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Placebo effect and why they work


I'm just wondering how the placebo effect works on people. If a patient is given fake drugs , how does that make him better? So what if they feel more "assured", how would that help the body immunity (t cells, phagocytes, etc) fight the infection better? How does phycological emotions affect the physical aspects of our immunity? Also I've read an interesting article online showing us that placebo effect works even when you know you are given fake drugs? This really complicates my understanding. How would such a approach even work? http://www.health.harvard.edu/blog/placebo-can-work-even-know-placebo-201607079926


Why Do Placebos 'Work'?

We all know the placebo effect is a powerful thing—it can ease pain, alleviate depression, turn CBD into a billion-dollar industry, and more. Less widely understood is why it works—how the human brain, in tandem with various other organs, can turn a simple sugar pill into something that, in some cases and for certain ailments, works just as well as the real, patented, super-expensive, active-ingredient-containing thing. For this week’s Giz Asks , we asked the leading experts on the placebo effect to illuminate this process for us.

John Kelly

Distinguished Professor of Psychology at Endicott College and Deputy Director of the Program in Placebo Studies at Harvard Medical School

Actually, placebos do not “work.” Because they are inert, placebos cannot have any direct effects on healthcare outcomes. Instead, the improvements in patient symptoms attributed to the placebo effect are due to the psychological components associated with the treatment ritual and the context within which it takes place. For example, the positive expectations that result from a warm and empathic therapeutic relationship between patient and clinician. This is not to say that placebo effects are “all in the patient’s head” or that they are not “real.” There is abundant evidence from pharmacological and neuroimaging studies that the placebo effect is associated with genuine neurobiological responses in patients. The point is that these effects are attributable to the psychological components of the treatment context, and not to the placebo treatment itself.

Magne Arve Flaten

Professor, Biological Psychology, Norwegian University of Science and Technology, and co-editor of Placebo and Pain: From Bench to Bedside

Placebos work because people expect them to work, which initiates changes in the brain that has consequences for e.g. the experience of pain.

Firstly, the person must believe that the placebo is in effective treatment. Secondly, the person must receive that treatment (a pill, acupuncture or other treatment) against some symptom (pain e.g.). Thirdly, this will induce an expectation in the person that the symptom will be reduced. That expectation is also a process in the brain. Fourthly, that expectation in the brain leads to changes in other parts of the brain, so e.g. the impact of pain in the brain is reduced. That reduction in the symptom is the placebo response.

Luana Colloca

Associate Professor, Pain and Translational Symptom Science, University of Maryland School of Nursing, and co-editor of Placebo and Pain: From Bench to Bedside

A placebo refers to a physiologically inert substance, pill, or intervention that produces a therapeutic effect. The placebo pill in itself does not have any effect. Rather it is the action of taking a pill or undergoing a procedure that produces the beneficial effect. What the placebo leverages is the expectation of relief that is based on the verbal suggestions of benefit, memories of a past beneficial experience, and other cognitive factors. These expectations are what give rise to the placebo effect.

In addition, social learning, the process of observing someone else have a therapeutic effect from an intervention has been shown to elicit the placebo effect. Furthermore, placebos have been found to engage various body systems including opioidergic, dopaminergic, and endocannabinoid systems in producing their modulatory effects. Therefore, placebos work via the creation of expectancies and the activating of these endogenous modulatory mechanisms to produce effects that mimic that of a pharmacological treatment. Namely, expectancies of a therapeutic outcome facilitate the activation of modulatory systems controlling symptoms and recovery processes.

We have demonstrated that the violation of expectancies, such as when a discrepancy between what is expected and what is actually received causes an extinction of placebo effects. Several studies have documented the release of endogenous neuropeptides crucially involved in placebo-induced benefits in pain, Parkinson’s disease, and depression. Placebo effects can be elicited in patients suffering from chronic disorders even when patients appear to be unresponsive to pharmacological interventions. The challenge is to understand why some people respond to placebos with clinically relevant effects, some respond to placebos minimally, and some do not respond to placebos at all. For example, the use of the combination of specific genetic variants within some genes and the careful evaluation of patients’ phenotypes, integrated into clinical practice for assessing the individual’s potential to benefit from placebo effects. Gaining a deeper understanding of the biological and behavioral predictors of placebo effects related healing processes has important implications for precision and personalized medicine and can guide more effective mechanistic-driven therapeutic strategies.

Michael Thase

Professor, Psychiatry, Perelman School of Medicine (University of Pennsylvania)

Within the context of ongoing care or treatment research, the placebo effect represents all aspects of the treatment process other than the specific effect of the intervention (e.g., the passage of time, the expectation of benefit, the sense of being helped, talking to caring people, restoration of morale, etc.). In such settings, the easier to treat the illness and the better the prognosis of the patient/participant, the higher the likelihood of a placebo response.

Part of the response to the actual pill placebo is no doubt classical conditioning (popularized by the image of Pavlov’s dogs, but human have conditioned responses, too). Studies of pain medications, for example, demonstrate the positive placebo responses are mediated by activation of the endogenous opiate (aka endorphin) system.

Expectancy probably plays a larger role in placebo responses than classical conditioning and, with this in mind, the side effects and time course of placebos mimic their matching acting medications (e.g., headache pills takes minutes to hours, placebo antidepressants take weeks, etc.)

