Drug may stop migraines before headache starts

When taken at the first signs of a migraine, before headache pain begins, a drug called ubrogepant may be effective in helping people with migraine go about their daily lives with little or no symptoms, according to a new study published in the August 28, 2024, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study focused on people with migraine who could tell when an attack was about to happen, due to early symptoms such as sensitivity to light and sound, fatigue, neck pain or stiffness, or dizziness.

Ubrogepant is a calcitonin gene-related peptide receptor antagonist, or CGRP inhibitor. CGRP is a protein that plays a key role in the migraine process.

"Migraine is one of the most prevalent diseases worldwide, yet so many people who suffer from this condition do not receive treatment or report that they are not satisfied with their treatment," said study author Richard B. Lipton, MD, of Albert Einstein College of Medicine in Bronx, New York, and Fellow of the American Academy of Neurology. "Improving care at the first signs of migraine, even before headache pain begins, can be a key to improved outcomes. Our findings are encouraging, suggesting that ubrogepant may help people with migraine function normally and go about their day."

The study involved 518 participants who had migraine for at least one year and two to eight migraine attacks per month in the three months before the study. All of the participants regularly experienced signs that a migraine would be starting within the next few hours. Participants were asked to treat two attacks during a two-month period.

Researchers divided participants into two groups. The first group received a placebo for their first set of pre-headache symptoms of migraine, followed by taking 100 milligrams (mg) of ubrogepant for their second instance of symptoms. The second group took ubrogepant for the first instance and placebo for the second instance.

Participants evaluated limitations on their activity in their diary using a scale ranging from zero to five, with 0 meaning "not at all limited -- I could do everything"; 1, "a little limited"; 2, "somewhat limited"; 3, "very limited"; or 4, "extremely limited."

Twenty-four hours after taking the drug or a placebo, 65% of people who took ubrogepant reported themselves as "not at all limited -- I could do everything," or "a little limited," compared to 48% of those who took the placebo.

Researchers found that as early as two hours post-medication, people who took the drug were 73% more likely to report that they had "no disability, able to function normally," than those who took the placebo.

"Based on our findings, treatment with ubrogepant may allow people with migraine who experience early warning signs before a migraine occurs to quickly treat migraine attacks in their earliest stages and go about their daily lives with little discomfort and disruption," said Lipton. "This could lead to an improved quality of life for those living with migraine."

Lipton noted that participants showed that based on their headache warning symptoms, they could reliably predict impending migraine headaches. These findings apply only to those with reliable warning symptoms.

A limitation of the study was that participants recorded their symptoms and medication use in electronic diaries, so it is possible some people may not have recorded all information accurately.

Read more at Science Daily

Placebos reduce stress, anxiety, depression -- even when people know they are placebos

A study out of Michigan State University found that nondeceptive placebos, or placebos given with people fully knowing they are placebos, effectively manage stress -- even when the placebos are administered remotely.

Researchers recruited participants experiencing prolonged stress from the COVID-19 pandemic for a two-week randomized controlled trial.

Half of the participants were randomly assigned to a nondeceptive placebo group and the other half to the control group that took no pills.

The participants interacted with a researcher online through four virtual sessions on Zoom.

Those in the nondeceptive placebo group received information on the placebo effect and were sent placebo pills in the mail along with and instructions on taking the pills.

The study, published in Applied Psychology: Health and Well-Being, found that the nondeceptive group showed a significant decrease in stress, anxiety and depression in just two weeks compared to the no-treatment control group.

Participants also reported that the nondeceptive placebos were easy to use, not burdensome and appropriate for the situation.

"Exposure to long-term stress can impair a person's ability to manage emotions and cause significant mental health problems long-term, so we're excited to see that an intervention that takes minimal effort can still lead to significant benefits," said Jason Moser, co-author of the study and professor in MSU's Department of Psychology.

"This minimal burden makes nondeceptive placebos an attractive intervention for those with significant stress, anxiety and depression."

The researchers are particularly hopeful in the ability to remotely administer the nondeceptive placebos by health care providers.

Read more at Science Daily

Neuroscientists discover brain circuitry of placebo effect for pain relief

The placebo effect is very real. This we've known for decades, as seen in real-life observations and the best double-blinded randomized clinical trials researchers have devised for many diseases and conditions, especially pain. And yet, how and why the placebo effect occurs has remained a mystery. Now, neuroscientists have discovered a key piece of the placebo effect puzzle.

Publishing in Nature, researchers at the University of North Carolina School of Medicine- with colleagues from Stanford, the Howard Hughes Medical Institute, and the Allen Institute for Brain Science -- discovered a pain control pathway that links the cingulate cortex in the front of the brain, through the pons region of the brainstem, to cerebellum in the back of the brain.

The researchers, led by Greg Scherrer, PharmD, PhD, associate professor in the UNC Department of Cell Biology and Physiology, the UNC Neuroscience Center, and the UNC Department of Pharmacology, then showed that certain neurons and synapses along this pathway are highly activated when mice expect pain relief and experience pain relief, even when there is no medication involved.

"That neurons in our cerebral cortex communicate with the pons and cerebellum to adjust pain thresholds based on our expectations is both completely unexpected, given our previous understanding of the pain circuitry, and incredibly exciting," said Scherrer. "Our results do open the possibility of activating this pathway through other therapeutic means, such as drugs or neurostimulation methods to treat pain."

Scherrer and colleagues said research provides a new framework for investigating the brain pathways underlying other mind-body interactions and placebo effects beyond the ones involved in pain.

