This is your brain on placebo effects

Visiting the doctor for a sore back often leads to instant relief after taking a prescribed pill, but the real question is: what’s truly healing you – the pill or your mind?

Imagine discovering that your effective medication was nothing more than a sugar pill; would this revelation make you question the pill’s efficacy or marvel at your brain’s remarkable capabilities?

In 2015, these questions were explored in a fascinating piece in Nature Reviews Neuroscience, The neuroscience of placebo effects: connecting context, learning and health.

Authors Tor Wager, an associate professor of psychology and neuroscience at the University of Colorado Boulder, and Lauren Atlas, a neuroscientist at the National Center for Complementary and Integrative Health, NIH, described the emerging neuroscience evidence of placebo effects.

The research implicates multiple brain systems and neurochemical mediators, including opioids and dopamine, in the effects. The review looked at the brain systems involved in placebo effects, focusing on placebo analgesia or pain relief and a conceptual framework linking these findings to the mind–brain processes that mediate them.

What is the placebo effect?

There isn’t just one placebo effect. There are many. Therefore, it’s far more accurate to talk about placebo effects.

The placebo is anything that seems to be an actual medical treatment but isn’t. For example, a placebo could be a pill, injection, cream, surgery, or other form of therapy. What all placebos have in common is they contain no active substance that can affect your health, but you feel better after taking them.

Wager and Atlas explain,

“Placebos are drugs, devices or other treatments that are physically and pharmacologically inert. Placebo interventions do not, by definition, have any direct therapeutic effects on the body. However, all treatments are delivered in a context that includes social and physical cues, verbal suggestions, and treatment his­tory. This context is actively interpreted by the brain and can elicit expectations, memories and emotions, which can influence health­ related outcomes in the brain and body.

Placebo effects are brain–body responses to context information that promote health and well­being. When the brain responds to context information instead of promoting pain, distress and disease, they are called nocebo effects.

Placebos have been used throughout the history of medicine to soothe the emotions of troubled patients and are still used for this purpose today. It’s widely believed that placebos can make people feel better.”

Wager & Atlas, 2015

If you expect the treatment to make you feel better, you will.

Certain conditions are more susceptible to placebos, such as depression, pain, sleep disorders, irritable bowel syndrome (IBS), and menopause. Conditions such as broken bones or cancer show minimal – if any – response to placebos.

This is not to say that situations that improve with placebos are “all in your head,” but rather that complex brain processes, including feelings, ideas, social cues, and environmental circumstances influence them.

Further, this doesn’t mean medical treatments do not affect such conditions. Instead, feeling better is partly due to the rituals surrounding healthcare, the care provider’s manner, and the patient’s memories, expectations and mindset.

As Wager and Atlas explain,

“Whether treatment consists of an active drug or a placebo, the clinical setting that surrounds treatment includes multiple types of context information that are perceived and interpreted by the patient’s brain.

The external context includes treatment, place, social cues, and verbal suggestions.

The internal context consists of memories, emotions, expectancies and appraisals of the meaning of the context for future survival and well-being.

These features combine to make up the treatment context and are the ‘active ingredients’ of placebo effects.”

Wager & Atlas, 2015

Placebos are very effective for pain (if given with care).

The placebo effect is seen most powerfully in studies of pain. In a 2008 study conducted at Harvard University, people suffering from abdominal pain due to IBS were treated with sham (fake) acupuncture. People believed acupuncture would treat their pain, but the needles were never inserted. Nevertheless, 32% of patients treated with sham needles reported pain relief.

In a follow-up study, an attentive, empathetic acupuncturist inserted the fake needles. The extra care and attention given to the IBS sufferers resulted in a jump to 63% reporting relief from their IBS symptoms. This result demonstrates that when clinicians deliver warm, supportive treatment, they can influence treatment outcomes.

The dark side of the placebo: the ‘nocebo’ effect.

Placebo has a dark side, otherwise known as the ‘nocebo’ effect, which is when the placebo causes the pain, distress or disease to worsen. The nocebo effect was highlighted in a 2010 study of 3264 workers with acute, disabling low back pain sent for an MRI.

