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Permalink Reply by Dr. Krishna Kumari Challa on March 25, 2022 at 8:21am

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How Does the Placebo Effect Work?

Placebo analgesia might be all in the head but with some help at the receptor site!

For decades, placebo effects have plagued clinical trials, with as many as one third of patients responding to supposedly inactive treatments for conditions like depression and pain.^1,2 Instead of discarding these responses, some researchers were intrigued: What neurobiological mechanisms could explain how a “fake” treatment produced real effects?

As early as the 1980s, researchers identified a key role for endogenous opioids in placebo analgesia: Administering the opioid blocker naloxone also blocked the pain-relieving effects of a placebo.³ Tor Wager, a neuroscientist at Dartmouth College, wanted to identify how endogenous opioid activity was altered in key brain regions during placebo pain relief. Using a radiolabeled μ-opioid receptor agonist, researchers assessed the availability of these receptors; greater endogenous opioid activity would mean less receptor binding by the labeled tracer. When participants were experiencing placebo-induced pain relief, the brain scans revealed altered endogenous opioid activity in several regions including those involved in pain modulation and emotion processing and regulation.⁴

But how do these brain regions work together to create a conscious experience? Researchers believe that pain is influenced by both bottom-up processes, like the signals coming in through peripheral nerves, and top-down processes, like attention. Placebos might intervene at either end. “They can block what's coming up from the spinal cord, which is the textbook definition,” said Wager. “And they can change how the brain constructs the experience of pain.” Recent research from Wager’s lab suggests that the latter may be more prevalent, indicating that nociceptive systems in the brain responded similarly to a painful stimulus regardless of whether the person reported feeling less pain due to a placebo treatment.⁵ Instead, said Wager, “[the placebo] works by changing the central value and motivational systems, so it's changing the suffering and changing the evaluation of pain.”

1. Furukawa TA, et al. Lancet Psychiat. 2016;3(11):1059-1066.
2. Sanders AE, et al. JAMA Netw Open. 2020;3(4):e202907.
3. Grevert P, et al. Pain. 1983;16(2):129-143.
4. Wager TD, et al. PNAS. 2007;104(26):11056-11061.
5. Botvinik-Nezer R, et al. Nat Commun. 2024;15(1):6017.
6. https://www.the-scientist.com/ts-digest/issue/what-s-the-difference...

Permalink Reply by Dr. Krishna Kumari Challa on September 2, 2024 at 9:10am

Incredible Placebo Study Shows Fake Pills Can Reduce Stress

The placebo effect is wild. Taking a sugar pill with no active medical ingredients can somehow trigger a psychedelic reaction in some people, if that's what they're expecting. Even more incredibly, placebos can work when people aren't being deceived too – when they know what they're taking isn't medication. In a new study, psychologists show this strange phenomenon can be leveraged as a simple way to reduce stress, at least in the short term for moderate levels of distress.
Exposure to long-term stress can impair a person's ability to manage emotions and cause significant mental health problems.
So it is interesting to see that an intervention that takes minimal effort can still lead to significant benefits.
MSU psychologist Darwin Guevarra and team prescribed a placebo for a group of 32 volunteers and offered no treatment to another group of 32 people.

The 64 participants all reported experiencing prolonged stress during the COVID-19 pandemic. Their stress levels, anxiety, and depression were measured before, in the middle, and at the end of the two-week trial.

The catch was, the placebo group knew they were getting pills with no active ingredients. They were instructed to take the inert plant fiber pills twice a day and had to fill out a pill-taking adherence survey daily.

Incredibly, those taking the placebo still had a decrease in stress, anxiety, and depression compared to the no-treatment group, despite knowing what they were taking was just a placebo.
As the sample size was small in this case, the researchers caution that more work needs to be done to see if the results hold true across different cultures and age groups and for longer time periods.

How this fascinating brain trickery works is not yet fully understood.
The data suggest that the effects of non-deceptive placebos on affective outcomes cannot be solely attributed to explicit expectations.
Other researchers have suggested that non-deceptive placebos may work through mechanisms such as implicit expectations, conditioning from prior experience with active treatment, and embodied cognition."

Whatever the exact mechanisms, the researchers suggest using a placebo to treat people experiencing moderate stress may help prevent them from deteriorating into more severe conditions.

"Remotely administered non-deceptive placebos have the potential to help individuals struggling with mental health concerns who otherwise would not have access to traditional mental health services," the researchers points out.

"This ability to administer non-deceptive placebos remotely increases scalability potential dramatically."
Other researchers argue there's not enough evidence to use placebos for treatments yet, as studies like these that support their effectiveness are small and too short-term.

This makes placebos perfect for use as a control in clinical trials to help eliminate biases, but more extensive research is required to confirm their therapeutic value.

