Open-label placebos may defy logic, but scientists explore promising new treatment possibilities.
“You are the active ingredient.”
So proclaims the chic, sleek website of Zeebo Effect, a South Burlington, Vermont, company that sells elegant light blue and white capsules packaged in stylish silver-capped bottles. The pills are guaranteed to contain absolutely nothing that can alter a consumer’s physiology, but as the ad copy suggests, taking them may nonetheless help remedy a variety of ills. That’s because they’re carefully designed to take advantage of the natural curative process inherent in human beings that’s known as the placebo effect, company founder Uwe Heiss explains in a self-published book available for free download on the website.
People generally know placebos as the inactive faux pharmaceuticals that researchers use for the control group in clinical trials testing the efficacy of new medicines, but placebos can take many forms based on the type of clinical intervention being tested—even including sham surgeries. Often, such trials compare one group of subjects, who receive the genuine experimental drug or surgical intervention, to a second group, the controls, who get an inactive substance or sham surgery that they believe could be the real thing. The power of this belief can be profound: People who swallow the mock meds often respond as if they took the real thing. The placebo effect can be so strong in some clinical trials that it produces bothersome results, masking the effect of the genuine drugs.
Zeebo Effect sells its totally inert capsules as “honest” or “ethical” placebos—frankly inactive, but still potentially capable of producing noticeable improvements in the wellbeing of consumers who take them for a variety of conditions.
Is this a joke?
Definitely not. While the product may strike some people as an exercise in slick marketing to gullible consumers, it in fact represents a commercial application of an idea gaining increasing acceptance in the advancing, but still very far from completely understood, scientific study of the placebo effect.
Making treatments safer
A growing body of evidence shows that placebo effects associated with reduction in pain can allow people to reduce consumption of opioid drugs. Placebos have also proven able to alleviate symptoms of Parkinson’s disease, irritable bowel syndrome, traumatic brain injury, several psychiatric disorders, and other conditions. The research consensus has moved far beyond earlier views of the placebo effect as merely a bothersome source of experimental bias that can distort trial results.
Instead, studies reveal a dynamic process underlying the placebo effect—one that depends not on drugs and their chemical or biological components but on a different kind of “active ingredient.” People often respond positively to the fact that they are receiving treatment in the first place. They find hope, they develop expectations, and they form relationships with their health care providers, all of which can help them heal.
Rather than trying to suppress, ignore, or minimize the forces that underlie the effect, some researchers are now working to understand and potentially harness them for healing and for making some treatments safer. The Society for Interdisciplinary Placebo Studies (SIPS) represents many of those scientists. With nearly 200 members hailing from universities, hospitals, and research institutes across North America, Europe, and Asia, according to its website, it aims to “use multidisciplinary tools (neuroscience, psychology, cognitive science, history, anthropology, and philosophy) to examine the physiological and psychological mechanisms underlying placebo effects, and to develop ethically acceptable methods to harness the placebo effect to improve treatment outcomes.”
Health care practitioners have known that these effects can and do result in improvements of clinical symptoms.
Heiss sees his company’s Zeebo pills as part of this movement. Besides selling the pills—which are officially classified as dietary supplements—online to individual customers, the company also supplies them to scientific institutions for use in research trials.
There are several trials using Zeebo “as an open placebo, an honest placebo” and mentioning it by name, Heiss tells NEO.LIFE. Because of this, he says, the product “now has a track record of having helped people with lower back pain and with anxiety” in studies reported in the journals Pain, American Family Physician, and Nature. The experiments did not explore any properties of the pills, which have no active ingredients and were presented as such to the research subjects who took them, but rather the power of the placebo effect itself.
Heiss, of course, “is biased” by his business interests, says Luana Colloca, a physician-researcher and professor at the medical and nursing schools of the University of Maryland and a member of the steering committee for the Society for Interdisciplinary Placebo Studies. But she adds, “merely ingesting a pill or an injection or having a surgical procedure can activate [an individual’s] endogenous responses.” Even though for many years, “placebo effects have been dismissed and considered a nuisance in trials,” she wrote in a 2019 review article, “clinicians and other health care practitioners have known that these effects can and do result in improvements of clinical symptoms.”
In fact, “as has been documented in the literature,” Colloca says, some providers wishing to satisfy people who seek help for intractable “moderate low-impact symptoms” knowingly prescribe in place of placebos real pharmaceuticals, including antibiotics and vitamins. They understand these will have no effect against the conditions in question. Such prescribing can carry significant risks, including needlessly exposing people to side effects and, in the case of misused antibiotics, fostering drug resistance.
But this is not the only thing that makes such use unacceptable, she says. More fundamentally, deceiving patients violates the ethical requirement to respect their autonomy, values, and preferences. So the best strategy is to tell them honestly that nobody expects the placebo to cause improvement based on its pharmacological properties. Instead, it can potentially activate their own endogenous processes.
That idea, Colloca says, is “becoming very popular in the literature.”
