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:-

Magnesium in the Central Nervous system

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.

Clonidine, ADHD and Autism

Clonidine has been used for more than half a century as an antihypertensive drug, to lower blood pressure.

It later found favour as a treatment for ADHD, drug withdrawal treatment, tobacco withdrawal treatment and a wide range of psychiatric disorders.  Off label usage of Clonidine includes autism.

Until recently it appeared to researchers to be a centrally acting α₂ adrenergic agonist, but recent research indicates than instead it is a centrally as an imidazoline receptor agonist.  This would account for its actions other than lowering blood pressure. Maybe it is both.  The good thing is that it is centrally acting (i.e. acting on the brain and the CNS) and it does appear to work. 

Adrenergic Agonist

As a centrally-acting α-adrenergic receptor agonist, Clonidine has more affinity for α₂ than α₁. It selectively stimulates receptors in the brain that monitor catecholamine (epinephrine, norepinephrine and dopamine) levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that controls the production of catecholamines.  By fooling the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure.

Imidazoline Receptors

There are three classes of imidazoline receptors:

• I₁ receptor – mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure
• I₂ receptor – an allosteric binding site of monoamine oxidase and is involved in pain modulation and neuroprotection.
• I₃ receptor – regulates insulin secretion from pancreatic beta cells

L-Monoamine oxidases (MAO)

MAOs are enzymes that act as catalysts.  There are two types of MAO: MAO-A and MAO-B

MAO- A is an enzyme that degrades amine neurotransmitters such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT).

MAO-B is an enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters, including dopamine (DA).

The differences between the selectivity of the two enzymes are utilized clinically.  MAO- A inhibitors have been used in the treatment of depression, and MAO-B inhibitors are used in the treatment of Parkinson's disease

Selective MAO-B inhibitors preferentially inhibit MAO-B, which mostly metabolizes DA. If MAO-B is inhibited, then more DA is available for proper neuronal function, especially in Parkinson's Disease. 

Clinical significance

Because of the vital role that MAOs play in the inactivation of neurotransmitters, MAO dysfunction (too much or too little MAO activity) is thought to be responsible for a number of psychiatric and neurological disorders. For example, unusually high or low levels of MAOs in the body have been associated with schizophrenia, depression, attention deficit disorder, substance abuse, migraines, and irregular sexual maturation.

MAO inhibitors are one of the major classes of drug prescribed for the treatment of depression, although they are often last-line treatment due to risk of the drug's interaction with diet or other drugs. Excessive levels epinephrine, norepinephrine or dopamine may lead to a hypertensive crisis, and excessive levels of serotonin may lead to serotonin syndrome.

MAO-A inhibitors act as antidepressant and antianxiety agents, whereas MAO-B inhibitors are used to treat Alzheimer’s and Parkinson’s diseases.

Clonidine in ADHD

In the US, the FDA has licensed clonidine for use in children with ADHD.

Pediatric doses of clonidine are calculated based on the child's body weight. Clonidine dosage for ADHD in children is 5 micrograms per kilogram of body weight per day orally in four divided doses. Children who require a daily dosage of 0.2 mg usually can use the 0.3 mg trans-dermal patch. If ADHD is associated with sleep disturbances, low to moderate doses of clonidine can be taken at bedtime.

Clonidine in Autism

Not surprisingly, since clonidine is effective in ADHD, it also shows promise in autism. 

Other ADHD drugs, like Ritalin, have problematic side effects.  The US Center for Disease Control reported in 2012 that an estimated 6.4 million children ages 4 to 17 had been diagnosed with ADHD at some point, a 53 percent increase over the past decade. Approximately two-thirds of those currently diagnosed have been prescribed drugs such as Ritalin or Adderall. Those drugs can help patients with both mild and severe symptoms, but they can also cause addiction, anxiety and psychosis.  In the UK, it is suggested that about 3% of children may have ADHD.  Drug use is far lower than in the US, but 657,000 prescriptions were written by doctors for drugs like Ritalin in 2012.

Use of ADHD drugs 'increases by 50% in six years'

There have been studies of clonidine in autism; here a fairly recent one:-

Use of clonidine in children with autism spectrum disorders

Perhaps even more interesting is a lively debate among parents who have tried it:-

Clonidine for autism?

It does seem to work, but nobody seems to be following it up.