Remotely administered non-deceptive placebos reduce COVID-related stress, anxiety, and depression

https://iaap-journals.onlinelibrary.wiley.com/doi/10.1111/aphw.12583

Permalink Reply by Dr. Krishna Kumari Challa on May 22, 2025 at 1:19pm

How the placebo effect tricks the mind into relieving pain

The detailed mechanism of how the placebo effect reduces the perception of pain in rats has been uncovered by  neuroscientists. These findings, published in Science Advances, could potentially lead to ways to harness the placebo effect in therapy.

If you're convinced you are taking a powerful painkiller, it could well reduce your perception of pain, even if the painkiller turns out to be a sham.

That's the power of the placebo effect. The brain, tricked into anticipating a benefit, produces the benefit itself.

Harnessing the placebo effect for pain relief could help to reduce dosages of painkillers, lowering the risk of both side effects and becoming dependent on medication.

Because it's a psychological effect, the placebo effect is much easier to induce and monitor in humans than in animals. But since only relatively noninvasive techniques can be used on people, it's hard to determine what's happening on a neural-circuit level.

The researchers conditioned rats by injecting them with a painkiller over four days. The animal came to associate injections with pain relief, so that when they were injected with a saline solution, the placebo effect kicked in. Many researchers didn't think that animals could experience the placebo effect. But the researchers succeeded in inducing it in rodents by using Pavlovian conditioning.

About a third of the rats exhibited the full placebo effect, another third had a partial placebo effect, and the remaining third hardly experienced any pain relief.

The research team was then able to study what was going on in the animal brains using neuroimaging methods that are too invasive to use on people.

Several brain regions were found to activate in response to placebo in neuropathic animals. That's very similar to results in humans. 

The team found that the placebo effect occurred as a result of brain signals related to the endogenous opioid system in the medial prefrontal cortex, a region at the front of the brain, which in the presence of the placebo injections set off the descending pain inhibitory system.

They strongly suspect that the same mechanism operates in people. The mechanism is similar to how pain relief occurs in humans.

Hiroyuki Neyama et al, Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia, Science Advances (2025). DOI: 10.1126/sciadv.adp8494

Permalink Reply by Dr. Krishna Kumari Challa 6 hours ago

Placebo effect can work as well as real medicine, but your body may need permission to use it
The placebo effect produces measurable physiological changes, such as endorphin and dopamine release, and can rival active treatments in effectiveness, even in surgical and veterinary contexts. Its efficacy is strongly influenced by social cues, authority, and ritual, suggesting that human biology evolved to respond to external signals before committing resources to healing. The placebo response cannot be self-activated at will and is dependent on structured social interactions, highlighting the deep integration of social context in human physiological regulation. This reliance on external permission to access internal healing mechanisms underscores both the power and limitations of the placebo effect.

The first time the placebo effect really got under my skin was when I read that roughly one-third of people with irritable bowel syndrome improve on placebo treatments alone. Usually this statistic is presented as a fascinating quirk of medicine. My reaction was anger.

Humanity possesses an extremely effective treatment, with essentially zero side effects—and patients need someone else's permission to use it.

The placebo effect refers to the improvements in symptoms that patients experience after they're given an inert treatment like a sugar pill. Driven by expectation, context and social cues rather than pharmacology, the placebo effect is often dismissed as all in the mind. But decades of research have shown it is anything but imaginary.

Placebo treatments can trigger measurable changes in the brain, immune system and hormone function. In studies on pain, placebos cause the brain to release endorphins, the body's natural opioids. In Parkinson's disease, placebo injections increase dopamine activity in the brain. The placebo effect isn't magic. It's biology.

Having spent nearly a quarter-century teaching evolutionary medicine, I've come to see placebos not as curiosities of clinical trials but as windows into how human biology responds to social signals. And it's that relationship that is exactly what makes the placebo effect unsettling.

Medicine works, even when it isn't medicine

The placebo effect is so reliable that researchers must account for it in nearly every clinical trial.

When testing a new drug, scientists compare its effects to what patients experience on a placebo treatment like sugar pills, saline injections or sham surgery. If the drug doesn't outperform the placebo, it rarely reaches the public. Placebo responses are common and powerful enough to rival active treatments.

Even surgery isn't immune to the placebo effect. In several well-documented studies of knee procedures, patients who received sham operations—incisions without the full surgical repair—improved almost as much as those who received the real procedure.

Clearly something real is happening inside the body. But the strangest part of the placebo effect is not that it works. It's what makes it work.

The prescription of belief

Placebo treatments tend to be more effective when delivered by credible authorities. Pills work better when prescribed by doctors wearing white coats. Expensive pills outperform cheap ones. Injections produce stronger responses than tablets.

Some researchers have even removed the deception from placebo experiments entirely. In open-label placebo studies, patients are directly told they are receiving a placebo; and yet many still report significant improvement.

