Clonidine and Guanfacine for ADHD, mast cell activation, sleep disorders, tics and some self-injurious behavior (SIB)

 

Both clonidine and guanfacine were raised recently to me, they have been covered in various earlier posts and in my book. Here is a round-up of the information.

These two drugs are α2A-adrenergic receptor agonists originally used to treat high blood pressure. Subsequently many additional uses of these drugs have been discovered.

I was asked about its use to treat mast cell activation syndrome (MCAS) and the mechanism by which it achieves this effect is interesting.

Calming mast cells – the ones that release histamine during an allergic reaction

Clonidine/guanfacine, as alpha-2 adrenergic agonists, inhibit mast cells primarily by interacting with the central and peripheral nervous systems, leading to a decrease in the release of inflammatory mediators. Its mechanism involves stimulating alpha-2 adrenergic receptors, which in turn suppresses the release of norepinephrine and other neurotransmitters.

In terms of mast cell stabilization, clonidine/guanfacine is thought to reduce intracellular calcium levels and inhibit the degranulation process that releases histamine and other pro-inflammatory substances. Lower intracellular calcium prevents the activation of key signaling pathways that normally trigger mast cell activation and degranulation.

This stabilizing effect helps prevent excessive allergic and inflammatory responses, making clonidine/guanfacine beneficial in conditions where such inhibition is useful.

Clonidine/guanfacine have some calcium channel-blocking properties, though they are not classified as a traditional calcium channel blocker. By indirectly lowering intracellular calcium levels, clonidine/guanfacine inhibit the signaling pathways that lead to mast cell degranulation and the release of inflammatory mediators. The end result is a reduction in cellular excitability and a dampening of the inflammatory response, including mast cell stabilization.

Clearly, you could just go directly to a calcium channel blocker like verapamil.

Clonidine/guanfacine and indeed verapamil are not seen as first line treatments for MCAS but may well be beneficial.

Conventional First-Line Treatments for MCAS

Antihistamines

H1 blockers (e.g., cetirizine, loratadine) to manage allergic-type symptoms like itching, hives, and flushing.

H2 blockers (e.g., famotidine, ranitidine) to control gastrointestinal symptoms and histamine release in the stomach.

Mast Cell Stabilizers

Cromolyn sodium is often considered one of the most effective mast cell stabilizers for MCAS, especially for gastrointestinal symptoms.

Ketotifen, another mast cell stabilizer with antihistamine properties, can also be helpful.

Rupatadine and azelastine are also potentially beneficial as mast cell stabilizers.

Leukotriene Inhibitors

Medications like montelukast can help manage symptoms related to leukotrienes, which are other mediators released by mast cells.

Aspirin

Aspirin can play a role in managing MCAS, particularly in controlling specific symptoms like flushing, hives, and inflammation. Its primary action in MCAS involves inhibiting prostaglandin D2 (PGD2), which is one of the inflammatory mediators released by mast cells and contributes to the vascular symptoms seen in MCAS.

Sleep disorders

Some people with autism do not sleep well.

Clonidine/guanfacine can help some individuals fall asleep faster and stay asleep longer by promoting relaxation and calming overactivity in the brain.

It is sometimes used in pediatric populations, such as children with autism or ADHD, to help with sleep initiation and minimize frequent nighttime awakenings.

Clonidine/guanfacine, being alpha-2 adrenergic agonists, lower the activity of the sympathetic nervous system (the fight-or-flight response).

Clonidine/guanfacine is typically prescribed at a low dose for sleep, as higher doses can lead to daytime drowsiness. Taking clonidine at night, about 30-60 minutes before bed, is common practice.

Guanfacine has a longer half-life than clonidine, which means it provides a more sustained effect throughout the night and may lead to fewer night-time awakenings. This can be particularly useful for individuals who need consistent support for sleep through the night.

Tics

Clonidine/guanfacine have long been used off-label to treat Tourette’s syndrome, which is a tic disorder.

Clonidine/guanfacine can help manage some stereotypical behaviors (repetitive, non-functional behaviors) in individuals with autism, when these behaviors are driven by hyperactivity, impulsivity, or anxiety.

Clonidine/guanfacine helps manage tics by calming the nervous system, modulating norepinephrine release, reducing stress, and helping with impulse control.

