You swear the reason your headache won’t go away is because you bought the generic pain reliever instead of the name brand…your spouse stops taking his newly prescribed statin because he is experiencing muscle pain, just as his pharmacist warned might happen…you receive a call from a member of your book club letting you know that she tested positive for COVID-19, and suddenly you notice you have a sore throat. If you can relate to any of these scenarios, you have experienced the power of the “nocebo effect,” the opposite of the placebo effect.

Nocebos Defined

A nocebo is anything—a pill…a story in the news…a doctor’s words…a list of side effects on a bottle of medication—that triggers medical side effects or adverse events. Unlike a placebo, which stimulates a positive response in a patient despite containing no active ingredients, a nocebo tricks you into thinking that you’re ill when you’re perfectly fine…or in more pain than you actually are…and it can slow recovery. (“Placebo” means “I shall please,” and “nocebo” means “I shall harm” in Latin.) The nocebo effect is the direct result of personal expectations, past experiences and/or verbal suggestions. Both placebos and nocebos are rooted in the power of suggestion and brain chemicals being released, but only one is a threat to your well-being.

Nocebos are powerful and have been proven to exist in multiple studies exploring the mind-body connection in pain, chronic fatigue, depression and more. Consider a study published in Journal of the American College of Cardiology in which participants were assigned to take either atorvastatin (Lipitor), a placebo pill or no pill at all for one month at a time over a period of 12 months. During the months when participants were given pills, they did not know whether they were taking the drug or a placebo. They were asked to rate the severity of any negative effects on a scale of 0 to 100. Keep in mind that statin side effects often are mentioned in the media and discussed by doctors when prescribing, so most of the participants had heard statins could cause unpleasant symptoms.

Telling results: During the months when the participants did not take a pill, they reported an average score of 8/100. In months when they took a statin, 16.3/100 and 15.4 in the placebo months. The study authors determined that 90% of symptoms experienced by participants taking atorvastatin were also felt by those taking the placebo and thus could be blamed on the nocebo effect.

How Nocebos Work

The nocebo effect engages a complex set of mechanisms in the nervous system that can amplify how people perceive touch, pain, pressure, temperature and more. Example: We know that when someone expects pain to occur, even nonpainful stimulations are perceived as painful and minimally painful stimulations as highly painful. At the molecular level, the body is releasing hormones called cholecystokinins that facilitate pain transmission, an evolutionary adaptation that primes the body to respond to a dangerous situation.

We also know from neuroimaging studies that certain parts of the brain become activated in anticipation of pain and other negative stimuli—enough so that they can override the effects of even the strongest pain medications. Recent study: Patients who received morphine after a surgery felt relief. But when they were told that their morphine had been stopped, they reported an increase in pain—even if the medicine hadn’t actually been stopped. (This phenomenon is called nocebo hyperalgesia.) On the flipside, when painkillers were stopped without notifying the patient, there were few complaints.

A third mechanism involves the autonomic nervous system (ANS), the branch of the nervous system that controls bodily functions that are not under conscious control, such as heartbeat, breathing, digestion and more. The nocebo effect may be a result of the ANS responding to negative expectations, fear or anxiety. This could explain how a 26-year-old man showed up in the emergency room appearing drowsy and pale with dangerously low blood pressure and an elevated heart rate, saying, “Help me, I took all my pills,” before collapsing…and yet lived to tell the tale. He had been enrolled in a clinical trial for depression and had a change of heart after attempting suicide by swallowing 29 capsules of what he believed to be antidepressants. ER staff began treating him for an overdose, but his symptoms wouldn’t improve. A physician from the trial was contacted and revealed that the patient had been in the placebo group—the pills were inert. Within 15 minutes of being told this, the patient’s blood pressure and heart rate returned to normal. The nocebo effect had caused his frightening symptoms.

Who Is Most at Risk?

Anyone can experience the nocebo effect, but people with a history of anxiety, depression or other psychiatric ­disorders are more prone, as are patients with negative expectations of or negative prior experiences with a treatment. Even though the nocebo effect might seem similar to hypochondriasis, the latter is an anxiety disorder. You don’t need to have a mental health condition to be susceptible to nocebos. Women may be more sensitive to nocebos, but there are conflicting findings. (That said, women are more responsive to placebos compared with men.) Pessimists and people with type-A personalities also may be more nocebo-prone.

Living through a health outbreak, such as H1N1 influenza, Ebola or COVID-19, heightens anxiety and can intensify the nocebo effect. Many people who have developed a headache, sore throat and more over the last two years convinced themselves that they were infected with COVID-19, thanks to the nocebo effect.

COVID-19 and nocebos: Researchers followed 74 people during the stay-at-home orders in Baltimore between May and June of 2020. Among the 72 participants not diagnosed with COVID during that time, 70% reported symptoms associated with the virus.

Moreover, a preregistered prospective longitudinal study conducted with a US national sample of 551 individuals indicated that post-vaccine side effects are predicted by prevaccine expectations of side effects, worry about COVID-19 and depressive symptoms.

Outsmart the Nocebo Effect

Nocebos can thwart treatments and contribute to illness. Examples: Many people who start taking cholesterol-lowering statin drugs discontinue them due to side effects. Widespread discontinuation has led to an increase in fatal heart attacks and strokes. But how many of those side effects are just nocebos causing needless consequences? How many COVID tests will be run over the next few years, straining the health-care system, due to the nocebo effect?

Reading this article is the first step in breaking the pattern. Simply knowing that your brain can create new or worsening symptoms through the process of anticipation can help blunt the nocebo effect. Other steps…

Ask your doctor for help. Health-care providers have the challenging job of striking a balance between being honest with patients about potential treatment side effects…but not being so open about every possible side effect under the sun that they spark anxiety. Self-defense: If you tend to be anxious, ask your doctor to tell you only about the most common side effects…or request that he/she focus on how well-tolerated your treatment tends to be. Also, don’t read the long list of possible side effects attached to your new medication if you tend toward anxiety. Many are relatively rare but can trigger a nocebo effect nonetheless.

Avoid negative stories and blogs. Reading about another patient’s negative experience with a treatment can act as a nocebo—simply knowing that she developed pain or nausea from a certain drug can contribute to an increase in your own pain or nausea. This may have to do with the fact that the areas of the brain involved in feeling empathy for others also are responsible for the way we interpret pain. Self-defense: If you’re starting a new drug and want reassurance from other people but know you are susceptible to the nocebo effect, Google strategically—search “chemotherapy + breast cancer + success story,” not “­chemotherapy + breast cancer + vomiting.”

Try not to get caught up with labels and prices. Consumers often think expensive and name-brand medications work better than cheaper or generic ones. In a study in Neurology, patients with Parkinson’s disease (PD) were given one of two placebo injections and were told that it was a dopamine-agonist medication used to treat PD. One of the ­placebos was described as expensive…the other as cheap. Four hours later, those who received the “cheap” version then received the “expensive” version, and vice versa. Both placebos improved patients’ motor function, but the benefit was larger among those who received the “pricier” drug first. Self-defense: Don’t fear that the price or brand name of your medication will make it less effective. If your doctor prescribes a generic drug, rest assured that it is pharmaceutically equal to its name-brand counterpart.

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