The Scientific Magic of Belief: How Do Placebo Treatments Really Work?
Maedot Abate
Illustrations by Anne Goldsmith
They’re not called “gazebos,” as Eddie from the 2017 film IT so passionately proclaims. Placebos, while colloquially referred to as “sham” treatments, are essential components of research within the field of clinical medicine [1]. They are primarily used as a point of comparison to determine if newly developed drugs have any sizable positive impact on a patient's health. Ideally, those receiving the real treatment should see significantly better outcomes than those receiving the “sham” treatment — otherwise, the drug serves no medical purpose! But how exactly do placebos work? And why do they work despite seemingly not affecting the physical body?
Perhaps you have experienced the placebo effect in your day-to-day life. Let’s say you’re sitting in a hot, stuffy room, and are desperate for a breeze to cool off. You ask a friend to open the window in the next room to let some air in, and after agreeing to do so, they walk into the other room. Unbeknownst to you, your friend prefers the room’s current temperature, and has left the window closed without letting you know. You, however, believe that the window is now open, and that cool air is coming in. This belief induces a placebo effect: you now feel cooler due to the incoming “breeze.” In reality, the temperature of the room has not changed in the slightest, so why are you able to physically feel a difference? The perceived environmental cues — verbal compliance from your friend, and them heading to the other room — are processed at the cognitive level, resulting in a positive physical outcome. You now feel much cooler, thanks to that “open” window!
Placebos in clinical trials operate similarly, with the goal being that the “breeze” — or the effect of the treatment — is much more potent after taking an active drug than with the placebo [1]. Just as you physically “cooled off” after processing cues from your surroundings, placebos in clinical settings also rely on the environmental context in which they are administered [2]. The environmental context can include factors ranging from verbal cues from the person administering the placebo, whether or not the patient is in a clinical environment (at home vs. a doctor’s office, for instance), and personal variables such as the patient’s preexisting beliefs about the treatment’s efficacy [2]. All these factors can impact how successful the placebo is in producing the desired health outcome. For example, let’s say a new drug for arthritis has just been developed. To approve the drug, scientists must first ensure that the drug treatment will generate a far better outcome for the patient than receiving no treatment at all. To control for any bias, all participants in a placebo trial are usually made to believe that they are receiving the actual drug. Some patients will then be treated with the actual drug (group A), while others will be treated with a harmless and inactive substance such as a sugar pill, or saline (group B). This inactive substance is the placebo [1]. After some time, researchers compare the symptoms of the participants in groups A and B. In the case of this arthritis drug, symptoms like joint stiffness, pain, or swelling would be noted. If all other variables are controlled for, and the patients in group A fare significantly better after treatment, their health improvement is assumed to be caused by the medication [1]. If both groups of patients retain a similar set of symptoms, then the actual drug is no more effective than a placebo, and it’s back to the drawing board for the scientists.
Until a few decades ago, the placebo effect was thought to be a purely psychological phenomenon, or the result of cognitive and behavioral changes that emerge when a person expects or believes something [3]. However, the nervous system — comprising the brain, nerves, and spinal cord — has recently been found to play an active role in producing the effect [3]. This newfound understanding emerged when naloxone (commonly known as Narcan), a drug that is used to counteract opioid overdose by blocking its dangerous symptoms, was found to simultaneously counteract the placebo effect [4]. Natural opioid compounds synthesized by the body, such as endorphins, play a role in reducing pain — a process which naloxone prevents from occurring. If a patient is given a placebo but is told it’s an opiate painkiller, they report feeling less pain, a typical example of the placebo effect. However, if a patient receives naloxone in addition to the placebo, they report much higher pain levels. Considering placebos are usually associated with pain reduction, the strange painful consequence of combined placebo and naloxone treatment suggests that the placebo effect may be both a psychological and physiological phenomenon [4]. The discovery that physiological changes can inhibit the placebo effect brought about new questions of how placebos can affect the neurochemical makeup of our brains. Now, a new subcategory of research has begun incorporating both the psychological and physiological elements of placebo processing in the brain, with the goal of implementing this knowledge to improve the field of drug discovery and patient treatment.
Unlocking Pain Relief: The Physical Effects of Placebos on Our Brains
Placebos rely on a complex system of neurons that get activated to stimulate a response in the brain and produce a physical outcome. Neurons are cells that receive and process sensory information from the outside world, including pain, heat, and light [5]. Picture these neurons as a long chain of rooms and hallways, where each room is a neuron’s cell body responsible for receiving this sensory input. The hallway represents the neuron’s axon, responsible for carrying signals to the next room (the subsequent neuron). Signals moving through these doors and hallways produce an electrical signal called the action potential, which originates in the cell body and travels down the axon to the next neuron. However, the action potential cannot open the door to the next room alone; it requires chemicals called neurotransmitters to do so. These “keys” are molecules that convey the received information from one neuron to the next by interacting with specialized receptors on the doors, or “locks” [6]. After these neurotransmitters unlock the doors, the signal is taken on a journey through billions of rooms and hallways, all in a span of seconds, until a physical response occurs.