This effect has been noted by our reader AW.

Self-injurious behavior (SIB)

Self-injurious behavior (SIB) is usually considered the worst feature of autism. It becomes a learned behavior which can be very hard to extinguish.

Clonidine/guanfacine is on the long list of sometimes effective therapies. Take a note of this!

 

Clonidine as a Treatment of Behavioural Disturbances in Autism Spectrum Disorder: A Systematic Literature Review

Clonidine has a limited evidence base for use in the management of behavioural problems in patients with ASD. Most evidence originates from case reports. Given the paucity of pharmacological options for addressing challenging behaviours in ASD patients, a clonidine trial may be an appropriate and cost-effective pharmaceutical option for this population.

Beneficial Effects of Clonidine on Severe Self-Injurious Behavior in a 9-Year-Old Girl with Pervasive Developmental Disorder

ADHD

ADHD is very commonly diagnosed these days.

The genes involved in ADHD, autism, bipolar and schizophrenia are overlapping, so it is not surprising that many people are now being diagnosed with both ADHD and autism.

What I find very odd is that people with ADHD line up for medical treatment, but most people with comorbid autism think there cannot be a medical treatment for their autism because it is just how their brain is “wired-up differently.” It is hard to reconcile these views - both conditions are clearly treatable.

Most ADHD treatments are stimulants. Medications like methylphenidate (Ritalin, Concerta) and amphetamine-based drugs (Adderall, Vyvanse) are typically considered first-line treatments for ADHD. They work by increasing levels of dopamine and norepinephrine in the brain, which help improve focus, attention, and impulse control in people with ADHD.

Not all individuals with ADHD can tolerate stimulants, and in some cases, they may experience unwanted side effects like anxiety, sleep disturbances, or increased irritability.

The most common non-stimulant options are Clonidine and Guanfacine. They does not directly increase dopamine or norepinephrine but instead reduces norepinephrine release, promoting a calming effect.

Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor (NRI), which increases norepinephrine in the brain by blocking its reuptake.

After years of off-label use in by 2010 both clonidine and guanfacine were FDA approved for use in ADHD.

 

Conclusion

As I mentioned to one reader, we should take note that both clonidine and guanfacine are approved for use in children (with ADHD) and so there is plenty of safety information and dosage guidance.

The effective dose for MCAS, sleep disorders, tics and SIB may well vary from person to person but the safe boundaries are well established from ADHD.

In general, guanfacine tends to be better tolerated than clonidine.

AW might note that guanfacine can cause sleep problems, including insomnia or vivid dreams.

Here is a useful list I found:

Common Side Effects:

Sedation/Drowsiness: Like clonidine, guanfacine can cause drowsiness, especially during the initial stages of treatment or when the dose is increased.

Fatigue: Many people report feeling fatigued or tired when starting guanfacine, which can affect daytime functioning.

Low Blood Pressure (Hypotension): Guanfacine also lowers blood pressure, potentially leading to dizziness or light-headedness, particularly when standing up quickly.

Dry Mouth: This is another common side effect, similar to clonidine, and may cause discomfort.

Headache: Some people experience headaches, especially when starting treatment.

Stomach Problems (e.g., abdominal pain, constipation): Gastrointestinal side effects can occur in some individuals, such as constipation or stomach discomfort.

Irritability and Mood Swings: In some cases, guanfacine may cause irritability or emotional instability.

Less Common but Serious Side Effects:

Bradycardia (slow heart rate): As with clonidine, guanfacine can cause a slow heart rate, which could be concerning for individuals with underlying heart issues.

Rebound Hypertension: Discontinuing guanfacine too abruptly can cause rebound hypertension (a sudden increase in blood pressure), so it should be tapered gradually under a healthcare provider’s guidance.

Sleep disturbances: In some cases, though less common than with clonidine, guanfacine can cause sleep problems, including insomnia or vivid dreams.

Glutamate Inhibitors to Treat Some Autism and ADHD

 A festive queue at the pharmacy for Glutamate Inhibitors

We have now established that much autism and indeed other disorders, from Down Syndrome to Schizophrenia, features a degree of excitatory/inhibitory (E/I) imbalance.

