Drug overdoses in the United States have risen sharply over the past two decades. Nearly 92,000 people died from overdoses of illegal drugs and prescription opioids in 2020 – more than five times the number of deaths in 2000 – and synthetic opioids like fentanyl are a major culprit.
Naloxone (an injectable drug also marketed as Narcan nasal spray) has saved countless lives, but it only works for opioid overdoses and has other limitations. Now, in an effort to identify a more universal treatment for drug overdoses, a team of scientists from the University of Maryland have tested a chemical compound — Pillar[6]MaxQ (P6AS) – as an antidote to methamphetamine and fentanyl. Their findings, published today in the journal Chemistrywere very promising.
“Opioids already have a reversal agent in naloxone, but there are a variety of non-opioid drugs of abuse – such as methamphetamine, PCP, mephedrone, ecstasy (MDMA) and cocaine – which do not have no specific antidote,” said the study’s lead author, Lyle Isaacs, a professor in UMD’s Department of Chemistry and Biochemistry. “This is one of the huge opportunities for our compound.”
In vitro et Direct lab tests have shown that P6AS successfully sequesters fentanyl and methamphetamine, a non-opioid stimulant, and attenuates their life-threatening biological effects. Additional in vitro tests have revealed that P6AS also binds strongly to other drugs, including PCP, ecstasy and mephedrone, suggesting that P6AS might one day be used to counter a wide range of drugs.
The study was conducted by Isaacs’ lab in collaboration with researchers from UMD’s Department of Cell Biology and Molecular Genetics and Department of Psychology. Although the synthesis and chemical properties of P6AS were first documented in 2020 by Isaacs and Weijian Xue, a former postdoc associated with the Department of Chemistry and Biochemistry, this study reports its first Direct applications.
P6AS functions as a molecular container, meaning it binds and sequesters other compounds in its central cavity.
“When we put molecules in our containers, we can turn off their biological properties and thus reverse any effects they might have,” Isaacs explained. “We have measured the interaction between our container and a variety of drugs of abuse – things like methamphetamine, fentanyl, ecstasy, PCP and others – and we find that this new container we have made binds many of them very strongly.”
Direct tests revealed that the effects of methamphetamine might be reversed by administering P6AS five minutes later, which is “still a bit short for real-life situations,” Isaacs explained. The effects of fentanyl, however, might be reversed by administering P6AS up to 15 minutes later, which is closer to federal guidelines for drug reversal agents.
Unlike naloxone, which blocks a drug of abuse from binding to receptors in the brain, the UMD team’s molecular container targets drugs directly into the bloodstream.
“Our compound absorbs the drug into the bloodstream and we believe helps promote its excretion in the urine,” Isaacs said. “It’s called a pharmacokinetic process, where we try to minimize the concentration of free drug present in the body.”
Whether this compound helps promote the excretion of a drug from the body needs to be tested experimentally. If it works as the researchers believe, it might be particularly helpful for overdoses of fentanyl, which is up to 50 times stronger than heroin and up to 100 times stronger than morphine. Its potency and lingering effects in the body are why some patients continue to overdose even following receiving naloxone. Isaacs thinks excretion of fentanyl might help prevent this phenomenon, known as renarcotization.
Isaacs said it will likely be years before the new compound is approved for human use. However, he envisions it might be given as an injection, much like naloxone but potentially with wider applications. Isaacs thinks it might even be used to treat overdoses of extremely potent drugs like carfentanil, which has been linked to a string of overdose deaths in recent years.
“There are other synthetic opioids that are much more potent than fentanyl — things like carfentanil, which are hard to reverse with naloxone,” Isaacs said. “Additionally, people are getting so much fentanyl that multiple doses of naloxone are needed, so there’s room for a new, improved agent that might help in those situations.”
