Researchers have discovered a potential new way to reverse fentanyl overdose using modified cannabidiol (CBD) as a negative ectopic modulator of the opioid receptor binding site. Preliminary in vitro testing showed that the modified cannabidiol successfully reversed the effects of fentanyl, and further in vivo testing is planned to assess its ability to counteract respiratory depression, a major overdose effect.
According to the Centers for Disease Control, 100,000 Americans die from drug overdoses every year, the vast majority of which are caused by taking synthetic opiates such as fentanyl. While naloxone is currently the only antidote available to treat opioid overdose, it is less effective against synthetic opioids like fentanyl.
Indiana University researchers have discovered a new way to reverse the effects of fentanyl, which is 50 to 100 times more potent than morphine. Their findings, published in the Journal of Medicinal Chemistry, may lead to a new way to reverse overdoses, either through a new product or in conjunction with Naloxone.
"Synthetic opioids bind very tightly to opioid receptors," said Alex Straiker, senior research scientist at the Gill Center for Biomolecular Science. Naloxone must compete with opioids for the same binding site in the central nervous system to counteract an overdose, but in a fentanyl overdose, naloxone and fentanyl bind to different sites, meaning there is no competition."
Straiker began measuring the effects of opioid receptors on a signaling molecule called cAMP. The researchers conducted chemical tests on 50 structurally related molecules to determine which compounds showed the most promise as effective negative ectopic modulators.
Researchers discovered that cannabidiol (or CBD) can act as a negative ectopic modulator at the binding site. However, high concentrations are required in initial testing. Researchers modified the structure of cannabidiol to make it more potent and found that cannabidiol successfully reversed the effects of fentanyl in in vitro diagnostics (tests performed on blood or tissue samples).
"We have identified parts of the structure that are important for the desired detoxification effect," Strack said. "Some of these compounds are more potent than the lead compounds. We are already working with a third lab to model the binding site, which may help identify additional compounds."
The next step is to test their findings in living subjects (i.e., living organisms) to determine whether it can reverse respiratory depression, a major effect of drug overdose.