I came across a “science-based” blog written by an academic physician affiliated with an Ivy League medical school. I saw that he’d written an article about the placebo with the word “myths” in the title, and I thought, this should be interesting. It turned out to be interesting, but not for the reasons I thought it would be. I was surprised by the amount of misinformation in his blog post, which inspired me to write this article.
The author’s opening statement “Placebo effects are largely misunderstood, even by professionals, and this leads to a lot of sloppy thinking…” is ironic because that statement accurately describes his article. His blog post seems to be a diatribe against complementary and alternative medicine (CAM) masquerading as false accusations about the placebo effect.
The author attempts to discredit the power of the placebo effect by saying it is due to several phenomena found in all clinical trials. These phenomena include spontaneous remission, bias, co-interventions, regression to the mean, and signal detection ambiguity. He is correct in that the presence of these phenomena in a clinical study may be the reason some patients seem to get better while on a placebo, he’s wrong in that they have nothing to do with the real placebo effect. Let me explain why.
Classical clinical trials are very poor for understanding the placebo effect because of the existence of these phenomena, but researchers who understand the placebo effect know how to control for them to tease out the real psychophysiological placebo effect.
You control for spontaneous remission by adding a no-treatment group, for regression to the mean by careful selection of variables being studied, for signal detection ambiguity by choosing objective instead of subjective measurements, for bias by the careful blinding of subjects and researchers, and for co-interventions by a more careful design of the clinical trial.
Once you adequately control for these variables, the real placebo effect emerges, which involves genetics, expectation, learning; and reproducible changes in the brain, neurotransmitters, and hormones.
Image courtesy of Benedetti F, Carlino E, Pollo A. How placebos change the patient’s brain. Neuropsychopharmacology. 2011;36(1):339–54.
Let’s take a look at the author’s “myths” about the placebo, some of which are blatantly untrue.
“Myth #1 — “The” placebo effect.”
He gets it right in that there is not a single placebo effect but many. What he gets wrong is defining these many placebo effects as the various non-psychophysiological variables that must be controlled for to determine the real placebo effect. The “many placebo effects” concept has nothing to do with spontaneous remission, bias, or regression to the mean.
These many placebo effects have to do with the various biological mechanisms involving different body systems that are triggered by the psychosocial contexts surrounding therapy. Expectation plays a role through a reduction in anxiety and activation of reward circuits in the brain. Learning plays a role through conditioning involving reproducible changes in the endocrine and immune systems.
Expectation is a major player in the placebo’s ability to decrease pain as demonstrated by the reduced effectiveness of painkillers when they are administered covertly. The pain-killing effect of the placebo is mediated by the body’s opioid and cannabinoid systems and is antagonized by naloxone and cholecystokinin. Brain imaging studies show there are several distinct areas involved in placebo pain reduction, including those involved with dopaminergic reward mechanisms.
One of the world’s leading placebo effect researchers, Fabrizio Benedetti, M.D., says, “There is not a single placebo effect but many. Therefore, different systems and apparatuses as well as different diseases and treatments are affected by placebos in different ways.”(1)
“Myth #2 — Placebo effects can cause healing”
The author says placebos cannot cause healing. Healing occurs on many levels — physical, emotional, and spiritual. How someone heals versus how someone is cured is like comparing apples to oranges. Healing implies some type of improvement whereas curing implies a cure or resolution of disease.
What I think the author is trying to say is that no one is cured by a placebo. He then uses an an example that you can’t cure cancer with a placebo. He’s correct in that there’s no clinical proof of this, but science also doesn’t know how to study the spontaneous remission of cancer.
Science can’t explain how someone with incurable stage 4 cancer can have their cancer completely regress and be cured without ever having been treated by traditional chemotherapy or radiation. There are several cases of unexplained spontaneous remission of various types of cancers documented in the medical literature.(2,3) Do we know for certain that mechanisms involving the placebo effect played no role in these miracle cures? No.
The placebo effect is a part every therapeutic encounter regardless of whether a placebo is used in that encounter. This is because simply trusting a healthcare practitioner or feeling supported by one can positively influence the outcome of someone’s illness. That’s because belief, expectation, and a reduction in anxiety are all players in the initiation of the physiologic mechanisms involved in the real placebo effect. In addition, the words a healthcare provider uses in a therapeutic encounter can have a powerful influence on the patient in a positive (placebo) or a negative (nocebo) way.
Just because we don’t know how to adequately study whether someone can be cured by a placebo doesn’t mean it can’t happen. By its very definition, the placebo induces clinical improvement, which reflects that some type of healing is taking place.
“Myth #3 — Animals and babies cannot have a placebo effect”
From a purely scientific standpoint, we’ll never know if babies experience a placebo effect because it’s unethical to do placebo studies on babies. So he was safe on that one:-) But from a common sense standpoint, he’s incorrect.
