Biological, clinical, and ethical advances of placebo effects

Summary

For many years, placebos have been defined by their inert content and their use as controls in clinical trials and treatments in clinical practice. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. There is also evidence that placebo effects can exist in clinical practice, even if no placebo is given. Further promotion and integration of laboratory and clinical research will allow advances in the ethical use of placebo mechanisms that are inherent in routine clinical care, and encourage the use of treatments that stimulate placebo effects.

Introduction

The notion of something called “placebo” started with St Jerome's mistranslation of the first word of the ninth line of Psalm 116, when instead of translating the Hebrew “I will walk before the Lord”, he wrote “Placebo Domino in regione vivorum” (“I will please the Lord in the land of the living”). By the 13th century, when hired mourners waited for Vespers for the Dead to begin, they often chanted the ninth line, and so were called “placebos” to describe their fake behaviour.¹ Later, in The Canterbury Tales, Chaucer named his sycophantic, flattering courtier Placebo. The introduction of placebo controls, which entailed the administration of fake procedures to separate the effects of imagination from reality, began in the 16th century with progressive Catholic efforts to discredit right-wing exorcisms.² Individuals “possessed” by the devil were given false holy objects and if they reacted with violent contortions—as if they were genuine relics of the holy cross or consecrated wafers—it was concluded that their possession was in their imagination. This idea of placebo controls was then used in medical experiments, beginning with the Franklin commission's debunking of the psychic force of mesmerism or animal magnetism in 1784.³

The use of the word placebo in a medical context to describe innocuous treatments to make a patient comfortable dates from at least the end of the 18th century.⁴ The earlier, unsavoury connections undoubtedly led to the tainted reputation of placebos and placebo effects that persisted until very recently.¹ Mainstream interest in placebo effects only began with the widespread adoption of the randomised controlled trial (RCT) after World War II, when it was noticed that people improved—sometimes dramatically—in placebo control groups.⁵ Soon after, in his famous proto-meta-analysis, Henry Beecher claimed that about 35% of patients responded positively to placebo treatment.⁶ Beecher, however, encouraged an inflated notion of the “powerful placebo” because he failed to distinguish the placebo response from other confounding factors. Since this time, there has been increasing interest in investigating placebo effects by rigorous research methods, especially in the past 10 years. In this Review, we assess whether advances in understanding of placebo mechanisms in both laboratory and clinical settings could lead to a reconsideration of placebo effects with implications for clinical practice.