Allergies and the Histamine Connection


Certain substances cause our body’s immune system to overreact and produce histamine as a response to proteins found in foods, insect venom, or airborne allergens.  Normally these agents are inhaled or absorbed through the skin.  The body’s immune system creates antibodies to attack the foreign substance by releasing chemical histamines in the body.


When too much histamine is released into the body, several allergy symptoms may occur.  These include skin irritations, such as rashes, hives or eczema.  The eyes are also affected and may become watery, inflamed, irritated or scratchy.  Nasal passages can become swollen, and airways congested with runny nose and sneezing.  Too much histamine in the airways may bring about allergy-induced asthma as well.  This can lead to shortness of breath, coughing and wheezing.

The Antihistamine Solution

Antihistamines are used to treat allergy symptoms and come in pill form, liquids, tablets, and capsules.

Antihistamines treat:

  • Skin rashes and hives
  • Runny nose, sneezing, congestion, or itching
  • Nasal passage swelling
  • Runny, itchy eyes

Treatment for an Allergic Reaction

The body releases chemicals known as, “histamines” as a response to contact with allergens such as pet dander, pollen, ragweed or dust mites, for example.  This causes the swelling, itching or stuffiness that accompany an allergic reaction.  Antihistamines work to either reduce the level of histamine released in the body, or block it altogether to lessen allergy symptoms.

Allergy treatments may include medications such as steroids, allergy shots, or antihistamines.

These may be either prescribed by a physician or purchased OTC (over-the-counter).

Antihistamines: These are used to treat allergy symptoms and generally fall into two categories, sedating and non-sedating.  Older antihistamines fall into the first category.  These medications relieve allergy symptoms, but cause drowsiness, and several other side effects such as dry mouth.  Non-sedating antihistamines, often considered a newer class of medications do not cause as much drowsiness.

All antihistamines work to lessen or prevent the amount of histamine that causes an allergic reaction in the body such as, swelling, itching, tearing, and breathing issues and secretions.

Antihistamines come in pill form as creams, nasal sprays, lotions, nose drops, and eye drops.

Other allergy drugs may include:

Corticosteroids: These work to reduce inflammation and include creams, ointments, nasal sprays, and tablets.

Mast cell stabilizers: These must be taken regularly to prevent allergic reactions.  Some inhalers such as (Cromolyn Sodium) may be used for the prevention of asthma.   

Leukotriene inhibitors: These drugs target specific leukotriene receptors in the body to reduce allergic symptoms.

Nasal anticholinergics: These medications work to reduce nasal discharge only.

Decongestants: These drugs constrict blood vessels in the nose, which help limit the secretions that come from the inner lining.  They are available in nasal sprays, liquids, and pills.

Immunomodulators: These help to relieve skin allergies and are topical.

Auto injectable epinephrine: This drug application is used to treat anaphylaxis, a severe allergic response to food, insect venom, or other substances.

UrticariaThe Management and Treatment of Hives

Hives, also known as, “urticaria” will affect about 20 percent of people in their lifetime.  Several different substances, causing an allergic reaction that creates itchy patches of skin that become swollen red welts, trigger this skin condition.  Certain activities may exacerbate hives such as, stress, alcohol, or exercise.


The symptoms of hives are itchy, raised, red or skin-colored bumps.  “Blanching” also occurs when the center of a red hive is pressed and it turns white. 


Common triggers include:

  • Food Allergies (Food allergy rash)—Peanuts, eggs, nuts, shellfish
  • Medications—Antibiotics, Ibuprofen, aspirin
  • Insect venom—Bee sting allergy
  • Physical stimuli—Sun, heat, cold
  • Latex allergy
  • Blood transfusions
  • Infections—viral or bacterial
  • Pet dander
  • Plants—pollen, certain plants such as poison ivy, poison oak

Allergist Prescribed/OTC Medication

Treatment for hives includes both low-sedating and non-sedating antihistamines available by prescription or over-the-counter.  These may be taken along with anti-itch creams or salves, or cold compresses to reduce the swelling from hives.  Severe urticaria may require a temporary steroid such as Prednisone, a corticosteroid medication, or an immune modulator to reduce more severe symptoms.  In cases where the tongue or lips swell, or breathing is affected, a physician may prescribe an Epinephrine injector to be kept on hand in case of anaphylaxis, a potentially fatal severe allergic response.

It is important to identify, avoid, and eliminate triggers if possible including:

  • A food allergy or foods that may cause an allergic response
  • Scratching or rubbing
  • Harsh soaps
  • Pressure from tight-fitting clothing
  • Temperature, including cold air or water
  • Excessive sun exposure
  • Specific medications

Chronic Hives—Not Forever

Chronic hives may occur if urticarial symptoms exist for more than six weeks.  If no known cause can be found for the condition, it is said to be, “idiopathic”, or “unknown”.  Many of these cases can be linked to immune disorders, however.  Chronic hives may also be associated with other medical conditions, such as cancer, thyroid disease, or other hormonal disorders.  In general, even chronic hives disappear over time, however.

Anaphylactic ShockA Life-threatening Condition

This potentially fatal condition occurs as a severe allergic response toward a particular substance.  When this happens, the body can quickly shut down.   Breathing becomes labored, and blood pressure drops rapidly.  Thinking becomes unclear as the brain becomes starved for oxygen.  Cell-fluids in the throat can cause it to swell shut and death can occur within three to four minutes of exposure to a specific allergen. 

Anaphylaxis is a severe reaction to a food allergy such as peanuts or seafood.  It can also occur in persons allergic to bee stings or other insect venom. This is a life-threatening condition that needs emergency medical treatment to prevent anaphylactic shock.  It is important to note that the body may not react to initial exposure, but may produce a large amount of histamine upon subsequent episodes of exposure to specific allergens.

General symptoms of anaphylaxis may develop within seconds or minutes and include:

  • Pain in the abdomen
  • Abnormal breathing sounds
  • Anxiety
  • Tightness in the chest
  • Cough
  • Diarrhea
  • Breathing difficulties
  • Swallowing difficulties
  • Light-headedness, dizziness
  • Hives, itching
  • Nasal congestion
  • Nausea, vomiting
  • Heart palpitations
  • Skin redness
  • Slurred speech
  • Swelling in the eyes, face, or tongue
  • Unconsciousness
  • Wheezing

Emergency Medical Care

At this time, an injection of the hormone, epinephrine, (which is naturally produced in the adrenal glands) is the only treatment for anaphylactic shock.  This works to open the airways by constricting the blood vessels in the body.  Unfortunately however, the effects of an injection only last about 10-20 minutes and the drug must be administered before, or at the onset of symptoms.  It is critical to get help immediately upon exposure to a known allergic substance that could lead to anaphylaxis.

Allergies or Sinus Infection? —Similar Symptoms

According to the Centers for Disease Control, the recent number of adults diagnosed with sinusitis in the United States is about 28.5 million.  That’s roughly, 12.1% of the adult population, and at least some of these cases can be attributed to allergies alone.

Bacterial Causes of Sinus Infection

Seasonal allergies affect many of us in different ways, especially in the area of the sinuses and the sinus passages.  Pollen from trees, plants, and grasses often causes stuffy noses, runny eyes and achy heads.  Sometimes, however this can lead to a more serious condition known as, “sinusitis”, or swelling and inflammation of the sinuses, (the air cavities surrounding the nasal passages). This may prevent normal drainage of the mucus the body creates to protect the lungs from foreign invaders such as dust and debris.

As mucus collects in the nasal passages bacteria begins to grow.  This may cause infection of the surrounding tissue that can spread through the sinus cavities.

While allergy symptoms may appear similar to that of a sinus infection, a physician must diagnose this through a physical examination, an x-ray of the sinuses, or a specific test for bacteria of nasal discharge.

Sinusitis and Sinus Infection—Acute and Chronic

Symptoms of sinus infection may range from discharge that is thick and yellow, or green in color that runs from the nose, or down the back of the throat.  The nasal passages will generally also be obstructed, causing congestion.  There may be swelling in the face, around the nose, cheeks, eyes, or forehead, and it may be more difficult to taste or smell.

There are two types of sinusitis, which include, acute sinusitis, and chronic sinusitis.  (Sinusitis can be caused by infection or allergy irritation). 

Acute sinusitis:  This is the temporary inflammation of the sinuses where mucous membranes in the nose, sinuses, or throat become inflamed due to allergies.  The swelling caused by allergies blocks mucus from draining, causing pressure to build in the sinus area.

Chronic sinusitis:  If symptoms persist for more than 12 weeks, or if persons experience more than three sinus infections in one year, then sinusitis is considered chronic.  Over 50 percent of people with moderate to severe asthma have chronic sinusitis.

Sinus Infection Treatment—Getting Allergy Relief

A sinus infection may be treated in a variety of ways depending upon the severity of the infection. 

Unblocking the Nasal Passages:

This is the initial first step that is needed to treat a sinus infection.  Without proper drainage, the bacterial infection will remain in the nasal cavity causing further inflammation and damage to the tissues.  A physician may flush sinus passages or advise the patient to inhale steam, or sleep with a vaporizer to loosen phlegm. 

Options in Allergy Medicine

Nasal steroids:

Sprays containing steroids can be used to decrease inflammation of the nasal lining. 


Physicians prescribe a course of antibiotics to fight infection in the sinus cavities.

Oral steroids:

These may be prescribed for chronic sinusitis, but are powerful with significant side effects.  Generally they are only prescribed when other medications have failed. 

