The Power of Nothing?
Unpacking the placebo effect.
The placebo effect is a phenomenon where individuals experience– or perceive to experience– improvements in symptoms or conditions after receiving a treatment with no known medical benefits. This effect demonstrates the powerful influence of the mind on physical health and has implications for medical research and treatment.
So, is there any value to placebo? Can we ethically prescribe placebos to people knowing there are no active ingredients?
(To be clear, I am not talking about the use of placebos as controls in research trials. Placebos help separate the specific effects of the treatment from other factors that might influence outcomes. This allows researchers to determine how much of the observed effect is due to the active treatment itself.)
In this newsletter, I am talking about the use of placebos OUTSIDE of the research trial setting.
This is a hotly debated topic with strong opinions on both ends of the spectrum. I, myself, have historically taken a hard line against certain products that may show benefits through the placebo mechanism (on the basis that they are marketed and $old as having therapeutic benefits through implausible biological mechanisms), and have only recently opened myself up to the potential for benefit in certain controlled scenarios.
That being said, there are a few non-starters for me when it comes to placebo:
Placebos should never be used as replacements for treatments or therapeutics recommended by clinicians.
Placebos should not be used for serious illness or medical conditions.
The use of placebos should not delay proper diagnosis or necessary medical interventions.
Placebos should not be marketed or sold as miracle cures or with false claims about their efficacy.
The placebo effect should not be used to justify or promote pseudoscientific or unproven treatments.
Placebos should not be used in a way that exploits vulnerable populations or takes advantage of people's desperation.
The cost of placebos should not be inflated or used as a means of financial exploitation.
The use of placebos in research must adhere to strict ethical guidelines and oversight.
Note: I was going to include another point, “Placebos should not be administered deceptively or without informed consent” – but then I asked myself, would that counteract the mechanism through which placebo works? (Put a pin in this. I’m going to come back to open-label placebos a bit later.)
I also want to be crystal clear upfront: I think the sale of homeopathic products (which are, essentially, sugar pills) is unethical– and I will explain why…
The ethical concerns surrounding homeopathic products stem from their claims that go beyond the potential for a placebo effect (see non-starters #4-5). These products often assert specific therapeutic benefits based on their ingredients, suggesting a direct physiological mechanism of action. This stands in stark contrast to the scientific understanding of how these preparations work – or rather, don't work.
The fundamental issue for me lies in the lack of biological plausibility and the pseudoscientific claims of biological plausibility that are made to sell these products (for a hefty profit, might I add– see #7). Homeopathic preparations are typically diluted to such an extreme degree that they often contain no molecules of the original substance. This conflicts with established principles of chemistry and pharmacology, as there's no known mechanism by which such dilute solutions could have the claimed effects.
From an ethical standpoint, presenting homeopathic products as having specific therapeutic effects may prevent people from seeking evidence-based treatments for their conditions, potentially leading to harm (see #1-3). Moreover, it exploits the hopes and fears of vulnerable individuals, especially those dealing with chronic or serious illnesses (see #6).
This approach stands in contrast to the [potentially] ethical use of placebo effects in conventional medicine. In medical practice, placebo effects are recognized and sometimes utilized, but typically with full disclosure to patients. Proponents of the use of placebo say that their goal is to harness the mind-body connection to enhance overall treatment efficacy, not to replace evidence-based treatments– and that is something I want to dig into further.
In essence, the ethical dilemma of homeopathic products centers on the discrepancy between their marketed claims and the scientific understanding of their effects. While placebo effects can be powerful and potentially beneficial, presenting a product as having specific physiological effects when it likely functions solely as a placebo raises significant ethical questions. These concerns touch on issues of informed consent, truthful marketing, and responsible healthcare practices, making it a complex and contentious topic in the realm of medical ethics.
Okay, so let’s dig into the data on placebo…
I “phoned a friend” and had Dr. Sarah Scheinman (a brilliant, insightful gem of a human who holds a PhD in neurobiology) weigh in. Here’s what she shared.
