What Is Homeopathy?
In the opinion of most US medical professionals, homeopathy is nothing but quackery. While herbs and supplements have remained largely outside of mainstream medicine, physicians have no problem accepting in principle that these could have effects in the body. In contrast, homeopathy is an approach to healing that sounds quasi-magical: homeopathic remedies are so phenomenally diluted that they contain no material substance in them except pure sugar (see below). Proponents of homeopathy claim that these so-called “high-potency” remedies possess some sort of healing energy field—a concept that does not sit well with medical professionals accustomed to seeing the world from a scientific perspective.
Nonetheless, homeopathy is used widely even today, especially in the United Kingdom, but also in the US and other countries. Some studies seem to provide evidence that homeopathic remedies can be effective.
The term homeopathy is formed from the combination of two Greek words: omio meaning “same” and pathos meaning suffering.1 This etymology reflects the homeopathic belief that a substance that causes certain symptoms in a healthy person can cure an ailing person of similar symptoms. Although this theory sounds superficially similar to the principle behind vaccines, homeopathy actually functions in a distinctly different manner. The homeopathic theory has some relationship to ancient healing traditions, but in many ways stands uniquely on its own ground, unrelated to other approaches.
The Origin of Homeopathy
Homeopathy is the invention of Samuel Christian Hahnemann, born in 1755 in Dresden, Germany, and educated as a physician.
The medical practices of the 18th century were remarkably unhelpful and invasive. A good example is bloodletting. Doctors commonly bled their patients of a pint of blood or more per treatment, in the belief that it would accelerate healing. More likely, however, bloodletting impaired the patients' ability to recover, rather than strengthened it, and the practice is undoubtedly responsible for many deaths.
Physicians also used strong laxatives to "cleanse" the body. These purgatives included very toxic drugs containing mercury or arsenic, and they too contributed to the great danger attendant on being visited by a doctor.
Samuel Hahnemann quickly became disillusioned by the standard medical procedures of his time; he gave up his medical practice and supported his family in part by translating old scientific and medical texts into German. In 1790, while translating William Cullen’s Materia Medica, he was struck by the lack of experimental basis for Cullen’s suggested uses for drugs. Hahnemann wondered how doctors could justify prescribing toxic substances without even knowing their effects on healthy people. He came to believe there was a correlation between the resulting symptoms of toxic doses of a given substance and the symptoms that the substance was being used to cure.
To explore his new theory, Hahnemann began collecting reports of accidental poisonings. Later, he tested various substances on himself and documented his reactions to them.
For example, he had read that Cinchona officinalis, or Peruvian bark, was used by South American Indians to treat malaria. Hahnemann took a high dose of Cinchona officinalis and his body reacted by breaking out in fever. Since malaria is characterized by fever, he perceived his own fever as evidence that a substance used to treat an ailment produced similar symptoms in a healthy individual.
Hahnemann then set out to experiment systematically with this hypothesis, ingesting other substances and carefully noting his reactions to them. He also gave substances to other healthy people. Hahnemann took detailed notes of the reactions. He recorded not only major physical symptoms, such as fever, but practically any sensation experienced by the person, including such details as a desire to lie down on one’s left side and restlessness that is worse in the early evening.
These "provings", as he called them, were recorded in homeopathic medical texts (such as the Homeopathic Materia Medica) and became the basis for homeopathic treatment.
Currently, provings are done in a different manner, using homeopathic dilutions of substances rather than the substances themselves. Currently, provings are more often done using high dilutions of substances; in other words, the homeopathic remedy is tested, not the underlying substance. This method is safer, even if not entirely consistent with the original theory.
The Three Laws
Based on his observations, Hahnemann postulated three major laws of homeopathy: the first two proposed early in his practice, the third after 20 years of practicing. (There are at least six other relatively minor laws as well.)
The first law is known as the Law of Similars, or “like cures like.” This law states that “a substance that produces a certain set of symptoms in a healthy person has the power to cure a sick person manifesting those same symptoms.” The second law, or Law of Infinitesimals, states that diluting a remedy makes it more powerful.
These two laws in combination define the method of creating homeopathic remedies. The following is an example: the substance ipecac (today, an over-the-counter household remedy for poisoning) causes vomiting. According to the first and second laws of homeopathy, diluted ipecac would potentially treat vomiting, and the more it were diluted, the more effective it would be.
