# Anti-inflammatory and analgesic potential of minor cannabinoids in vivo

## TL;DR

This study explores the anti-inflammatory and pain-relieving effects of minor cannabinoids like CBN and CBL in mice, finding they reduce inflammation and pain but with notable side effects.

## Contribution

The study provides the first in vivo assessment of CBL's effects and compares anti-inflammatory and analgesic potential of minor cannabinoids.

## Key findings

- CBN and CBL reduced LPS-induced inflammation and cytokine levels in mice.
- High doses of CBN and CBL attenuated neuropathic cold allodynia but caused side effects like catalepsy.
- CBN's effects involved CB1, A2A, and TRPV1 receptors, while CBL's effects were mainly A2A-dependent and CB1-independent.

## Abstract

The cannabis plant produces many bioactive compounds, including the major cannabinoids THC and CBD, and many lesser studied “minor” phytocannabinoids including cannabinol (CBN), cannabichromene (CBC), cannabicyclol (CBL), and cannabigerol (CBG). These compounds are touted for various ailments, including pain, inflammation, and anxiety, but experimental data on their effects are lacking, especially that of CBL, which has yet to be assessed in vivo.

To assess in vivo activity, adult male and female C57BL/6J mice were administered each compound and tested repeatedly in the tetrad battery. The potential analgesic effects in chronic pain states were assessed using the lipopolysaccharide (LPS)-induced hindpaw inflammatory pain and chronic constriction injury (CCI) neuropathic pain paradigms. Lastly, to address common psychological comorbidities of pain, CBN, CBL, and CBG were assessed in the tail suspension and marble burying tests.

Cannabinol (≥ 25 mg/kg) induced classic cannabinoid effects, including acute antinociception. These effects were differentially and partially blocked by selective antagonism of CB1, adenosine A2A, or TRPV1 receptors. CBL (≥ 50 mg/kg) induced hypothermia that was fully blocked by A2A antagonism but had no apparent CB1-mediated activity. LPS-induced edema and paw proinflammatory cytokine levels were reduced by either CBN or CBL (100 mg/kg). CCI-induced cold allodynia was attenuated by either CBN (≥ 50 mg/kg) or CBL (100 mg/kg), but only at high doses that also induce catalepsy and hypothermia. None of these minor cannabinoids displayed anxiolytic- or antidepressant-like activity without concomitant locomotor effects.

Together, these findings suggest that CBN produces anti-inflammatory effects via cannabinoid receptor-dependent and -independent pathways, whereas CBL acts primarily through CB receptor-independent mechanisms.

The online version contains supplementary material available at 10.1186/s42238-025-00384-7.