When a placebo is administered to a person, their expectations can influence which neurotransmitters relay the signal from neuron to neuron, and therefore what health benefits the patient ultimately experiences [7]. Neurotransmitters do not work in isolation; the placebo effect modulates communication between several of these molecules to bring about an appropriate response to environmental cues. Dopamine is one such neurotransmitter, playing a role in the brain’s reward, pleasure and motor-control systems [8]. The rush of relief you felt when your friend “opened” the window, for instance, was likely a result of neural activity tied to dopamine release. Placebo administration can also prompt the release of a neurotransmitter called serotonin, which functions as a mood stabilizer [9]. Opioids are another type of chemical that function similar to neurotransmitters, attaching to receptors on our neurons to act as pain and immunity regulators [10]. This is why patients who ingest naloxone report feeling more pain; naloxone blocks opioids from activating these receptors, effectively “barricading” the doors needed to activate their neural networks and weakening their brain’s ability to regulate pain [4].
In order to understand the neural mechanisms underlying the placebo effect, scientists turn to innovative brain imaging techniques to identify which brain regions are activated in response to placebo administration. One such technique is functional magnetic resonance imaging (fMRI), which tracks brain activity via changes in blood flow that occur in response to neural activation [3]. fMRI imagery has demonstrated that opioid receptors in the brain are activated following placebo administration; when these receptors are triggered, they ultimately lessen pain levels [8]. This is because the placebo activates a pathway that causes the brain to release endogenous opioids — or opioids secreted within the brain— which then activate these receptors to facilitate pain relief. The increase in endogenous opioid levels is traced by fMRI through changes in blood flow [11, 4]. Another imaging technique that allows us to visualize placebos neurologically is Positron Emission Tomography (PET), which tracks molecular movement using radioactivity and identifies changes in biochemical activity within brain tissue [12]. PET scans can demonstrate if administering a placebo leads to increases in metabolic activity, which includes the synthesis and breakdown of essential molecules in the body [12]. These molecules affect the secretion and activation of the neurotransmitters involved in generating the placebo effect. For patients diagnosed with depression, PET scans have shown that administering a placebo leads to higher levels of glucose metabolism in the brain, which facilitates the synthesis of neurotransmitters that improve patients’ ability to regulate their emotions [13]. These imaging techniques demonstrate that the placebo effect impacts neurological function through its alterations to metabolic activity and neurotransmitter levels within particular brain regions [9].
The brain regions that are most responsive to the placebo effect typically receive and transmit signals associated with pain, emotional expectation, and motor function [14]. These regions include the anterior cingulate cortex (essential for emotional regulation and pain management), the prefrontal cortex (involved in complex decision making and emotional regulation), and the amygdala (responsible for our emotional processing) [7, 14]. Opioid receptor activity tracked via fMRI reveals that patients’ expectation of pain relief activates the anterior cingulate cortex, increasing this region’s endogenous opioid activity [4]. The PET scans tracking metabolic activity post-placebo show a spike in activity in the thalamus (transmitter of external signals to other brain regions) and anterior cingulate, suggesting that the emotional regulatory pathways activated by placebos could have mood-stabilizing effects comparable to active antidepressant treatments [12]. It’s important to note, however, that ample data exists on how placebos affect these brain regions because they are the most frequently studied in drug efficacy trials [14]. Further research that focuses on other brain regions may reveal placebo-induced neural activity elsewhere in the brain.
Using these imaging techniques, however, is limited by the level of precision with which they can track brain function. PET scans have restricted spatial resolution, which means that due to the large pixel sizes of images, the ability to distinguish between different regions of the brain situated close together is diminished [15]. fMRI does not directly measure neural activity, but rather relies on increases in brain blood flow to determine where activity is taking place [1]. This may prevent it from tracking the precise effects of placebos on neurotransmitter release and metabolic activity. These limitations can make it difficult to determine whether or not brain activity is the direct result of the placebo effect. Despite their drawbacks, these techniques are standard in the field of neuroscience to track the effects of injury, disease and drug intake on brain function, making them generally reliable in revealing the complex neural mechanisms underlying these phenomena [16].
