A placebo can heal. Its “dark twin”—the nocebo—can cause illness, even when the substance administered is inert. Scientists have identified a neural pathway that transforms the expectation of harm into actual physical symptoms, and they have demonstrated that this effect can be mitigated without resorting to deceiving the patient. Yet, there remains a significant gap: both doctors and patients are largely unaware of how this process works. We explore why, at times, words can cause more pain than pills.
Oxford. Dr. Jeremy Howick sits at his desk, reviewing the results of a massive meta-analysis—comprising 20 systematic reviews and 1,271 randomized controlled trials, involving a total of 250,726 patients. None of these individuals received actual medication; instead, they were given “placebos”—sugar pills containing not a single molecule of an active ingredient. A placebo in action. To the researcher’s surprise, nearly half of the patients reported a worsening of their condition—a “reverse placebo” effect. Reported side effects included headaches, nausea, and dizziness. All from nothing. The inert pill itself caused the illness. It seems the placebo has a “dark twin.”
Nocebo: Illness from Nothing
In truth, this mystery was not new. As early as 1961, British physician Walter P. Kennedy published a short article titled “The Nocebo Reaction” in the journal Medical World. While working with patients in clinical trials, Kennedy observed a pattern—which he modestly termed an “unoriginal observation”—whereby individuals receiving an inert substance reported experiencing non-specific side effects. The very same ones that Jeremy Howick later identified in the results of a meta-analysis.
It was back in 1961 that the world was introduced to the term “nocebo”—derived from the Latin nocere, meaning “to harm.” Incidentally, “nocebo” is not just a functional counterpart to “placebo,” but a linguistic one as well; the latter translates from Latin as “I shall please.”
For better or worse, it took science another half-century to realize that the “nocebo” phenomenon is far more complex and distinct than it might appear. It is not merely a matter of psychology or hypochondria—it is biology. More precisely, it involves a specific neural pathway that can be measured, blocked, or activated.
Where the nocebo resides
May 2026. A paper by Sandra Poulson and Lauren Martin is published in the journal Nature Communications. The title—to put it mildly—is daunting: “Cholecystokinin signaling from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice.” “Mice” is perhaps the only readily understandable word here. In plain language, the researchers discovered, for the first time, the origin and destination of the “nocebo” signal—revealing how our brain can essentially conjure up an illness out of thin air. The mechanism, as it happens, is quite straightforward—resembling, in a way, a train route.
The point of departure is the anterior cingulate cortex (ACC)—a brain region responsible for the emotional dimension of pain and the anticipation of a threat. The destination is the lateral periaqueductal gray (lPAG), a structure located in the midbrain that regulates pain signals. The “cargo” being transported is cholecystokinin. It projects to the IPAG and amplifies pain.
Now, regarding the mice: the researchers pursued two different approaches. One group of mice learned to associate a specific room with pain; subsequently, when placed in that room, they experienced pain even in the absence of any external stimulus. Another group of mice observed a cage mate suffering from pain, which in turn increased their own sensitivity to pain.
The researchers then disabled the identified neural pathway—the one connecting the ACC to the IPAG—using various methods, including chemical interventions and optogenetics (where specific neurons are “switched off” using light).
The results were unequivocal: once the neural pathway was blocked, the mice ceased to experience pain—as if the first group had never learned to associate the room with suffering, and the second group had never witnessed the agony of their companion.
Has an “off switch” been found?
The discovery that this neural pathway could be manipulated sparked intense debate, effectively splitting the scientific community. Even before the study published in May, Dr. Simone Meyer from Leiden University conducted her own experiment. She recruited 66 healthy women and divided them into groups, then initiated a process of “re-learning.” Participants were explicitly informed: “The pill you are taking is a placebo; it contains no active medication.” The researchers then introduced what could be described as a “cheat code”: they asked the participants to associate taking the pill with a positive outcome—specifically, a reduction in pain. In other words, the subjects knew they were taking a placebo, yet they consciously convinced themselves that it would still be effective.
According to Meyer, this process allows the brain to overwrite a negative association with a positive one. And the results were staggering: the nocebo effect does not simply vanish—it transforms into a placebo effect. A dummy treatment begins to function like a real medicine.
The effect size was d=1.13. According to standard classification, this is a very large effect. For context, most similar interventions yield an effect size in the range of 0.3–0.5.
Meyer concluded that the nocebo effect can be mitigated without deceiving the patient—and without the need to administer substances or “blind” neurons.
The Dodo Effect: The Paradox of Three Paths
It would seem that the solution has been found—an ethical, effective approach that requires neither surgery nor deception. It’s ready to be implemented and put to use. But as it turns out, things aren’t that simple. Another researcher, Darina Rubanets from Jagiellonian University in Poland, challenged Meyer’s findings—not by questioning the effectiveness of the methods, but by questioning how that effectiveness is understood.
In June 2026, Rubanets conducted a study, later published in the journal PAIN, involving 168 participants. She compared three distinct methods, all theoretically capable of mitigating the nocebo effect. The first was the same type of “re-education” used by Meyer. The second was “verbal modeling”—essentially telling a person that others experience less pain (e.g., “This helped Scarlett, so it might help you, too”). The third was “operant conditioning,” where a person is rewarded for reporting lower levels of pain—much like giving someone a piece of candy because their stomach hurts a little less.
