New Alternative To Popular Naloxone Found To Combat Opioid Overdose Better

Compounds derived from marijuana may be able to reverse opioid overdoses, according to new research. With the recent efforts in the United States to make naloxone, a swift-acting opioid antidote, available without a prescription, the medication has proven to be lifesaving. However, it may not be as effective against potent synthetic opioids like fentanyl.

In a novel approach, researchers are now exploring the potential of cannabidiol (CBD), a marijuana component, as a possible alternative to the popular antidote. The team has reported that CBD-based compounds can reduce fentanyl binding and amplify the effects of naloxone.

The researchers will unveil their findings at the American Chemical Society (ACS) spring conference.

“Fentanyl-class compounds account for more than 80% of opioid overdose deaths, and these compounds aren’t going anywhere — it’s just too much of an economic temptation for dealers,” explains co-author Alex Straiker. “Given that naloxone is the only drug available to reverse overdoses, I think it makes sense to look at alternatives.”

The project’s other co-principal investigator, Michael VanNieuwenhze, Ph.D., has suggested that a new option could exist in either of two forms.

“Ideally, we would like to discover a more potent replacement for naloxone,” VanNieuwenhze adds. “However, finding something that works synergistically with it, reducing the amount needed to treat an overdose, would also be a success.”

The work will be presented at the meeting by Jessica Gudorf, a graduate student in VanNieuwenhze’s group, where all the researchers are affiliated with Indiana University Bloomington.

Opioids are a group of compounds used to manage pain, but they are sometimes sold illicitly. When consumed excessively, these drugs can obstruct breathing, which can prove fatal. According to the U.S. Centers for Disease Control and Prevention, over half a million people have died due to opioid overdoses between 1999 and 2020, and this number continues to rise.

Compared to other opioids like heroin or morphine, fentanyl and its synthetic relatives bind more tightly to opioid receptors in the brain. Naloxone counteracts an overdose by competing with the drug molecules for the same binding sites on the receptors. However, since fentanyl binds so tightly, it has a competitive advantage over naloxone, and increasing evidence suggests that reversing these types of overdoses may necessitate multiple doses of the antidote.

According to Gudorf, researchers have extensively investigated the approach taken by naloxone, but have yet to discover a way to enhance its effectiveness.

“Our work opens the door to making new blockers that work through a different mechanism,” she remarks.

Earlier research proposing that CBD could interfere with opioid binding stimulated the current endeavor. In a 2006 study, a German research team concluded that CBD indirectly hinders opioid binding by altering the receptor’s shape. When administered with naloxone, they discovered that CBD hastened the medication’s effect by compelling the receptors to release opioids.

To intensify these effects, Gudorf modified the structure of CBD to produce derivatives. Taryn Bosquez-Berger, a graduate student in Straiker’s team, tested these new compounds in cells using DAMGO, an opioid that is only used in laboratory experiments. To gauge their efficacy, she observed a molecular signal that decreases when this type of drug binds. Using the feedback from these experiments, Gudorf refined the structures she had created.

After conducting further experiments, the team eventually narrowed down their options to 15 compounds. They then tested these compounds at different concentrations against fentanyl, with and without naloxone. Several derivatives proved effective at reducing fentanyl binding, even at very low concentrations, and also outperformed naloxone in blocking opioids. Two of these compounds demonstrated a synergistic effect when used with the antidote.

The team has now initiated tests on mice to assess whether these promising derivatives can affect behaviors related to fentanyl use.

“We hope our approach leads to the birth of new therapeutics, which, in the hands of emergency personnel, could save even more lives,” Bosquez-Berger adds.

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