Though traditionally thought of as a purely psychological phenomenon, the placebo effect has a distinct neurobiological basis. The idea that expectations, beliefs, and/or conditioning can both structurally and functionally shape the brain is not a new one. In fact, synaptic plasticity, the cellular mechanism of learning/memory first proposed in 1949 by the Canadian psychologist Donald Hebb, predicates that repeated experiences rewire the connections between brain cells (neurons) and strengthen existing connections. To this end, beneficial responses to the context in which a treatment is delivered, as opposed to the specific biological actions of the intervention itself, have been linked to several brain regions, circuits, and neurotransmitters.
For instance, the autonomic nervous system, the portion of the peripheral nervous system that regulates involuntary physiological processes, is associated with responses to contextual cues that evoke emotional memories, such as pain. In fact, placebo analgesia, the experience of pain relief following the administration of an inert treatment, is associated with marked changes in autonomic activity, indicating a physiological basis for cognitive expectancy. Similarly, placebos also affect the neuroendocrine system and are mediated via forebrain control of the hypothalamus-pituitary hormone system, a brain system that controls many important biological functions by regulating hormone release. The stress hormone cortisol and the pro-hunger hormone ghrelin are a few examples of hormones that have been implicated in the placebo effect.
Modern neuroimaging techniques that provide broad-scale, real-time snapshots of brain activity, further support the neurobiological underpinnings of the placebo effect. Specifically, two of the most salient brain regions that have been implicated in responses to placebos are the thalamus, the relay station for the processing of sensory input in the brain, and the basal ganglia, important for regulating motivation and motor control. Large-scale studies have also implicated the prefrontal cortex, the region of the brain involved in planning, thinking, and reasoning, in the placebo effect suggesting that cognitive/affective processes, in conjunction with sensory/physiological processes, are involved in the placebo paradigm.
Finally, genetic variations in neuro-modulatory pathways including dopamine, opioid, serotonin, and endocannabinoid may also have an impact on placebo responsiveness. Specific candidate genes may even predict the effectiveness of a placebo in patients with IBS, headache, post-operative pain, and fibromyalgia. However, the placebo effect is complex and multifaceted so although certain genetic variants may provide some insight into placebo responsiveness, it is unlikely that a single polymorphism or isolated genetic variant underlies the entire phenomenon.
Ultimately, the placebo effect underscores the powerful relationship between the brain’s expectations and physiological responses. A comprehensive understanding of the neurobiological systems that modulate placebo responsiveness could be leveraged in conjunction with biologically active clinical treatments to enhance patient outcomes and have profound translational implications.
In other words: the placebo effect isn't “just in our heads” - it has a real biological basis in our brains and bodies. When we expect a treatment to work, even if it's just a sugar pill, our brains can change both in structure and function. This is similar to how we learn and form memories. Several parts of our brain and nervous system are involved in the placebo effect, including areas that control automatic body functions, process sensory information, and regulate hormones. And some data show that placebos can affect things like pain perception, stress hormones, and even hunger signals. Brain scans show that when people respond to placebos, areas involved in thinking, planning, and processing sensations become active. Interestingly, our genes might also play a role in how well we respond to placebos. While no single gene is responsible, certain genetic variations might make some people more likely to experience strong placebo effects. Understanding how placebos work in the brain and body could potentially help doctors enhance the effectiveness of real medical treatments, leading to better outcomes for patients.
Alternatively, others whom I respect have taken the stance that placebos are bunk– and that they do not have any positive effect. Dr. David Robert Grimes (who is another brilliant and well-respected scientist) has been vocal about this and credits phenomena like “regression to the mean” for any documented success of placebo.
The thinking is that observed improvements in placebo groups are not due to any real placebo effect, but simply reflect natural healing or symptom fluctuation (regression to the mean). I think they're suggesting that people tend to seek treatment when their symptoms are at their worst, and over time, these symptoms naturally improve or fluctuate back toward their average state, regardless of any intervention.
