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Can nutritional supplements help treat some cases of autism?

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Emily Singer
21 March 2013

Pill potential: There is little hard evidence on the benefit of different nutritional supplements for autism.

The mention of nutritional supplements to treat autism might make some scientists wary. Little rigorous research has been done on their effects, and what research exists is often inconclusive.

In the past year, however, researchers have found specific genetic problems that point toward a metabolic deficiency in some cases of autism. These studies open up the possibility that supplements such as carnitine or certain amino acids may help treat autism.

The findings are exciting because they suggest that some forms of autism may be preventable. But scientists don't yet have data on whether supplementing the diet in these cases can prevent the disorder or improve symptoms. Nor do they know whether the potential benefits will be limited to those with specific genetic deficiencies or be effective more broadly.

Some teams are looking more rigorously at the benefit of supplements across a larger population.

In January, a large-scale study from Norway showed that women who take folic acid supplements during early pregnancy reduce their risk of having a child with autism1. And a small, placebo-controlled trial of N-acetylcysteine (NAC), an antioxidant used to treat acetaminophen overdose, found that the supplement improves irritability in children with autism2.

Despite the promise, scientists say it's important to tread carefully and keep expectations in check.

Joseph Gleeson, professor of neurosciences at the University of California, San Diego, published a study in September on a rare metabolic deficiency that may be treatable with certain amino acids. After the publication, he cautioned parents not to give it to their children until there was evidence of if and when it worked.

"We had people tell us, 'I know you said don't start this, but we did,'" he says.

Following the genes:

Last May, Arthur Beaudet and his collaborators showed that a small deletion in a gene called trimethyllysine hydroxylase, epsilon (TMLHE), which is involved in synthesizing carnitine, raises autism risk. (Carnitine helps transport fatty acids into the mitochondria, the cell's energy producer, which has also been implicated in autism.)

The study looked specifically at TMLHE, but Beaudet says that common variations in a number of genes have been shown to influence carnitine levels in the blood. He says environmental factors, such as diet, illness or even the microbes living in the gut, may also alter carnitine and, potentially, the risk of autism.

Beaudet's team is studying children with severe carnitine deficiency, a rare condition, and trying to get carnitine testing implemented on a wider scale.

It's not yet clear how broadly applicable the findings will be. "We already have a lot of patients who take carnitine and don't see striking behavioral effects," says Gleeson, who is not involved in the carnitine study. "Whether it will have a striking effect when used at optimal dosage, I don't know."

Beaudet says he hopes to work with researchers studying infants at high risk of autism — those who have an older sibling with the disorder and a 20-fold higher risk of developing the disorder than does the general population.

"I would like to see if nutritional supplementation from birth can push down this rate," says Beaudet. "But I don't know if I can convince anyone to buy into a trial like this."

It's not yet clear how lack of carnitine affects the brain, but Beaudet's team aims to answer that question by studying animal models — including worms, fruit flies and mice — with abnormal carnitine metabolism.

In September, Gleeson's team published a study identifying rare mutations in a gene called branched-chain ketoacid dehydrogenase kinase (BCKDK) in a pair of siblings with autism. BCKDK is involved in the breakdown of branched-chain amino acids, a set of molecules that are essential for building proteins.

Gleeson says he doesn't yet have enough people with the mutation to start a clinical trial of supplements. His team has shown, however, that giving the amino acids to mice lacking the enzyme helps restore their brain levels of other amino acids to normal. 

To test whether the treatment might work for other forms of autism, his team is testing the amino acids in other mouse models of autism.

Diet dilemma:

These new studies aren't the first to link metabolic problems and autism3. Some children with untreated phenylketonuria, an inherited metabolic condition, or other rare inherited metabolic disorders also show symptoms of autism.

It's unclear how common these disorders are among people with autism. A 2011 study found that only 2 of 274 children with autism tested positive for a metabolic disorder. But Beaudet and Gleeson's studies, as well as ongoing sequencing studies of autism, may expand the number of disorders that fall into this category.

Other researchers are looking at whether supplements can lower autism risk or symptoms generally.

A study of more than 800 children, published in July, found that mothers who take 600 micrograms of folate during the first month of pregnancy are less likely to have a child with autism4.

