It’s All In Your Head: How Brain Circuitry Causes Placebo Effect

By Crystal Lindell

The placebo effect is very real. But how and why it happens has mostly remained a mystery. 

However, new research may shed light on what exactly is happening in our brains when just the expectation of pain relief is sufficient for people to feel better, even when the pill or treatment they’re taking has no therapeutic value.

The discovery may even lead to new treatment options. 

In studies on laboratory mice, researchers at the University of North Carolina School of Medicine discovered a pain control pathway that links the front of the brain, through the middle region of the brainstem, to the cerebellum in the back of the brain.

They then showed that certain parts of this pathway are activided in mice when they anticipate pain relief. 

“Our results do open the possibility of activating this pathway through other therapeutic means, such as drugs or neurostimulation methods to treat pain,” says lead researcher Greg Scherrer, PharmD, associate professor in the UNC Department of Cell Biology and Physiology, who conducted the study along with colleagues at Stanford, the Howard Hughes Medical Institute, and the Allen Institute for Brain Science. 

The research, recently published in the journal Nature, provides a new framework for investigating the brain pathways underlying other mind-body interactions beyond the ones involved in pain.

“We all know we need better ways to treat chronic pain, particularly treatments without harmful side effects and addictive properties,” Scherrer said. “We think our findings open the door to targeting this novel neural pain pathway to treat people in a different but potentially more effective way.”

How Scientists Studied Placebo Effect

The placebo effect is basically the brain’s way of trying to help us feel better. As such, just the expectation of pain relief is often enough to make our brains release hormones and natural chemicals that provide relief. Positive thinking and even prayer have been shown to provide similar benefits to patients, without the use of medication. 

The scientific community’s understanding of the placebo effect primarily came from human brain imaging studies, which showed increased activity in certain brain regions. However, those studies did not have enough precision to show what was actually happening in those brain regions. 

So Scherrer’s team designed a set of complex experiments to learn in more detail what was happening in the brain.

First, they created a method to generate in mice the expectation of pain relief. Then they used a series of experiments to study the anterior cingulate cortex (ACC) of their brains, which had previously been associated with the placebo effect. 

The experiments helped them see the intricate neurobiology of the placebo effect on the receptors, neurons, and synapses of the brain. When mice expected pain relief, it boosted signaling along the pain pathway.

“There is an extraordinary abundance of opioid receptors here, supporting a role in pain modulation,” Scherrer said. “When we inhibited activity in this pathway, we realized we were disrupting placebo analgesia and decreasing pain thresholds. And then, in the absence of placebo conditioning, when we activated this pathway, we caused pain relief.”

In a 2021 study, researchers had a similar breakthrough when studying the placebo effect. Researchers at Dartmouth University conducted an analysis of neuroimaging studies involving over 600 healthy people who participated in placebo studies. Their findings showed that placebo treatments reduced pain-related activity in multiple areas of the human brain.

Cannabis Works No Better Than Placebo in Pain Studies

By Pat Anson, PNN Editor

The placebo effect is responsible for much of the pain relief experienced by participants in clinical trials of cannabis, according to new analysis that also found a “strong positive bias” in media coverage of the studies.

Researchers at the Karolinska Institute in Sweden analyzed the results of 20 placebo-controlled studies of cannabis products involving almost 1,500 people with chronic pain conditions. The cannabis products were administered as pills, sprays, oils, smoke or vapor; and most of the studies were conducted in the United States, UK or Canada.

Researchers found that many participants reported significant pain relief, but there were no differences in pain reduction between those who used cannabis products and those who used a placebo, a sham treatment that should have no effect.

“There is a distinct and clinically relevant placebo response in studies of cannabis for pain,” says Filip Gedin, PhD, a researcher in the Department of Clinical Neuroscience at Karolinska and lead author of the study published in JAMA Network Open.

Gedin and his colleagues also examined coverage the 20 studies received in the news media using Altmetric, a method of evaluating mentions in the media as either positive, negative or neutral. They did not identify the publishers of the 136 news articles that were analyzed or provide any examples of their coverage.

Researchers found that the cannabis studies received much greater media attention than other clinical studies and tended to be more positive, regardless of what the studies’ outcomes actually were. The media coverage of cannabis was so positive, in fact, that researchers wonder if it might influence findings in future studies.  

“The positive media attention and wide dissemination may uphold high expectations and shape placebo responses in future trials, which has the potential to affect the outcome of clinical trials, regulatory decisions, clinical practice, and ultimately patient access to cannabinoids for pain relief,” Gedin wrote. “We therefore consider this question to be of high importance, as the positive reporting toward cannabinoids regardless of study quality and effect size may subsequently lead to increased expectations that may ultimately influence the outcomes in clinical trials.”