Nasal steroids: 

Sprays are helpful for many people to decrease inflammation, but can often lead to damage of the nasal lining.


Some patients with chronic sinusitis that have not responded to antibiotics or other medications may be candidates for functional endoscopic sinus surgery (FESS), or a “balloon sinuplasty” to help clear sinus pathways and allow for normal drainage of mucous.

Can Allergies Cause Headaches?The Truth About Whether Sinus Allergies Can Lead To a Sinus Headache

Sometimes allergies or hay fever can lead to sinus pressure and headaches in the front of the head or around the eyes.  A physician must diagnose true sinus headaches since they may also be confused with migraine pain because of their location.  Sinus pressure caused by blocked or inflamed sinus passages may press on the nerves surrounding the ocular area and head causing severe headaches for some allergy sufferers. 

If an infection occurs due to bacteria from mucus build up, the sinus passages will remain swollen and inflamed causing pressure and possible headache pain to persist. 

Allergy Headache—The Sinus Pressure and Pain Connection

It is important to note that many people who “self diagnose” their headache as a sinus headache really suffer from migraine pain.  (Research finds there is a link between migraines and allergies). 

There are four pairs of paranasal sinuses contained in the skull that help the voice resonate and make the skull lighter.  Within this area, severe headache pain may occur in connection with allergies, sinusitis and sinus infection.  Physicians use specific criteria to diagnose true sinusitis (rhinosinusitis) headaches.

These include:

  • A headache must be present in the front of the head with additional pain in the ears, face, or teeth.  There must also be clinical evidence of either acute or chronic rhinosinusitis.  (A nasal endoscopy, CT, or MRI could provide this, as well as some type of nasal or sinus culture performed by a physician).
  • A headache must be present at the same time as rhinosinusitis symptoms.
  • Within a period of seven days of successful treatment, (or reduced symptoms) of acute or chronic rhinosinusitus, the headache and/or facial pain disappears.

Allergies—Our Overactive Immune System

Over 50 million Americans suffer from chronic allergies each year. Caused by an overreaction of the body’s own immune system, symptoms may range from sneezing, coughing or mild skin irritation to more serious conditions such as allergy induced asthma or life threatening anaphylytic shock. While the Centers for Disease Control report that allergies are the 6th leading cause of chronic illness in the nation, and that over $18 billion is spent annually for treatment, some persons may be at higher risk than others for allergy related illnesses.

Persons at risk include:

Infants who have already developed cow’s milk allergies
Small children who have asthma or food allergies
Anyone who has developed an allergic reaction to an insect bite or bee sting
Any person with a preexisting allergic condition
Anyone with close family members with allergies including hay fever, skin allergies, food allergies, or allergies to insect stings

So, what are allergies and why do we get them?

Normally, the body’s own immune system produces antibodies to protect itself from substances that cause illness or infection. In the case of allergies however, the body mistakenly identifies allergens as harmful agents, triggering the immune system to release chemicals such as, histamine that produces allergy symptoms. These can irritate and inflame the skin, clog sinuses and airways, and negatively affect the digestive system.

Allergies may be relatively minor, causing only minimal discomfort, but can also escalate to a serious condition known as, “anaphylaxis”, requiring emergency medical treatment.

While the majority of allergies cannot be cured, most can be treated to relieve symptoms.

Food Allergies and Seasonal Allergies—Among the Most Common

Many people suffer allergic reactions to certain foods, and plant and tree pollens during specific times of the year.

Food Allergens: peanuts, tree nuts, wheat, soy, fish, shellfish, eggs, milk

*Peanut Allergy—An allergy to peanuts can be especially serious since it can cause anaphylaxis.

Airborne Allergens: pollen, animal dander, dust mites, mold

Insect Stings: bee stings, wasp stings, hornet stings, yellow jacket stings, and fire ant stings

Materials Allergies: Latex is a common substance that may promote an immune system response. Proteins found in latex rubber, used in gloves, condoms and other products cause contact skin allergies for some people.

Drug Allergies: These can affect the skin or other tissue or organs
of the body. This includes Penicillin or Penicillin derivatives.

Allergic Reactions—Signs and Symptoms

These vary depending on the substance and the area of the body affected. This includes the digestive system, nasal passages and skin.

Seasonal allergy symptoms/airborne allergies: sneezing, runny nose, stuffy nose, red, swollen eyes, watery eyes, itching on the roof of the mouth

Food allergy symptoms/food allergies: swelling of the lips, tongue, throat, face, mouth, hives, anaphylaxis

Insect sting allergies: swelling at the sting site,
hives or itching covering the body, wheezing, coughing, chest tightness, shortness of breath, anaphylaxis

Drug allergies: hives, itchy skin, skin rash, swelling in the face, wheezing, anaphylaxis

Atopic dermatitis—a skin allergy also known as “eczema” that may cause skin to become red, peel or flake

Medical conditions associated with allergies include asthma, conjunctivitis, eczema, dermatitis and sinusitis, hives and hay fever.

Anaphylaxis—Life Threatening Consequences

Anaphylaxis is a life threatening condition caused by a severe allergic response requiring emergency medical assistance. Some foods and insect stings can cause anaphylaxis, causing the body to go into anaphylactic shock.

Signs of anaphylaxis include:

Tight chest
Cardiac arrhythmia
Face Flushing
Loss of consciousness
Loss of blood pressure
Shortness of breath/ragged breathing
Skin rash
Weak/rapid, pulse
Upset stomach/nausea/vomiting

Risks and Concerns

An allergy may increase your risk of:
Atopic dermatitis (eczema)
Infections of the ears or lungs
Fungal complications of your sinuses or your lungs
Bronchopulmonary aspergillosis, (a hypersensitivity response to the fungus Aspergillus if you’re allergic to mold)

Can Allergies Be Prevented?

Once the body develops an allergic reaction to a certain substance there is generally no way to prevent that allergen from reacting with the body again. Eliminating a particular substance from a person’s environment or controlling the amount of exposure a person has to an allergen is the general protocol surrounding treatment for allergies. This can be done by avoiding particular foods that trigger allergic responses, installing air filtration systems that filter out pet dander, dust mites, pollen, and dust particles, and taking medication to minimize the symptoms and effects of allergies.
Multiple Allergy Treatments—Many Forms

Allergies may be treated by prescription medications, or over the counter products. These are available in the form of pills, liquids, nasal sprays, inhalers, eye drops, skin creams and injections.

Antihistamines—Antihistamines block histamine, a symptom-causing chemical released by your immune system during an allergic reaction.

Pills and liquids—Oral antihistamine to ease symptoms

Nasal sprays— Relieves sneezing, runny nose, sinus congestion, postnasal drip

Eye drops—Antihistamine for itchy, red, swollen eyes

Decongestants— Offers immediate relief from sinus and nasal congestion.

Pills and liquids—Oral decongestants

Nasal sprays and drops—For short applications

Corticosteroids—Corticosteroids relieve symptoms by suppressing allergy-related inflammation. Most of these medications require a prescription.

Nasal sprays—Prevention and relief of stuffiness

Inhalers—Daily use for asthma prevention

Skin creams—For relief of itching, scaling, redness, swelling, or irritation

Immunotherapy—Gradual increased exposure to allergens to build tolerance

Allergy Shots as Treatment

Regularly scheduled allergy injections can also be taken to either prevent the symptoms of an allergy from occurring or to lessen the severity of the symptoms.

Emergency epinephrine shots—self administered shots to treat anaphylaxis

Food Allergies in Children

There are, without question, few conditions that cause more widespread parental concern and confusion than food allergies. Because of the potential for severe consequences, such as swelling of the lips or throat, breathing problems or, in the extreme case, sudden death, parents justifiably are concerned for their children’s safety. This concern extends beyond the home, to school, birthday parties, summer camp, and other activities. In addition to classical food allergy, children are frequently labeled food allergic primarily because of intestinal symptoms such as colic, vomiting and diarrhea. Other groups of children may be placed on avoidance diets because of frequent colds, eczema, hives and other rashes, and asthma. Thus, a myriad of symptoms or diseases are ascribed to “food allergy”.

Even physicians have difficulty organizing the possibilities and explaining to parents some of the subtleties of food allergies and related conditions, and those that may mimic these problems. The problem may be aided by agreeing on a definition, which is not always an easy task for the medical establishment. However, for the purposes of this discussion, a food allergy will be defined as a group of symptoms associated with a food that can potentially cause harm to more than one organ or body system at a time. An example is the patient who has vomiting, and develops hives and difficulty breathing after eating peanuts. This association is made stronger if the patient has a positive skin test to the food in question, confirming the presence of a specific IgE, the unique antibody responsible for a particular allergy. This is different from the problem of intolerance, where the problem lies in the inability to digest a particular food, such as milk and other dairy products (lactose intolerance), because of an enzyme deficiency. The distinction between skin test-positive food allergies and other food related problems is important because food allergies can potentially lead to very severe symptoms or even fatalities.

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What are the main symptoms of food allergy? The first warning sign often begins in the mouth and throat. Lip tingling, mouth and throat itching, and lip swelling may occur within seconds of contact with the offending food. A person may also experience nausea or may actually vomit and/or have diarrhea. A feeling of flushing or itchiness may ensue. Within ~ minutes to 2 hours, sensitive persons may develop hives on their skin and often swelling of the face and throat. In most severe reactions, breathing problems, that resemble asthma, as well as dizziness, weakness and fainting (true loss of consciousness) may develop rapidly and be fatal if not treated quickly (anaphylactic shock).