Clonidine Stimulation Test

Regular readers will know my interest in TRH and GH.  At least there is no doubt about Clonidine’s effect on GH (growth hormone).  If you want to test pituitary function to see how well GH is being produced, the standard test is the:-

Clonidine GH stimulation Test

For those interested in GH, if you were to take Clonidine, smoke a cigarette and then have your GH measured, the Endocrinologist would have a surprise.

Nicotine from cigarette smoking enhances clonidine-induced increase of serum growth hormone concentrations in men

“These findings suggest that in man nicotinic cholinergic and adrenergic mechanisms might interact in the stimulation of GH secretion.”
 

Interestingly, one of the milder side effects of the ADHD drug Ritalin is growth retardation. According to Professor Tim Kendal, who created the national guidelines in the UK for treating ADHD: - “In children, without doubt, if you take Ritalin for a year, it's likely to reduce your growth by about three-quarters of an inch.

Conclusion

Clonidine looks like another old drug that has been stumbled upon by somebody doing some off label experimentation.  It does seem to have good results in ADHD and Autism.  The good thing is that it is FDA approved and is available in both oral and time release transdermal forms.

I do not think anybody really understands how it works in ADHD or other psychiatric disorders; undoubtedly, there is another, as yet unidentified, mode of action.

 

For those who want more info:- 

The Clinical Utility of Clonidine

Note ulcerative colitis, ADD and even growth delay.

 

Clonidine treatment for short stature

 

 

 

Creatine, the Sub-types of Autism is Affects, and the Missing $26 million

Poly Genetic Theory of Autism

Autism appears to be the result of the expression of multiple abnormal genes acting in concert, likely initiated by some external factor(s).  This would explain why there are so many variants of autism and why there can seem to be autistic-like traits in close relatives.

 

 

Gene-based Autism Research

Several candidate genes have been identified, such as those linked to fragile X syndrome, tuberous sclerosis etc.  Researchers then follow the science from the target gene to identify a possible therapy.  At this point the researchers then seem to lose their scientific logic; they then try and apply their new therapy to all kinds of autism, i.e. the ones without the “faulty gene”.

This really goes back to our current limited understanding of the brain, medicine is more art than science, and we should perhaps suspend logic and accept this trial and error approach as valid.  At least call it trial and error.

Creatine

Creatine is an organic acid produced naturally in the body.  It helps to supply energy to all cells in the body. This is achieved by increasing the formation of adenosine triphosphate (ATP).

Creatine is not an essential nutrient, as it is manufactured in the human body from L-arginine, glycine and L-methionine.

Its main use as a supplement/drug is among people wanting to develop their muscles, like athletes and bodybuilders.  Taking the standard dose of 5-10 mg has the same effect as eating a very high protein diet.  In people with muscle wasting diseases, Creatine is also used.  What I found interesting was the research showing an effect in depression.  There are marked similarities between conditions like depression and ASD.

We will return later in the post to another reason that Creatine may be relevant to autism; it appears to be something the research community did not notice.  Now back to those professional researchers:-
 

Creatine Deficiency

Science has identified three types of Creatine deficiency and all three lead to mental retardation and/or autism.  Two types are very rare, but are treatable; the third type is far more common, affecting about a million people worldwide, and is currently untreatable in humans.  In mice, this third type has been “cured”, but the money is not yet available to develop and test a human version of the therapy.
 

Disorders of Creatine transport and metabolism

 

1.      AGAT 

AGAT (L-Arginine:glycine amidinotransferase) is an enzyme.  This enzyme is needed for the body to produce Creatine.  AGAT deficiency will cause Creatine deficiency  and lead to mental retardation and autism.

For those regularly following my blog, please note the following: It has been suggested that AGAT activity in tissues is regulated in a number of ways including induction by growth hormone (GH) and thyroxine (T4).

The actual genetic mutation associated with AGAT involves a tryptophan codon being converted to a stop codon at residue 149.

You may recall in my post on serotonin, we learnt about its precursor tryptophan and how it appears to be degraded in the autistic brain.

http://epiphanyasd.blogspot.com/2013/11/central-serotonergic-hypoactivity-in_4.html

One particular paper was:-

Decreased tryptophan metabolism in patients with autism spectrum disorders

2.     GAMT

GAMT (Guanidinoacetate N-methyltransferase) is another enzyme required to produce Creatine.  As with AGAT deficiency, if you are deficient in GAMT, autism and mental retardation will follow.

Treatment

If diagnosed, defects of Creatine biosynthesis are treated with Creatine supplements and, in GAMT deficiency, with ornithine and dietary restriction of arginine through limitation of protein intake.
 