The Placebo Paradox

It is the human experience, in the face of pain, to want to feel better. As a result -- and in conjunction with millennia of evolution -- our brains can search for ways to help us feel better. It releases chemicals, which can be measured. Positive thinking and even prayer have been shown to benefit some patients. And the placebo effect -- feeling better even though there was no "real" treatment -- has been documented as a very real phenomenon for decades.

In clinical research, the placebo effect is often seen in what we call the "sham" treatment group. That is, individuals in this group receive a fake pill or intervention that is supposed to be inert; no one in the control group is supposed to see a benefit. Except that the brain is so powerful and individuals so desire to feel better that some experience a marked improvement in their symptoms. Some placebo effects are so strong that individuals are convinced they received a real treatment meant to help them.

In fact, it's thought that some individuals in the "actual" treatment group also derive benefit from the placebo effect. This is one of the reasons why clinical research of therapeutics is so difficult and demands as many volunteers as possible so scientists can parse the treatment benefit from the sham. One way to help scientists do this is to first understand what precisely is happening in the brain of someone experiencing the placebo effect.

Enter the Scherrer lab

The authors of the Nature paper knew that the scientific community's understanding of the biological underpinnings of pain relief through placebo analgesia -- when the positive expectation of pain relief is sufficient for patients to feel better -- came from human brain imaging studies, which showed activity in certain brain regions. Those imaging studies did not have enough precision to show what was actually happening in those brain regions. So Scherrer's team designed a set of meticulous, complementary, and time-consuming experiments to learn in more detail, with single nerve cell precision, what was happening in those regions.

First, the researchers created an assay that generates in mice the expectation of pain relief and then very real placebo effect of pain relief. Then the researchers used a series of experimental methods to study the intricacies of the anterior cingulate cortex (ACC), which had been previously associated with the pain placebo effect. While mice were experiencing the effect, the scientists used genetic tagging of neurons in the ACC, imaging of calcium in neurons of freely behaving mice, single-cell RNA sequencing techniques, electrophysiological recordings, and optogenetics -- the use of light and fluorescent-tagged genes to manipulate cells.

These experiments helped them see and study the intricate neurobiology of the placebo effect down to the brain circuits, neurons, and synapses throughout the brain.

The scientists found that when mice expected pain relief, the rostral anterior cingulate cortex neurons projected their signals to the pontine nucleus, which had no previously established function in pain or pain relief. And they found that expectation of pain relief boosted signals along this 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.

Lastly, the scientists found that Purkinje cells -- a distinct class of large branch-like cells of the cerebellum -- showed activity patterns similar to those of the ACC neurons during pain relief expectation. Scherrer and first author Chong Chen, MD, PhD, a postdoctoral research associate in the Scherrer lab, said that this is cellular-level evidence for the cerebellum's role in cognitive pain modulation.

"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."

Read more at Science Daily

Understanding subjective beliefs could be vital to tailoring more effective treatments for depression and ADHD

Taking into account whether people believe they are receiving a real treatment or a fake one (placebo) could provide better insights that could help improve interventions for conditions such as depression and ADHD.

A team of psychologists, led by Professor Roi Cohen Kadosh from the University of Surrey, analysed five independent studies that covered different types of neurostimulation treatments to understand the role of patients' subjective beliefs.

These patients included both clinical patients being treated for ADHD and depression, as well as healthy adults.

The study found that patients' beliefs about whether they were receiving real or placebo treatments explained the treatment outcomes in four of the five studies.

On some occasions, the subjects' beliefs explained the treatment's results better than the actual treatment itself.

Assumptions about the treatment intensity also played a significant role in the treatment.

Professor Roi Cohen Kadosh from the University of Surrey said that the results have provided a twist that scientists must consider in future research:

"The common wisdom is that the same medical treatment would produce similar results across patients, but our latest study suggests a fascinating twist. While you'd expect uniform improvements in a group of people with depression undergoing the same neurostimulation treatment, outcomes can vary widely.

"What's truly eye-opening is that this variability could be largely influenced by the participants' own beliefs about the treatment they're receiving. In essence, if an individual believes they're receiving an effective treatment -- even when given a placebo -- that belief alone might contribute to significant improvements in their condition."

In the first study analysed, 121 participants were treated with different forms of Transcranial Magnetic Stimulation (rTMS) for depression.

The results showed that participants' perceptions about receiving real or placebo treatment mattered more than the actual type of rTMS in reducing depression.

The second study involved 52 older people with late-life depression who received either a real or placebo of deep rTMS.

Surrey researchers found that the effect of treatment on reducing depression scores depended on the combination of the participants' perceptions about receiving real or placebo treatment and the actual treatment they received.

In the third dataset, researchers investigated the effects of home-based Transcranial Direct Current Stimulation (tDCS) treatment on 64 adults diagnosed with ADHD.

At the end of the study, participants' beliefs about the treatment they thought they had received were also collected.

This study differed from the first two as both the subjects' beliefs and the actual treatment had a dual effect on reducing inattention scores.

In the fourth study, 150 healthy participants got varying doses of tDCS for mind wandering.

Those who believed they got a more potent dose reported more mind wandering, even if the actual treatment wasn't a factor.

The fifth study analysed the impact of transcranial random noise stimulation on working memory.

Unlike previous studies, participants' beliefs didn't affect the results, highlighting the varying influence of beliefs in brain stimulation research.

Thus, Roi Cohen Kadosh and his team show how subjective beliefs can vary in their effect on research -- from fully explaining results beyond the actual treatment, to interacting with the treatment, to having no influence at all.

Dr Shachar Hochman, a co-author on this work from the University of Surrey, said:

"The concept that a placebo or sham treatment can mimic genuine treatment effects is well-established in science. While researchers have closely monitored this phenomenon, it has been typically catalogued separately from the in-depth analyses of the actual treatment outcomes. What sets our study apart is that we have brought together these two datasets -- subjective beliefs and objective treatment measures. This has the potential to reveal new insights into treatment efficacy."

