THE EFFECTS OF CANNABIDIOL ON PERIPHERAL CLOCK
Authors: Wang *Hsiaohsieh , Nozaki Chihiro , Shibata Shigenobu , Asahi Toru 
Published: February 2025

Abstract

Introduction
Cannabidiol (CBD) is one of the cannabinoid that is said to improve anxiety and sleep without psychoactive and psychotomimetic effects [1]. In small animals, CBD is found to increase sleep time by enhanced production of neurotransmitters e.g. dopamine when co-administered with THC [2]. However, the effects of CBD on the circadian clock, the major regulatory mechanism of sleep, have not been investigated.

Aims & Objective
To elucidate the effects of CBD on the circadian clock, especially on the so-called peripheral clock.

Method
11-month-old PER2:LUC knock-in female mice were used. Mice were divided into six groups based on different formulations of CBD: CBD isolate (99% crystalline) in MCT (Middle chain triglyceride) oil, CBD isolate in 5% EtOH/5% cremophor/water, and water-soluble CBD nanopowder in water, with respective vehicle controls. The drug was orally administered at ZT4 (ZT: Zeitgeber time) and ZT16 for three days, then the PER2 gene expression was observed from the liver, kidney, and submandibular gland by an in- vivo imaging system (IVIS) [3]. Acro was applied to calculate the phase of circadian rhythm through regulated cosine waves with collected data from IVIS. When the phase shifted advanced, representing the circadian clock moving forward[4].

Result
The phase advance in the liver and the submandibular gland is observed when MCT or CBD in MCT (CBD/MCT) was administered at ZT4 (Fig. 1). However, it did not differ between the MCT and CBD/MCT groups. Furthermore, neither the vehicle nor the CBD affected the peripheral clock when administered at ZT16.

Discussion & Conclusion
Here we found that CBD does not affect the peripheral clocks of animals. This is consistent with clinical studies showing that taking CBD does not lead to continuous sleep improvement [5]. Furthermore, the CBD/MCT and MCT groups shifted phases to the same degree, suggesting that it may be the MCT oil rather than the CBD that affects the circadian clock. Since MCT oil was commonly used for dissolving the CBD product commercially, further detailed studies are needed to determine the effects of other CBD products on the circadian clock.

References
[1]Devinsky O, Cilio MR, Cross H, et al. (2014) ‘Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.’ Epilepsia. 2014 Jun;55(6):791-802. doi: https://doi.org/10.1111/epi.12631
[2]Shannon S, Lewis N, Lee H, Hughes S. (2019) ‘Cannabidiol in Anxiety and Sleep: A Large Case Series.’ Perm J. 2019; 23:18-041. doi: https://doi.org/10.7812/TPP/18-041
[3]Tahara Y, Kuroda H, Saito K, et al. (2012) ‘In vivo monitoring of peripheral circadian clocks in the mouse.’ Curr Biol. 2012 Jun 5;22(11):1029-34. doi: https://doi.org/10.1016/j.cub.2012.04.009
[4]Yu Tahara, Shigenobu Shibata (2017). Entrainment of the mouse circadian clock: Effects of stress, exercise, and nutrition. Free Radic Biol Med. 2018 May 1;119:129-138. doi: 10.1016/j.
[5]Cairns EA, Benson MJ, Bedoya-Pé rez MA, Macphail SL, Mohan A, et al. (2023) ‘Medicinal cannabis for psychiatry-related conditions: an overview of current Australian prescribing.’ Front Pharmacol. doi: 10.3389/fphar.2023.1142680.