The Calorie Restriction Society: Depriving Their Way To A Longer Life?

salad1So some of you lab rats may already know that experiments on animals have shown that calorie restriction results in better health and longer lives in rodents, flies, and worms.

It turns out there is a Calorie Restriction Society dedicated to finding out if the same sorts of benefits are seen in humans. There are roughly 500 dedicated members. But the president, Brian Delaney, estimates that tens of thousands of people worldwide are participating in some capacity, and maybe 2,000-3,000 are following a rigorous form of the diet. And the program is a lot more popular with males than females. Some of the practitioners are actually participating in studies on calorie restriction, while others are just sort of serving as guinea pigs in their own experiments. Many get labs done prior to starting calorie restriction and then periodically compare their new numbers, to figure out whether various markers of health are improving.

The goal of the CRS diet is to “obtain optimal nutrition from the fewest calories.” Unlike in anorexia, the goal isn’t to look skinny. Weight loss is viewed as an undesirable byproduct of consuming 30% fewer calories than is typically recommended. Adherents are hopeful that their calorie restriction will translate into a longer lifespan: 110, 120, or even 130 years or longer. And guess what? One of the main proponents is Dr. Ray Wolford, who was one of the original Biopsherians I wrote about in my last blog post.

The weight loss is supposed to be one of the worst parts of the diet. Just to give you some idea about how skinny we’re talking about, the president of the CRS is 5’11” and his weight ranges between ~ 130-140 lbs. So pretty thin, but not beyond the pale. The constant hunger, on the other hand, appears to be something people can get used to. That’s what they say anyway!

The early research on calorie restriction in primates is kind of mixed. A study on rhesus monkeys published in Nature found that calorie restricted animals don’t live longer. So that’s sort of a bummer. But there was a lot of encouraging health data! The diet improved cholesterol and oxidative stress levels in males but not in females. And it reduced the incidence of cancer, which is good.

Human studies are also pretty ambiguous. Calorie restriction results in heart function that resembles that of people decades younger. And testosterone levels in calorie restricted-males are lower than those associated with a typical diet (it’s hypothesized that calorie restriction tips the balance in favor of longevity vs reproduction). Some natural experiments also suggest that calorie restriction prevents cancer. Norwegian women who were adolescents when World War 2 limited the amount of food available have a reduced incidence of breast cancer, and so do women who struggle with anorexia early in life. But it appears that calorie restriction can’t be too severe, or it may actually predispose individuals to cancer later in life; Israeli Holocaust survivors subjected to starvation had higher rates of breast cancer, as did Dutch women who lived through the Hunger Winter. And calorie restriction may cause problems with maintaining bone density, so that has to be added to the con side.

A calorie restricted diet probably isn’t in the cards for me. I love food too much! But it does seem like, on balance, reducing calorie consumption is a good idea for most of us. And sort of extreme calorie restriction, like that advocated by the CRS, might not be a bad idea. The whole idea of the CRS is kind of intriguing to me.

Biosphere 2: Better than Fiction

biosphere2I have vague memories of learning about Biosphere 2–the huge, hermetically sealed bubble built in the middle of the Arizona desert–in school. I think there was some Scholastic-type newsletter about it, with a photo of all the Biospherians in their jumpsuits, and a rundown of all the ecosystems present in the big globe. Remember how much time kids in the 80s-early 90s spent learning about the rainforest? I’m pretty sure we must have learned about Biosphere 2 during the media blitz that accompanied the Biospherians’ entrance into their new home. And I’m sure what we read was totally optimistic, as coverage of current science for elementary school students usually is. But what happened after their big entrance? Were they really able to live totally sustainably for years in their big glass bubble? I had no idea.

Last week, when I came across a retro report on Biosphere 2 in the New York Times, it was like getting a forgotten part of my childhood back!  (For anybody who hasn’t seen it yet, the retro report series is awesome. And one of my favorite reporters, Michael Winerip, wrote this one up.) The retro report movie and the accompanying article were long on interest but short on detail.  Rumors of cults? Starvation? Oxygen shortages? A division among the Biospherians that erupted into physical violence? I wanted to know more! So I did some digging, and here is what I found.