Not all children with food allergies experience all the symptoms. Most commonly, the symptoms do not involve more than localized itching in the mouth and an episode of hives. Commonly, young infants will have their eczema flare when they eat certain foods. This happens within 30 minutes to 2 hours after eating. Itchiness will develop and, over the next six to eight hours, the child’ s eczema may flare badly. This type of reaction, although seldom leading to anaphylaxis, is uncomfortable for the child.

Another group of patients, who suffer from hay fever, may get lip and tongue tingling and a feeling of swelling in the mouth when they eat fresh fruits and vegetables. They have ns real prsblems with the cooked variety. These patients rarely develop a severe total body reaction. Again, it may not be life-threatening to eat the food, but the symptoms are nevertheless bothersome. Sometimes, children with unexplained hives, poor growth or asthma suffer from a food allergy.

What are the main foods implicated in allergic reactions? In our pediatric population, there are seven “offenders” that account for over 90% of food allergies. They are milk, eggs, fish, wheat, soy, peanut* and tree nuts. This list is likely influenced by the prevalence of these foods in our diets. In countries where peanuts are not eaten, peanut is not a major cause of allergy. Rice allergy, which in North America is rare, is more common in Asian countries. This observation and other scientific evidence suggests that avoidance of these allergens in the early months of life may decrease the risk offood allergy in later life. Many food allergies are life long; however, some of the most common allergies seen in infancy, such as milk, egg, soy and wheat allergies, disappear in almost 70% of children by the age of 5 years. If a less common food is suspected as a cause of symploms, the parent should discuss this with the child’s doctor to arrange appropriate testing and treatment.

What arc the best tests for food allergies? A good history taken by a physician who has experience with these problems is the most important aspect of the assessment of an allergic child. Many concerns about food allergies can be dispelled by paying attention to certain important facets of the history. What are the areas of the body affected? Do the symptoms recur every time a food is eaten? How long after eating the food does the problem occur? These and other questions help discern if there is a real food allergy, an intolerance caused by enzyme deficiency or no real problem at all. After a good history, it is often important to confirm the allergy with skin tests. Allergy skin testing is a very sensitive indicator of whether or not the food is significant in producing the reaction that has occurred. A positive history and skin test is a good indicator that the problem is, indeed, allergic. Negative skin tests suggest that perhaps a different food is the cause of the problem or that the symptoms are not caused by allergy. Skin tests may be performed with the fresh food itself, or with commercially-available allergy testing products. For some children, especially if they have severe eczema or are very young, a blood test for allergy, known as a RAST test, may be performed. Be wary of blood tests that are touted as a way to screen many foods at once or that promise to explain symptoms other than those classic for food allergies. These tests are often very costly and do not generally measure the antibodies related to development of allergies. Muscle strength testing after eating or touching a food or food tests using drops of food placed under the child’s tongue have not been scientifically substantiated as reliable indicators of food allergy.

Food challenges are occasionally suggested by the physician if skin tests are negative or if there is still a question about the diagnosis. These should only be done by physicians with experience in food allergy. They are safe, since these tests generally start with extremely small amounts of the food substance in question, with increasing doses being given if the patient tolerates the previous amount taken. If someone can eat a significant amount of a specific food with no symptoms developing within two hours, they are likely not allergic to the substance in question. Food challenges can be very useful in complicated cases of food allergy.

How are food allergies treated? The most important facet of the treatment is the elimination and avoidance of the substance from the child’ s diet. This may be a hardship in some cases, such as in egg, milk or wheat allergy. This approach entails reading labels carefully and knowing the commercial synonyms for products listed on labels; for example, milk can be listed as whey, casein or lactoserum. This is a critical part of food allergy treatment since, in very sensitive patients, contact with even small amounts of a food can lead to severe symptoms or even death.

There are also medications that are given to treat symptoms in case of accidental food ingestion. Antihistamines such as diphenhydramine (Benadryl) should be given if any contact with a food allergen is suspected, especially if there are symptoms such as hives, or skin and/or throat itchiness. In case of a more severe allergy, adrenaline (Epi-pen, Ana-kit) injected rapidly under the patient’ s skin can be life saving. Your physician should explain how and when to use adrenaline if your child requires this medication.

It is unfortunate that our bodies do not always appreciate some of the finer foods in life. However, it is more unfortunate that several people die each year from food allergies. If you suspect food allergy, discuss this matter with a physician. The testing and counseling of your child may be crucial to his/her overall well being in the future.

* The peanut is a legume, like peas, rather than a nut.

Multiple Chemical Sensitivity

“ABSTRACT.  Consensus criteria for the definition of multiple chemical sensitivity (MCS) were first identified in a 1989 multidisciplinary survey of 89 clinicians and researchers with extensive experience in, but widely differing views of, MCS.  A decade later, their top 5 consensus criteria (i.e., defining MCS as[1] a chronic condition [2] with symptoms that recur reproducibly [3] in response to low levels of exposure [4] to multiple unrelated chemicals and [5] improve or resolve when incitants are removed) are still unrefuted in published literature.)  Along with a 6th criterion that we now propose adding (i.e., requiring that symptoms occur in multiple organ systems), these criteria are all commonly encompassed by research definitions of MCS.  Nonetheless, their standardized use in clinical settings is still lacking, long overdue, and greatly needed–especially in light of government studies in the United State, United Kingdom, and Canada that revealed 2-4 times as many cases of chemical sensitivity among Gulf War veterans than undeployed controls.  In addition, state health department surveys of civilians in New Mexico and California showed that 2-6%, respectively already had been diagnosed with MCS and that 16% of the civilians reported an “unusual sensitivity” to common everyday chemicals.  Given this high prevalence, as well as the 1994 consensus of the American Lung Association, American Medical Association, U.S. Environmental Protection Agency, and the U.S. Consumer Product Safety Commission that “complaints [of MCS] should not be dismissed as psychogenic, and a thorough workup is essential,” we recommend that MCS be formally diagnosed–in addition to any other disorders that may be present–in all cases in which the 6 aforementioned consensus criteria are met and no single other organic disorder (e.g., mastocytosis) can account for all the signs and symptoms associated with chemical exposure.  The millions of civilians and tens of thousands of Gulf War veterans who suffer form chemical sensitivity should not be kept waiting any longer for a standardized diagnosis while medical research continues to investigate the etiology of their signs and symptoms.”


*”archives of Environmental Health”, May/June 1999 [Vol. 54 (No. 3)]

The Maximum Intradermally Tolerated Dose (MITD) Method of Food Allergy Testing and Immunotherapy: New Concepts


by Joseph B. Miller, M.D.

(“The Environmental Physician”, Fall 1994)


I have long noted that the symptom-relieving dose in intradermal relief-dose (“neutralizing”) testing was almost always 0.05 ml of the strongest concentration that produced a negative wheal. Any concentration stronger than this almost always produced a positive wheal, equivalent to a mild local reaction, sometimes accompanied by symptoms, equivalent to a mild systemic reaction. The strongest negative wheal concentration (SNWC) usually did neither; it was almost always totally tolerated, both locally and systemically.

In a 4-year analysis of 50,421 consecutive tests, I found that the strongest negative wheal concentration was the symptom-relieving concentration in 98.8% of tests in which symptoms were elicited. So in these tests, the strongest negative wheal concentration could be termed the “maximum intradermally tolerated concentration”. In the remaining 1.2% of symptom-associated tests, relief occurred on the second (or in one patient, the third) negative wheal concentration. In this 1.2%, the SNWC failed to relieve, i.e., the induced symptoms continued on. Therefore, the SNWC was not totally tolerated, although it produced a negative wheal. The second negative wheal concentration, which did provide relief in these tests was, therefore, the maximum intradermally tolerated concentration in these instances. Summing up, in essentially 100% of all tests in which symptoms were induced and relieved, the maximum intradermally tolerated dose was the effective immunotherapeutic dose. This was true of both inhalants and foods. I feel justified, therefore, in defining this allergy testing procedure as the Maximum Intradermally Tolerated Dose (MITD) Method. This contrasts it with the Maximum Subcutaneously Tolerated Dose Method of build-up treatment for inhalants long employed in allergy immunotherapy.

I then utilized the strongest negative wheal concentration to treat clinically food-sensitive and inhalant-sensitive patients who produced positive wheals but no symptoms on testing; by wheal-based testing alone, these patients almost invariably obtained the same remarkable immunotherapeutic relief on the strongest negative wheal concentration, despite displaying no symptoms on testing. Finally, I found that the subset of patients with clinically food-induced or inhalant-induced syndromes, who did not display test symptoms and who also did not produce positive wheals even on 0.05 ml of Concentration #2, almost invariably obtained the same remarkable relief on immunotherapy with Concentration #2.

This suggested that testing could be made more efficient by first finding the strongest negative wheal concentration in all tests, and secondly utilizing the second negative wheal concentration when needed in the 1.2% of symptom-associated tests in which symptoms might remain. The same principle turned out to be true with other extracts, e.g. Influenza Virus Vaccine, Candida extract, oak-ivy extract, and others. This has standardized and streamlined the procedure and made it more objective, more efficient, more error-free, and more free of test symptoms. It has also freed us from the concept that provocation and neutralization of symptoms were necessary for successful diagnosis and treatment.