The study revealed a paradox that Rubanets dubbed the “Dodo effect”—a reference to the character from Alice in Wonderland. In Carroll’s story, the Dodo organizes a race in which everyone wins and everyone receives a prize. Similarly, Rubanets’s research concluded that all three methods work—and, what’s more, they all work equally well. But if three different paths lead to the same destination, one must ask: which one is actually the “right” one?
Perhaps the specific method doesn’t matter at all. Could it be the physician’s attention that counts? Or the ritual itself? Or perhaps the patient’s own expectations? We don’t know—and that, in itself, is a problem. If we do not understand exactly what three effective methods have in common, we cannot guarantee that any one of them will work in a different situation. Furthermore, we cannot predict when—or even if—a method might fail. And, naturally, we cannot improve a method, because we simply do not know what there is to improve.
Meyer believes a solution exists and urges action. Rubanets is more cautious. Both are right in their own way. Meanwhile, as they debate, the nocebo effect continues to take hold—quietly, imperceptibly, day after day.
The most unsettling part is that it requires no doctor, no clinical setting, and no physical contact. One only needs to go online and read something—and the nocebo effect is right there.
Words That Cause Harm
In May 2026, the journal Psychological Research published a study by Alessandra Barbon of the University of Trento. The researcher gathered groups of healthy older adults, aged 65 to 80, and asked them to perform a task involving attention and perception. Before beginning, participants were told that an “acoustic device” was currently influencing their brains. One group was informed that this “miracle device” would enhance their memory and attention, while the other was told it would impair them. In reality, the device was fake; it did nothing at all. The researchers created the illusion of a therapeutic intervention to test how information alone—whether potentially harmful or helpful—affects people.
As it turned out, those who were told the device would impair their memory did, in fact, “fail the test.” Conversely, those who were told the opposite showed no objective improvement, yet their self-confidence soared. In effect, the researchers demonstrated the power of words—and confirmed that the nocebo effect operates through the transmission of information. Simply telling someone that something might harm them is enough to trigger a process in the brain.
Between Science and Practice
Six months prior to Alessandra Barbon’s study, the journal PLOS ONE published the results of a survey involving 807 European healthcare professionals. It revealed that 55.8% of them had observed the nocebo effect in their patients—witnessing individuals feel worse after receiving a placebo, or developing symptoms that should not have been present.
A survey of 438 pediatricians, published in the European Journal of Pediatrics that same year (2026), painted an even starker picture: only 6.8% of the respondents had received training on how to communicate about potential side effects, and just 41.3% indicated that they were even aware of the nocebo effect.
A January 2026 survey of 650 anesthesiologists in Germany and Austria confirmed this concerning trend: while 92% of these specialists use communication strategies to shape patient expectations—which is entirely logical—only 23% employ strategies to mitigate the nocebo effect. In other words, almost everyone communicates with patients in a way that shapes their expectations, yet hardly anyone knows how to protect them from negative outcomes.
This is the gap. Science has proven that the nocebo effect exists, identified its underlying mechanism, and even discovered ways to weaken it—yet this knowledge has failed to reach those who should be putting it into practice.
This is where another study, one that offers a glimmer of hope, comes into play. In May 2026, the journal Psychology & Health published a paper by Emily Spotts from the University of Toledo. She conducted three experiments involving more than 500 participants: one group was shown a short video explaining what the nocebo effect is and how it works, while another group watched a video on an unrelated topic. Then, they measured how people behaved afterward.
The result was simple and striking. People who were aware of the nocebo effect were less inclined to search for information about side effects online, and they were less likely to “stumble upon” alarming stories. No, they didn’t avoid information entirely—but …stopped looking for things that might trigger a nocebo effect.
This seems like the simplest solution. It’s inexpensive. It’s ethical. There’s no need to lie or withhold information. You simply need to explain to people how their own brains work.
The First Step
The nocebo effect is not a sign of weakness, nor is it mere hypochondria or just “psychology.” It is a brain process—a specific neural pathway that can be measured, blocked, or activated. The anterior cingulate cortex sends a signal, which is then received by the lateral periaqueductal gray matter. Cholecystokinin amplifies the pain. All of this happens automatically—faster than we can even form a conscious thought.
Scientists have already discovered ways to mitigate the nocebo effect without resorting to deception—through open re-education, positive programming, and public awareness. These methods exist and have been scientifically validated; some produce effects that are considered substantial within the field of psychology.
Yet, there is a problem. Some researchers advocate for their implementation, noting that they work. Others argue that we should wait, as the underlying mechanisms remain poorly understood. Meanwhile, many physicians are not even aware that the issue exists. Some debate how to treat it, while others do not even realize there is something to be treated.
We live in a world saturated with anxious expectations. Every report about side effects, every conversation regarding the dangers of vaccines, every frightening diagnosis—each serves as a signal to the brain. And the brain responds. This happens not because of some personal weakness, but because that is simply how the brain is wired.
But if we understand how this process works, we have the power to change it—perhaps not immediately or entirely, but we can make a difference.
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