A bizarre medical mystery can be added to the list of growing concerns about opioid use in the U.S. Since 2012 more than a dozen illicit drug users have shown up in hospitals across eastern Massachusetts with inexplicable amnesia. In some cases the patients’ memory difficulties had persisted for more than a year. Yet this bewildering condition does not appear to be the result of a simple case of tainted goods: The drug users do not appear to have used the same batch of drugs—or even the same type of substance.

To get some answers, the state’s public health officials are rolling out a new requirement that clinicians who come across any patients (not just opioid users) with these types of memory deficits—along with damage to the hippocampus—must report the cases to the state. On April 3 state public health officials received the legal green light from the Massachusetts public health commissioner to make this a required, reportable condition. This technical change, which will last for one year, authorizes public health workers to collect this information and reassures clinicians that they can—and must—share case reports. In the next couple of days workers will notify emergency room personnel as well as addiction counselors and neurology specialists about the new designation via e-mail.

The new reporting requirement, state officials hope, will help epidemiologists learn how widespread the issue of potential opioid-linked amnesia may be and whether patients have specific factors in common. The change was first reported by BuzzFeed News.

Massachusetts officials first documented this string of amnesia cases in the U.S. Centers for Disease Control’s Morbidity and Mortality Weekly Report (MMWR) back in January. “No clear etiology exists, but at time of initial evaluation, 13 of 14 [patients] tested positive for opioids or had opioid use recorded in their medical history,” medical workers tracking this issue wrote. Most of the patients tested positive for one or more drugs including opiates, benzodiazepine, marijuana, PCP or other substances.

Although extremely rare, the amnesia–drug link is also not completely unprecedented. In the past there have been several documented cases where similar amnesia was detected among cocaine users. In 2013 there was also one case reported in France where the same kind of memory loss was associated with heroin inhalation.

To better understand the recent wave of cases, Scientific American spoke with state epidemiologist Alfred DeMaria, medical director of the Massachusetts Department of Public Health’s infectious disease bureau.

[An edited transcript of the interview follows.]

What a puzzling situation. Can you walk us through how these patients present?
Basically, it’s one of two ways: They wake up in the hospital after an acute medical condition—usually an overdose or toxicity from drugs—with an unusual degree of confusion and rockiness. The other way a patient gets medical attention, is, say, the patient’s family saw him on Friday when he seemed fine and then when they talk to him on Sunday morning he doesn’t remember seeing them on Friday or what happened the day before, and this short-term amnesia leads him to get medical attention. With both cases, the patient may have no memory of what has gone on in the previous 48 hours.

So this memory loss is limited to recent events?
Usually it’s relatively short term, yes, and the issue, according to their MRIs, seems to be damage to the hippocampus—an area of the brain that usually helps process information into memories. These patients don’t really have problems with long-term memory. For example, as a neurologist involved in these cases described it: They can drive to work because they have been driving to work for 20 years, so they have no trouble doing that. But if they have to go someplace new and they are given directions, just simple directions, they get in the car and can’t remember what they were just told. So the issue is also processing new memories.

Your case descriptions mentioned that for a couple of these patients their memory impairment lasted a year or more.
Yes. Their memory gets better and everything is relative to the amount of damage to the hippocampus, presumably. But that’s the kind of deficit they have.

What do you think is the likely cause of the amnesia?
Substance abuse is not a simple thing. People who are using substances very rarely use just one. So that can complicate trying to understand causality. We don’t know if people who have a history of opiate drug use were using other drugs, too.

Do you have a working hypothesis about what’s going on?
There is some evidence that pharmaceutical versions of fentanyl can have an effect on the hippocampus—so I think our favorite hypothesis is that, with all of the synthetic fentanyl out there, it is a contamination of that drug or some fentanyl-like chemicals that could be causing this effect. There is no standardization in an illicit synthetic fentanyl lab, so who knows what is in there or even what kind of fentanyl it is. Really, this is just a hypothesis, though. There are some reports that methamphetamine can also do similar things to the hippocampus, so we wouldn’t want to write that off either.

Since your original report of these 14 cases in the MMWR in January have you heard about additional cases in Massachusetts?
No, it’s really interesting. The MMWR got a lot of attention, especially in Massachusetts, but we had no extra cases reported, which surprised us. We thought with all of this attention, we would see another wave of reports.

If no more cases appear, how would you explain what happened?
Maybe we can’t. If we don’t see any more cases, then maybe this was just a transient contamination. That would be good from a public health and medical standpoint, but it won’t let us know what’s going on.

Regarding your fentanyl theory, isn’t diagnosing fentanyl use difficult because it’s not typically tested for in the emergency room?
We are hoping that in the case of amnesia reports, clinicians will have access to expanded toxicological screens and coverage for them because then more extensive tests would be medically indicated. Routinely, such expanded testing studies are not done—even on overdose deaths related to drugs like fentanyl—so we are hoping that now clinicians will call us and say, “I saw this patient last night and she or he is in the hospital now and the MRI shows this hippocampal ischemia pattern. So what do you want us to do?” Then, we are going to collect some information but also say we would like you to try to get this expanded toxicology screen and an MRI to look at the hippocampus.

How are the MRIs of these patients unique?
It is a bilaterally symmetric effect on the hippocampus. It’s not really vascular—it’s not a stroke where you get a clot or a bleed and then there’s no blood supply. It looks more like a toxic effect that affects the metabolism of the hippocampus. Some of these patients overdosed and had low flow [of oxygen] to the brain during their overdose, and we have gotten a lot of advice and criticism saying this is just an overdose and there’s nothing new here. But our response is if it’s just an overdose, why is the damage almost exclusively limited to the hippocampus?

What could be the biological mechanism at work here?
There are two things I think of in terms of this outbreak: One is an outbreak related to shellfish poisoning a number of years ago. That was with something called domoic acid that actually causes amnesia not all that dissimilar to this, but more severe. In fact, a lot of people have contacted us and asked if we had thought about domoic acid. There’s no reason to think people were exposed to it here, though. I’m suspecting what’s similar here is that it’s a toxin that hones in on the hippocampus.

Back in the 1980s we saw a similar amnesia situation, only then it was a contamination of drugs out in California. Someone was manufacturing a drug that was an analogue of the opioid meperidine and made a mistake in manufacturing that produced a similar chemical, a product called MPTP, that caused Parkinson’s disease–like symptoms. I keep thinking, might the recent amnesia cases be something like these two?

Is this recent phenomenon being seen outside Massachusetts?
We have heard from some clinicians in Oregon who think they have seen multiple cases like this, and from what they describe it seems like they may have.

Are there any plans for the Council of State and Territorial Epidemiologists to declare this a reportable condition nationwide?
No.

Is it likely there is something else at work hereperhaps several factors working together, including genetics, that make for a toxic stew?
Absolutely. I don’t know the causes so I’m not going to hone in on one thing to the exclusion of anything else. It’s likely a combination of factors. That’s why even if there is something out there that’s toxic, maybe only some people are susceptible to its effects. Maybe many people are exposed but only a few are vulnerable.