Cannabinol (CBN) is a mildly

psychoactive A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

phytocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoac ...

that acts as a low

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

at both CB₁ and CB₂ receptors. This activity at CB₁ and CB₂ receptors constitutes interaction of CBN with the

endocannabinoid system The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the central nervous system ( ...

(ECS). Although CBN shares the same

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

as other

phytocannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

(e.g.,

Delta-9-tetrahydrocannabinol Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. It is the principal psychoactive constituent of ''Cannabis'' and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) de ...

, Δ⁹-THC), it has a lower

for CB₁ receptors, meaning that much higher doses of CBN are required in order to experience effects, such as mild sedation. It was the first cannabinoid to be isolated from cannabis and was discovered in 1896.

Pharmacology

Pharmacodynamics

Both THC and CBN activate the CB1 (K_i = 211.2 nM) and CB2 (K_i = 126.4 nM) receptors. Each compound acts as a low affinity partial

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

CB1 receptor Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the ''CNR1'' gene. And discovered, by determination and characterization in 1988, and cloned in 1990 for the first time. The human CB1 rece ...

s with THC demonstrating 5x–10× greater affinity to the CB1 receptor. Like THC, CBN has a higher selectivity for CB2

receptors Receptor may refer to: *Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...

which are located throughout the central and

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...

, but are primarily associated with

immune function The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as cancer cells, parasitic worms, and also objects such as ...

. CB2 receptors are known to be located on immune cells throughout the body, including

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

s, and

B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

s. These immune cells have been shown to decrease production of immune-related chemical signals (e.g.,

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

s) or undergo

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

as a consequence of CB2 agonism by CBN. In cell culture, CBN demonstrates antimicrobial effects, particularly in instances of antibiotic-resistant bacteria. CBN has also been reported to act as an ANKTM1 channel agonist at high concentrations (>20nM). While some

have been shown to interact with

nociceptive In physiology, nociception , also nocioception; ) is the sensory nervous system's process of encoding noxious stimuli. It deals with a series of events and processes required for an organism to receive a painful stimulus, convert it to a molecular ...

and immune-related signaling via

transient receptor potential channel Transient receptor potential channels (TRP channels) are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC ( "C" for canonical), TRP ...

s (e.g., TRPV1 and TRPM8), there is currently limited evidence to suggest that CBN acts in this way. In preclinical rodent studies, CBN,

anandamide Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...

and other CB1 agonists have demonstrated inhibitory effects on GI motility, reversible via CB1R blockade (i.e., antagonism). In considering the efficacy of cannabis-based products, there remains controversy surrounding a concept termed “the entourage effect”. This concept describes a widely reported but poorly-understood synergistic effect of certain cannabinoids when phytocannabinoids are coadministered with other naturally-occurring chemical compounds in the cannabis plant (e.g.,

flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...

terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic compound, organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeabl ...

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

s). This entourage effect is often cited to explain the superior efficacy observed in some studies of whole-plant-derived cannabis therapeutics as compared to isolated or synthesized individual cannabis constituents.

Putative receptor targets

The table highlights several common cannabinoids along with putative receptor targets and therapeutic properties. Exogenous (plant-derived) phytocannabinoids are identified with an asterisk while remaining chemicals represent well-known

endocannabinoids Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoact ...

(i.e., endogenously produced cannabinoid receptor

ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...

Neurotransmitter interactions

DSI_DSE_Diagram_-_Mechanism_of_Action_of_eCB_ligands_at_CB1R_in_the_brain

In the brain, the canonical mechanism of CB1 receptor activation is a form of short-term

synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...

initiated via

retrograde signaling Retrograde signaling in biology is the process where a signal travels backwards from a target source to its original source. For example, the nucleus of a cell is the original source for creating signaling proteins. During retrograde signaling, in ...

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

CB1 agonists such as 2AG or

AEA The AeA (formerly the American Electronics Association) was a nationwide non-profit trade association that represented all segments of the technology industry. It lobbied governments at the state, federal, and international levels; provided acces ...

(two primary endocannabinoids). This mechanism of action is called depolarization-induced suppression of inhibition (DSI) or depolarization-induced suppression of excitation (DSE), depending on the classification of the

presynaptic neuron Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

acted upon by the retrograde messenger (''see diagram at left''). In the case of CB1R agonism on the presynaptic membrane of a GABAergic interneuron, activation leads to a net effect of increased activity, while the same activity on a glutamatergic neuron leads to the opposite net effect. The release of other neurotransmitters is also modulated in this way, particularly

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

dynorphin Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin ...

oxytocin Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include Human bonding, ...

, and

vasopressin Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...

Pharmacokinetics

When administered orally, CBN demonstrates a similar metabolism to Δ⁹-THC, with the primary active metabolite produced through the hydrolyzation of C9 as part of

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

in the liver. The active metabolite generated via this process is called 11-OH-CBN, which is 2x as potent as CBN, and has demonstrated activity as a weak CB2

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.11-OH-THC has been reported to have 10× the potency of Δ⁹-THC. Due to high lipophilicity and first-pass metabolism, there is low

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of CBN and other cannabinoids following

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. CBN metabolism is mediated in part by

CYP450 Cytochromes P450 (P450s or CYPs) are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for example, they have not been found in ''Escherichi ...

