John M. Kelley, PhD

Associate Professor, Endicott College

Deputy Director, Program in Placebo Studies, Harvard Medical School

Staff Psychologist, Massachusetts General Hospital

Placebo Effects – Clinical Data

Overview of Goals

1. Demonstrate that the placebo effect is powerful

2. Show that the placebo effect can be decomposed

into separate factors

3. Show that these placebo effects are active not only

when placebos are administered but also when

active treatments are delivered.

4. Describe a method by which placebo effects might

be harnessed in medical and psychiatric treatments

Beecher (1955). JAMA, 59, 1602-1606

Hrobjartsson (2014). NEJM, 344(21), 1594-1602

Components of the Placebo Response

• Regression to the mean

• Natural history of the disorder

• Change in life circumstances (diet, exercise,

social support, stress reduction, rest)

• Other psychological or physical treatments

• Placebo effect

Kaptchuk (2008). BMJ, 336, 998-1003.

Placebo Acupuncture Needle

Placebo Acupuncture Needle

Needle Set Up Placebo Needle Genuine Needle

Streitberger (1998). The Lancet, 352, 354-365.

Design

• 262 patients with IBS

• Randomized to 3 treatment groups:

(1) Waitlist control (N=87)

(2) Limited placebo acupuncture (N=88)

(3) Augmented placebo acupuncture (N=87)

• 3-week trial, 2 treatments per week

Outcomes at 3-week end point

©2008 by British Medical Journal Publishing Group

Kam-Hansen (2014). Science Translational Medicine, 6, 218ra215

Treatment Conditions

• Within-subjects experiment in 66 migraine patients

• 7 migraines attacks treated in random order as follows:

• No Treatment

• Told Placebo, Given Placebo

• Told Uncertain, Given Placebo

• Told Drug, Given Placebo (deception)

• Told Placebo, Given Drug (deception)

• Told Uncertain, Given Drug

• Told Drug, Given Drug

3 x 2 Design

Two factors crossed with each other:

Labeling (expectancy)

- “Placebo”

- “Drug or Placebo”

- “Drug”

Pill Type

- Active Drug (Maxalt)

- Inactive Placebo

First Proposal for Open-Label Placebo

Walter Brown, MD:

“Among less severely depressed patients … the placebo

response rate is close to 50% and often indistinguishable

from the response rate to antidepressants … I propose that

the initial treatment for selected depressed patients should

be four to six weeks of placebo. Patients so treated should

be informed that the placebo pill contains no drug but that

this treatment can be helpful.”

Brown (1994). Neuropsychopharmacology, 10(4), 265-269.

Rationale for Placebo Efficacy

Clinicians explained that placebos are inactive substances like a

sugar pill, which contain no medication. They also noted that:

(1) In RCTs, placebo response often rivals response to active

treatment;

(2) Classical conditioning is a possible mechanism for

automatic self-healing;

(3) Placebo-treated patients who are more compliant have

better outcomes; and

(4) Positive expectations increase placebo effects, but it is OK

to have doubts.

Clinicians delivered the rationale in a natural and supportive

manner that allowed for questions and answers.

Kaptchuk (2010). PLOS ONE, 5(12), e15591

Design

• 3-week trial of open-label placebo in 80 IBS patients

• Prior to randomization all patients were given a rationale for

why placebos might be effective :

(1) The placebo effect is powerful in RCTs

(2) The body can automatically respond to placebos

(3) A positive attitude is helpful but not essential

(4) Taking the pills faithfully is essential

• Patients were randomly assigned to either:

(1) Open-Label Placebo Pill, twice daily (N=43)

(2) No Treatment Control (N=37)

Kelley (2012). Psychotherapy and Psychosomatics, 81:312–314

Design

• 20 MDD patients recruited for a 4-week trial

• Prior to randomization all patients were given the persuasive

rationale for why placebos might work that included

(1) The placebo effect is powerful

(2) The body can automatically respond to placebos

(3) A positive attitude is helpful but not essential

(4) Taking the pills faithfully is essential

• Patients were randomly assigned to either:

(1) Open-Label Placebo Pill, twice daily (N=11) for 4 weeks

(2) Waitlist Control (N=9) for 2weeks, followed by 4 weeks

of Open-Label Placebo

Improvement by Group at 2 Weeks

Measure Waitlist Open-Label d p

HamD-17 -0.67±4.00 1.64±4.52 .54 .26

QIDS -0.22±2.44 2.27±3.88 .77 .13

SDQ 1.38±10.77 3.70±18.98 .15 .75

Note: All values are means ± SD. Positive scores indicate

improvement.

Ham-D-17 Improvement at 2 Weeks

-1

0

1

2

Waitlist

Control

Open

Placebo

Improvement after 4 Weeks of Placebo

Note: All values are means ± SD. Positive scores indicate

improvement.

Measure Pre Post Change d p

HamD-17 18.00±4.94 14.75±6.61 3.25±6.01 .57 .03

QIDS 14.85±2.68 12.10±4.34 2.75±3.84 .76 .005

SDQ 146.94±19.71 138.75±27.65 9.89±15.71 .34 .02

Pre-Post Ham-D Scores (N=20)

18.0

14.8

0

2

4

6

8

10

12

14

16

18

20

Baseline 4 Weeks

Criticisms of Open-Label Placebo

• Are we testing open-label placebo or are we testing the

rationale?

• Isn’t generalization limited to patients who are willing to take

open-label placebos?

Where do we go from here?

• Larger 2-arm trial of open-label placebos vs. waitlist

control

• 3-Arm trial

• Waitlist control

• Open-Label Placebo

• Open-Label Drug

Thank you for your attention!

My Principal Collaborators

• Ted Kaptchuk

• Irving Kirsch

• Tony Lembo

• Maurizio Fava

• Rami Burstein