It is very likely that there are multiple underlying causes for this and so there may be multiple treatments.  We can even potentially use a treatment for one cause (ALS) to improve outcomes in others.  So we can (partially) solve a problem without fully understanding its origin, as frequently is the case in biology.

An E/I imbalance might cause anxiety in the adult with Asperger (treatable with Baclofen), contribute to MR/ID in the child with Down Syndrome and contribute to seizures and cognitive loss in someone with severe autism.

Very interestingly in the comments to a previous post, Agnieszka has pointed out why common penicillin type antibiotics (beta-lactams) improve many people’s autism.  This is very common observation and our other guest blogger Seth Bittker found the same in his son. Nat’s guest speaker at her autism conference also found this in his son.

The Glutamate Transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene.   It is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Glutamate is an excitatory neurotransmitter, so it encourages neurons to fire.

By upregulating the GLT1 transporter you increase the inactivation of glutamate and so shift the Excitatory/Inhibitory balance towards inhibitory.

Agnieszka highlighted this paper from Johns Hopkins:-

Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.

It actually gets more interesting and relevant to treatment.

Mutations in SLC1A2 which decrease expression of the GLT-1 protein are associated with amyotrophic lateral sclerosis (ALS). 

The drug riluzole approved for the treatment of ALS upregulates GLT-1.

This would suggest that Agnieszka, Seth and John Rodakis might want to pay a visit to the pharmacy and pick up some riluzole.  It is certainly worth investigating.

I did check and there is even a trial on Riluzole in autism and evidence of existing off-label use.  They have not of course made Agnieszka’s connection; they seem to be just trying it because nothing else seems to help. That really is trial and error and makes this blog look positively scientific by comparison.

A Pilot Study of Riluzole Versus Placebo in the Treatment of Children and Adolescents With ASD(RILISE)

Drug: Riluzole

50mg once daily (QD) for 12 weeks for participants 6-11 years old; 50mg twice daily (BID) for 12 weeks for participants 12-17 years old

Riluzole in Autistic Disorder

A reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223 is under development for the treatment of generalized anxiety disorder and mood disorders  by Biohaven Pharmaceuticals.

  

Anyway, are there any other ways to inhibit Glutamate?

Yes, our reader Valentine just stumbled on one, tizanidine, but there are at least two others. 

α2 adrenergic agonists

Three other known inhibitors of glutamate happen to be α2 adrenergic agonists

·        Clonidine

·        Guanfacine

·        Tizanidine

All three of the above are already used in ADHD and sometimes in autism, but not to reduce glutamate.

I wrote a post about Clonidine use in autism a long time ago.

Clonidine, ADHD and Autism

Guanfacine is an ADHD drug known to inhibit glutamate release.

Guanfacine shown safe and effective in autism treatment

At five sites, children with ASD and moderate to severe hyperactivity were either given guanfacine or a placebo tablet for eight weeks, in a randomized and double-blind clinical trial. The research team collected information from parents and measured each child’s overall response. After eight weeks of treatment, extended release guanfacine was superior to placebo for decreasing hyperactivity and impulsiveness.

Our reader Valentina seems to have stumbled upon tizanidine, but finds it helpful for her son. Tizanidine is a α2 adrenergic agonists but also inhibits glutamate.  It is one of the drugs used off-label by Dr Chez in ADHD and autism

Pediatric safety of tizanidine: clinical adverse event database and retrospective chart assessment

Henney HR 3rd¹, Chez M.

CONCLUSION:

The overall safety of tizanidine in the pediatric group appeared good; however, the adverse event profile differed from that in adults. This difference most likely reflects the off-label use of tizanidine as adjunctive treatment for attention disorders and autism. The frequency and nature of adverse events in adults were consistent with the tizanidine prescribing information as reported for its approved indication, i.e. management of spasticity.

Conclusion

Ideally you would have a comparison of the four drugs:

·        Riluzole

·        Tizanidine

·        Clonidine

·        Guanfacine

We know clonidine is not an autism wonder drug, but then what is?

I think Riluzole is likely to be a good one, but very likely what works best will vary from person to person.

Perhaps a positive response to beta-lactam (penicillin) antibiotics is a biomarker for people who will respond to Riluzole? It should be.

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.