Generic Name: Leucovorin

Jan 20, 2020  Kirkman – TMG 500 mg with Folinic Acid & Methyl B-12 -Hypoallergenic – On January 20, 2020 By Falsegrip In ExerciseWellness Many clinicians are now utilizing higher doses of Trimethylglycine (TMG). Development issues alone than I recommend starting with DMG, along with a multi-vitamin that has folic acid (preferably Folinic Acid or L-Methyl-Folate) in it. New Beginnings Nutritionals – www.nbnus.com carries a wide variety of supplements that support Methylation. DMG generally comes in 125mg doses.

VA CLASSIFICATION
Primary: VT120
Secondary: AD900; BL400; AN400
Commonly used brand name(s): Wellcovorin.
Other commonly used names are
citrovorum factor and folinic acid .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antidote (to folic acid antagonists)—
antianemic—
antineoplastic adjunct—
Indications
Accepted
Methotrexate toxicity (prophylaxis and treatment)
Pyrimethamine toxicity (prophylaxis and treatment) or
Trimethoprim toxicity (prophylaxis and treatment)—Leucovorin is indicated as an antidote to the toxic effects of folic acid antagonists such as methotrexate, pyrimethamine, or trimethoprim. Leucovorin also is indicated as a rescue after high-dose methotrexate therapy in osteosarcoma and as a part of chemotherapeutic treatment programs in the management of several forms of cancer.
Anemia, megaloblastic (treatment)—Leucovorin is indicated to treat megaloblastic anemias associated with sprue, nutritional deficiency, pregnancy, and infancy when oral folic acid therapy is not feasible.
—Leucovorin is not recommended for use in the treatment of pernicious anemia or other megaloblastic anemias secondary to lack of vitamin B ₁₂, since it may produce a hematologic remission while neurologic manifestations continue to progress.
Carcinoma, colorectal (treatment adjunct)—Leucovorin is indicated for use in combination with fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer^{01}.
[Carcinoma, head and neck (treatment adjunct)]¹—Leucovorin is indicated for use in combination with agents such as fluorouracil or high-dose methotrexate, as second-line treatment of squamous cell head and neck carcinoma.^{08}
[Ewing's sarcoma (treatment adjunct) or ]¹
[Lymphomas, non-Hodgkin's (treatment adjunct)]¹—Leucovorin is indicated for use in combination with high-dose methotrexate as second-line treatment of Ewing's sarcoma and non-Hodgkin's lymphomas.^{08}
[Tumors, trophoblastic (treatment adjunct)]¹—Leucovorin is indicated for use in combination with high-dose methotrexate as first-line treatment of gestational trophoblastic neoplasms.^{08}
Unaccepted
Leucovorin has not shown benefit over other regimens in the treatment of breast carcinomas.^{08}
Leucovorin has not shown benefit in the treatment of gastric carcinomas.^{08}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
511.51 ^{07}
Mechanism of action/Effect:
Antidote (to folic acid antagonists)—Leucovorin is a reduced form of folic acid, which is readily converted to other reduced folic acid derivatives (e.g., tetrahydrofolate). Because it does not require reduction by dihydrofolate reductase as does folic acid, leucovorin is not affected by blockage of this enzyme by folic acid antagonists (dihydrofolate reductase inhibitors). This allows purine and thymidine synthesis, and thus DNA, RNA, and protein synthesis, to occur. Leucovorin may limit methotrexate action on normal cells by competing with methotrexate for the same transport processes into the cell. Leucovorin given at the appropriate time rescues bone marrow and gastrointestinal cells from methotrexate but has no apparent effect on pre-existing methotrexate nephrotoxicity.
Absorption:
Rapidly absorbed after oral administration; saturation of absorption is reached at doses greater than 25 mg. Bioavailability is approximately 97% for a 25-mg dose, 75% for a 50-mg dose, and 37% for a 100-mg dose ^{01}{02}.
Distribution:
Crosses blood-brain barrier in moderate amounts; largely concentrated in liver.
Biotransformation:
Hepatic and intestinal mucosal, mainly to 5-methyltetrahydrofolate (active). After oral administration, leucovorin is substantially (greater than 90%) and rapidly (within 30 minutes) metabolized. Metabolism is less extensive (about 66% ^{06} after intravenous and 72% after intramuscular administration) and slower with parenteral administration.
Half-life:
Terminal half-life for total reduced folates—6.2 hours ^{01}.
Onset of action:
Oral—20 to 30 minutes.
Intramuscular—10 to 20 minutes.
Intravenous—Less than 5 minutes.
Time to peak serum reduced folate concentration
Oral—1.72 ± 0.8 hours.
Intramuscular—0.71 ± 0.09 hour.
Peak serum reduced folate concentration
After 15 mg dose:
Oral: 268 ± 18 nanograms per mL (approximately 1 micromolar [1 × 10 ^-6 Molar]).
Intramuscular: 241 ± 17 nanograms per mL (approximately 1 micromolar [1 × 10 ^-6 Molar]).
Duration of action:
All routes—3 to 6 hours.
Elimination:
Renal—80 to 90%.
Fecal—5 to 8%.
Precautions to Consider
Pregnancy/Reproduction
Pregnancy—
Studies have not been done in either animals or humans.
FDA Pregnancy Category C.
Recommended for treatment of megaloblastic anemia caused by pregnancy.
Breast-feeding
It is not known whether leucovorin is distributed into breast milk. However, problems in humans have not been documented.
Pediatrics
Leucovorin may increase the frequency of seizures in susceptible pediatric patients by counteracting the anticonvulsant effects of barbiturates, hydantoin anticonvulsants, and primidone ^{01}.
Geriatrics
No information is available on the relationship of age to the effects of leucovorin in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require adjustment of dosage in patients receiving leucovorin as a rescue from the effects of high-dose methotrexate.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Anticonvulsants, barbiturate or
Anticonvulsants, hydantoin or
Primidone (large doses of leucovorin may counteract the anticonvulsant effects of these medications)
Fluorouracil (concurrent use of leucovorin may increase the therapeutic and toxic effects of fluorouracil ^{01}{03}; although the two medications may be used together for therapeutic advantage, caution is necessary ^{01})
Sulfamethoxazole and trimethoprim (concurrent use of leucovorin may be associated with increased morbidity rates and treatment failure when used for the treatment of pneumonia due to

