It was a year and counting since the pain in my right wrist had taken me down that slippery slope from Advil to codeine. “Carpal tunnel syndrome” proclaimed my primary care physician. And with that I joined the intrepid bench scientists and computer programmers with telltale beige wrist braces who despite the pain of every click, kept pipetting, kept coding. I was working in the pharmaceutical industry at the time and although I didn’t get addicted to the array of pain meds on my bedside stand, they did make it hard to concentrate. Only when I arrived at what was for me the last resort, surgery, was I willing to abdicate the logic of relief. The incision in my transverse carpal ligament recommended by the surgeon made sense, but it was so permanent. As my colleague who was disappointed in his surgery observed, positive results were no guarantee.
I was in pain, I was exhausted, I had nothing to lose. I called the number of the acupuncturist that my old friend, who had a black belt in aikido, had emailed me months ago, with the words “Just try it!!!” punctuated by three exclamation points.
Sitting in the waiting room of the acupuncturist, I studied what looked like subway maps on the human body. The stations had strange names like TW14 or L11. A strong smoky smell created a peculiar mix of curiosity and inertia that kept me sitting there long enough for a small woman to emerge from a bloodred door and usher me in. She began by asking me what I ate and what I did for exercise. Then she asked to look at my tongue. “Mmm, mhmm,” she nodded as she peered into my mouth. “Lie down,” she motioned brusquely to the massage table. The dull-orange sheet was pilled but looked clean. I hesitantly reclined. Taking my hand in hers, she placed her fingers delicately on my pulse, continuing her soft affirmations. Whatever she was learning from my pulse was most certainly flawed by my growing discomfort. Suddenly she reached away from the table, and in one fluid motion swung around and stuck a needle into my fingertip. Then another and another. It was ridiculous and intriguing. The thought of it hurt, but I hardly felt a thing; I was pinned.
Just as I was getting accustomed to this thing called acupuncture, she asked me to turn on my side and then she got up on the table. The shock of her hovering over me was no match for the pain that was about to come. She measured the back of my upper arm in finger lengths, and then finding a region around the middle, she palpated in closing circles till she found what she was looking for and again without notice, stuck in the needle. The burning was immediate and hot. “Aaahhh!” A sound both guttural and high-pitched, dragged from me involuntarily as the pain of the past year gathered together to make one last point. She twisted the needle, and another wave of heat and burn fired up and out my arm. As she made her way off the table, I was momentarily distracted by her descent. She was an older woman, of small stature, and very nimble. When I returned my focus to the matter at hand, I felt for the familiar pain in my wrist. It was gone. A year’s struggle, gone. I searched my arm, my elbow, my wrist for the pain. Nothing.
She deftly placed several more needles across my body, now supine, and left me alone for some twenty minutes. Laying there I got used to the needles, some stuck in those same subway stops I had studied in the waiting room. Just as I was drifting off, she reappeared, rattling off a series of stern instructions. “Drink a lot more water, especially today,” she said, casually pulling out needles from across my body. “Eat no red meat, do not drink alcohol, take a teaspoon of apple cider vinegar and honey every day.” She wrapped her thin left hand over her right arm and pressed on a point at the center of the back of her arm. “If the pain returns, just rub this spot on the back of your arm, right here.” She motioned for me to get up off the table. “OK, come back in two weeks.” And with these few precepts, she showed me out the red door.
Returning to the safety of my car, I glanced at the discarded beige wrist support, waiting patiently on the passenger seat. I wriggled my fingers, flexed, and then rotated my wrist. Still nothing, no pain. Deeply relieved and totally perplexed, I drove back to work that afternoon. I was an associate director of drug development at a biopharmaceutical company. I was headed back to the heart of biotech in Cambridge, Massachusetts. Over the years, when the pain in my wrist would return, I massaged that same spot, and sure enough, the pain would dissipate. I would contemplate the how and why of that clinical encounter for years to come. Why did that work? Was it the power of acupuncture or just a placebo effect?