The origins of Biosphere 2. Apparently the idea for Biosphere 2 was hatched on the Synergia Ranch, in New Mexico. The ranch was founded in 1969 by a guy named John Allen; it was an ecovillage/commune that counted some future Biospherians as members. The commune members, or Synergists, practiced organic farming, ate silently at mealtimes as they contemplated their food, and were part of an improv troupe called the Theater of All Possibilities. One Synergist, Texas oil billionaire Ed Bass, provided the funding for Biosphere 2 (~200 million from 1985–2007). Some people were discomfited when they learned about Mr. Allen’s vision, in which biospheres like this one would serve as refuges in an apocalyptic world laid to waste by nuclear war or some other disaster. So the PR people tended to focus on the neato science aspects of it. Ecology, rainforests and coral reefs, sustainability, etc. Originally, the biosphere was conceived of as a grand 100-year experiment. But it didn’t proceed exactly as planned.

Mission 1. The adventure began in September of 1991, when the 8 Biospherians (4 men and 4 women) sealed themselves in the bubble. The sphere, which covered an area the size of two and a half football fields, included a number of different ecosystems: a rainforest, an ocean with a coral reef, mangrove wetlands, a savannah grassland, a fog desert, an agricultural area, a human habitat, and a below-ground area that housed infrastructure. In all, 3,800 species of animals and plants were sealed inside, including hummingbirds, monkeys (!), and earthworms. Prior to the spherians’ entrance, two Native Americans in full dress and a Tibetan Buddhist monk participated in a sunrise prayer for their success.

The primary goal was to figure out whether the Biospherians could live totally sustainably for 2 years–with no food, air, or other supplies from the outside. Although the Biospherians were often called scientists in the media, only one, Roy Walford, was actually trained as a scientist. Walford was the crew’s physician, and his research interests focused on aging and diet. Apparently, inside the sphere, the residents soon broke into two factions: one group supported director John Allen and one questioned his methods. The anti group felt that the spherians should be formulating research hypotheses that would then be evaluated by the Science Advisory Committee. The pro-Allen faction, was against this idea. Apparently, despite the magnitude of this scientific endeavor, no regular scientific records were kept during the Mission! In February 1993, the 10-member scientific advisory team resigned. One of the remaining sources of scientific advice for the project was the mysterious Institute of Echotechnics. There were rumors that critics in the world of science were silenced by threats of lawsuits. However, a group of respected scientists wrote up a report on the project at the request of Ed Bass. Among other things, the report criticized the lack of a well-developed scientific plan, the project’s excessive secrecy, and possible “embellishments” of data. Walford later said, “Management thinks it knows more science than it does, but they don’t understand that in doing science you have to be asking a particular question, not just collecting a lot of random data. They have been [called] environmental zealots, and I think that’s true.”

930926_B2CrewAfterReentry_HM_UAThere were also allegations that the anti-Allen faction was punished with extra work and the withdrawal of privileges. Fights turned nasty–there was even spitting involved. It’s natural for a small group of people in trying circumstances to become short-tempered. But critics have pointed out that the way in which the spherians were chosen and prepared probably contributed to the level of dysfunction. Astronauts, for example, are carefully chosen for space missions. They must have stable psychological profiles, be very physically fit, and have extensive training in their fields. The Biospherians, by contrast, selected themselves. They were enthusiastic environmentalists and most of them were good friends, but they were not trained scientists (with the exception of Walford), they didn’t have any special training for their roles in the biosphere, they made decisions by consensus as questions came up rather than following a pre-established plan, and there was no real external scientific oversight. In other words, chaos may have been inevitable.