Dmg With Folinic Acid Side Effects

Pneumocystis carinii in patients with human immunodeficiency virus (HIV) infection ^{01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
For treatment of anemia (as the sole agent):
» Pernicious anemia or
» Vitamin B ₁₂ deficiency (may produce a partial hematologic response ^{06} while neurologic manifestations continue to progress)
This medication should be used with caution when the following medical problems exist
Sensitivity to leucovorin
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
For patients receiving high-dose methotrexate
» Creatinine clearance determinations (recommended prior to initiation of high-dose methotrexate with leucovorin rescue therapy or if serum creatinine concentrations increase by 50% or more)
» Creatinine concentrations, serum (recommended prior to and every 24 hours after each methotrexate dose, until plasma or serum methotrexate concentrations are less than 5 × 10 ^-8 Molar, to detect developing renal function impairment and predict methotrexate toxicity. An increase of greater than 50% over the pretreatment concentration at 24 hours is associated with severe renal toxicity)
» Methotrexate concentrations, plasma or serum (recommended by some clinicians every 12 to 24 hours after high-dose methotrexate administration to determine dose and duration of leucovorin treatment needed to maintain rescue. May aid in identifying patients with delayed methotrexate clearance; toxicity appears to be related at least as much to the length of time that methotrexate concentrations are elevated as to the peak concentrations achieved. In general, monitoring should continue until concentrations are less than 5 × 10 ^-8 Molar)
» pH determinations, urine (recommended prior to each dose of high-dose methotrexate therapy and about every 6 hours throughout leucovorin rescue, until plasma or serum methotrexate concentrations are less than 5 × 10 ^-8 Molar, to ensure that pH remains greater than 7 so as to minimize the risk of methotrexate nephropathy from precipitation of methotrexate or metabolites in urine)
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence rare
Allergic reaction (skin rash, hives, or itching; wheezing)
seizures—reported with use in cancer chemotherapy^{04}
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Leucovorin (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to leucovorin
Use in children—May increase frequency of seizures in susceptible pediatric patients
Other medical problems, especially pernicious anemia or vitamin B ₁₂ deficiency (for treatment of anemia as the sole agent)
Proper use of this medication
» Importance of taking as directed and not missing doses; taking at evenly spaced times
» Checking with physician before discontinuing medication or if vomiting occurs shortly after dose is taken
» Proper dosing
Missed dose: Checking with physician right away; possible need for additional leucovorin; importance of not increasing dose unless directed by physician
» Proper storage
Side/adverse effects
Signs of potential side effects, especially allergic reaction and seizures
General Dosing Information
A 15-mg dose produces a serum reduced folate concentration of approximately 1 micromolar (1 × 10 ^-6 Molar).
For use as an antidote to folic acid antagonists
Patients receiving leucovorin as a “rescue” from the toxic effects of methotrexate should be under supervision of a physician experienced in high-dose methotrexate therapy.
Leucovorin should be administered orally or parenterally. Leucovorin should not be administered intrathecally for the treatment of accidental overdoses of intrathecally administered folic acid antagonists. Leucovorin may be harmful or fatal if administered intrathecally. ^{01}