Hahnemann’s third law, the Law of Chronic Disease, states that “when disease persists despite treatment, it is the result of one or more conditions that affect many people and have been driven deep inside the body by earlier allopathic therapy.”2
The word allopathic, which is sometimes today used to describe conventional medicine, was also a creation of Hahnemann and was used as the opposite of “homeopathic.” Allopathic means “other than the disease,” while homeopathic means “same as the disease.” In other words, homeopathy uses remedies that, when taken in high doses by healthy people (according to the first law), cause symptoms similar to those of the disease it is intended to treat. However, the allopathic remedies used by conventional physicians, such as prednisone for asthma, do not have the same relationship. They simply relieve the symptoms, and for that reason (according to homeopathic theory), don’t get to the heart of the problem.
Hahnemann felt that allopathic treatments were actually harmful. A person with a skin rash provides an example. To Hahnemann, such a condition represents the body’s attempt to “release” a deeper illness. Homeopathic treatment would seek to facilitate such a release. In contrast, allopathic remedies, like cortisone cream, “suppress” the rash and thereby drive the illness back into the body.
Note that herbal remedies are also allopathic, according to this principle. Taking St. John’s wort for depression, according to homeopathy, is just as likely to worsen the underlying problem as using Prozac. Furthermore, herbs, like drugs, are said to interfere with the effectiveness of homeopathic remedies. Thus, contrary to popular opinion, homeopathy and herbal medicine are not compatible.
In further work developing the third law, Hahnemann elaborated on the various types of deeply buried diseases that could be the roots of many illnesses. He focused ultimately on psoriasis and syphilis as the primary underlying “miasms” beneath many health problems. However, this feature of his theory is less popular with today’s practitioners of homeopathy.
The Practice of Homeopathy: Constitutional Homeopathy vs. Disease-Oriented Homeopathy
Hahnemann’s theory of homeopathy is now known as constitutional (or classical) homeopathy. This holistic art looks at the symptom picture of a person, including psychological, emotional, physical, and hereditary information, and tries to choose an appropriate remedy. Recently, however, a simplified form of homeopathy has developed, disease-oriented (or symptomatic) homeopathy, in which remedies are given based solely on specific diseases.
Both types of homeopathy have been studied scientifically, although disease-oriented homeopathy has received more attention for the simple reason that it is easier to study.
The Practice of Homeopathy: Constitutional Homeopathy vs. Disease-Oriented Homeopathy Hahnemann’s theory of homeopathy is now known as constitutional (or classical) homeopathy. This holistic art looks at the symptom picture of a person, including psychological, emotional, physical, and hereditary information, and tries to choose an appropriate remedy. Recently, however, a simplified form of homeopathy has developed, disease-oriented (or symptomatic) homeopathy, in which remedies are given based solely on specific diseases.
Both types of homeopathy have been studied scientifically, although disease-oriented homeopathy has received more attention for the simple reason that it is easier to study.
Homeopathy is highly respected in Britain, where it is part of the national health care system. It is also widely used in India and, to a lesser extent, France, Germany, the Netherlands, Greece, South Africa, and South America. In the United States, homeopathy is becoming more widespread again after a period of decline.
In the US, over-the-counter homeopathic remedies are available in pharmacies and healthfood stores. Unlike herbs and supplements, manufacturers of homeopathic products are allowed to make strong healing claims on the labels, in part because one of the founders of the organization that became the Food and Drug Administration, Senator Royal Copeland, was a homeopathic physician. He made sure that homeopathic medicines were given a specially protected status.
The second law of homeopathy requires that a homeopathic treatment be diluted for maximum effect. Hahnemann developed techniques to control the concentration, or dilution, of substances to create homeopathic remedies. First, he took the substance and preserved it in a solvent, usually alcohol. The substances he used were plants and minerals. After letting the substance stand for a month, he poured off the liquid, which became the “mother tincture.” Next, he took one drop of tincture and added it to 99 drops of pure alcohol. He then mixed the liquid by banging the container on a hard surface, a process called "succussion." Homeopathic practitioners believe that succussion is essential to creating an effective remedy.