Read more at Science Daily

Placebo reduces feelings of guilt

People don't always behave impeccably in relationship to others. When we notice that this has inadvertently caused harm, we often feel guilty. This is an uncomfortable feeling and motivates us to take remedial action, such as apologizing or owning up.

This is why guilt is considered an important moral emotion, as long as it is adaptive -- in other words, appropriate and in proportion to the situation. "It can improve interpersonal relationships and is therefore valuable for social cohesion," says Dilan Sezer, researcher at the Division of Clinical Psychology and Psychotherapy at the University of Basel.

Whether feelings of guilt can be reduced by taking placebos is something that researchers at the Faculty of Psychology at the University of Basel have been exploring. Their findings have now been published in the journal Scientific Reports.

Open-label placebos work

In order to arouse feelings of guilt, test subjects in the study were asked to write about a time when they had disregarded important rules of conduct, or treated someone close to them unfairly, hurt or even harmed them. The idea was that the study participants should still feel bad about the chosen situation.

Participants were then randomized to three conditions: Participants in one group were given placebo pills with being deceptively told that this was a real medication while participants in another group were told that they are given a placebo. Both groups were told that what they had been given will be effective against feelings of guilt. The control group was given no treatment at all. The results showed that feelings of guilt were significantly reduced in both placebo groups compared with those without medication.

This was also the case when the subjects knew they had been given a placebo. "Our study therefore supports the intriguing finding that placebos work even when they are administered openly, and that explanation of the treatment is key to its effectiveness," states the study's lead author, Dilan Sezer. Participants in this study were all healthy, had no psychiatric disorders and were not being treated with psychotropics.

Clinical applicability not yet proven

Where feelings of guilt are irrational and continue for longer periods of time, they are considered maladaptive -- in other words, disproportionate. These emotions can affect people's health and are also, among other things, a common symptom of depression.

Scientific studies have shown that placebo effects can be powerful in treating depression. But the finding that open-label placebos can also be useful for such strong emotions as guilt is new. It stands to reason, says Dilan Sezer, that we should try to harness these effects to help those affected. "The administering of open-label placebos, in particular, is a promising approach, as it preserves patient autonomy by allowing patients to be fully aware of how the intervention works." The results of the study are an initial promising step in the direction of symptom-specific and more ethical treatments for psychological complaints using open-label placebos, Sezer continues.

Read more at Science Daily

Open-label placebo works as well as double-blind placebo in irritable bowel syndrome

 For decades, the power of the placebo effect was thought to lie in patients' belief that they were -- or at least, could be -- receiving a pharmacologically active treatment. A new study by physician-researchers at Beth Israel Deaconess Medical Center (BIDMC) suggests that patients don't need to be deceived to receive benefit from treatment with placebo.

In a randomized clinical trial published in the journal PAIN, researchers found participants with moderate to severe irritable bowel syndrome (IBS) who were knowingly treated with a pharmacologically inactive pill -- referred to as an honest or open-label placebo -- reported clinically meaningful improvements in their IBS symptoms. People who received the open-label placebo experienced improvements that were significantly greater than those reported by participants assigned to a no-pill control group. There was no difference in symptom improvement between those who received open-label or double-blind placebos. The results build on the research team's previous findings and challenge the long-held notion that concealment or deception are key elements in the placebo effect.

"The clinical response to open-label placebo in this six-week trial was high, with 69 percent of participants who received open-label placebo reporting a clinically meaningful improvement in their symptoms," said first and corresponding author Anthony J. Lembo, MD, Professor of Medicine in the Division of Gastroenterology at BIDMC. "IBS is one of the most common reasons for healthcare consultations and absenteeism from work or school. Effective treatment options for IBS are limited, and we hypothesized it may be possible to ethically harness the placebo effect for clinical benefit."

For the rigorously designed clinical trial, researchers enrolled 262 adult participants, 18 to 80 years old with at least moderately severe irritable bowel syndrome, as measured by the validated IBS-Severity Scoring System (IBS-SSS), which measures frequency and severity of abdominal pain and distention, quality of life and other relevant factors across a scale of 0-500. Participants were examined, filled out baseline questionnaires and were randomized into one of three study arms; open-label placebo; double-blind (which included double-blind placebo or double-blind peppermint oil); or no-pill control. During their examinations, all participants discussed the placebo effect, the trial and its aims with their physicians.

The open-label group received pill bottles labeled "open-label placebo," and were told that the pills inside were pharmacologically inert, but could make them feel better through the placebo effect. The double-blind group received pill bottles labeled "double-blind placebo or peppermint oil." Participants in the double-blind group received either a placebo or an identical pill containing peppermint oil, but neither they nor the research team knew which they received. All participants who received pills were instructed to take one pill three times a day, 30 minutes before meals. The no-pill control group received no pills but otherwise followed identical study protocol. During return visits three and six weeks into the study, all participants completed questionnaires, were verbally asked about adverse events and briefly met with a study physician.

Lembo and colleagues -- including senior author, Ted J. Kaptchuk, Director of the Program in Placebo Studies and the Therapeutic Encounter at BIDMC -- found that improvement in IBS-SSS scores from baseline to the six-week endpoint was significantly greater in the open-label placebo group compared to the no-pill control group. Additionally, participants in the double-blind placebo group also saw superior symptom improvement compared to the no-pill control group, but the double-blind and open-label groups were not different from each other.

