For decades, the placebo effect — the phenomenon where a patient’s condition improves after receiving an inert treatment, often a sugar pill, because they believe it to be real medication — has fascinated and sometimes confounded the medical community. But what happens when you remove the deception and tell patients outright that they are receiving a placebo?
A lot, it turns out.
For a long time, scientists assumed telling patients they were getting a placebo would reduce the effect because the patients wouldn’t think they could be getting the actual treatment in a randomized trial. Surprisingly, a growing body of research suggests that these “open-label placebos” can still lead to positive health outcomes, and many past studies of open-label placebos give patients an explanation of why they might work.
A new study, published in BMJ Evidence-Based Medicine, showed that this explanation is important — and even beneficial.
Maximizing the Placebo Effect
The study tested open-label placebos for premenstrual syndrome (PMS) — the physical and emotional symptoms that many people with a menstrual cycle experience in the days or weeks leading up to their period, which can include moodiness, fatigue, and irritability.
The study enrolled 150 participants and assigned them to one of three groups: A no-treatment control, a placebo group receiving no explanation, and a placebo group where participants were informed about the demonstrated effectiveness of placebos for PMS in prior research. (Participants in all groups could continue their usual medications, with the exception of those taking psychopharmacological drugs, who were excluded.)
The research found a significant improvement in PMS symptoms in the placebo group that received an explanation about placebo effects.
The explanation took about 15 minutes, said Antje Frey Nascimento, PhD, a professor of psychology at the University of Basel in Basel, Switzerland, who led the study. It included that “placebos are powerful, that placebo effects are prevalent in PMS, that placebo effects work somehow automatically.”
She added that they told participants about the conditioning process by which placebos might work — since childhood you connect taking a pill with some alleviation of symptoms, so when you take a placebo for PMS, it might also improve symptoms.
All participants tracked their PMS symptoms across three menstrual cycles. During that time, those randomly assigned to the placebo groups received pills to take twice daily for 6 weeks.
Getting a placebo accompanied by a clear explanation led to a 79.3% reduction in symptom intensity and an 82.5% decrease in how much those symptoms interfered with their lives. Those who received a placebo without explanation reported a 50.4% decrease in symptom intensity and a 50.3% drop in life interference. Those with no additional treatment had a 33% reduction in symptom intensity and a 45.7% decrease in life interference.
The sizable reduction even in the no-treatment group could be a result of keeping a symptom diary, Nascimento explained, or the Hawthorne effect, a psychological phenomenon in which individuals alter their behavior due to their awareness of being observed. However, the placebo with explanation led to significantly better PMS symptom management than no treatment or placebo without explanation.
“We picked PMS because it’s really prevalent and it’s really understudied,” said Nascimento. She also said placebos have a significant effect in PMS intervention trials, accounting for 40% of the observed benefits. Furthermore, she pointed out common treatments — SSRIs [selective serotonin reuptake inhibitors] (antidepressants) and hormonal birth control pills — have side effects. Placebos have none.
‘Open-Label’ Placebo Power — What Do We Really Know?
A large body of evidence shows placebos can lead to measurable changes in the brain, particularly MRI studies showing placebos lead to widespread reductions in pain-related brain activity. PET imaging has also shown that placebos can increase dopamine and opioids in the brain, brain chemicals linked to positive experiences and reduced discomfort.
Placebos have long been a “nuisance” for pharmaceutical companies, said Luana Colloca, MD, PhD, a professor of pain and translational symptoms at the University of Maryland, Baltimore. She explained that every time a clinical trial tries to evaluate a treatment, especially in pain medicine, the placebo has a sizable effect. But those effects generally come in “deceptive” placebo trials, in which participants don’t know they’re getting a placebo.
The idea of testing placebos when people are fully aware they’re receiving them is a relatively new frontier in research.
Open-label placebos were first studied in 1965, but that study was criticized because it involved people who had mental disorders and might not have understood what they were consenting to, explained Colloca.
The idea of openly administered placebos remained largely unexamined until a pivotal 2008 study indicated they could decrease attention-deficit/hyperactivity disorder medication reliance in children. Then a 2010 study revealed significant effects of open-label placebos for irritable bowel syndrome (IBS).
The researchers in the IBS study provided a specific explanation to patients receiving placebos, telling them that: “Placebo pills, something like sugar pills, have been shown in rigorous clinical testing to produce significant mind-body self-healing processes.” The potential importance of this explanation, however, had not been a primary focus of research prior to this.
“In reality, we still don’t know why the act of taking a pill, even if you don’t believe in the medication’s therapeutic effect, can trigger a benefit. So I love this study because they try to understand the mechanisms,” said Colloca, who was not involved in the study. She noted that “the rationale can help to somehow maintain an expectation of relief.”
Since 2008, open-label placebos have shown at least some modest benefit for various types of pain, cancer-related fatigue, allergic rhinitis, major depression, and menopausal hot flashes, among others.
But even though placebos can be beneficial, “we are still far away from having a mechanism to introduce this in clinical practice,” Colloca said, at least in the United States. As far as she is aware, she said Germany is the only country with a mechanism for providers to give placebos.
In Germany, near where she lives, Nascimento said it’s possible to get placebos at a pharmacy, and they come in many colors and shapes.
Colloca said that the United States should be working on ways to make giving placebos a possibility — “it is a little bit outside the box, and so it’s a matter of engaging regulatory entities like the FDA [US Food and Drug Administration].”
And for PMS, Colloca wonders, “if women improve with placebo, why do we need to expose them to medications that can somehow have side effects?”