All drug trials must have a control group. People in this group receive an inert substance, also known as a placebo — a “fake” drug that does not contain an active ingredient.
If the trial is testing a specific pill, the control group will receive a pill that looks identical but does not contain an active ingredient. If testing a vaccine, the control group will receive a placebo injection.
However, there is a curious phenomenon whereby people taking placebos sometimes notice changes consistent with what they expect to happen.
Therefore, many will notice an improvement in symptoms — the so-called placebo effect. Others, however, will notice side effects that might be expected from the drug being trialed, and they may be unpleasant.
This is known as the nocebo effect. The phenomenon of experiencing adverse symptoms that are expected but without an actual cause was identified in 1961 by Walter P. KennedyTrusted Source.
The term derives from the Latin word “nocere,” meaning “to harm,” and was first used to describe adverse effects caused by a placebo.
Lee Chambers, psychologist and founder of Essentialise Workplace Wellbeing, explained for Medical News Today:
“People get the idea of the sugar pill that cured people — the placebo effect — […] because it’s a little bit of magic, really […] People need to see that it can also be magic that you don’t want.”
One study defined the nocebo effect as “unpleasant or adverse outcomes triggered by the treatment context, beyond any inherent pharmacological effects of the treatment itself.”
So the mere act of taking a tablet or having an injection might cause side effects, which are not due to any drug it contains. And it can happen to those on prescribed medication, not just in trials.
Cause of the nocebo effect
If the medication itself is not responsible for the side effects, why do they happen? The need for medical professionals to gain informed consentTrusted Source might go some way to explaining the nocebo effect.
People undergoing medical treatment must give informed consent for that treatment. To gain informed consent from a patient or trial participant, physicians have to explain the risks and benefits of the treatment in detail, including possible side effects.
Older researchTrusted Source has suggested that when participants in a trial are told about side effects, they are likely to experience them whether they are taking the active drug or not.
So, can negative expectations produce negative outcomes? According to Chambers, this could be the case: “While it’s such a complex mix of things […] on the basic level, it’s having negative side effects because you have been told there might be negative side effects.”
Dr. Fabrizio Benedetti, professor of neuroscience at the University of Turin Medical School, Italy, who has published widely on the nocebo effect, agreed, noting that “[m]any adverse events may be attributable to nocebo effects and not so much to the drug itself.”
A recent studyTrusted Source of COVID-19 vaccination trials illustrates this. Researchers who analyzed data from 12 trials found that 35% of people given placebo injections experienced systemic effects — effects experienced in areas of the body other than the treatment site, such as headache and fatigue — following the first dose.
This was compared with 46% of those given the real vaccine. Therefore, the authors of this study suggest that some 76% of adverse effects reported by those given the real vaccine were nocebo effects. In other words, they were not caused by the vaccine but by participants’ expectations.
Dr. Benedetti was unsurprised by these findings: “It has long been known that nocebo effects occur in many conditions, such as pain and Parkinson’s disease. Therefore, it is not surprising that they also take place in COVID-19 vaccination. If you expect a negative outcome, you can get it.”
Physical or mental causes?
These symptoms experienced are undoubtedly real, so if they are not due to active treatment, what might be the cause? Experts have attributed the nocebo effect to both psychological and neurobiological causesTrusted Source.
Dr. David A. Merrill, adult and geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, CA, explained:
“A lot of factors come into play. For example, our prior experiences with the health system and related treatments. If you’ve personally had complex health stressors with a difficult treatment course, you might be anticipating more difficulty with additional treatments. We’re evolved to anticipate outcomes and avoid harm.”
The psychology may be that negative expectations are fulfilled. If a patient hears that a treatment may cause drowsiness, and then feels drowsy, they will blame that sleepiness on the treatment.
In addition, people who have negative expectations of side effects may be more aware of symptoms and, therefore, more likely to report them.
And studiesTrusted Source have found that those who experience anxiety and depression may also be more likely to experience the nocebo effect.
Philip Morris International met with the Food and Drug Administration on Friday afternoon to present its argument for why the tobacco giant and Altria should be allowed to import and sell Iqos devices in the U.S., CNBC has learned.
A person familiar with the company’s meeting said Philip Morris told the FDA that Iqos is unique, both in its design and ability to convert smokers. Additionally, the company is arguing that the U.S. International Trade Commission overstepped its bounds, given that the FDA is in charge of regulating which tobacco products and alternatives can be sold, this person said.
The meeting with regulators is the latest development in a patent dispute with rival R.J. Reynolds, a subsidiary of British American Tobacco. In late September, the ITC ruled that the Iqos device infringed on two of Reynolds’ patents. The Biden administration is conducting a 60-day administrative review until Nov. 29 to decide if the sale and import of the cigarette alternative will be banned.
