How to increase Oxytocin (OT) effects in the autistic brain? OT nasal spray, L. reuteri DSM 17938, Magnesium, Estradiol, Nicotinamide riboside …

 Struggle to make friends? Consider Oxytocin

Today’s post was going to be about FMT super-donors, but instead we have a post about new insights into using oxytocin to treat autism.  From personal experience I can say that you really can target oxytocin receptors to affect mood/behavior; I have no personal experience of FMT (fecal microbiota transplants), but thousands of people use it for many conditions.  The FMT post will be next.

Oxytocin and vasopressin are two hormones, made in the hypothalamus, that are established targets for autism treatment. They are released into the bloodstream where they carry out their best-known functions, but they are also released from the hypothalamus directly into the brain where these hormones have entirely different functions.

Both oxytocin and vasopressin can be given as nasal sprays to enter the central nervous system (CNS) rather than just the blood stream.  This means you get the brain effects of the hormone, also known as the “central effects”.

As was discussed previously in this blog and is highlighted more recently in the article below, you can use certain bacteria in the gut to signal to the hypothalamus to produce more oxytocin.  This is really clever and it works in humans, not just research animals.  It also has the advantage of producing a more continuous effect than is found using the intranasal method to deliver oxytocin. 

When you sever the vagus nerve, the bacteria in the gut continues to produce the required chemicals, but the signal to the brain has been lost. The hypothalamus no longer produces increased oxytocin and so the behavioral/mood effect is lost. This has been proven in the research.

Gut microbes may treat social difficulties in autism mice

In science speak, “the results suggest that a peptide or metabolite produced by bacteria may modulate host oxytocin secretion for potential public or personalized health goals”.  It also appears that oxytocin improves wound healing. So perhaps old people with leg ulcers, which never seem to get better, might benefit from a daily dose of L. reuteri DSM 17938, it also might make them feel better due to those central effects.

Oxytocin in the brain acts via oxytocin receptors

As we learned years ago in this blog, you can increase the effect (turn up the volume) of receptors using a PAM (positive allosteric modulator).  Interestingly, magnesium is a PAM of the oxytocin receptor (OTR).  Many people with autism are supplementing magnesium, perhaps those using intranasal oxytocin should join them. 

A very recent paper has investigated in detail how oxytocin receptors function.

Crystal structure of the human oxytocin receptor

The peptide hormone oxytocin modulates socioemotional behavior and sexual reproduction via the centrally expressed oxytocin receptor (OTR) across several species. Here, we report the crystal structure of human OTR in complex with retosiban, a nonpeptidic antagonist developed as an oral drug for the prevention of preterm labor. Our structure reveals insights into the detailed interactions between the G protein–coupled receptor (GPCR) and an OTR-selective antagonist. The observation of an extrahelical cholesterol molecule, binding in an unexpected location between helices IV and V, provides a structural rationale for its allosteric effect and critical influence on OTR function. Furthermore, our structure in combination with experimental data allows the identification of a conserved neurohypophyseal receptor-specific coordination site for Mg2+ that acts as potent, positive allosteric modulator for agonist binding. Together, these results further our molecular understanding of the oxytocin/vasopressin receptor family and will facilitate structure-guided development of new therapeutics. 

Magnesium and mood disorders: systematic review and meta-analysis

Another consequence of ERβ under-expression in autism

Also interesting to those following autism research, is the role of ERβ (estrogen receptor beta).  It is well known that in the brains of those with autism, there is a lack of ERβ.  A lack of ERβ is likely to lead to lower oxytocin in the brain and CSF (spinal fluid).  In many types of autism, we know that the level of oxytocin in CSF is reduced.

If you activate ERβ you both increase expression of oxytocin receptor (OTR) and also increase the level of oxytocin measured in the CSF.  You can activate ERβ with estrogens, like estradiol or even phytoestrogens like soy.  The ideal therapy to use would be DHED.

https://epiphanyasd.blogspot.com/2018/02/dhed-delivering-estradiol-only-to-brain.html

The cheap diuretic spironolactone may very well indirectly increase the level of oxytocin in CSF.

