The Placebo Response. Just say the words and you generally get a negative response. People think of a placebo as some no good trick used by devious people to deceive some unsuspecting innocent person. It’s accepted in the medicine and research world as a way to test true effects of a substance or intervention versus an effectthat can’t be attributed to the actual intervention. We’ve been taught to separate out the chemical effects of the medicine from any effect that surrounds it. So placebo is generally thought of as an undesirable thing. No one wants the placebo pill that may only help a little bit because you think it helps. We want the real pill. But what if we switch the thinking around, and instead focus on the way the placebo works, using that as a conduit to see how belief influences effects; and in particular, how belief influences performance.

Let’s delve into the mysterious world of the placebo and combine my two loves of neuroscience and exercise science to see how belief effects performance.

How Placebo’s work: The power of belief

How can a placebo actually work? How does it affect real physiology, sometimes profoundly? The answer lies in our expectations and beliefs.

We can essentially get a placebo response via either expectancy or conditioning. In expectancy, if a person truly believes that X will do Y, then we might get a nice little placebo response. So if our doctor, who is an authority figure, prescribes us a medicine, and we think it will make us better, the chances are that if we have a lot of faith in our doctor, we’ll get a small but substantial benefit, even if the medicine was inert. On the other hand, conditioning occurs when we train that response in the body. The classic pavlov’s dogs experiment is a crude example of this. More on this later.

I have a somewhat favorite saying of ‘our expectations govern reality.’ What this means is that how we see and expect things to occur influences our experiences. How we experience any situation is entirely biased and blinded but our expectations going in. As a very simple track related example, whether we see a race as a success or failure is dependent on how we see it going in. If we set really high goals of winning or running faster than 4:00 mile, and we run 4:01 and get 5th. It’s a failure, while maybe our teammate who has run 4:10 sees that as amazing. Or maybe, we might have seen that as amazing 3 weeks prior before we knocked our PR down from 4:05 to 4:00. The point is our experiences are completely manipulated by surrounding factors.

In an interesting piece by Halson and Martin (2013), they point out that what we experience is actual a combination of the actual experience + what we should experience (or expect to experience). If we translate this to the world of exercise and placebos, it should be obvious that the actual experience (taking an inert pill) is influenced by what we expect to experience. The reality is that this shouldn’t surprise you. The

supplement industry thrives off of this concept. We expect to recover better when we take that super mega testosterone boosting supplement, so we kind of do. But how do they actually work, or is it all in our head?

Without delving into it too much, most of the research points to placebos modifying activity in the brain. For instance, when we look at pain research, using placebo analgesia can decrease the activity of the brain related to pain (Enck, 2013). And what we get after that is a subsequent increase in opiods to further modulate pain perception. So we get a combined neural activity change that leads to an actual biochemical change. The same holds true for other types of placebos. You might have a shift in activity in areas related to emotional regulation, or controlling the stress response. In the research world they have found placebos affecting areas involved in mood, respiration, cardiovascular function, immune function, hormonal systems, pain, motor function, and GI function. For a review of many of these I suggest Enck et al. paper in Nature.

What affects the placebo response?

Describing it as valuable (more expensive placebos work better…)

Complicating the procedure (acupuncture works better than pills. An injection works better than both. A sham surgery seems to work even better.)

Showing empathy and care

Having authority

Explaining why it works.

Negative expectations on if it will work from an authority.

All of the above, and likely more, can impact how strong or weak the placebo response is. It makes sense because all of the above impact our expectations. Of course we expect a more expensive treatment to work better, or for a well known doctor to help us more than some joe schmo. Perhaps scariest is the nocebo effect related to the last point. If a Doctor emphasizes there expectation that the treatment will not work, the likelihood of it working diminishes, even if the drug really should work.

Along the same lines, side effects can be modulated via the placebo effect. A patient can get actual side effects from a placebo that contains nothing simply by the doctor listing out the potential side effects. What happens is essentially that the brain makes note of these side effects and amplifies it’s perception and awareness of them. It’s similar to the idea if you tell yourself to look for a yellow object in a sea of people, yellow objects will stick out slightly more as you’ve increased your perception of that color.

