A History of Placebos and Their Regulations

From the lecture series: The Science of Mindfulness — A Research-Based Path to Well-Being

By Ronald D. Siegel, PsyD, Harvard University

For over 50 years, doctors have used placebos to cause real effects through fake cures, including pills, acupuncture, and surgeries, just to name a few. How have things changed with review boards and lawyers being involved?

Placebo drugs concept. Doctor holds pills and placebo's.
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Placebos are substances—usually inactive—things like sugar or starch pills, that are given to people with some suggestion that they might help.

The dose-response curve of most placebos is remarkably similar to aspirin, ibuprofen, or acetaminophen. It reaches maximum efficacy in 20 to 30 minutes and then it tends to trail off in its effectiveness after four to six hours.

Which Placebos Work Best?

It turns out that among placebo pills, bigger pills are more effective than smaller pills and two pills tend to be more effective than one pill.

Active placebos are much more effective than passive placebos. An active placebo isn’t just sugar or starch; it’s a medicine that in some way causes some response in the body which is uncomfortable. It’s like giving somebody niacin that will make them flush, or giving them something that will give them a dry mouth—a reaction so that the person can feel a change in the body, even if that change in the body has nothing to do with the purported effect of the placebo.

This is a transcript from the video series The Science of Mindfulness: A Research-Based Path to Well-Being. Watch it now, on The Great Courses Plus.

To be truly effective though, it helps to move beyond pills. Injections tend to be more effective than pills; active injections—injections of substances that change how we feel in the body—are more effective than injections of saline.

The Remarkable Power of Placebos

Examples can help illustrate this point more clearly. One that dates from the 1970s involved treatment for temporomandibular joint disorder (TMJ), a pain that occurs in the joints of the jaw muscles and the jaw joint. It was thought, in the 1960s and the 1970s, that the epidemic of temporomandibular joint problems that were occurring at the time was probably due to the deterioration of the joints. Oral surgeons were busy putting replacement disks into the joint. One solution used Teflon for, for some of them. But the problem was that the Teflon started to deteriorate, creating big problems.

One enterprising group of dentists thought that it wasn’t about the structure of the jaw, but the patient’s attitude toward the TMJ symptoms. They decided to try an intervention called “sham tooth grinding.” What they did was they created a dental instrument about an inch in diameter, and maybe six or eight inches long, that vibrated a lot.

They told patients that they were going to realign their bite and they would put this instrument into the patient’s mouth, and shake, rattle, and roll. They vibrated the jaw for some 40 or 45 minutes, after which they told the patient they had reconstituted or restructured the shape of the patient’s teeth so that they should have a better bite now, and this should resolve the difficulty. Sixty-four percent of the patients who had sham tooth grinding had total or significant relief a year after simply one application of the procedure.

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Solving Angina Pain

Human heart pain as an anatomy medical disease concept
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There was a common surgery that was done for angina pain. Angina pain is pain that comes from partial or greater occlusion of blood vessels in and around the heart, a kind of chest pain. Doctors found that they could do something called “mammary artery ligation” to resolve this with the following surgery: First, they would open up the chest cavity. They made an incision from the collar bone down most of the way to the naval. Then they would saw through the breastbone, retract the rib cage, and tie off the mammary artery, and then sew people back again. The logic behind this was that by tying off the mammary artery, the heart could be induced to grow collateral vessels, like creating a natural bypass.

The procedure often worked well. They had an 80-90% success rate of people recovering from angina pain with the surgery. The only fly in the ointment was that once in a while, someone would subsequently die—not usually from the surgery, but from other causes. Upon autopsy, they never found the collateral vessels. It raised the question: What could be causing the relief from the pain?

One enterprising group of doctors thought to test the procedure more scientifically. They took the next series of patients that came into their hospital, who were appropriate candidates for mammary artery ligation, and they performed most of the surgery as usual.

They did the incision from the collar bone down, sawed through the breastbone, and then retracted the ribcage. But they didn’t touch the heart. They sewed people back up again and informed them that they had had successful mammary artery ligation. They then followed these patients and saw what happened once they healed. Approximately 80-90% success rates—the same success rates that they had with the real mammary artery ligation.

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Ethical Considerations

As a modern person, you may be thinking there’s an ethical problem with this. Indeed, perhaps there was an ethical problem. It’s difficult to find this journal article. It just so happens that the journal article reporting on the surgery was published by The New England Journal of Medicine, published in 1959 without a single mention of ethical issues. The next year, it caused quite a stir. Another team of doctors reproduced the surgery on a new group of patients, also not telling them about it. That was published in The American Journal of Cardiology in 1960.

Legal Considerations

After that, the lawyers got involved. They raised the issue that procedures like this could not be done on people, as they have to be given informed consent. While I’m very sympathetic to that argument, it entered us into the Dark Ages in a sense. How are we to know going forward, when a surgical intervention seemed to be helpful to people and eliminate pain, or reduce pain—how could we know whether it was a placebo effect or the effect of the surgery? Frankly, we couldn’t.