Oxytocin and Estrogen Receptor β in the Brain: An Overview

Oxytocin (OT) is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release OT into the bloodstream to promote labor and lactation; however, OT neurons also project to other brain areas where it plays a role in numerous brain functions. OT binds to the widely expressed OT receptor (OTR), and, in doing so, it regulates homeostatic processes, social recognition, and fear conditioning. In addition to these functions, OT decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter OTR expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase OT peptide transcription, suggesting a role for OT in this estrogen receptor β-mediated anxiolytic effect. Further research is needed to identify modulators of OT signaling and the pathways utilized and to elucidate molecular mechanisms controlling OT expression to allow better therapeutic manipulations of this system in patient populations.

NAD and Nicotinamide Riboside to boost Oxytocin

Today we see that recent research from Japan shows that in those people with autism who have reduced NAD, they may well be able to improve behavior/mood by increasing the level of their oxytocin using Nicotinamide Riboside (NR).

Nicotinamide riboside (NR) is a special form of vitamin B3, sold as an expensive supplement.  The FDA say it is safe for use in humans.

Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder

Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

NR elevates brain NAD⁺ and cerebrospinal OT

Social preference deficit and anxiety of CD157KO males are best corrected at a relatively low dose of NR

The results demonstrated that the daily oral administration of NR rescued the social behavioural impairments observed in male CD157KO mice. NR had essentially no effects on social behaviour in wild-type male mice. The beneficial effects of NR appear to depend on restoration of CSF OT levels because the NR-induced OT elevation was only detected in CD157KO mice, which have a CSF OT deficit.

In the course of identifying a nutritional intervention for CD157KO mice, we reproduced the anxiety-like and social-avoidance-like deficits reported previously. Reproducibly lower levels of CSF OT in male CD157KO mice make these mice an attractive model of autism, anxiety disorder, or social avoidance in neurodegenerative diseases. Significantly, this model responds to both OT and NR as a treatment.

The challenge of polygenic diseases of incomplete penetrance is that they are difficult to understand mechanistically. Multiple genetic and environmental (biochemical) factors may converge to dysregulate pathways that are altered in common conditions such as ASD. We note that one potentially hopeful point when studying polygenetic diseases is that brain systems are redundant, and thus, it may be possible to increase normal functions that are only partially encoded by genetically damaged circuitry.

NAD⁺ is consumed by CD38 in formation of cyclic ADP-ribose. It then participates in OT release in the hypothalamus. In our study, ADP-ribosyl cyclase activity was maintained at a similar range as that in wild-type animals (data not shown). A recent study suggested that NR supplementation did not change CD38 expression. However, in vitro studies have shown that NAD⁺ applied to the mouse hypothalamus leads to OT release. It is reasonable to assume that an elevation in NAD⁺ levels by NR in the hypothalamus is responsible for repair of the OT release.

Future work will probe CD38 dependence and the cell-type dependence of the beneficial effects of NR on CD157KO behaviour, the potential benefits of NR in other ASD models, and the potential of NR to become a safe nutritional intervention, in addition to OT, for at least some types of ASD in human populations.

NAD+ is reduced in older people

There is a lot of research into combating the effects of aging.  It is agreed that the older you get, the less NAD+ you have and so research has looked at numerous ways to raise it.

The CD157KO mice model of autism does feature reduced NAD+, but nobody knows how common reduced NAD+ is in autism.

If you have low levels of NAD+ there will be negative consequences.

I think you can consider NAD+ depletion in a similar way to oxidative stress, both are inevitable and damaging features of aging.

Most healthy younger people are likely wasting their time and money worrying about oxidative stress and NAD+.  These are the people with “detox” diets and juices.

However, most old people and some young people with autism really stand to benefit from correcting oxidative stress and any reduced NAD+.

  

Therapeutic potential of NAD-boosting molecules: the in vivo evidence

Hallmarks of NAD homeostasis

NAD⁺ is not merely a redox co-factor, it is also a key signaling molecule that controls cell function and survival in response to environmental changes such as nutrient intake and cellular damage. Fluctuations in NAD impact mitochondrial function and metabolism, redox reactions, circadian rhythm, immune response and inflammation, DNA repair, cell division, protein-protein signaling, chromatin and epigenetics.