Parenteral administration of leucovorin is recommended if it appears that absorption may be impaired as a result of nausea and vomiting.
High-dose methotrexate administration should not be initiated unless leucovorin is physically present and ready to be administered ^{06}, since rescue is critical.
A variety of dosage schedules of leucovorin in combination with high-dose methotrexate have been used. Since this regimen is still largely investigational, the prescriber should consult the medical literature in choosing a specific dosage. Alkalinization of urine (with bicarbonate and/or acetazolamide) and intravenous hydration (1000 mL per square meter of body surface area over six hours prior to beginning the methotrexate infusion and 3000 mL per square meter of body surface area per day during the methotrexate infusion and for two days after the infusion is completed) are also important to prevent renal toxicity caused by methotrexate and/or its metabolites.
Administration of leucovorin should be consecutive to rather than simultaneous with methotrexate administration so as not to interfere with methotrexate's antineoplastic effects. However, leucovorin has been administered simultaneously with pyrimethamine and trimethoprim in oral or intramuscular doses ranging from 400 mcg (0.4 mg) to 5 mg to prevent megaloblastic anemia due to high doses of these medications.
In general, it is recommended that the first dose of leucovorin be administered within the first 24 to 42 hours of starting a high-dose methotrexate infusion (within 1 hour of an overdose), in a dosage to produce blood concentrations equal to or greater than methotrexate blood concentrations (leucovorin in a dose of 15 mg produces peak plasma concentrations of approximately 1 micromolar [1 × 10 ^-6 Molar]). Duration of leucovorin administration varies with the dosage of methotrexate and plasma concentrations achieved (including rate of elimination); in general, leucovorin administration is continued until methotrexate concentrations fall to less than 5 × 10 ^-8 Molar.
A larger dose and/or longer duration of leucovorin treatment may be required in patients with aciduria, ascites, dehydration, gastrointestinal obstruction, renal function impairment, or pleural or peritoneal effusions because excretion of methotrexate is slowed and the length of time for plasma methotrexate concentrations to decrease to nontoxic levels (<5 × 10 ^-8 Molar) is increased. It is recommended that duration of leucovorin administration in these patients be based on determination of plasma methotrexate concentrations.
For use as an adjunct to fluorouracil for colorectal carcinoma
Patients receiving leucovorin in combination with fluorouracil should be under supervision of a physician experienced in cancer chemotherapy ^{01}.
Oral Dosage Forms
Note: The dosing and strengths of the dosage forms available are expressed in terms of leucovorin base (not the calcium salt).
LEUCOVORIN CALCIUM TABLETS USP
Usual adult and adolescent dose
Antidote (to folic acid antagonists)
To methotrexate:
Oral, 10 mg (base) per square meter of body surface area every six hours until methotrexate blood concentrations fall to less than 5 × 10 ^-8M.^{02}
To pyrimethamine or trimethoprim:
Prevention—Oral, 400 mcg (0.4 mg) to 5 mg (base) with each dose of the folic acid antagonist.
Treatment—Oral, 5 to 15 mg (base) per day.
Megaloblastic anemia, secondary to folate deficiency
Oral, up to 1 mg (base) per day.
Note: Doses higher than 25 mg should be given parenterally because oral absorption is saturable at doses above 25 mg^{02}.
Usual pediatric dose
See Usual adult and adolescent dose.
Strength(s) usually available
U.S.—
5 mg (base) (Rx) [Wellcovorin (scored)][Generic] (scored)
15 mg (base) (Rx)[Generic] (scored)
25 mg (base) (Rx) [Wellcovorin (scored)]