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Full Disclosure

We emerged from the Dark Ages around the year 2000 due to the efforts of a team of enterprising surgeons and researchers at the University of Texas. They came up with a plan by which they could conduct placebo-controlled surgery and get it passed by an institutional review board because it was designed ethically.

They took subjects and they told them in advance that they were going to be randomly distributed to either arthroscopic debridement—making little incisions around the knee to do arthroscopic surgery and smoothing out the structures under the kneecap— and arthroscopic lavage, which meant washing out the structures under the kneecap, or the incisions only. That was the placebo group.

The study was very well done; the surgeons did the surgery, but they never saw the patients again. The researchers followed them in the postoperative period and then over the next two years. The researchers were completely blind to the condition; they had no idea who had had the surgery, and who had not had real surgery but only had placebo interventions.

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This subject said that he was glad to have participated because beginning a week after the surgery, once the incisions healed, he had felt much better, and he’d been free from knee pain for the last two years. He said, “I think the surgeons were top-notch because clearly they cured me. But the researchers, they were very sweet, very nice supportive people, but they weren’t as competent as the surgeons.”

The reporter asked, “What makes you say that?” In reply, he said, “Well, the other day, when they finished the study, the researchers got all confused. They thought I was in the placebo group.”

Everybody improved: Real surgery had no advantage over the placebo at any point during two years following surgery. This is powerful stuff.

Acupuncture and Placebos

Patients undergoing acupuncture on the body
(Image: Leonardo da/Shutterstock)

Let’s look at acupuncture. These effects aren’t simply limited to surgery. In 2005, there were two large, high-quality trials in patients with headache. They found little difference between the effects of acupuncture and placebo acupuncture, but a big difference between placebo acupuncture and no acupuncture at all. It turned out that placebo acupuncture was pretty much as good as real acupuncture.

Then in 2002, there were 131 consecutive lower back pain patients at a university in Germany who were randomly assigned to three groups and each group received active physiotherapy across the whole study. The control group got no further treatment, the second acupuncture group got 20 sessions of traditional acupuncture, and then there was a sham acupuncture group that received 20 sessions of sham acupuncture.

Sham acupuncture is an interesting procedure. They inserted needles, but they placed them in superficially, between 10 and 20 millimeters away from the true acupoints, outside of the meridians. The needles themselves weren’t simulated, as they often are in real acupuncture. They found significant improvement in traditional acupuncture for chronic low back pain compared to the routine care—the physical therapy—but no difference from sham acupuncture. Sham acupuncture worked just as well.

Josephine Briggs—a doctor and the director of the National Institute for Health, the Center for Complementary and Alternative Medicine here in the United States—came concluded that acupuncture is a particularly effective placebo intervention. It’s so well-designed as a whole ritual: It involves breaking of the skin—which we know works better than simply taking pills, it requires time, and the person has a full-body experience when they go in for acupuncture.

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Knowing It’s a Placebo

Perhaps even more remarkably, we now know that placebo intervention works even when people know that they’re getting a placebo intervention.

There’s a center for placebo studies in one of the Harvard teaching hospitals. There, they took 80 patients who were randomized to either open-label placebo pills or they were in the no-treatment control group that got the same quality and type of interaction with the providers, but no placebos. In other words, participants were told the placebo pills are made of an inert substance, like sugar pills; they have been shown in clinical studies to provide significant improvement in irritable bowel syndromes through mind-body self-healing processes. The subjects had irritable bowel syndrome, and they were told the truth, which is that sugar pills do help with this disorder. The people with the open-label placebos had significantly higher global improvement scores on their irritable bowel syndrome symptoms at both the 11-day midpoint of the study, and at the 21-day endpoint.

What was fascinating was that after the study, the patients who were given the placebo pills requested more of the placebo treatment. Researchers told the participants that the pills were inert. The subjects, however, insisted on the placebos as they were the treatment that had improved their symptoms. Understandably, they became upset when the researchers couldn’t provide the pills because various ethical and legal strictures made it so that they weren’t allowed to do it.

Common Questions About Placebos

Q: What makes a placebo work?

Placebos work by playing on a person’s expectations. Although they are chemically inert, they can influence how a person reacts and expects their illness to go. They don’t actually cure an illness, but they do go some way in mitigating the effects of the illness psychologically and perhaps even with dopaminergic help in making a person feel better.

Q: Is a placebo safe?

Generally, placebos are safe, but given the complex physiology of people, there is always a chance of some unforeseen reaction.

Q: Are doctors allowed to prescribe placebos?

Many doctors do prescribe placebos, but it is extremely unethical unless the patient is told that it is a placebo.

Q: Are homeopathic treatments placebo?

No. As with all things medical, some small amount of placebo effect likely exists, but homeopathic treatments have been shown to be effective in peer-reviewed laboratory experiments.

This article was updated on September 26, 2020

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