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CBD Can Reverse Opioid Overdoses, Study Suggests

By Alexander Beadle

Published: Apr 05, 2023   
A vial of oil in a gloved hand near a cannabis leaf.

Image credit: iStock

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In March, the US Food and Drug Administration announced that it had approved a Narcan (naloxone hydrochloride) nasal spray for nonprescription, over-the-counter use for the first time.

Naloxone is a rapid-acting medication that can reverse the effects of opioid overdose. In widening access to this life-saving drug, the FDA said that the move could “help reduce opioid overdose deaths throughout the country.”

But while naloxone can save lives in many cases, it is less effective at reversing overdoses caused by powerful synthetic opioids such as fentanyl.

In a new presentation given at the spring meeting of the American Chemical Society (ACS), researchers from Indiana University Bloomington (IU Bloomington) reported new findings that suggest that CBD could help to combat fentanyl overdose and boost the effects of naloxone.

The need for new treatments

Compared to other opioids, such as heroin or morphine, fentanyl and the synthetic opioids bind more tightly to the opioid receptors in the brain.

To reverse an overdose, naloxone works by out-competing the opioids for access to the same binding sites on the brain receptors that the opioids are seeking. This is why the strong binding power of fentanyl and other synthetics is a problem – naloxone can no longer put up enough of a fight for the binding sites, and so it may require multiple doses of naloxone to successfully reverse an overdose.

Previous research by researchers at the University of Bonn, Germany, has suggested that CBD could indirectly hamper opioid binding through a different mechanism, by altering the physical shape of certain opioid receptors. More recently, the same lab at IU Bloomington has published studies examining this same action of CBD against other receptors in the body.

In their new research, the IU Bloomington researchers sought to combine and further these approaches, by assessing whether CBD or other CBD-like compounds might affect fentanyl binding.

“Our work opens the door to making new blockers that work through a different mechanism,” Jessica Gudorf, a graduate student at Indiana University Bloomington and the presenter of the work at the meeting, said in a statement.

New CBD-like molecules could reverse fentanyl overdoses

For this new work, the researchers synthesized 50 structural derivatives of CBD. Each new compound was then tested in cell assay experiments with a substance called DAMGO – a synthetic opioid that is commonly used in lab studies due to its high selectivity for the mu-opioid receptor – and a fluorescent signaling compound.

“At a molecular level, opioid receptors inhibit the synthesis of a really important intracellular messenger called cyclic AMP [adenosine monophosphate],” Taryn Bosquez-Berger, a graduate student who was involved in the research, explained during an online briefing. “So we wanted to target this inverse relationship for our experiment by taking cyclic AMP molecules with a fluorescent protein which is going to light up when it is connected with these molecules.”

“With lower intensities [of fluorescence] in the cells correlating with opioid receptor activation and higher intensities correlating with receptor inhibition, we were then able to go through several rounds of testing of these compounds, ultimately testing 50 compounds in this specific assay,” Bosquez-Berger said.

With these assay results, plus additional computational modeling data, the researchers were able to identify 15 promising compounds for further testing using fentanyl, both with and without the presence of naloxone.

They found that several derivatives could reduce fentanyl binding, even at what Bosquez-Berger described as “incredibly low” concentrations, while also outperforming naloxone. Additionally, two compounds showed a synergistic effect when used in combination with the naloxone, suggesting that CBD-derivatives could one day be used in conjunction with the well-known rescue medication.

Towards a new treatment for opioid overdoses

Over 106,000 drug overdose deaths were reported in the US in 2021, most linked to synthetic opioids such as fentanyl. Against such a backdrop, researchers are eager to identify improved methods for reversing life-threatening overdoses.

“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,” Alex Straiker, PhD, co-principal investigator of the new study, said in a statement. “Given that naloxone is the only drug available to reverse overdoses, I think it makes sense to look at alternatives.”

“Ideally, we would like to discover a more potent replacement for naloxone,” added Michael VanNieuwenhze, PhD, the other co-principal investigator for the project. “However, finding something that works synergistically with it, reducing the amount needed to treat an overdose, would also be a success.”

The researchers say that, since completing these cell studies, they have now begun to test the most successful derivatives in mice models of 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,” said Bosquez-Berger.


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