Folinic Acid Deficiency Symptoms

Canada—
5 mg (base) (Rx)[Generic] (scored)
15 mg (base) (Rx)[Generic] (scored)
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container. Protect from light^{02}.
Parenteral Dosage Forms
Note: The dosing and strengths of the dosage forms available are expressed in terms of leucovorin base (not the calcium salt).
LEUCOVORIN CALCIUM INJECTION USP
Usual adult and adolescent dose
Antidote (to folic acid antagonists)
To methotrexate (inadvertent overdose):
Intramuscular or intravenous, 10 mg (base) per square meter of body surface area every six hours until methotrexate blood concentrations fall to less than 5 × 10 ^-8 Molar.
Note: If, at 24 hours following methotrexate administration, the serum creatinine is increased by 50% or greater over baseline or serum methotrexate is greater than 5 × 10 ^-6 Molar, the dose of leucovorin should be 100 mg (base) per square meter of body surface area every three hours intravenously until methotrexate concentrations are reduced to appropriate levels.
To pyrimethamine or trimethoprim:
Prevention—Intramuscular, 400 mcg (0.4 mg) to 5 mg (base) with each dose of the folic acid antagonist.
Treatment—Intramuscular, 5 to 15 mg (base) per day.
Megaloblastic anemia, secondary to folate deficiency
Intramuscular, up to 1 mg (base) per day.
Note: Because of its calcium content, leucovorin calcium injection should be administered by intravenous injection slowly, at a rate that does not exceed 160 mg of leucovorin per minute.^{05}
Usual pediatric dose
See Usual adult and adolescent dose.
Strength(s) usually available
U.S.—
Not commercially available.
Canada—
10 mg (base) per mL (Rx)[Generic] (without preservative)
Packaging and storage:
Store in the refrigerator between 2 and 8 ºC (36 and 46 ºF). Protect from light.^{05}
Stability:
Intravenous solutions containing leucovorin calcium in lactated Ringer's injection, Ringer's injection, or 0.9% sodium chloride injection are stable for up to 24 hours at room temperature. When diluted in 5% dextrose in water injection or 10% dextrose injection, intravenous solutions containing leucovorin calcium are stable for 12 hours at room temperature. When diluted in 10% dextrose in 0.9% sodium chloride injection, solutions are stable for 6 hours at room temperature^{05}.
Incompatibilities:
Leucovorin calcium injection is incompatible with fluorouracil; precipitation will occur if these agents are combined in the same infusion solution^{01}.
LEUCOVORIN CALCIUM FOR INJECTION
Usual adult and adolescent dose
Antidote (to folic acid antagonists)
To methotrexate (inadvertent overdose):
Intramuscular or intravenous, 10 mg (base) per square meter of body surface area every six hours until methotrexate blood concentrations fall to less than 5 × 10 ^-8 Molar.
Note: If, at 24 hours following methotrexate administration, the serum creatinine is increased 50% over baseline or serum methotrexate is greater than 5 × 10 ^-6 Molar, the dose of leucovorin should be 100 mg (base) per square meter of body surface area every three hours intravenously until methotrexate concentrations are reduced to appropriate levels^{01}. Only solutions prepared with sterile water for injection (i.e., without benzyl alcohol) should be used for doses greater than 10 mg per square meter of body surface area.
To pyrimethamine or trimethoprim:
Prevention—Intramuscular, 400 mcg (0.4 mg) to 5 mg (base) with each dose of the folic acid antagonist.
Treatment—Intramuscular, 5 to 15 mg (base) per day.
Megaloblastic anemia, secondary to folate deficiency
Intramuscular, up to 1 mg (base) per day.
Carcinoma, colorectal (treatment adjunct)
Intravenous, 200 mg per square meter of body surface area over a minimum of three minutes, followed by fluorouracil 370 mg per square meter of body surface area intravenously^{01}, or
Intravenous, 20 mg per square meter of body surface area, followed by fluorouracil 425 mg per square meter of body surface area intravenously^{01}.
Either regimen is given daily for five days, and the course may be repeated at four-week intervals for two courses and then at four- to five-week intervals, as determined by toxicity to the previous course^{01}.
Note: Only solutions prepared with sterile water for injection (i.e., without benzyl alcohol) should be used, since the dose is greater than 10 mg per square meter of body surface area.
Because of its calcium content, leucovorin calcium for injection should be administered by intravenous injection slowly, at a rate that does not exceed 160 mg of leucovorin per minute.^{01}
Usual pediatric dose
Antidote (to folic acid antagonists) or
Megaloblastic anemia—See Usual adult and adolescent dose .
Carcinoma, colorectal (treatment adjunct)—Dosage has not been established.
Size(s) usually available:
U.S.—
50 mg (base) (Rx)[Generic] (without preservative)
100 mg (base) (Rx) [Wellcovorin (without preservative)][Generic] ( without preservative)
350 mg (base) (Rx)[Generic] (without preservative)
Canada—
50 mg (base) (Rx)[Generic] (without preservative)
100 mg (base) (Rx)[Generic] (without preservative)
350 mg (base) (Rx)[Generic] (without preservative)
Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 20 and 25 °C (68 and 77 °F), unless otherwise specified by manufacturer. Protect from light^{01}.
Preparation of dosage form:
Leucovorin calcium for injection is prepared for parenteral use by adding 5 or 10 mL of bacteriostatic water for injection (preserved with benzyl alcohol) to the vial containing 50 or 100 mg (base), respectively, producing a solution containing 10 mg per mL. If doses greater than 10 mg per square meter of body surface area are to be used, sterile water for injection should be used for reconstitution and the resulting solution used immediately^{01}.
Caution: Use of diluents containing benzyl alcohol is not recommended for preparation of medications for use in neonates. A fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.
Stability:
Reconstituted solutions prepared with bacteriostatic water for injection (preserved with benzyl alcohol) should be used within 7 days^{01}. Intravenous solutions containing leucovorin calcium in 10% dextrose injection, 10% dextrose in 0.9% sodium chloride injection, lactated Ringer's injection, or Ringer's injection have been found to maintain at least 90% of labeled potency when used within twenty-four hours.
Incompatibilities:
Leucovorin calcium for injection is incompatible with fluorouracil; precipitation will occur if these agents are combined in the same infusion solution^{01}.

