I was honored to be an invited panelist at the Defeat Autism Now! (DAN) Conference convened by the Autism Research Institute in 1995.  Dr. Bernard Rimland called the conference to bring together 30 of the most knowledgeable people in the field and he wisely included the orthomolecular voice in an otherwise academic chorus, which focused on peptides and immune disorders.  One thing we all had in common, however, was the awareness that autism has changed since Leo Kanner's landmark paper describing a handful of cases in 1943.  The most noticeable event has occurred in the past decade, which has witnessed an alarming increase in the number of children with language delay and attention deficit.  The more severe language delay cases usually are given a diagnosis of autism at age 3 to 4; those who develop sufficient speech to communicate are usually spared the stigma of diagnosis until their attention deficit becomes more disabling, usually upon entrance to Kindergarten.

At the time I suspected that vitamin A deficiency might play a role in autism because it is essential for growth and development of every cell in the body.  I had observed that many mothers were avoiding animal fats, and therefore curtailing vitamin A for their children.  There was animal research to back up such a connection but only recently have I seen a human study that supports this idea.  Scientists at Salk Institute recently reported their observations that early brain development is affected by vitamin A deficiency, leading to defects in memory and learning ability.[i]

Recently I have become aware of the powerful adverse effects caused by homocysteine in people with diets low in B vitamins and especially in those with one or more of 8 genetic enzyme defects.  The extreme cases are rare but they cause severe brain disease--and death--in children.  Milder cases may not ever be diagnosed, although they can cause mental symptoms, including schizophrenia. There is evidence that about half of all adult psychosis (schizophrenia and manic depressive disorder) is related to homocysteine.  For example, in one study the enzyme MTHFR, which methylates homocysteine, thus producing methionine and enabling the vital process of methylation, to succeed in regenerating adenosine, thymidine and other nucleic acids was found defective in 7 of 11 schizophrenics.  These patients did not respond to vitamin B12 but did recover after treatment with folic acid.[ii]

Zinc deficiency seems to affect almost all of the autistic children I have examined.  There is good reason to consider this as an aggravating factor if not a direct cause of the damage.  In the first place, zinc is essential for activation of vitamin B6 into the pyridoxal form required for production of the zinc-ATP complex that participates in the enzyme, cystathionine synthase, which controls the major path for removal of excess homocysteine.[iii]   Note that B6 activity is dependent on adenosine which is part of the ATP (adenosine tri-phosphate).  Adenosine is also in short supply at times, for it is dependent on THF (tetrahydro folate), which is in turn sensitive to T3, which depends on adequate selenium for activation.  That chain of nutrition dependent links is often broken.

One reason these molecules aren't better known is that they have long names and lots of abbreviations.  Follow this description (if you can): Di Methyl glycine (DMG) is analogous to Di methyl ethanolamine (DMAE).  Add a methyl group to each and you have TMG and TMAE.  But these are commonly known as betaine and choline.  Now here is the key: TMAE, i.e. choline, is a larger molecule than DMAE, and we know DMAE, i.e. deanol, crosses into the brain more readily than does choline.  In fact, the brain restricts the entrance of choline by a mechanism that converts it to phosphatidylcholine first.  This mechanism uses another nucleic acid product, uridine, and requires energy.  Deanol by-passes these complicated steps and is more readily available to the nerve cell, where it picks up a methyl group, which converts it into choline, making it available also as a precursor for production of the neurotransmitter, acetylcholine.  Thus both deanol and choline are recognized as "smart molecules" which promote neurotransmission, stimulate the nerve synapses, and actually promote nerve regeneration. 

The same sort of chemistry applies to DMG and TMG.  Dimethylglycine is smaller and more readily available than Tri methylglycine.  I haven't seen actual research to document this point but the clinical results suggest that something of this sort must go on in order to give DMG the beneficial effects that have been reported by parents of autistic children.  While it may have other effects, it certainly has substantial benefit by providing a methyl group to protect the brain against homocysteine.  It also may be an extra source of methyl groups for nucleic acid and myelin sheath repair.

By now I have tested 12 of my autistic patients for homocysteine and found half with dangerously high levels that probably play a part in their disability.  This has opened up a new approach to treatment that has also proved helpful in most of these cases.  This is a promising lead and it deserves to be tested under controlled conditions.  Homocysteine is a known cause of blood vessel disease in adults and research rates it as much more hazardous than cholesterol. 

