Marijuana-Derived Compounds Could Revolutionize Opioid Overdose Treatment

CBD (yellow stick structure) interferes with binding of an opioid (green and red) by stabilizing an opioid receptor (gray) in its inactive form. Credit: Charles Kuntz

The opioid epidemic has been a growing problem in the United States for years, with over half a million people dying from opioid overdoses between 1999 and 2020. Despite the availability of naloxone, a fast-acting opioid antidote, the rise of powerful synthetic opioids, such as fentanyl, has made it less effective in reversing overdoses. Researchers at Indiana University Bloomington are now exploring the potential of cannabidiol (CBD), a component of marijuana, to provide an alternative solution.

The team recently presented their findings at the spring meeting of the American Chemical Society (ACS) and reported that compounds based on CBD could reduce fentanyl binding and enhance the effects of naloxone. With fentanyl-class compounds accounting for more than 80% of opioid overdose deaths, Alex Straiker, Ph.D., co-principal investigator for the project, believes that it is essential to look for alternatives to naloxone.

The Need for Alternative Options

Fentanyl and its synthetic relatives bind more tightly to opioid receptors in the brain than other opioids such as morphine and heroin. While naloxone can reverse overdoses by competing with drug molecules for the same binding sites on the receptors, fentanyl's ability to bind readily makes it more challenging to reverse. This has led to the need for multiple doses of naloxone to reverse these kinds of overdoses.

The researchers believe that exploring other options to improve naloxone's performance could be the key to saving more lives. Michael VanNieuwenhze, Ph.D., co-principal investigator for the project, explains that they are looking to discover a more potent replacement for naloxone, or something that works synergistically with it, reducing the amount needed to treat an overdose.

CBD as a Possible Alternative

CBD is a non-psychoactive component of marijuana that has gained popularity in recent years for its potential health benefits. Earlier research suggested that CBD could interfere with opioid binding by altering the shape of the receptor. When used with naloxone, CBD accelerated the medication's effect, forcing the receptors to release opioids.

Jessica Gudorf, a graduate student in VanNieuwenhze's group, altered CBD's structure to generate derivatives, inspired by this earlier research. Taryn Bosquez-Berger, a graduate student in Straiker's group, tested these new compounds in cells with a substance called DAMGO, an opioid used only in lab studies. The researchers then tested the most successful derivatives in mice to investigate whether they could alter behaviors associated with taking fentanyl.

Promising Results

The team narrowed the field to 15 successful derivatives, which they tested at varying concentrations against fentanyl, with and without naloxone. Several derivatives could reduce fentanyl binding even at incredibly low concentrations, outperforming naloxone's opioid-blocking performance. Two of these also showed a synergistic effect when combined with the antidote.

The findings suggest that the team's approach could lead to the development of new therapeutics that emergency personnel could use to save more lives. Bosquez-Berger explains that their work opens the door to making new blockers that work through a different mechanism than naloxone, potentially providing a more effective solution.

The Future of Opioid Overdose Treatment

While the team's findings are promising, there is still much research to be done before these compounds can be used to treat overdoses in humans. However, their work provides hope that an alternative to naloxone could be found, potentially saving more lives in the ongoing fight against the opioid epidemic.

As opioid overdose deaths continue to rise, the need for effective treatment options becomes more urgent. The potential of CBD-derived compounds to provide an alternative to naloxone in reversing opioid overdoses is a promising development in the fight against the opioid epidemic. The research presented by Indiana University Bloomington at the American Chemical Society's Spring 2023 meeting could pave the way for new treatments that are more effective against powerful synthetic opioids such as fentanyl.

Journal Information:  ACS Spring 2023: Progress towards more efficacious medicine: Antibiotics and antidotes, www.acs.org/meetings/acs-meetings/spring-2023.html