Revised: 08/14/2000

References
Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.

1. Leucovorin calcium for injection package insert (Immunex—US), Rev 02/97.
   

2. Leucovorin calcium tablets package insert (Immunex—US), Rev 3/96.
   

3. Fluorouracil injection package insert (Roche—US), Rev 2/88.
   

4. Meropol NJ, Creaven PJ, Petrelli NJ, et al. Seizures associated with leucovorin administration in cancer patients. J Natl Cancer Inst 1995 Jan 4; 87: 56-8.
   

5. Leucovorin calcium injection package insert (Novopharm—Canada); Rev. 04/94.
   

6. Panel comment, 1989
   

7. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1997. p. 414.
   

8. Reviewers' consensus regarding the inclusion of AMA DE off-label uses in the USP DI, 6/2/00.
   

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Adding supplements is the next reasonable step toward improving your child’s health and function. The following supplements are so commonly lacking in our diet that it is safe and acceptable to give them to your child without testing for deficiencies. These include zinc, omega-3 fatty acids, vitamins C and D, magnesium, and,if your child is dairy-free, calcium.

The following daily doses would be appropriate the average-sized five year old child:

• zinc (15-30 mg) (Make sure that zinc is given with food.)
• cod liver oil (1-2 tsp),
• vitamin C (500mg),
• vitamin D (2000 units),
• magnesium (100-300 mg),
• and 200- 400 mg of calcium (if your child is dairy free).

Add one supplement at a time and wait for 5-7 days before adding the next supplement. Keep a notebook and record when you started the supplement and any improvements or signs of intolerance. The purpose of these supplements is to repair deficits of nutrients with widespread effects, therefore, you may notice many improvements. For example, with zinc you may see improvements in sleep, immune function skin, growth, and sometimes appetite (taste buds). Cod liver oil may improve eye contact and decrease strange eye movements, agitation or hyperactivity, and enhance skin health and immune defenses. Vitamin D has major importance in immunity, (as does vitamin C), and in addition, helps with detoxification and reduction of oxidative stress. Magnesium may prove helpful with relaxation, sound sensitivity, sleep, bowel movements (in larger doses it is a good laxative). Calcium may also be calming and is often helpful with children who press on or gouge their eyeballs. These children may require higher doses up to as much as 2000 mg per day.