Next, the researchers performed a post hoc analysis of the participants who experienced large clinical improvements -- those who improved by at least 50 points and by at least 150 points, considered strong and very strong clinical responses, respectively. A greater percentage of participants in the open-label placebo and double-blind placebo groups reported a 50 point reduction in IBS severity score compared to the no-pill control group (approximately 70 percent in each placebo group compared to 54 percent in the no pill control group). Similarly, approximately 30 percent of open-label placebo and double-blind placebo participants reported a 150 point reduction in IBS symptoms, compared to only 12 percent of the no-pill group.

Read more at Science Daily

New study gives the most detailed look yet at the neuroscience of placebo effects

 A large proportion of the benefit that a person gets from taking a real drug or receiving a treatment to alleviate pain is due to an individual's mindset, not to the drug itself. Understanding the neural mechanisms driving this placebo effect has been a longstanding question. A meta-analysis published in Nature Communications finds that placebo treatments to reduce pain, known as placebo analgesia, reduce pain-related activity in multiple areas of the brain.

Previous studies of this kind have relied on small-scale studies, so until now, researchers did not know if the neural mechanisms underlying placebo effects observed to date would hold up across larger samples. This study represents the first large-scale mega-analysis, which looks at individual participants' whole brain images. It enabled researchers to look at parts of the brain that they did not have sufficient resolution to look at in the past. The analysis was comprised of 20 neuroimaging studies with 600 healthy participants. The results provide new insight on the size, localization, significance and heterogeneity of placebo effects on pain-related brain activity.

The research reflects the work of an international collaborative effort by the Placebo Neuroimaging Consortium, led by Tor Wager , the Diana L. Taylor Distinguished Professor in Neuroscience at Dartmouth and Ulrike Bingel, a professor at the Center for Translational Neuro- and Behavioral Sciences in the department of neurology at University Hospital Essen, for which Matthias Zunhammer and Tamás Spisák at the University Hospital Essen, served as co-authors. The meta-analysis is the second with this sample and builds on the team's earlier research using an established pain marker developed earlier by Wager's lab.

"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 Wager, who is also the 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."

Across the studies in the meta-analysis, participants had indicated that they felt less pain; however, the team wanted to find out if the brain responded to the placebo in a meaningful way. Is the placebo changing the way a person constructs the experience of pain or is it changing the way a person thinks about it after the fact? Is the person really feeling less pain?

With the large sample, the researchers were able to confidently localize placebo effects to specific zones of the brain, including the thalamus and the basal ganglia. The thalamus serves as a gateway for sights and sounds and all kinds of sensory motor input. It has lots of different nuclei, which act like processing stations for different kinds of sensory input. The results showed that parts of the thalamus that are most important for pain sensation were most strongly affected by the placebo. In addition, parts of the somatosensory cortex that are integral to the early processing of painful experiences were also affected. The placebo effect also impacted the basal ganglia, which are important for motivation and connecting pain and other experiences to action. "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."

The findings revealed that placebo treatments reduce activity in the posterior insula, which is one of the areas that are involved in early construction of the pain experience. This is the only site in the cortex that you can stimulate and invoke the sense of pain. The major ascending pain pathway goes from parts of the thalamus to the posterior insula. The results provide evidence that the placebo affects that pathway for how pain is constructed.

Prior research has illustrated that with placebo effects, the prefrontal cortex is activated in anticipation of pain. The prefrontal cortex helps keep track of the context of the pain and maintain the belief that it exists. When the prefrontal cortex is activated, there are pathways that trigger opioid release in the midbrain that can block pain and pathways that can modify pain signaling and construction.

The team found that activation of the prefrontal cortex is heterogeneous across studies, meaning that no particular areas in this region were activated consistently or strongly across the studies. These differences across studies are similar to what is found in other areas of self-regulation, where different types of thoughts and mindsets can have different effects. For example, other work in Wager's laboratory has found that rethinking pain by using imagery and storytelling typically activates the prefrontal cortex, but mindful acceptance does not. Placebo effects likely involve a mix of these types of processes, depending on the specifics of how it is given and people's predispositions.

"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," explains Bingel. "The study's findings will also contribute to future research in the development of brain biomarkers that predict an individual's responsiveness to placebo and help distinguish placebo from analgesic drug responses, which is a key goal of the new collaborative research center, Treatment Expectation ."

Read more at Science Daily

Placebos prove powerful even when people know they're taking one

How much of a treatment is mind over matter? It is well documented that people often feel better after taking a treatment without active ingredients simply because they believe it's real -- known as the placebo effect.

A team of researchers from Michigan State University, University of Michigan and Dartmouth College is the first to demonstrate that placebos reduce brain markers of emotional distress even when people know they are taking one.

Now, evidence shows that even if people are aware that their treatment is not "real" -- known as nondeceptive placebos -- believing that it can heal can lead to changes in how the brain reacts to emotional information.

"Just think: What if someone took a side-effect free sugar pill twice a day after going through a short convincing video on the power of placebos and experienced reduced stress as a result?," said Darwin Guevarra, MSU postdoctoral fellow and the study's lead author. "These results raise that possibility."

The new findings, published in the most recent edition of the journal Nature Communications, tested how effective nondeceptive placebos -- or, when a person knows they are receiving a placebo -- are for reducing emotional brain activity.

"Placebos are all about 'mind over matter," said Jason Moser, co-author of the study and professor of psychology at MSU. "Nondeceptive placebos were born so that you could possibly use them in routine practice. So rather than prescribing a host of medications to help a patient, you could give them a placebo, tell them it can help them and chances are -- if they believe it can, then it will."