In 1964, I was practicing by conventional allergy concepts–and suffering from severe daily migraine. At that time, I did not know that migraine was largely a food-allergy syndrome. I was unable to determine the cause or obtain relief from my own background, and received no help from multiple physicians of several pertinent specialties.

Then I heard a lecture by Dr. Carleton Lee on an intradermal food test procedure which he called provocation-neutralization. Migraine was at the top of his list of responding syndromes. I immediately tested myself, and reproduced (“provoked”) headache with specific concentrations of extracts of milk, wheat, corn, and chocolate–my favorite foods. Much to my astonishment, I found, with each of these extracts, that a concentration different from the provoking concentration relieved (“neutralized”) the headache within ten minutes.

I then used subcutaneous injections containing the relieving doses of these foods twice a week. After three weeks, my migraine headaches were virtually gone–and still are.

For the past 30 years, I have been studying this remarkable system of allergy immunotherapy in carefully selected patients, and have added to the long list of responding syndromes and useful extracts other than foods. In addition, I have been interested in systematizing and teaching methods of obtaining greater efficiency, precision, and objectivity, and have published some of my experiences.(1-10) This report contains descriptions of more recent observations and concepts.

The Unique Rapid Relief Response:

Intradermal testing utilizes 1:5 serial concentrations (dilutions) of food extracts (some now term this a sequential-incremental system). One such concentration, specific for each food extract in each patient, provides rapid relief of symptoms that may have been induced by just-prior intradermal injections of other concentrations of that extract. When later administered subcutaneously as a regularly-scheduled immunotherapeutic injection, 0.05 ml of this concentration usually will then provide a major degree of protection from the symptoms caused by ongoing exposures to this food.

The individualized treatment doses for all the foods are combined into a single immunotherapeutic solution. This solution can be injected subcutaneously in judiciously selected patients with remarkable effectiveness and safety, and with virtually complete freedom from significant local or systemic side effects.

No build up of doses is needed, and none is desirable. Nothing can be gained by build-up, and much can be lost by building from relieving doses to overdoses. The optimal, effective, safe maintenance doses of all the allergens in the solution have already been determined by intradermal testing. They cannot get any better. Therefore, the very first subcutaneous treatment injection contains the full maximally effective, maximally safe maintenance doses of all the foods.

Favorable response usually occurs very rapidly. Relief of chronic food (or inhalant, etc.) symptoms begins by the time testing is completed in 55% of my patients. Injection by injection, this percentage increases. Within 3 weeks, 93% of my patients have achieved marked relief.

It is characteristic for relief to occur shortly after each immunotherapeutic injection. If symptoms are present at the time of an injection, relief occurs within 30 minutes in 40% of the patients, within one hour in 60%, within two hours in 77%, and on the same day in 88%. Some who take their injections at bedtime note their improvement on arising.

The Maximum Intradermally Tolerated Concentration Has Provided Relief in Virtually 100% of Tests:

I recently analyzed 50,421 consecutive tests perfumed on 1,525 patients over four years in my office. In this series, 98.8% (6,748 tests) of relief-providing (neutralizing) doses in the 6,829 tests which had produced symptoms in 834 patients occurred on the strongest negative wheal concentration (SNWC). In the remaining 81 symptom-associated tests (1.2%), in which test symptoms did not clear on the SNWC, the symptoms cleared on the second (77 tests, or 1.12%), or the third (4 tests, or 0.06%) negative wheal concentration. No weaker concentrations than these were required in this series.

Seven patients accounted for two-thirds of the second negative wheal doses (55 of the 81 tests). After retesting, their doses reverted to the strongest negative wheal dose. One of these patients (E.L.), in 1989, accounted for 38 of the 77 second negative wheal doses and all four of the third negative wheal doses. After she improved as was later retested, all her doses reverted to the strongest negative wheal dose. I have had no tests in which the third negative wheal dose was required since then, and even the need for the second negative wheal dose has become progressively less frequent.

This reversion to the SNWC is the usual situation. Thus, for homeostasis, the human immune protective system displays an almost universal need for the strongest negative wheal concentration. This may be looked upon as the anti-inflammatory non-wheal-producing concentration on step weaker than the pro-inflammator wheal-producing concentration. Even in the 1.2% of tests in which the body is unable to tolerate the SNWC on initial testing, a brief course of immunotherapy usually quickly produces tolerance and need, then, for the strongest negative wheal concentration.

In the 1.2% of tests in which the strongest negative wheal concentration is not the symptom-relieving concentration, the strongest negative wheal concentration cannot be called a tolerated dose at that time because it is accompanied by a continuation of test symptoms. Therefore, in these few instances, the second (or third) negative wheal concentration is the maximum intradermally tolerated concentration. So in this four-year study, the term “maximum intradermally tolerated concentration” has defined 100% of tests in which symptoms were induced and relieved. Therefore, this method can be accurately described as the Maximum Intradermally Tolerated Dose Method. (It could also be termed the Relief Dose Method or the Optimal Dose Method, since both these terms describe it also.)

Even so, there is a rare instance in which a test is not completed, either because of an inability to find a relieving dose that day, or because of the discomfort or possible danger to continuing the test. Many such patients can be retested successfully later with milder or no symptomatology.

Selection of patients for initial testing must consider many factors. Some patients are not selected for testing at all, and some are discontinued from testing if they experience uncomfortable symptoms or poor neutralizing capacity.

The remarkable consistency of physiologic need of the body for the strongest negative wheal concentration has an additional beneficial aspect. When the history indicates allergenicity of a food, inhalant, or other incitant, but no symptoms can be induced during intradermal testing, 0.05 ml of the strongest negative wheal concentration will almost invariably provide relief in therapy–without ever having produced symptoms during testing. In other words, patients who do not display symptoms on testing, but do display positive wheals, can be tested successfully and relieved of life-long suffering by whealling alone. Therefore, we can provide the same striking benefits to non-symptom-reacting patients who are allergically sensitive and who display positive wheals but do not display symptoms on testing.

Thirdly, there is also a subset of patients who display neither symptoms nor positive wheals on testing. In these patients, 0.05 ml of Concentration #2 is negative for all or many active allergens. Innumerable clinical trials have revealed that in these instances, 0.05 ml of Concentration #2 is not only tolerated, producing neither symptoms nor positive wheals, but is also almost invariably protective in immunotherapy. It provides relief to patients who have failed to find help even in multiple major medical centers. It is a near-universal protective dose in such patients, providing rapid relief (usually in one-half to two hours) after each injection, as well as ongoing protection by means of regularly scheduled immunotherapeutic injections.

The Wheal is an Almost Infallible Guide to the Perfect Treatment Dose Whether or Not Symptoms are Induced:

This primarily wheal-based system provides an objective, precise, reliable, repeatable method of testing. Unlike primarily symptom-based test systems, dependent on provocation of symptoms by the intradermal, sublingual, or subcutaneous route, it puts this method onto firm objective footing and provides relief for patients who do not display symptoms by any route of test administration of antigens.

Wheals are measurable, visible, palpable, and photographable for objective evidence of accuracy in testing and for correlating symptom-initiation or subsidence with wheal positivity or negativity. This wheal-based test system also provides precision in determining the perfect treatment dose. The ultimate evidence of effectiveness of wheal-based testing is the ongoing relief of symptoms during regularly scheduled immunotherapy, the return of symptoms when the regularly scheduled injection is delayed, and the rapid relief (usually within 30 minutes to 2 hours) when the delayed injection is finally administered. The willingness, or rather eagerness, of the patients to continue these injections for years speaks further to effectiveness, as does the success of MITD therapy in infants as young as three months of age.

The near-infallibility of the wheal in indicating the optimal therapeutic dose has been consistently overlooked. Investigators have simply not adequately studied intradermal serial concentration (sequential-incremental) testing. Many conventional allergists do not employ intradermal testing, particularly for foods. Most of those who do, utilize only a single concentration (usually 1:1000) of an antigenic extract. This cannot provide the quantitative bioassay-type information obtained by testing with a series of concentrations of different strengths. Furthermore, they usually intradermally test several antigens simultaneously, so if symptoms arise, they do not usually know which antigen caused them. In addition, they consider all test symptoms as adverse systemic reactions, and miss the opportunity to seek the perfect treatment dose by determining the strongest negative wheal concentration of the causative antigen.

Test and Treatment Dose Volumes:

The treatment dose of each allergen is invariably 0.05 ml, but in testing, two volumes are used. These are the 0.01 ml volume, which usually produces about a 4 mm wheal, and the 0.05 ml volume which usually produces about a 7 mm wheal. The 0.01 ml volume is not readily measurable on the syringe so is defined as the volume that produces approximately a 4 mm wheal.

The 0.05 ml volume produces a greater symptom response than the 0.01 ml volume, and a highly reliable relief response in both testing and immunotherapy. In addition, it is virtually 100% reliable in producing wheal responses that correlate with symptom responses. The 0.01 ml volume usually produces fewer, milder, or no symptoms in testing, but is slightly less reliable in correlating wheals with symptom responses.

Therefore, in order to minimize test symptoms, I test all patients to all antigens with 0.01 ml volumes until I have determined the SNWC with the 0.01 ml volume. I then “verify” negativity by administering 0.05 ml of that concentration. In 89% of such tests, the 0.05 ml volume has produced a negative wheal as did the 0.01 ml volume, and this dose has been the effective treatment dose. However, in 11% of such instances, the 0.05 ml volume has produced a positive wheal when the 0.01 ml volume had produced a negative wheal. In these 11%, 0.05 ml of the next weaker concentration has been negative and has been the effective treatment dose.

