People who claim to have been cured or aided by unconventional approaches often owe their success to what's known as the placebo effect, a remarkable phenomenon in which a fake treatment—an inactive substance such as distilled water, sugar, or a saline solution—can sometimes improve a patient’s condition simply because the person expects or believes that it will be helpful. Contrary to how many people view the placebo effect, it’s not casual mind over matter. Neither is it mind-body medicine. The placebo effect has become a catchall term for a positive change in health that cannot be credited to medication or treatment. This change can be due to many things, from spontaneous improvement and reduction of stress, to misdiagnosis, classical conditioning, or for reasons we have yet to understand scientifically. Likewise, the placebo effect is an intense area of study today. We know that complex neuronal circuitry that can involve our emotions, hormones, neurotransmitters, and memory gives rise to these effects.
The placebo effect has existed since we first roamed the earth. In the eighteenth century, physicians regularly administered inert pills when they had no real drug in their arsenal. By the latter half of the nineteenth century, the medical community began viewing disease in purely chemical and physical terms, so by 1900 placebos fell out of favor as therapy. That is, until the curious case of Mr. Wright sparked new interest in the phenomenon and inspired a new era of exploration of the science of the effect, which continues to this day.
In the mid-1950s, a man who doctors called Mr. Wright was dying from lymphoma—cancer of the lymph nodes, which are an important part of the immune system. His neck, groin, chest, and abdomen were riddled with tumors the size of baseballs. The doctors had tried everything to no avail. Mind you, at this time medicine had little for treating cancer, unlike today, when powerful chemotherapies can dramatically improve the life and longevity of many cancer patients. According to a 1957 report by psychologist Bruno Klopfer, who worked at UCLA, Mr. Wright was optimistic that a new anticancer drug called Krebiozen would save him. He was already bedridden and struggling to breathe when he received his first injection of the drug. Three days later he was walking around and joking with the nurses. The tumors had shrunk by half, and after ten more days of treatment the hospital discharged him. But the other lymphoma patients in the hospital who also received Krebiozen showed no improvement.
That would have made a great, albeit somewhat unbelievable, story if it ended there. But over the next two months, Mr. Wright read press reports questioning the efficacy of Krebiozen. He grew concerned and then his cancer returned. What did his doctors do? They lied to him. They told him an improved, doubly effective version of the drug was arriving the next day. To say Mr. Wright was thrilled is an understatement. When the “medicine” arrived, the doctors gave him an injection; it did not contain any Krebiozen, but Mr. Wright vastly improved. He improved more so than the first time and walked out of the hospital symptom-free. Once again, however, reports about Krebiozen’s uselessness emerged, and after two months of being healthy, Mr. Wright died within days of reading the bad news.
Mr. Wright’s experience shows pointedly that a person’s expectations and beliefs can mightily a effect the course of an illness. But how do we explain this from a biological standpoint? What causes this to happen in a body? For it can’t be just psychological factors tied to an inactive substance, can it? What’s really going on?
Studies over the past several decades repeatedly show the efficacy of such sham treatments. Placebos can not only help alleviate ailments with a psychological component, such as pain, depression, and anxiety, but also lessen the symptoms of bona de physical illnesses such as inflammatory disorders and Parkinson’s disease. Occasionally, as in Mr. Wright’s case, placebos have led to tumor shrinkage.
Some of the latest research has demonstrated that the placebo effect does not always come from a conscious belief in a drug. It can come from subconscious associations between recovery and the experience of being treated, from the feeling of getting a shot to a doctor’s white coat and smell of an exam room. Which is how some people can experience the benefits of the placebo effect without necessarily believing in the treatment itself. That’s right. Even if you know that you are receiving a placebo, also known as a sugar pill, you can still reap the benefits of the placebo effect. While this won’t work for all illnesses, it can work for many illnesses that are symptom based, such as headaches, irritable bowel syndrome, or anxiety. Such subliminal conditioning can control physiology, including the release of hormones and immune responses. Some of the most remarkable research to highlight the biology of the placebo effect has come from studying rats—animals that clearly cannot harbor beliefs about whether a certain drug will work.
Researchers have unraveled some of the biology of placebo responses, showing that they stem from active processes in the brain. One team of researchers, for example, conditioned rats by injecting them with the drug cyclosporine A—which suppresses the immune system and is used to prevent transplanted organs from being rejected by the body—while also feeding the rats water sweetened with the artificial sugar saccharin. The rats apparently associated the cyclosporine with the sweet drink, so that, later, feeding them the drink alone led their immune systems to partially shut down. The scientists hypothesized that the rats’ brains sent messages to the immune system upon drinking the sweet water. Mind you, unlike humans, rats cannot consciously believe the drink is therapeutic, so some unconscious, associative learning causes these effects. Translation: A placebo effect does not hinge on a person’s hoping for or believing in a positive outcome.