I hope what you see is that expecations matter. And it’s not just about the placebo or nocebo response. If we start translating this into the real world, which we will shortly, then does it not make sense that if we start expecting workouts to not work, or expect a certain workout to be incredibly hard, then it likely will. But before diving into that, let’s look at the strange world of conditioning responses.

Conditioning Responses:

But it goes beyond simply believing that something will happen. What has been found more recently is that we can actually condition placebo responses. So if I were to give you an injection of an immunosuppresent, you would get the subsequent immunosuppresent effects. But what is interesting is that if one day, we gave you your typical injection but this time it was of saline instead, you would still get an

immunosuppresent effect. Your body had been trained to expect that, so it did.

In a fascinating opinion piece in Nature by Enck et al. (2013), they mention how conditioning can occur and the potential uses for it in medicine. What several studies have found is that by combining a normal dose of a medicine with some easily recognizable sensory stimulus (i.e. taking a drug that has a particular odor), that if we were to give a placebo with that odor, for example, that we would get the same effect as the medicine would have had. There have been studies that have used a protocol to reduce medication by inserting placebo treatments interspersed with actually taking the pill. As a an example, you might insert the placebo every third day, and what they found was that the efficacy of the drug stayed the same, even though total drug amount decreased. They’ve done this with immunosuppressant’s, corticosteroids, and ADHD medications.

One of the central ideas with placebos is that conscious conditioning is the reason they work. What this means, is that as discussed above, if you manipulate a persons expectations, you increase the effect. So whether it is having a doctor explain to them why it will work, or seeing and feeling a needle go into the skin, it is that conscious knowledge that manipulates the belief, and ultimately the placebo response.

In an experiment by Jensen et al. (2012), they investigated whether the placebo response was triggered via conscious or nonconscious mechanisms. They tried to trigger the response via using a clearly visible stimuli versus a visual stimulus that went by so quick that it would only be recognized subconsciously. So what they did was provide a “thermal pain stimuli” which basically means they changed the temperature on a part of the body. All the subjects had to do was feel the change in temperature, and rate the pain.

Under the experiment condition, what they did was stare at a computer screen which flashed a picture of a face depicting what a face would like with either low or high pain. During the conscious test, the cues stuck around long enough for the subjects to see them, but during the nonconscious experiment, the faces flashed so quickly that it

couldn’t reach conscious levels.

What happened? The faces essentially acted as a way of conditioning placebo responses. If a high pain face was shown, pain scores were higher. So they conditioned the placebo response, but more importantly it occurred both consciously and nonconsciously. So they could condition a response, even if the person wasn’t consciously aware of it.

Furthermore, what seems important is the balance between conscious and unconscious conditioning. In other research mentioned in the article (by Benedetti et. Al) there have been studies where people still get the placebo response even when they are being told that they are getting a placebo. For instance, in one such study, subjects were conditioned to have an endocrine response from an injection. They were conditioned via actually having a drug that effects the immune system given periodically. So the next time they were given an injection, even when it was a placebo, the body responded by modulating the endocrine/immune response as if it had received the actual drug. But what is interesting is that this same response occurred even when people were told they were getting a saline injection. So what we had in this case was a battle of conditioned response in terms of nonconscious vs. conscious. The brain sub-consciously acknowledged the injection, but that was so strong that even the conscious knowledge of knowing it was a placebo didn’t diminish the full response.

Additional studies have shown that the doctor interaction can transfer subconscious effects on the placebo response. The brain therefore takes both conscious and sub conscious feedback and tries to paint a picture. When we have contrasting information, it seems to sort through what might be the best guess and it goes for it. So even if we know we are getting a placebo injection, the fact that it is an injection makes our

brain say, wait a minute last time we got an injection we had this response.

Placebo in Medicine?

The fact is, we have our own built in placebo guided medical approach. It’s called homeopathy. Now before some natural guru slams me as being uneducated and not open minded enough to see how homeopathy works, I’m not saying it doesn’t work. I’m saying it works as a placebo only, and that’s not a horrible thing.