There are also negative placebo effects, sometimes called nocebos, in which expectancy or classical conditioning elicits worsening.

Fabrizio Benedetti

Professor of Physiology and Neuroscience at the University of Turn Medical School, and the author of Placebo Effects: Understanding the mechanisms in health and disease , among other books

A placebo is a treatment, be it pharmacological or not, that has no specific therapeutic properties for the condition being treated, e.g. fresh water, flour, an empty syringe. In other words, it is a fake therapy which the patient believes to be true. The placebo effect is the effect that follows the administration of a fake therapy. However, it is important to stress that what matters is not so much the fake therapy itself, namely, water or flour, but the psychosocial context around the patient and the treatment or, in other words, the whole ritual of the therapeutic act. Therefore, the placebo effect is a psychological effect deriving for the patient’s expectations, trust, hope, beliefs. The patient undergoes a therapeutic ritual, say an injection, s/he believes it is true, expects a benefit, and sometimes this is enough to produce an improvement.

Placebos, i.e. fake therapies, work because expectations, hope, trust, beliefs are capable of triggering in the patient’s brain the same mechanisms that are activated by drugs. Therefore, placebos and drugs share a common mechanism of action. It is important to point out that this holds true for some medical conditions only, such as pain, motor performance, anxiety, depression, that it, all those conditions whereby psychological factors are important in the course of illness. Conversely, placebos cannot kill the bacteria of pneumonia, nor can they stop cancer growth or prevent pregnancy.

Although it may sound weird, sometime placebos work even though patients know what they are receiving is a fake treatment. After all, this is not surprising, as we are conditioned to many rituals in our life. It is not different from watching a horror movie. You know everything is fake: the victim is an actor, the knife is made of plastic, blood is actually tomato juice. None the less, you are scared and do have physiological reactions: increase in heart beating, sweat, shivers, and the like.

In conclusion, placebos work because psychological factors are crucial in many circumstances. The doctor’s words are sometimes as important as drugs, and today neuroscience tells us that words hit the same targets of drugs. Actually, it would be better to say that it is drugs that hit the same targets of words, as words and social interaction emerged during evolution much earlier than drugs.

Charlotte Blease

PhD, Program in Placebo Studies, Harvard Medical School

There are many senses in which a placebo can “work.” So, strictly speaking, we can’t answer unless we know what sense of placebo we are talking about.

There are two nuanced ways in which the term placebo is currently used. First, for centuries doctors adopted a kind of medical vernacular when they speak of giving patients ‘placebos.’ In clinical settings docs have (and surveys show, frequently still do) prescribe pills or suggest treatments that our beguiling MDs don’t believe will actually work. Rather, they want to instill some hope in us patients (or get rid of us). For example, doctors might prescribe antibiotics for a recurrent viral infection—even though they know that the ‘ingredients’ will not target the malady. Of course, this raises many ethical questions. Notwithstanding, in this sense, a placebo works, if it gets rid of us pestering patients, calms us down, or makes us feel a bit better (which I’ll get to later).

Second, placebos in research mean something rather different. Here placebos are ‘controls’—or a kind of measuring tool—used to test for the efficacy of new healthcare interventions such as drugs. In randomized clinical trials, there are typically three groups of participants: one group of patients is randomly allocated to the new treatment another group is given a ‘placebo’ and a third group is on a waitlist. Placebo treatments should ideally be identical to the real treatment except for those components that the medical researchers believe to be crucial to it working. For example, if you are testing a new antibiotic, ideally the placebo should look and taste just like the real thing (but it shouldn’t be an antibiotic). Participants and the clinicians dispensing the treatments should also be blind to the allocation. This is to control for all surprisingly noisy ways in which human psychology can interfere with reporting in clinical trials. For example, we respond differently when we’re being observed, prodded, and analyzed (called Hawthorne effects). We also people-please (called “responder biases”)—for example, we might report to our clinician we feel better when, in fact, we don’t (like telling a waiter the meal was great, when it was mediocre). And sometimes, when we expect we are going to get better, we actually do feel better. These are called placebo effects: the genuine, salubrious psychobiological effects that are studied by health scientists. So—taken together—for a placebo to work in a clinical trial it has to control for all of this noise. That way, researchers can zero in on the actual effects of the treatment.

Now, if we are really asking “Why do drugs that have no active ingredients help us to get better?” the honest answer is that it depends on: (a) our symptoms and (b) the stuff that happens around the prescribing of the placebo pills. Placebo effects don’t shrink tumors but they are effective for pain, depression, fatigue, and other symptoms. To further complicate matters, placebos won’t do their magic—i.e. give rise to placebo effects—unless we believe that they’ll work, and this, in turn, may be modified by how empathetic our practitioner is, or how competent we believe the doctor dispensing the placebos to be. To confuse matters further, we may not need a ‘placebo’ or a doctor to elicit these beneficial effects. We may just need someone caring who exudes just the right amount of care and attention.

Ted Kaptchuk

Professor of Medicine and Professor of Global Health and Social Medicine at Harvard Medical School, and Director of the Harvard’s Program in Placebo Studies and the Therapeutic Encounter (PiPS)

Perceptions and placebo responses are “Bayesian inferences.” People/patients have chronic pain in all kinds of situations: they have pathophysiology but no symptoms symptoms and not pathophysiology and everything in between. This means that perceptions/sensations (including symptoms like pain and fatigue) are not only information the body senses and registers there like a computer print-out. The bottom-up (afferent pathways) are getting signals all the time. The nerves only send up the “difference that makes a difference.” Most of the signals don’t go upwards. If they did the brain would be in overload and fry.