There are many ways to boost NAD+.

Classes of NAD+ boosting molecules and known effects in humans

NAD+ Precursors              

Niacin/ nicotinic acid (NA), Nicotinamide riboside (NR) Nicotinamide (NAM) etc.

CD38 Inhibitors                 

Flavonoids (Quercetin, Luteolin, Apigenin, fisetin, rutin and naringin)             

Luteolinidin.  Kuromanin/ Chrysanthemin, an anthocyanin (food pigment)    

PARP Inhibitors    

BGB-290, Olaparib, Rucaparib, Veliparib, CEP-9722, E7016, Talazoparib, Iniparib, Niraparib, PJ34, DPQ, 3-aminobenzamide

                       

SARM Inhibitors

XAV939                    

NAMPT Activators

P7C3 

Conclusion

Some readers of this blog do give intranasal oxytocin as a therapy.  There have been numerous studies on children with autism, some discussed in earlier posts.  Oxytocin needs to be kept chilled, not to lose its potency.

Eleven previous posts in this blog refer to Oxytocin.

https://epiphanyasd.blogspot.com/search/label/Oxytocin

As to whether stimulating oxytocin receptors is going to be worthwhile in your case of autism, you will just have to try it and see.

I found that the Biogaia Protectis probiotic (L. reuteri DSM 17938) had very clear effects, which were very much hallmark effects of oxytocin.  This is easy and inexpensive to try.

Some readers of this blog do use Nicotinamide Riboside (NR), which we saw today can increase oxytocin by increasing NAD+.

There are very many reasons why you do not want to be lacking in NAD+, other than oxytocin, but if you already have plenty NAD+ you will unlikely see a benefit from yet more.

Magnesium is a very common autism supplement; it is often given with vitamin B6; both can be used to treat stress.

Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial

Cesarian Delivery and Autism – another inconvenient truth?

Brasil is the C-section capital of the world, with rates in the public sector of 35–45%, and 80–90% in the private sector.

A recent study from the Karolinska Institute in Sweden, analysing 61 previous studies, has again shown a connection between birth by Cesarian Section and an increased risk of autism or indeed ADHD. 

C-sections account for just 16% of births in Sweden, but 32% in North America.

This of course prompted a reaction to reassure future mothers that they have nothing to fear, from experts in obstetrics who of course know nothing about the etiology of autism.  Mothers should be reassured, but trashing the study helps nobody.  Instead of a 1% risk of non-trivial autism, it rises to 1.3%. You still have more than a 98% chance of having a neurotypical child, all other factors being equal.  Without a medically necessary C-section, death is a real possibility.

It was a couple of years ago that the Karolinska Institute highlighted the fact that those with severe autism currently have a life expectancy of under 40 years.  Another inconvenient truth.

Association of Cesarean Delivery With Risk of Neurodevelopmental and Psychiatric Disorders in the Offspring 

Question  Is birth by cesarean delivery associated with an increased risk of neurodevelopmental and psychiatric disorders in the offspring compared with birth by vaginal delivery?

Findings  In this systematic review and meta-analysis of 61 studies comprising more than 20 million deliveries, birth by cesarean delivery was significantly associated with autism spectrum disorder and attention-deficit/hyperactivity disorder.

Meaning  The findings suggest that understanding the potential mechanisms behind these associations is important, especially given the increase in cesarean delivery rates for nonmedical reasons.

Abstract

Importance  Birth by cesarean delivery is increasing globally, particularly cesarean deliveries without medical indication. Children born via cesarean delivery may have an increased risk of negative health outcomes, but the evidence for psychiatric disorders is incomplete. 

Conclusions and Relevance  The findings suggest that cesarean delivery births are associated with an increased risk of autism spectrum disorder and attention-deficit/hyperactivity disorder, irrespective of cesarean delivery modality, compared with vaginal delivery. Future studies on the mechanisms behind these associations appear to be warranted. 