To test nondeceptive placebos, the researchers showed two separate groups of people a series of emotional images across two experiments. The nondeceptive placebo group members read about placebo effects and were asked to inhale a saline solution nasal spray. They were told that the nasal spray was a placebo that contained no active ingredients but would help reduce their negative feelings if they believed it would. The comparison control group members also inhaled the same saline solution spray, but were told that the spray improved the clarity of the physiological readings the researchers were recording.

The first experiment found that the nondeceptive placebos reduced participants' self-reported emotional distress. Importantly, the second study showed that nondeceptive placebos reduced electrical brain activity reflecting how much distress someone feels to emotional events, and the reduction in emotional brain activity occurred within just a couple of seconds.

"These findings provide initial support that nondeceptive placebos are not merely a product of response bias -- telling the experimenter what they want to hear -- but represent genuine psychobiological effects," said Ethan Kross, co-author of the study and a professor of psychology and management at the University of Michigan.

Read more at Science Daily

The placebo effect and psychedelic drugs: Tripping on nothing?

A new study suggests that, in the right context, some people may experience psychedelic-like effects from placebos alone. The researchers reported some of the strongest placebo effects on consciousness in the literature relating to psychedelic drugs. Indeed, 61% of the participants in the experiment reported some effect after consuming the placebo.

There has been a lot of recent interest in the use of psychedelic drugs to treat depression. A new study from McGill suggests that, in the right context, some people may experience psychedelic-like effects from placebos alone. The researchers reported some of the strongest placebo effects (these are effects from "fake" medication) on consciousness in the literature relating to psychedelic drugs. Indeed, 61% of the participants in the experiment reported some effect after consuming the placebo.

"The study reinforces the power of context in psychedelic settings. With the recent re-emergence of psychedelic therapy for disorders such as depression and anxiety, clinicians may be able to leverage these contextual factors to obtain similar therapeutic experiences from lower doses, which would further improve the safety of the drugs," said Jay Olson, a Ph.D. candidate in McGill's Department of Psychiatry and the lead author on the research paper that was recently published in Psychopharmacology.

Setting the mood

Participants, who were expecting to take part in a study of the effects of drugs on creativity, spent four hours together in a room that had been set up to resemble a psychedelic party, with paintings, coloured lights and a DJ. To make the context seem credible and hide the deception, the study also involved ten research assistants in white lab coats, psychiatrists, and a security guard.

The 33 participants had been told they were being given a drug which resembled the active ingredient in psychedelic mushrooms and that they would experience changes in consciousness over the 4-hour period. In reality, everyone consumed a placebo. Among the participants were several actors who had been trained to slowly act out the effects of the ostensible drug. The researchers thought that this would help convince the participants that everyone had consumed a psychedelic drug and might lead them to experience placebo effects.

Strong effects for a placebo

When asked near the end of the study, the majority (61%) of the participants reported some effect of the drug, ranging from mild changes to effects resembling taking a moderate or high dose of an actual drug, though there was considerable individual variation. For example, several participants stated that they saw the paintings on the walls "move" or "reshape" themselves. Others described themselves as feeling "heavy... as if gravity [had] a stronger hold," and one had a "come down" before another "wave" hit her. Several participants reported being certain that they had taken a psychedelic drug.

Read more at Science Daily

Even psychological placebos have an effect

The color green can have a positive effect on the personal condition, as long as this effect was previously attributed to it.

Placebo effects do not only occur in medical treatment -- placebos can also work when psychological effects are attributed to them. Psychologists from the University of Basel reported these findings in the journal Scientific Reports, based on three studies with over 400 participants.

Psychotherapy and placebos are both psychological interventions that not only have comparable effects, but that are also based on very similar mechanisms. Both forms of treatment are heavily influenced by the relationship between patients and those treating them, as well as by the expectations of recovery. Whereas placebo research mostly focuses on a biomedical model -- an inert pill is provided with a medical rationale, which produces a corresponding effect -- little is known about the effect of placebos provided with a psychological rationale.

"Green is calming"

Placebos can also have effects when specific psychological effects are attributed to them. This is the conclusion that researchers from the Division of Clinical Psychology and Psychotherapy at the University of Basel reached in three independent experiments with 421 healthy participants. The accompanying explanation -- the narrative -- played a key role when dispensing the placebos, as did the relationship between the researchers and the participants.

The researchers used the color green as the placebo in the video experiments, examining it both with and without a psychological narrative ("green is calming because it activates early conditioned emotional schemata"), as well as in the context of a neutral or a friendly relationship.

After viewing the videos, the participants assessed their subjective condition with questionnaires over several days. The results showed that the placebo had a positive effect on the participants' well-being when it was prescribed together with a psychological narrative and in the context of a friendly relationship. The observed effect was strongest after administering the placebo but remained evident for up to one week.

Ethical implications

"The observed effects were comparable with those of psychotherapeutic interventions in the same populations," says principal investigator Professor Jens Gaab. The fact that psychological placebos can have significant effects is not only important for understanding psychological interventions: "It challenges both research and clinical practice to address these mechanisms and effects, as well as their ethical implications."

Read more at Science Daily

Omega-3s from fish oil supplements no better than placebo for dry eye

Omega-3 fatty acid supplements taken orally proved no better than placebo at relieving symptoms or signs of dry eye, according to the findings of a well-controlled trial funded by the National Eye Institute (NEI), part of the National Institutes of Health. Dry eye disease occurs when the film that coats the eye no longer maintains a healthy ocular surface, which can lead to discomfort and visual impairment. The condition affects an estimated 14 percent of adults in the United States. The paper was published online April 13 in the New England Journal of Medicine.

Annual sales of fish- and animal-derived supplements amount to more than a $1-billion market in the United States, according to the Nutrition Business Journal. Many formulations are sold over-the-counter, while others require a prescription or are available for purchase from a health care provider.

