Biology 202
2003 First Web Paper
On Serendip

The mind has often been referred to as the organ of consciousness. Daily functions such as thinking, breathing, and most any task we do rely heavily on use of this precious organ. However, through the use of placebos, it is becoming clear that the mind may have an even greater influence on our daily lives, influencing our perceptions of well- being. The placebo, which is Latin for to please, is a sugar-pill that is given under the guise of being a medication thought to treat an ailment. The use of placebos has shown us that the mind has tremendous potential to induce physiological changes in our body based solely on its perceptions. In example, as we swallow a sugar pill thinking that it is Prozac, we may actually physically feel fewer symptoms of depression as a result of the mind's perception (1). The placebo effect (the phenomenon of perceived benefit from a mock stimulus) has recently opened further doors to our understanding of how the mind works. Once thought of as an inactive, harmless mock substance, placebos have now shown that they induce brain activity. Therefore, the perceived benefit that once was laughed off as fooling the patient, may actually be a consequence of very real physical responses created by the mind, and generating a very real benefit. This paper will explore the various placebo studies that have helped us define and redefine the role of the mind.

The placebo effect is a powerful effect that can consistently induce a perceived benefit. Once the placebo was identified as a tool capable of generating a desired response, it became more widely used as a control in clinical trials. As a result, the placebo has been extensively studied throughout history, and yields a significant amount of data on its clinical effect. Irving Kirsch and Guy Sapirstein used meta-analysis to analyze 19 clinical trials (1). In total, the results of 1460 patients receiving antidepressant medication and 858 receiving a placebo sugar pill were analyzed. This analysis combined the results from these 19 different studies and generated an effect size (which is calculated as the mean of the experimental group minus the mean of the control group, divided by the pooled standard deviation SD). Once Kirsch and Sapirstein subtracted mean placebo response rates from mean drug response rates, they found a mean medication effect of 0.39 SDs (1). For each type of medication, the effect size for the active drug response to drug response is between 1.43 and 1.69, and the placebo response is between 74% and 76% of the active drug response. This means that 75% of the effect attributed to the perceived use of anti-depressants was due to the placebo. The perception of clinical benefit from antidepressants was largely attributed to the perceptions of the mind, and not to the actual chemical make-up of the pills patients were taking. The placebo effect shows us that the mind heavily influences our perceptions of wellness and health.

The placebo effect is often thought of as an act of fooling the mind into perceiving a benefit that has no physical basis. This depiction of the mind as a naïve and foolish organ may be incomplete and ill-representative of the mind's abilities. Indeed, the mind may orchestrate a physical response in the body based on its perceptions alone. In one study done by Luparello et al (2), 40 asthmatics were exposed to a single placebo twice, and told each time that it was a different substance being administered. Each of the participants were told that they were inhaling a bronchoconstrictor as part of an industrial air pollutant study, when they were really only inhaling saline, an inert substance. Of the 40 asthmatics, 12 had extreme asthmatic attacks, and 7 others experienced a significant increase in airway resistance, although not enough to induce a full-blown attack. None of the other patients in the study had any adverse reactions, suggesting that the experience was specific to the asthmatic condition. When the same patients were told that the inhaler contained a bronchodilator, the attacks were reversed and their airways opened up. Three minutes after administration of the placebo, the mean thoracic gas volume ratio rose from 0.07 to 0.13 L/sec/cm H20/L (normal, 0.13 to 0.35) (2). Here, the same saline solution that has caused discomfort within the 19 patients also brought about relief when it was administered a second time. The same administered placebo seems to have produced adverse effects in the patients of this study. While the mind may be labeled as an organ easily fooled by placebos, whose benefit has no physical basis, it is clear that the mind may have an even greater role in behavior. The mind's perceptions of either an irritant or bronchodilator induced airways to physically open or close, and thereby physically experience relief or an attack. The mind may have greater physiological capabilities, and may have a greater role in physical as well as perceived responses that we experience daily.

