Say Yes to Sugar Pills: A Study of Placebo

Use in Clinical Trials

Rachel Bruning
Northwest High School

Abstract
Currently, randomized double-blind placebo-controlled clinical trials are considered by many
researchers to be the gold standard of clinical trials intended to test the efficacy of a drug. As set
forth by regulations of the United States Food and Drug Administration, these specific trials are
encouraged in the second phase of clinical trial testing. This study examines how one such trial
might be conducted. Informed consent was obtained from the 56 students from whom data was
collected prior to experimentation. Each participant was randomly assigned to receive eight fluid
ounces of caffeinated Diet Coca Cola or non-caffeinated Diet Coca Cola, thus belonging to the
experimental or control groups, respectively. Neither the participant nor the experimenter knew
which protocol each participant received until the experiment concluded. Participants were
assessed in two manners; the first being their resting heart rate and their heart rate after
consuming one of the protocols, the second being their self-reported energy level on a scale of 1-
10 before consuming one of the protocols and again afterwards. Statistical analyses demonstrate
that the difference in the change in heart rate between the experimental and control group is
statistically significant (p < 0.05), while the difference in the change in self-reported energy level
between the experimental and control group is not statistically significant (p > 0.05).

Introduction substance, such as a sugar pill, used as a

Since its introduction into
mainstream biomedical research in 1955 (as
per the publication of The Powerful
Placebo by Harvard medical researcher, Dr.
Henry Beecher, in the same year), the
placebo and its use in modern clinical trials
has been a topic of great discussion among
doctors and researchers (Kaptchuk). Both a
placebo and its effects are ambiguous terms
since scientists are still trying to discover the
exact neurobiological and psychological
processes that contribute to the placebo
effect. Even so, a general consensus in the
medical field is that a placebo is an inert
scientific tool to understand the placebo
effect (Miller, Colloca, and Kaptchuk).
Thus, the placebo effect can be defined as
some kind of helpful or therapeutic
change in response to the administration of
a placebo (Howland).
Due to the nature of the placebo,
researchers have been able to harness its
effects in clinical pharmacology in order to
determine the efficacy of a drug in trial. The
gold standard for these trials are
randomized, double-blind, placebo-
controlled trials (RCTs) (Howland). In a
double-blind RCT, participants are typically