This first step creates a remedy with a dilution of one part in 10 2, or 100. This dilution would be noted by “c,” for centesimal (indicating a dilution of two factors of 10), or by the terms 2x or D2 (x and D each indicate one factor of 10). The dilution is then continued, always adding one part of tincture to 99 parts alcohol, and succussing at each step. Such a process carried out six times leads to a 6c remedy (or 12x or D12), and so forth.
Sometimes homeopathic remedies are made with substances that are insoluble. In this case, they are ground up, mixed with lactose, and then made into remedies. At times, people make homeopathic remedies by diluting one part of tincture to nine drops of alcohol at each step, to make a 1x or D1 dilution.
The complete process of creating homeopathic remedies is called “potentization,” based on the theory that each successive dilution makes the remedy more potent. Today, you can buy homeopathic remedies that consist of small white milk sugar pills into which the potentized solution has been absorbed. Other remedies are in the form of liquids to ingest or creams to use externally.
Special Forms of Homeopathic Remedies
In addition to standard homeopathic remedies that use unrelated substances that happen to produce a similar symptom, there are two special forms of homeopathic remedies that use substances specifically related to the condition.
Isopathic remedies are made from the actual substance that causes the condition. For example, homeopathically prepared cat dander (containing zero molecules of cat dander) might be used to treat cat allergy.
Nosodes are made from infected animal tissues or bodily secretions. For example, tuberculosis-infected glands from a cow could be homeopathically diluted to create a remedy for human tuberculosis.
A Note About Safety
Although serious objections remain regarding the possible efficacy of homeopathy, there is little doubt that in one respect, at least, Samuel Hahnemann achieved his aim when he invented the treatment: even if it doesn’t work, it cannot possibly cause direct harm.
As described earlier, homeopathy came into being during a period in history when conventional medicine was very often more harmful than helpful. It was the age of “heroic medicine,” during which treatments were chosen more for the drama of their effects than any evidence of efficacy. The most dramatic effects, however, were frequently the most dangerous. Bleeding sick patients or inducing vomiting or diarrhea were more likely to kill people than help them.
Today, conventional medicine is far safer (not to mention more effective). Nonetheless, most pharmaceutical medications present at least some risk. Not so with homeopathic treatments. On a chemical basis, there is nothing in them (or, for low potency formulations, next to nothing); for this reason, it is as difficult to conceive of any manner in which homeopathic remedies could cause harm as it is to believe that they can cure. Homeopathic tablets are, by nature, completely nontoxic.
However, according to the principles of classical (or constitutional) homeopathy, versus disease-oriented (or symptomatic) homeopathy, these remedies can cause problems. On the way toward a cure, temporary exacerbation of symptoms are said to occur frequently. Such “homeopathic aggravations” are supposed to indicate a “release” of underlying problems, and are therefore seen as ultimately helpful, if temporarily unpleasant. However, there is no meaningful scientific evidence that such aggravations take place at any higher rate than could be accounted for by chance (and patient’s expectation).9
Despite its widespread acceptance in some countries, most modern scientific authorities do not take homeopathy seriously, putting it in the same category as perpetual motion machines, ghosts, and ESP. There are several reasons for this intense skepticism, but the most important focuses on a basic fact of chemistry. Simply put, there’s absolutely nothing material in a “high-potency” homeopathic remedy; some force of nature unknown to modern science would have to be involved if homeopathy is effective.
Here’s why. In the process of making a 30x homeopathic remedy, the original substance is diluted by a factor of one part in 1030. This is such an enormous dilution that not even one single molecule is likely to remain. Such a remedy is merely pure sugar (if the form is a sugar pill) or pure water (if the form is a tincture). Even higher dilutions are in use, some so vast that you could use the entire earth as the starting material, and still not end up with a single molecule of the original material in the resulting remedy.
Because of this chemical reality, the comparison of homeopathy to vaccinations, as advanced by many homeopathic practitioners, falls short. Vaccinations contain a great deal of substance, an amount that can be measured and weighed, and which stimulates the immune system. High potency homeopathic remedies, by contrast, contain nothing at all. (Low potency remedies do contain a measurable amount of substance, but they are supposedly less effective than the high potency forms, which are physically content-free.)
Some researchers have speculated that homeopathic remedies produce subtle alterations in the structure of the water in which they are dissolved.3 However, studies with highly sensitive equipment have failed to find any evidence of such structural changes,10,13 and chemistry, as it has been understood both before and after the development of quantum mechanics, makes it highly implausible that liquid water could retain any changes of the type hypothesized.