For example, suppose 0.01 ml/#2 produces a positive wheal and no symptoms. The next dose will be 0.01 ml/#3. If this produces a negative wheal, the next dose will be 0.05 ml/#3. If this produces a negative wheal, it is the treatment dose, and the test has been completed. However, in 11% of tests, the 0.05 ml/#3 will produce a positive wheal, in which case 0.05 ml/#4 will produce a negative wheal, will relieve any symptoms that may have been induced, and will be the effective treatment dose.

Deletion of Concentration #1 From Testing:

Stable extracts are critical for accurate testing and retesting. Non-glycerinated extracts arrive at the office in various stages of decreasing potency, and the decrease continues after dilution, requiring much retesting. Glycerinated extracts are remarkably stable and are little subject to loss of potency even when later diluted and even at room temperature. Almost all of my patients have tolerated glycerinated extracts, and I use them almost exclusively. The chief disadvantage is that glycerin produces a non-specific positive wheal in 80% of tests with the #1 concentration, which contains 10% glycerin. This does not occur with #2 or weaker concentrations.

When a positive wheal has occurred on Concentration #1, I have been unable to distinguish whether it was a non-specific positivity due to glycerin or a specific positivity due to allergen, despite measuring schemes by which the non-specific and specific responses have been said to be distinguishable.

In my experience, the #1 concentration is rarely useful as a relief-dose concentration. When it has been utilized in immunotherapy, it has usually soon started producing symptoms, and the #2 concentration has been needed for relief. Furthermore, delayed overdose reactions are more likely to occur from the #1 concentration than from any other. On the other hand, 0.05 ml of #2 has been a near-universal beneficial immunotherapeutic and protective dose in patients who display a negative wheal and no symptoms on 0.05 ml of #2. Therefore, I now rarely use Concentration #1 in testing. This has markedly decreased the incidence of delayed overdose reactions, has made test procedures more accurate and less time consuming, and has greatly reduced the need for retesting.

Wrap-up Injections:

If testing is completed in one day, ten combined treatment doses are made up, and one is administered to the patient before leaving the office. If testing requires more than one day, a “wrap up” injection of all doses determined the first day is administered subcutaneously at the end of the day. All doses determined over a two-day period will be injected subcutaneously at the end of the second day; and so on each day. When testing is completed, the first complete immunotherapeutic injection is administered in the office. In all instances, the patient is observed for thirty minutes for both local and systemic reactions. Characteristically, there is no local or systemic reaction, and the patient often volunteers that he is already feeling better, often after the first or second wrap-up injection. In the event of a local reaction or the induction of symptoms from a wrap-up injection, the antigens tested that day must be omitted from the treatment injections until they can be retested. In this manner, the accuracy of doses and the safety and effectiveness of the injections are verified, and the possibility of adverse reactions from subsequent injections is minimized.

Some Fundamental Concepts in Testing:

Some physicians with minimal or no personal experience with the relief-dose or MITD method of testing seem to think that it is a “mathematical” symptom-based system in which symptoms are produced in every test by a concentration either stronger or weaker than the relieving concentration, and that no symptoms occur on relieving concentrations. This is far from the truth, and has led to major investigative errors. So let us correct these errors by taking a close look at overdose, relief-dose, and underdose wheals and their accompanying symptoms as they actually occur.

  1. Overdoses Produce Positive Wheals but may or may not Produce Symptoms:

Overdoses (concentrations stronger than the relieving concentration) do not always produce symptoms, but virtually always (98.8%) produce a characteristic positive wheal. This wheal is blanched, hard, raised, and disk-shaped i.e., with sharply demarcated cliff-like borders, like a disk). It is as though the underlying mediator-activated dermal capillaries with their attached mast cells have extruded fluid into the site of the intradermal injection, ballooning up the wheal to the point that the skin over the wheal has become stretched and blanched. Although there is a relatively large amount of allergenic material in the positive wheal, symptoms are not always expressed, or at least not in the ensuing 10 minutes. They may finally be expressed 10 to 30 minutes later, or even hours later after the patient has left the office.

  1. Relief Doses and Underdoses Produce Negative Wheals but may or may not Produce Symptoms:

When a positive (overdose) wheal is produced, consecutively weaker concentrations in the 1:5 series are then injected intradermally at 10-minute intervals. A concentration is soon reached which produces a negative wheal. This is the first (strongest) negative wheal concentration. All concentrations weaker than this (underdose concentrations) will also produce negative wheals.

The negative wheal is not blanched, hard, raised, or disk-like. Rather, it is relatively soft and flat, and may be either neutral-colored or erythematous, but not blanched. The borders are sloping and irregular in shape as though the injected material has been draining out of the wheel, absorbing into the underlying tissues, leaving the wheal somewhat shrunken and deflated, with frayed out, slightly wrinkled, uneven borders.

In addition, the positive overdose wheal will have usually (not always) grown 2 mm or more in average diameter in 20 minutes. By contrast, the negative wheal usually grows less than 2 mm in average diameter. The blanching, hardness, and discoid characteristics are the most reliable indicators of positivity, even more than the 2 mm growth of the wheal, and constitute the strongest indication of overdosage and the need to inject the next weaker concentration.

Common Errors in Symptom-Based Testing:

  1. The Erroneous Rejection of Relieving Doses if Accompanied by Symptoms:

As described, a positive overdose wheal does not always produce symptoms, and not always in the ensuing 10 minutes. When the strongest concentration which produces a negative wheal is then injected, the overdose symptoms often emerge within minutes after this negative-wheal injection. Therefore, the symptoms arise after the administration of the negative wheal relieving dose, and may not have cleared by the end of the ten minute observation period. Then the relieving dose may be rejected by the physician because of the emergence and persistence of symptoms, and a weaker dose (an underdose) prematurely chosen for that antigen. This leads to poor therapeutic response and a need for retesting, due to the erroneous conclusion by the physician and patient that the poor therapeutic response indicates a defect in the system.

  1. The Erroneous Acceptance of Underdoses as Treatment Doses:

The same error is made when symptoms arise after the injection of the strongest negative wheal dose, even when no positive wheal dose has been previously injected. The error consists in then injecting the next weaker concentration (an underdose), after which the symptoms often subside, possibly because of the increasing benefit of the previously injected strongest negative wheal dose. This results in erroneous acceptance of the underdose as the treatment dose, and also results in treatment with the underdose. This, too, leads to a poor response and a need for retesting.

One of the most common errors in this system of testing is the use of underdoses as treatment doses. This error can usually be avoided by simply repeating the strongest negative wheal dose one or more times to allow it to finally clear out the induced symptoms rather than prematurely going to weaker doses.

In 761 tests (1.5% of the 50,421 consecutive tests being reported on), test symptoms failed to clear on a single test injection of 0.05 ml of the strongest negative wheal concentration. A second injection of the identical concentration produced clearing in 576 (76% of the 761 tests). A third such identical injection was required in 138 (18%), a fourth in 40 (5%), and a fifth in 7 (1%). More than five identical doses were not required in this series.

If using repeated neutralizing doses does not clear the symptoms, or symptoms worsen while repeating the strongest negative wheal concentration, 0.01 ml of the second negative wheal concentration is then indicated. Usually symptoms will begin to improve on this test dose. If symptoms do begin to improve or at least do not worsen on 0.01 ml of the second negative wheal concentration, then 0.05 ml is utilized and will almost always provide final clearing of the symptoms. If symptoms worsen on the second negative wheal dose, a return to the first negative wheal dose will often provide relief, although it had not done so previously. NOTE: Regardless of how many repetitions of the symptom-relieving dose are required during testing, the immunotherapeutic dose need only be 0.05 ml.

  1. The Erroneous Acceptance of Overdoses as Treatment Doses:

Symptoms sometimes occur on a positive overdose wheal and then clear before the 10 minutes are up. A useful clinical concept is that the antigen or the wheal has become gradually more tightly “bound” so that no more antigen escapes from it, at least for the time, so the symptoms clear. Because of symptom clearance, overdoses may be used erroneously as relief doses when testing is based entirely on symptom-clearing.

Accepting overdoses as treatment doses often results in delayed absorption of the antigen from the un-neutralized bound wheal after the patient has finished that test or even after he has left the office (delayed overdose symptoms). Furthermore, overdoses do not stand up to the final test of accuracy in immunotherapy in that they fail to optimally protect the patient from exposures to that antigen, or even cause mild local reactions or symptoms after therapeutic injections. An adverse local or systemic reaction to a therapeutic injection virtually never occurs when the doses are correct, so their occurrence is almost always a signal that retesting is indicated.

This third error can be avoided, and the need for retesting reduced, by never accepting a positive wheal concentration as a relieving concentration, even if symptoms subside on that concentration.

So, during symptom-based testing, errors may arise because of three seemingly paradoxical responses:

(1) An overdose can be accompanied by no test symptoms or even by relief of test symptoms, yet will not be a suitable dose for immunotherapy;

(2) An under dose can be accompanied by relief of test symptoms, yet will not be a suitable dose for immunotherapy;

(3) A relieving dose can be accompanied for ten minutes or longer by newly-arisen test symptoms rather than by relief, yet will be the safe, effective dose for immunotherapy.

Under dose Symptoms Require Constant Vigilance but are Infrequent and are Usually not Reliably Repeatable:

An under dose concentration is defined as any concentration weaker than the relieving concentration. Surprisingly, an under dose concentration can at times cause “under dose symptoms” on intradermal administration, rarely if at all on subcutaneous administration. These under dose test symptoms sometimes occur more rapidly and more dramatically than the symptoms produced by overdose concentrations, and can be severe.