Simply having an MRI made the back pain worse, even if the MRI showed minimal damage or degeneration. Doctors attributed the increase in pain to anxiety caused by MRI reports, which give findings scary names like “broad-based disc bulge,” “degenerative changes,” and “spondylolysis.”

Professor Lorimer Mosely, a pain researcher from the University of South Australia, wrote about the nocebo effect in an article for The Conversation.

“Your brain considers all credible evidence of danger when it’s producing pain. But, like it or not, if you are a human, your pain is, in fact, produced in your head, and it will produce it more readily and more intensely if you have what you think is clear MRI evidence that something is wrong.”

The neurobiology of placebo effects

The emerging field of placebo neuroscience draws from multiple disciplines, including Parkinson’s disease (PD), pain, learning, emotion, depression, and motivation.

Some of our earliest understanding of the neurobiology of placebo effects came from the startling findings that both placebo medication and sham surgery improved motor (movement) symptoms in people suffering from PD.

We think the placebo effect may be so prominent in PD because of the neurotransmitter dopamine — the same neurotransmitter lost in the brains of people with PD. It turns out that dopamine also underlies one component of the placebo effect. When patients take a placebo pill or undergo sham surgery to treat their motor (movement) symptoms, the dopamine released at the expectation of possible healing improves motor symptoms.

Modern brain imaging techniques have also offered new insights into the neural mechanisms of placebo effects, in particular in studies of pain. Pain is processed at multiple levels of the nervous system, and placebo treatments can reduce pain­-related neural activity in all these regions.

Evidence suggests placebos cause the release of neurochemical mediators from the periaqueductal grey (PAG) in the brainstem. The PAG directly connects to the spinal cord and modulates sensory pain circuits. The PAG receives input from the limbic system, amygdala, nucleus accumbens, hypothalamus and pre-frontal cortex. The inputs ensure the PAG is under tight emotional, motivational and mindset control. PAG pathways provide one potential mechanism by which thoughts, feelings and suggestions directly impact pain perception.

How to ‘harness the power’ of placebos.

Harvard Medical School researchers, including Dr Ted Kaptchuk and colleagues, believe we’re a long way from fully understanding the placebo effect. In a health letter, they state,

“Rather than dismiss it, we should try to understand the placebo effect and harness it when we can.”

Here are some things you can do (and think) based on what placebo research has discovered so far:

• Ensure you’re getting the support, care and attention you need from your healthcare provider. Placebo effects research has shown how meaningful a supportive doctor-patient relationship can be (it is one of the key ingredients).
• Recognise that it might be ‘in your head’ — but there’s nothing wrong with that. Behind the subjective experience of feeling better (and worse) are objective changes in brain chemistry that researchers have only started to understand.
• Find treatments you can believe in. Expectations that an intervention will have some benefit increase the chances it will.
• Keep your healthy scepticism. (There are some scathing take-downs of the idea we can ‘harness the power of placebo). Quacks and charlatans can exploit the placebo effect to peddle useless and even harmful treatments. Stick to treatments that are known to be directly effective.

A final word of caution

Expectations appear to have much to do with the placebo effects (as exemplified in people with Parkinson’s disease). If we believe that an intervention can help a condition, a certain percentage of people who receive it will experience some benefit. How large a rate varies tremendously and depends on the condition, the strength of belief, the subjectivity of the response, and many other factors.

‘Harnessing the power of placebo effects’ is a great idea, but it should not make you feel that your attitude or mindset is the cause of illness. A bad attitude does not cause disease. And feeling ‘unhappy’ is never why you’re not healing from an illness.

Placebo effects don’t cure diseases. They don’t shrink tumours. Nor do they fix broken bones. They generally work to make you ‘feel’ better. Tapping into placebo effects using tools from mind-body medicine is usually very safe and works well when combined with usual medical care. But every mind-body technique may have its risks and side effects. Talk with your healthcare provider about any concerns you may have.

---

2023 New (🌱 ) and Important (🌟 )Research Updates:

🌱 A genetic component for the placebo effect.