There are other problems with homeopathy as well. For one, it is hard to understand why a substance that produces certain symptoms when taken in overdose should cure a disease that just coincidentally happens to possess the same symptoms. This hypothesis appears too pat, too tidy and perfect, to reflect the messy world of human illness.
Furthermore, the detailed symptom pictures upon which constitutional homeopathy are based seem to be far too specific and personal to offer any likelihood of universal truth. For example, the homeopathic remedy sulphur is said to be useful for people who have red lips, stooped posture, and a tendency toward untidiness in personal affairs. A small selection of other supposed characteristics of this remedy include mid-morning hunger and a tendency for increased discomfort of whatever physical symptoms they may be experiencing between 10:00 and 11:00 a.m. and after exposure to cold air or motion.
As noted above, these symptoms were assembled through multiple experiences of overdose (homeopathic provings). However, from a scientific perspective, it is difficult to believe that the majority of people who overdose on sulphur experience symptoms largely similar to these (as well as to the several pages of other symptoms commonly associated with the remedy). In any case, modern knowledge of the difficulties involved in evaluating the effects of medical treatments indicates that provings must be conducted in a double-blind and placebo-controlled manner to be valid. Otherwise, participants are likely to experience symptoms simply because they expect to, and observers will tend to observe the expected symptom picture as well. Unfortunately, few of the provings used to define the treatments chosen by homeopaths were performed in a scientifically reliable way.4 Large, rigorous studies have failed to find any difference in symptoms or biochemical measures between healthy people given homeopathic treatments or placebo.5,11,12,14
Thus, on the face of it, homeopathy seems to be a method that shouldn’t have a ghost of a chance of being true. However, some studies have found evidence that homeopathic remedies do, in fact, relieve symptoms of illness. Many of these were double-blind, placebo-controlled studies, the most meaningful kind of study. This presents a conundrum to impartial scientists.
How can this contradiction be resolved?
One possibility is that homeopathy operates via some mysterious new force that science has yet failed to discover. Another, less optimistic interpretation, is that the positive trials may be too flawed to mean anything—even though they were double-blind.
In 1997, scientists Klaus Linde, Nicola Clausius, and others published a groundbreaking review of all placebo-controlled trials of homeopathic remedies. This article appeared in a prestigious British journal, The Lancet.6 The authors wanted to determine whether there was enough evidence in total to say that homeopathy has benefits beyond the placebo effect. The results of this meta-analysis were positive and have been widely quoted by advocates of homeopathy to conclude that the method has been proven effective.
However, not all double-blind, placebo-controlled trials are created equal. Fairly subtle design flaws can invalidate the results of a study that, on first glance, seems rigorous. In 1999 the authors re-analyzed the data and noticed a direct relationship between the quality of the study and the amount of benefit seen: the higher the quality, the less the benefit.7,8 Based on this, Linde et al. concluded that their original meta-analysis overestimated the extent to which homeopathy has been proven more effective than placebo. A 2005 evaluation of all the evidence regarding homeopathy also failed to find convincing evidence that homeopathy is more effective than placebo.15
Since then, however, further positive studies have been reported, some of which appear to be quite well designed. So does homeopathy actually work?
Maybe. But when a method seems, on the face of it, scientifically impossible, it properly requires a high level of evidence before it can be accepted as true. Homeopathy has certainly not yet achieved this level of evidence, and therefore must be regarded at present as unproven therapy.
To understand how a visit to a homeopathic physician works, consider the following imaginary scenario: Sam has felt tense and nervous for months. His workload has increased dramatically since he started a new job last year. He has not been sleeping well, and he’s lost weight. His conventional physician recommends a stress-reduction program consisting of gentle exercise and regular relaxation, but he decides to try classical homeopathy instead.
His initial homeopathic consultation consists of a lengthy interview. The homeopath makes note of small nuances that would not be considered important by a conventional physician. Aside from his nervousness, Sam has been suffering from frequent nosebleeds, easy bruising, dry cough, hoarseness of voice at times, and occasional diarrhea and stomach aches.
