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Sunday, 17 November 2013

Magnesium in Autism and other Neurological/Psychiatric Diseases


You may have my read earlier posts about the surprising role of potassium in autism; in those posts I also noted the importance of magnesium for the body to maintain a sufficient level of potassium.  I had thought I had really finished this subject once and for all.

Last week I was discussing my findings with the Endocrinologist.  She was asking how I could possibly tell whether a new therapy was working, given that I already have others in place.  I thought this was a very good question; I replied that if you only change one thing then you can determine whether a therapy is good, bad or has no effect.  If you are new to autism, you are not aware that the condition has many separate dimensions; it is not just a linear scale from 1 to 10.
A few days ago there was an excellent example.  Monty, aged 10 with autism, has an assistant, Nela, who goes to school with him.  When I asked how he was that day, Nela said that he was not as good as recently; he was not making good eye contact and not answering the teacher’s questions.  I asked more details and then Nela mentioned he had been covering his ears.  Then I had to think what had changed.  No potassium/magnesium supplement at breakfast.  Could it really make such a difference, and so quickly?  The only way to tell was to give K/Mg straight away.  It was like “a curtain had lifted”; Nela’s words not mine.
Rather shocked by this further proof, and since almost nothing has been written about potassium and autism; I thought I would do some digging about the other mineral, magnesium.  I was aware that in autism, people do give magnesium and vitamin B6, but I was unaware about its broader role in other neurological/psychiatric Diseases.
There is a big question about what controls the flow of magnesium across the blood brain barrier (BBB).  It clearly must cross somehow, but it is not a simple process.  Because of this, researchers at MIT tried to find a form of magnesium that would easily cross the BBB, they succeeded in mice; but it is far from clear that their new compound magnesium l-threonate has the same effect in humans. 
From the research, it is clear that most people do not have enough magnesium in their diet and anybody with any kind of neurological or psychiatric disorder should make sure their diet is rich in this mineral.  The rest of this post is really for those who want to know why supplementing Potassium and Magnesium should be good for anybody with ASD.  If you do not feel the need to know why, just go buy your supplements.
All you could ever want to know about the neuroscience of magnesium is available in one place, and for free:-

We have to thank Robert Vink, from Adelaide, Australia and Mihai Nechifor from Iaşi, Romania for this 355 page collection of research papers; if only there was one for potassium.
I made a summary of the parts I found interesting that relate to what I am interested in.  Many of the papers are not too science-heavy and you can skip through them.  
  • Magnesium levels are reduced in acute and chronic brain diseases
  • Extracellular magnesium deficiency induces apoptosis, mainly through increased oxidative stress  



Neuronal apoptosis can be triggered by three main mechanisms:

1)    Lack of growth factors;

2)    Overstimulation of glutamate receptors; and

3)     Oxidative stress.

Magnesium could play a (different) role in each of these signalling pathways.

Brain magnesium decline is a ubiquitous feature of traumatic brain injury and is associated with the development of motor and cognitive deficits.
Experimentally in TBI, parenteral administration of magnesium up to 12 h post-trauma restores brain magnesium homeostasis and profoundly improves both motor and cognitive outcome.

Magnesium has been shown to attenuate a variety of secondary injury factors, including brain edema, cerebral vasospasms, glutamate excitotoxicity, calcium-mediated events, lipid peeoxidation, mitochondrial permeability transition, and apoptosis.

Magnesium therapy has failed in clinical trials. Increase in brain free magnesium concentration seems to be essential to confer neuroprotection, and intravenous magnesium administration only marginally increases CSF magnesium concentration, which suggests that the integrity of the blood—brain barrier and the regulation of magnesium in the cerebrospinal fluid are largely maintained following acute brain injury and limit magnesium bioavailability in the brain.

Calcium and Mg cellular contents classically follow the same pathway – when Mg increased, calcium also increased. This May explain the significant correlation between Erc--Mg and intracellular calcium values as well as the fact that in children who have low intracellular calcium values, Mg therapy increased intracellular calcium levels. It can be hypothesized that a genetic factor, which modulates Na+/Mg2+ exchanger activity, may be important in the regulation of Mg


  




Schizophrenia and bipolar disorders are two of the most severe CNS conditions. Changes in plasma and intracellular magnesium concentration, as well as in other bivalent cations, have been found in both psychoses. Our data, as well as that of other authors, has shown that schizophrenic, paranoid patients admitted in the acute state and without previous treatment, have significantly decreased intracellular magnesium levels compared to healthy subjects. Therapy with haloperidol (a typical antipsychotic) or with risperidone (an atypical antipsychotic) both significantly raised the intracellular magnesium concentration without causing significant changes in plasma magnesium concentration. The increase in intracellular magnesium concentration was positively correlated with the improvement in clinical  symptomatology.
We consider that magnesium acts foremost by reducing glutamate release and by its Action upon NMDA receptors, and results in an augmentation in the activity of the GABAergic systems. Unlike the hypothesis that only implicates zinc deficits in the Pathogeny of schizophrenia, we consider that both intracellular magnesium and extracellular zinc deficits are equally involved in schizophrenia pathogeny.