Acupuncture is an ancient healing tradition. Honed over centuries, the theories behind acupuncture are complex and elegant. Of the complementary and alternative medicines, now termed integrative medicine, studied in the United States, acupuncture has demonstrated the greatest efficacy in treating pain. Sham acupuncture can also elicit strong placebo responses. Sham acupuncture needles are designed like a trick sword; instead of the needle penetrating the skin, it disappears into a shaft. Clinical trials of acupuncture often find similar effects between acupuncture performed with real needles compared to placebo or sham needles.1
Placebos, like sham acupuncture needles, are inert simulacra of active drugs, devices, or other treatments. However inert a treatment may be, placebos and their administration can have striking ameliorative properties. When the administration of inert treatment leads to a clinical benefit, it is called a placebo effect. Even though the placebo interventions themselves have no biological qualities that would induce a physiological change, placebo effects can be long-lasting and are at times competitive with the clinical benefits of active treatments. Herein lies the placebo’s paradox, which has puzzled and provoked researchers and clinicians for centuries—that is, until the underlying mechanisms began to emerge.
Acupuncture is not alone in inducing a robust placebo response. The administration of the placebo form of many Western therapies and even surgery can bring about powerful placebo effects. In fact, pharmaceutical drug development, particularly the development of novel drugs in neurological and psychological disease areas, is finding it increasingly difficult to demonstrate efficacy beyond that of a placebo. And it’s not just drugs; some sham surgeries were found to be as beneficial as the well-established surgical procedures they were being compared to. Why does this happen? And importantly, what does this mean for medicine, especially Western medicine, and healing in the present day? Does the placebo effect tell us something about how human beings heal? And therefore how we, as scientists and clinicians, approach our research and patients?
This book is not about whether acupuncture, Western medicine, or surgery works. It is about neurobiological mechanisms that influence almost every clinical encounter we engage in, regardless of whether the treatment is active or inert. Throughout this book, we learn of the power of these underlying mechanisms, and my goal is to examine the intentional and unintentional uses of placebos in the past and present, and how they have benefited or harmed people whose lives they touched.
The word placebo comes from the Latin “I shall please” and was used to describe hired mourners in the fourteenth century who were paid to simulate mourning at the funerals of those who could afford it.2 These hired mourners were nicknamed placebos after their characteristic chant “Placebo Domino in regione vivorum,” I will please the Lord in the land of the living. In this early iteration of the placebo, these mourners aided the process of grieving, giving permission to those in attendance to give way to whatever emotions might need catharsis. Even though placebos functioned to support a psychological process necessary to the human psyche, they were considered to be fake and negatively associated with death. Geoffrey Chaucer reinforced this negative connotation by naming the sycophant in the Merchant’s Tale Placebo.
Despite these negative undertones, placebos would make their way into medical vernacular through the writings of William Cullen, one of the most influential physicians in the eighteenth century. This is where I pick up the story of placebos in chapter 1, “Placebos: A Brief History.” In this chapter, I examine how placebos were ensnared by quackery and patent medicine, and emerged as controls in clinical trials.
Patent or proprietary medicines were remedies marketed and sold directly to consumers without any regulatory approval. The most powerful attribute of these nostrums was not their contents, which were often inert and at times harmful, but instead their trademarked names. From “Mrs. Winslow’s Soothing Syrup” and “Dr. Sawen’s Magic Nervine Pills” to “Lydia E. Pinkham’s Vegetable Compound” and “Dr. J. W. Coblenz’s No. 1 Tonic,” there was a patent medicine for just about everything. The power of a trademark, and information to drive the experience and perceived benefit of a treatment, was not lost in the development of modern-day drug manufacturers that continue to shape expectations of the clinical benefits through the packaging, names, and advertisements of therapies.3
Our expectations are informed by our personal experience, the observed experiences of others, and cues and symbols, through which associative learning or conditioning can guide our expectations for a given outcome. Expectations and associative learning are critical drivers of a response to placebos, and I explore their effects in chapter 2, “How Expectations and Conditioning Shape Placebo Effects.”
The idea that inert, sham, or placebo interventions can induce neurobiological effects that in turn promote positive clinical outcomes may appear to be paradoxical to our mechanistic understanding of the cause and treatment of disease. But is it? In chapter 3, “The Brain on Placebos,” I look at the amazing developments in neuroimaging that are revealing the inner workings of placebo effects. I will track the neurobiological changes that are induced by placebo treatment in experimental studies of analgesia in healthy participants. I will also briefly discuss the neurobiological correlates of the placebo effect in patients with Parkinson’s disease and depression, demonstrating that we are hardwired to override a modicum of pain and suffering. The hardwired neurobiological mechanisms at the heart of placebo effects are not limited to placebos. They have been observed in the many situations in which our expectations rewrite our perception and even experience of incoming information. In this way, these mechanisms represent a back door to enhancing both wellness and suffering.