The doctor asks whether cold drinks relieve his stomach pain, and Sam nods. Next, the homeopath asks him several questions about his family history, personality, and psychological tendencies. Sam says that he is outgoing and friendly and likes company. “You wouldn’t happen to be afraid of thunderstorms,” she asks, and Sam answers that, in fact, he is. The interview continues for an hour.
Based on her analysis of Sam’s “constitution” as revealed by close questioning, the homeopath carefully selects a homeopathic remedy that matches, based on the classic description in the Homeopathic Materia Medica. This text reports the symptoms to be expected when taking an overdose of various substances. These descriptions are complex and elaborate, covering physical and psychological symptoms that developed in the people who undertook the experiment; taken together, they represent the “symptom picture” of the remedy.
Sam’s homeopath chooses the remedy Phosphorus, because its symptom picture matches him closely. He is told to take the remedy for 3 months. During the period of treatment, he is advised to avoid the use of any pharmaceutical drugs, medicinal herbs (such as St. John’s wort), or foods with drug-like properties (eg, coffee) because they have properties that might “antidote” (counteract) the effect of treatment. At the end of 3 months, he is advised to call for a follow-up visit, at which point he may be given a new remedy to treat “deeper” problems that may emerge.
Note: This description applies to practitioners using classical or constitutional homeopathy. Many alternative practitioners use homeopathic remedies to treat particular diseases and use herbs and supplements in conjunction with them.
Acetic Acid: Surgery Support
Aconite: Sports Injuries, Surgery Support
Aconitum: The Common Cold
Aconitum Napellus: Ear Infections, Surgery Support
Ambra Grisea: Vertigo
Antimonium Crudum: Warts
Apis Mellifica: Rheumatoid Arthritis
Arnica: Bruises, the Common Cold, Head Injury, Sports Injuries, Stroke, Surgery Support, Venous Insufficiency
Arnica Montana: Childbirth Support, Fibromyalgia, Sports Injuries
Arsenicum Album: Cancer Chemotherapy Support
Artemisia Cina: the Common Cold
Asafoetida: Irritable Bowel Syndrome
Asclepias Vincetoxicum and Sulphur: Asthma
Aurum: High Blood Pressure
Baryta Carbonica: High Blood Pressure
Belladonna: Bladder Infections, Breast Engorgement, Childbirth Support, the Common Cold, Ear Infections, Migraines, Radiation Therapy Support, Sports Injuries, Stroke
Bellis Perennis: Sports Injuries, Surgery Support
Berberis Vulgaris: Bladder Infections, Rheumatoid Arthritis
Bryonia: Breast Engorgement, Rheumatoid Arthritis, Fibromyalgia
Bryonia Cretica: Rheumatoid Arthritis
Calcarea Carbonica: Osteoarthritis, Premenstrual Syndrome (PMS), Rheumatoid Arthritis, Venous Insufficiency, Warts
Calcarea Fluorica: Osteoarthritis, Rheumatoid Arthritis
Calendula: Minor Burns, Sports Injuries, Surgery Support
Cantharis: Bladder Infections, Minor Burns
Carbo Vegetabilis: Surgery Support, Tinnitus
Caulophyllum: Childbirth Support
Causticum: Rheumatoid Arthritis, Warts
Chamomilla: Diarrhea, Premenstrual Syndrome (PMS), Sports Injuries
China Regia: Surgery Support
Chininum Sulphuricum: Tinnitus
Cimicifuga: Childbirth Support
Colocynthis: Irritable Bowel Syndrome
Cuprum: the Common Cold
Drosera: the Common Cold
Echinacea: Insect Bites and Stings
Echinacea Angustifolia: Sports Injuries
Echinacea Purperea: Sports Injuries
Equisetum: Bladder Infections
Eupatorium Perfoliatum: the Common Cold
Euphorbium: Hay Fever
Euphrasia: the Common Cold
Ferrosi Phosphas: the Common Cold
Ferrum Phosphoricum: Ear Infections
Galphimia Glauca: Hay Fever
Gelsemium: Migraines, Stroke