Altria launched the Iqos device in the United States two years ago, but it began development of the product more than a decade ago before Philip Morris International was spun off from the company. The device heats tobacco without burning it, which is meant to give users the same rush of nicotine without as many toxins as smoking a cigarette.
Philip Morris sells the device in dozens of international markets and has granted Altria a license to sell it in the U.S. While Iqos don’t represent a large portion of Altria’s U.S. business, it’s part of the company’s shift away from traditional tobacco products, which have seen falling demand.
The U.S. Trade Representative will make a recommendation to President Joe Biden after listening to input from a number of agencies, including the FDA, which regulates tobacco products.
“The presidential review process can disapprove of the ITC’s final determination on a few counts, and we believe there is a pretty strong case for that,” said Deepak Mishra, head of Philip Morris International’s Americas region, in an interview with CNBC Thursday.
The company’s argument to keep selling Iqos includes the public health benefit of the device. Altria said it counts 20,000 U.S. consumers as users of the device, and say they could revert back to cigarettes if Iqos disappears from shelves.
“We are pretty convinced that the vast majority will go back to smoking cigarettes,” Mishra said. ”… It actually comes close to the taste and ritual of a cigarette, which is why we have a very strong conversion of smokers that switch to Iqos.”
Mishra said this was an argument the company planned to make as it urges the Biden administration to overturn the ITC ruling.
The next step in the administrative review is a Trade Policy Staff Committee meeting, which will likely happen this week, the person familiar with the meeting said. The group includes a number of federal agencies, including the FDA, U.S. Department of Agriculture and the Department of Commerce.
If the administration sides with R.J. Reynolds in the dispute, Iqos could be off of U.S. shelves for months as it waits for a decision on a separate claim from Reynolds with the U.S. Patent and Trademark Office, according to Mishra. That process is expected to take another six to 12 months, but Mishra said the company is more optimistic about the outcome given its success in similar cases outside the United States. British American Tobacco has already pursued similar legal action against Philip Morris in 11 international markets and the European Patent Office.
In the worst case scenario for Altria and Philip Morris, the two companies would have to go back to the drawing board, moving production to the U.S. or changing up the design enough to avoid patent infringement claims.
“Infringement of our intellectual property undermines our ability to invest and innovate and thereby reduce the health impact of our business,” Reynolds American spokesperson Kaelan Hollon said in a statement when the ITC ruled in its favor. “We will therefore defend our IP robustly across the globe.”
Shares of Philip Morris have climbed 12% this year, giving it a market value of $145 billion. Altria’s stock is up 9% in the same time, raising its market value to $83.1 billion.
Conditioning and past experience
Another explanation may lie in conditioning. The color of tablets is a case in point. A 1996 studyTrusted Source found that people associate red, yellow, or orange tablets with stimulant effects and blue or green tablets with sedative effects.
The researchers gave otherwise identical blue tablets to one group and pink to the other. The group taking the blue tablets reported more drowsiness.
And those who have experienced adverse drug effects in the past are more likely to report them after a new treatment.
“I’d definitely say past experiences play a part… You get a list of side effects. People will often look and think, ‘in the past, I’ve been susceptible to this one.’ If people had more awareness, they’d look at that list in a different way.”
– Lee Chambers
One part of the nocebo effect that is a result of neurobiology is nocebo hyperalgesiaTrusted Source, where the expectation of pain increases the pain experienced.
When a person anticipates pain, they release cholecystokininTrusted Source, which allows pain transmission. If that anticipation and anxiety can be reduced, the pain will also be reduced.
Dr. Merrill explained how this happens: “Sensations can be amplified by our brain in feedback loops triggered by fear, which results in amplification of pain and other symptoms. This does not mean the pain is not real, but rather that the pain is primarily signaling fear rather than damage.”
Effect on treatment
The real risk with the nocebo effect is when it affects treatments or drug trials. If a person attributes negative side effects to an effective treatment, they might stop that treatment, losing the benefits along with the side effects. Over-reporting of side effects in a drug trial may mean that the drug does not get licensed.
This can have a real impact on health outcomes, as Lee Chambers outlined: “You don’t want someone to discontinue something that’s beneficial because of these negative effects that they feel they are having because of it. It [the nocebo effect] can increase those reported side effects… and lead to negative health outcomes.”
Some studiesTrusted Source have suggested that reducing information about side effects might reduce the nocebo effect, but there are ethical problems. When asked whether he thought withholding such information could be justified, Dr. Benedetti was clear:
“In general, my answer is NO, it is not justified, but many clinician scientists and bioethicists propose an ‘authorized omission,’ whereby patients sign an informed consent in which it is stated that ‘some pieces of information will be omitted, otherwise the therapeutic outcome could be altered….’. There is a lively debate on this point!”