3.     X-linked Creatine deficiency

The final type of Creatine deficiency is much more common, but is much more difficult to treat.  The defect is the Creatine transporter that should allow the Creatine into brain cells, where it plays a critical role in the brain’s energy needs.  No matter how much Creatine you give to people with this disorder, they cannot use it, because their Creatine transporters (CRTs) are defective.

Fortunately, thanks to Dr Joseph Clark, Professor of Neurology at the University of Cincinnati, there is light at the end of the tunnel.  Dr Clark has been researching the Creatine metabolism for some years.  Very unusually, he has been sharing his experiences with us, via his blog.

To cut a long story short, the good doctor has figured out that by using an analog (a modified version) of Creatine called cyclocreatine he could normalize the function of mice with  X-linked Creatine deficiency.  All he now has to do, is to make it work in humans, fully test it and get it FDA approved.  The problem is there is no more money.  In his blog post he tells us that all he needs is:-

$26 million and three more years

Here is the official report from the University:- 

Cyclocreatine Normalizes Cognition in Creatine Deficient Mouse

 

Peter’s thoughts on Creatine

I started looking at Creatine because it appears to stimulate IGF-1 (insulin-like growth factor 1).  This is not a fact well-known to endocrinologists, but it is very well known to athletes and body builders.  They take Creatine orally and it stimulates muscle growth.  Research has even measured the change in IGF-1 in muscle tissue resulting from Creatine supplementation.

In a recent post I pointed out that IGF-1 is itself being used in autism trials, as is a novel Australian analog of IGF-1 [1-3] called NNZ-2566.  The big advantage of NNZ-2566 is that it is taken orally.

The release of IGF-1 is stimulated by growth hormone GH.  Secretion of growth hormone (GH) in the pituitary is regulated by the hypothalamus, which release the peptides Growth hormone-releasing hormone (GHRH) and Growth hormone-inhibiting hormone (GHIH) into the blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.

Stimulators of growth hormone (GH) secretion include:

• peptide hormones
• GHRH  through binding to the growth hormone-releasing hormone receptor
• ghrelin through binding to growth hormone secretagogue receptors
• sex hormones
• increased androgen secretion during puberty (in males from testis and in females from adrenal cortex)
• estrogen
• clonidine and L-DOPA by stimulating GHRH release

·         α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine 
      (Interestingly clonidine is a drug used for ADHD, or autism-lite, as I call it)

• hypoglycemia, arginine and propranolol by inhibiting somatostatin release
• deep sleep
• niacin as nicotinic acid (Vitamin B3)
• fasting
• vigorous exercise

Factors that are known to cause variation in the levels of (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals. These are chemicals found in both household and industrial products that are known to interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of normal cell metabolism. 

Based on my earlier primary research, I am pretty sure that in the sub-type of autism I am dealing with, there is a deficiency of either GH or TRH, in the brain.  As I result, I am interested in mention of these hormones.

 SHANK3 deficiency
(also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome)

IGF-1 is being trialled at Mount Sinai Hospital in New York in autistic children with SHANK3 deficiency.  In true “art” rather than “science” approach, the plan is then to trial IGF-1 on children without SHANK3 deficiency.

Here is a good explanation.

If you live in the Big Apple:-

Where Can I Get Testing?

The Icahn School of Medicine at Mount Sinai offers genetic testing for Phelan-McDermid Syndrome/22q13 Deletion Syndrome and for SHANK3 mutations. A blood sample is needed to conduct the test. For more information about testing, visit The Seaver Autism Center, call (212) 241-0961  

It appears that SHANK3 deficiency accounts for about 1% of autism cases.

If, as is hoped, IGF-1 turns out to be a useful therapy in SHANK3 deficient children, it will be tried on all ASD kids.  If it works, then what was the relevance of SHANK3 in the first place?   It seems pretty odd to me.  I think most likely our current understanding of genetics is so basic, as to be flawed.

I am working via observation, rather than genetics; I know what circumstances produce near neurotypical behaviour, I just need to understand what is going on biologically.  This is how I ended up with TRH and/or GH.

Conclusion

Well if the Mount Sinai study is successful, as it probably will be, we should find Dr Clark in Cincinnati and give him $26 million.  Then we put creatine and cyclocreatine in a pill and give it to ALL people with ASD, since 99% will never get their sub-type diagnosed. 

Either the creatine, the cyclocreatine or the extra IGF-1 will do some good, depending on the sub-type – something for everyone. And no needles.