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

2C9 and 3A4. The metabolism of CBN may be catalyzed by UGTs ( UDP-glucuronosyltransferases), with a subset of UGT isoforms (1A7, 1A8, 1A9, 1A10, 2B7) identified as potential substrates associated with CBN

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

. The

of CBN following administration via

inhalation Inhalation (or inspiration) happens when air or other gases enter the lungs. Inhalation of air Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...

(e.g., smoking or vaporizing) is approximately 40% that of

intravenous administration Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

. A small study of six cannabis users found a highly variable half life of 32 ± 17 hours upon intravenous administration. Similar to CBD, CBN is metabolized by the

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...

and

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

liver enzymes and thus the half-life is sensitive to genetic factors that effect the levels of these enzymes.

Chemistry

Chemical structure

Cannabinoid receptor agonists are categorized into four groups based on chemical structure. CBN, as one of the many phytocannabinoids derived from '' Cannabis Sativa L'', is considered a classical cannabinoid. Other examples of compounds in this group include dibenzopyran derivatives such as Δ⁹-THC, well-known for underlying the subjective "high" experienced by cannabis users, as well as Δ⁸-THC, and their synthetic analogs. In contrast, endogenously produced cannabinoids (i.e., endocannabinoids), which also exert effects through CB agonism, are considered

eicosanoid Eicosanoids are lipid signaling, signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosa ...

s, distinguished by notable differences in chemical structure. Compared to Δ⁹-THC, one additional aromatic ring confers CBN with a slower and more limited metabolic profile (see ). In contrast to THC, CBN has no double bond isomers nor

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

s. CBN can degrade into

HU-345 HU-345 (cannabinol quinone) is a drug that is able to angiogenesis inhibitor, inhibit aortic ring angiogenesis more potently than its parent compound cannabinol (CBN). It exhibits no psychoactive effects on the body. HU-345 can be derived thr ...

from oxidation. In the case of oral administration of CBN, first-pass metabolism in the liver involves the addition of a hydroxyl group at C9 or C11, increasing the affinity and specificity of CBN for both CB1 and CB2 receptors (see 11-OH-CBN).

History

CBN was the first cannabinoid to be isolated from

cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...

extract in the late 1800s. Specifically, it was discovered by Barlow Wood, Newton Spivey, and Easterfield in 1896. In the early 1930s, CBN's structure was identified by

Cahn Cahn is a Germanized form of the Jewish surname Cohen, another variant of which is Kahn. People with the surname Cahn * Andrew Cahn (born 1951), British civil servant * Anne Hessing Cahn (c. 1930–2024), German-born American political auth ...

, marking the first development of a cannabis extract. Its structure and chemical synthesis were achieved by 1940, followed by some of the first preclinical research studies to determine the effects of individual cannabis-derived compounds ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

''.

Society and culture

Legal status

CBN is not listed in the schedules set out by the

United Nations The United Nations (UN) is the Earth, global intergovernmental organization established by the signing of the Charter of the United Nations, UN Charter on 26 June 1945 with the stated purpose of maintaining international peace and internationa ...

Single Convention on Narcotic Drugs The Single Convention on Narcotic Drugs, 1961 (Single Convention, 1961 Convention, or C61) is an international treaty that controls activities (cultivation, production, supply, trade, transport) involving specific narcotic drugs and lays down a ...

from 1961 nor their

Convention on Psychotropic Substances The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 February ...

from 1971, so the signatory countries to these international drug control treaties are not required by these treaties to control CBN.

United States

According to the 2018 Farm Bill, extracts from the ''Cannabis sativa L.'' plant, including CBN, are legal under US federal law as long as they have a delta-9 Tetrahydrocannabinol (THC) concentration of 0.3% or less.

Biosynthesis

This diagram represents the biosynthetic and metabolic pathways by which phytocannabinoids (e.g., CBD, THC, CBN) are created in the cannabis plant. Starting with CBG-A, the acidic forms of certain phytocannabinoids are generated via enzymatic conversion. From there, decarboxylation (i.e., catalyzed by combustion or heat) yields the most well-known metabolites present in the cannabis plant. CBN is unique in that it does not arise from a pre-existing acidic form, but rather is generated through the oxidation of THC. CBN is unique among phytocannabinoids in that its biosynthetic pathway involves conversion directly from Δ⁹-THC, rather than from an acidic precursor form of CBN (e.g., Δ⁹-THC arises through decarboxylation of THC-A). CBN can be found in trace amounts in the

Cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...

plant, found mostly in cannabis that is aged and stored, allowing for CBN formation through the oxidation of the cannabis plant's main psychoactive and intoxicating chemical,

tetrahydrocannabinol Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. It is the principal psychoactive constituent of ''Cannabis'' and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) de ...

(THC). This process of oxidation occurs via exposure to heat, oxygen, and/or light. Although reports are limited, CBN-A has also been measured at very low levels in the cannabis plant, thought to have formed via hydrolyzation of THC-A (''see Phytocannabinoid Biosynthesis diagram, below'').

References

External links

Erowid
Compounds found in ''Cannabis sativa'' {{Cannabinoid receptor modulators Benzochromenes CB1 receptor agonists CB2 receptor agonists Natural phenols Phytocannabinoids Transient receptor potential channel modulators