The decision of what this difference is ultimately. figured out using an architecture of Bayesian inference. Is this symptom real or am I getting [a] false signal? When patients enter the ritual/drama of healing/take placebos… this negotiating sometimes (not always) favors the healing encounter… The nerves allow healing to happen… That is, start to feel less pain or fatigue because the healing that is happening is allowed to register.

Beth Darnall

Associate Professor of Anesthesiology, Perioperative and Pain Medicine (Adult MSD) and, by courtesy, of Psychiatry and Behavioral Sciences (General Psychiatry & Psychology (Adult)) at the Stanford University Medical Center

People often think placebo means fake treatment. In reality, placebo effects are comprised of non-specific contextual factors, an individual’s beliefs about a treatment, and historical factors. There are multiple mechanisms that explain why placebos work.

Consider the example of pain. If we believe a treatment will reduce our pain, we are more likely to engage with the treatment. Similarly, if we like our doctor and believe they have our best interests at heart, we are more likely to engage with a treatment. We are more likely to be attuned to pain reductions if we are expecting them (confirmation bias). Having expectations for pain relief may reduce attention to pain and anxiety about pain, both of which are associated with reduced pain processing in the brain. Researchers who study placebo analgesia show that it is associated with hormonal changes, autonomic responsivity, and brain activity, thereby underscoring that the placebo exerts multiple psychobiological effects and is multifactorial.

On the flip side, if we think something will increase our pain, we can experience nocebo effects—actual increased pain. One interesting study conducted by Bingle, Tracey, and colleagues examined the effect of expectations on response to heat pain testing and intravenous opioid administration in healthy individuals. Everyone who participated in the experiment experienced heat pain (thermode placed on the hand) and an intravenous solution under three different conditions. In the first condition, while participants received heat pain, they were told they were receiving a powerful painkiller through the IV. In the second condition, while they received heat pain they were told they were receiving an inert solution through the IV. In the third condition, while they received heat pain they were told they were receiving a solution that would increase their pain. There was deception used in this study. In actuality, in all three conditions participants were receiving remifentanil, an opioid medication. Every participant underwent each of the described three experimental conditions, and the only thing that was different was the participants expectations as to what they would experience—more or less pain. The researchers found that when participants were told they were receiving a powerful painkiller, the analgesic benefit of remifentanil was doubled relative to when participants believed they were receiving the inert solution. When participants believed they were receiving a medication that would increase their pain (nocebo), the analgesic benefit of remifentanil was completely abolished. The researchers correlated the participants pain reports with neuroimaging findings showing increased or reduced pain processing based on their expectations and experience of actual pain. This study does not mean that pain is not real, or that it is all in our minds. Rather, it illustrates the power of our mind. These results are especially important to consider in the face of today’s medical climate where patients who have taken prescription opioids long term are suddenly being denied access to the medication, or are being force tapered. These circumstances will understandably cause people to experience nocebo responses, and this has been shown to contribute to reduced opioid analgesia while opioids are decreasing. This is a recipe for patient suffering. It is my wish that we use placebo/nocebo science to inform more compassionate patient care.


How does astrology work?

Hardened scientists will tell you astrology doesn't work. Believers will tell you it does. Who is right? They are both right. It depends on what you mean by the word "work". Astrology is the belief that the alignment of stars and planets affects every individual's mood, personality, and environment, depending on when he was born. Astrologers print horoscopes in newspapers that are personalized by birth date. These horoscopes make predictions in people's personal lives, describe their personalities, and give them advice all according to the position of astronomical bodies. A survey conducted by the National Science Foundation found that 41% of respondents believe that astrology is "very scientific" or "sort of scientific". Let us break the original question into two separate, more specific, questions: 1) Does the position of astronomical bodies affect a person's life? 2) Can horoscopes make people feel better? These questions are both very different. Both can be determined scientifically.

Does the position of astronomical bodies affect a person's life (beyond basic weather)?
No. The position and orientation of the sun relative to earth does cause seasons. Anyone who has shoveled snow off his walk in January when he would rather be at the beach can tell you that the astronomical bodies definitely affect our lives. Solar flares cause electromagnetic disturbances on earth that can disrupt satellites and even cause blackouts. The position of the moon causes ocean tides. If you are a fisher, the position of the moon can have a significant effect on your livelihood. The solar wind causes beautiful aurora, and sunlight itself is the main source of energy for our planet. But all of these effects fall under the umbrella of basic weather not astrology. Astrology purports that astronomical bodies have influence on people's lives beyond basic weather patterns, depending on their birth date. This claim is scientifically false. Numerous scientific studies have disproven that astronomical bodies affect people's lives according to their birth date. For instance, Peter Hartmann and his collaborators studied over 4000 individuals and found no correlation between birth date and personality or intelligence. In one of the most famous experiments, Shawn Carlson had 28 astrologers make predictions and then tested the accuracy of their predictions. Before conducting the experiment, he fine-tuned the method so that various independent scientists agreed the method was scientifically sound, and also so that all of the astrologers agreed the test was fair. As published in Nature, he found that the astrologers could do no better at predicting the future than random chance. These results agree with fundamental science.

