A more recent post on this subject is here:
http://epiphanyasd.blogspot.com/2014/08/nac-for-long-term-use-in-autism.html
NAC (N-Acetyl Cysteine) is an anti-oxidant that is part of the autism therapy I have implemented. I have now received feedback from other parents who are also surprised by the positive effect it has on their child with autism. So far, it has had a positive impact in 100% of cases.
In the literature, there are several schools of thought as to why NAC is effective.
- As a free radical scavenger in its own right
- As a precursor to Glutathione (GSH)
- As a glutamate antagonist
- Reducing homocysteine
In my research into the autism comorbidity asthma, I also came across plenty of talk about oxidative stress and anti-oxidants. NAC is used, but it seems like they are looking for something stronger.
The main impact is as a precursor to Glutathione (GSH)
I recently learnt that in autism (or at least the one my son is affected by) the reason is without doubt number two. The other roles (scavenger/antagonist) are irrelevant.
The reason I know this, is that after a few months NAC effectively stopped working. This coincided with an asthma flare-up. Now, I initially thought that the asthma attacks had released inflammatory cytokines and that these had stimulated the ever-present neuro-inflammation in the brain.
This is highly plausible and indeed I have literature showing which cytokines are released by asthma attacks. So I thought that by firmly dealing with the asthma, I would at the same time subdue the autism. This did not happen.
So after a few days I came up with "plan B", which did prove to be successful. I hypothesised that the NAC had stopped working because I was not giving enough vitamin B12, which is part of the chemical process in which GSH is synthesised from NAC. I have no means of knowing how much is needed exactly. In related processes both vitamin B6 and B9 are also involved.
I increased the B vitamins and within hours things began to revert towards the previous behavioural equilibrium.
So it was most likely the failure of NAC to produce GSH, and thus reduce oxidative stress, that had sparked the asthma flare-up. (this is will be covered on my later post of asthma as a comorbidity in autism)
But how much B12 is needed to synthesise GSH?
In your diet you have vitamins B6, B9 and B12, but it is unclear how much is needed to synthesise GSH. A further complication is that B vitamins are not well absorbed in the gut, and some people absorb them better than others. Older people are known to absorb B12 poorly. There are expensive sub lingual B vitamin supplements, but there is no evidence that they actually work better.
There are at least two NAC products targeted at older people to protect them from memory loss and Alzheimer's disease:-
Both products combine NAC with vitamins B6, B9 and B12,
Over the counter NAC Cerefolin NAC Betrinac
N-acetylcysteine (NAC) 600mg 600mg 600mg
Vitamin B9 (folate) 1,000 mcg 800 mcg
Vitamin B6 25mg 20mg
Vitamin B12 1,000mcg 1,000mcg
Both products are for preventing memory loss, rather than just increasing GSH.
For a comprehensive look into B vitamins including their role in the brain, and how they are (or are not) absorbed, take a look at this link from the US Office of Dietary Supplements.
Reducing homocysteine
Homocysteine is linked with strokes, and particularly in the US there are doctors who use NAC for the purpose of lowering homocysteine.
Dr. Baum, medical director of the Mind/Body Medical Institute, a Harvard affiliate, recommends 1,000 micrograms (mcg) of folate, plus 25 milligrams (mg) of vitamin B6, 1,000 mcg of B12, and 1,800 mg of the amino acid N-acetyl-cysteine (NAC). "With folate, B6, B12, and NAC supplements, almost everyone will have normal homocysteine levels," says Dr. Baum.
There is even a discussion about the role of homocysteine in autism. A very recent paper from Poland is: A focus on homocysteine in autism
I think think that high homocysteine, just like low GSH, is a marker of oxidative stress. In some of the literature it is stated that homocysteine cause oxidative stress.
Here is another paper: Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism
If you read all the papers you will come across various graphics showing biological cycles within the body, like the one below. This is how I know that the various B vitamins are needed.
Vitamin B12 Therapy
I really just need to know how much B12 is needed and how to give it. In the end the best resource turned out to be a bulletin from a US medical insurer, and here it is:-
| Clinical Policy Bulletin: Vitamin B-12 Therapy |
The document is very thorough; here are some key parts:-
Background
Vitamin B-12 belongs to the family of cobalamins. It is available in all animal-derived foods, and is absorbed at a rate of 5 mcg per day. After being ingested, vitamin B-12 becomes bound to intrinsic factor, a protein secreted by gastric parietal cells. The vitamin B-12/intrinsic factor complex is absorbed in the terminal ileum by cells with specific receptors for the complex. The absorbed complex is then transported via plasma and stored in the liver. Since the liver stores 2,000 to 5,000 mcg vitamin B-12 (adequate for up to 5 years), dietary deficiency of cobalamin (Cbl) is rare. In most cases, vitamin B-12 deficiency is due to an inability of the intestine to absorb the vitamin, which may result from an autoimmune disease that reduces the production or blocks the action of intrinsic factor, or from other diseases that result in intestinal malabsorption. The most frequent underlying cause of vitamin B-12 deficiency is pernicious anemia, which is associated with decreased production of intrinsic factor.
