Autism Biomarkers – Serotonin: LSD, SSRIs & Cyproheptadine/Periatin

Researchers are always looking for biomarkers of autism as a diagnostic tool; I am more interested in biomarkers as an indicator of might be going wrong and hence, perhaps, an indicator of what to do about it.

Going back more than half a century, just such a biomarker was found.  Increased platelet levels of 5-HT (5-Hydroxytryptophan) were found in 30-40% of the autistic population.  5-HTP increases the production of the neurotransmitter serotonin and so it was suggested that hyperserotonemia may be a factor in autism.

  

Hyperseratonemia (Serotonin syndrome)

Hyperseratonemia is not treated by reducing the amount of serotonin, rather by using a receptor antagonist that in effect blocks the serotonin effect.

  

SSRIs and other anti-depressants

Several classes of drugs target the 5-HT system including  anti-depressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as well as the psychedelic drugs and empathogens.

In you live in the US, you will have heard of Prozac (vitamin P) which is a very widely prescribed anti-depressant.  It is in a class of drug called Selective Serotonin Re-uptake Inhibitors or SSRI.  Many autistic children in the US are prescribed SSRIs like Prozac. In Japan Prozac is illegal.

SSRIs are believed to increase the extracellular level of serotoinin by inhibiting its reuptake.  Excessive use of SSRIs is known to lead to hyperseratonemia.  If you are already prone to hyperserotonemia, like 40% of autistic kids, it would seem that SSRIs could be potentially dangerous drugs.

A good deal of research does exist on the use of SSRIs in autism and it pretty much shows that they do not do much good, (and they certainly can have nasty side effects).  Look at page 6, in the review paper below that included all kinds of drugs trialled in autism.

Psychotropic Medications in Children with Autism Spectrum

Disorders: A Systematic Review and Synthesis for Evidence-Based Practice

LSD and other serotonin antagonists

LSD is a banned substance in the US and Europe, but in the time before I was born, it was being used to treat autism.  LSD, among other things, is a serotonin antagonist.  There are indeed several papers published on its use in autism and other conditions.

I was quite surprised to see Ivaar Lovaas, the “father” of Applied Behavioural Analysis (ABA) was merrily giving autistic children LSD at UCLA in the early 1960s.

Modification of Autistic behaviour with LSD-25

These old studies are quite interesting and if you want more just click here.

I am not suggesting you take your child to Amsterdam, but if you look on Google you will see that adults with ASD are indeed using LSD therapy.

It now appears that after being banned from use decades ago, medical research with LSD has been restarted.

Fortunately, there are other serotonin antagonists that are available and will not land you in trouble.  The one that attracted my attention is Cyproheptadine or Periactin.

Cyproheptadine in Research

There has been just one study published on autism and Cyproheptadine and that was in 2004.  It is not exactly what we need, since it was being trialed as an adjunct therapy to haloperidol.  Haloperidol is an antipsychotic.

If you live in the US you will be familiar with Risperidone, which is another antipsychotic shown to be effective in autism. In the UK, only specialists such as child psychiatrists can prescribe risperidone for children with autism.  Risperidone can cause side effects like uncontrollable shaking.

So the trial was in effect to see the effect of the antipsychotic + Cyproheptadine vs antipsychotic + placebo.  This is not exactly what we want, but better than nothing.

As you will see in the charts below, the addition of Cyproheptadine did indeed make a marked improvement.  Sadly this research has not been followed up on.

    

Cyproheptadine in the treatment of autistic disorder: a double-blind placebo-controlled trial… -

Serotonin and Emotional Response

There was a recent study looking at how the emotional response of adults with autism was affected by lowering serotonin levels, I could not find the full version.

Cognition and behaviour: Serotonin may alter emotion response

Conclusion

Elevated blood levels of serotonin may or may not be a “red herring” in autism research.  The evidence is far from complete and it is not going to be a magic bullet.  Nonetheless, I suspect lowering serotonin levels may have far more impact than those expensive high EPA Omega 3 pills many parents are feeding to their kids.

The latest research does actually indicate that genetic differences cause the high levels of 5-HT in autism.  100% conclusive research does not exist showing the value of counteracting this genetic difference.  A safe, cheap, serotonin antagonist, Cyproheptadine /Periactin does exist; and it is available OTC in some countries.

Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior

Vitamin P may be good for you!