Be aware when giving mineral supplements that labeling can be confusing, as the minerals are actually a salt containing two ingredients (e.g. calcium carbonate, zinc picolinate, magnesium glycinate, etc.). In each case, the second component is heavier than the mineral, and the label needs to be read carefully to obtain the correct and desired dose. For example, a bottle of calcium carbonate may read “l000 mg”. The fine print may show that 2 capsules provide 1000 mg of calcium carbonate (and may or may not tell you that calcium carbonate is 40% calcium, so that 2 capsules give you 400 mg of calcium and 600 mg of carbonate). When we speak of dosages of mineral supplements, we mean elemental minerals, or the mineral itself, and not the entire compound.

Administering Supplements

You will undoubtedly meet resistance when you decide to give your child a strange tasting powder or oil, and succeeding with some of the unpleasant tasting supplements requires ingenuity and perseverance. When Bernie Rimland (who might be called the Father of biomedical treatments for autism), was asked by a parent how to get her child to take supplements, his succinct answer was, “Who’s bigger?”. It usually requires tough love and experimentation. I also encourage parents to be honest, telling their child, “This is medicine,” which means 1) “You have to take it,” 2) “It probably tastes bad,” 3) “It’s good for a person,” and perhaps 4) “It’s the doctor’s orders, not mine, so don’t blame me, I’m sorry it tastes bad.”

The most reliable to administer supplements is with a medicine syringe, just as you would give an antibiotic. You can likewise sweeten it with juice concentrate, maple syrup, etc. If you use a syringe you’ll most likely have to train your child to accept the syringe, by repeated practice. One of our patients who had a severely restricted diet, but learned to accept the syringe, would eat soup from a syringe, but only if she was told it was medicine. Other parents have found smoothies or homemade sorbet or fruitsicles, or for the rare child who eats it, soup, to work as a vehicle to administer supplements. Failing this, several companies have formulated many of their supplements in naturally flavored, sugar free liquids or powders to make them more palatable. And some supplements such as zinc, vitamin D, magnesium, calcium, buffered vitamin C are easily concealed in juice or food. We are happy to recommend specific brands of supplements and remedies should you choose to work with us.

Introduce Probiotics and Digestive Enzymes

If your child has bowel problems of any sort, or a history of repeated infections and antibiotics, it is reasonable to offer help with probiotics and digestive enzymes. Probiotics, or beneficial bacteria for the bowel, come in a variety of forms and packages. In brief, I suggest you add a combination containing strains of Lactobacillus and Bifidus, in doses between 20 billion per day and 900 billion per day. You’ll be using capsules or powders which list dose and strains information on their label. Some children respond much better to one product than to another, and so it is worth trying one brand for a few weeks, and then switching to something different (e.g. one containing Bacillus Subtilis or Saccharomyces Boulardi), if no improvements are noted. It may be particularly beneficial to feed your child cultured foods such as coconut kefir or sauerkraut or unpasteurized pickles or other home cultured foods which contain lots of good bacteria.

In addition to probiotics, digestive enzymes may provide considerable benefit for abnormal stools, abdominal pain, food intolerance, and difficult behaviors. As with probiotics, there are a number of good products available, and it is useful to try several different preparations in order to obtain the best results. It is valuable to do a two to three week trial with at least two different preparations, including a plant based enzyme and a pancreatic (animal based) enzyme, as their effects can be quite different.

A small number of children react negatively to probiotics or to enzymes, and can’t take them (but may benefit at a later date after correcting other factors such as bacterial or fungal overgrowth).

Supplements for Specific Conditions

As you add supportive therapies, be sure to continue to reference your problem list and grading system regularly, to address the four questions posed above. Next we want to consider more selective supports, based on your child’s symptoms and diet.