In under dose reactions, it is a useful clinical concept that the antigen has been absorbed into the circulation rapidly to impact target organs abruptly rather than being bound in the skin over a longer period of time and released slowly as in a positive overdose wheal. It is interesting that under dose symptoms occur predominantly on intradermal test injections rather than subcutaneous treatment injections. This suggests a role for intradermal Langerhans Cell activation, since these potent cells are present in the epidermis but not in subcutaneous tissues.

Overdose vs. Underdose Symptoms:

Opposing mechanisms of homeostatis (exemplified by sympathetic vs. parasympathetic actions, norepinephrine vs. acetylcholine, etc.) are suggested by some test reactions. Overdose symptoms are often different and opposite to under dose symptoms. Overdose symptoms are often slower in onset and may be accompanied by tenseness, irritability, flushing, warm skin, and “hot sweats”, resembling over-stimulation of neuromuscular as well as hemodynamic homeostatic mechanisms. On the other hand, under dose symptoms are often more rapid in onset and are more often accompanied by limpness, weakness, faintness, pallor, cool skin, and “cold sweats”, resembling inhibition or depression of these homeostatic mechanisms. The important clinical point is that, when under dose symptoms occur rapidly, the immediate intradermal injection of the strongest negative wheal dose usually relieves the under dose symptoms quickly.

Because of the rapid and dramatic onset of symptoms which have sometimes occurred from under doses, it is important for physicians to be constantly vigilant in awareness of this possibility. The purpose of this vigilance is to be ready to immediately administer stronger (rather than weaker) concentrations for quick relief whenever negative-wheal under dose symptoms should occur. Repeated reminders of this over the years were to counter the common error of always going weaker when symptoms occur. It is important to head for the positive wheal landmark, which guides us to the next weaker concentration, the strongest negative wheal concentration, which almost invariably provides relief.

To summarize, symptoms can arise of subside on overdoses, relief doses, and under doses. Symptom changes alone are simply not reliable guides to the selection of treatment doses, much less to double-blind studies.

Errors in Double-Blind Studies Using Symptom-Based Testing:

Somehow the message concerning constant underdose vigilance became interpreted erroneously by some non-users, and possibly even by some users of this system. Jewett(11) developed the notion, possibly from his own test experiences, that every underdose must produce such symptoms reliably and repeatedly. This is far from the truth.

It was this false assumption that led Jewett, a professor of orthopedics with no background in either allergy management or the relief-dose allergy system, to devise a flawed protocol and perform a predictably “negative” double-blind study. His simplistic theory was that the whole test system was based on the assumption that every under dose produces symptoms, and that the failure of under doses to always produce symptoms reliably and repeatedly was proof that the entire testing and treatment system was invalid.

The fact is that under dose symptoms are uncommon; they only occurred in 2.88% of all tests in which symptoms occurred in the 50,421 consecutive tests analyzed in my office. And when it does occur, retesting the same extract in the same patient usually results in failure of under dose symptoms to recur on the second test. It is not reliably repeatable, so it cannot be a valid basis for a double-blind study. The scientific world does not know this because it has no hands-on experience with the system, and hailed Jewett’s persuasively written paper of a fallacious study as definitive proof of the ineffectiveness of the entire system.


When the body’s dosage needs change during the course of therapy, retesting determines the new dosage needs and restores response immediately. This is particularly true if the initial relief doses are weak. The need for retesting may occur early if some of the doses were erroneous initially due to symptom-based testing. So retesting when indicated is an important part of maintaining optimum response. However, testing by current concepts described in this paper has markedly reduced the need for retesting.

Convincing the Patient During Testing vs. During Treatment:

Some physicians will undoubtedly still prefer to test by trying to produce and relieve test symptoms rather than utilizing the primarily wheal-based system described. When it occurs, the production and rapid relief of symptoms is very convincing to the patient and to the physician. However, dependence on symptom production for diagnosis of food (or inhalant) allergy misses the majority of real clinically important allergens, since many will produce symptoms on ingestion (or inhalation) but not on skin testing. I prefer to provide more appropriate coverage and to eliminate or minimize test symptoms, and let patients be impressed by the rapid, marked relief they obtain within days or weeks after starting immunotherapy.

Test Symptoms Must be Relieved:

It must be emphasized that whealing is not the only factor involved. When symptoms occur, they must be relieved, even if the relieving concentration is the second negative wheal concentration, or even the third.

If a symptom-relieving concentration cannot be found, symptoms can be relieved by one or more small doses of Sus-Phrine, e.g. 0.03 to 0.05 ml. Sus-Phrine is a preservative-free quick-acting long-lasting aqueous solution and suspension of epinephrine. This can be supplemented if needed by other medications such as a steroid, e.g. prednisone 30 mg. in the office and possibly again in the evening if indicated. (Neither epinephrine nor steroids interfere with testing or wheal responses.) They physician’s judgement and the nature of the symptoms must determine such procedures.


Relief dose testing can be made much more accurate and efficient, and the need for retesting much diminished, by first seeking the strongest negative wheal concentration (SNWC). By testing only with 0.01 ml volumes until the SNWC is determined, and then verifying with 0.05 ml, much test symptomatology can be eliminated. Use of 0.05 ml of the SNWC will relieve induced test symptoms in 98.8% of tests in which symptoms are induced. Essentially, all of the remaining symptom-associated tests (1.2%) will produce relief on the second negative wheal concentration. When a single dose of the SNWC fails to relieve, one or more repetitions of this dose (as long as symptoms are not worsening), will often provide relief and prevent the error of prematurely changing to underdose concentrations. This can markedly diminish the incidence of underdose symptoms. Overdose reactions also can be markedly reduced by avoiding the use of Concentration #1.

When relief occurs on the strongest negative wheal dose, any dose stronger than this will produce a positive wheal, a symptom, or both–so it is the strongest intradermally tolerated dose. When symptoms persist on this dose, it is not a tolerated dose; then the next weaker dose will almost invariably provide relief, thus becoming the maximum intradermally tolerated dose (the strongest dose that does not produce a positive wheal or a symptom). Summing up, in essentially 100% of tests, this procedure can thus be described and defined as the Maximum Intradermally Tolerated Dose Method.


  1. Miller JB: Food Allergy: Provocative Testing and Injection Therapy. Springfield: Charles C Thomas, Publisher, 1972.
  2. Miller JB: Relief At Last! Neutralization for Food Allergy and Other Illnesses. Springfield: Charles C Thomas, Publisher, 1987.
  3. Miller JB: Intradermal provocative-neutralizing food testing and subcutaneous food extract injection therapy, in Food Allergy and Intolerance, Brostoff J and Challacombe SJ (Ed.). London: Bailliere Tindal, 1987, pp 932-946.
  4. Miller JB: A double-blind study of food extract injection therapy: A preliminary report. Annals of Allergy, Vol. 38, No. 3, March 1977, pp 185-191.
  5. Miller JB: Hidden food ingredients, chemical food additives, and incomplete food labels. Annals of Allergy, Vol. 41, No. 2, August, 1978, pp 93-98.
  6. Miller JB, Lee C, Binkley EL, and Hardt S: Relief of Influenza symptoms by the provocative-neutralizing method–A preliminary report. Journal of the Medical Association of the State of Alabama, Vol. 41, No. 7, January, 1972, pp 493-502.
  7. Miller JB: Influenza: Rapid relief without drugs. Clinical Medicine, Vol. 81, No. 9, September, 1974, pp 16-19.
  8. Miller JB: Treatment of active herpes virus infections with influenza virus vaccine. Annals of Allergy, Vol. 42, No. 5, May, 1979, pp 295-305.
  9. Miller JB: Rapid relief of varicella and infectious mononucleosis through immunotherapy. Annals of Allergy, Vol. 47, No. 5, 1981, pp 135-136.
  10. Miller JB: Relief of premenstrual symptoms, dysmenorrhea, and contraceptive tablet intolerance. The Journal of the Medical Association of the State of Alabama, Vol. 44, No. 2, August, 1974, pp 57-60.
  11. Jewett DL, Fein G, Greenberg M: A double blind study of symptom provocation to determine food sensitivity. NEJM, Vol. 323, NO. 7, August 16, 1990, pp 429-33.

The Case for Neutralizing (Optimal Dose) Immunotherapy

by Joseph B. Miller, M.D.

(“The Environmental Physician“, Fall 1991)

The neutralizing (optimal dose) method of intradermal skin testing and subcutaneous immunotherapy represents a major technological advance. It constitutes the safest, most effective, and most rapidly beneficial method of allergy skin testing and immunotherapy available today.

Each subcutaneous immunotherapeutic injection usually provides rapid relief of allergy symptoms, often in 30 minutes. The unusual rapidity, effectiveness, and safety of this response is based on the fact that the absolute precise best dose of each individual allergen is included in the treatment solution.

The Rapid-Relief Response

Bookman(1) has described what experienced allergists have always known. He reported that an occasional patient on build-up inhalant injection therapy would note marked improvement within 30 minutes to two hours after an injection of a given submaximal dose of an inhalant allergy extract. Usually the relief would continue for nearly a week. This near-universal clinical observation has been recently confirmed by a carefully controlled study at Johns Hopkins which reported favorable response to ragweed extract long before the maximum tolerated dose was reached.(2)

Allergists have long been puzzled by this rapid-relief phenomenon. Relief was not supposed to occur after any one injection.