For those who don’t know, homeopathy is a practice where homeopathic “doctors” prescribe diluted liquid preparations. Without going too far into it, some guy in the 1800’s decided that in order to cure someone; we should give them something that causes those symptoms. So if you have a fever, we should prescribe a medicine that would cause a fever in a normally healthy person. This is known as the “like cures like” principle. But, he took it a step further and said that we need to dilute that substance and that (and here’s the kicker) the more we dilute the substance the more powerful it gets. That is all pseudoscience BS. Makes no sense what so ever. But that’s the back story, and before someone says “that sounds like vaccines”, let’s get to the next part.

Homeopathic remedies are sooo diluted that there isn’t even a single molecule of the original substance is in the remedy. Back when Oscar Pistorious was going through his trial, I commented on a substance he was taking to increase testosterone levels (here). It contained bovine testicles, but in actuality it was a homeopathic remedy, so it may have started with bovine testicle extract, but it was so diluted that it didn’t contain a single

molecule of bovine testicle in the remedy. To give you an idea of the scale, creating a homeopathic remedy would be like me dropping one drop of coffee into one of the great lakes, then taking a random glass and dipping it into that great lake, drinking it, and saying that I was on a super caffeine buzz. That’s how diluted they are . Now that we have that out of the way, homeopathicremedies are simply water. That’s it.

But they provide a fascinating prism through which to evaluate placebos and belief. In the research, homeopathy works no better than placebos (duh, they’re the same…), but the fact that it works at all is fascinating. I have friends, even pro runners, who swear by their homeopathic remedies, and some have shown demonstrable improvements in some sort of outcome. So what? The point is that homeopathy is a great demonstration of placebo and belief. What happens when you go see a naturopath or homeopathic doctor? They are kind, they genuinely care (and believe their pseudoscience nonsense), they offer a solution that they believe in, take time to understand your issues, and give you a complex sounding “medicine” prescribed for you, with a complicatedsounded reason for why it will work.

All of those things influence belief AND your expectations on what should occur. The Doctors are essentially selling the highest form of placebo that they can. And it will generally improve the patient by a couple percent, versus doing nothing. Compare that to the cold shouldered doctor who spends 2 minutes diagnosing you and not explaining anything, and it’s no wonder that crazy people have built an entire industry on selling a placebo, and it is thriving.

What does this have to do with Running?!?!

Fatigue is a mysterious process. We used to think we had it all figured out and could blame lactic acid. But what research lately shows is that fatigue is best thought of as emotion. Fatigue is a sensation. What the feeling of fatigue actually is a battle between your drive and will to push versus your body trying to keep you safe from harm and maintaining homeostasis. It is this tug of war that creates the sensation of fatigue.

Yes, the physical stuff matters. The glycogen depletion, the acidosis, and so forth matters. What that is though is feedback to the brain. It’s no different than you driving the car, looking at the gas gauge and deciding to drive a little more economical because you’re about to run out of gas. That’s what your brain does. If it’s running low on fuel instead of showing you the gauge, what it does is emits the feeling of pain or fatigue. If you get closer and closer to empty, that warning signal gets stronger. The bodies trying to slow us down so that we don’t do damage, while we are trying to push our gas tank as close to E as possible.

Which brings me to the point that, if placebos can affect pain perception, then it should make sense that it can influence fatigue too! And it turns out it can. I recent study (http://bjsm.bmj.com/content/47/17/e4.7?etoc) took athletes and had them perform 5k time trials, once with a placebo drink that they were told would enhance performance. The results showed that, the placebo did in fact enhance performance.

Before we get into the efficacy of that, let’s posit another question. Going back to the use of conditioning on the placebo response in medicine. I mentioned that we can condition a medical and then endocrine response. In one study they conditioned changes in both cortisol and growth hormone via the same mechanism mentioned previously (use

the drug initially with some sort of sensory stimuli, then eventually replace the drug with a placebo but keep the sensory stimuli. )

But what about in terms of endocrine responses such as EPO? Would you get a bump in EPO, if you illegally conditioned with injecting an EPO, testosterone, or GH booster and then injected saline but conditioned the response? Could that be a new way to dope that decreases the chance of getting caught. Or perhaps closer to reality, is the use of altitude tents largely guided by a placebo response or even a conditioned response. Altitude tents are largely variable in termsof increasing performance. Even with some professionals, yes spending more time in the tent mattered a lot, but there were still some who showed little benefit despite spending a good amount at it. Does the placebo effect play arole, as well as some individual responder/non-responder mechanism.

