The success of medical practice essentially depends upon the faculty of sagacious discernment. One who is carried away by every wind of doctrine, and who recommends every new medicine which is in vogue and becomes popular, without considering the evidence and fair probability of its efficacy, will frequently administer mort, and sometimes injurious remedies, to his patients.
—John Haygarth, Of the Imagination, January 1, 1800
Over two hundred years have passed since Franklin debunked Mesmer, and Haygarth did the same to Perkins, publishing Of the Imagination, as a Cause and as a Cure of Disorders of the Body. During that time, the developments in psychological, pharmacological, neurobiological, and genetic studies of placebo effects have done much to broaden our understanding of their full complexity. Still, we resist acknowledging their power. Perhaps this is because of the centrality of mechanism in explaining the action of drugs. We identify pathways perturbed in disease, design drugs that target these pathways, and conduct animal studies and clinical trials to derive evidence in patients that these interventions work. Yet many diligently designed and developed compounds fail to demonstrate efficacy beyond that of a placebo.
In creating justifications for these failures, we invariably attribute them to the wrong dose, wrong patient demographic, or wrong outcome measure. In so doing, we seek to layer objectivity over results we don’t quite understand and cannot quite control. By invoking a mechanism of failure, we are back on even footing and can try again.
In focusing on why the drug failed, we are missing that other mechanism, the one that didn’t fail. This other mechanism gives rise to placebo effects. Via brain regions like the vmPFC, this mechanism attaches meaning, expectations, and in turn a neurological response to stimuli. Armed with a mechanism, placebos are finally moving, albeit slowly, into that privileged space of cause and biological effect.
The COVID-19 pandemic inadvertently highlighted the real-life powers and limitations of placebo as well as nocebo effects. Notably, placebos were no match for the virus. For example, no matter how much we wished, prayed, or expected that hydroxychloroquine would work, it didn’t.1 After several placebo-controlled clinical trials, it was clear that hydroxychloroquine, like placebos, was no match for the virus. Despite the urgent need to counteract SARS-CoV-2, the virus that causes COVID-19, promising vaccines and antiviral drugs like remdesivir all had to first demonstrate safety and efficacy beyond a placebo before being made publicly available.2
SARS-CoV-2 has taken over six million lives worldwide as of this writing. At the same time, nocebos and powerful negative expectations are everywhere. Notwithstanding evidence that face masks could greatly reduce the spread of the virus, wearing them became a political statement instead of a prophylactic measure. While vaccines with demonstrated effectiveness are almost universally available, vaccine hesitancy as a result of negative information has greatly reduced people’s willingness to be vaccinated. On an individual level, as we saw throughout this book, negative information can shape personal beliefs and expectations, which in turn result in adverse effects and poor treatment adherence. What COVID-19 showed us was that on a population level, negative information and its downstream nocebo effects can compromise our public health with devastating health, social, and economic repercussions.
If and when the COVID-19 pandemic finally ends, and we emerge from behind our masks and sheltering places, we will have to deal with the many challenges that faced us before. Pain and depression will still be with us, and so too the challenges of developing novel effective neuropsych drugs. Quite likely, novel treatments that are only as efficacious as a placebo will continue to fail. To counteract this trend, numerous strategies are on the horizon, from educating participants and investigators about the placebo response, to the development of machine learning algorithms to predict placebo responders and digital therapeutics that promise to revolutionize medicine. Even the possibility of using placebos to treat patients is back on the table.
With demonstrated clinical benefits in numerous conditions over the seventy-five years of clinical trials, and now a confirmed and compelling mechanism of action, one might wonder why we have not deployed placebos as treatments in modern clinical medicine. Although deemed unethical according to central tenets of patient autonomy, several studies suggest that use of placebos by physicians is still widespread.3 Some physicians report using impure placebos (low doses of an active treatment, vitamin, or supplement), and in countries like Canada, Portugal, and Germany, pure placebos like sugar pills or saline injections are prevalent.4 In fact, Germany has gone one step further. In 2012, the German Medical Association, after careful assessment and deliberation, concluded that the use of placebos in clinical practice was justified.5 Specifically, the scientific advisory board found that placebo use was “acceptable” in three circumstances: for patients with a minor condition, when there is no other effective treatment available, and when treatment with a placebo is likely to succeed. Not surprisingly, this announcement was met with trepidation from concerned bioethicists who worried that patients’ rights were being violated. As this debate continues, researchers have taken the unprecedented step of breaking the blind. Now, in over a dozen trials, patients have been treated with an open-label placebo (OLP), or a placebo without deception.