The dangers of homocysteine were first observed in children with homocystine in their urine in 1962; and the link to atherosclerosis in the general population was proposed in 1968 by Kilmer McCully.  This was regarded almost as heresy.  He lost his job at Harvard over it; and the controversy remains very much alive to date despite much supporting evidence, such as the following case.

Matt is a 23 year old autistic child, now grown up, living in an apartment and working in a supervised rehabilitation setting.  His speech is limited and impaired by stammering, which interfere with his ability to hold a job.  His rehabilitation counselor recommends tranquilizer therapy to minimize the negative effects of anxiety.  He was diagnosed with autism at age 3, a neurologist confirmed lack of eye contact, inability to imitate and physical clumsiness.  He improved after age 6 when an orthomolecular psychiatrist treated him with 2 grams of niacinamide and extra B1, B6 and C.  He began speaking in sentences two weeks later.  Before that he had been speaking in short phrases, such as: “go school”; or "put shoes me on.”  One night he said: 'remember when we did….etc.  His mother was astounded.  However he had psychotic symptoms during adolescence, especially after wheat intake.  One day he began talking to his watch, and the watch was giving him instructions.   His mother is convinced that he has stayed well by avoiding wheat since then. 

Gestation was uneventful and birth weight was 8 lb 3 oz after a long labor of 23 hours.  His Apgar score was low at first but then recovered.  He was jaundiced in the hospital but it cleared in a week.  However he did not suck well and could only get 2 ounces per feeding!  He was nursed for six months. Ear infections occurred 3 or 4 times per year as a baby and he was treated with antibiotics.  He had constant diarrhea as a baby, but fevers were not an obvious problem.  Vaccine reactions were not apparent.  He was not given fluoride treatments but has no cavities anyway. 

My initial laboratory studies showed normal blood count, urinalysis, and chemistry panel.  Vitamins and minerals were within normal limits except copper was marginally low and ferritin, the iron storage protein, was high enough (336) to suggest over-load or a degree of liver irritation, perhaps related to long-time intake of an iron-containing multivitamin.  Fatty acids of the red blood cells were measured and found 10% low in DHA, 10% too high in odd-numbered very long chain fatty acids (C25:0) and 50% high in a long chain fat that reflects deficient intake of essential fatty acids (C23:0).  High C25:0 may be due to sluggish oxidation of fatty acids, possibly due to impaired electron transport in the mitochondria.  This is an indication for a trial on coenzyme Q, copper and possibly riboflavin--which requires T3 for activation to coenzyme (FAD), and hence is dependent again on selenium, etc.

Follow-up testing was not available, but his clinical course was positive.  In the next year he calmed down noticeably.  His stammer also improved, especially during the low carbohydrate phase of my Balance Point Test diet.™  However his biggest improvement was unexpected.  It turned out that he had been wetting the bed almost every night for many years and medication (Ditropan, Imipramine) had failed to help.  However, now within a month after treating with betaine (TMG) 1 gram two times per day this had almost ceased!  The frequency declined from 28 times per month to only twice.  He also slept better and became calmer and more relaxed. 

This treatment with betaine had begun after a methionine loaded test of total plasma homocvysteine was elevated.  Matt had a normal test result (4.8 uM/L) after an overnight fast just a month earlier, but I re-ordered the test because about a third of the cases are otherwise missed.  Thus after giving him 3 grams of methionine 6 hours before the test sample was taken, the result was almost tripled. (13.8uM/L).  It is believed this reflects a B6 problem or a defect in the excretion path of homocysteine.  This may also account for the benefits he got as a child in megavitamin therapy, since one of the vitamins contained vitamin B6, probably at a dose well over 100 mg per day.

By now I have had the pleasure of observing substantial benefits in a number of autistic individuals, just from this one, safe and inexpensive adjunct to the treatment of developmental brain disease, including patients with autism, ADD, chronic bowel disease.  This is not to dismiss other treatments, especially since the treatment of homocysteine may involve one or more of at least half a dozen factors in addition to betaine, such as folic acid, cobalamin (B12), pyridoxal (B6), N-acetyl cysteine, taurine, serine, choline, and di-methylglycine (DMG).  Thyroid and riboflavin (B2) are also helpful in some cases.  But TMG has a remarkable benefit just the same, possibly because it buttresses the capacity of the liver to metabolize methionine, which can be dumped on the liver in rather large quantities after meals. 