Fundamentally, there are four forces of nature: gravity, electromagnetism, the strong nuclear force, and the weak nuclear force. If an object affects a person, it must do so by interacting through one of these fundamental forces. For instance, strong acid burns your skin because the electromagnetic fields in the acid pull strongly enough on your skin molecules that they rip apart. A falling rock crushes you because gravity pulls it onto you. A nuclear bomb will vaporize you because of nuclear forces. Each of the fundamental forces can be very strong. The problem is that they all die off with distance. The nuclear forces die off so quickly that they are essentially zero beyond a few nanometers. Electromagnetic forces typically extend from nanometers to kilometers. Sensitive equipment can detect electromagnetic waves (light) from the edge of the observable universe, but that light is exceptionally weak. The gravity of a star technically extends throughout the universe, but its individual effect on the universe does not extend much beyond its solar system. Because of the effect of distance, the gravitational pull of Polaris on an earth-bound human is weaker than the gravitational pull of a gnat flitting about his head. Similarly, the electromagnetic waves (light) reaching the eye of an earth-bound human from Sirius is dimmer than the light from a firefly flitting by. If the stars and planets really had an effect on humans, then gnats and fireflies would have even more of an effect. Even if the gravity of the planets was strong enough to affect you, an alignment of the planets would not lead you to win the lottery for the simple reason that a literal alignment of the planets never happens in the real world.

Can horoscopes make people feel better?
Yes. But it has nothing to do with the horoscopes being right. Horoscopes make people feel better because of a psychological effect known as the placebo effect. The placebo effect is when the belief in a useless method actually makes a person feel better. It is the belief itself, and not the method, that causes the improvement. The placebo effect has been scientifically verified. If you give pills to ten sick patients containing only water, but tell them it is a powerful new drug that will help them, and then have ten sick patients not take the pills, then over time the patients taking pills will show better health. Because of the placebo effect, a new drug must not just be proven to make patients feel better. It must be proven to perform better than a placebo. In accurate medical experiments, the control group is not a collection of untreated patients. Rather, the control group is a collection of patients receiving a placebo. The placebo effect is the mechanism at work with astrology. Many people believe in astrology. When they read their horoscope and follow its advice, they feel better. But it is the belief itself and not the astrology that is making them feel better. Many pseudo-scientific treatments – from crystal healing to homeopathy – help people through the placebo effect. Believing in a treatment that does not actually do anything may help, but believing in a treatment that does is even better. Sticking to scientifically proven treatments gives you the benefit of the belief and the benefit of the treatment's action. For instance, instead of reading your horoscope each morning, go for a walk. Exercise is proven to be good for body and mind, and your belief in its effect will also help you.


Mechanisms of the placebo effect and of conditioning

A placebo is a sham treatment, such as a pill, liquid, or injection without biological activity, used in pharmacology to control for the activity of a drug. However, in many cases this placebo induces biological or psychological effects in the human. Two theories have been proposed to explain the placebo effect: the conditioning theory, which states that the placebo effect is a conditioned response, and the mentalistic theory, which sees the patient's expectation as the primary cause of the placebo effect. The mechanisms involved in these processes are beginning to be understood through new techniques of investigation in neuroscience. Dopamine and the endorphins have been clearly shown to be mediators of placebo effects. Brain imaging has demonstrated that placebos can mimic the effect of the active drugs and activate the same brain areas. This is the case for placebo-dopamine in Parkinson's disease, for placebo-analgesics or antidepressants, and for placebo-caffeine in the healthy subject. It remains to be understood how conditioning and expectation are able to activate memory loops in the brain that reproduce the expected biological responses.


Is A Placebo A Sham If You Know It's A Fake And It Still Works?

Placebos are commonly thought of as fake treatments that people think are real. But they may be helpful even if you know they're fake.

Placebos can't cure diseases, but research suggests that they seem to bring some people relief from subjective symptoms, such as pain, nausea, anxiety and fatigue.

But there's a reason your doctor isn't giving you a sugar pill and telling you it's a new wonder drug. The thinking has been that you need to actually believe that you're taking a real drug in order to see any benefits. And a doctor intentionally deceiving a patient is an ethical no-no.

So placebos have pretty much been tossed in the "garbage pail" of clinical practice, says Ted Kaptchuk, director of the Program for Placebo Studies and the Therapeutic Encounter at Beth Israel Deaconess Medical Center. In an attempt to make them more useful, he has been studying whether people might see a benefit from a placebo even if they knew it was a placebo, with no active ingredients. An earlier study found that so-called "open-label" or "honest" placebos improved symptoms among people with irritable bowel syndrome.

And Kaptchuk and his colleagues found the same effect among people with garden-variety lower back pain, the most common kind of pain reported by American adults.

The study included 83 people in Portugal, all of whom had back pain that wasn't caused by cancer, fractures, infections or other serious conditions. All the participants were told that the placebo was an inactive substance containing no medication. They were told that the body can automatically respond to placebos, that a positive attitude can help but isn't necessary and that it was important to take the pills twice a day for the full three weeks.

Then half the group was assigned to simply continue their usual treatment regimens, which included things like non-opioid painkillers, rest and alternative or complementary remedies. (They were also given the opportunity to use the placebo pills at the end of the study, if they chose.) The other half were assigned to continue with their usual treatment, but to also take the placebo.