Very many things are known to slightly increase the odds of a person having autism and the more risk factors you have the more severely autistic you may be.  This ranges from maternal stress (anything from experiencing a hurricane, work stress, life trauma) to maternal/paternal age, obesity, gestational diabetes, alcohol/drug abuse, illness during pregnancy etc. This combines with whatever is in the parents’ DNA and random mutations that are bound to occur.    

A more rational reaction might be to investigate further why there might be a link and how you could counter any risk to children born by cesarian section.  You only have to read the existing research, or this blog.

There are 2 very good reasons why there should be a link between autism and C section, both have been covered in this blog.

1.     The microbiome comes from the mother. Science is only recently starting to understand the role of bacteria in health, but we know that it plays a key role in conditioning/calibrating the immune system of babies.  Once the immune system has been calibrated it is set for life.  Early exposure to bacteria is necessary and humans evolved to expect it.  If your immune system is over/under sensitive there will be consequences. Birth via C-section avoids exposure to bacteria in the birth canal, unless the newly arrived baby is “seeded” with bacteria from the mother. Mother’s milk is another key source of transferring the mother’s microbiome to the baby. 

2.     We saw that the birthing hormone Oxytocin plays a key role in triggering the “GABA switch” in new-borns. This is the process which transforms immature neurons with high chloride to mature neurons with low chloride shortly after birth.  During natural birth there is a surge in the hormone Oxytocin that is transferred to the baby, this causes the chloride transporter KCC2 to be further expressed and the “opposing” transporter NKCC1 to fade away.  In many people with severe autism their neurons remain in the immature state their entire life.  Just as you can replace the bacteria transfer lost in birth via C-section, there would be absolutely no reason why you could not replicate the surge in Oxytocin to "flip the GABA switch".

The recent study showed that elective C-sections (where the baby is in perfect health and not distressed) are associated with the elevated risk of both Autism and ASD.

Regular readers of this blog would probably be surprised if C-section did not increase autism prevalence.

The important thing is to acknowledge this likely connection and mitigate it, rather than try and fault the numerous studies that have shown the same effect.

The same of course applies to reducing the very small risk from vaccines, rather than construct new studies in a contrived way to show there is zero risk.   If you can safely and cheaply reduce the risk of a negative reaction to vaccines, why wouldn’t you?  Just follow Johns Hopkins example and give Ibuprofen or Montelukast (Singular) for a few days before and after and remember to never give Paracetamol/Acetaminophen (Tylenol) in response to fever after a vaccine. Paracetamol/ Acetaminophen reduces the body’s key antioxidant GSH just when the baby/child may need its neuroprotection most.

Some conditions are associated with preterm births, a good example is Cerebral Palsy (CP), which is twice as common in babies born very early. CP is rarely genetic and is usually considered to be caused by a complication during pregnancy, birth or shortly thereafter. I think you would find a correlation between C-sections and CP, but in this case I doubt you would find it in elective C-sections.   In other words C-sections do not “cause” CP, but they may be associated with it. The ID/MR often found in CP might be elevated by C-section and, if so, would be treatable.

Conclusion

In order to halt the rise in incidence of the disabling kinds of autism there should be steps taken to reduce some of the very many factors that are driving the increase, albeit each one sometimes by a tiny amount.

This would be a good application of all those thousands of autism research papers, many of which have shown what factors contribute to increased risk, that now sit gathering dust.

We are not at the stage of wide scale gene editing, but many simple steps can be taken today to improve future health.  This does not mean do not vaccinate, or avoid medically necessary C-sections; vaccinations and C-sections have saved millions of lives. But, why would you not want to take a good thing and make it even better?  That is what we humans tend to be good at, like the Swedes and their Volvos.

Perhaps take your C-section with a generous smear of Mum's bacteria and a shot of synthetic oxytocin?  

There will be more on Cerebral Palsy in a later post on D-NAC (Dendrimer N-Acetyl Cysteine). 

                                                               

Electro Convulsive Therapy (ECT) and Cannabidiol (CBD) in Autism

Today’s post is another one to fill in some of the gaps in this blog.

Psychiatrists have long been using electric shocks, of one kind or the other, to treat their patients. There is even a special school in the US (the Judge Rotenberg Center) where they used electric shocks as aversive therapy, until very recently.  