The effect is strongest in women with a mutation in an enzyme called methylenetetrahydrofolate reductase (MTHFR), which is involved in a chemical reaction involving folic acid. MTHFR mutations have been weakly linked to autism.

A second, much larger study, published in January, provides further support that folic acid early in pregnancy can reduce the child's risk of autism by about 40 percent1.

The antioxidant NAC has also shown preliminary promise. A study published in June of 31 people with autism, half taking the supplement and half on a placebo, found that those taking the drug improved on a test of irritability. (The only two drugs approved by the U.S. Food and Drug Administration for autism both treat irritability.)

Antonio Hardan, who led the NAC study, says he was inspired to study the supplement in part because parents were already using it, despite little evidence of its benefit. But he says he was also interested in its antioxidant properties.

"There is some evidence to suggest oxidative stress is abnormal in individuals with autism," says Hardan, associate professor of child and adolescent psychiatry at Stanford University School of Medicine in California. NAC also targets a signaling chemical in the brain called glutamate, which has also been implicated in autism, he says.

The fact that nutritional supplements are available over the counter has both benefits and drawbacks for clinical research. It's often easier to get approval to study these molecules in people. But because they are more loosely monitored than traditional drugs, the quality can vary widely, and researchers often need to do quality control tests themselves.

"We had huge issues over how and where to get NAC, and the quality," says Hardan.

It's also more difficult to find funding for these types of trials, because pharmaceutical companies aren't interested. The NAC study was funded by a private, parent-run foundation. With the promise of the pilot trial under his belt, Hardan is applying for funding for a larger trial from the National Institutes of Health.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Surén P. et al. JAMA 309, 570-577 (2013) PubMed

2: Hardan A.Y et al. Biol. Psychiatry 71, 956-961 (2012) PubMed

3: Zecavati N. and S.J. Spence Curr. Neurol. Neurosci. Rep. 9, 129-136 (2009) PubMed

4: Schmidt R.J. et al. Am. J. Clin. Nutr. 96, 80-89 (2012) PubMed

Comments

Name: ASD Dad
21 March 2013 - 9:29PM

N-Acetylcysteine Benefits

"Much of n-acetylcysteine’s benefits centre on its ability to serve as a precursor to glutathione, one of the body’s main intracellular antioxidants. Since the 1970’s, n-acetylcysteine has been the primary treatment for acetaminophen (i.e. paracetamol) poisoning1. Paracetamol poisoning is induced primarily by depletion of glutathione stores in the liver. Oral n-acetylcysteine is transported to the liver where it counteracts the drop in glutathione levels caused by paracetamol administration2. One of the other original indications for n-acetylcysteine is as a mucolytic agent, which is something that dissolves or breaks down thick mucus – usually to help relieve respiratory difficulties. Its effect is based on its ability to break the disulphide bridges of the high-molecular-weight glycoproteins of the mucus, resulting in reduced viscosity. In many European countries it is widely prescribed for this purpose."

4. Aitio ML. N-acetylcysteine – passe-partout or much ado about nothing? Br J Clin Pharmacol. 2005;61(1):5–15.Zafarullah M, et al. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003;60:6–20
5. Cobley JN, et al. N-Acetylcysteine's attenuation of fatigue after repeated bouts of intermittent exercise: practical implications for tournament situations. Int J Sport Nutr Exerc Metab. 2011;21(6):451-461.

Name: Lola
24 September 2013 - 2:13PM

Is there a children's brand you recommend sara? My 8 yr old is taking focalin, I would like to give him natural supplements.

Name: Sarah
22 March 2013 - 5:03PM

yes, they can help! I have been supplementing my son since he was dxed at age three. He is now nine. He gets Omega 3, B complex, Phosphatidly Sterine with DHA, Lutimax, L-Carnitine, Magnesium-calcium-zinc combined, and Endomune (a probiotic). I have also used Enhansa (curcumin) and Trienza (an enzyme supplement) with good results. While he is not out of the woods yet, he is having a good year in school and has made tremendous progress since age 3. As a parents I much prefer a natural nutritional alternative to a medication.

Name: passionlessDrone
22 March 2013 - 8:00PM

Hi Emily Singer -

Nice article that speaks toward the problem of incremental learning and desperate parents. You might consider adding anti-inflammatories to the list; i.e.,

Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial.

Cox-2 inhibitors may not strike everyone as a 'supplement', but they also aren't what people would consider when they thought, 'autism drug'.

