Placebos, Dopamine and Your Nucleus Accumbens

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New drugs are generally tested in randomized control trials in which half of a group of patients get the new therapy and half get the equivalent of a sugar pill. It is well-known that a lot of people taking sugar pills feel better. This is known as the placebo effect—the phenomenon in which a patient's symptoms are alleviated by an otherwise ineffective treatment, apparently because the individual expects or believes that it will work.

Brain scanning researchers at the University of Michigan believe that they have pinpointed why the placebo effect works in some patients and why others are immune to it. The press release reporting the new study notes:

Using two different types of brain scans, U-M researchers have found that the extent to which a person responds to a placebo treatment is closely linked to how active a certain area of their brain becomes when they're anticipating something beneficial.

Specifically, the research finds strong links between an individual's response to a placebo "painkiller", and the activity of the neurotransmitter known as dopamine in the area of the brain known as the nucleus accumbens. That's a small region at the center of the brain that's involved in our ability to experience pleasure and reward, and even to become addicted to the "high" caused by illicit drugs.

The researchers injected volunteers with a painful saline solution and then told them that some would receive a painkiller injection and others would receive a placebo. In fact, all of the "painkiller" injections were placebos.

The PET scans and pain ratings revealed that as a group, the volunteers experienced significant pain relief from the placebo. But when researchers looked at each individual's results, they found that only half of the volunteers reported less pain when they received the "painkiller" placebo.

These placebo responders, as they were dubbed, had significantly more dopamine activity in their left nucleus accumbens than the other volunteers, beginning when they were told the painkiller medicine was about to begin flowing into their jaws. It also turned out that these individuals had also all anticipated the "painkiller" would give good pain relief before they even received it.

Meanwhile, of the seven individuals who didn't experience the placebo effect, four actually reported feeling more pain when the "painkiller" was delivered – a phenomenon that has been dubbed the "nocebo" effect and has been observed in other situations.

My speculative question is would weeding out placebo responders through pre-clinical trial brain scanning improve the process of determining the efficacy of new drugs?

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  1. My speculative question is would weeding out placebo responders through pre-clinical trial brain scanning improve the process of determining the efficacy of new drugs?

    That’s a good question. Clearly for drugs with a neurological or psychiatric effect there’s the potential that such an action might lead to skewed results rather than more accurate results.

    Also, I understand that stress and mood may speed recovery from a variety of conditions. Perhaps weeding out people prone to the placebo effect would also weed out people who have particular patterns of stress and mood. This could bias results one way or the other.

    In other words, removing the people most prone to the placebo effect might have other, more subtle effects on the study.

  2. Not anytime soon. To do so, you would need to know who is and is not a placebo responder to a much higher degree of accuracy than the level to which you are attempting to the efficacy of the new drug. Otherwise, you start attempting to control a “random” (actually, an unknown) variable at the onset of the testing and adjusting your test population based on that control rather than just controlling for it mathematically at the end.

    Unless placebo response is a very highly predictable (repeatable) phenomenon at the individual level, it’s easier to hire a math nerd to account for yet another variable once all your data is in.

  3. thoreau wins the scientific “why not” portion of the thread. I was just attempting to explain that logistically/operationally, it’s easier to account for than to control.

  4. It’s not a “placebo effect” if you know that what you are taking doesn’t have the active ingredient. When I drink decaf coffee, I still get all the physical effects of caffeine.

  5. What if the “placebo responders” have other idiosyncratic reactions to drugs?

    Weeding them systematically out of trials would mean that a segment of the population is untested. It could mean that complications that hit only them would take a long time to be detected.

  6. I can just see it now.
    Each person will be required to undergo placebo response testing at the beginning of purchasing their health insurance plan. A person who responds well to placebos will be given a sugar pill of some fancy name for pain reduction, and if it works, everyone will have lower health insurance premiums. If not, at least we gave it a shot, eh?

  7. I wonder what the orientation of the placebo susceptible set is to the nanny stater set.

    It would go a long way towards explaining the fealty many citizens have for our sad sack sugar pill of a gov’t.

  8. When I was age 12 some friends and I smoked a joint rolled with Oregano. I actually think I got some small placebo buzz, but I don’t really remember though…

  9. Maybe Thoreau was saying this, but how does correlation of dopamine levels in a placebo study of painkillers translate to drug studies involving less obvious linkages (say, chemo therapy or even Erectile Dysfunction?).

    I would find it more interesting if there were a correlation in these type of studies (I suspect dopamine wouldn;t be the thing they’d notice). I’d also find it more interesting if it was done double blind, where some subjects, unbeknownst to the researchers, actually got pain killers.