FDA Proposes Ban On Electric Shock Devices Used On Autistic Children 

Cannabis, in the form of Cannabidiol (CBD), is currently the subject of an autism trial in Israel, home to some very innovative people.

Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT), formerly known as electroshock therapy, and often referred to as shock treatment, is a psychiatric treatment in which seizures are electrically induced in patients to provide relief from mental disorders. The ECT procedure was first conducted in 1938 is often used as a last line of intervention for major depressive disorder, mania, and catatonia.

As of 2001, it was estimated that about one million people received ECT annually.

Several hundred people with autism have been treated with ECT in the US. 

Transcranial Magnetic Stimulation (TMS)

Do not confuse ECT with Transcranial Magnetic Stimulation (TMS).

Transcranial magnetic stimulation (TMS) is a magnetic method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator is placed near the head of the person receiving the treatment. The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. This is rather similar to the way the base station of a rechargeable electric toothbrush works.

A big fan of TMS is Manuel Casanova, a neurologist and Autism blogger. 

A while back I watched a BBC documentary following an autistic girl adopted from a Serbian orphanage by a US family. All was going well until she later developed a serious problem with aggression and self-injury that was being treated by monthly visits to the hospital for electroconvulsive therapy.  The shocks did indeed seem to do the trick and suppress her aggressive tendencies. She is an example of what I call double tap autism, where an autistic person later suffers a profound setback for some reason. 

Video:- 

My Child, ECT (electric shock) and Me (click the picture below)

Long article from Spectrum News:- 

How ‘shock therapy’ is saving some children with autism 

What I found interesting was that you could see that when you took away the SIB, the girl was pretty high functioning. She could read, write and do math.

This made me recall a previous idea of mine that you might grade people’s autism in terms of both their good days and their bad days.  So on a scale of 100, this girl might have been 30/100.  On a bad day she was a major danger to herself and those around her and so she scored 100, but on a good day she was able to be part of the family and be educated.  She clearly had autism but not such a severe kind, so she might score a 30.

The point missed by the BBC was that in this example, electric shock therapy was not an autism therapy, it was an SIB therapy and it appears to have been a pretty effective one.

Many people with autism do not have flare-ups, they do not have SIB; they are pretty constant in their behavior, so they might be a constant 30/30.  

Cannabis 

Much is written on the internet about the use of cannabis for all kinds of conditions, the ones relevant to this blog are autism and epilepsy.  There is a study currently underway in Israel where they are using CBD oil, the non psychoactive part of cannabis, as an autism therapy.

As you might expect they had no difficulty recruiting people to participate in the study, which is still ongoing. 

Israeli Doctors to Use Cannabis to Treat Autism in First-of-its-kind Study

 In pioneering study, Israeli researchers target autism with cannabis 

Israeli Study Shows Medical Cannabis Can Treat Autism In Children

Dr. Aran is the Director of the Neuro-pediatric unit in Shaare Zedek Medical Center and his latest research involves treating the symptoms of autism using medical marijuana. “So far,” Aran tells NoCamels, “our impression is that it’s working.”

The clinical study began in January 2017 in Jerusalem at the Shaare Zedek Medical Center. There are 120 participants, including children and young adults, diagnosed with various degrees of ASD ranging from mild to severe. Dr. Aran hopes to have final results by December 2017.

According to Dr. Aran, “there are theories” for why medical cannabis can alleviate symptoms of autism, “but we don’t know exactly how. There are theories and models but we don’t know. It can’t be explained.”

This is worrisome given that cannabis is being given to children with little knowledge of why or how it may help. Of course, “We are worried with children because of the long-term impact. But it is considered mostly safe and we have already tested it with epilepsy.” Other studies, like the one published in Seizure: European Journal of Epilepsy 2016, conducted in Israel, successfully demonstrated that cannabis reduced the number of seizures of children with epilepsy. Nonetheless, Aran admits that “There are always worries that something will happen that we don’t know about.”