Hamamelis: Hemorrhoids, Sports Injuries, Venous Insufficiency
Hepar Sulphuris Calcareum: Sports Injuries
Homeopathic Cough Syrup: the Common Cold
Homeopathic Mouthwash: Cancer Chemotherapy Support
Human Growth Hormone: General Health and Well-being
Hypericum: Sports Injuries, Surgery Support
Isopathic Remedies: Hay Fever, Insect Bites and Stings
Kali Carbonicum: Osteoarthritis
L52: the Flu
Lachesis: the Common Cold, High Blood Pressure, Migraines
Ledum: Insect Bites and Stings, Surgery Support
Ledum Palustre: Osteoarthritis, Radiation Therapy Support, Rheumatoid Arthritis
Lycopodium: Gastritis, Irritable Bowel Syndrome
Mercurius Solubilis: Cancer Chemotherapy Support, Sports Injuries
Millefolium: Sports Injuries
Natrum Muriaticum: Migraines, Warts
Natrum Sulph: Head Injury
Nitricum Acidum: Hemorrhoids, Warts
Nux Vomica: Gastritis
Opium: Surgery Support
Oscillococcinum: the Flu
Phosphorous: the Common Cold, Surgery Support
Phytolacca: the Common Cold
Plantago: Surgery Support
Pulsatilla: Ear Infections, Gastritis, Premenstrual Syndrome (PMS)
Raphanus: Surgery Support
Raphanus Sativus Niger: Surgery Support
Rhus Tox: Fibromyalgia, Osteoarthritis, Sports Injuries
Rhus Toxicodendron: Osteoarthritis, Rheumatoid Arthritis, Sports Injuries
Sarcolactic Acid: Sports Injuries
Solidago: the Common Cold
Staphysagria: Bladder Infections, Surgery Support, Warts
Strychnos Nux Vomica: Rheumatoid Arthritis
Sulphur: Cancer Chemotherapy Support, Migraines, Radiation Therapy Support, Warts
Symphytum: Sports Injuries
Symphytum Officinale: Osteoarthritis
Thuja occidentalis: Warts
Uragoga Ipecacuanha: the Common Cold
Urtica: Insect Bites and Stings
- Lockie A. The Family Guide to Homeopathy. Simon and Schuster; 1989.
- Weil A. Health and Healing. Houghton Mifflin Company; 1995.
- Gray B. Homeopathy: Science or Myth. Berkeley, CA: North Atlantic Books; 2000:51-99.
- Dantas F, Fisher P. A systematic review of homeopathic pathogenetic trials (“provings”) published in the United Kingdom from 1945 to 1995. In: Ernst E, ed. Homeopathy: A Critical Appraisal. London: Butterworth Heinemann; 1998:69-97.
- Fisher P, Dantas F. Homeopathic pathogenetic trials of Acidum malicum and Acidum ascorbicum. Br Homeopath J. 2001;90:118-125.
- Linde K, Clausius N, Ramirez G, et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet. 1997;350:834-843.
- Linde K, Scholz M, Ramirez G, et al. Impact of study quality on outcome in placebo-controlled trials of homeopathy. J Clin Epidemiol. 1999;52:631-636.
- Ernst E, Pittler MH. Re-analysis of previous meta-analysis of clinical trials of homeopathy [letter]. J Clin Epidemiol. 2000;53:1188.
- Grabia S, Ernst E. Homeopathic aggravations: a systematic review of randomised, placebo-controlled clinical trials. Homeopathy. 2003;92:92-98.
- Anick DJ. High sensitivity 1H-NMR spectroscopy of homeopathic remedies made in water. BMC Complement Altern Med. 2004 Nov 1. [Epub ahead of print]
- Brien S, Lewith G, Bryant T. Ultramolecular homeopathy has no observable clinical effects. A randomized, double-blind, placebo-controlled proving trial of Belladonna 30C. Br J Clin Pharmacol. 2003;56:562-568.
- Vickers AJ, van Haselen R, Heger M. Can homeopathically prepared mercury cause symptoms in healthy volunteers? A randomized, double-blind placebo-controlled trial. J Altern Complement Med. 2001;7:141-148.
- Walach H, Jonas WB, Ives J, et al. Research on homeopathy: state of the art. J Altern Complement Med. 2005;11:813-829.
- Witt CM, Bluth M, Hinderlich S, et al. Does Potentized HgCl(2) (Mercurius corrosivus) Affect the Activity of Diastase and alpha-Amylase? J Altern Complement Med. 2006;12:359-365.
- Ernst E. Is homeopathy a clinically valuable approach? Trends Pharmacol Sci. 2005 Sept 12. [Epub ahead of print].