The study of genetics in the relation to placebos, otherwise dubbed the “placebome”, has increased in recent years. Multiple genes have been identified as potentially contributing to the placebo effect, all of which are associated with dopamine, serotonin, or other neurotransmitter pathways. Therefore, it’s likely that the placebo effect is the result of a complex interplay between our thoughts, behaviour, environment, and genetics.

🌱 Placebo effects are influenced by the expectations formed from product branding.

In one study, scientists gave people who experience headaches both active ibuprofen and placebo tablets that were labelled as either Nurofen or a generic brand. Participants didn’t report a difference in the level of pain relief between active ibuprofen and placebo when they were both branded as Nurofen. However, the generically branded placebo was reported as less effective than generically branded ibuprofen. The generically branded placebo was also reported as being less effective and having more side effects than the Nurofen branded placebo.

Another 2019 study found that if people are given a placebo cream with a higher price tag, they report greater pain relief than if they’re given the same cream with a lower price tag. This improved placebo effect also corresponded to changes in brain activity in areas associated with expectation and reward.

🌱  The clinician-patient relationship is an important component of placebo effects.

In one paper, clinicians were made to believe that a pain relief treatment was effective without knowing it was a placebo. When these clinicians later administered the placebo to patients, those patients were then more likely to report reductions in pain. This was associated with subtle changes in facial expressions when the clinicians believed in the effectiveness of the pain relief. Though the underlying mechanisms behind the clinician-patient relationship are still relatively unknown, early evidence has suggested that oxytocin, also known as the love hormone, may play a role.

🌱  Research into the effect of pain relief placebos in the brain is ongoing.

Though these placebos do influence areas involved in pain processing, scientists have now shown that this is a relatively small contributor to the overall effect. Rather, activity changes in other brain regions associated with cognition, emotions and self-regulation, as well as sensory and motor areas, play a larger role. The widespread changes in neural activity in regions across the entire brain likely create the perceived reduction in pain. Interestingly, studies comparing placebo pain relief and nocebo pain increases have found that entirely separate brain networks also control the two effects.

🌟 Most research focuses on placebos where the patients believe the treatments being administered are real.

This means that people’s positive beliefs and expectations are based on the idea that they are taking active medication. But scientists have now also started investigating open-label placebos, where patients are aware they’re being given a placebo without any deception. A large-scale review published in 2021 found that open-label placebos positively affect various conditions, including pain, allergic rhinitis, cancer-related fatigue, menopausal hot flashes, and ADHD.

🌟  The effectiveness of open-label placebos is still heavily influenced by patient expectations.

A 2017 study found that patients who receive an open-label placebo treatment without further information on placebo effectiveness show no difference compared to those provided no treatment. But if patients are given an open-label placebo alongside a persuasive rationale about how placebos can be effective treatments, then people experienced a significant therapeutic effect that was like those given a deceptive placebo.

🌟  The nocebo effect is also heavily influenced by patient expectations.

In a 2022 meta-analysis that compiled data from 59 studies, researchers found that expectations and anxiety from the specific situation result in the nocebo effect, not whether someone is typically an anxious person.

Scientists are now turning their attention to how to prevent this nocebo effect from occurring in clinical settings. In 2019, researchers found that providing patients with an information sheet about the nocebo effect reduced the number of reported side effects, with 86% of people finding the nocebo information to be helpful. Another 2022 study also found that a single education session on the nocebo effect for patients about to start chemotherapy significantly reduced subsequent reports of side effects during treatment. Though it’s only preliminary evidence, these studies suggest that educating people on the nocebo effect can help to shift patient expectations and reduce negative side effects.

---

In late 2015 I was invited to participate in an SBS Insight TV show examining the remarkable, and at times inexplicable, impacts of placebos. We met a man who ran faster, thinking he was using an EPO-like substance, only to find out he was injecting saline; and a woman who used her knowledge of the placebo effect to heal herself. How do researchers navigate the ethics of using placebos, given it involves deception? And are GPs using the placebo effect without patients realising it?

Catch a replay on YouTube.