Because omega-3 essential fatty acid deficiency is so common and the adverse effects so relevant to neural development and repair, dietary sources, such as fish oil and flax oil, should be tried early in treatment.  The omega-3 essential fatty acids they provide are essential for cell membrane structure and function, and anti-inflammatory effects in general.  Borage and Primrose oils, which provide omega-6 essential fatty acids, such as GLA, are also helpful in some cases; however the omega-6 fatty acids promote arachidonic acid activity, which is pro-inflammatory.  Hence they should be tried later along with dietary sources, such as calves or lambs liver, kidney, lamb, and shellfish, either broiled or in stews.  Note: Vitamin E, at least 400 iu, per day, is recommended in order to prevent peroxidation due to the extra intake of ultra-polyunsaturated essential fatty acids.

Disturbed fatty acid metabolism is often improved by supplemental carnitine 500mg, riboflavin (50 mg), and copper (1-2 mg).  These team up to promote oxidation of the Very Long Chain Fatty acids (lignoceric, hexacosanoic and octacosanoic) that are frequently observed in fatty acid blood testing of autistic patients.  Since copper is over-stimulating to most autistic children, especially at the beginning of treatment, it must be witheld a few weeks (or longer) until zinc, iron, selenium and essential fatty acid treatments have had a chance to take hold.  Zinc and copper are opposite in their behavioral effects, but zinc is commonly deficient in autistic children, and this opens the door to copper dominance and over-stimulation.  How is this so?  Zinc is a natural inducer of the protective intestinal metallothionein system, a layer of cysteine containing proteins in the wall of the gut.  This system regulates the absorption of zinc and blocks the excessive absorption of copper. 

In the first several weeks of zinc supplementation, while induction of this system is in process, supplemental ubiquinone, 30 mg is a helpful adjunct, to substitute for copper in the electron transport chain in case of copper deficiency.  After that copper and zinc should be re-checked if possible and supplementation of copper can be considered.   Trace minerals need to be clinically evaluated individually for best results in treating autism but here is a rough outline:

Zinc 25 mg, followed by Selenium, Chromium, and Molybdenum, all at 25-50 mcg twice per day.  Then iron 10 mg, manganese 10 mg, and copper 1-2 mg.  Supplementation should be twice a day and in that order.

It makes sense to continue taking any that seem helpful but adjust doses relative to results and there should be follow-up mineral testing every 3 months.  Amino acid supplements are often helpful, especially if there is intestinal malabsorption, wheat intolerance, lactose intolerance or food allergy.  Free amino acid formulas are efficient; so is Seacure™, a proprietary microbial digest of fish protein

The antibiotic fatty acid, lauric acid (Monolaurin™), has been particularly beneficial in my experience, especially for those children with signs of irritable bowel and dysbiosis, which usually improve in a few days after only 1 capsule twice a day.  Probiotic agents, such as Lactobacillus acidophilus, Lactobacillus sporogenes, Lactobacillus plantarum, and Lactobacillus salivarius have also been appreciated by my patients.

Other non-specific orthomolecular treatments for autism:

Vitamin C 1000 mg twice a day

Bilberry with grape seed extract 280 mg

DMAE (deanol) at doses of 25 to 250 mg per day (reduce dose or stop for a time if irritability occurs).

Piracetam and Cavinton have also been given favorable reports by parents.

CNS extract has been helpful in my small experience with it, just a few cases.

That is a formidable list of treatments.  Many children are so uncooperative that it is difficult to persuade them to ingest even a single nutrient!  But eventually most parents succeed in carrying out orthomolecular treatment programs and children almost always gain at least partial benefit.  It is probable that earlier treatment will yield better results.

To prevent toxic-build up in newborn nurseries, use paints that do not contain volatile organic compounds.  Livos (800 621 2591), Gliddens Spread 2000 (800 367-0862), Sinan (916-753-3104), andAFM Safecoate (619-239-0321).  In addition, unbleached and undyed carpets may be purchased from Nature's Carpet or Allpure wool rugs from the Environmental Home Center (800 281 9785).  Synthetic carpets are tainted with over a hundred toxic and carcinogenic chemicals.  See articles in the environmental Magazine.  http://www.emagazine.com

© 2010 Richard A. Kunin, M.D.



[i] Evans et al: Neuron, 12/22/98

[ii] Regland B, Germgard T, Gottfries CG: Homozygous thermolabile methylenetetrahydrofolate reductase in schizophrenia-like psychosis.  J Neural Transm 1997;104:931-41.


[iii] Zinc and the regulation of vitamin B6 metabolism.  Nutr Rev 1990;488(6):255-8.


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