- pD

@ASD Dad - I bet you might find this one of interest.

Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation

It is nothing short of a guidepost to *prevention*. But, oh, such a dangerous path to tread given our collective ignorance. So tempting, though. . . .

Name: Greg Boustead
25 June 2013 - 4:15PM

Hi passionlessDrone- Thanks for your comment. This article was more focused on the efficacy of true nutritional supplements (and the confusion surrounding them), but a good look at potential adjunctive treatments in autism that optimize or improve upon existing treatment options might be worthwhile.

Name: Teresa Binstock
26 March 2013 - 3:00PM

Studies by S. Jill James, Ph.D., and colleagues are important in regard to supplements likely to help autistic children. For example:

Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism.
http://www.ncbi.nlm.nih.gov/pubmed/15585776

Name: Harold Rongey, Ph.D.
26 March 2013 - 8:03PM

As a nutritionist I suggest we go back a step in our thinking. While supplements can be very helpful in many instanances, it is far more beneficial if we take a look at what the nutritional needs are for a healthy diet. The nutrients that have been found lacking in those with autism and the related neurological disorders can and do include several of the amino acids: tryptophan, methionine, cystine, tyrosine, glutamic acid, serine, proline, and lysine. The minerals include phosphorus, magnesium, zinc, copper, calcium and iron. The vitamins choline, B-6, B-12, folic acid, A,D,E and several of the fatty acids as well as cholesterol. It is far easier to provide these nutrient in total with proper food choices than to cherry pick a few individual nutrients. The best source as to the needs for a healthy diet as well as the composition of the foods in the diet I recommend the USDA SR 24 Nutrient Database and the USDA Choline report 2008 for what I have found to be valid information.

Name: Joanne Murphy
19 April 2013 - 1:45PM

Dr Rongey, for a typically-developing, otherwise healthy child I would totally agree that all you need do is provide a sensible nutritious diet, consumption of which is gently, but firmly and consistently enforced, and sit back, job done. However ASD children are notorious for their heroic food refusal. Not only will they not eat their vegetables, they won't eat ... anything not crunchy, anything not smooth, any fruit, anything yellow, anything green, anything salty, anything not salty, anything that comes out of the red pot ... and so on and so forth. In fact our local ASD centre will shortly be offering a parent education class rather optimistically/ bravely titled "No more white food!". I used to wonder why my son would not eat a new thing after I offered it to him more than 30 times, as per the ubiquitous advice of various child rearing articles. I assumed it was just another example of how I was a crap parent ... until the ASD diagnosis. It might be "far easier to provide ... nutrient in total with proper food choices", but with most ASD kids all you will end up with is smiley vegetable faces congealing on the plate. Given that significant minorities of ASD children suffer digestive comorbidities, and/ or have demonstrated vitamin or mineral deficiencies, and/ or exhibit real benefits from certain supplement regimes (such as magnesium-vitamin B6, or carnitine), in my view supplementation is almost unavoidable to support the health of most autistic children.

Name: Lori D
18 July 2013 - 2:56AM

Well said Joanne! I have a son with autism and getting him to eat a fruit or vegetable is next to impossible for the most part. He gags when I peel a banana. He has major issues with smell and textures. So a healthy diet is just another addition to my wish list for my son..

Name: Sarah
1 April 2013 - 7:30PM

Harold,

What is your opinion on juicing? I was thinking of buying a juicer so I can make juice drinks for my son.

Name: paolo mainardi
4 April 2013 - 8:56PM

Recent papers put in evidence the role of brain inflammation in several neurological diseases, in epilepsy, too. And seizures are often reported by autistic children. Today it's well know that a brain inflammation increases BBB permeability. But Riazi reports that an intestinal inflammation is able to produce a brain inflammation, moreover to produce an intestinal inflammation decreases epileptogenic threshold and produce anxiety in animals. In this way, a chronic intestinal inflammation could be considered the mother of different diseases. Then it's correct to use a diet in autim, but the aim of this diet has to be to decrease intestinal inflammation, then to improve intestinal flora and to decrease intestinal permeability. In the while the diet has to be able to supply intestinal cells to allow to them to survive. Only in this way a diet could be helpful to improve autistic disorder, in other way to add vitamins, or other food supplements could be also dangerous.

