Placebos, Nocebos, and Double-blinds
by Jerry Lowenstein

Throughout recorded history, and undoubtedly long before writing was invented, humans have concocted medicines and treatments for their ailments. Anyone can assert that his or her potions, herbs, manipulations, or incantations relieve colds, headaches, lower back pain, anxiety, or depression. The challenge to modern scientific medicine is to separate treatments that truly cure or prevent disease from the vast numbers of nostrums based on grandma's remedies, folklore, magical or religious beliefs, commercial exploitation, quackery, and plain old wishful thinking.

Among the therapies offered the public in a current California "medical" consumer publication are embryonic shark tissue transplants, manual lymphatic drainage, Rolfing, numerology, bio-energy alignment, self-expression healing, live-cell therapy, past-life regression, and dry hydrotherapy. These "alternative" modes of healing have their enthusiastic advocates. How can the rest of us judge whether they are helpful, harmful, or neither?

The scientific method is a late entry into medical practice. Because of the "placebo effect," no scientifically minded physician will accept the validity of a new treatment unless it passes the double-blind test. A placebo (from the Latin meaning, "I will please") is an empty capsule or a sugar pill. Though they lack any active ingredients, placebos "work" in about a third of the patients who take them. The sufferers feel better and conditions such as hypertension and asthma, that are known to be aggravated by stress, may objectively improve. Therefore, a treatment has to do better than the placebo in a statistically valid number of patients before it can be pronounced an effective medical therapy.

Why do placebos work for so many people? Walter A. Brown, a psychiatrist, has been investigating this phenomenon for many years. In his article "The Placebo Effect" (Scientific American, January 1998), he writes, "The healing environment is a powerful antidote for illness. The decision to seek medical assistance restores some sense of control. The symbols and rituals of healing--the doctor's office, the stethoscope, the physical examination--offer reassurance. An explanation for the illness and a prognosis, when favorable, reduce fear; even when the report is unfavorable, it allays the anxiety of uncertainty. And merely the act of taking a pill can have a therapeutic effect."

The best way to find out whether a treatment beats a placebo is the double-blind trial. Patients are randomly selected to receive either a placebo or a medication. Neither the patients nor the doctors know who is getting what until the trial period is completed and the results are compiled.

I participated in a long-term double-blind trial, the Physicians Health Study sponsored by Harvard Medical School. About 20,000 middle-aged male physicians were enlisted ten years ago to test whether aspirin helps to prevent heart attacks and whether vitamin A helps to prevent cancer. Earlier studies had suggested beneficial effects from both compounds, but not enough cases had been recorded to be statistically significant, and the double-blind approach had not been used.

Could our most popular painkiller and a much-used vitamin supplement combat the two most common causes of death among American men? Twenty thousand was a large enough sample to prove definitely whether the drugs were having a real effect on health and mortality rather than merely reflecting chance variation. (The incidence of coronary disease is much higher in men than in women. However, heart disease is a significant cause of death and disability in women too, and currently a number of long-term observations, including the Nurses Health Study, are focusing on women.)

On alternate mornings I took a large white pill (that might be aspirin or placebo) or a capsule full of reddish granules (that might be vitamin A or placebo). We medical guinea pigs fell into four groups: 1. those taking aspirin and vitamin A; 2. those taking aspirin and placebo capsules; 3. those taking placebo pills and vitamin A; and 4. those taking placebo pills and placebo capsules.

The aspirin part of the study was stopped after five years, because the data clearly showed that the two groups taking aspirin were having only about half as many heart attacks as the two groups taking placebo pills. On the basis of these results, it was strongly recommended that all middle-aged men, not just doctors, take an aspirin every other day. The vitamin A part of the study went on for several more years, and recent data analysis indicates that vitamin A not only does not prevent cancer but seems to slightly increase the risk of lung cancer in smokers.

The results solidly show that aspirin reduces heart attacks and that vitamin A does not prevent cancer. These conclusions could never have been reached on the basis of individual experience or belief.

People not trained in scientific methodology are more likely to rely on their own experience and opinions than to wait for the results of a five- or ten-year double-blind study, with its complicated standard deviations and calculations of probable significance. When the AIDS epidemic first hit during the 1980s, activists insisted that double-blind trials for potential AIDS medications be suspended. They wanted to have the new drugs right away, regardless of whether these drugs had been proved safe and effective. It's certainly understandable that people facing an early death wanted a cure "right now" without having to go through the tedious process of scientific validation.

Unfortunately, impatience with scientific procedure is an invitation to quacks, charlatans, and gurus to exploit the desperation of the afflicted without actually ameliorating disease or prolonging lives. AIDS activists have undergone an educational experience during the past decade, and most of them have now come to realize that there are no magical short-cuts to achieving results against AIDS or any other disease. Research, double-blind testing, and statistical analysis are the ways to get lasting results.

The quack "cancer cure" Laetrile, an extract of apricot pits, was strongly promoted by some members of Congress 20 years ago and licensed in 27 states including California, over the objections of the California Medical Association and the American Cancer Society.

A member of my family was recovering nicely from breast cancer after surgery and hormonal therapy, and her lung metastases had shrunk until they were no longer visible on x-ray. One day she turned on the TV and watched a famous comedian telling the world how Laetrile had cured his wife of throat cancer. My relative was so impressed by the star's testimonial that she quit taking her medications and signed on for Laetrile. The tumor promptly recurred, and she expired miserably from pulmonary failure.