"The trial provides the most reliable and generalizable evidence thus far on omega-3 supplementation for dry eye disease," said Maryann Redford, D.D.S., M.P.H., program officer for clinical research at NEI. Despite insufficient evidence establishing the effectiveness of omega-3s, clinicians and their patients have been inclined to try the supplements for a variety of conditions with inflammatory components, including dry eye. "This well-controlled investigation conducted by the independently-led Dry Eye Assessment and Management (DREAM) Research Group shows that omega-3 supplements are no better than placebo for typical patients who suffer from dry eye."

The 27-center trial enrolled 535 participants with at least a six-month history of moderate to severe dry eye. Among them, 349 people were randomly assigned to receive 3 grams daily of fish-derived omega-3 fatty acids in five capsules. Each daily dose contained 2000 mg eicosapentaenoic acid (EPA) and 1000 mg docosahexaenoic acid (DHA). This dose of omega-3 is the highest ever tested for treating dry eye disease. The 186 people randomly assigned to the placebo group received 5 grams daily of olive oil (about 1 teaspoon) in identical capsules. Study participants and the researchers did not know their group assignment.

Blood tests at 12 months confirmed that 85 percent of people in the omega-3 group were still compliant with the therapy. In the omega-3 group, mean EPA levels quadrupled versus no change in the placebo group. Mean levels of oleic acid, the constituent of olive oil, remained stable in both treatment groups.

Importantly, unlike in most industry-sponsored trials, all participants were free to continue taking their previous medications for dry eye, such as artificial tears and prescription anti-inflammatory eye drops.

"Omega-3s are generally used as an add-on therapy. The study results are in the context of this real-world experience of treating symptomatic dry eye patients who request additional treatment," said study chair for the trial, Penny A. Asbell, M.D., of the Department of Ophthalmology at the Icahn School of Medicine at Mount Sinai in New York City.

Patient-reported symptoms were measured as change from baseline in the Ocular Surface Disease Index, a 100-point scale for assessing dry eye symptoms, with higher values representing greater severity. After 12 months, mean symptoms scores for people in both groups had improved substantially, but there was no significant difference in the degree of symptom improvement between the groups. Symptom scores improved by a mean of 13.9 points in the omega-3 group and 12.5 points in the placebo group. A reduction of at least 10 points on the index is considered significant enough for a person to notice improvement. Overall, 61 percent of people in the omega-3 group and 54 percent of those in the control group achieved at least a 10-point improvement in their symptom score, but the difference between the groups was not statistically significant.

Likewise, there were no significant differences between the groups in terms of improvement in signs of dry eye. Signs of dry eye were evaluated by the clinician using standardized tests that measure the amount and quality of tears and the integrity of the cornea and the conjunctiva, the surface tissue that covers the front of the eye.

"The findings also emphasize the difficulty in judging whether a treatment really helps a particular dry eye patient," said the leader of the coordinating center for the study, Maureen G. Maguire, Ph.D., of the Department of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia. "More than half the people taking placebo reported substantial symptom improvement during the year-long study."

Read more at Science Daily

The Nocebo Effect Shows Pain Isn’t All in Your Brain

Everybody’s heard of the placebo effect — the phenomenon in which people report positive health impacts of drugs that are, in fact, nothing more than sugar pills. But there’s also an opposite reaction called the nocebo effect, when patients report negative side effects — dizziness, headaches, nausea — from drugs that aren’t really drugs.

Both the placebo and nocebo effect are known to wreak havoc on drug trials. In fact, it’s become nearly impossible to win approval for new pain meds because the placebo effect is so strong, making the real medication seem weak in comparison. And research shows that when you list a bunch of potential negative side effects to participants in a drug trial, participants will report back those very symptoms whether they get the real drug or a placebo.

Until recently, the placebo and nocebo effects were thought to be entirely psychological, our brain tricking itself into believing that we feel good or bad. But advances in real-time functional MRI technology have revealed a two-way signaling pathway between pain receptors along the spine and higher-order processing areas in the brain. It turns out that the brain feels pain because the body says, “Ouch!”

A team of German researchers developed a new fMRI protocol that allowed them to measure real-time nervous system activity in both the spinal cord and the brain. The idea was to trigger a nocebo response and pinpoint exactly where it was coming from — the body, the brain, or both.

In a paper published in the journal Science, lead investigator Alexandra Tinnermann of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, described her team’s experiment involving two types of anti-rash creams. Nearly 50 participants were divided into two groups. One was treated with a supposedly cheap rash cream from a generic-labeled box. The other was treated with what they were told was an expensive, brand-name cream. In truth, both creams were identical and neither contained any active ingredients.

Both groups were told that their anti-rash cream — both cheap and expensive — had one potential side effect, that it might increase their sensitivity to pain. To determine the strength of the side effect, participants were told, the researchers were going to treat half their arm with a control cream and the other half with a target drug, either the expensive or cheap version of the cream. Heat pads were then applied to each half of the arm to compare pain levels.

In reality, though, all the creams were identical. 

When asked to rate their pain, both groups exhibited a nocebo response, citing increased pain sensitivity in the region treated with the target cream as opposed to the control. But interestingly, the people who received the “expensive” treatment exhibited a much stronger nocebo response, rating their pain as twice as bad compared to the “cheap” group.

In their paper, Tinnermann and her colleagues equate the participants’ nocebo response to earlier findings from placebo studies, theorizing that “participants infer that expensive medication contains a more potent and effective agent and, consequently, produces more side effects.”

But the more interesting question is where the nocebo effect originates. Clearly there’s some higher-order brain activity required to look at a package and determine if a cream is “cheap” or “expensive.” But does that mean that the pain is all in the patient’s head?