Why have we evolved to be sensitive to expectation and placebo effects? Medical historians and physicians are fond of saying that early medicines were all placebos. That may be so, but if it has taken until now for effective drugs to be made, how did we survive the pain and suffering of primitive times? Surely survival of the fittest meant survival of those who could overcome and manage bodily hurt and harm?4 Historical records tell us that as we evolved, we assigned trusted people in the community to know and recall which plants and animals in our environment were beneficial to our health. Over time, these shamans, sangomas, mudangs, curanderos, and curanderas developed tried-and-true rituals and symbols that accompanied the dispensation of these remedies, cultivating in human societies a link between the act of treatment and the neurobiological mechanisms that override pain and suffering.
Today, nowhere is this more powerfully demonstrated than in the clinical encounter in the proverbial doctor’s office. There, symbols include not only the mise-en-scène-—the stethoscope, white coat, and exam table—but also the ritual and practice of the doctor visit. Think about it: from the moment we are born, many of us enter into a room of masked people in scrubs or white coats; we are literally in the hands of medicine. What follows for many of us is years of associative learning and conditioning. Reinforced by our parents, we learn to return to the doctor’s office when we are unwell, or for checkups and disease preventive vaccinations. If we have positive or at least beneficial experiences, we build an expectation that though the pills will be bitter and the vaccination might hurt, these interventions will protect us from or cure disease. No matter the treatment, if administered with care and confidence, and if we are not afflicted by infectious diseases or cancer that operate outside our command, we have a good chance of feeling better.
Expectation and conditioning promote placebo effects, but they can induce negative or nocebo effects as well. From COVID-19 vaccination resistance to reluctance to use statins in cardiovascular disease prevention, negative information can have adverse effects on the individual, and therefore collectively have detrimental impacts on public health. In chapter 4, “Nocebo Effects in Modern Medicine,” I discuss this so-called opposite of the placebo effect in medicine and popular culture. In this book, I argue, as many others have, that the neurobiological mechanisms that mediate expectation and drive placebo and nocebo effects can enhance the benefits of treatment, but also make us vulnerable. Thus we see that this mechanism can be co-opted for better or worse.
For the last seventy-five years, placebos have played a pivotal role as controls in clinical trials. As controls, placebos work best when used in studies of diseases in which a placebo response has little clinical benefit. For the most part, these are trials of cellular (cancer), viral (COVID-19), or bacterial (pneumonia) proliferation, where belief or expectation can do little to fight the spread of the disease. Although placebo effects appear to have little impact on the outcome of these trials, it’s important to note that it’s not that patients enrolled in cancer, antiviral, or antibacterial trials are not having a placebo response. Rather, the biological pathway stimulated by placebo effects is no match for these diseases. In neurological, psychological, and some cardiovascular conditions like hypertension, however, the placebo-targeted biological pathways can have real and durable effects. Further, there is growing evidence that genes and drugs can independently and combinatorially influence a placebo response in clinical trials. In chapter 5, “Placebos in Clinical Trials,” I look at the role of placebo controls in randomized clinical trials of pharmaceuticals and the challenges of demonstrating efficacy beyond a placebo in conditions characterized by high rates of placebo responses.
Recently, placebo or sham surgeries have demonstrated remarkably positive effects in the placebo or control treatment arms for well-established surgeries. In chapter 6, “The Placebo Effect in Surgery,” I examine the use of sham surgery as a control and discuss how present-day findings are influencing our belief in the efficacy of some surgeries. Improving clinical trials relies on being able to predict placebo responders so we can harness and manage placebo effects. In chapter 7, I explore the question of “Who Responds?” to placebos, and take a look at what psychology and genetics tell us about predicting placebo responders.
And finally, in chapter 8, “Placebo Redux,” I focus on the role placebos are playing in current times, and the new challenges and opportunities provided by technological advances like virtual reality, artificial intelligence, and digital therapeutics, termed digiceuticals.
Placebos are a back door to one of our most valuable assets: our health.
Placebos are a back door to one of our most valuable assets: our health. In hacker terms, a back door is a hidden entrance that can provide access to manipulate and establish control of a network. As neuroimaging studies bring the mechanisms of the action of placebos into clear view, we are learning that there are regions in the brain that can be induced, through expectations, to override the networks that process incoming sensations of pain or other symptoms. Variously championed by well-meaning healers and assaulted by quacks, the access that placebos offer to our health and well-being has been hiding in plain sight. Only now as the levers of the powerful placebo are being revealed are we in a position to understand our individual and collective roles and responsibilities. Surely it is incumbent on us to safeguard and use the power of placebos for good.