Scientific Overview
Stress and Stress Tolerance
HPA Axis
Circadian Rhythms
Immune System
Placebo Effect
Chronic Fatigue Syndrome
Chronic Pain
Psychiatric vs Organic Debate
Irritable Bowel Syndrome
Chronic Lyme Disease
Recovery from ME/CFS

The Placebo Effect

There is a vast array of alternative remedies, many of which purport to treat a wide range of different illnesses. Some of these treatments are based on relaxation or meditation and only claim to reduce stress, while others make wild claims, unsubstantiated by any sort of scientific tests, that they can cure illnesses such as CFS. Even though many of these remedies have very questionable theories behind them—and could not possibly work for the reasons given by their practitioners—the fact remains that many of these remedies do sometimes seem to lead to miraculous recoveries (sometimes albeit temporarily), due to the placebo effect.

It is well known that if patients are given a pill which does not have any active ingredients—such as a sugar or chalk pill—a significant percentage of patients will sometimes improve in health over those patients not given any treatment at all, depending on the health condition being treated. In many studies the amount of improvement due to placebo alone is 50% or higher. Sometimes this improvement is due to the normal resolution of symptoms that would have happened even in the absence of the treatment (termed "natural course"). However in many cases the placebo itself gives a significant improvement over no treatment at all.

The placebo effect is more effective in treating certain symptoms and illnesses than others. The greatest effect tends to be for symptoms related to abnormalities in central nervous system functioning (and symptoms over which the CNS has an influence), such as depression, anxiety, headaches, fatigue and gastrointestinal symptoms. It is particularly effective as a painkiller, due to the ability of the body to release its own opioid neurotransmitters within the brain. The placebo effect can also significantly influence the immune system, and has been shown to have a significant effect on Parkinson's disease due to the release of dopamine in the brain.

For this reason, there is a requirement in most countries that all new drugs go through at least one large-scale, high quality double-blind placebo-controlled trial before they can be approved. One set of patients is given the drug being tested, and a second group is given a sham treatment. In the case of tablets, both pills look and taste exactly the same (as far as is possible), and neither the patient nor the physician administering the treatment know which pill the patient has been given. The fact that the doctor does not know whether the patient is given the active treatment is important, as his or her body language could potentially give a clue to the patient as to which treatment is being administered. Placebos are also used to test the efficacy of certain surgical treatments, such as deep-brain stimulation.

If the real drug is not significantly better than the placebo then the drug is not allowed to be sold as a treatment. This is the case even if the drug did cause an improvement in a significant number of patients (over those not given any treatment) due to the placebo effect.

The difference between scientifically tested drugs and what might be called "quack" treatments is that, in the latter, although the treatment may work in some (or even many) cases, it is no better than a placebo.

While it might be tempting to think that the placebo effect is relatively minor, or that it only affects weak-minded or suggestible people, this is far from the truth. The published research studies on antidepressants show that placebos generally give an improvement of about 30%, whereas the figure for active treatments is usually only about 40%, not much better than placebo.

So the question arises—what is wrong with prescribing a "quack" treatment that relies completely on the placebo effect if it works in some cases? The most obvious problem is the fact that it may or may not work—it is mostly down to the psychology of the patient. If the treatment does not work, then the patient has spent time and money on something that is essentially a waste of time. Relying on a treatment that's only benefit comes from the placebo effect can also be potentially dangerous, as it prevents the patient from using more effective treatments. In the case of something minor like hay fever this is not an issue, but for more serious illnesses such as cancer, it could mean the difference between life and death.

There is also a negative placebo effect (or "nocebo"), which is the opposite of a placebo. If someone is taking a medicine and they expect to have side effects, this can sometimes be enough to cause phantom side effects such as headaches, pain and nausea. The nocebo effect is also thought to be the reason why things such as witch doctor and voodoo curses work.

What Causes the Placebo Effect?

While the placebo effect has a psychological origin, it can have very real physiological effects on the body. Contrary to popular opinion, it is not necessary to believe in the placebo effect for it to work. What seems to be most important is the purpose and motivation that the placebo treatment gives the patient.

Although the placebo effect is mainly thought of as a short-term painkiller, or "believing" that a treatment worked when it has no actual effect, we now know that the brain has a large infleunce over physiological processes in the body, the immune system, and physical health.

There are a number of factors which can compromise normal health and immune function. The most often cited culprit is excessive stress, which results in high levels of adrenaline and cortisol, which then act to suppress the immune system. Cortisol in high levels will suppress all parts of the immune system, while adrenaline mainly affects NK cells. In the short-term, high levels of adrenaline actually results in increased levels of NK cells (by a factor of up to 600%). However in the long-term this effect is reversed—after seven days, the same levels of increased adrenaline result in reduced NK cells. Adrenaline also appears to favour the TH2 immune response, resulting in a shift from TH1 to TH2, similar to that seen in CFS patients.

Research shows that depression and chronic stress result in reduced NK cytotoxicity and increased CD4/CD8 ratios, and chronic stress causes increased Epstein-Barr Virus titers, likely as a result of stress hormones and the autonomic nervous system. This could explain why relaxation techniques which reduce stress can boost the immune system and result in cures from certain illnesses.