Until recently, we had no technique for deliberately reproducing this rapid-relief effect. Now, by optimal-dose testing and treatment, we can reproduce this rapid-relief effect for all of the allergens in the treatment solution with a high degree of reliability.

How is the Rapid-Relief Response Achieved?

Optimal-dose testing involves administering intradermal test injections, one at a time, of 0.01 ml of consecutively stronger or weaker concentrations of an allergy extract in a 1:5 dilution series every 7-10 minutes. The first goal of testing is to determine the strongest concentration which produces a negative wheel. The second goal is to determine the strongest negative-wheal concentration that relieves any symptoms induced by preceding test doses. The two concentrations are usually the same, i.e. the strongest negative wheal concentration is almost always the concentration that relieves test-symptoms, if such symptoms occur.

The optimal dose (treatment dose) is 0.05 ml of this concentration. This has provided protection and relief in 99.7% of tests in my patients. My books and other publications detail the technique and many of its applications.(3-24)

The Maximum Tolerated Intradermal Concentration is the Optimal or Rapid-Relief Concentration and is Both Effective and Safe

The optimal intradermal test dose produces a negative wheal (no local reaction) and relieves (not causes) any symptoms that may have been induced by preceding test doses (no systemic reactions). Therefore, it is properly termed the “maximum tolerated intradermal concentration”. This terminology is to distinguish it from the conventionally employed maximum tolerated subcutaneously administered dose, which can cause both local and systemic reactions.

The maximum tolerated intradermal concentration is truly the maximum tolerated. The next stronger concentration would invariably produce a positive wheal (local reaction) or symptoms (systemic reaction), or both. The absence of both local and systemic reactions, and the marked effectiveness in protecting from and relieving symptoms induced by subsequent natural exposure to the antigen, make this a uniquely safe and effective procedure.

This safety allows the patient to self-administer his injections for protection on a regular schedule. He can also self-administer additional (“booster”) injections for quick relief whenever he encounters a sufficient natural exposure to an allergen to breach the protection of his regularly scheduled injections. Furthermore, the same system of testing and treatment are equally applicable to foods as well as inhalants, and also to many other substances (hormones, viruses, contactants, chemicals, etc.).

The Imprecision of Orthodox Allergy Procedures

Orthodox allergy skin testing provides no information concerning the precise dosage needed for each individual allergen. Therefore, orthodox allergy treatment solutions usually contain equal amounts of all allergens, regardless of the fact that the patient may be much more sensitive to some allergens than to others.

Subcutaneous injections of this solution in increasing dosage usually are administered until a large local or significant systemic reaction occurs. This is usually followed by a reduction in dosage.

This reduction is usually temporary in order to keep the dosage maximally strong, and yet (hopefully) not cause major local or systemic side effects. In practice, however, major local and/or systemic side effects do occur at times, sometimes including urticaria, laryngeal edema, acute severe asthma attacks, or anaphylaxis.

These reactions to orthodox build-up therapy occur chiefly because patients are not usually equally allergic to all their allergens. Their adverse reaction is to the one or more allergens in the solution to which they are most sensitive.

Subcutaneous optimal-dose treatment injections simply do not cause these severe reactions because they contain the “just right” dose of each individual allergen. With optimal-dose immunotherapy, each allergen dose is analogous to Goldilocks’ bowl of porridge. It is not too strong and not too weak, but “just right”. Therefore, no build-up of dosage is required. The first dose is the maintenance dose.

The Rapidity of the Optimal-Dose Response

Some patients report relief while still undergoing testing. Thirty percent of patients report relief after the first post-testing treatment injection. Ninety-five percent have reported marked relief by the tenth injection (3 or 4 weeks). If “rush” immunotherapy is desired for rapid relief, several injections can be administered safely each day without the dangers of the urticaria, laryngeal edema, acute asthma, or anaphylaxis often encountered in orthodox rush immunotherapy.(25,26)

After this initial relief has been established, each optimal-dose injection will usually provide relief of symptoms induced by natural exposure to any or all of these allergens. This relief usually occurs within 30 minutes to two hours. Furthermore, in contrast to orthodox build-up injections, optimal-dose injections provide protection from and relief o the patient’s actual symptoms, not a hoped for but seldom achieved beneficial change in igG and igE levels which may have no relationship to patient benefit.

The Objectivity of the Optimal-Dose Test

Each relief dose is precisely determined by objective parameters, namely measurement to determine if the wheal has grown 2mm or more in 10 minutes, plusinspection and palpation of the wheal to determine the presence or absence of blanched, hard, raised, and discoid characteristics. (A discoid wheal is “ballooned up” and has a sharply demarcated border like a disc, rather than being frayed out around the edges, “deflated”, and absorbing into the surrounding skin.)

A positive wheal typically grows at least 2mm in 10 minutes and is blanched, hard, raised, and discoid. If test doses induce no symptoms, the optimal dose is 0.05 ml of the strongest concentration which does not produce a positive wheal. If test symptoms occur, the optimal dose is 0.05 ml of the strongest concentration which does not produce a positive wheal and which also relieves the induced symptoms.

In a recent study of 24,556 consecutive intradermal optimal-dose tests for inhalants and foods performed over a period of two years in my office, the first (strongest) negative wheal concentration was the treatment concentration in 99.7% of tests. In 0.27%, the second negative wheal concentration was the treatment concentration, and in 0.02%, the third. No tests in this series required any weaker concentrations than this.

The Dangers of Orthodox Immunotherapy

Optimal-dose immunotherapy conveys none of the three main dangers involved in conventional immunotherapy. These consist of starting injection therapy with a too-strong starting dose of one or more antigens in the treatment solution; building immunotherapy dosage to a gross overdose and causing a reaction along the way; or maintaining very strong doses in a brittle or asthmatic patient whose health and strength are not necessarily at the same level with every injection and who may suffer a severe reaction to a dosage which has been tolerated in the past.

The Slow Response to Orthodox Immunotherapy

Textbooks of orthodox immunotherapy suggest that the allergist warn the patient in advance that he may not notice improvement for a year or two. Furthermore, if he has not noted slight improvement after two or three years, a discussion of whether or not to continue therapy may be considered.

This contrasts with the marked and almost invariable improvement that occurs within one to three weeks with optimal-dose immunotherapy. Furthermore, this same testing technology and the same safety and benefits of treatment occur with foods and many other antigens as well as inhalants, thus greatly increasing the number of patients that can be helped by clinical allergy procedures.

Both Orthodox and Optimal-Dose Procedures
are Based on Clinical Experience

It is paradoxical that orthodox allergists attack optimal-dose procedures because they were derived from clinical experience rather than research. The fact is that orthodox procedures are also based on opinions derived from clinical experience, not research. Here are three quotations from the “bible” of conventional methodology.(27) The underlined and parenthetical material is mine.

  1. “…the scientific data now available simply do not provide information sufficient for physicians to make totally objective decisions. There are answers based on the approaches that have evolved through long and extensive clinical experience. In spite of the lack of directed clinical research, this experience provides background for decisions about many details. These questions and answers present one viewpoint, with the full recognition that these opinions are not derived from research in many cases but rather from experience.”
  2. Physicians “customarily include equal concentrations of each antigen (in the treatment solution) once a decision has been made to include that particular antigen in the treatment schedule.”
  3. “If immunotherapy that is being given (in addition to environmental control and medication compliance) does not seem to be effective after a period of two to three years, then serious consideration should be given to its continuation.”


The Body Requires a Specific Optimal Treatment Dose for Each Individual

Antigen, and Changes its Needs from Time to Time

The fact is that one allergen may require a relatively strong dose, another a relatively weak dose. Other allergens may require doses of various intermediate strengths.

The body’s dosage needs for individual allergens may vary over time. Whenever the body’s dosage needs change, the new dosage needs can be determined quickly and precisely by retesting. Retesting restores optimal response immediately.

Thus, each optimal-dose injection contains the just-right dose for each allergen in each patient’s treatment solution for the state of his immune mechanism at a given time. In summary, the optimal-dose system provides a safe, effective, rapidly beneficial, precise, objectively-determined, patient-specific, allergen-specific and time-specific treatment.

Optimal-Dose Immunotherapy Saves Time and Money

An additional benefit of optimal-dose immunotherapy is the tremendous saving of time and money. Each orthodox build-up injection requires a visit to a physician’s office for safety. It is recommended that these injections be given only in office with resuscitative equipment.

Furthermore, in Britain, the post-injection waiting period in the office has recently been required by decree of the Committee on Safety in Medicine (equivalent to our FDA) to be increased from the old standard of twenty minutes to a new standard of two hours. This has virtually eliminated the use of orthodoximmunotherapy in Britain.

However, the use of optimal-dose immunotherapy has not been affected by this ruling, as the injections are eminently safe and can be self-administered by the patient in his own home. This is much more practical and economical, since it does not require the time loss and inconvenience of having to go to an appropriate physician’s office or hospital for each injection.

In addition many patients are seeing one or more other specialists (e.g. neurologists for migraine, gastroenterologists for diarrhea, etc.), taking multiple medications, and undergoing repeated diagnostic workups or hospitalizations. These can be very expensive, and can usually be markedly decreased or eliminated by optimal-dose therapy.