Fighting wasn’t the only thing that made life inside the sphere unpleasant. Oxygen levels dropped and carbon dioxide levels soared, making it very difficult to breathe. Later, researchers figured out that the concrete in the structure was absorbing oxygen, and the high organic matter in the soil also appears to have contributed to the oxygen/carbon dioxide problems. It got so bad that oxygen from outside had to be pumped in, and eventually a carbon dioxide scrubber was installed, which critics said voided the project’s raison d’etre (remember: nothing in or out, including air). In the end, all of the vertebrates except for the Biospherians and the pollinating insects died as a result of the wildly fluctuating carbon dioxide levels. Plus, the spherians had the bad luck of entering during an unusually cloudy time, which impaired the photosynthesis of the plants. Because the crops did not grow well, the Biospherians had very little to eat, and they lost weight — a lot of it. They had to resort to eating emergency food supplies, including seeds that were meant for planting. The coral reef dissolved into sludge. Cockroaches flourished, until they were eaten by an army of ants that seemed to appear out of nowhere. Although in the beginning there were domesticated animals, there wasn’t enough food to support them. The residents had to kill them. And one detail that especially interested the public and may have been difficult for the Biospherians to get used to: there was no toilet paper.

After the mission, a number of glaring mistakes were identified. When populating the various ecosystems with plants, species from all over the world were chosen and clumped together. Rather than resembling a natural ecosystem, in which different species have evolved to occupy different niches, brand new combinations of species were inadvertently being tried out. It did not work well, and  a few very successful species tended to crowd out the rest. The soil chosen was way too rich in organic matter, which contributed to the oxygen/carbon dioxide problems. And crops (like peanuts and soybeans) that depend on species-specific soil bacteria called rhizobia to grow didn’t get what they needed. These were all problems that agricultural specialists could have identified quickly. In fact, experts at the University of Arizona pointed out the problems with the rich organic soil, but they were ignored.

Eventually, the crew threw in the towel. The mission ended exactly two years after it started, in 1993. It’s pretty amazing they toughed it out for so long! I would have been banging on the air lock after a week.

Mission 2. The second mission lasted from March 1994–September 1994 and included 7 Biospherians. This time, having learned from the problems encountered during Mission 1, it was decided that spherians would rotate in and out in 180 day shifts and scientists and other personnel would be allowed to visit. By April of that year, some of the top managers of the project (including John Allen and Margaret Augustine) were replaced. Apparently Biosphere 2, which was originally conceived as a money-making venture, was requiring big infusions of cash and funder Ed Bass had had enough. A few days after Allen and Augustine were dismissed, two of the original Biospherians broke into the sphere, breaching the airlocks and deflating the system’s air pressurizer. They said their goal was to warn their comrades inside about the change in management. In the aftermath, a number of people connected to the Biosphere project accused John Allen of running a cult, including former Biosphere official Stephen Storm and the mother of Biospherian Abigail Alling. Among other things, they accused Allen of brainwashing and even physically abusing the Synergists who lived on his ranch.

Post-Biosphere Events. Eventually Ed Bass washed his hands of Biosphere 2.

First, Columbia University bought the facilities in 1995 and used them to conduct experiments. A lot of their work focused on manipulating carbon dioxide levels to simulate global warming.

Then, in 2oo7, the University of Arizona took over research at the sphere. It’s in their hands now. If you want to learn more about current research, you can visit their website. It seems like they are leveraging the unique blend of ecosystems to do some interesting ecology experiments.

I did a literature search to try and figure out what kind of scientific legacy this project left behind. It’s biggest contribution seems to have surrounded the hunger the biospherians were subjected to–a lot of great studies on calorie restriction came out of the work. As miserable as it must have been to be constantly hungry, the low-calorie, nutrient-rich diet that they ate contributed to pretty excellent health among the Biospherians. Their cholesterol, blood pressure, and glucose levels all fell. Perhaps Biosphere 2 should be rebranded as a health spa!

The early years of Biosphere 2 were a sort of fascinating debacle, but there may be many decades of research that lie ahead. Maybe it will end up lasting 100 years.

Want to go visit the Biosphere after reading all of this? You’re in luck. They give tours! And apparently they are pretty good–Trip Advisor reviewers gave them 4 out of 5 stars. Next time I’m in Arizona…

Leprosy: holding steady for 400 years

0613_leprosy_skullIn a new Science article, Genome-wide comparison of medieval and modern Mycobacterium leprae, Verena J. Schuenemann and colleagues managed to amplify ancient pathogen DNA from individuals suffering from leprosy hundreds of years ago. Leprosy is one of my many dorky fascinations. This winter, I dragged my sister to visit a former leper colony on the gorgeous Hawaiian island of Molokai. Getting there involved riding a mule down a sheer cliff face–it was a pretty exhilarating experience for someone with a life as tame as mine. And the palpable sense of history there, where a few patients with Hansen’s disease still reside, was really moving. Anyway, you can imagine that I was pretty stoked to see this study on leprosy in the headlines.