    In the end, doesn;t this type of study end up delivering some correlation–any correlation–because that’s what it’s looking for? Just askin’.

  10. What kind of person volunteers for a study where they say:

    “Let’s start out by injecting something really painful in your arm”.

    I think you are starting out with a pretty skewed sample.

  11. Wow- this is a big step, the placebo effect is perhaps one of the biggest mysteries in pharmacology, this study actually makes it seem a soluable problem.

    Gaijin- Nope, they were looking for this specific correlation or something like it. A number of people have been looking towards the accumbens in this vein for a while. This study just puts it together fairly well. The left accumbens activation is especially interesting in light of recent work on the lateralization of affect. Left activations in a number of brain regions generally correlate with positive mood.
    It is difficult to predict whether this finding will map onto drugs other than painkillers,as certain types analgesia is linked to some extent to activity in the dopamine system of which the accumbens is a part. On the other hand, negative affect is linked with increased morbidity and mortality in any number of disorders, so the finding may generalize. At this point I would say we need more studies.

  12. So, faith healing could alleviate pain in someone who believes in faith healing.

    Say a friend has a medical condition that causes constant pain, but no long term damage. Several doctors tell him there is no know cure. The sales staff at a health food store sells him a mixture of fructose and water. He feels better immediately, and the treatment only costs $5 per month to maintain. Is it better to tell him fructose is sugar and explain about the placebo effect or to stay silent and be glad he isn’t suffering any more?

  13. I always figured placebo’s didn’t work on me because I’m skeptical by inclination. Which raises the question (I never beg 😉 Can skepticism be traced to dopamine?

  14. The sales staff at a health food store sells him a mixture of fructose and water. He feels better immediately, and the treatment only costs $5 per month to maintain. Is it better to tell him fructose is sugar and explain about the placebo effect or to stay silent and be glad he isn’t suffering any more?

    Basically, your friend is drinking corn syrup. And here at H&R we all know what corn syrup does. It will mess you up real good, man!

  15. I wanna know how placebo responders correlate with those whose brains react strongly to religious belief.

  16. I was thinking of the same question as I read it. I don’t think we’d want to weed out the placebo responders, but we might want to identify them and use the knowledge to more intelligently analyze the trial results.

  17. I suspect this has a lot of neuroanatomic overlap with religion. A lot of recent work by Steve Maier and others suggests that the ability to control one’s environment is more important than mere pain or pleasure:In one study humans were willing to undergo more than six times as many shocks if they were allowed to control when they got them. So control seems more highly valued than pain per se. At the level of the brain “control” seems to equate with the successful correlation of expected outcomes with dopamine spikes in the mesolimbic dopamine system of which the accumbens is a part. Being able to have a predictable controlable relationship with the world is why I think so many of us are more likely to hold on to a fairly ridiculous set of beliefs rather than accept fundamental uncertainties about reality or uncontrollable certainties like death.

  18. I think the premise of the very good question rules out the cognitive too quickly, a common result of those who are philosophically inclined to believe we are just a bunch of complex cause and effect chemicals. It assumes that there are some people biologically who are just programmed to be placebo-affected.

    But such reactions could be intelligence, experience, and situation specific — a cognitive issue. Someone who might be convinced there is a ready painkiller injection available and get all dopaminic, may not be so easily convinced if it was say offered in a multicolored pill or other less credible form, and so their dopamine won’t activate under that circumstance.

    Someone otherwise well-educated and “skeptical” might believe in a traditional Chinese medicine placebo (it happens quite a bit) and respond to, say, a placebo acupunture, whereas a “credulous” evanglical Christian who views such as questionable voodoo might not be inclined to get all dopaminic after a needle is stuck in his toe.

    Thoughts are not necessarily epiphenomena of biochemical processes or tendencies.

  19. It’s not a “placebo effect” if you know that what you are taking doesn’t have the active ingredient.

    Then what do you want to call it? I heard some years ago of a study in which people were given inert placebos (not all placebos are inert — it just means “I please”), had it explained thoroughly to them what they were getting, and still reported benefit. So it’s been known for some time that the effect does not depend on fooling people. Probably it’s a subset of the Hawthorne effect.

  20. “Say a friend has a medical condition that causes constant pain, but no long term damage. Several doctors tell him there is no known cure. The sales staff at a health food store sells him a mixture of fructose and water. He feels better immediately, and the treatment only costs $5 per month to maintain. Is it better to tell him fructose is sugar and explain about the placebo effect or to stay silent and be glad he isn’t suffering any more?”

    Apparently it wouldn’t hurt to tell him, because the placebo effect is not based on his not knowing. He may be able to get fructose cheaper once he knows the secret ingredient.

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