Also increasingly prominent is evidence of open placebos related to improvement in the symptoms of a number of conditions. A July 2020 study looked at “non-deceptive placebos” presented openly as inactive. Led by researchers at the University of Michigan, the study found that placebos reduced both subjects’ self-reported feelings of emotional distress and an objective metric called the late positive potential, an EEG-measured neural biomarker used to gauge emotional distress.
This finding provides support for the “genuine psychobiological effects” of non-deceptive placebos, writes Darwin Guevarra, formerly of Michigan and now a postdoctoral researcher at Michigan State University and his co-authors in Nature Communications last year. Colloca also points to what she calls clear evidence of the ability of placebos to reduce pain and other symptoms, as well as release such brain chemicals as dopamine, serotonin, endogenous cannabinoids, and opioids.
Emotional distress is exactly the sort of condition where this could happen. Placebos work, Colloca notes, only for conscious symptoms where the person has the ability to perceive an improvement.
“For example, if I tell you that your pain may improve, your rigidity may improve, your tremor may improve, you know exactly what I mean,” Colloca says. “[But not] if I tell you your cortisol level will improve.”
Because “cognitive processes that are behind the placebo effect definitively play a role,” she says, placebos cannot affect imperceptible phenomena “like the size of a cancer or the count of the white cells in the blood.” Placebos would thus be inappropriate as a treatment for underlying disease processes that are out of the reach of consciousness, and because of such limitations to placebos’ power, she warns, we need to be clear about what they can and cannot do. “[And] we need to be very cautious when we convey messages to society,” she says.
Still, interest in harnessing this power to modulate the symptoms that can respond is growing among doctors seeking ways to use placebos in treatment, Heiss says.
J. Leon Morales-Quezada, a physician and researcher at Spaulding Rehabilitation Hospital in Boston, for instance, sees open placebos as a potential means of curbing the crisis of opioid use. “We are using placebo as treatment inside a clinical trial” aiming to help reduce the amount of opioids that pain patients need, he says. In a small pilot study, his team conditioned people to take pills openly presented as placebo along with opioids prescribed for their pain. After a set period, they stopped getting the drug and received only placebo. Compared to a control group who received only regular treatment throughout, the placebo group decreased their opioid consumption by 56 percent, Morales-Quezada says, and “more important,” the two groups experienced “similar” levels of pain control.
“We haven’t said placebo is going to be superior in pain control to opioids,” he adds, but that it can “help to decrease opioids while maintaining the same level” of pain relief, thus cutting down on soporific side effects, overdoses, and addiction risk. With preliminary data showing placebos can do exactly that, he and colleagues are now beginning to test the proposition in a larger clinical trial supported by the U.S. National Institute on Drug Abuse, one of the National Institutes of Health. He hopes that, if confirmed, this work could eventually provide doctors a viable “alternative option” to current prescribing practices. Heiss even foresees “a no-risk, win-win situation” in which doctors could one day give placebos before prescribing drugs to see if symptoms improve without medications and their attendant risks.
Greater than the sum of your pills
The code of ethics of the American Medical Association states, “the use of placebo, when consistent with good medical care, is distinct from interventions that lack scientific foundation.” Such use “may be effective” as well as ethical if given with the patient’s cooperation and consent and never “merely to mollify a difficult patient.”
Evidence-based medicine needs to take into account the magnitude of placebo responses.
Understanding the power of placebos can also impact health care through growing efforts to rethink clinical trial design. The traditional clinical trial essentially assumes that the effects of placebo and active drugs add up to 100 percent of the effects observed in experiments. Scientists have thus generally evaluated treatments by subtracting the effects observed for the presumably inert placebo control from the effects observed for the active experimental drug. The difference, they assumed, equals the effect of the drug alone. The size of placebo effects can vary among individuals, conditions, and experimental factors. Though this assumption has never been proven, it has been a feature of modern drug trials, “since their introduction in the 1940s,” writes Karen Lund of Arhus University in Denmark and her co-authors in the journal PLOS ONE.
But in recent years, some patient advocates and researchers have increasingly suspected that this traditional assumption is not true. A growing body of evidence shows that the effect of any given drug could be larger than the difference between the treatment group and the control group, “particularly in studies where the placebo response is large,” Lund and her co-authors write. Therefore randomized clinical trials “are likely to underestimate the drug’s effect,” and this could lead to failed clinical trials and the rejection of effective treatments. The upshot? “Until we are able to understand and control for placebo responses and improve trial designs,” Lund and her co-authors add, “evidence-based medicine needs to take into account the magnitude of placebo responses.”
Thus, a more precise understanding of the placebo effect could, paradoxically, lead to approval of larger numbers of effective treatments.
“Patients could be helped more if we were skillful in soliciting the placebo effect,” Heiss says. “There’s a beautiful new opportunity here.”
Editor’s note: This story was updated on 10/15/21 to reflect the correct spelling of a person’s name in the first paragraph.