In patients with untreated bipolar disorder, our data showed a significant decrease In intracellular magnesium concentration and plasma zinc concentration during the manic episode. 

Therapy with mood modulators (carbamazepine and valproic acid) increased total intracellular magnesium and plasma zinc concentrations without having a significant effect on total plasma magnesium concentration. Other data showed that lithium also increases intracellular magnesium concentration. The fact that mood modulators with different mechanisms of action have in common the increase of intracellular magnesium concentration is an argument to consider this augmentation as an important element of their mechanism of action.




 Magnesium in Depression

One 2008 randomized clinical trial showed that Mg was as effective as the tricyclic Antidepressant imipramine in treating Major Depression (MD). Intravenous and oral Mg protocols have been reported to rapidly terminate MD safely and without side effects. Brain Mg deficiency reduces  serotonin levels, and antidepressant drugs have been shown to have the action of raising brain Mg.

Excessive calcium, glutamate and aspartate intake can greatly worsen MD.

We believe that, when taken together, there is more than sufficient evidence to Implicate inadequate dietary Mg as contributing to the cause of MD, and we suggest that physicians prescribe Mg for its prevention and treatment.
Magnesium in autism

In this chapter (21) , a brief overview of pharmacology and genetics of magnesium
transport will be followed by a review of clinical and biological studies of Mg vitamin B6 supplementation in attention deficit/hyperactivity disorder (ADHD) and autism (autistic spectrum disorders family, ASD) in children.

Although no study carried out on a rational basis has been published to date, some experimental and/or clinical works support a positive effect of such therapy in these pathologies.

All the individual observations report a decrease in hyperactivity and a stabilisation of scholarly behaviour with treatment. These data strongly support the need for a controlled study to confirm or invalidate these assumptions.

Magnesium is known to be crucial for brain activity and its involvement in the prevention of neurobehavioural  diseases seems to be established. A  clinical double-blind study with Mg-B6 treatment over placebo cannot be accepted for regulatory and ethical reasons. 

This review brings additional information about the therapeutic role of a Mg-B6 regimen In children with ADHD or ASD/autism syndrome. This effect seems to be associated, At least in part, to a cellular Mg depletion as evidenced by intraeythrocyte Mg measurements.

Children with ADHD or PDD/ASD (pervasive developmental disorders/autistic spectrum disorders), including autism, exhibit low Erc-Mg levels.

Parents frequently showed similar low Erc-Mg values suggesting a genetic defect in Mg transport. Installing a Mg-B6 supplementation for some weeks restored higher intraerythrocyte Mg values and significantly reduced the clinical symptoms of these diseases.


Conclusion

Magnesium turned out to be a surprisingly interesting subject for me.  While it is clear that the science is only partially understood, at least we know that magnesium levels in the diet are important.  In the ideal world you would be able to take a special magnesium molecule that better penetrates the BBB; it does not yet exist for humans.  

Perhaps, in some types of autism, the BBB is compromised enough to allow magnesium to enter more freely. Perhaps this is why some people with ASD respond to Mg + B6 treatment, while others do not. 

Again we learnt that in human biology everything is interconnected.  Low brain Mg lowers serotonin, which is the opposite of what we want.  The thyroid axis is known to play a role in regulation of the Mg metabolism.  When Mg levels increase, so do Ca levels.  Intra/extra cellular levels of all electrolytes in the brain are very important; it is part of the brain's control system. 

The so-called ion channels are how the brain controls itself, when one malfunctions there is likely to be a cascade affecting them all.  We know from Dr Ben-Ari that the NKCC1 transporter is the location of one much malfunction, I suspect there are many others.




3 comments:

  1. Which form of magnesium do you find most helpful for your son?

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  2. For us it is potassium that helps. We give 250mg potassium twice a day, it does also include 75mg of magnesium. Epsom baths did nothing good. Magnesium may indeed help other people.

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  3. I had read, based on the E-book and links, that magnesium threonate was the preferred form. We are going to give it a try at 6mg/kg/d and pyridoxine at 0.6mg/kg/d, which is what most of the case studies used, and see what happens. Thanks so much for the link!

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