The placebo effect is a well-documented but poorly understood condition in which a patient responds to a sham drug or treatment that should have no therapeutic value. A 2018 study at Northwestern University, for example, found that about half of patients who took a sugar pill they thought was an analgesic had a 30% reduction in pain – a level considered good enough for an actual painkiller.    

In another study, researchers identified some participants as “placebo responders” who are more likely to respond to a sugar pill because their brains react differently – which may explain why some patients find a medication effective and others don’t.    

Whatever the cause, researchers at the Karolinska Institute say more effort is needed to understand the placebo effect and how media coverage could make it even more potent.

“We cannot say with 100% certainty that media coverage is responsible for the high placebo response observed in our review,” Gedin wrote in an op/ed published in The Conversation.

“But given placebos were shown to be just as good as cannabis for managing pain, our results show just how important it is to think about the placebo effect and how it can be influenced by external factors – such as media coverage. For treatments, such as cannabinoids, that receive a lot of media attention, we need to be extra rigorous in our clinical trials.”

Study Finds Placebos Disrupt Pain Signals in Brain

By Pat Anson, PNN Editor

Much of the pain relief that a person gets from taking an analgesic medication is due to individual mindset, not the drug itself, according to new research that looks at how the human brain responds to a placebo.

The placebo effect is a well-documented but poorly understood condition in which a patient responds to a drug or treatment that is designed to have no therapeutic value. A 2018 study, for example, found that about half of patients who took a sugar pill they thought was an analgesic had a 30% reduction in pain – a level considered effective for an actual painkiller.    

To better understand how that is possible, researchers at Dartmouth University conducted a meta-analysis of 20 neuroimaging studies involving 603 healthy people who participated in placebo studies. Their findings, recently published in Nature Communications, showed that placebo treatments reduced pain-related activity in multiple areas of the brain.

"Our findings demonstrate that the participants who showed the most pain reduction with the placebo also showed the largest reductions in brain areas associated with pain construction," explains co-author Tor Wager, PhD, a Neuroscience Professor who is principal investigator of the Cognitive and Affective Neuroscience Lab at Dartmouth.

"We are still learning how the brain constructs pain experiences, but we know it's a mix of brain areas that process input from the body and those involved in motivation and decision-making. Placebo treatment reduced activity in areas involved in early pain signaling from the body, as well as motivational circuits not tied specifically to pain."

By examining brain images, researchers were able to identify the placebo effect in regions of the brain that process pain signals (nociception) and generate pain sensations.

They found that placebos strongly affect the thalamus, which processes sights, sounds and other types of sensory input; as well as the basal ganglia, which is important for motivation and pain-related activities.

Placebo treatments also reduced activity in the brain’s posterior insula, which is one of the areas involved in creating pain sensations. This suggests that placebos change the pathway for how pain is processed in the brain. 

"The placebo can affect what you do with the pain and how it motivates you, which could be a larger part of what's happening here," says Wager. "It's changing the circuitry that's important for motivation."

Previous research has found that placebos activate the brain’s prefrontal cortex, which triggers the release of natural, pain-relieving hormones that can block pain signals from being processed.

Researchers say placebo effects likely involve a combination of different brain reactions, depending on the placebo and people's predispositions. In other words, there is no uniformity in the placebo response because everyone is different.

"Our results suggest that placebo effects are not restricted solely to either sensory/nociceptive or cognitive/affective processes, but likely involves a combination of mechanisms that may differ depending on the placebo paradigm and other individual factors," said co-author Ulrike Bingel, PhD, a professor at the Center for Translational Neuro- and Behavioral Sciences at University Hospital Essen.

A 2016 study that looked at brain images of osteoarthritis patients found that about half had mid-frontal brain regions that had more connectivity with other parts of the brain, making them more likely to respond to the placebo effect. That could help could explain why some respond well to pain medication, while others do not.

Can Sugar Pills Relieve Chronic Pain?

By Pat Anson, PNN Editor

“Sugar pills relieve pain for chronic pain patients”

That is the actual headline in a news release issued this week by the Feinberg School of Medicine at Northwestern University. If you’re a pain sufferer and that doesn’t make you laugh or get your blood boiling – then the rest of this article probably will.

So be forewarned.

In an age when many chronic pain patients are being urged to try yoga, meditation, acupuncture and plain old aspirin, Northwestern researchers have concluded that many could find pain relief in a sugar pill.

That conclusion is based on a lengthy but small study of 63 patients with chronic back pain.  Twenty patients were given no treatment, while the rest were given a placebo – a sugar pill that they were told was pain medication. No one was given an actual painkiller.

Over the course of 8 weeks, participants tracked their pain on a smartphone app, MRI brain images were taken, and psychological profiles of each patient were made.

The study, published in the journal Nature Communications, found that about half the patients who took the placebo had a 30 percent reduction in pain, a level considered just as effective as a real painkiller.

