# Validation and pharmacological profiling of a non-psychoactive THC analog, a novel and selective CB2 receptor agonist, in proof of concept studies using rodent models of heroin addiction

> **NIH NIH U18** · STANFORD UNIVERSITY · 2020 · $241,871

## Abstract

Project Summary
America is currently facing a dire opioid epidemic, which affects two million people and causes more than 130
overdose deaths per day on average. Heroin is one primary culprit. Current treatments for heroin addiction—for
instance methadone—directly target the opioid system; this approach is limited by high abuse potential, relatively
high cost, and strict regulation of clinical use. These challenges highlight an urgent need to develop a non-opioid
pharmacological intervention for heroin addiction, particularly one that does not target the opioid receptors.
Based on associations between legalized use of medical marijuana and a reduction in opioid prescription rates
and deaths, preclinical studies showing that cannabinoids affect addictive-like behavior, and our own preliminary
results in rodent models of heroin addiction, we aim to develop and test the efficacy of a selective cannabinoid
2 receptor (CB2R) agonist in treating heroin use disorder. This drug would be a non-psychoactive analog of
tetrahydrocannabinol (THC), which would not activate the cannabinoid 1 receptor (CB1R) believed to be
responsible for the psychoactive effects of THC.
Both CB1R and CB2R are G-protein-coupled receptors that are part of the endocannabinoid system and are
expressed in the brain. CB2R’s location in the brain (mesolimbic dopamine (DA) system) and prior evidence that
altering the mesolimbic DA system promotes or prevents drug reward, dependence, and addiction, support the
investigation of CB2R as a therapeutic target for modulating heroin drug-seeking behavior. In rodent models,
selective CB2R agonists have been shown to reduce cocaine self-administration (SA) or block cocaine-induced
conditioned place preference (CPP). Our preliminary studies demonstrate that cannabis extract and THC (but
not cannabidiol (CBD)) can reduce several heroin-addictive behaviors in rats and that both acute and chronic
dosing of THC mitigates the negative effects of naloxone-precipitated withdrawal in heroin-addicted mice.
The goal of this project is to repurpose CB2-C48, a highly selective CB2R agonist developed in a drug discovery
program for pain, as a potential therapeutic for heroin addiction. We have used the following target profile for
selection of the CB2R agonist : 1) Potent agonist of CB2R; 2) High receptor selectivity (>100-fold over CB1R);
3) Good in vitro and in vivo stability properties; and 4) High CNS penetration. SA1 will characterize CB2-C48 as
a candidate tool compound, with the target profile outlined above, for species selectivity, pharmacokinetic (PK),
and preliminary safety studies, while SA2 will assess the efficacy of CB2-C48 as a selective CB2R agonist in
proof of concept efficacy studies in in vivo rodent models of heroin addiction.

## Key facts

- **NIH application ID:** 10106480
- **Project number:** 1U18DA052415-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Annelise Emily Barron
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $241,871
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106480

## Citation

> US National Institutes of Health, RePORTER application 10106480, Validation and pharmacological profiling of a non-psychoactive THC analog, a novel and selective CB2 receptor agonist, in proof of concept studies using rodent models of heroin addiction (1U18DA052415-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10106480. Licensed CC0.

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