Participants rated their pain levels and their difficulty in performing daily activities, like getting dressed or climbing stairs, at the beginning and the end of the three-week study. And researchers found that people who received the placebo saw their scores for both usual and maximum pain levels drop by 30 percent, compared to 9 percent and 16 percent declines for the control group. The placebo group also reported a 29 percent reduction in their score for difficulty in performing daily activities, while the control group saw no change. (A higher score on that test indicated more difficulties.)

That translates to a tangible reduction in pain, says Kaptchuk, who is also a professor at Harvard Medical School. "Patients would feel the difference and physicians would notice it," he says.

The study was published earlier this month in the journal Pain.

"These kinds of studies show that a package of care that includes an ethical placebo can have a benefit," says Jeremy Howick, a senior researcher in the University of Oxford's Nuffield Department of Primary Health Care Sciences who researches placebos but wasn't involved in this study. "You might not need to deceive patients to get an effect."

The idea of actually telling people they are getting a placebo is a relatively new line of research. The vast majority of studies that have tested placebos have compared people getting no treatment to people getting a placebo that they thought was a real treatment. A 2010 Cochrane Review of that sort of randomized trial across a variety of conditions found no major clinical effects, generally, though the authors said there was a modest effect in outcomes reported by patients.

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In other words, placebos can make people feel better. In a 2011 study by Kaptchuk and colleagues, placebo treatments used in asthma patients produced almost no change in an objective measure of lung function, while the group taking the active drug, albuterol. saw an improvement. But patients said their asthma symptoms improved when they took albuterol, a placebo inhaler or a fake acupuncture treatment, and the reported improvements were better than in patients given no treatment at all.

There's also the question of what, exactly, a placebo is. It's usually defined as a substance that has no therapeutic effect for a given condition. But there's no question that people also benefit from the entire interaction with a physician. "It's absolutely not the pill," Kaptchuk says. "It's what surrounds the pill," he says. That includes a trusting relationship between the doctor and patient. In that situation, if you think the treatment might possibly work — even if you have been told the pill is inactive, as in the back pain study — the brain can fill in the picture and improve symptoms, he says.

Kaptchuk describes this latest study as a proof of principle, and says it has to be replicated among larger groups of people over longer periods of time. But if it pans out, he says he thinks open-label placebos could be a helpful "watch and wait" strategy for people who are considering taking medications for common conditions where urgency isn't a problem. Meantime, he's part of a study at Dana-Farber Cancer Institute looking to see if open-label placebos can reduce fatigue in cancer survivors.

But for placebos to have a place in everyday care, he says, will take a shift in medicine. "It will take patients demanding it," he says.


WHY ARE THESE STUDIES IMPORTANT? WHAT DOES THE FUTURE HOLD?

The authors point out that placebo effects make the study of new treatments very difficult. This is because the effect of a new treatment has to be much greater than the placebo effect, which can be quite large.

If the placebo effect is strong, it is harder to prove that a drug or treatment is effective. This means that most research trials have to use many more people than they would if the placebo effect was very small or did not exist at all. This makes the studies cost more and take longer to accomplish. Better understanding of the placebo effect will help us to design faster, more effective studies to better combat disease. Perhaps one day we will also learn how to better harness the positive parts of the placebo effect to use as part of medical therapy.


Placebos Do Work: Let's Consider Why

"We not only know placebos work," Dr. Harriet Hall explains in a fascinating, well-researched article in Skeptic, "we know there is a hierarchy of effectiveness":

* Placebo surgery works better than placebo injections
* Placebo injections work better than placebo pills
* Sham acupuncture treatment works better than a placebo pill
* Capsules work better than tablets
* Big pills work better than small
* The more doses a day, the better
* The more expensive, the better
* The color of the pill makes a difference
* Telling the patient, "This will relieve your pain" works better than saying "This might help.

To help convey the power of persuasion that doctors routinely wield, Dr. Hall's article opens with a treatment anecdote that gives a flavor of the article to come:

"Jane D. was a regular visitor to our ER," she recalls, "usually showing up late at night demanding an injection of the narcotic Demerol, the only thing that worked for her severe headaches. One night the staff psychiatrist had the nurse give her an injection of saline instead. It worked! He told Jane she had responded to a placebo, discussed the implications, and thought he'd helped her understand that her problem was psychological. But as he was leaving the room, Jane asked, "Can I get that new medicine again next time instead of the Demerol? It really worked great!"

In short, when we think something will work, its chances of doing so increase dramatically. Dr. Hall then refines that idea by giving it a sharper explanation: "What’s effective is not the placebo," meaning the benefit patients derive from a "dummy" pill, "but the meaning of the treatment." She hypothesizes that the power of the effect depends on four variables: patient expectancy motivation (the desire to improve one's health) a certain amount of conditioning, including from advertising and endogenous opiates, or pain-relieving chemicals produced in the brain, which copy the effect of pain-relievers such as opiates.

To that end, it isn't so surprising to hear her claim: "A substantial percentage of the effects from antidepressants may be placebo effects." Her assertion jibes with one that PT blogger Dr. Philip Newton made on this site last December: "In some controversial cases, such as selective serotonin reuptake inhibitor (SSRI) anti-depressants," he wrote, "placebo effects are thought to account for a major proportion of the positive effects of a drug."