Luana Colloca, a professor, researcher, and physician in the department of anesthesiology at the University of Maryland School of Medicine, has been studying the nocebo effect for a decade and wrote an accompanying commentary in the same issue of Science. Colloca has run trials where participants were told that pain medication was stopped, when it fact it was continued, and people immediately reported higher levels of pain. She’s also seen the opposite, where pain meds were covertly turned off and participants reported no increased pain.

Despite the clear psychological component of the placebo and nocebo effect, Colloca says studies like the anti-rash experiment point to something more complicated at play. First off, we know that pain requires more than the brain.

“The reason we can say this stimulus is painful, it’s hurting me, is because there’s a signal from our arm reaching the spinal cord, and then from the spinal cord to the brain,” Colloca told Seeker.

And that’s exactly what the fMRI scans found in the rash-cream experiment. When participants thought they were being treated with an expensive cream, the nerve endings in the peripheral nervous system (as opposed to the central nervous system) sent more pain signals to the spinal cord, which were then transmitted to the brain.

“This is revolutionary,” said Colloca. “For the first time, we switch from a concept and phenomenon that we believed was merely psychological to something more — a neurobiological phenomenon. You believe that you’re going to experience more pain and your spinal cord lets in more information from the periphery signaling an increase of pain.”

Read more at Seeker

Homeopathic Products Under FDA Scrutiny

The Food and Drug Administration is re-examining its position on whether it should regulate homeopathic products, which are often sold alongside (and may be confused with) proven medications with active ingredients in pharmacies across the country.

In 1988 the FDA decided not to require that homeopathic remedies go through the same drug-approval process as standard medicines. Hearings began Monday in Washington and should the FDA decide that homeopathic products fall under its purview, manufacturers would need to prove that their products are safe and effective.

Homeopathy has been extensively studied, and researchers have concluded that it does not work.

In 2010 the British Science and Technology Select Committee conducted an examination of whether homeopathy has any medical or scientific validity; its report concluded that “there is no evidence that homeopathy works beyond the placebo effect (where a patient gets better because of their belief in the treatment).”

Australia’s National Health and Medical Research Council also investigated the effectiveness of homeopathy in a report released last month. It, too, reached the same damning conclusion: “there are no health conditions for which there is reliable evidence that homeopathy is effective.”

According to an article in the “Washington Post” while homeopathy advocates defend their practice, some welcome the proposed FDA oversight. “Ronald Whitmont, a homeopathic doctor in New York and president of the American Institute of Homeopathy, said his organization supports the FDA’s actions to crack down on poor manufacturing practices. ‘There are always bad apples in the manufacturing world, and they need to be policed just like in any other industry,’ he said. ‘We are behind the FDA. Their concern is our concern.’”

Whitmont added that he hoped that the FDA would not end up questioning the legitimacy of homeopathy’s practices or principles. One homeopathic practitioner even claimed in 2012 that homeopathic products could be used to somehow treat and prevent domestic violence.

Earlier this month the Canadian government took similar steps toward regulating homeopathy in the province of Ontario. A new law, the Ontario Homeopathy Act, provides a mechanism for homeopaths to self-regulate in a similar manner to doctors and nurses. Critics of the law, however, expressed concern that the effect would be to legitimize “the health-care equivalent of dowsing rods.”

Among those who testified in favor of the FDA revising its position was Michael De Dora, Director of Public Policy for the Center for Inquiry, a non-profit educational organization dedicated to evidence-based public policy. “I think the FDA is finally revisiting the issue of regulating homeopathy because of several troubling and prominent cases related to homeopathy,” De Dora told Discovery News. “In 2010, there was a situation in which homeopathic products for teething children containing too much belladonna put several kids in the hospital.

More recently, homeopaths have been claiming to own cures for everything from asthma to more pressing public health issues, such as Ebola which has prompted to FDA to write letters and issue consumer warnings.

Still, perhaps the greatest harm caused by homeopathy is not necessarily caused by the products themselves—which, when properly prepared, rarely contain anything other than water and inactive ingredients such as sugars and binding agents—but by the fact that people often rely on homeopathic products to the exclusion of proven scientific remedies.”

Following his testimony De Dora said he was “encouraged by the critical questions the FDA panel posed. The FDA would have never held this hearing if they didn’t have some inclination to regulate homeopathy.

Read more at Discovery News

'Witchcraft' Used to Fight Sex Trafficking in Africa

The British government is using a powerful new tool in its efforts to end sex trafficking and slavery in Africa: witchcraft — or at least belief in magic.

“The Independent” newspaper recently revealed an innovative method to help West African women who have been forced into sex trafficking:

“Britain’s anti-slavery commissioner is examining radical new plans to prosecute sex traffickers by ‘reversing’ the juju spells that terrorize many of their victims into staying silent. More than 100 Nigerian women were identified last year as having been trafficked into sexual slavery with their obedience ensured by magic rituals that threaten them with infertility or death if they reveal what has happened to them.” 
“The level of terror instilled by juju led British police to spend two years trying to dispel the fears of women so they could give evidence in the first case of its kind in Europe, in 2011.”

The victims are often reluctant to testify in court against those who abducted and forced them into prostitution, in part because of fear of magical retribution. Kevin Hyland, England’s first anti-slavery commissioner has been in contact with anti-trafficking officials in Nigeria who have located witch doctors believed to have placed curses on the victims and forced them to remove the curse or face criminal prosecution.

Using magic — or, more accurately, belief in magic — as a way to stem human trafficking is not only a novel idea, but likely a very effective one. Belief in the power of magic is very strong throughout much of sub-Saharan Africa, and many live under the (real or perceived) threat of magical retribution, and the fear that witch doctors — or those who hire them — have power over their fortunes, health and lives. In some cases belief in magic helps spread AIDS in Africa.