Autism and related disorders are very complex and each child’s physiology is unique. While none of the below-listed interventions are dangerous, choosing the right supports and their proper sequence can get very complicated. When possible, it is best to work with us or another trained physician to guide you in the supplementation process.

Children Who Don’t Eat Meat

If she doesn’t and hasn’t eaten meat in her life, iron will be most likely deficient, and can be safely supplemented at 15-30 mg per day. (Blood testing by your physician for Fe and TIBC and/or ferritin will identify iron deficiency if present). Iron may improve energy and immune function, but can be constipating. If you are supplementing iron and/or zinc, the blood levels should be checked within 6 months, to be sure that iron or zinc levels don’t get too high, or that zinc doesn’t cause copper to drop too low. We would like to see both serum zinc and copper levels at 100 mcg/dl.

Children Who Eat Few Fruits and Vegetables

If your child eats very few fruits and vegetables, B vitamins and trace minerals (including selenium, chromium, manganese, molybdenum in particular) may be helpful. Many supplement companies make balanced trace mineral supplements which also contain 10-25 mg of zinc, thereby replacing your zinc supplement.

B Vitamins

B vitamins, while grouped as a single type of supplement, mainly because they are water soluble and work somewhat in concert, are actually very different one from another, and deserve a separate discussion. Our children are most commonly helped by methyl B12, B6, reduced folic acid (folinic acid or methyl folate), and B3. Contrary to popular opinion, it is not necessary to give all the B vitamins when supplementing, though there is often a deficiency or need for several of them which may benefit from a complete B supplement. We like to give methylB12 as the first B vitamin, preferably by injection, and have found this to be of great benefit for a significant number of children we treat.

Notable benefits in speech, understanding, sleep, behavior, mood, energy, and executive function have been noted in children with autism related issues. A small percent of children become hyperactive after methylB12, and need to have lower and/or less frequent doses or be switched to hydoxyB12. A very small number simply do not tolerate B12 at all. Please note that B12 is far more effective by injection than by oral route or lotion or nasal spray.

If your physician is willing to write a prescription for it, we can provide information regarding compounding pharmacies to assist you in getting your prescription filled. We can also assist in providing guidance about how to safely and easily give the shots (which are very nearly painless, except for the angst of the parent giving the shot). The usual starting dose is (methylB12, 25 mg/ml), 0.01 ml per 10 pounds of body weight, given by very shallow subcutaneous injection every 3 days. If your physician is not comfortable helping you with this, we can help you if your child becomes a patient of record with the Evergreen Center. If you can’t get injectable methyl B12, then by all means do a trial with oral methyl B12 (available as lollypops, lozenges, powder or pills).

Vitamin B6 in combination with magnesium has been used successfully in autism for decades, and shows benefit in around 30% of children. When effective, it seems to help make children more comfortable in their bodies, calming and improving problem- solving through communication and better access to their own resources. Starting doses of around 50 mg are commonly used, and may be increased stepwise up to maximum of 8 mg per pound. It should be combined with magnesium in the doses described above. Vitamin B6 can cause a sensory nerve problem in high doses, but there has been no demonstration of this problem in autistic children receiving these maximum doses over long periods of time. However, as always, it is essential to be gentle and observant. We don’t raise doses if we see signs of intolerance, which consist of agitation or disturbed sleep, and if these symptoms occur, it should be discontinued. A later trial may be beneficial when the digestive tract is functioning well, and when the child has a good intake of protein.

Folinic acid or methyl folate are active forms of folic acid which work together with B12 to enhance energy production and transport, neurotransmitter synthesis, myelin production, detoxification, cellular communication, immune function, gene expression and regulation. Folic acid, which is found in many supplements, but not in foods, requires activation by an enzyme which is frequently impaired in children with chronic health problems. As a consequence, it is preferable to use either folinic acid (available by prescription as Leucovorin, or over the counter) or methyl folate (available by prescription as Deplin, or over the counter). Support of the folate pathway is frequently helpful in children with autism, and is extremely safe, even at very high doses. Children may become agitated if dose is excessive. Starting with a dose of 400 mcg (0.4 mg) per day, one may raise the dose by doubling every 5-7 days, to a dose of 1600 mcg. We have found that some children need extremely high doses of 5000 to 80,000 mcg per day, due to a blockage in the mechanism for transport of folate into the nervous system. These extremely high doses are best given by prescription (Leucovorin is available in 25,000 mcg tablets, and Deplin in 15,000 mcg tablets). It is important to note that blood levels of both vitamin B12 and folic acid are a poor indicator of nutritional status, as these vitamins are critical in brain function, and blood levels correlate poorly with brain levels (due to impairments in brain uptake of these vitamins which are occur frequently in children with autism). If the blood levels are low, then the brain is likely also deficient, but is blood levels are high, this may indicate a block in brain uptake, with actual brain deficiency.

