# Investigating the bidirectional relationship between circadian rhythms and cannabinoid use

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $443,883

## Abstract

PROJECT SUMMARY/ABSTRACT
Cannabis use is on an upward trajectory due to recent decriminalization and legalization. This increased use is
associated with numerous health and behavioral effects, including risk for developing cannabis use disorder
(CUD). Despite the growing use of cannabis and cannabis-derived products as sleep aids due to their ability to
promote sleep, evidence suggests that chronic cannabis use paradoxically leads to disrupted sleep and circadian
rhythms. Moreover, sleep disturbances such as insomnia are a hallmark feature of cannabis withdrawal and
increase risk of relapse and continued use. However, very little is known about the molecular and cellular
mechanisms underlying the bidirectional relationship between circadian rhythms and cannabis use. The effects
of cannabinoids on sleep may be driven, in part, through their interaction with the core molecular clock, which
consists of a series of transcriptional-translational feedback loops that control circadian-dependent (near 24
hour) gene expression. Notably, the endocannabinoid and circadian systems are tightly linked, with
endocannabinoids showing diurnal rhythms in expression in the periphery and brain, including the nucleus
accumbens (NAc). Moreover, cannabinoids directly impact the molecular clock and influence peripheral and
behavioral rhythms. However, the effects of cannabinoids on molecular rhythms in the brain and differences
between cell types differentially implicated in cannabis use have not been investigated. Measures of molecular
rhythms in human postmortem brain are challenging since each brain represents a single circadian timepoint.
However, an innovative analysis uses “time of death” (TOD) to fit subjects on a 24-hr ‘clock’, making it possible
to reconstruct molecular rhythm patterns in the human brain. Using this approach, we and others have
demonstrated robust molecular rhythms of the human brain transcriptome, with altered rhythms in psychiatric
and substance use disorders. The central hypothesis of this R01 proposal is that there are bidirectional
relationships between molecular rhythms and cannabinoid use, with cannabinoids disrupting cell type-specific
molecular rhythms in the NAc, and these disruptions contributing to escalating cannabinoid use. To test this
hypothesis, we will use a rat model to determine how cannabinoid self-administration affects cell type-specific
molecular rhythms in the NAc, as well as EEG-based measures of sleep/wake rhythms and sleep architecture
(Aim 1). We will then determine whether cell type-specific molecular rhythm disruption in the NAc is sufficient to
cause changes in self-administration (Aim 2). Lastly, we will perform translational studies to determine how
molecular rhythms are altered in distinct cell types of the NAc using single nucleus RNA sequencing (snRNA-
seq) in subjects with CUD (Aim 3). Together, these studies will be the first to examine molecular rhythms in the
human brain of subjects with CUD and explore ...

## Key facts

- **NIH application ID:** 10982878
- **Project number:** 1R01DA061227-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kyle Ketchesin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $443,883
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10982878

## Citation

> US National Institutes of Health, RePORTER application 10982878, Investigating the bidirectional relationship between circadian rhythms and cannabinoid use (1R01DA061227-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10982878. Licensed CC0.

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