# Cannabis use and the endocannabinoid system in bipolar disorder

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $595,332

## Abstract

Cannabis is used by more than half of all people with bipolar disorder (BD), which may increase with continued
legalization across the United States. Some but not all of the deleterious cognitive effects of cannabis are
likely exaggerated in people with BD, given that the brain's endocannabinoid (ECB) system affects the function
of dopaminergic (DA) circuitry, which is thought to be dysregulated in BD. For example, administration of the
cannabinoid1 (CB1) receptor agonist delta-9-tetrahydrocannabidiol (THC) - the primary active ingredient in
cannabis - increases DA release in the striatum. This effect is especially problematic in BD individuals who
have reduced expression of the dopamine transporter (DAT), the mechanism driving homeostatic regulation of
DA levels. On the other hand, cannabidiol (CBD) is the other major ingredient of cannabis and does not
increase DA levels, so cannabis containing high CBD may not be as deleterious. A better understanding of the
consequences of chronic cannabis use on critical cognitive functions and ECB/DA neurochemistry in BD could
further the development of treatments for BD and substance use disorders. The proposed use of cross-
species measures and parallel studies in both humans and rodents enables a more nuanced understanding of
both the neurobiology and clinical applicability of the ECB system in BD. Aim 1 will determine the effects of
chronic cannabis use on cognitive functions relevant to BD, in chronic cannabis users and non-users
compared to healthy comparison (HC) participants. A battery of cognitive and behavioral tests that measure
domains such as arousal, inhibitory control, feedback-based decision making, reward preference, and temporal
perception will be administered. Aim 2 will identify the effects of acute exposure to controlled doses of THC
and CBD on cognition and determine the resulting levels of endogenous cannabinoids such as anandamide
(AEA) and the DA metabolite homovanillic acid (HVA) via lumbar puncture. Infrequent cannabis-using BD and
HC participants will be randomized to receive one of 3 preparations of placebo, THC, or THC/CBD and will be
tested on the cognitive-behavioral battery. Aim 3 will determine the interactive effects of reduced DAT function
(a validated mouse model for BD) and THC/CBD treatment (acute, chronic, and withdrawal states) on
cognition, neuropathology, plus ECB, DA receptor, and AEA expression in mice. The rodent behavioral tests
have direct translational applicability to the human tests described above. It is hypothesized that BD
participants and mice with reduced DAT expression will show interactive and additive effects of chronic
cannabis use both on cognition and on ECB and HVA levels, due to complex interactions between the ECB
and DA systems. Acute THC exposure may decrease arousal and improve temporal perception in BD and KD
mice but impair inhibition and decision making, whereas CBD will not exert as deleterious effects. In addition
to shedding new light...

## Key facts

- **NIH application ID:** 10115013
- **Project number:** 5R01DA043535-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** WILLIAM PERRY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $595,332
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115013

## Citation

> US National Institutes of Health, RePORTER application 10115013, Cannabis use and the endocannabinoid system in bipolar disorder (5R01DA043535-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10115013. Licensed CC0.

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