OLP clinical trials have demonstrated that clinical benefit from a placebo treatment can be preserved with OLPs or honestly prescribed placebos.6 In randomized clinical trials of conditions such as chronic low back pain, cancer-related fatigue, IBS, and allergic rhinitis, patients reported significant benefit from OLPs compared to no treatment or care-as-usual controls.7 The theory of how OLPs work builds on the placebo neuroimaging studies and predictive coding theories discussed earlier in this book. Briefly, the brain uses prediction processing to reassess incoming information in favor of the clinical improvement of symptoms.8 The honest information conveyed by the physician about the potential of the placebo treatment to improve the condition of the patient supports this reassessment, seeding a shift in the perception of symptoms.
OLPs work best when administered with the clinician sharing the plausible rationale of how placebos work and an overview of the positive effects of placebos in previous clinical trials. Additionally, physicians are encouraged to allow the patient to suspend belief while creating an openness to the possibility, but not an absolute certainty, that the placebo pills might work. The key instruction to patients is that they must adhere to the treatment. The ritual of pill taking thus promotes a top-down revision of the patient’s perception of their condition as moving toward symptom relief. More OLP trials are ongoing, and although these trials are small, their demonstration of efficacy to date is striking and suggests a path forward to once again using placebos in the clinic to benefit patients.
Placebos are not just being leveraged in the clinic. ZEEBO and the XPILL are trademarked placebos that are commercially available direct to consumers over the internet. Although they have not been tested in clinical trials, it is likely that they will do as well as a number of placebos.
Smartphones, the “Pac-Men” of the electronics industry, gobbled up cameras, radios, clocks, and calculators. Now that gaping mouth is set on the pharmaceutical industry. As of June 2020, AKL-T01, having gone through clinical trials and regulatory review, is now an FDA-approved prescription treatment for attention deficit and hyperactivity in children. But AKL-T01 is not a pill; it’s a video game. Trademarked EndeavorRx, AKL-T01 joins the growing number of digiceuticals, or digital health technologies, that coach patients to manage their conditions while tracking medication intake, lifestyle, behavior, food intake, and physical activity. The clinical trial results for these interventions are generally quite impressive. In the case of AKL-T01, patients randomized to the active intervention had significant improvement in the test of variables of attention with minimal adverse events compared to a control app, which in this case was a word puzzle.9
Digital health technologies now have their own specialty academic journals, like Lancet Digital Health, to manage and publish the outflow of research in this relatively new field. Virtual reality has also emerged as a platform with promising results in the treatment of psychiatric illnesses as well as chronic and acute pain.10 Still, many initial trials of virtual reality interventions are thought to be lacking in rigorous scientific methodology, and do not tend to include a placebo control, or for that matter, any control.11
As these fields develop, factors that influence clinical outcomes like sample size, clinically relevant measures, and what represents an acceptable comparator or placebo control have to be addressed.12 When it comes to interventions administered through virtual reality or other digital mechanisms, the line between a device and placebo control can be blurred, and we will need to identify the “active” elements. Is it the device, a given image, or the application that brings this all together?
From benign patriarchal palliative to quackery and clinical trial control, placebos have played many roles in the history of medicine. In many guises as bread pills, metal rods, sugar pills, or sham surgery, theirs has been a command performance. However inert the placebo, their administration has striking ameliorative properties—the placebo’s paradox. This ability of placebos to reduce suffering from a myriad of symptoms is intricately linked to the symbols and rituals that over centuries were enlisted in the service of healing. In contrast, negative verbal or contextual information induce negative expectations, and whether intentional or unintentional, are coded to elicit harm.
With the identification of neurological drivers of placebo effects, the curtain has been pulled back, and the stigma and mystery are giving way to mechanism. As I discussed throughout this book, placebo treatment can access neural processes linked to brain regions like the vmPFC that can in a top-down fashion reshape our experience of incoming signals based on positive (placebo) or negative (nocebo) expectations. Thus placebo effects along with their opposite, nocebo effects, represent a back door to the amelioration or exacerbation of the experience of pain and other negative symptoms.
Given this potential for benefit or harm, the clinician, as trusted healer, the person we go to in our hour (or all too frequently, only fifteen minutes) of need, has an ethical responsibility to safeguard this back door. As I examined in this book, this has not always been the case. When medicine was more patriarchal, an “all-knowing” physician could prescribe an “impure placebo,” a treatment for patients who had exhausted all possible known treatments. But the back door is known to many, and we were and are all too vulnerable to the promises of quacks as well as today’s carefully crafted social media messages designed to control our beliefs and attitudes about our health.
Safeguarding the back door is the work of us all.
Clinicians, researchers, drug developers, and patients all have differing opinions on placebos. By now you have probably formed your own opinion on the benefit, harm, uselessness, or utility of placebos and the placebo effect. Of one thing we can be certain: no matter how we see them, placebos represent what was for many years ignored, hidden, or wild, but was always a back door to influencing our health and wellness. Through the pages of this book, we have seen the mechanism underlying placebo effects used in the service of healing and the propagation of harms. How we use this at once new and ancient mechanism is not only up to clinicians and clinical trialists. Safeguarding the back door is the work of us all.