Name: usethebrainsgodgiveyou
3 May 2013 - 3:43PM

Related, yet not. http://ghr.nlm.nih.gov/condition/pyridoxine-dependent-epilepsy

It's not as though it hasn't happened before. We are all looking for that needle in a haystack that will change the course of our children's lives.

Also,PKU. Something added, something taken away have kept some children out of institutional living and early death and brought them to a much better prognosis.

Name: zeinab
25 June 2013 - 7:59AM

What would you say to adesperate parent not helped bymainstream medicine who tried supplments and saw improvements at schools. I am gonna try suplements introduce them slowly andd ifsaw improvements i dont need a testto prove me right. i havet tried amino acids but i was thinking about it after i heal the gut with probiotics, digestive enzymes and provide the brain nd body with nutrients

Name: gayathri
10 August 2013 - 6:32AM

i strongly recommend the nutritional supplements for kids and even to adults to face the upcoming diseases and to prevent.once the health is damaged, we cant get it back to its normal, so we can spend now itself to maintain our healthy in a good way, so that it doesnt affect.contact me at gthr.raju@gmail.com

Name: Reeita D.
28 August 2013 - 8:58PM

My son age 25 has autism and epilepsy. he also has adhd and learning disorder. give me a suggestion for a safe herbal treatment. email at nonficiton@yahoo.com. tks.

Name: Michael L
18 January 2014 - 5:53PM

Take a look at Effect of a vitamin/mineral supplement on
children and adults with autism, Adams et al. BMC Pediatrics 2011, 11:111
http://www.biomedcentral.com/1471-2431/11/111

Abstract
Background: Vitamin/mineral supplements are among the most commonly used treatments for autism, but the research on their use for treating autism has been limited.

Method: This study is a randomized, double-blind, placebo-controlled three month vitamin/mineral treatment study. The study involved 141 children and adults with autism, and pre and post symptoms of autism were assessed. None of the participants had taken a vitamin/mineral supplement in the two months prior to the start of the study. For a subset of the participants (53 children ages 5-16) pre and post measurements of nutritional and metabolic status were also conducted.

Results: The vitamin/mineral supplement was generally well-tolerated, and individually titrated to optimum benefit. Levels of many vitamins, minerals, and biomarkers improved/increased showing good compliance and absorption. Statistically significant improvements in metabolic status were many including: total sulfate (+17%, p = 0.001), Sadenosylmethionine (SAM; +6%, p = 0.003), reduced glutathione (+17%, p = 0.0008), ratio of oxidized glutathione to reduced glutathione (GSSG:GSH; -27%, p = 0.002), nitrotyrosine (-29%, p = 0.004), ATP (+25%, p = 0.000001), NADH (+28%, p = 0.0002), and NADPH (+30%, p = 0.001). Most of these metabolic biomarkers improved to normal
or near-normal levels. The supplement group had significantly greater improvements than the placebo group on the Parental Global Impressions-Revised (PGI-R, Average Change, p = 0.008), and on the subscores for Hyperactivity (p = 0.003), Tantrumming (p = 0.009), Overall (p = 0.02), and Receptive Language (p = 0.03). For the other three assessment tools the difference between treatment group and placebo group was not statistically significant. Regression analysis revealed that the degree of improvement on the Average Change of the PGI-R was strongly associated with several biomarkers (adj. R2 = 0.61, p < 0.0005) with the initial levels of biotin and vitamin K being the most significant (p < 0.05); both biotin and vitamin K are made by beneficial intestinal flora.

Conclusions: Oral vitamin/mineral supplementation is beneficial in improving the nutritional and metabolic status of children with autism, including improvements in methylation, glutathione, oxidative stress, sulfation, ATP, NADH, and NADPH. The supplement group had significantly greater improvements than did the placebo group on the PGI-R Average Change. This suggests that a vitamin/mineral supplement is a reasonable adjunct therapy to
consider for most children and adults with autism.

Name: parispak
16 April 2014 - 4:25PM

IT IS WONDERFUL AND FRUITFUL ARTICLE...IM CONDUTING A RESERACH ON AUTISM AND ITS RELATIONSHIP WITH NUTRITION. U ALL ARE INVITED TO SUGGEST ME AT parispak1@yahoo.com SHAZIA AQEEL CHOHAN.

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