“Sham” Treatments Become Genuine: Targeting Disease with Placebos
Tracking placebo-responsive neural activity has become an increasingly popular technique in recent clinical trials exploring this fascinating phenomenon [4]. Many of these trials target pain-related disorders, because the physiological processes underlying pain reception in the brain are particularly well understood in clinical medicine [4]. Disorders like Irritable Bowel Syndrome (IBS) and chronic migraines, for example, are characterized by periods of prolonged pain and discomfort [17, 18]. Current research focuses on how brain activity changes when pain-relieving placebos are administered, and how successfully they can alleviate any associated symptoms. For instance, PET scans have been used to determine how placebo treatment affects the level of intestinal discomfort felt by IBS patients [17]. PET data reveals an increase in prefrontal cortex activity and reduction in amygdala activity following placebo administration [17]. These findings indicate that when IBS patients expect pain relief they enter a calmer emotional state, activating the brain areas necessary to regulate pain [17].
People with chronic (i.e. long-term) motor disorders, like Parkinson’s disease, have also benefited from placebo treatments. For instance, many patients with Parkinson’s who believe that they are receiving treatment medication experience improvements in hand movement even without the administration of active medication. Data from PET scans has revealed that this effect in the brain likely results from an activation of dopamine receptors in response to expectation-driven dopamine release [19]. However, there are still drawbacks to these applications, as the benefits gained from placebo treatment have only been successful short-term [20]. Because it appears that the placebo effect is only a temporary method of alleviating pain and improving movement control, clinical research is now pointed towards identifying ways to sustain these responses over longer periods of time — at least until an active pharmaceutical drug is found to be more effective for treatment [20].
When Placebos Meet Genomes: The Placebome Theory
Placebos vary extensively in how they interact with one’s neurological system, as well as how the person being treated responds. But what if we could accurately predict how well one would benefit from being given a placebo, even before administering it to them? By examining an individual’s DNA, could we reliably determine who will respond well to a certain placebo treatment? The newly emerging placebome (placebo + genome) theory suggests that we can, positing that genetic differences among patients can give rise to differences in neural responses when a placebo is administered [21]. Our genetic makeup is intricately linked to neural and biochemical activity in our bodies; common traits like lactose intolerance and having a sweet tooth, for example, are the result of chemical activity driven by the instructions encoded in our genes [22, 23]. Similarly, the placebome theory states that individual differences in the genes coding for essential molecules in neural systems, such as proteins and neurotransmitters, can also alter how the placebo effect manifests in patients [21].
Understanding how genes mediate a placebo response requires the identification of genetic biomarkers, which are the specific sections of genes involved in encoding the molecules of interest [21]. Biomarkers differ from patient to patient, and help account for individual differences in the number of molecules that are synthesized as well as the rate at which they are made; both the number and rate of molecule production can impact the degree of placebo response induced [21]. In patients with IBS, three variations of biomarkers, which code for a key protein that interacts with dopamine, have been identified [24]. Of these variations, only one activates a dopamine pathway that reduces pain significantly after a placebo is given [24]. In addition, fMRI imaging on people with social anxiety disorder has shown that those bearing a particular biomarker experience higher levels of serotonin release in response to a placebo, which is indicated by a reduction in amygdala activity [25]. By utilizing patients’ genetic predispositions to placebo treatment, it is possible to identify the most placebo responsive patients, and choose them to participate in clinical trials [21]. Doing so can generate more precise data on the efficacy of actual drugs in drug-test trials, and reduce the cost of recruiting participants. The placebome-focused approach is also a great preventative measure for identifying individuals that have the potential to react adversely to placebo administration, which can prevent risking patient health during clinical research trials [26]. While our understanding of the placebome theory is in its early stages, it holds great potential to pave the way for personalized medical care for patients with chronic illnesses.
Fake It ‘Till You Make It
Evidence of the placebo’s peculiar effect on the brain suggests that our expectations and beliefs have tremendous potential to influence our physical states. However, there is still a lot to learn about the neurological processes underscoring this phenomenon. We have yet to determine if there is a primary neural pathway or cluster of pathways associated with placebo activity, or if it is possible to modify genetic biomarkers to make patients more placebo-responsive. These questions may soon be answered as the many new drug-discovery projects exploring this field of clinical medicine begin transforming how we approach treatment for short-term and chronic illnesses. And maybe with our newfound appreciation for the mind’s great potential, we can change how we approach our responses to daily life, too. Perhaps the next time you’re stuck in a steamy space and ask a friend to let in some air from another room, you may not have to bother checking to confirm if the breeze is real – just sit back, relax, and let your brain cool you down.
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