The concept of a placebo has previously been thought of as a benign sugar pill that is inactive. However, a recent study by Leuchter et al (3) suggests that a placebo may actually activate a distinct and separate part of the brain, the prefrontal cortex. In this study, Leuchter et al 51 depressed patients received one of two medications, fluoxetine (24 patients) or venlafaxine (27 patients), in a nine-week placebo-controlled study. The brain activity of each of the patients (post administration of the pills) was then analyzed through the use of quantitative electroencephalography (QEEG). Both QEEG power and cordance, which measures blood flow and energy use in the brain, were examined. Among the three arms (fluoxetine, venlafaxine, and placebo) the placebo responders were the only group showing a significant increase in brain activity. In the prefrontal region, the placebo had a treatment response of 0.98 compared to the treatment response of the fluoxetine, which was 0.06 (3). Administration of a placebo appears to be an active treatment, rather than the no-treatment comparison it has been thought to provide. In this case, the placebo not only does induce brain activity, but it does so in a way that is distinct from the way the experimental drugs (antidepressants) do. The mind therefore is not an organ that is fooled by the placebo effect into generating a standard set of brain function specific to what it believes the placebo to be. Rather, the mind creates a response that is specific to the placebo, and distinct from what we previously called "active" substances (or experimental drugs). The mind therefore must have the ability to discern what is a placebo and what is an experimental, and thereafter generates a physical response accordingly. This sophisticated ability of the mind to discriminate further shows us that the mind is a complex organ capable that is not fooled, but creates very informed responses.

Placebos can no longer be thought of as the wool being pulled over the mind's eyes. These sugar pills induce the mind to create a very real and physical response that may be specific to the placebo; as a result, use of a placebo can become a very seductive treatment option for many. With the on-going use of placebos, both as a control, and potentially as a treatment alternative, several issues emerge: Is the use of placebos ethical? Furthermore, can it be guaranteed that placebos will generate a safe, and effective, result? While these pills may seem benign by being less active than experimental drugs, the risk for harmful and unethical consequences still does exist.

Results from one recent study have brought this issue to the forefront. Freed et al conducted a study examining the outcomes of 40 patients, ages 34-75, who had severe Parkinson's disease (4). In this study, the patients either underwent neuronal transplantation surgery or sham surgery (placebo). These patients were randomly assigned to the different groups. In the patients who underwent the sham surgery, holes were drilled into their skulls but the dura (the outermost of the three meninges) was not penetrated. While all of the patients had hoped to receive this neuronal transplant, only half actually did. The rest had the placebo surgery. Freed et al found that although there was no notable effect among the older patients in either transplantation or placebo surgeries, the younger transplantation recipients showed much improvement as compared with the placebo surgery group (4). No one from the placebo surgery group benefited from the procedure. Results were measured using the standardized scoring system of the Unified Parkinson's Disease Rating Scale (UPDRS) and the Schwab and England scale. They measure symptoms of Parkinson's disease including mentation/mood and performance in the activities of daily living, respectively. Freed et al further analyzed results looking for growth of transplants by using 18F-fluorodopa PET scans. These tests all concluded that the only group that benefited from the study was the younger transplantation group, leaving many concerned due to the lack of improvement in their condition. Half of those in the placebo group experienced additional pain, and some experienced trauma. In addition to not benefiting from the procedure, many experienced significant pain from the placebo surgery. In this case, the mind could not be induced into generating the type of physical response that is desired from this surgery. And further, the potential for pain as well as harm are also clear in this example. It is clear that the ethics behind placebos, given that they are active substances that can induce very real physical responses need to be taken seriously. The mind is a complex organ that may not always respond in the way that we hope it will.

The placebo effect has shed great light on the complex functions of the mind. The mind has the remarkable ability to generate a physiological and real response to placebos. Furthermore, the mind can discern a placebo from an experimental drug, as we see through the specific activation of the prefrontal cortex by the placebo. The mind has functions and capabilities that are larger than just thinking, breathing and walking. It not only controls our perceptions of our well-being, but may control the physicalities of our well-being more extensively than was previously thought. While the placebo effect has yielded important information on the powers of the mind, we need to think more responsibly about the use of placebos, and the potential effects of these active stimuli on the brain. Given that placebos do activate the brain, we need to re-address our notions of these pills as inactive sugar pills. What if placebos could have the potential to affect the mind in a way that is not positive? What if placebo pills, and furthermore surgeries, could be harmful to the patient? The ethics of placebos, and the role of the mind in responding to them, should not be underestimated as we move forward in our studies of how the mind works. Our well-being depends on it.

References

1) Kirsch, Irving, PhD and Guy Sapirstein, PhD. Listening to Prozac but Hearing Placebo: A Meta-analysis of Antidepressant Medication. Prevention & Treatment, Volume 1, June 1998.

2) Luparello, T.J., Lyons, H.A., Bleeker, E.R. & McFadden, E.R. (1968). Influences of suggestion on airway reactivity in asthmatic subjects. Psychosomatic Medicine, 30, 819-825.

3) Leuchter AF, Cook IA, Witte EA, Morgan M, & Abrams M. (2002) Changes in brain function of depressed patients during treatment with placebo. American Journal of Psychiatry, 159: 122-129.

4) Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, & Fahn S. (2001) Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease. New England Journal of Medicine, 10:710-719.


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