It is key to note that the participants are receiving cannabidiol (CBD), a non-psychoactive compound, as opposed to the more commonly known tetrahyrdrocannabinol (THC), which creates the “high” feeling. Therefore, the benefits they seem gain from the treatment “help the children cooperate more,” reduce behavioral problems, and “improve their functioning.”

While the study offers much hope for the children and families affected by ASD, Aran warns that “It won’t cure the symptoms, that’s for sure. It will never cure autism. But it certainly can help the quality of life of the families.” 

The lead researcher recently made some revealing comments, he suggested that the results so far are very positive and that it seems that the quality of life has been improved but it does not cure the symptoms. That made be draw the connection to the adopted child in the US; the therapy does indeed seem to be helpful because it is treating the “100” in the 30/100. So it may not improve cognition or reduce stereotypy, but it makes life better, just like the girl receiving the electric shocks.  Hopefully when they publish the results Dr Aran will be much more precise as to the effect of his therapy, since perhaps I am inferring too much from his comments. 

Why does any of this matter?

Well if you want to solve a problem, you have to define it and the more precisely you can define it, the more likely you are to find a solution.

If you have a girl who is a stable 30/30 with no SIB and no epilepsy, it might well be shown that neither electric shocks nor CBD oil will help here.

If you have a girl who is 30/100 with SIB and epilepsy it might well be the case that both electric shocks and CBD oil might help here; but it appears that neither will improve her core autism (which is the 30).

Mode of Action

Neither the doctors using electric shocks nor CBD oil claim to fully understand the mode of action. There are of course various plausible theories.

In the case of CBD it is an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain. It has also been shown to act as a 5-HT_1A receptor partial agonist, and this action may be involved in the antidepressant, anxiolytic, and neuroprotective effects of cannabidiol. It is an allosteric modulator of the μ- and δ-opioid receptors as well.  Cannabidiol's pharmacological effects have additionally been attributed to PPARγ agonism and intracellular calcium release.

Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

  

Do the therapies “work”?

What we have seen in this blog to date is that there are very many things that do seem to help specific people.  It is sometimes hard to figure out for sure the mode of action; but if high doses of biotin, or vitamin B6, or anything else consistently improve someone’s condition over years of use you have to take note.

The electric shocks did indeed seem to successfully control SIB for 3-4 weeks.  Maybe someone clever might figure out the biological cause triggering her SIB and so provide an alternative  drug therapy, but for now it seems she will go once a month for more shocks.

There are people who think long term use of CBD oil will have negative effects and I guess monthly electric shocks may also have some unforeseen consequences.

The Israeli researchers seem pretty keen on pursuing CBD oil and so they may well end up with a large enough clinical trial to make people take notice.

I do not see hundreds of parents signing up to a clinical trial of electric shock therapy, so it looks likely to be a niche therapy used by one or two clinicians.

CBD oil is the sort of therapy that will appeal to many parents and it is being trialed on so many different people we will soon know if there are harmful long term effects.

  

My Take

It looks to me that electroconvulsive therapy is rather crude and while it does evidently help some people, it might not be without serious risk. If the person has uncontrollable SIB, it looks a risk worth taking.

Short term use of CBD oil looks a safer bet, but if the effect required is just calming/sedating there may be other ways to achieve this.  Many parents are already using CBD oil as a home autism therapy.

There are hundreds of clinical trials completed, or in progress, using CBD to treat everything from ulcerative colitis to anxiety. It is being trialed in schizophrenia and even Dravet Syndrome and other kinds of epilepsy.  There is even a trial of a CBD chewing gum to treat Irritable Bowel Syndrome. CBD actually now has designated orphan drug status with the FDA for Dravet Syndrome.

I have no plans to use either therapy; I seem to have addressed the variable nature of my case of autism.  I am more interested in treating the core autism symptoms, the “30” in the 30/100; it is clear that much more remains possible.  

Tackling the “30”

An interesting recent finding came from a study on Oxytocin at Stanford. This time researchers had the good sense to actually measure the level of the oxytocin hormone in the blood of the trial participants before and after they started having oxytocin squirted up their noses. 

Oxytocin improves social abilities in some kids with autism, Stanford study finds 

Not surprisingly it was people with low natural levels of oxytocin who were the favorable responders and interestingly those in the placebo group who also responded actually increased their natural level of oxytocin production.