Or conversely, can we condition an EPO response with an altitude tent, the way it is done with medicine. I’ve wanted to do this experiment where we would track changes in EPO with the use of an altitude tent. But instead of simply tracking the response, at some point we simply switch the machine so that it says it’s decreasing the oxygen tent, but instead is doing nothing. Would we get a conditioned response of EPO increase just because our body expects it given it has happened in the past and we’ve got all this big expensive equipment.

So what?

I once coached with a coach who would tell his athletes fake splits while doing workouts or measure loops/miles short so that the athlete saw a faster split. In fact, in one instance, they had athletes do a workout in the outside lane of the track, and measured the interval reps short in that lane to make sure the workout was a success. This is the perfect example of a coach manipulating a workout and creating a placebo like effect by improving belief because the athletes think they are working out faster than they actually are.

Does this mean we should all go around lieing to our athletes and telling them that they are doing better workouts than they are? Absolutely not. But there are some interesting questions that arise from this line of thinking.

A somewhat timely article by Halson and Martin entitled ‘Lying to Win” (2013) (here) ask this question. Should we as coaches lie to our athletes to get a placebo response or to manipulate belief? Should we as scientists or doctors use the placebo effect to our advantage?

My answer is No, with a caveat that yes, we should exploit the placebo response, or cognitive manipulator, but not by intentional deceiving of things like splits.

If we simply lied to the athlete or patient, the reality is we’d be working on conscious conditioning only. Unless we were a psychopath, our subconscious signals would be shouting that we don’t actually believe what we are saying. If we are crazy like some homeopaths and really believe that diluted water will cure all, we aren’t lieing. We believe it, even if our belief is wrong. So it’s exploiting the effect because consciously and subconsciously we are giving out the same signals.

Instead, what we should focus on is instilling confidence in our belief in the athlete, patient, or medicine. What that means, is that instead of lieing to an athlete and telling them faster splits, genuinely tell them they are in their best shape of their life. Give clear expectations of where they should be in the race, and make sure your and there expectations are on the same page. Show them how expectations effect performance.

In the same article, I found the statements by a good friend, Trent Stellingwerff, very intriguing. Stellingwerff brought up the fact that the effects of proven ergogenic aids don’t aggregate. Meaning that if we get a 2% boost from caffeine, another 1% from beta alanine, and 2% from beet root juice, if we took all of them, we don’t get a 5% bump in performance. They all act on different physiological systems, so why is there no additive effect? The authors speculate that, they all act on a central mechanism that

regulates performance (i.e. like the one talked about with fatigue above).

What it means to me is instead of telling an athlete to take this drink that you know is a placebo to improve performance, give them something that actually seems to, and sell it hard that it does. Don’t just say, this may or may not work, or give the research speak that in 10 studies it improved performance but in 3 it didn’t so hopefully you are in the 10. Say that this stuff works really well, it’s strongly research backed (10 vs. 3 is strong!), and it works because of X, Y, and Z.

In the medical (and real) world, they need to take a hint from the naturopath, homeopath, whateveropath. The stuff you do surrounding the visit matters. Just as when we run, the brain receives fatigue on what’s going on around it to determine when we should slow down, when we are interacting we consciously and sub consciously collect feedback. And that feedback impacts the efficacy of the treatment outcome.

You don’t need to deceive to take advantage of the placebo response. You just have to frame the placebo response as a cognitive modulator. We’re looking at manipulating activation in the brain, altering opiods, etc. The placebo response is simply a way to train the brain. The lessons to be learned are that expectations matter and that conditioning responses is possible. Change the expectations and you alter reality. Placebo conditioning is nothing more than training the brain.

My take aways from the fascinating and complex world of placebos is two fold. First, we can train the brain. Second, expectations matter. Be aware and frame them in the right way.