# Cannabis use and the endocannabinoid system in bipolar disorder

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $50,395

## Abstract

Abstract (Parent grant): 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 addit...

## Key facts

- **NIH application ID:** 10158156
- **Project number:** 3R01DA043535-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** WILLIAM PERRY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,395
- **Award type:** 3
- **Project period:** 2018-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158156

## Citation

> US National Institutes of Health, RePORTER application 10158156, Cannabis use and the endocannabinoid system in bipolar disorder (3R01DA043535-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10158156. Licensed CC0.

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