Researchers said patients who responded to the sugar pills had a similar brain anatomy and psychological traits. The right side of their emotional brain was larger than the left, and they had a larger sensory area than people who did not respond to the placebo. The placebo responders also were more emotionally self-aware, sensitive to painful situations and mindful of their environment.

“This is the first brain imaging RCT (randomized controlled trial) specifically designed to study chronic pain patients receiving placebo pills compared to a no treatment arm,” said senior study author A. Vania Apkarian, PhD, a professor of physiology at Northwestern University Feinberg School of Medicine.  

“Daily pain ratings from a smart phone revealed that patients receiving placebo pills showed stronger pain reduction and a higher response rate compared to patients in the no treatment arm, indicating that placebo pills successfully induced analgesia that could not be explained by the natural history of the patient or the mere exposure to the study.”

Doctors ‘Should Seriously Consider’ Placebos

Although his study is small and needs to be replicated, Apkarian thinks doctors should put his findings to work.

"Clinicians who are treating chronic pain patients should seriously consider that some will get as good a response to a sugar pill as any other drug," he said. "They should use it and see the outcome. This opens up a whole new field."

Giving pain patients sugar pills would not only save healthcare costs, Apkarian says they would eliminate the risk of addiction and other side-effects from pharmaceutical drugs.

"It's much better to give someone a non-active drug rather than an active drug and get the same result," Apkarian said. "Most pharmacological treatments have long-term adverse effects or addictive properties. Placebo becomes as good an option for treatment as any drug we have on the market."

The medical community has long known about the potency of the placebo effect and put it to use. Doctors as far back as the late 18th century used placebo treatments “more to please than benefit the patient.”

Today, the gold standard of clinical trials is a “placebo-controlled study” in which some participants are given sugar pills and sham treatments. The medication or therapy being studied has to be found more effective than the placebo for the study to be considered a success.

Time magazine recently published a cover story on placebos, sharing the stories of real patients who find relief in placebo pills even though they know they’re fake.

You don’t need to enroll in a clinical study to take placebos. You can buy a bottle of Zeebo’s “honest placebo pills” for $14.95 on Amazon. Some of the reviews for Zeebo are hilarious.

“I have not bought this product, but just reading about it brightened my day. And the comfort of knowing that if I ever needed a good placebo, its right here available with free shipping and two day delivery. I feel better already!” said one reviewer.

“The pills do every thing promised, which is nothing,” wrote another reviewer. “I purchased them in the forlorn hope that they would fool my demented wife that they helped to relieve her chronic pain. I didn't expect much going in and I wasn't disappointed.”

Placebo Effect is All in Our Heads

By Pat Anson, Editor

A new study has given researchers a better understanding why some people given a simple sugar pill will say it significantly reduces their pain.

It’s all in their heads.

Using functional magnetic resonance brain imaging (fMRI), scientists at the Northwestern Medicine and the Rehabilitation Institute of Chicago (RIC) have identified for the first time the region of the brain that's responsible for the "placebo effect" in pain relief. It’s an area in the front part of the brain -- called the mid frontal gyrus -- that also plays a key role in our emotions and decision making.

In two clinical trials involving 95 patients with chronic pain from osteoarthritis, researchers found that about half of the participants had mid frontal gyrus that had more connectivity with other parts of the brain and were more likely to respond to the placebo effect.

The use of fMRI images to identify these “placebo responders” and eliminate them from clinical trials could make future research far more reliable. It could also lead to more targeted pain therapy based on a patient’s brain images, instead of a trial-and-error approach that exposes patients to ineffective and sometimes dangerous medications.

"Given the enormous societal toll of chronic pain, being able to predict placebo responders in a chronic pain population could both help the design of personalized medicine and enhance the success of clinical trials," said Marwan Baliki, PhD,  a research scientist at RIC and an assistant professor of physical medicine and rehabilitation at Northwestern University Feinberg School of Medicine.

“This can help us better conduct clinical studies by screening out patients that respond to placebo and we can just include patients that do not respond. And we can measure the efficacy of a certain drug in a much more effective manner.”

Baliki told Pain News Network that differences in the brain could explain why some prescription drugs – such as Lyrica (pregabalin) – are effective in giving pain relief to some patients, but not for others.

“If we do the same with Lyrica, maybe we can find another area of the brain that can predict the response to that drug,” he said.

The study findings are being published in PLOS Biology.

"The new technology will allow physicians to see what part of the brain is activated during an individual's pain and choose the specific drug to target this spot," said Vania Apkarian, a professor of physiology at Feinberg and study co-author. "It also will provide more evidence-based measurements. Physicians will be able to measure how the patient's pain region is affected by the drug."

Currently, most clinical studies involving pain are conducted on healthy subjects in controlled experimental settings. Those experiments usually induce acute pain through immersion in cold water, pressure or some other type of applied pain. Baliki says there are significant differences between acute and chronic pain, and the experiments often translate poorly in clinical settings where pain is usually chronic.