Now if the tittle makes sense to you, either you are a Prozac fan, or you were around in the 1940s and 50s when there actually was a vitamin P.

This blog is about autism, and in the US lots of such kids are prescribed the powerful antidepressant Prozac. We are more interested in the other vitamin P; these days they are called flavonoids.  This post will meander into other health problems but will return to ASD later on.

Flavonoids are found in plants and there are 5,000 of them.  In plants they have various functions, one of which is to provide colour (usually yellow, red and blue); in humans it is proposed that certain flavonoids may account for the beneficial properties of certain foods, ranging from chocolate to red wine.

There are many food supplements sold that contain flavonoids, three of the popular ones seem to be:-
 

·         Rutin

·         Quercetin

·         Luteolin

There is even a special mix made for autistic people called NeuroProtek.

 

In Vitro or in Vivo?

Some things work well in the test tube but not so well in us humans.  In vitro means in the glass and in vivo means in us living creatures.

Well, flavonoids have wonderful antioxidant properties, but it seems that is in only true in the test tube.  In vivo they are rather a flop.  Yet, if you read all the advertising for these flavonoid supplements, they rave about the antioxidant properties.

 

A great discussion of flavonoids is presented by the Linus Pauling Institute at Oregon State University. I have summarized much of it here and added the autism part.

 

Some flavonoids are good for you, but not as antioxidants

If flavonoids are not good antioxidants, why are they supposed to be good for you?  It seems that they have an entirely different role as signalling molecules.

Concentrations of flavonoids required to affect cell-signaling pathways are considerably lower than those required to affect cellular antioxidant capacity. Flavonoid metabolites may retain their ability to interact with cell-signaling proteins even if their antioxidant activity is diminished. Effective signal transduction requires proteins known as kinases that catalyse the phosphorylation (transferring a phosphate group (-PO₄)) of target proteins at specific sites.

The results of numerous studies in cell culture suggest that flavonoids may affect chronic disease by selectively inhibiting kinases.

Cell growth and proliferation are also regulated by growth factors that initiate cell-signaling cascades by binding to specific receptors in cell membranes. Flavonoids may alter growth factor signaling by inhibiting receptor phosphorylation or blocking receptor binding by growth factors.

All this leads naturally to think that modulation of cell-signaling pathways by flavonoids could help prevent cancer.  Mechanisms proposed include:-

Stimulating phase II detoxification enzyme activity: Phase II detoxification enzymes catalyse that promote the excretion of potentially toxic or carcinogenic chemicals.

Preserving normal cell cycle regulation: Once a cell divides, it passes through a sequence of stages collectively known as the cell cycle before it divides again. Following DNA damage, the cell cycle can be transiently arrested at damage checkpoints, which allows for DNA repair or activation of pathways leading to cell death if the damage is irreparable. Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer.

Inhibiting proliferation and inducing apoptosis (cell death): Unlike normal cells, cancer cells proliferate rapidly and lose the ability to respond to cell death signals that initiate apoptosis.

Inhibiting tumor invasion and angiogenesis: Cancerous cells invade normal tissue aided by enzymes called matrix-metalloproteinases. To fuel their rapid growth, invasive tumors must develop new blood vessels by a process known as angiogenesis.

Decreasing inflammation: Inflammation can result in locally increased production of free radicals by inflammatory enzymes, as well as the release of inflammatory mediators that promote cell proliferation and angiogenesis (creation of new blood vessels) and inhibit apoptosis (beneficial cell death).

Modulation of cell-signaling pathways by flavonoids could help prevent cardiovascular disease by:

Decreasing inflammation: Atherosclerosis is now recognized as an inflammatory disease, and several measures of inflammation are associated with increased risk of heart attack.

Decreasing vascular cell adhesion molecule expression: One of the earliest events in the development of atherosclerosis is the recruitment of inflammatory white blood cells from the blood to the arterial wall.

Increasing endothelial nitric oxide synthase (eNOS) activity: eNOS is the enzyme that catalyzes the formation of nitric oxide by vascular endothelial cells. Nitric oxide is needed to maintain arterial relaxation. Impaired nitric oxide-dependent vasodilation is associated with increased risk of  cardiovascular disease.

Decreasing platelet aggregation: Platelet aggregation is one of the first steps in the formation of a blood clot that can occlude a coronary or cerebral artery, resulting in myocardial infarction or stroke, respectively. Inhibiting platelet aggregation is considered an important strategy in the primary and secondary prevention of cardiovascular disease.

