That’s because it’s rarely screened for when someone comes into the emergency room after an overdose, despite the fact that fentanyl was responsible for about three quarters of all opioid overdose deaths in the state of Massachusetts in the first half of 2016. In fact, the only time fentanyl screening is routinely performed is for autopsies to determine the precise cause of death after an overdose.

Because the appearance of this syndrome parallels the rise of fentanyl overdose deaths, clinicians who have investigated the syndrome from the beginning suspected fentanyl, even though there was no evidence that anyone in this cluster had used fentanyl. “We know fentanyl is out there, we know that people are using it, we know it’s driving a lot of the phenomena that we see,” said Dr. Alfred DeMaria, the state epidemiologist for Massachusetts. “But we don’t have that documentation of fentanyl.”

The first patient appeared at a Boston area hospital in 2012 following what was presumed to be a heroin overdose. By late 2016, doctors had identified 14 patients with this syndrome, and all but one had a known history of opioid use or had tested positive for opioids.

The hallmarks of the syndrome are severe anterograde amnesia—the inability to form new memories—and a distinctive pattern of damage to the hippocampi. The hippocampi are twin, c-shaped structures close to the center of the brain that are the epicenter of initial learning and memory.

A Potent Drug

Ironically, fentanyl was originally designed in 1960 as a safer form of anesthesia than morphine. But the same qualities that make it ideal for surgery make it addictive and deadly when used illegally and difficult to detect in blood or urine samples.

The designer, a Belgian chemist named Paul Janssen, tweaked the structure of a molecule similar to morphine so that it could slip quickly past the blood brain barrier, making it extremely fast-acting. He also tinkered with its design to make it bind more tightly to the brain’s opioid receptors, which makes it more potent. In surgeries, doctors usually use far less of the drug, and can induce pain relief within one to two minutes. It’s effect is short-lived, generally lasting just a few hours or even less. This fast-in and fast-out mechanism gives anesthesiologists much better control during an operation.

The flip side is that it’s easier for someone to overdose outside the controlled setting of a surgery and harder to detect when they do. “Fentanyl and fentanyl analogs are very potent,” said Nicholas Manicke, a chemist at Indiana University-Purdue University Indianapolis who has helped develop a rapid test for new synthetic cannabinoids and fentanyl and its analogues. “The amount of drug that a person would take is less than they might take with heroin. And that also translates to a smaller concentration in the blood.” Because fentanyl clears the body so quickly, blood samples have to be taken as soon as a patient comes into the hospital.

Manicke’s rapid drug test consists of a small, square, inexpensive cartridge into which a few drops of blood plasma can be loaded. Any drugs in the cartridge are run through a mass spectrometer, which matches the suspect molecule to a database of about 20 synthetic drugs, all within five minutes. The product is still in development, but a screening method like this is orders of magnitude faster than sending blood or urine samples out to a toxicology lab, which is expensive and can take weeks to deliver results.

To find out whether fentanyl is responsible for the syndrome, last May the Massachusetts Department of Health made this new form of amnesia a so-called “Reportable Disease Syndrome,” encouraging clinicians who saw patients that fit this pattern to send out for advanced toxicology screens that could detect the presence of fentanyl. That alert resulted in the four new patients from 2017 that are described in yesterday’s report in the New England Journal of Medicine. All four patients’ drug tests were positive for fentanyl, and two of them had no other drugs detectable.

Despite this new evidence, the jury is still out as to whether fentanyl is truly the culprit. It now seems far less likely that a contaminant in the drugs is behind the outbreak, but proof that someone developed this syndrome after using pure, pharmaceutical grade fentanyl would help rule that out.

The report’s authors note that one plausible cause of the unique pattern of brain damage is excitotoxicity, a kind of storm in the brain caused by excessive stimulation of neurons. They point to studies that showed severe damage to neurons in the hippocampus of rats who were given fentanyl. It’s likely that insufficient oxygen caused by slowed breathing during an overdose makes matters worse.

The fact that only a tiny percentage of opioid overdose survivors develop this syndrome leads investigators to believe that genetics is also likely to play a role.

As to whether any other drug is responsible, Dr. DeMaria said, “Nothing else has emerged. You have scientific plausibility and consistency. What we don’t have is proof of cause and effect.”