You awake with a nighttime headache and stagger to the cupboard for two Aspirin. In the dark, you mistakenly down two vitamin D tablets. Twenty minutes later you feel the “Aspirin” kick in and your pain abate. Welcome to the world of the placebo response.
Briefly stated, a placebo – from the Latin verb form meaning “I shall calm, soothe or appease” – is an inert or inactive treatment which elicits a positive therapeutic response because the patient expects it to be effective. Researchers have found placebos to be a useful tool in modern medical trials, in which the positive beneﬁts and negative side-effects of a drug or procedure are gauged against those of an inactive pill or other non-therapy.
Many physicians also pay allegiance to the placebo reaction in day-to-day clinical practice. For example, a physician might write a prescription for acetasalicylic acid – the generic name for Aspirin – rather than simply telling the patient to take this common over-the-counter medication, says Alan Scoboria, a professor of psychology at the University of Windsor. This simple ruse may heighten the patient’s expectations of improvement, provoking the placebo response. Similarly, physicians might try for a placebo response by prescribing a drug not active in a patient’s condition or in too low a dose to normally be effective.
Dr. Scoboria, who has been researching the placebo response for 10 years, says it ﬁgures most prominently in treatments whose outcomes are rated subjectively by the patient on standard scales – those for anxiety, depression and chronic pain, for example. In 2008, he and his colleagues published an overview of a large number of trials that had tested patient responsiveness to antidepressants like Prozac and Paxil. These medications belong to a class of drugs known as selective serotonin reuptake inhibitors, or SSRIs.
The randomized, placebo-controlled trials each lasted from six to eight weeks and the results were submitted to a large regulatory data–base of the U.S. Food and Drug Agency. The patients were all rated as severely depressed, with scores of 20 to 22 on the Hamilton Depression Rating Scale. The HAM-D runs from zero (no depression) to 40 (very severe depression).
In the majority of studies submitted, there was a drop in symptoms of about 10 points with the drugs, and a drop of about 8.5 with a placebo. “So about 75 percent to 80 percent of a drug’s effects were duplicated by placebo, and about four out of ﬁve patients did about as well on placebo,” says Dr. Scoboria.
“We are currently reviewing the studies used to approve several of the newer antidepressants, and we continue to debate the implications of the placebo response with researchers and clinicians,” he continues.
It’s all in the head
Driving the placebo response is a psychological mechanism of expectancy regulated by circuits in the brain’s frontal lobe – areas involved with the processing of beliefs, expectations and rewards.
“There is a long tradition in psychology showing that altering expectancies can lead to important changes,” says Dr. Scoboria. He notes, however, that such placebo ﬁndings raise an ethical question: “Is it fair to the millions of severely depressive people who have been doing well on antidepressants to tell them that dummy pills would do them about as much good?”
At the biochemical level, the key player behind the placebo response is probably the brain chemical dopamine, says Jon Stoessl, a professor of neurology at the University of British Columbia who studies the placebo effect in Parkinson’s disease.
“The placebo response in Parkinson’s disease is clearly related to the release of the neurotransmitter dopamine in the striatum of the brain,” he says. “And dopamine release in the ventral striatum – the reward part of the brain – may be a necessary underpinning of the placebo response in other conditions such as pain and possibly depression.”
In a recent study, Dr. Stoessl found that Parkinson’s patients who were expecting active therapy but received only placebo experienced a substantial release of dopamine – even though Parkinson’s is associated with a severe depletion of this neurotransmitter. Other research by Dr. Stoessl has suggested that placebos can augment the effects of active medications, a ﬁnding that could have dosing implications. “It is possible that we could, with adequate consent, intermittently replace an active drug with placebo,” he says.
Placebo responsiveness seems to be driven partly by personality, especially the type that seeks novelty, fun and rewards. In a recent study, McGill University neuroscientist Petra Schweinhardt induced leg pain via saline injections in 22 male university students and then “treated” their pain with an inactive skin cream. She found that subjects who scored high on novelty seeking, fun seeking and reward responsiveness showed a bigger placebo response. These “fun seekers” also had more grey matter in the ventral striatum, she says, suggesting a three-way relationship between placebo response, brain structure and personality traits.
If conﬁrmed in larger trials, these ﬁndings could help pharmaceutical companies avoid testing experimental drugs on people with strong placebo responses, says Dr. Schweinhardt, whose next step is to take a closer look at the relationship between the brain’s reward-processing system and pain. “I think that placebo analgesia is just a special case of reward anticipation – the anticipation of clinical beneﬁt,” she says.
Back at the University of Windsor, Dr. Scoboria’s colleague, psychology professor Fuschia Sirois, conﬁrms the role of personality and cultural factors in the placebo effect. “Agreeableness, extroversion, sociability and trust in others are personality traits associated with a greater placebo response,” she says.
Openness to new experiences – mirroring Dr. Schweinhardt’s novelty seekers – is another, she says. This runs counter to the early perception of placebo reactors as passive, suggestible, easily duped and lacking in emotion. Anxiety-ridden people respond better as well, which may help to explain why the placebo effect is so notable in depression trials, in which the mere taking of a pill seems to allow patients to calm down sufﬁciently to work on the problems causing their misery.
Cultural influences have an impact, too, adds Dr. Sirois. “One of the key factors is expectations and beliefs, not just about a speciﬁc treatment but also about the person administering it and the healing environment. If you take a Westerner conditioned to have conﬁdence in such situational cues as the white coat and stethoscope, the diplomas on the wall, the efﬁcient clinical setting, he may respond better than someone from a Third-World culture who has no such reinforcing expectations.”
Interesting differences emerge even within single nations: Germans, for example, are high placebo reactors in ulcer drug trials but low reactors in trials of hypertension drugs.
In the future, medicine may routinely harness placebo power to design trials more effectively, improve clinical outcomes and reduce drug doses and side effects. In the meantime, the potency of the placebo effect is a strong reminder to clinicians of the innate ability of the brain to trigger bodily healing.