Measures that fail to address the victims’ underlying belief system are unlikely to be successful because to the extent that a problem is psychosomatic, the root of the problem will be ignored. It is not helpful for a psychologist to simply tell an obsessive-compulsive sufferer, for example, that he doesn’t have to open and close his front door seven times before entering his home; he will still feel the compulsion to do so regardless of any arguments or evidence that it’s unnecessary.

Disordered thoughts and compulsions can be dampened by medication, but at the end of the day what’s needed to address the root of the problem is a new way of framing or understanding the issue. If the Nigerian women truly believe that they have been cursed, no amount of denying or debunking — especially by foreign British doctors — will convince them otherwise: You have to fight fire with fire, or magic with magic.

Curses and Placebos

Belief in the power of curses is a form of placebo effect, which only works if the patient believes it’s effective. The power of the placebo is strong indeed; it can give pain medications a boost, and even enhance athletic performance; recent research revealed that runners who (wrongly) believed that they were performing with doped blood run faster than they thought they could.

Belief in curses and evil spirits caused singer Olivia Newton-John to have a blessing or cleansing ritual performed on a Florida home she was selling; she was concerned that potential buyers might be scared off by the spirit of a man who’d committed suicide there.

While the idea of curses may seem antiquated or confined to the poor and superstitious Third World, that is not the case. Plenty of wealthy and educated Americans believe in curses, and in fact it is not unusual for self-proclaimed psychics to con their clients into believing that a curse has been placed upon them, and that the psychic can help remove the curse — for a fee, of course.

Read more at Discovery News

How Placebos Can Help You Run Faster

Just believing that you're blood doping is enough to help you run faster, recent research found.

When the runners found out that they'd been given nothing more powerful than an injection of salt water, many were red-faced and a little embarrassed, lead author Ramzy Ross said. While the subjects may have felt duped, however, it's actually another testament to the power of expectation on our health, placebo experts said. Other work has shown that placebos can soothe a baby's cough, relieve migraine pain, and even mend torn knee cartilage as well as surgery.

One of the key issues in placebo research is parsing out what makes them work, said John Kelley, deputy director of the Program in Placebo Studies at Harvard Medical School and an associate professor of psychology at Endicott College.

The two most common components, he said, are conscious expectations and classical conditioning. Think of the first as what you could verbalize: In the case of the runners, for example, most would say that taking erythropoietin (EPO) would improve their aerobic capacity and delay fatigue. As for classical conditioning, just as Pavlov's dogs started salivating when the physiologist entered the room in anticipation of being fed, people experience physical responses to certain associations.

In fact, even when researchers tell subjects they're taking a placebo, so-called open label studies still show a positive placebo effect.

Researchers attribute it to the conditioning response, Kelley said. It works best in people who have been treated previously for a condition. People with migraine headaches who experienced pain relief by taking a certain drug in the past also felt better when taking a pill that looked similar -- even when they knew it was not the actual drug.

By that rationale, athletes who have previously blood doped for real might fare even better on sham EPO, Kelley said. Previous research on cyclists showed that the benefits of taking morphine during workouts were maximized when the cyclists were preconditioned to using it first. Ramzy's team also delivered the placebo to the runners via injections instead of pills, knowing that most people have a stronger reaction to more invasive procedures.

Read more at Discovery News

Researchers identify brain network with mapping technique

Investigators at The Feinstein Institute for Medical Research have utilized a new image-based strategy to identify and measure placebo effects in randomized clinical trials for brain disorders. The findings are published in the August issue of The Journal of Clinical Investigation.

Parkinson's disease is the second most common neurodegenerative disease in the US. Those who suffer from Parkinson's disease most often experience tremors, slowness of movement (bradykinesia), rigidity, and impaired balance and coordination. Patients may have difficulty walking, talking or completing simple daily tasks. They may also experience depression and difficulty sleeping due to the disease. The current standard for diagnosis of Parkinson's disease relies on a skilled healthcare professional, usually an experienced neurologist, to determine through clinical examination that someone has it. There currently is no cure for Parkinson's disease, but medications can improve symptoms.

A team of researchers at the Feinstein Institute's Center for Neurosciences, led by David Eidelberg, MD, has developed a method to identify brain patterns that are abnormal or indicate disease using imaging techniques. To date, this approach has been used successfully to identify specific networks in the brain that indicate a patient has or is at risk for Parkinson's disease and other neurodegenerative disorders.

"One of the major challenges in developing new treatments for neurodegenerative disorders such as Parkinson's disease is that it is common for patients participating in clinical trials to experience a placebo or sham effect," noted Dr. Eidelberg. "When patients involved in a clinical trial commonly experience benefits from placebo, it's difficult for researchers to identify if the treatment being studied is effective. In a new study conducted by my colleagues and myself, we have used a new image-based strategy to identify and measure placebo effects in brain disorder clinical trials."

In the current study, the researchers used their network mapping technique to identify specific brain circuits underlying the response to sham surgery in Parkinson's disease patients participating in a gene therapy trial. The expression of this network measured under blinded conditions correlated with the sham subjects' clinical outcome; the network changes were reversed when the subjects learned of their sham treatment status. Finally, an individual subject's network expression value measured before the treatment predicted his/her subsequent blinded response to sham treatment. This suggests that this novel image-based measure of the sham-related network can help to reduce the number of subjects assigned to sham treatment in randomized clinical trials for brain disorders by excluding those subjects who are more likely to display placebo effects under blinded conditions.

From Science Daily