Placebo effect researchers have repeatedly proven that adult humans experience real placebo effects, so it’s only a biased imagination that says real placebo effects can’t occur in babies. Babies are humans and all humans can be conditioned, which is one of the mechanisms involved in the real placebo effect.(7)
A review of the scientific literature shows that animals do experience placebo effects. A randomized double-blind clinical trial was performed on dogs with clinically proven osteoarthritis to test the effectiveness of the non-steroidal anti-inflammatory drug carprofen. Fifty-six percent of the dogs had a positive objective response to placebo, which was surprisingly higher than the subjective improvement reported by dog owners and veterinarians in the study.(8)
In a clinical study published in 1975, rats were conditioned over three days with saccharin-flavored water (placebo) paired with cyclophosphamide, an immunosuppressant. Their suppressed immune systems were allowed to recover and then they were given only the saccharin-flavored water (placebo). Testing then showed that conditioned rats given only the placebo were immunosuppressed as if they had also been given cyclophosphamide.(9)
The saccharin-flavored water (placebo), was able to suppress their immune systems because they had been previously conditioned by the distinctly flavored water paired with cyclophosphamide. Conditioning, or learning by association, is a well-known mechanism of the real placebo effect and occurs in both humans and animals.
Several years later, the same researcher published a similar conditioning study on mice genetically predisposed to develop systemic lupus erythematosus (SLE). It showed the development of SLE was significantly delayed in the mice conditionally immunosuppressed.(9) Researchers concluded that this is “definitive evidence that a pharmacologically inactive conditioned stimulus — a placebo treatment — can exert a substantial and positive therapeutic influence on the course and outcome of a disease state in animals.”(10)
“Myth #4 — Fanciful or alternative treatments yield better placebo effects”
In the discussion of this “myth,” the author labels alternative medicine treatments as deceptive pseudoscientific therapies. He also states that many alternative medicine practitioners say that their expertise lies in maximizing the placebo effect. Is this derogatory stereotyping?
Anyway, I kind of wish he’d have stuck to the “fanciful” concept as there’s evidence that the more fanciful or extravagant the therapy appears to a patient, the more powerful the placebo effect. For instance, expensive placebos work better than cheap placebos in Parkinson’s disease, placebo injections work better for osteoarthritis of the knee than placebo pills, and brand name placebos work better than generic placebos for pain.(11,12,13)
In the end, it’s my hope that more physicians, especially those in teaching institutions, will become better educated about the mechanisms and implications of the real placebo effects. Studying the real placebo effects offers valuable insight into the mysterious and often powerful mind-body connection. As Dr. Benedetti puts it, “it would be useful to consider the placebo effect as an experimental approach to analyze how a complex mental activity interacts with the neuronal circuitry of the brain.”
Real placebo effects induce reproducible psychophysiologic effects in the body and are a part of every traditional and alternative medicine therapeutic encounter. A better understanding of placebos has the potential to improve the way pharmaceutical companies develop new medical therapies and the way healthcare providers deliver care.
More research to better delineate the mechanisms behind the placebo effect may result in the development of ways to improve their effectiveness, as well as understand their limitations, depending on the context in which they are used.
1.Benedetti F. Placebo Effects, Understanding the Mechanisms in Health and Disease. Oxford University Press; 2009.
2. Ogawa R, Watanabe H, Yazaki K, et al. Lung cancer with spontaneous regression of primary and metastatic sites: A case report. Oncol Lett. 2015;10(1):550–552.
3. Shimizu H, Kochi M, Kaiga T, Mihara Y, Fujii M, Takayama T. A case of spontaneous regression of advanced colon cancer. Anticancer Res. 2010;30(6):2351–3.
4. Goebel MU, Trebst AE, Steiner J, et al. Behavioral conditioning of immunosuppression is possible in humans. FASEB J. 2002;16(14):1869–73.
5. Vasseur PB, Johnson AL, Budsberg SC, et al. Randomized, controlled trial of the efficacy of carprofen, a nonsteroidal anti-inflammatory drug, in the treatment of osteoarthritis in dogs. J Am Vet Med Assoc. 1995;206(6):807–11.
6. Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science. 1982;215(4539):1534–6.
7. Mcmillan FD. The placebo effect in animals. J Am Vet Med Assoc. 1999;215(7):992–9.
8. Kelley JM. Placebo effect of medication cost in Parkinson disease: a randomized double-blind study. Neurology. 2015;85(8):742–3.
9. Bannuru RR, Mcalindon TE, Sullivan MC, Wong JB, Kent DM, Schmid CH. Effectiveness and Implications of Alternative Placebo Treatments: A Systematic Review and Network Meta-analysis of Osteoarthritis Trials. Ann Intern Med. 2015;163(5):365–72.
10. Fehse K, Maikowski L, Simmank F, Gutyrchik E, Meissner K. Placebo Responses to Original vs. Generic ASA Brands During Exposure to Noxious Heat: A Pilot fMRI Study of Neurofunctional Correlates. Pain Med. 2015;16(10):1967–74.