X 354022565X
"Runner's high"
The runner's high may be attributed to endocannabinoids rather than
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.
See also
-
List of cannabinoids
-
List of hallucinogens
-
Cancer and nausea § Cannabinoid
-
Cannabinoid receptor antagonist
-
Endocannabinoid enhancer
-
Endocannabinoid reuptake inhibitor
External links