 

Green tea and even red wine were supposed to have wonderful antioxidant properties; apparently this is not true after all.  They do seem to be good for you, but for completely different reasons.

People who consume larger amounts of flavonoids do seem to be healthier; but sadly that does not prove that eating flavonoids makes you healthy.  It might just be that a healthy diet just happens to be flavonoid-rich.

There is on-going research and multiple clinical trials into the possible benefits of flavonoids in these areas:-

Cardiovascular Disease

The results of some controlled clinical trials suggest that relatively high intakes of some flavonoid-rich foods and beverages, including black tea, purple grape juice, and cocoa (dark chocolate) has health benefits.

Cancer

The research is ongoing, it seems to show that those people with a diet rich in flavonoids have a lower risk of certain cancers; but it seems that tea consumption has no benefit here.

Neurodegenerative Disease

It is not clear to what extent flavonoids can cross into the brain thought the BBB (blood brain barrier).  Research is ongoing to see whether Parkinson’s disease, Alzheimer’s and dementia are correlated to flavonoids in the diet.  With 5,000 flavonoids this will take some time!

 

Flavonoid Content in Food

 

There are 5 principal types of flavonoids

1.    ANTHOCYANIDINS

Examples:- Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin

Supplements available include: Bilberry, elderberry, black currant, blueberry, red grape, and mixed berry extracts.  Don’t forget the red wine.

 

2.    FLAVONOLS

Examples:- Quercetin, Kaempferol, Myricetin, Isorhamnetin

The flavonol aglycone, quercetin, and its glycoside rutin are available as dietary supplements without a prescription in the U.S. Other names for rutin include rutinoside, quercetin-3-rutinoside, and sophorin. Citrus bioflavonoid supplements may also contain quercetin or rutin.

Flavonols are found in yellow onions, scallions, kale, broccoli, apples, berries and teas.

3.    FLAVONES

Examples:-  Luteolin, Apigenin

The peels of citrus fruits are rich in polymethoxylated flavones: tangeretin, nobiletin, and sinensetin. Although dietary intakes of these naturally occurring flavones are generally low, they are often present in citrus bioflavonoid supplements.

Flavones are found in parsley, thyme, celery, hot peppers, and chamomile

4.     LAVANONES

Examples:- Hesperetin, Naringenin, Eriodictyol

Citrus bioflavonoid supplements may contain glycosides of hesperetin (hesperidin), naringenin (naringin), and eriodictyol (eriocitrin). Hesperidin is also available in hesperidin-complex supplements

Lavanones are found in citrus fruits and juices, e.g., oranges, grapefruits, lemons

5.    FLAVANOLS 

A.    Monomers (Catechins)

examples:- Catechin, Epicatechin, Epigallocatechin Epicatechin gallate, Epigallocatechin gallate

B.    Dimers and Polymers:
examples:-  Theaflavins,  Thearubigins, Proanthocyanidins

Here is where to find them:-

Catechins: Teas (particularly green and white), chocolate, grapes, berries, apples
Theaflavins, Thearubigins: Teas (particularly black and oolong)
Proanthocyanidins: Chocolate, apples, berries, red grapes, red wine

 

USDA Database for the Flavonoid Content of Selected Foods

If you want to know which food contains how much of each flavonoid, just click on the link to go to a large database held by the US Department of Agriculture.

 

USDA Database for the Flavonoid Content of Selected Foods

 

Another flurry of Patents

Not for the first time, I have noted that a flurry of patents have been filed in connection with autism.  This time it’s a couple of guys from the University of South Florida who see promise in the flavonoids :-  luteolin, diosmin, and diosmin's aglycone form, diosmetin.

 

The more prolific publisher is Theoharis Theoharides.  Here is an excerpt, from his patent:-

  

 

Theoharides is a big believer the benefit of luteolin.  Here is his main hypothesis Neuro-inflammation, blood-brain barrier, seizures and autism.

A more recent paper, again about luteolin is:- Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release,which is inhibited by luteolin

I like the fact that he is questioning the permeability of the BBB (blood brain barrier) in autism.  It seems entirely plausible and would account for many things.

  

Conclusion

 

Well I was already convinced that red wine was good for me.  Now I just have add the right vitamin P.

Time for a cup of tea, better make it chamomile (for the luteolin) and some dark chocolate.

Monty is still rather young for the red wine.  If he was French, though ….