In a systematic review of randomized trials on vitamin B-6, B-12, and folic acid supplementation and cognitive function, Balk and colleagues (2007) stated that despite their important role in cognitive function, the value of B vitamin supplementation is unknown. A total of 14 trials met selection criteria; most were of low quality and limited applicability. Approximately 50 different cognitive function tests were assessed. Three trials of vitamin B-6 and 6 of vitamin B-12 found no effect overall in a variety of doses, routes of administration, and populations. One of 3 trials of folic acid found a benefit in cognitive function in people with cognitive impairment and low baseline serum folate levels. Six trials of combinations of the B vitamins all concluded that the interventions had no effect on cognitive function. Among 3 trials, those in the placebo arm had greater improvements in a small number of cognitive tests than participants receiving either folic acid or combination B-vitamin supplements. The evidence was limited by a sparsity of studies, small sample size, heterogeneity in outcomes, and a lack of studies that evaluated symptoms or clinical outcomes. The authors concluded that there is insufficient evidence of an effect of vitamin B-6, B-12, or folic acid supplementation, alone or in combination, on cognitive function testing in people with either normal or impaired cognitive function. This is in agreement with Clarke et al (2007) who stated that randomized trials are needed to ascertain the relevance of vitamin B-12 supplementation for the prevention of dementia.
Vitamin B-12 therapy can be administered orally or by injection. Vitamin B12 tablets of up to 5,000 mcg may be obtained over the counter without a prescription.
In a review on vitamin B-12 deficiency, Oh and Brown (2003) noted that, because most clinicians are generally unaware that oral vitamin B-12 therapy is effective, the traditional treatment for B-12 deficiency has been intramuscular injections. The authors cited evidence that demonstrates, however, that oral vitamin B-12 has been shown to have an efficacy equal to that of injections in the treatment of pernicious anemia and other B-12 deficiency states (Elia, 1998; Lederle, 1998; Kuzminski et al, 1998; Lederle, 1991). The authors explained that, although the majority of dietary vitamin B-12 is absorbed in the terminal ileum through a complex with intrinsic factor, there is mounting evidence that approximately 1 % of a large dose of oral vitamin B-12 is absorbed by simple diffusion which is independent of intrinsic factor or even an intact terminal ileum.
Kuzminzki et al (1998) reported on the outcome of 33 patients with vitamin B-12 deficiency who were randomized to receive oral or parenteral vitamin B-12 therapy. Patients in the parenteral therapy group received 1,000 mcg of vitamin B-12 intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90, while those in the oral treatment group received 2,000 mcg daily for 120 days. At the end of 120 days, patients who received oral therapy had significantly higher serum vitamin B-12 levels and lower methylmalonic acid levels than those in the parenteral therapy group.
On treating B12 deficiency :-
Although the daily requirement of vitamin B-12 is approximately 2 mcg, the initial oral replacement dosage consists of a single daily dose of 1,000 to 2,000 mcg (Lederle, 1991; Oh and Brown, 2003). This high dose is required because of the variable absorption of oral vitamin B-12 in doses of 500 mcg or less. This regimen has been shown to be safe, cost-effective, and well tolerated by patients.
CONCLUSION
Long term high dose NAC will require careful supplementation with B vitamins. If NAC is using up vitamin B12 faster than your child is absorbing it from food and supplements, B12 will be used up from the liver and other vitamin stores in the body. These stores will eventually be depleted and vitamin B12 deficiency will result, if you continue to give NAC. This is best avoided.
If money is of no concern, best to buy Cerefolin NAC or Betrinac. If on a budget, then use the cheap NAC available on-line or in your pharmacy; but be careful to supplement far higher amounts of B6, B9 and B12 than the RDA (recommended daily amount).
Cerefolin NAC and Betrinac have 400 times the RDA of B12, 4 times the RDA of B9 and 15 times of B6. But each of these tablets only has 600mg of NAC. In the autism trials the dose of NAC is 4 times higher.
It is evident that B12 is the key vitamin that acts as a precursor with NAC to form GSH (Glutathione), so this is the one to keep a close eye on should your child's NAC appear "to stop working".
It looks like 1,000 mcg of B12, of which 1% may be absorbed, is a fair place to start. Such supplements are relatively inexpensive, and widely available.