In 1896 Cannabinol was first discovered in Cannabis by Thomas Barlow Wood, W.T Newton Spivey, and
Thomas Easterfield.[5] In the early 1930s CBNs structure was identified by
Robert Sidney Cahn,[6][7] marking the first development of a
cannabis extract.
Its structure and chemical synthesis were achieved by 1940, followed by some of the first
basic research studies to determine the effects of individual cannabis-derived compounds
in vivo. Although CBN shares the same
mechanism of action as other
phytocannabinoids (e.g.,
Delta-9-tetrahydrocannabinol, Δ9-THC), it has a lower
affinity for CB1 receptors, meaning that much higher doses of CBN are required in order to experience effects, such as mild sedation.
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
eicosanoids, 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
§ CBN Formation & Metabolism). In contrast to THC, CBN has no
double bond isomers nor
stereoisomers. CBN can degrade into
HU-345 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).
Synthesis and metabolism
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 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 (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).
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 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. This metabolism starkly contrasts that of Δ9-THC in terms of potency, given that
11-OH-THC has been reported to have 10× the potency of Δ9-THC.
CBN was the first cannabis compound to be isolated from
cannabis extract in the late 1800s. 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.[8]
Both THC and CBN activate the
CB1 (Ki = 211.2 nM) and
CB2 (Ki = 126.4 nM) receptors.[9] Each compound acts as a low affinity partial
agonist at
CB1 receptors with THC demonstrating 10–13× greater affinity to the CB1 receptor.[9][10][11][8][12][13] Compared to THC, CBN has an equivalent or higher affinity to
CB2receptors,[9][8] which are located throughout the central and
peripheral nervous system, but are primarily associated with
immune function. CB2 receptors are known to be located on immune cells throughout the body, including
macrophages,
T cells, and
B cells. These immune cells have been shown to decrease production of immune-related chemical signals (e.g.,
cytokines) or undergo
apoptosis as a consequence of CB2 agonism by CBN.[14] In cell culture, CBN demonstrates antimicrobial effects, particularly in instances of antibiotic-resistant bacteria.[15] CBN has also been reported to act as an
ANKTM1 channel agonist at high concentrations (>20nM).[10] While some
phytocannabinoids have been shown to interact with
nociceptive and immune-related signaling via
transient receptor potential channels (e.g., TRPV1 and TRPM8), there is currently limited evidence to suggest that CBN acts in this way.[10][16] In preclinical rodent studies, CBN,
anandamide and other CB1 agonists have demonstrated inhibitory effects on GI motility, reversible via CB1R blockade (i.e., antagonism).[10]
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.,
flavonoids,
terpenoids,
alkaloids). 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.[17]
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 (i.e., endogenously produced cannabinoid receptor
ligands).
Full Name
Known Receptor Targets
Putative Therapeutic Properties
*Cannabichromene (CBC)
Agonist at CB2,[18] TRPV3, and most potent phytocannabinoid at TRPA1[18][16]
Very low efficacy at TRPV1 and TRPV4, but may reduce expression of TRPV4 in the presence of inflammation[16]
High affinity for CB1 but no observed functional activity[18]
Conflicting reports but generally described as negative allosteric modulator at CB1 & CB2, altering THC activity when THC & CBD are coadministered[19]
Agonist at TRPA1,[16] TRPV1 (high potency at this “capsaicin receptor” without ablative effects[16]), TRPV2, TRPV3, PPARγ, 5-HT1A, A2 and A1 adenosine receptors[19]
Differing activity across TRP channels: highest potency phytocannabinoid at TRPV2; modest activity at TRPV3, TRPV4, TRPA1, and TRPM8; no activity observed at TRPV1[16]
Importantly, 11-OH-THC, the active metabolite generated via first-pass-metabolism of THC, demonstrates different binding profile at TRP channels[16]
Potential relevance to sleep induction (e.g., increased adenosine levels[19]) and increased quality of sleep[16]
Dose-dependent anxiolytic effects,[16] with anxiogenic effects at high doses
In combination with CBD, potential efficacy in treatment of spasticity, neuropathic pain and muscle spasticity (see Sativex: THC-containing therapeutic approved in Europe as treatment for Multiple Sclerosis)
*2-Arachidonoylglycerol (2-AG)
Partial agonist at CB1 (e.g., on lysosomal surface, increasing lysosomal integrity) and CB2[19]
Agonist at GPR55, GPR18, GPR119, PPAR, and robust activation at TRPV4[16][19]
In the brain, the canonical mechanism of CB1 receptor activation is a form of short-term
synaptic plasticity initiated via
retrograde signaling of
endogenous CB1 agonists such as
2AG or
AEA (two primary endocannabinoids). This mechanism of action is called depolarization-induced suppression of inhibition (DSI) or depolarization-induced suppression of excitation (DSE),[21] depending on the classification of the
presynaptic neuron 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,
dynorphin,
oxytocin, and
vasopressin.[21]
Pharmacokinetics
A small study of six cannabis users found a highly variable half life of 32 ± 17 hours upon intravenous administration.[22] Similar to CBD, CBN is metabolized by the
CYP2C9 and
CYP3A4 liver enzymes and thus the half-life is sensitive to genetic factors that effect the levels of these enzymes.[23]
According to the 2018 Farm Bill,[25] 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,[26][27] though sales or
possession of CBN could potentially be prosecuted under the
Federal Analogue Act.[28]
^Johansson E, Ohlsson A, Lindgren JE, Agurell S, Gillespie H, Hollister LE (September 1987). "Single-dose kinetics of deuterium-labelled cannabinol in man after intravenous administration and smoking". Biomedical & Environmental Mass Spectrometry. 14 (9): 495–499.
doi:
10.1002/bms.1200140904.
PMID2960395.
^"Section 1308.11 Schedule I". Code of Federal Regulations. Office of Diversion Control, Drug Enforcement Administration, U.S. Department of Justice. Archived from
the original on February 9, 2012.