Both THC and CBN activate the CB1 (K_i = 211.2 nM) and CB2 (K_i = 126.4 nM) receptors.^[5] Each compound acts as a low affinity partial agonist at CB1 receptors with THC demonstrating 5x–10× greater affinity to the CB1 receptor.^{[5][6][7][8][9][10]} Like THC, CBN has a higher selectivity for CB2 receptors^[5][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.^[11] In cell culture, CBN demonstrates antimicrobial effects, particularly in instances of antibiotic-resistant bacteria.^[12] CBN has also been reported to act as an ANKTM1 channel agonist at high concentrations (>20nM).^[6] 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.^[6][13] In preclinical rodent studies, CBN, anandamide and other CB1 agonists have demonstrated inhibitory effects on GI motility, reversible via CB1R blockade (i.e., antagonism).^[6]

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.^[14]

Neurotransmitter interactions

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),^[18] 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.^[18]

When administered orally, CBN demonstrates a similar metabolism to Δ⁹-THC, with the primary intoxicating metabolite being produced through a hydroxylation reaction that occurs in the liver. The active metabolite generated via this process is called 11-OH-CBN, which is around two times as potent as CBN, and has demonstrated activity as a weak CB2 antagonist. This metabolism starkly contrasts that of standard cannabis edibles in terms of potency, given that 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 of CBN and other cannabinoids following oral administration. CBN metabolism is mediated in part by CYP450 isoforms 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. The bioavailability of CBN following administration via inhalation (e.g., smoking or vaporizing) is approximately 40% that of intravenous administration.

A small study of six cannabis users found a highly variable half life of 32 ±  17 hours upon intravenous administration.^[19] 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.^[20]

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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 exposure to air and light. 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).