Vitamin B3 (niacinamide, also niacin, which is a form of B3 better avoided in children with autism, as it may cause intense and unpleasant flushing), has also been called the “sleep vitamin,” as it enhances serotonin and melatonin levels. Niacinamide thus may be calming, and it sometimes helps reduce stimming behaviors. It also is essential in the energy and antioxidant pathways which are so critical to healthy brain function. Niacinamide should be given with an equal or greater dosage of supplemental vitamin C (for 500 mg of B3, give at least 500 mg vitamin C). The usual doses in 40-50 pound children are 250 to 500 mg per day. In very high doses, vitamin B3 can cause liver stress, which is always associated with nausea and or decreased appetite. And so a reduction in appetite should be taken as an indication to stop B3 and/or check the ALT liver enzyme level in blood.

Though TMG, DMG, and DMAE are not officially B vitamins, they are water-soluble nutrients which are safe, occur naturally in the brain, and are often helpful in children with autism related disorders. Both TMG and DMG help improve immune function, and may improve speech, awareness, and attention. Both can cause overstimulation or agitation, and TMG is somewhat more likely to do so. If this should occur, the child will calm down to baseline within a day or two of discontinuing the supplement. Some children clearly respond better to TMG, and some to DMG, and some to the two together. For TMG, we use doses of 175 mg to start, and may move to doses as high as 1000 mg per day with further benefit. One good study used a TMG dose of 2000 mg per day without problem in any of the children. For DMG, we generally start with 125 mg per day, working up as tolerated to 500 mg or higher per day. Dr. Rimland reported that children with severe agitation or aggression have , in some cases ,responded to DMG doses of up to 2000 mg per day.

DMAE has brought improvements in disposition, behavior and language, with doses of 50 to 300 mg daily. Higher doses are safe, and could be used if the child is showing encouraging improvements on lower doses. Occasionally, children will become agitated on DMAE, and it must be discontinued.

General Comments Regarding Supplementation

It is worth commenting on the experience that children with autism may react paradoxically to almost any remedy offered. While dangerous reactions are extremely rare (except for the possibility of harm to self or others if a child becomes extremely agitated or aggressive), is not common in most parents’ experience that their child will react unpredictably to an intervention. The most common adverse reaction is agitation, which most likely reflects a discomfort he’s not able to explain. In some cases, the agitation is a sign of a healing crisis, or a healthy readjustment occurring with some resistance. Nevertheless, in all cases it is an indication to reduce the dose, or stop the remedy and provide further support to the body before offering it again. This experience is in line with the finding that children with autism are often very different from one another, so that it is not reliable to predict an effect in one child based on an effect seen in another child. We need to work with our child as an individual, while still learning from the experiences of other children.

While all of the remedies and interventions described above are safe and approved for use without prescription, we strongly encourage you to work with a physician. It is best, when possible, to establish a doctor-patient relationship with the Evergreen Center. If you do not have physical access to our center or to a physician supportive of your work with your child, please contact us for further education and support at info@childrenandautism.com.

The above described remedies represent a good group of supports which should help to improve your child’s health, and may also improve many of his symptoms and problems. Autism is very complex, and there are many more interventions, sometimes including prescription medications which may be needed to make further gains. These include herbal supplements, sulfur supports (glutathione, NAC, Epsom salt baths, MSM, taurine), other vitamins (B’s, K, E, carotenoids, biopterin), amino acids, laxatives, prescription or natural antimicrobials (for parasites, yeast, bacteria) both, hormones (thyroid, cortisol, growth hormone, oxytocin, secretin), detoxification remedies (chelation, intravenous remedies, etc.), anticonvulsant medications, intestinal anti-inflammatories, and so on. As we learn more about autism, promising new remedies emerge, which are especially helpful with some of our children.