As we know there are other ways to increase you level of oxytocin, one of which is via certain L. reuteri probiotic bacteria.

Oxytocin would fit in the tackling the “30” category, for those with naturally lower levels of this hormone.

The Stanford researcher is again Dr Hardan, from that interesting phase 2 trial of the antioxidant NAC.  He is now planning a larger oxytocin trial. Has he forgotten about making a phase 3 trial of NAC?   

Self Injurious Behavior (SIB)

You do wonder why some clinician does not compile a list of all the known causes and therapies for self-injurious behavior (SIB) in autism.  There is even a study planned at Emory University to test the efficacy of NAC to treat SIB, but with only 14 participants, I do not really see the point.

We do know that a small number of people with SIB respond well to NAC. If just 10% are responders, you would need a really large trial prove anything at all. With 14 participants you should have just one, but as luck might have it, it could be none.

With a more scientific/engineering approach you might identify five sometimes effective SIB therapies, and then go systematically through testing each therapy on each person with SIB. Then you would have some useful data.    

As I mentioned in a recent comment, the late Bernie Rimland from ARI, was a big believer in high dose vitamin B6 to treat SIB.  For some people it is a nicotine patch, for my son in summer it is an L-type calcium channel blocker.

The reality is that numerous complex dysfunctions can lead to SIB, but so do some simple things like untreated pain and inflammation, which could be from IBS/IBD or even tooth eruption/shedding or just tooth decay.

Vitamin A (and ATRA) Upregulate Oxytocin via CD38

 A familiar site to Maja, the confluence of the Sava and the Danube

Today’s post is to document an interesting discovery by Maja, one reader of this blog.  She is just ahead of some Korean researchers, who very recently published a paper in Experimental Neurobiology on the same subject.

Maja noticed that giving a small dose of fish oil produced the same benefits as those often claimed for Oxytocin; she then did some investigation and noted that an enzyme called CD38 upregulates oxytocin in the brain.  The level of CD38 is affected by inflammatory cytokines and certain vitamins.  In particular, all-trans retinoic acid (ATRA) increases CD38. All-trans retinoic acid (ATRA) is made in the body from vitamin A.  ATRA is also called vitamin A acid.

Maja suggested this paper:-

All-trans Retinoic Acid Upregulates Reduced CD38 Transcription in Lymphoblastoid Cell Lines from Autism Spectrum Disorder

Deficits in social behavior in mice lacking the CD38 gene have been attributed to impaired secretion of oxytocin. In humans, similar deficits in social behavior are associated with autistic spectrum disorder (ASD), for which genetic variants of CD38 have been pinpointed as provisional risk factors. We sought to explore, in an in vitro model, the feasibility of the theory that restoring the level of CD38 in ASD patients could be of potential clinical benefit. CD38 transcription is highly sensitive to several cytokines and vitamins. One of these, all-trans retinoic acid (ATRA), a known inducer of CD38, was added during cell culture and tested on a large sample of N = 120 lymphoblastoid cell (LBC) lines from ASD patients and their parents. Analysis of CD38 mRNA levels shows that ATRA has an upmodulatory potential on LBC derived from ASD patients as well as from their parents. The next crucial issue addressed in our study was the relationship between levels of CD38 expression and psychological parameters. The results obtained indicate a positive correlation between CD38 expression levels and patient scores on the Vineland Adaptive Behavior Scale. In addition, analysis of the role of genetic polymorphisms in the dynamics of the molecule revealed that the genotype of a single-nucleotide polymorphism (rs6449182; C>G variation) in the CpG island of intron 1, harboring the retinoic-acid response element, exerts differential roles in CD38 expression in ASD and in parental LBC. In conclusion, our results provide an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids.

In December some Korean researchers also suggested that ATRA might be used therapeutically to increase Oxytocin.  Maja discovered that vitamin A can also be used, which makes sense.

The Korean paper reviews the existing literature and clinical trials on oxytocin in autism, and I suggest those interested should read it.

Some people clearly benefit from oxytocin, some do not and some suffer side effects.