The movies and T.V. are potent sources of information and misinformation. Science and cinema often don't mix. Hollywood went boom, light, and camera for the heroic saga of "Lorenzo's Oil," the tale of a husband and wife (Nick Nolte and Susan Sarandon) whose little boy had the rare x-linked disease with the unpronounceable name adrenoleukodystrophy. Male victims of this hereditary disorder suffer from brain and nerve deterioration that develops over a period of five to fifteen years, and they eventually become mute, blind, and paralyzed before they die.

In this terrible disease, molecules known as very-long-chain fatty acids accumulate in the tissues and the plasma. Whether these molecules cause the disease, or are simply a by-product of the hereditary biochemical defect, is unknown. The boy's family compounded a mixture of oleic and erucic acid, an oil which when consumed reduces the plasma levels of very-long-chain fatty acids. In the movie version, this oil slowed the son's deterioration--a triumph of parental love and devotion over medical conservatism.

For most sufferers, unfortunately, the outcome is far less dramatic.

A French team of pediatricians and neurologists studied the effects of Lorenzo's oil treatment on patients with adrenoleukodystrophy: five boys, 14 men, and five women (who have a milder form of the disease than men). Over a period of three years these patients were monitored closely with physical examinations, blood tests, measurements of nerve conduction, and brain imaging.

None of the patients improved. Several got worse. The medical team found "no evidence of a clinically relevant benefit from dietary treatment with oleic and erucic acids ("Lorenzo's oil")." Several thousand physicians read this negative report in the New England Journal of Medicine in 1993, but millions more saw, and are still seeing, the movie with its fallacious upbeat promise of an effective remedy for this awful disorder.

The most effective underminer of scientific medicine in our nation today is not, however, misrepresentation in TV and the movies, but, surprisingly enough, the hallowed American system of justice.

The conflict between adversary law and scientific data is exemplified by the silicone breast implant story. By 1992, implant surgery had been performed for 30 years, between one and two million women had had the procedure for cosmetic breast enhancement or post-mastectomy reconstruction, and 90 percent of them professed to be pleased with the results.

This situation changed abruptly when some articles appeared suggesting an association between implants and scleroderma, a rare disease of connective tissue which stiffens the skin, esophagus, and lungs. By 1995, 400,000 women had filed claims against implant manufacturers.

Marcia Angell, managing editor of the New England Journal of Medicine, got interested in the subject when the Journal published two articles indicating that implants do not cause disease. She has written a book, Science on Trial: The Clash of Medical Science and the Law in the Breast Implant Case. Silicone is used in prostheses, catheters, and many medical devices because it produces little or no reaction in the tissues with which it comes into contact. Implants generally consist of a tough silicone envelope containing silicone gel. Occasionally the implants leak gel into the surrounding tissues. To date, 17 studies involving thousands of women have failed to support any relationship between implants and scleroderma, regardless of whether or not leakage occurred, but the litigation goes on unabated, and juries have awarded millions in settlements.

In the United Kingdom, where judges rather than juries decide cases involving scientific judgment, there has been no such plague of lawsuits. The judicial system there accepted the overwhelming scientific evidence that there is no increased risk of disease from breast implants. A reviewer of Angell's book, writing in the British journal Nature, remarked that "it is the law, rather than science, that is on trial in these cases. They teach that the alternative to science is not justice but ignorance; lacking scientific evidence of causation, litigation becomes a lottery."

The breast implant story is an example of the placebo effect's evil twin, the nocebo effect (from the Latin, "I will harm"). Just as the hope and expectation that a treatment will help often alleviates anxiety and improves symptoms, the conviction that some medical procedure has done damage will raise anxiety and aggravate old symptoms or create new ones. The term "nocebo effect" describes adverse reactions experienced by patients who expect the worst rather than the best from their treatments. Depressed individuals with a generally pessimistic outlook on life have been observed to be the most susceptible to the nocebo effect.

Surveys reveal that about a third of all Americans use "alternative medicines' (including herbal remedies, embryonic shark tissue transplants, aromatherapy, and dry hydrotherapy)--just the proportion that respond to placebos in double-blind trials. The vast majority of these alternatives have never been tested in double-blind trials, and so we have no evidence, aside from the claims of their purveyors and the testimonials of believers, as to the virtues of these therapies.

Congress has funded an Office of Alternative Medicine to investigate and apply the scientific method to testing some of these therapies, a number of which are championed by congressmen who claim to have benefited by them.

I'm all in favor of any therapy, alternative or otherwise, that works for an individual sufferer, and I hope that important new remedies will emerge, just as aspirin and digitalis emerged from traditional herbal brews and potions. I'm only too well aware of the limitations of standard medical therapies to cure or control diseases, especially those that inevitably come with advancing age. It's not easy to apply scientific methods to intensely personal matters like life, death, and health. The practitioner's challenge is to balance science with individual care and compassion.

As we look back over the advances of the past century, we do seem to be making progress in the understanding and treatment of human disease, though we still have a long way to go. What progress we have made is based on scientific research, observation, and testing, not on faith and magical thinking. Placebos and nocebos have undoubtedly been with us since our remote ancestors first became aware that they were vulnerable to illness and death. Scientific methods take us beyond these two mirages of health and disease to a clearer view of the real things.

Jerold M. Lowenstein is professor of medicine at the University of California at San Francisco and chairman of the Department of Nuclear Medicine at California Pacific Medical Center in San Francisco.