I do think that might explain some of the improvements we see people experience when they take a homeopathic “remedy,” for example– it is likely that, in time, a person’s headache (or whatever ailment prompted them to seek a remedy) simply got better with time. Thanks, immune systems!
But, I must admit that I have been compelled by some of the neurobio data I’ve reviewed. I sense that placebo effects involve various psychological and neurobiological mechanisms beyond simple regression to the mean. While regression to the mean is a real phenomenon that researchers must consider, it doesn't negate the existence or importance of placebo effects. Well-designed studies can differentiate between regression to the mean and true placebo responses.
So, here I am… considering that placebos have applications in the real world. Potential benefits: they may provide symptom relief, particularly for conditions that are influenced by psychological factors. As a cost-effective alternative to expensive treatments, placebos may offer a more accessible option for some patients. Additionally, placebos typically have fewer side effects compared to active medications, making them a safer choice in certain situations. Studying placebos also provides valuable insight into the complex mind-body connection, enhancing our understanding of human physiology and psychology. Maybe there are some palliative care benefits, as well…
But…and this is a BIG BUT… the use of placebos is not without drawbacks and ethical concerns. One significant risk is that patients might forego effective, potentially life-saving treatments in favor of placebos. There are also ethical issues related to deception in medical practice, as traditionally, administering placebos involved some level of misleading the patient. Placebos may mask underlying causes of conditions without addressing them, potentially delaying proper diagnosis and treatment. Furthermore, the effectiveness of placebos is inconsistent across individuals and conditions, making their use unpredictable.
Nuanced perspectives on placebos have emerged in recent research. Studies on open-label placebos suggest that placebos may work even when patients know they're receiving one, challenging traditional notions about the necessity of deception.
This Harvard Health blog post describes research that suggests that open-label placebos can be effective for various conditions, including irritable bowel syndrome, chronic low back pain, and cancer-related fatigue. The mechanisms behind this effect are not fully understood, but they may involve conditioning, patient expectations, and the ritual of taking medication.
There's also growing recognition of placebo components in real treatments, suggesting that understanding the placebo effect could enhance the effectiveness of actual medical interventions. (Conversely, the nocebo effect, where negative expectations lead to negative outcomes, highlights the powerful influence of the mind on treatment results.)
While they should NOT be used as a replacement for medical treatment (especially for more serious conditions), maybe placebos can be used complementarily alongside proven treatments to enhance overall effectiveness. I see real value in understanding and potentially utilizing the placebo effect. The challenge lies in finding ethical ways to harness its benefits without compromising patient care or trust in the medical system. This might involve being transparent about placebo use, integrating placebo-like elements into real treatments, or using placebos as complementary rather than primary treatments.
One thing I keep coming back to is the use of placebos in a very controlled way– for example when prescribed by qualified clinicians who can determine their appropriate and safe use. Clinicians possess the necessary medical knowledge, clinical experience, and ethical training to make informed decisions about when a placebo might be beneficial in light of a patient's full medical history, current condition, and potential risks. They can ensure that using a placebo won't delay or interfere with necessary treatments for serious conditions. Moreover, they can monitor the patient's response and adjust the treatment plan as needed. In certain cases, such as managing chronic pain or addressing mild psychological symptoms, a clinician-prescribed placebo could offer benefits with minimal risk.
However, the direct sale of placebos to consumers (homeopathy, I am looking at you…), especially when marketed with inaccurate claims of biological plausibility, is problematic and potentially dangerous. The ethical use of placebos in medical practice involves transparency, informed consent, and careful consideration of the patient's best interests. This nuanced approach is lost when placebos are marketed directly to consumers as if they were active medications.
While placebos have a place in healthcare when used judiciously by trained professionals, their direct sale to consumers based on misleading claims is not justifiable. It's crucial to maintain the integrity of medical treatments and protect consumers from potentially harmful or exploitative practices. The focus should be on advancing our understanding of placebo effects within the framework of evidence-based medicine, rather than commercializing placebos for profit. Just my two pennies.
xoxo,
Jess