Researchers have of course long-known and long-studied the effect of placebos, and just as obviously try to minimize the effect by controlling for it. In "Listening to Prozac but Hearing Placebo," however, a significant meta-analysis of SSRI antidepressants given to 2,318 patients with depression, Drs. Irving Kirsch and Guy Sapirstein found in 1998 that "the placebo response is a predictor of the drug response," which is rather telling, and a relation they chart quite dramatically on the following graph:

Not only that, but "the placebo response was constant across different types of medication (75%), and the correlation between placebo effect and drug effect was .90." As they put it, "These data indicate that virtually all of the variation in drug effect size was due to the placebo characteristics of the studies," which calculated placebo as the single largest factor, accounting for 50.97% of SSRI efficacy.

"Our results are in agreement with those of other meta-analyses," Kirsch and Sapirstein explained, "revealing a substantial placebo effect in antidepressant medication." "They also indicate that the placebo component of the response to medication is considerably greater than the pharmacological effect."

Kirsch and Sapirstein's study never got the airtime it deserved. A serious, well-executed meta-analysis, it was quickly drowned out by a litany of other studies that assessed the efficacy of antidepressants in comparative terms with each other, rather than as a base-level investigation of efficacy, with each drug studied relative to placebo alone. The shift in emphasis played a big role in tilting interest more toward comparative pharmacology, shunting the effect of placebos aside.

Still, Dr. Hall's striking article hopefully will return our attention to the exciting opportunities and real quandaries (medical and ethical) that the placebo effect poses, in so far as it can have a documented, substantial, and lasting impact on patients without costs or side effects. Hence the pun in my title: placebos do work—which is to say, they have effects that are part of the treatment process and should not be discounted as such.

The placebo indicates that the mind and its sometimes unconscious effects are incredibly powerful instruments in treatment, and that we're getting but half the story in focusing so relentlessly on biology and genes, to the expense of so much else.

Granted, offering placebo alone to patients (something I'm not advocating) would raise charges of quackery and suspicions that the doctor or psychiatrist is inherently against medication, a position viewed with great skepticism today. To put that another way, patients so often expect medication that if the doctor or psychiatrist doesn't prescribe any the patient can view that outcome (and physician) negatively, as minimizing their problem and even as hinting that they've wasted time.

With that level of expectancy, however, the placebo effect is doubtless ramped up even more, accounting for still-greater pharmaceutical effects, something that's worth taking into consideration, not least because it adds a benefit or a wrinkle—depending on perspective—to the treatment options available.

I am suggesting that we pay a lot more attention to how those forms of persuasion influence medical and psychiatric practice across the board.


How the Placebo Effect and Culture Affect Healing Outcomes

As we’ve discussed the placebo response over the past couple of weeks—and how physicians can harness that power through their manner and behaviors—it is important to recognize the immense impact that cultural context can have on our healing process.

The following excerpt is from my book, How Healing Works, and provides my experience in understanding just how influential cultural context can be on the effect of a placebo in triggering our own inherent ability to heal and recover. I trust it will help you (and your doctor) recognize how best to implement placebo treatments moving forward.

It’s been revealed that the healing effect from fake treatments could vary from 0% to 100%—even for the same disease and same treatment—depending on the context and cultural meaning in which they were delivered. In other words, the cultural context influences the meaning, which in turn influences the biology, the pathology, and the outcome. The effects were very specific.

In fact, the meaning and context surrounding how a treatment was delivered had a much greater impact on healing than the treatment modalities themselves. Inert treatments for pain worked better if you gave them by needle rather than a pill gave them in the hospital rather than at home, applied them more often rather than less frequently, charged more for them rather than less, and delivered them with a positive and confident message rather than a neutral or skeptical message.

Acupuncture was found to be more effective the closer the study was conducted to China, where acupuncture was developed and is widespread. I suspect surgery works better in the West, though no one has studied that. It seemed that the magnitude of a person’s healing depended less on the suggestibility and belief of the individual patient than on the collective belief of the culture and the ritual created to deliver that belief.

Professor Ted J. Kaptchuk, director of the Center for Placebo Studies at Harvard Medical School, is one of the world’s most respected researchers on the placebo response. In a recent analysis, he sheds light on the variability of these effects by comparing three types of healing encounters: Navajo ceremonial chants, acupuncture treatment in the Western world, and the biomedical provision of health care. He describes each encounter as being surrounded by beliefs, narratives, “multi-sensory dramas,” and culturally defined influences, all of which can be described as rituals in the treatment of illness.

Looking at this research, I began to wonder if one of my patients got better from surgery not because it was “real,” but because surgery was more culturally meaningful to him than the other treatments he had undergone? I was skeptical of this explanation.

The patient had been through many treatments and should have benefited even if they were from placebo effects. But two studies conducted after I had seen him seemed to contradict this assumption. In those studies, patients were randomly assigned to get either the cement or balloon injections into collapsing disks (as he had received) or a fake procedure that mimicked the real injections but did not manipulate the spinal disc in any way. In both studies, patients who underwent the fake procedure did just as well as those who got the real procedure.

Sham Surgery Studies

I still found this hard to believe. Could it be that, at least for pain, the meaning and context of a treatment produced much of the healing, even in patients who were not suggestible? Even when “hard” procedures were used, such as surgery, that manipulated tissues and corrected anatomy? To test this assumption, my team and I did a meta-analysis of all surgery studies of chronic pain, whether in the back, knees, abdomen, or heart.

