The Drug Supply Is Changing. Naloxone Still Saves Lives.

Lacking regulatory quality control mechanisms, the U.S. illicit drug supply has always fluctuated, with contents and potency responding to both market pressures and law enforcement crackdowns. In recent years, the rise of synthetics—laboratory-produced substances that allow for rapid, inexpensive changes—has enabled these shifts to happen faster and with greater frequency. As a result, whether grappling with a substance use disorder or experimenting during adolescence, people who use illegal drugs rarely know exactly what they are putting in their bodies.

Due in part to this dangerous supply, the United States remains in the midst of an overdose crisis, with tens of thousands of Americans dying annually for more than a decade. Expanded health interventions have helped turn this tide in recent years: Deaths fell from over 110,000 in 2023 to about 69,000 in 2025, largely thanks to expanded treatment and community distribution of life-saving tools like fentanyl test strips and the overdose reversal medication naloxone (commonly known by the brand name Narcan). But with each new contaminant or novel substance that surges onto the market comes a shared fear that this progress will be lost and these proven interventions may no longer be effective. Fortunately, despite supply fluctuations, naloxone administration remains one of the most important steps in an overdose response. Here are some reasons why.

Naloxone is safe and effective

Naloxone is an opioid antagonist that binds to receptors in the brain, displacing opioid agonists like heroin or fentanyl and restoring breathing within minutes. Community-based studies show that when administered promptly, about 98 percent of recipients survive their overdose. Furthermore, the medication is so safe that it has been approved for over-the-counter sales. It can be administered to individuals of any age, from infants to seniors, and will not affect a person who has not taken an opioid. As an opioid antagonist, naloxone does not activate the receptors; therefore, it does not cause euphoria or intoxication. The one risk with naloxone (or any overdose reversal drug) is that a high dose given to an individual with opioid dependence can cause precipitated withdrawal symptoms including severe nausea, vomiting, and increased blood pressure, which can be dangerous without medical treatment. However, this risk can be mitigated without sacrificing overdose response by titrating doses to response and performing rescue breathing.  

Many novel substances are opioids

In 2025, over 63 percent of overdose deaths involved a synthetic opioid, with fentanyl accounting for the majority. However, although fentanyl remains the dominant synthetic opioid in the U.S. illicit drug market, it is not the only one. Many of the drugs now showing up in the supply are also synthetic opioids. For example, nitazenes can be up to 40 times more potent than fentanyl. Orphines are another group of opioids with potency ranging from comparable to fentanyl to much stronger. Both are responsible for a growing number of overdose deaths in several states. While these emerging opioids can sometimes be more potent than fentanyl, they do still respond to naloxone. Increasingly, experts recommend using standard doses administered at recommended intervals and paired with rescue breathing and close monitoring, even with high-potency opioids. This approach helps restore respiration while reducing the likelihood of withdrawals, which drive some people to use again and increase subsequent overdose risk.

Sedative overdoses usually involve naloxone

Another class of novel substances spreading within the U.S. illicit drug supply is veterinary sedatives, and deaths involving these substances are on the rise. Xylazine—the best known and most common among these—is a veterinary tranquilizer that causes hard-to-treat skin infections. It has spread throughout the country since about 2015 and is now found in almost every state. Another sedative becoming more common is medetomidine, which is similar to but more potent than xylazine and accompanied by serious withdrawal symptoms. Because these drugs are not classic opioids, many experts and lawmakers worry naloxone will not fully reverse sedation, although animal research suggests it may have some effect on xylazine. Regardless, roughly 99 percent of sedative-involved deaths also involved fentanyl or another synthetic opioid that will respond fully to the reversal medication. Therefore, individuals witnessing an overdose involving sedatives should still administer naloxone and engage in rescue breathing, just as they would for an opioid-only overdose. However, because the naloxone may not reverse sedation, current recommendations emphasize watching for breathing instead of consciousness “as a sign of resuscitation.”

Conclusion

The illicit drug supply in the United States is constantly changing, with potency fluctuating and new substances regularly entering the market. Fortunately, naloxone remains a highly effective medication that reduces the risk of fatal overdose. However, it is only effective if it is available and accessible. Friends and family of people who use drugs remain the most important overdose responders, as they are most likely to be present on scene.

Policymakers can increase layperson access to the lifesaving drug by:

• Continuing standing orders or pharmacist prescribing.
• Facilitating naloxone take-home programs through first responders and hospitals.
• Authorizing the administration and distribution of expired naloxone.
• Bolstering naloxone liability and Good Samaritan laws to protect lay rescuers.
• Targeting opioid settlement dollars to fund community-based naloxone purchases and free distribution.