Cannabinoid Agonist May Prevent Opioid Addiction

A drug compound previously shown to be safe for use in people may prevent opioid tolerance and physical dependence when used in combination with opioid-based pain medications, a new study in mice indicates.

Researchers have discovered that the CB2 cannabinoid agonist LY2828360, a drug previously tested to treat osteoarthritis pain appears to block neuropathic pain and decrease signs of opioid dependence.

When drug manufacturer Eli Lilly and Co. conducted human clinical trials of the drug to treat osteoarthritis pain, they found that the drug lacked efficacy. Researchers had not, however, tested the drug’s use in treating other kinds of pain and lessening opioid dependence.

“The potential to quickly begin using this compound in combination with opioid-based medication to treat pain and reduce addiction makes this discovery very significant. We already know this drug is safe for use in people, so moving into human trials will not require as many regulatory hurdles,”

explained lead investigator Andrea G. Hohmann, a chair of neuroscience and professor in the Indiana University Bloomington psychological and brain sciences department.

Urgent Need

The need for non-addictive alternatives to opioid-based pain medication is urgent due to the rapid rise in overdose deaths over the past decade. According to the Centers for Disease Control and Prevention, over 64,000 Americans died from drug overdoses in 2016, including from illicit drugs and prescription opioids.

To test the potential of the experimental drug to treat pain and reduce addiction symptoms, the scientists administered the compound and the opioid morphine to male mice with neuropathic pain. While morphine initially reduced the pain, mice quickly developed tolerance to morphine’s effectiveness, similar to people who require higher doses of opioid over time to achieve relief.

When a low dose of the experimental drug was combined with morphine, however, the mice no longer became tolerant to morphine, and that lack of tolerance remained even after researchers discontinued the experimental drug. The researchers also found the experimental drug could produce sustained pain relief on its own at higher doses.

Preventing Drug Tolerance

In another experiment, researchers gave mice either morphine alone or morphine in combination with the experimental drug, and then treated them with naloxone, which blocks the effect of opioids and induces opioid withdrawal symptoms. Remarkably, Hohmann says, the experimental drug also decreased the severity of these symptoms.

Together, the results suggest the experimental drug could, in combination with opioids, prevent tolerance, allowing satisfactory pain treatment with fewer side effects, or wean opioid-tolerant individuals off these drugs.

The researchers chose to explore the failed osteoarthritis drug because they had previously found that the compound acted in a unique way upon a target in the body known to play a role in pain relief.

This work was supported by the National Institutes of Health National Institute on Drug Abuse and National Cancer Institute.

Xiaoyan Lin, Amey S. Dhopeshwarkar, Megan Huibregtse, Ken Mackie and Andrea G. Hohmann
Role of CB2 in Morphine Tolerance and Dependence
Molecular Pharmacology February 1, 2018, 93 (2) 49-62; DOI:

Last Updated on December 7, 2022