These scientists gathered the bones and teeth of 22 medieval skeletons from Denmark, Sweden, and the UK, hopeful that at least a few would yield quality DNA. And they were in luck! Dealing with ancient DNA is always a tricky business, and the researchers were ready with a special capture technique to enrich for M. leprae DNA, making it easier to sequence by getting rid of contaminating DNA from other species. One tooth from Sweden, however, provided M. leprae DNA that was in such great condition that they didn’t even need to use the capture method (you can see the skull from which the tooth came here). It yielded a whole genome sequence on its own–and the tooth even contained more M. leprae DNA than human DNA. Pretty amazing!

In fact, the superb preservation of the M. leprae DNA was a recurring theme throughout the article. It actually sort of threw a wrench in the works, since one quality control measure that researchers use when dealing with ancient DNA is looking at the pattern of nucleotide misincorporation patterns, to make sure they are consistent with an ancient source. What does that mean? As DNA ages, more and more DNA bases are replaced by faulty copies, or nucleotide misincorporations. Therefore, ancient DNA should have a lot of nucleotide misincorporations. Usually, if an “ancient” sequence looks brand new, in terms of nucleotide misincorporations, you know you’re in trouble. You may be inadvertently studying modern DNA that has somehow contaminated your samples or laboratory. This case seems to be the exception, however. The other quality control measures in this study–like blank controls, independent replication by other groups, and identification of mycolic acids consistent with M. leprae–all looked good. It’s probable that the great preservation of the M. leprae DNA was due to the waxy, cell wall that surrounds the bacteria. Apparently, it protects the DNA inside from degradation. The same thing goes for M. tuberculosis, the cause of tuberculosis and a close relative of the leprosy bacterium; researchers have had pretty good luck finding ancient M. tuberculosis DNA that is in good shape. If you’re interested, you can find a couple of neat examples of recent ancient tuberculosis studies here and here.

Schuenemann et al. were able to obtain whole genome sequences from five of their ancient samples, representing each of the three countries (Sweden, the U.K., and Denmark) and dating from the 10th-14th centuries. They compared these whole genome sequences to 11 obtained from modern strains, which were collected in places like India, Thailand, the US, Brazil, Mali, the Antilles, and New Caledonia. And they found that there were very few genetic differences between all of the strains. In fact, one of the major conclusions that emerged from this article is that leprosy strains have changed very little since Medieval times. After building a phylogeny (i.e. a family tree for the bacteria), Schuenemann and colleagues found that the ancient European strains were most closely related to modern strains from Turkey and Iran. This may indicate that Medieval European strains originated in the Middle East. One popular hypothesis about why the number of leprosy cases in northern Europe shot up around the 11th century is that knights returning home from the Crusades ignited epidemics–this paper adds a little more evidence to support that theory.

The rather sudden disappearance of leprosy from Europe has been an enduring mystery in the annals of historical epidemiology. It has been estimated that there were almost 20,000 leprosaria (or leprosy hospitals/colonies) in Medieval Europe. Today, there is only one remaining colony for patients with Hansen’s disease in Europe. Obviously, antibiotics helped drive down the prevalence of the disease. But hundreds of years before we discovered a cure, leprosy was vanishing from Europe. Why? A change in the bacteria that made it less transmissible? Or a change in Europeans that made them less susceptible? Nobody knows! One of the authors’ conclusions that I found particularly interesting was that because there were so few genetic differences between ancient strains and modern strains, it’s unlikely that changes in the pathogen can explain why leprosy is no longer such a scourge. They hypothesized that other factors (like co-infections, social factors, or host immunity) were probably responsible for the susceptibility of Medieval Europeans to leprosy. These findings and this conclusion are similar to those that emerged from a comparison of ancient Y. pestis strains obtained from victims of the Black Plague and modern Y. pestis strains–there were no unique genetic differences in the ancient strain, so the authors (many of whom also worked on this leprosy article) concluded that genetic characteristics of the pathogen was unlikely to explain why the Black Plague was so deadly.