Research has also shown that positive expectations can enhance the immune system, even in the absence of stress. Experiments on mice have shown that the dopaminergic reward system in the brain enhances immunity via the sympathetic nervous system. The dopaminergic system involved in the immune-enhancing effect also increases social interaction, so the immune activation may be a way of protecting against infections transmitted during social interactions.

It is not simply stress, however, which can have negative effects of health and the immune system. Multiple studies have shown that low perceived social support can result in an increase in immune-modulating cytokines, which may lead to a state of chronic inflammation.

Alternative Therapies

It should also be noted that not all alternative treatments are purely placebo. Many herbs have medically active ingredients which have a real effect on the body. In fact many medicines, such as aspirin, are based on natural remedies. Similarly, there are many medical drugs which have little or no benefit over and above the placebo effect. On average, 75% of the effectiveness of anti-depressants is due to the placebo effect, and a number of independent studies have shown that some anti-depressants are essentially worthless as they have no benefit above placebo whatsoever.

The problem is that there is a lot of myth, pseudoscience and quackery associated with many alternative therapies. There are many myths about vitamin C helping to cure cancer and prevent cold viruses. Many well-designed studies have shown that vitamin C has no effect whatsoever in preventing colds, and recent epidemiological studies have shown that it has no effect on cancer. Some vitamins, such as vitamin E, have even been shown to increase the risk of dying.

Some therapies, such as homeopathy and bioresonance, have no science behind them and no conclusive research showing their effectiveness. (For bioresonance, every single study shows that it is worthless. For homeopathy, some studies show it is effective, but a greater number show it is ineffective. For such an extraordinary theory as homeopathy, it would require very good evidence to show it's effectiveness.)

Other alternative therapies, such as acupuncture, are more likely to have some real effect, although the nature of the effect probably isn't for the reasons given by the practitioners. Acupuncture, for example, has been shown to have a larger effect when a real needle is used to puncture the skin than when a fake needle is used which doesn't puncture the skin, even though the patient does not know which is being used. Other studies have shown that there is no difference in efficacy between needles placed in the "correct" acupuncture points over those placed at random. It is likely that any effect is due to the needle puncturing the skin and masking other pains in the body, rather than due to some mysterious "energy field". More research is needed to separate reality from quackery.

Placebo Effect in CFS

A study by Cho et al. found that the placebo effect in CFS trials varied from 6% up to 50%. The study found that behavioural treatments had the lowest placebo response, while infectious-immunological and alternative-complementary interventions had the highest.

A number of anti-viral treatments have been trialled for CFS, with most showing no difference from placebo (the only positive result is for Ampligen, although the FDA concluded that the clinical trials "did not provide credible evidence of efficacy.") A trial of Vlacyclovir by Lerner found that IgM antibody titers were reduced as much by the placebo as by active treatment.

Many CFS patients are treated with vitamin b12, but all of the placebo-controlled studies that have been done show no benefit over placebo, although the studies do show that there is a large placebo response. Even so, many CFS patients insist that b12 helps them, injected b12 in particular, saying that they immediately feel much better. However the improvement is generally temporary, even when patients continuing taking b12.

The double-blind placebo controlled rituximab trial found no difference in outcomes between the active treatment and placebo groups. However, they did find that 38% of patients were in remission at 4 year follow-up, presumably due to a combination of the placebo effect and natural course. This is similar to the 23-35% recovery rate after treatment with CBT or multi-disciplinary rehabilitation, and better than the median 5% recovery rate that is typical for CFS.


Wikipedia entry on the placebo effect

Weihraunch TR, Gauler TC, "Placebo - efficacy and adverse effects in controlled clinical trials", Arzneimittelforschung 1999 May;49(5):385-93

ter Riet G, de Craen AJ, de Boer A, Kessels AG, "Is placebo analgesia mediated by endogenous opioids? A systematic review", Pain 1998 Jun;76(3):273-5

Dodes JE, "The Mysterious Placebo", Skeptical Inquirer, 1997 Jan

Steven Novella, "The Poor, Misunderstood Placebo", Skeptical Inquirer, November/December 2010

Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams A, "Changes in brain function of depressed subjects during treatment with placebo", Am J Psychiatry 159:122-129, January 2002

Fake acupuncture 'aids migraines'

Khan A, Warner HA, Brown WA, "Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials", Arch Gen Psychiatry 2000;57:311-317

Ben-Shaanan, T. L., Azulay-Debby, H., Dubovik, T., Starosvetsky, E., Korin, B., Schiller, M., ... & Rolls, A. (2016). Activation of the reward system boosts innate and adaptive immunity. Nature Medicine, 22(8), 940-944.

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DISCLAIMER: is an educational resource for chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), burnout and related disorders, and is not giving medical advice. Seek advice from a medical practitioner before making any changes to your life, or if you experience worsening symptoms. CFS is a diagnosis of exclusion, so it is important to rule out other causes for illness.