A sleepy cannabis constituent: cannabinol and its active metabolite influence sleep architecture in rats

Jonathon C Arnold; Cassandra V Occelli Hanbury-Brown; Lyndsey L Anderson; Miguel A Bedoya-Pérez; Michael Udoh; Laura A Sharman; Joel S Raymond; Peter T Doohan; Adam Ametovski; Iain S McGregor

doi:10.1038/s41386-024-02018-7

A sleepy cannabis constituent: cannabinol and its active metabolite influence sleep architecture in rats

Neuropsychopharmacology. 2024 Nov 12. doi: 10.1038/s41386-024-02018-7. Online ahead of print.

Authors

Jonathon C Arnold^{1

2

3}, Cassandra V Occelli Hanbury-Brown^{4

5

6}, Lyndsey L Anderson^{4

5

6}, Miguel A Bedoya-Pérez^{4

6

7}, Michael Udoh^{4

5

6}, Laura A Sharman^{4

5

6}, Joel S Raymond^{4

6

7}, Peter T Doohan^{4

5

6}, Adam Ametovski^{4

6

8}, Iain S McGregor^{4

6

7}

Affiliations

¹ Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, NSW, Australia. [email protected].
² Discipline of Pharmacology, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. [email protected].
³ Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia. [email protected].
⁴ Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, NSW, Australia.
⁵ Discipline of Pharmacology, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁶ Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia.
⁷ School of Psychology, Faculty of Science, The University of Sydney, Sydney, NSW, Australia.
⁸ School of Chemistry, Faculty of Science, The University of Sydney, Sydney, NSW, Australia.

PMID: 39528623
DOI: 10.1038/s41386-024-02018-7

Abstract

Medicinal cannabis is being used worldwide and there is increasing use of novel cannabis products in the community. Cannabis contains the major cannabinoids, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD), but also an array of minor cannabinoids that have undergone much less pharmacological characterization. Cannabinol (CBN) is a minor cannabinoid used in the community in "isolate' products and is claimed to have pro-sleep effects comparable to conventional sleep medications. However, no study has yet examined whether it impacts sleep architecture using objective sleep measures. The effects of CBN on sleep in rats using polysomnography were therefore examined. CBN increased total sleep time, although there was evidence of biphasic effects with initial sleep suppression before a dramatic increase in sleep. CBN increased both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. The magnitude of the effect of CBN on NREM was comparable to the sleep aid zolpidem, although, unlike CBN, zolpidem did not influence REM sleep. Following CBN dosing, 11-hydroxy-CBN, a primary metabolite of CBN surprisingly attained equivalently high brain concentrations to CBN. 11-hydroxy-CBN was active at cannabinoid CB₁ receptors with comparable potency and efficacy to Δ⁹-THC, however, CBN had much lower activity. We then discovered that the metabolite 11-hydroxy-CBN also influenced sleep architecture, albeit with some subtle differences from CBN itself. This study shows CBN affects sleep using objective sleep measures and suggests an active metabolite may contribute to its hypnotic action.