We selected studies that compared real surgery to sham surgery, in which patients and doctors went through the ritual of surgery but no real correction of anatomy was done. We were able to determine the quality of the studies and then combine results into a single estimate of the contribution to healing pain from “true” surgery. The final analysis showed equally good improvement of any pain condition when the ritual of surgery was applied to the patient but no actual surgery was done.

These sham surgery studies showed that, at least for pain treatments, healing occurs from something else. Could it be that the millions of surgeries done every year to treat pain produce healing because they are powerful types of ritual placebos? Could it be that healing is connected to patients’ beliefs and behavior and to those around them more than the specific treatment they received?

Collective vs Individual Belief

Professor Kaptchuk has done two studies exploring to what extent the effect of treatment depends on collective belief versus individual belief. In one study, all patients with a painful abdominal condition (irritable bowel syndrome or IBS) were given a fake treatment—sham acupuncture. However, the social ritual was varied between groups to enhance the dose of collective belief. In one group the practitioner came in and said very little and delivered the treatment. In a second group, the practitioner explained how the treatment works and set the expectation that the treatment will work.

In the third group, a prominent physician from a prominent medical school delivered the treatment with a full explanation and a story about the good results others had obtained with the treatment. All the patients held about the same amount of individual belief in acupuncture at the beginning of the study. But the greater the social meaning produced by the ritual, the better the effect. In the third group, the benefit the patients experience is greater than that achieved by the best drugs approved for treatment of IBS.

In a second study by Kaptchuk, patients were actually told ahead of time that the treatment was fake. One group was given placebo pills with this description: “Placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body, self-healing processes.” This statement created an expectation that even these placebos have an effect. A second group of IBS patients was given no treatment but with the same quality of interaction with providers. The group given the placebo (and who knew it was placebo) had significantly better pain reduction and improved quality of life.

No matter what form the ritual takes, says Kaptchuk, these can have powerful influences on the healing process. “We cannot explain the effects of rituals using placebo treatments simply by belief and expectation,” Kaptchuk explains. “While belief may contribute some to the outcome in these studies, the effects produced by healing ritual are much larger than can be explained by what the patient believes about the treatment. The main reasons these effects occur is still a mystery.”

How The Body Reacts

Research suggests that healing rituals are associated with modulations of symptoms through neurobiological mechanisms, just like we see from drugs. They can not only affect pain, but change the immune system, alter organ function, shift brain processing, and even influence specific cell receptors and genes. One study, done by renowned placebo researcher Professor Fabrizio Benedetti of the University of Turin, Italy, demonstrated that if you link a placebo treatment ritual to a painkiller, you can continue to get pain relief with the placebo after withdrawing the painkiller. And even more remarkably, the placebo will work using the same cellular mechanism of the painkiller to which it was linked.

The body not only can learn to heal, it can be taught which specific mechanism in the body to use to produce the effect. Placebo effects, writes Kaptchuk, are often described as “non-specific.” He suggests instead that they should be considered—and further researched—as the “specific” effects of healing rituals.

To learn more about how your physician can leverage the power of the placebo effect in your health, see our Harness the Power of Placebo for Your Patients guide. And, of course, to read more about this topic and all of integrative health, check out How Healing Works.


Footnotes

This work was supported by National Institutes of Health Grant R01 AT 001415 (J.-K.Z.), Italian Ministry of University and Research-Fondo per gli Investimenti della Ricerca di Base Grant RBNE01SZB (F.B.), National Institute of Mental Health Grant MH-49553, and a physician-initiated grant from Eli Lilly & Company (H.S.M.), and by funding from the Mind, Brain, Body, and Health Initiative (T.D.W.). We thank the many collaborators and colleagues who have provided invaluable contributions to the work we describe here.

All authors contributed equally to this manuscript.

Correspondence should be addressed to Dr. Jon-Kar Zubieta, University of Michigan, Molecular and Behavioral Neuroscience Institute, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720. E-mail: zubietaumich.edu .

Copyright © 2005 Society for Neuroscience 0270-6474/05/2510390-13$15.00/0


1. INTRODUCTION

Three factors are of major importance in the suffering of badly wounded men [during the Second World War]: pain mental distress and thirst. Therapy has been almost entirely directed to pain, and this usually limited to the administration of morphine in large dosage.

Surveys from around the world consistently find that healthcare practitioners prescribe placebos quite often (Colloca, Enck, & DeGrazia, 2016 Fassler, Meissner, Schneider, & Linde, 2010 Howick et al., 2013). Placebo use, however, is criticized as being unethical for two reasons. First, placebos are supposedly ineffective (or less effective than “real” treatments), so the ethical requirement of beneficence (and “relative” nonmaleficence) renders their use unethical. Second, they allegedly require deception for their use, violating patient autonomy. Here, we take it as given that at least for some conditions, placebos have effects (see Howick, 2017 Howick et al., 2013 for discussion). The recent research on open-label placebos suggests that the second objection—namely the claim that placebos require unethical deception—is also invalid. If placebos can have effects even when patients are told they are placebos, then placebos do not require deception and ethical objections to placebo use lose their force.


Five myths about placebos


(Mehmet Dilsiz/For the Post)

Jo Marchant is a science journalist and the author of “Cure: A Journey Into the Science of Mind Over Body.”