But look more closely at how these studies are run. Patients are not simply handed a sugar pill and sent home. They receive an explanation from a clinician, in a medical setting, within a structured ritual of care: a context that may be doing much of the biological work.

Even when the deception disappears, the social scaffolding remains. The permission to heal is still being granted by someone else.

The placebo effect extends beyond the patient

The placebo effect is often framed as something happening inside an individual. But it does not operate in isolation.

Consider what happens in veterinary medicine. Dogs and cats cannot believe a treatment they're given will work; they have no concept of receiving medication. Yet when owners and vets believe an animal is being treated, they consistently report improvements in pain and mobility that medical tests do not confirm.

In one study of dogs with osteoarthritis, owners reported improvement roughly 57% of the time for animals receiving only a placebo.

The animals themselves may not have improved. But the humans caring for them perceived they had. The healing signal, it turns out, travels through the humans in the room.

When healing makes things worse

There have been times when going to the doctor made you less likely to survive. In the 19th century, mainstream medicine was built on bloodletting, purging and doses of mercury and arsenic—treatments that killed as often as they cured.

Homeopathy emerged in the late 18th century precisely in this context. Its founder, Samuel Hahnemann, was a physician horrified by the harm the conventional medicine of his time was causing. His highly diluted versions of contemporary remedies did nothing pharmacologically. But they also did not kill people, which put them decisively ahead of the competition.

Homeopathic patients not only survived but also reported dramatic recoveries from chronic ailments and acute infections alike. During the cholera epidemics of the mid-1800s, patients at homeopathic hospitals had lower death rates than those receiving standard care. Why was that?

The standard cholera treatment of the era was aggressive and exhausting; for a disease that already caused massive fluid loss, doctors often prescribed further bloodletting, along with toxic purgatives such as calomel—a form of mercury—to "flush" the system. In contrast, homeopathic care involved extreme dilutions of substances in water or alcohol, effectively providing hydration and a calm, structured environment without the physiological assault.

Death rates were lower not because homeopathy worked but because the placebo effect—combined with not poisoning patients—was more effective than the medicine of the day.

Healing is not free

The body needs resources to heal from injury and disease. Activating systems such as immune responses, tissue repair and inflammation at the wrong time can be dangerous.

A full-scale immune response is metabolically expensive, with fever increasing metabolic rate by roughly 10% per degree Celsius rise in body temperature. Triggered at the wrong time, this can deplete critical energy reserves needed for immediate survival, such as escaping a predator. Furthermore, misplaced or overzealous inflammation causes collateral damage to healthy tissues, potentially leading to chronic dysfunction.

Some researchers have proposed that placebo responses reflect a kind of biological health governor: a system that regulates when the body invests heavily in recovery. Cues from trusted individuals may be exactly the signal the body waits for before committing resources to recovery. A caregiver's reassurance, a physician's authority and the rituals of medicine may tell the body that conditions are finally stable enough to devote energy to healing.

If that interpretation is correct, the placebo effect is not a trick of the mind. It is an ancient biological system responding to social information.

Body under stress

The placebo effect resembles another system people struggle with today: the stress response.

Stress evolved to keep you alive in the face of acute danger—predators, famine, immediate physical threat. These days, this useful piece of biological engineering might fire when someone hasn't replied to your email. The system that once saved people's lives now makes many miserable over things that would have been unimaginable to their ancestors.

You can talk back to the stress response, consciously reappraising the threat—in other words, reframing a looming deadline not as a catastrophe but as a manageable challenge—to help quiet it. But notice what you cannot do: You cannot simply decide to activate your placebo response. You cannot will yourself to release pain-relieving endorphins by believing hard enough in a sugar pill. For that, you still need the ritual, the white coat, the authority figure. You need someone else.

The stress response, misfiring as it is, remains yours. The placebo response has been outsourced: not because it wasn't always social, but because even now, people still can't seem to access it on their own.

The uncomfortable implication

If belief can activate biological healing pathways, belief can also be manipulated. Charismatic figures, elaborate medical rituals and expensive treatments may produce real improvement in symptoms even when the underlying treatment is physiologically inert. That is how wellness culture works. It leverages the same social scaffolding of care to trigger the body's internal pharmacy, regardless of whether the treatment itself does anything.

The placebo effect is often celebrated as proof that the mind can heal the body. But I believe that may not be its most interesting lesson. It also reveals that human physiology evolved to take its cues from other people. Your brain, immune system and pain response are not isolated machines. They are deeply intertwined with social signals, expectations and trust.

In a world filled with doctors, advertisements, wellness influencers and elaborate medical rituals, that insight is both fascinating and profoundly maddening. People are walking around with one of the most powerful healing systems ever documented locked inside them, and they can reliably access it only when someone in a position of authority gives them permission.

This article is republished from THE CONVERSATION under a Creative Commons license. Read the original article.