I think the authors may well be correct about host factors accounting for the decline of leprosy in Europe. There is no question in my mind that things like nutrition and hygiene play a very important role in susceptibility to infection. But I also think ruling out important pathogenic changes because there are few genetic differences between strains is risky. When you see that a particularly virulent strain of bacteria has recently acquired a big chunk of DNA, especially one that contains genes linked to virulence, it’s easy to pinpoint the basis for that microbe’s nastiness. But failing to find big genetic differences doesn’t necessarily mean that important changes aren’t present. As we know from studies of viruses (like influenza and the λ bacteriophage) and bacteria (like Y. pseudotuberculosis), one or two tiny mutations can have a large effect on things like transmission and virulence. It’s really hard to look at a smattering of DNA substitutions and know what they mean! I’ll be curious to see what we learn about some of the genetic changes identified in the study in the future.

Congratulations to Schuenemann and the other scientists involved in this work for such an exciting study. I really envy the people who study Mycobacteria. I worked on the bacterium that causes syphilis, T. pallidum, for a long time. Being able to sequence a few ancient strains of this microbe could go a long way toward solving the mystery of this infection’s origins (you can find some of my relevant articles here and here and here). In particular, did Columbus introduce this disease into Renaissance Europe after returning from the New World? Unfortunately, T. pallidum DNA seems to be very sensitive to degradation. So there doesn’t seem to be much hope that ancient DNA is going to come to the rescue in this case! With the constantly improving sensitivity of sequencing techniques, though, who knows what the future holds?! The technological advances that have emerged since I began graduate school, ten years ago, have transformed the face of science. It’s an exciting time.

Voodoo Death and Public Health

images-1After being condemned by a medicine man, a terrified man dies of fear. A woman commits a taboo action, and, convinced that punishment will be swift and lethal, she perishes. This type of voodoo death was a subject of great interest in the first half of the 20th century. U.S. physicians stationed in Australia, South America, the Democratic Republic of Congo, or other far-flung places occasionally got the opportunity to examine the victims of voodoo curses. Though these doctors usually found nothing wrong with the patients via standard workups, they reported it was clear that their charges felt very ill. Often the cursed would pass away, although the physicians couldn’t figure out the physiological cause of death. Other times, the victim would get a lucky break–he or she might receive a countercharm or assurance from a sorcerer that the curse had just been a joke–and in these cases, a rapid recovery could occur.

In the 1940s, Walter Cannon wrote a great account of this type of Voodoo Death for American Anthropologist. He relayed some anecdotes about the phenomenon and raised the possibility that maybe there was something to it. Perhaps strong emotions, like fear, can actually do us in. Cannon hypothesized that the cause of Voodoo Death was a hyperreactive sympathetic nervous system brought on by emotional stress. Excess nervous system activity could result in a fall in blood pressure, eventually leading to death. He compared reports of Voodoo Death to cases of shock that had been described during war: subjected to a terrible stress (like a grenade going off nearby), some soldiers would quickly die, even though no gross injury was apparent. And everyone has heard stories about someone dropping dead or having a heart attack following shocking news. Same concept.

Being cursed in a culture that believes in sorcery certainly sounds like a stressful event. One researcher working in northern Australia pointed out the strong social dimensions of a voodoo curse. Once someone is cursed, they are excluded from social life. The cursed individual is treated as though he or she is already dead. The only social interaction they can expect after being cursed is being present for the commencement of their funeral rites. Surrounded by people more or less pressuring them to die, victims cooperate, refusing food or drink and accepting their fate. In this view, voodoo works because people believe in it. It’s like the well known phenomonen in which being given a placebo is followed by improved health–except for the opposite happens. In fact, this expectation of sickness has been given its own name: the “nocebo” concept.