I once interviewed a woman who’d fractured her spine. For months, she was laid up, barely able to walk. Finally, her doctor recommended an experimental treatment. She agreed to try it afterward her pain melted away. A decade later, she’s still playing golf.

In truth, she didn’t get the experimental spine treatment. She was given a placebo. The “placebo effect” is a phenomenon in medicine whereby patients feel better without the use of drugs. Although scientists have been studying placebos for decades, there are still a lot of misconceptions about how and why they work. Here are the most common.

1 . The placebo effect is all in the mind.

A significant proportion of patients feel better after taking placebos, but many scientists claim that this improvement is totally mental — that patients only think they feel better. Prominent doctors have called the placebo effect a “myth” or the “beer goggles of medicine.”

In reality, placebo treatments can cause measurable, biological changes similar to those triggered by drugs. Studies show that depressed patients on placebos experience increased activity in their prefrontal cortex, which eases their symptoms. Other research has shown that in patients with Parkinson’s disease, placebos trigger a flood of the neurotransmitter dopamine, just as their drugs do. And taking a placebo painkiller dampens pain-related activity in the brain and spinal cord and causes the release of pain-relieving endorphins.

2 . Placebos work only if patients think they’re real.

Expecting to feel better is a key ingredient in placebo responses, so it might follow that if a patient knows a treatment is fake, it won’t have any effect. Physicians and researchers have questioned the ethics of placebo use, suggesting that it requires doctors to willfully deceive their patients.

Over the past few years, however, scientists have found that this isn’t true. Honest placebos work, too. In one trial, patients with irritable bowel syndrome were told that they were taking a placebo, yet they still experienced significant relief from their symptoms compared with patients who got no treatment. Researchers have found the same effect for depression, migraines and ADHD.

There are several possible explanations. Some research shows that patients learn to associate taking a pill with a particular physiological response, so when they subsequently take a placebo, their bodies automatically mimic that response — a phenomenon known as conditioning. There’s also evidence that simply being cared for in a trial — even if patients know that a treatment is fake — eases anxiety and helps them feel that their conditions will improve.

3 . Neurotic, suggestible people are more likely to respond to placebos.

Doctors once took a very patronizing view of placebos. A 1954 article in the Lancet, for example, advocated placebos as a means to comfort “unintelligent or inadequate patients.” That belief — that placebo responders are pliable, suggestible souls who simply wish to “please the investigator” — persists today.

Recent studies, however, suggest that anyone can respond to a placebo. Crucial factors include patients’ attitudes toward a particular treatment, their previous experiences (whether, for example, they’ve responded well to a particular drug) and the information they’re given about a treatment. Genes also play a role.

About a quarter of the variation does seem to depend on personality. It’s not neurotic people who see benefits, though, but rather those who are optimistic, altruistic, resilient and straightforward. Scientists think this is because these personality types tend to be more engaged with their treatment and have more positive expectations for it. Neurotic and hostile people are least likely to respond.

4 . You have to take a placebo to get a placebo effect.

The placebo effect is commonly defined as what happens when a patient takes a placebo, or as the benefit experienced by someone in the placebo arm of a clinical trial.

It’s true that placebos won’t shrink a tumor, cure an infection or replace insulin in someone with diabetes. But many “real” medical treatments — particularly those that modify symptoms like pain, fatigue, nausea or depression — rely on the placebo effect. Common opioid painkillers such as Tramadol are about a third less effective if we don’t know we’re taking them, for example. In a study that followed 459 migraine attacks, the placebo effect accounted for 60 percent of the benefit of the painkiller Maxalt. Meanwhile, in mild to moderate cases of depression, the placebo effect is thought to account for almost all of the benefits of the drugs patients take.

5 . Drugs are always more effective than placebos.

An oft-cited 2001 analysis compared patients given placebos with those given no treatment in 130 trials. The researchers found little evidence that the placebos had powerful clinical effects. “Outside the setting of clinical trials, there is no justification for the use of placebos,” they concluded.

But that analysis lumped many different conditions together (from Alzheimer’s disease and anemia to marital discord and problems reaching orgasm). And it incorporated trials in which the drugs being tested didn’t work, either. A rigorous, more recent study of 152 trials found that placebo effects are often about the same as drug effects.

Of course, when patients take an active drug, they benefit from both the drug and the placebo effect. But medication can also do harm 16,000 Americans die from overdoses of prescription painkillers each year, for example. And in some cases — when people respond particularly well to placebos, or when drugs aren’t very effective or have significant downsides — patients might do better taking a placebo. A 2007 trial of more than 1,000 patients with back pain found no difference in benefits between real and sham acupuncture, a placebo intervention in which needles don’t deeply penetrate the skin. But both groups did significantly better than patients given conventional treatment (a combination of drugs, physiotherapy and exercise). For conditions like chronic pain, for which drugs aren’t especially effective, these placebo effects mean that patients can actually do better with alternative therapies than with conventional drugs, as this trial shows.

What’s more, neuroscientists are finding that beliefs and expectations about treatment influence the brain in ways drugs don’t. For example, taking a placebo can trigger areas in the prefrontal cortex that are involved in motivation and decision-making. This goes beyond easing symptoms to influence how patients cope with those symptoms: how much their conditions distress them, and whether they mope at home or go out and enjoy life. While drug effects last only as long as patients keep popping pills, these changes rely on their inner resources, which they can access at any time.

Twitter: @JoMarchant

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