In those that benefit from oxytocin, it might be simpler to upregulate the body’s own oxytocin via ATRA, or vitamin A.

Is this proof?

Of course there are other explanations possible for what Maja has noted.  She was using fish oil as a source of vitamin A, so it could be related to the other constituents.

However, I for one think it is highly plausible and does fit nicely with the ideas put forward by the Korean researchers and the earlier paper.

Vitamin A for all?

We know that autism genes include many for oxytocin, oxytocin receptors and indeed CD38, so anyone with those genes dysfunctional might benefit.

However, as we saw with biotin, more people may be affected to a lesser degree.

CD38 affects oxytocin secretion in the brain and CD38 is affected by inflammatory cytokines, so at times of elevated cytokine expression, CD38 and oxytocin might be reduced in people with no relevant genetic dysfunction.

You can have too much vitamin A, this is called Hypervitaminosis A.  You cannot suffer this condition by eating fruit and vegetables, but you can by eating too much preformed vitamin A from foods (such as fish or animal liver), supplements, or prescription medications; it can be prevented by ingesting no more than the recommended daily amount.

High intake of provitamin carotenoids (such as beta carotene) from vegetables and fruits does not cause Hypervitaminosis A, as conversion from carotenoids to the active form of vitamin A is regulated by the body to maintain an optimum level of the vitamin. Carotenoids themselves cannot produce toxicity.

So, too much cod liver oil can be bad for you, but you can eat carrots like Bugs Bunny and do no harm.  If you really overdo it, your skin may change colour to orange, something called carotenosis

You can buy vitamin A supplements as the preformed vitamin or as beta carotene.

Too much of a good thing?

In times gone by, children used to be given a tablespoon of cod liver oil daily, as a good source of vitamin D and vitamin A.  These days that amount of both vitamins would be seen as excessive.  Excess of both vitamins is bad for you, but easy to achieve, by accident, while trying to do a good thing.

Maja’s Dose

Maja achieved her positive results with a modest dose of fish oil (using 40% of one capsule) giving 3-4000 IU of vitamin A.

This is actually quite a high dose of vitamin A, if you look at the maximum safe dose.

I think many people are giving kids with autism much larger doses of fish oil and thus far too much vitamin A and D.  This has been raised as an issue by Seth, another reader of this blog.

CD38

CD38 has many other functions other than regulating oxytocin. In people who have an oxytocin dysfunction due to an upstrean CD38 dysfunction, correcting the lack of CD38 might be particularly beneficial.   

CD38 is used as a prognostic biomarker for leukemia.  This is a complex area of science.  In essence, it is an accepted fact that increased CD38 expression is associated with favorable prognosis in adult acute leukemia.

Leukemia is associated with Down Syndrome. 

Not surprisingly, both vitamin A and ATRA can be beneficial in treating leukemia.

ATRA (All Trans-Retinoic Acid) for acute myeloid leukaemia (AML)

CD38 expression is apparently easy to measure.

Perhaps in those numerous oxytocin trials for autism, they might want to bother measuring CD38?

The Recent Korean Paper

Here is what the Koreans have to say about Oxytocin:-

 Is Oxytocin Application for Autism Spectrum Disorder Evidence-Based?

CD38 is a transmembrane antigen that has been studied as a negative prognostic marker for chronic lymphocytic leukemia [72]. CD38 participates in the oxytocin secretion in the brain and affects maternal nurturing and social behavior [73]. Plasma levels of oxytocin are strongly reduced in CD38 knockout mice (CD38-/-mice) and subcutaneous oxytocin injection or lentiviralvector-mediated delivery of human CD38 into the hypothalamus rescued social memory and maternal care in these mice [73].

CD38 transcription is highly sensitive to cytokines and vitamins, including all-trans retinoic acid (ATRA), a known inducer of CD38 [75]. In a study on lymphoblastoid cell lines in patients with ASD and their parents, ATRA exhibited an upmodulatory potential on CD38 mRNA [75]. Although there have been almost no follow up studies on ATRA and ASD treatment, there is a possibility that substances affecting CD38 expression, such as ATRA, may be potential therapeutic candidates