Plenty of research has also been performed on humans to help make sense of the brain biology and active brain processes that take place. For instance, in people with Parkinson’s disease, use of placebos has been shown to increase dopamine binding in certain regions of the brain. The level of dopamine binding is correlated with the patient’s perceived improvement in their outcomes. Other studies have further revealed that placebos have the power to increase neuronal ring in certain areas of the brain associated with Parkinson’s disease and that these effects are correlated with improved motor performance. (Parkinson’s disease is a to-date incurable progressive disorder of the nervous system that affects movement and can eventually render someone immobile.)
In psychiatry, the term flight into health is tossed around a lot and is similar to the placebo effect. Flight into health is said to occur when an individual seems to make a spontaneous recovery when faced with the prospect of therapy or of addressing particular issues. So, for example, people complaining of depression may suddenly pronounce themselves well upon leaving the therapist’s office after just one visit. In some cases, the mere act of making the appointment will ease one’s depression a bit.
We still have a lot to learn about the neurobiology of the placebo effect. No single pathway describes and defines the placebo effect in all scenarios. The placebo effect is not a definitive outcome in each case that’s universal. It’s fluid, ever changing, and dependent upon context— much like headaches. Headaches are all different, experienced differently in each individual, and are probably the outcome of unique biological pathways under disparate circumstances. But one thing is true: The placebo effect is real, so people such as Mesmer (who was unknowingly working with it) can’t be all that bad if positive results are experienced in the absence of other authentic remedies. No doubt future research will eventually allow us to understand how a placebo-like effect can be leveraged for therapeutic purposes. It was just recently learned, in 2014, that the more invasive the procedure, the more significant the placebo effect—more so than medications.
To quote Ted J. Kaptchuk and Franklin G. Miller in The New England Journal of Medicine:
Medicine has used placebos as a methodologic tool to challenge, debunk, and discard ineffective and harmful treatments. But placebo effects are another story; they are not bogus. With proper controls for spontaneous remission and regression to the mean, placebo studies use placebos to elucidate and quantify the clinical, psychological, and biologic effects of immersion in a clinical environment. In other words, research on placebo effects can help explain mechanistically how clinicians can be therapeutic agents in the ways they relate to their patients in connection with, and separate from, providing effective treatment interventions. Of course, placebo effects are modest as compared with the impressive results achieved by lifesaving surgery and powerful, well-targeted medications. Yet we believe such effects are at the core of what makes medicine a healing profession.
I have had firsthand experience with a type of “reverse” placebo effect. Or, maybe it was showing that medicine isn’t always the answer, but a placebo certainly can be. Surgeons and anesthesiologists are always trying to find ways to minimize emergence agitation, which is the absolute misery and dysphoria that at least 50 percent of six-month- to six-year-olds experience after a brief surgery and anesthesia—even if the surgery is as quick as ninety seconds. Especially in infants, it’s hard to tell if it’s pain or just delirium. Usually it’s a combination of both.
We recently did a study at UCLA to see if giving oral acetaminophen (Tylenol) twenty minutes before ear-tube surgery would reduce emergence agitation (assuming that the child was, in part, in pain from the ear surgery). We had three groups—a placebo group, where the child received a nonmedicated syrup; a low-dose Tylenol group; and a high-dose Tylenol group. Who fared the worst? With worse pain, more emergence agitation, and irritability? The high-dose Tylenol group!
The low-dose Tylenol and placebo group fared about equally. The implications of these findings remain unclear. Perhaps the high-dose group had more stomach discomfort from more volume of medicine in their system; more likely, the higher level of agitation in the high-dose group was not due simply to chance—some children wake up more agitated than others, low-dose Tylenol, high-dose Tylenol, or no Tylenol at all.
I often also see placebo effects in the sidebar consults I get from family members of patients: “I’m doing a triathlon in seventeen days, and I think I have a sinus infection. Can you take a quick look?” They are already sitting in the exam chair of my office, their child on their lap, so I do what so many doctors swear they never will—I examine the family member, albeit cursorily. After a quick check, I often reply, “It’s just a cold—rest a bit, drink a lot of fluids, and you’ll be fine. You definitely don’t need antibiotics.” I swear I see an extra lift in their steps as they leave my office. Did my saying that they were not really sick make them better? Perhaps, in part, it did.
This article is excerpted in a modified format from Hype: A Doctor's Guide to Medical Myths, Exaggerated Claims, and Bad Advice—How to Tell What's Real and What's Not by Nina Shapiro, MD.
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