Optimal-Dose Immunotherapy is the True Gold Standard

The gold standard of orthodox allergists for food testing is the prick test followed by double-blind placebo-controlled challenges with opaque capsules containing powdered food antigens. Actually, prick tests for foods are very unreliable, and an opaque capsule challenge usually provides too small a dose to be an adequate stimulus to evoke an allergic response. Furthermore, capsules cannot be swallowed by small children.

Symptom induction by oral challenge usually requires four days of avoidance followed by at least two or more large closely-spaced feedings. Sometimes several feedings each day for several days or even for 1-2 weeks are required to induce symptoms. But even if orthodox procedures were reliable for diagnosis, they would still offer no information as to the precise treatment dose for each antigen, as does optimal-dose testing.

A New Approach is Required

Continued re-examination of limited old concepts, such as prick tests, opaque capsule challenges and orthodox rush procedures is analogous to earlier attempts to breed stronger horses and build better buggies. Applying the principles of the internal combustion engine to transportation was not initiated by horse-breeders or buggy-builders. It took a different mindset, beginning with a determination to find a better solution to the problem, even if novel, rather than an attempt to improve a technology which is well-established but limited. Hopefully, we can all open our minds to new approaches and move into the 21st century a stronger and more effective medical specialty.

Why is Change so Urgently Needed?

The 40 million patients with inhalant sensitivities can be provided far greater, safer, and quicker relief by optimal-dose immunotherapy rather than by orthodox immunotherapy. In addition, optimal-dose immunotherapy for foods can provide relief for most of the 24 million patients with migraine, the 18 million patients with gastrointestinal allergies (abdominal pain, diarrhea, “irritable bowel syndrome”, chronic ulcerative colitis, and Crohn’s disease), the 15 million children (and uncounted adults) with attention deficit hyperactivity and hypoactivity disorder, the 15 million patients with atopic dermatitis, and the 15 million people with chronic urticaria (total: 127 million).

Also, optimal-dose immunotherapy with influenza virus vaccine can provide the same 30-minute relief response for untold millions of patients with acute influenza. It is highly effective for the millions of patients with infections caused by members of the herpes virus family (herpes simplex I and II, herpes zoster, infectious mononucleosis, varicella).

Optimal-dose treatment with progesterone for premenstrual syndrome, dysmenorrhea, and hyperemesis gravidarum can provide the same rapid relief response in the many millions of women with these conditions.

Optimal-dose immunotherapy with oak/ivy extract can provide the same rapid relief response for millions of people suffering from oak/ivy dermatitis. Optimal-dose immunotherapy with extracts of Candida albicans can provide much relief to the millions of women with resistant vaginal candidiasis.

Additional uses of this exciting procedure are being studied. Investigation into the applicability of other extracts, vaccines, hormones, contactants, etc. is sorely needed. This is an expanding field with many additional potential applications. Decades may pass before sufficient i’s are dotted and t’s are crossed to satisfy all the no-sayers.

As physicians, we cannot in good conscience continue to withhold this valuable treatment. Patients with known responsive syndromes should not be made to suffer needlessly on when relief is safe, effective, quick, and available.

This is Only the Beginning

The discovery and development of the optimal-dose system seems to me to be in the same echelon of importance as the discovery of anesthetic agents, antibiotics, corticosteroids, and ground-breaking surgical procedures such as open-heart, endoscopic, and laser surgery. It is not just a superb method of treating food allergy (which it is), but a comprehensive system for re-balancing faulty, ongoing imbalanced immunologic mechanisms for a great many specific allergens and other incitants.

This does not make it a panacea any more than did the landmark discovery of the agents and procedures just listed. Each of these discoveries has started simple, just as did food neutralization. Each then developed into a major system of managing many medical problems. An example is the growth of the antibiotic concept from the first antibiotic to the many now available. The same is true of anesthetic agents, uses of steroid hormones, expanding surgical procedures, etc.

Furthermore, optimal-dose therapy is specific to the incitant being treated, which is the opposite of a panacea. The great breadth of applications is based only on the great breadth of ills caused by specific immunologic dysfunctions.

For the first time, we have a system for safely controlling immune dysfunction. We have barely begun. It will be fascinating to see the many new applications not yet dreamed of that the future will bring. It would be a shame if this great potential were to be suppressed by individuals and agencies who simply are not knowledgeable about its usage and its vast implications for the relief of the human condition.



  1. Bookman R: Observations and reflections of a practicing allergist. Annals of Allergy 45:4, pp 264-266, 1980.
  2. Hedlin G, Silber G, Naclerio R, Proud D, Eggleston P, Adkinson NF Jr: Attenuation of allergen sensitivity early in the course of ragweed immunotherapy. J Allergy Clin Immunol, September 1989, pp 390-399.
  3. Miller JB: Intradermal provocative-neutralizing food testing and subcutaneous food extract injection therapy, in Food Allergy and Intolerance, Brostoff J and Challacombe SJ (Ed.). London: Bailliere Tindall, 1987, pp 932-946.
  4. Miller JB: Food Allergy: Provocative Testing and Injection Therapy, Charles C Thomas, 1972.
  5. Miller JB: Relief at Last! Neutralization for Food Allergy and Other Illnesses, Charles C Thomas, 1987.
  6. Miller JB, Lee C, Binkley EL, and Hardt SH: Relief of influenza symptoms by the provocative-neutralizing method–A preliminary report, Journal of the Medical Association of the State of Alabama, Vol. 41, No. 7, January, 1972, pp 493-502.
  7. Miller JB: Relief of premenstrual symptoms, dysmenorrhea, and contraceptive tablet intolerance, The Journal of the Medical Association of the State of Alabama, Vol. 44, No. 2, August, 1974, pp 57-60.
  8. Miller JB: Influenza: Rapid relief without drugs, Clinical Medicine, Vol. 81, No. 9, September, 1974, pp 16-19.
  9. Miller JB: Influenza neutralization, Transactions of the American Society of Ophthalmologic and Otolaryngologic Allergy, Vol. 14, No. 1, October, 1974, pp 159-168.
  10. Miller JB: Management of migraine headaches, in Current Therapy of Allergy, Frazier CA (Ed.) New York: Medical Examination Publishing Company, Inc., 1974, pp 224-225.
  11. Miller JB: Food allergy: Technique of intradermal testing and subcutaneous injection therapy, Transactions of the American Society of Ophthalmologic and Otolaryngologic Allergy, Vol. 16, No. 1, October, 1976, pp 154-168.
  12. Miller JB: Virus and hormone neutralization, in Clinical Ecology, Dickey LD, (Ed.), Springfield: Charles C Thomas, Publisher, 1976, pp 597-605.
  13. Miller JB: A double-blind study of food extract injection therapy: A preliminary report, Annals of Allergy, Vol. 38 No. 3, March, 1977, pp 185-191.
  14. Miller JB: Management of migraine headaches, in Current Therapy of Allergy, Frazier CA (Ed.), New York: Medical Examination Publishing Company, Inc., 1978, pp 307-320.
  15. Miller JB: Optimal dose method of food allergy management, The Journal of Continuing Education in O.R.L. and Allergy, Vol. 40, No. 5, May 1978, pp 37-50.
  16. Miller JB: Hidden food ingredients, chemical food additives, and incomplete food labels, Annals of Allergy, Vol. 41, No. 2, August, 1978, pp 93-98.
  17. Miller JB: Immunotherapy of virus infections, Transactions of the American Society of Ophthalmologic and Otolaryngologic Allergy, Vol. 18, N. 1, September, 1978, pp 144-148.
  18. Miller JB: Treatment of active herpes virus infections with influenza virus vaccine, Annals of Allergy, Vol. 42, No. 5, May, 1979, pp 295-305.
  19. Miller JB: Management of food allergy, in Food Allergy: New Perspectives, Gerrard JW (Ed.), Charles C Thomas, Inc., September, 1980.
  20. Miller JB: The optimal-dose method of food allergy management, in Otolaryngologic Allergy, King HC (Ed.), Symposia Specialists, Inc., 1981, pp 253-283.
  21. Miller JB: Rapid relief of varicella and infectious mononucleosis through immunotherapy, Annals of Allergy, Vol. 47, No. 5, 1981, pp 135-136.
  22. Miller JB: Neutralization therapy update, in Allergy–Immunologic and Management Considerations, Spencer JT (Ed.), MEDED Publishers, Inc., 1982.
  23. Miller JB: Herpes: Rapid relief with influenza virus vaccine, The Journal of the Alabama Dental Association, Vol. 68, No. 3, Summer, 1984.
  24. Miller JB: Mini-dose therapy may relieve progesterone intolerance, Clinical Ecology, Vol. 2, No. 4, Fall, 1984, pp 224-226.
  25. Armentia-Medina A, Blanco-Quiros A, Martin-Santos JM, Alvarex-cuesta E, Moneo-Goiri I, Carreira P, Losada-Cosmes E: Rush immunotherapy with a standardized Bermuda grass pollen extract. Annals of Allergy, Volume 63: August 1989, pp 127-135.
  26. Horst M, Hejjaoui A, Horst V, Michel FB, Bousquet J: Double-blind, placebo-controlled rush immunotherapy with a standardized Alternaria extract. J Allergy Clin Immunol, February 1990, pp 460-472.
  27. Patterson R, Lieberman P, Irons JS, Pruzansky JJ, Metzger WJ, Zeiss CF: Immunotherapy, Allergy Principles and Practice, Middleton E Jr, Reed CE, Ellis EF, Second Edition, CV Mosby Co., 1983, p. 1131.