1
designated into two groups: one in which
they are given a real drug, the second in
which they are given a placebo of some sort.
Because the trial is considered double-
blind, neither the participant nor the
physician administering the drug or placebo
know which protocol each participant
received until the trial has finished
(Howland). The aim of this type of trial is to
use the placebo as a control against an active
drug, assuming participants receiving the
placebo experience similar physiological
changes, benefits, and side effects as those
receiving the actual drug. If the positive
effects of the drug are greater than the
placebo, then the drug is proved effective. If
the placebo effects are similar, then the drug
is proved to not have a specific, unique
pharmacological property that makes it
undoubtedly effective (Howland). As
researchers continue to surge ahead in using
placebos in clinical trials, many have
debated whether or not placebos should be
used in trials in the first place. While the
positive aspects of using placebos as the
control against which an active drug is
tested for effectiveness are numerous, many
researchers express concern about the
ethical dilemmas that arise from the use of
placebos in double blind RCTs.
Given the inherently indistinct nature
of placebos and the placebo effect,
researchers have raised a whole host of
questions regarding the ethical usage of
placebos in RCTs. First and foremost, that is
the deceptive nature of using a placebo.
Some scientists believe that by using
placebos in clinical trials, doctors deceive
patients by not being honest about whether
or not the patient actually received a real
drug intended to alleviate their symptoms
(Relton). A doctors primary concern should
be for the health and safety of his or her
patient. By prescribing a placebo without the
patients knowledge (even in the realm of
controlled experiments intended for use in
2
medical research), doctors are forced to
reckon with the idea of lying to their patient.
This threatens the trust that a patient has in a
doctor to receive honest advice, information,
and care. This concern is, as it should be, a
major factor in examining the
appropriateness of placebo use in clinical
trials.
In addition to that concern, many
believe placebo trials to be unethical
because they subject patients to potentially
harmful side effects that may deteriorate a
preexisting condition (Okie). If there are
therapies that have already been proven
effective in helping to treat certain
conditions, it is viewed as unethical to
assign affected patients a placebo without
knowing if the placebo effect will be strong
enough to relieve them of the symptoms
they experience, or if by withholding an
effective drug, participants are put at greater
risk of lasting damage (Rothman and
Michels; Okie). In 1992, researchers
investigating antidepressants through a
placebo RCT prescribed half of a group of
severely depressed individuals paroxetine (a
well-established antidepressant) and
prescribed the other half of the group the
placebo (Rothman and Michels). At the time
of the experiment, antidepressant drugs had
been well-studied and well-established for
years. Even so, those severely depressed
individuals, at risk for experiencing any
number of effects due to their severe
depression, were not promised the
prescription of the actual drug (Rothman and
Michels). For some scientists, this risk (that
being, potentially exacerbating a severe
preexisting condition) is too great a risk to
take. These ethical concerns are very
important in weighing the value of placebo
controlled RCTs against the adverse effects
of doing so.
In contrast, many scientists have
continued to use placebos in clinical trials
for a number of reasons, most importantly
because they provide distinct benefits for
RCTs that other methods simply do not
provide. Their role as the control against
which researchers measure the effectiveness
of a drug is vital to the success of RCTs
(Howland). If the placebo was not used in
trials, the next logical protocol would be to
test drugs in trial against an active control
(Rothman and Michels). According to
researchers Kenneth J. Rothman and Karin
B. Michels, professors at Boston University
and Harvard, respectively, this would not
definitively prove whether or not a drug is
effective because the active components
(those which elicit unexpected side effects,
either positive or negative) of the active
drug could interfere with how researchers
observe and analyze the symptoms patients
experience in response to the drug in trial.
This would not happen if a placebo is used
because the placebo is expected to mimic
the same side effects as the drug in trial. For
this reason, many experts in the field
consider the placebo to be a solid
benchmark necessary for determining drug
efficacy (Rothman and Michels).
The ultimate goal of using placebo in
these trials is for researchers to gain an
understanding of the most effective drugs so
that, in the future, doctors can prescribe
more effective drugs to their patients. As
mentioned previously, if the drug in trial
elicits a more positive response than the
placebo, then researchers can confidently
conclude that the drug is effective and ready
to proceed to the next stage of drug
development, eventually to be marketed and
distributed to consumers (Howland). If
scientists are able to successfully harness the
power of the placebo and the placebo effect
to improve drugs, then both physicians and
patients will reap the benefits. These
benefits may include both lower prescribed
doses of a drug and fewer side effects of
those drugs for patients (Dockser Marcus).
3
An additional benefit of improved drug
efficacy due to placebo-controlled RCTs is
patients improved compliance with doctors
orders (Dockser Marcus).
While these many benefits of
placebo-controlled RCTs are well-
documented and generally agreed upon in
the research community, significant ethical
concerns persist over the nature of these
trials. As it stands now, researchers will
continue to run RCTs controlled by
placebos. However, in doing so, they will
also strive to maintain the most ethical
practices as possible. The value of these
trials cannot be overstated, but the ethical
concerns that persist must be fully
acknowledged by doctors and researchers, as
well. This study will mimic how a
randomized double-blind placebo-controlled
clinical trial is run.
Methods
Participants
The 56 subjects who participated in
the experiment were all students from
Northwest High School in Germantown,
Maryland. The participant pool varied in
grade level, gender, age, and race. It is worth
noting, however, that none of this
information was collected at the time of the
experiment. Convenient sampling methods
were used considering the fact that every
participant was a student in Mrs. Emily
Asofkys second period Advanced Ulysses
class, third period Advanced Ulysses class,
and fourth period English class.
Prior to beginning the experiment,
students who were given the opportunity to
participate in the experiment were informed
of their right to terminate their participation
in the experiment at any point before,
during, or after the experiment for any
reason, no questions asked. Students
anonymity was protected for the entirety of
the experiment, as well as in any form in
which their responses would be collected for
statistical analysis and/or presentational
matters. Their participation in the
experiment was limited solely to a voluntary
basis.
Design and Procedure
In this study, the independent
variable was whether the subject was
assigned to the experimental or control
group. The experimental group is defined as
receiving eight fluid ounces of caffeinated
Diet Coca Cola. The control group is
defined as receiving eight fluid ounces of
non-caffeinated Diet Coca Cola. The
dependent variable in this study was the
change in students heart rates and self-
reported energy levels on a scale of 1-10 (1
being defined as extremely lethargic and
10 being defined as highly alert) from
before consuming the soda to after
consuming the soda. Those who were
assigned to the experimental group received
approximately thirty-one milligrams of
caffeine and those who were assigned to the
control group received zero milligrams of
caffeine.
The hypothesis of this experiment
was that if participants receive the
caffeinated soda, they will exhibit an
increased heart rate due to the caffeine in the
soda, as well as an increased energy level
due to an increased heart rate. It was also
hypothesized that the participants who
receive the non-caffeinated soda will
similarly exhibit an increased heart rate due
to their knowledge of the possibility of their
receiving the caffeinated soda. For the same
reason, it was hypothesized that they would
feel more energized (i.e. have an increase in
self-reported energy level) because of their
thinking that they received the caffeinated
soda, even when they did not.
The experiment was conducted on
Wednesday, November 30, 2016 and was
4
contained to the forty-seven minutes allotted
in the Northwest High School bell schedule
for one class period. The experiment was
contained in Mrs. Emily Asofksys
classroom.
The study began by randomly
assigning each participant to one of the two
groups so that each participant received
either the caffeinated beverage or the non-
caffeinated beverage. The soda was poured
into clear nine-ounce plastic cups so that the
students nor the experimenter were able to
identify the soda visually. Each cup had a
color-coded sticker on the bottom of the cup.
Those which held the caffeinated diet Coca
Cola (the experimental protocol) had a pink
sticker on the bottom of the cup. Those
which held the non-caffeinated diet Coca
Cola (the control protocol) had a yellow
sticker on the bottom of the cup. These
stickers were used at the conclusion of the
experiment in order to identify to which
group (i.e. experimental group or control
group) each participant belonged.
Prior to the beginning of the
experiment, students were told that they
would be involved in an experiment aiming
to determine whether or not one could
identify caffeinated soda versus non-
caffeinated soda by taste. They understood
the possibility and likelihood of receiving
either the caffeinated or non-caffeinated
soda. Students were instructed to complete a
list of survey questions that mirrored this
information. The questions are as follows:
1. What is your resting heart rate?
2. What food/drink have you consumed
today? Please note, if you are not
comfortable sharing this information,
it is not required.
3. What effects do you think caffeine
has on the body?
 4. On a scale of 1-10, how energized do The results obtained from the
you feel before drinking soda? experiment as compiled in Figure 1. The
data used to construct this graph is
5. What color sticker is on the bottom exclusively data collected during all three
of your cup? trials (i.e. data collected from the experiment
6. How would you describe the taste of run in second period, the exact same
the soda you received? experiment run in third period, and the exact
same experiment run in fourth period).
7. Do you think caffeinated soda and Using the Student T-Test for statistical
non-caffeinated soda taste different? significance, it is demonstrated that the
8. Circle any words below that you difference in the change in heart rate
would use to describe the soda you between the experimental and control
received. groups is statistically significant. The
difference in the change in self-reported
9. On a scale of 1-10, how energized do energy levels between the two groups is not
you feel after drinking soda? statistically significant. It was determined
that the p-value for the difference in the
10. What is your heart rate after drinking
change in heart rate between the
soda?
experimental and control groups is equal to
After distributing the survey to all 0.015, while the p-value for the difference in
students, they were instructed to take their self-reported energy levels between the
pulse and record their pulse in beats per same two groups is equal to 0.191. This data
minute on their survey sheet. At the same was calculated by using the final heart rate
time, students were instructed to self-report as a percent of the initial heart rate and the
their energy level. Students were then final self-reported energy level as a percent
instructed to drink the soda to which they of the initial self-reported energy level.
were randomly assigned. After thirty-five
minutes elapsed, the students completed the
experiment by the taking and recording their
final pulse, as well as recording their final
self-reported energy level. During those
thirty-five minutes, students completed the
remaining survey questions, though those
responses were not analyzed as data.
At the conclusion of the experiment,
students were debriefed on the nature of the
experiment in which they participated. They
were told that they were actually involved in
an experiment aimed to determine whether
or not their heart rates and self-reported
energy levels increased, decreased, or stayed
the same in response to the caffeinated Diet
Coca Cola or non-caffeinated Diet Coca
Cola.
Results