Not everyone agrees with the voodoo-death-caused-by-severe-stress-and-fearful-expectations hypothesis, of course. For example, some people think that the typical voodoo curse victim may be poisoned or simply denied food and water until they die. But in the 1970s, anthropologists like Barbara Lex voiced support for the theory that manipulating the autonomous nervous system via fear could be sufficient to result in death. Although we might consider Voodoo Death to be death by suggestion, the suggestion leads to a real physiological chain of events. A number of anthropologists who have championed this view have pointed out that their hypotheses can be tested. For example, if you examine a victim of a voodoo death curse, they should bare the telltale signs of parasympathetic activation: constricted pupils, pallid skin, etc. Unfortunately, or maybe fortunately, there haven’t been many cases of Voodoo Death easily accessible to researchers who want to gather this kind of data.

A doctor named Harry Eastwell, who provided psychiatric services to local communities in Northern Australia, described a scenario in which both psychological and physical deprivation were at work. The third most common “psychiatric” syndrome he treated in the region was a gross fear state, in which people (almost all males) were terrified that they were going to die from sorcery. Already in a sorry psychological state, these people may be prime candidates for “voodoo” deaths. Only two of his 39 patients suffering from this fear state died, though. And in both cases, mundane causes of death could be identified (although their state of fear may certainly have contributed to these proximal causes). Eastwell also reported that voodoo death could be averted by removing the victim from a situation in which everyone around them thought that death was a foregone conclusion and by treating any conditions that ailed them (like dehydration). After seeing a pattern in which water was either denied to a curse victim or they would not drink it themselves, he thought some of the mystique of the voodoo death had disappeared. While psychological forces were certainly at work, Eastwell believed that denial of fluids was an important cause of death in both victims of sorcery and those who suffered from other illnesses believed to be fatal. It should be noted that some researchers vehemently disagree that people in Northern Australia withhold food and fluids from the ill. So, like any interesting topic, the role of dehydration in hurrying along the cursed is controversial!

Although most voodoo deaths have been reported from the remote locations where cultural anthropologists used to do their fieldwork, similar anecdotes have emerged here in the U.S. For example, in 1960s Oklahoma, a healthy, successful man decided to sell a business that he operated with his demanding mother. Unhappy, she predicted that if he made the sale, something dire would happen to him. Two days later, despite having no previous history of breathing problems, he suffered his first asthma attack. Soon, he was in and out of the hospital for asthma that was out of control. One night, he called his mother and told her of his plans to reinvest the money from the sale of his business into a new venture. He also expressed optimism about his health prospects. She told him that no matter what he or his doctors thought about his chances of recovery, he should get ready for the worst. An hour later, he was dead. And this story isn’t entirely unique. I’m sure you can recall any number of stories about people who died of fright, or sadness, or because they had given up the will to live.

All of this makes you take a second look at your own culture. What proportion of illnesses and deaths are due to nocebo-type beliefs? Researchers have questioned whether certain surgical patients have a “predilection to death.” That is, these patients are convinced that they are going to die, and they may even view death as desirable. Not surprisingly, they are more likely to die. Although Voodoo Death sounds exotic, some researchers see Walter Cannon’s seminal paper on this subject as the beginning of a long and fruitful research agenda focusing on the link between emotions (like fear) and health outcomes. There is still a lot of confusion about whether and how Voodoo Death occurs in other places, but it seems we have been able to use this unusual topic to shine a light on an important cause of illness in our own society.

Are placebos getting more effective over time? What does it mean?

imagesThe placebo is the fake treatment at the heart of every clinical trial. It’s the sugar pill, the sham operation, the baseline to which the real treatment must be compared. The whole placebo thing started on a World War II battlefield, when a physician named Henry Beecher witnessed something extraordinary. A wounded soldier was in great pain, but Beecher and his colleagues had run out of morphine. A nurse gave the soldier an injection of salt water, telling him it contained the painkiller–and the man responded as though it really did. When Beecher returned to civilian life, he pointed out that this phenomenon, which he called the placebo effect, could be causing big problems in studies of new drugs. A new drug might seem effective because patients treated with it appeared to improve; but in truth it might not be more effective than, say, a sugar pill. Patients’ expectations might be responsible for a large part of the benefits that everyone had been ascribing to drugs. And If we can get more or less the same effect from a sugar pill, it doesn’t make sense to mess around with a medication that is bound to come with its own set of problems. That’s why in today’s clinical trials, we compare new treatments to either placebos or whatever the standard of care is (previous trials having shown the latter is more effective than placebo).