5
Figure 1
Discussion
The results of this experiment
conclude that the physiological effects of the
caffeinated soda (i.e. an increased heart rate)
were present in the experimental group but
not the control group. As I hypothesized,
those participants in the experimental group
who received the caffeinated soda felt the
effects of the caffeine by reporting feeling
more energized, as well. This is most likely
due to the fact that they received the
approximately thirty-one milligrams of
caffeine as they drank their soda. Similarly,
participants in the control group also
subjectively described that they felt the
effects of the caffeine by feeling more
energized, even though they did not receive
any stimulant (i.e. the caffeine found in the
experimental protocol) to cause an increase
in heart rate that could be associated with
the increased energy level.
A potential confounding variable
present in the experiment, however, is the
simple passage of time. This experiment was
conducted in the morning, so it is safe to
assume that students were sluggish coming
into class, but as the morning progressed, it
6
would be likely for them to become
increasingly less sluggish. This
phenomenon, though never proven, might be
a potential factor that explains the increase
in energy level. While one must contend
with this factor, it is far more likely that the
increase in energy level in the control group
is due to the placebo effect and the idea that
those participants felt more energized
because they believed that they received
caffeinated soda which they believed would
make them more energized.
This highlights how a double blind,
placebo-controlled RCT typically works.
Researchers randomly designate their
participants into two groups, the
experimental group who receives the true
drug therapy and the control group who
receives a placebo of some sort, be it a sugar
pill or otherwise. Ideally, they would both
experience the same subjective symptoms,
further illustrating how a placebo acts as a
control in such clinical trials. In this case,
both groups of participants felt the effects of
the caffeine, even though only half of them
actually received caffeine. Even though both
groups felt the effects of the caffeine, one
must concentrate on the fact that the
experimental group experienced a
physiological change not present in the
control group. It is thus possible to conclude
that the caffeine in caffeinated Coca Cola is
effective because the data shows that the
desired change (i.e. an increased heart rate)
was exhibited by the experimental group and
not the control group.
While it is possible to draw
comparisons between this experiment and a
real randomized double-blind placebo-
controlled clinical trial to demonstrate the
significant importance of these trials, one
must acknowledge that they are not exactly
the same thing. Specifically, the ethical
dilemmas that persist in trials involving a
true drug are only present to a much lesser
degree in this experiment. This is mainly
due to the fact that this experiment was, for
obvious reasons, not medically based.

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