Here’s something interesting, though. It turns out that placebo treatments appear to have been getting more effective over time, at least for some conditions. Take antidepressants, for example. From 1980 to 2005, the improvement effect reported in the placebo groups of clinical trials doubled. There is no evidence that the effectiveness of the placebo has increased for disorders such as epilepsy. So it’s not clear how general this trend of increasing effectiveness is. But why would the placebo effect be getting stronger for conditions like depression?

One possibility is conditioning/expectations on the part of the patient. Perhaps, based on past positive medical experiences, patients have come to associate contact with a medical professional with feeling better. In other words, because people believe that being involved in trials will improve their health, it does. Maybe current patients have higher expectations than past patients. But it’s also possible that the change hasn’t occurred in the patients. In that study of changes in the placebo effect over time in antidepressant trials, the researchers found that the response was only evident if you looked at expert ratings of depression. If you looked at patient self-reports, there was no increase in the effect of the placebo over time. So what does that mean? Possibly that observer ratings are not very reliable. Maybe over the years, physicians have been getting increasingly confident about their results, and this is reflected in their assessment of patients. The authors argued that it is unlikely that the placebo effect has actually doubled over the last two decades.

In the popular press, some writers have viewed the increasing effectiveness of placebo treatments as an impediment to getting new drugs approved. After all, the more effective a placebo treatment is, the more effective a new drug has to be to prove itself. The idea is that patients are missing out on potentially effective meds because the placebo is more effective than it ought to be. In truth, researchers have found that the more effective a placebo, the more effective the comparison drug tends to be. So drugs that aren’t more effective than placebo may just not be that effective over and above the expectation/conditioning effect. The placebo may just be a convenient scapegoat for unsuccessful trials.

Whatever the reasons for the increase in the placebo effect over time, it makes sense to harness placebo power. One group that has been able to figure out how to capitalize upon the placebo effect is the pharmaceutical industry. As has been pointed out, they understand how important it is to set up specific expectations within the minds of their consumers. They carefully manage advertisements, medication names, and the way that pills look in order to create the idea that a given medicine will have a certain result. And it seems to work!

How could a placebo be used effectively by the typical doctor, though? The big hurdle here is ethics. Most people feel it isn’t right for a doctor to give a patient a sugar pill and pass it off as a “real” treatment. Of course this makes sense. But it’s also true that a physician doling out a sugar pill could truthfully say, in many cases, that the treatment they are prescribing has been shown to significantly reduce pain for a given condition. For example, in one unique experiment, patients with irritable bowel syndrome were randomized to several groups. Some were put on a study waitlist (because just signing up for a trial can result in improvement), some were given a placebo by a curt medical practitioner, and some were given a placebo by a warm practitioner who expressed optimism about their condition.  Each of these assignments was associated with increasingly good responses. Roughly 30% of those who were on the waiting list reported adequate pain relief, about 40% of patients with the curt doctor said their pain was under control, and over 60% assigned to the warm doctor/placebo group felt their pain was manageable. The same trend was seen for quality of life. Obviously the ritual of seeking medical help and receiving compassionate care is an important part of getting better.

Even if the ethical problems can be overcome, however, logistical problems remain. In this day and age, most of us google the medications our doctors prescribe prior to filling them. How could a placebo fit into our system? What would the doctor say he was prescribing? What would your prescription say? Obviously your physician must be honest, and a placebo won’t work if you know it’s a placebo. The placebo works well in clinical trials, where secrecy is a design feature, but how would it translate into the real world?

As placebo treatments are increasingly considered worthy of study themselves, it will be interesting to see if and how medical treatment changes to accomodate what we’ve learned.

P.S. Thanks to Lotus Eater for pointing out that changes in the placebo effect over time have been documented!