2021 Autism PollyPill To Do List – Speech ↑ and Misophonia ↓

 

 A few ideas remain to be fine-tuned

Having started to develop my son’s polytherapy for autism back in December 2012, is there anything left to develop in 2021?

As we have seen, the biggest impact from interventions is when you start them very young, but improvement is possible at any age.

I was asked at the recent Synchrony autism conference what is next for the PolyPill?  and I replied that more spontaneous expressive language is my main target.  I have a good idea of what may help.

·        Calcium folinate, increased over 6 weeks to 45mg/day

·        Sulforaphane, with added Myrosinase in the form of Wasabi

I was contacted by a researcher from that Synchrony conference, suggesting that Low Level LED Therapy (LLLT) was worth trying to improve the use of speech.  It does seem to benefit people with many types of brain injury.  I did write a post on LLLT using lasers, not LEDs, in autism and there was a promising trial in Havana, which I shared with the researcher.

 

https://epiphanyasd.blogspot.com/2018/12/low-level-laser-therapy-lllt-for-autism.html

https://epiphanyasd.blogspot.com/2019/07/homeclinic-based-photobiomodulationlase.html

 

Many of the suggested modes of action of LLLT were in this graphic.

Click to enlarge the graphic

Another suggested mode of action for LLLT concerns improved drainage of lymph from the brain.  This is a known problem in some forms of dementia. Among alternative autism practitioners there are all kinds of manual lymphatic draining therapies.

  

PDE4 inhibitors 

Some readers are using PDE4 inhibitors as the anti-inflammatory component of their personal autism polytherapy.

The 3 “common” choices are: -

·        Pentoxifylline, cheap and even trialled a few decades ago in children with autism. It has a short half-life and is a non-selective PDE inhibitor.  It also has an interesting effect on HDAC, that can make chemotherapy work better.

·        Roflumilast, more expensive and normally used to treat exacerbations in COPD, but patented at a lower dose as a cognitive enhancer. It is more selective for PDE4 than Pentoxifylline and has a long half-life.

·      Ibudilast, common in Japan as an asthma therapy and now a potential treatment for MS (multiple sclerosis).  It is available in Germany, imported to order, with a prescription.

 

PDE inhibitors are not very selective and so some people get side effects.  The big one seems to be nausea. Side effects may well fade over time.

I did try Roflumilast at the supposedly cognitively enhancing dose of 100mcg, a couple of years ago, but it did cause nausea. The nausea may well fade away after a few weeks.  Roflumilast may also reduce the sensory gating problem common, in autism, but only at a dose of 100mcg, higher doses lost this effect.  All is in this old post below.

Impaired sensory gating is driven by HCN channels that need to be blocked.  The science shows us various ways this can be achieved, as I explained in the post below. You can target alpha-2A adrenergic receptors, reduce stress or reduce cAMP.

What is cAMP?  Look here: -

https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate

 

Cognitive Loss/Impaired Sensory Gating from HCN Channels - Recovered by PDE4 Inhibition or an α2A Receptor Agonist

… in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker.

Stress appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.

This would explain why stress makes people’s sensory gating problems get worse. So, someone with Asperger’s would get more distracted/disturbed at exam time at school for example, or when he goes for a job interview. Reducing stress is another method to improve sensory gating and indeed cognition. 

Alpha-2A adrenergic receptors near the HCN channels, on those dendritic spines, inhibit the production of cAMP and the HCN channels stay closed, allowing the information to pass through into the cell, connecting the network. These Alpha-2A adrenergic receptors are stimulated by a natural brain chemical norepinephrine, or by drugs like Guanfacine.

While the researchers at Yale patented the idea of HCN blockers to improve cognition, we can see how other existing ideas to improve cognition may indeed have the same mechanism, most notably PDE4 inhibitors.

One effect of a PDE4 inhibitor is that it reduces cAMP. So, a PDE4 inhibitor acts indirectly like an HCN blocker.

Not surprisingly recent research showed that low doses of Roflumilast improves sensory gating in those affected by this issue.

So rather than waiting for a brain selective HCN blocker, the potential exists to use a one fifth dose of Roflumilast today.

 

HCN channels play a role in many neurological conditions.  It does get rather complicated, but if you successfully target these ion channels you are definitely at the cutting edge of science. 

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases 

The low dose Roflumilast might be a good choice for Aspies who get bothered by noises like clocks ticking and people chewing gum.

Pentoxifylline is very cheap, but the short half-life means you might need to take it three times a day.

100mcg of Roflumilast is 1/5^th of a standard Daxas pill for COPD, which means crushing it and dividing in 5 parts.  This does also make it much cheaper, one pack would last you 5 months.

I will retry Roflumilast and also give Pentoxifylline a try. 

Based on the science, I think 100mcg of Roflumilast really should have a benefit in much autism.

I know other readers are using Pentoxifylline or Ibudilast.

All these PDE inhibitor drugs are normally used in adults. 

 

Misophonia

https://www.webmd.com/mental-health/what-is-misophonia#1

 

Misophonia is a disorder in which certain sounds trigger emotional or physiological responses that some might perceive as unreasonable given the circumstance. Those who have Misophonia might describe it as when a sound “drives you crazy.” Their reactions can range from anger and annoyance to panic and the need to flee.  The disorder is sometimes called selective sound sensitivity syndrome.

Individuals with Misophonia often report they are triggered by oral sounds  -- the noise someone makes when they eat, breathe, or even chew. Other adverse sounds include. keyboard or finger tapping or the sound of windshield wipers. Sometimes a small repetitive motion is the cause -- someone fidgets, jostles you, or wiggles their foot.

 

Impaired P50 gating

https://en.wikipedia.org/wiki/P50_(neuroscience)

 

In electroencephalography, the P50 is an event related potential occurring approximately 50 ms after the presentation of a stimulus, usually an auditory click.The P50 response is used to measure sensory gating, or the reduced neurophysiological response to redundant stimuli.

Research has found an abnormal P50 suppression in people with schizophrenia, making it an example of a biological marker for the disorder. Besides schizophrenia, abnormal P50 suppression has been found in patients with traumatic brain injury, recreational drug use, and post-traumatic stress disorder.

 

It looks to me that:-

 

Misophonia = Impaired P50 gating  = Impaired sensory gating

 

Recent clinical trials using Roflumilast: -

 

Cognitive Effects of Roflumilast in MCI Patients (ROMEMA)

dose 50 mcg   100 mcg

 

Roflumilast and Cognition (EEGrofl) 

dose 100mcg, 300mcg, 1,000 mcg

 

Roflumilast: A potential drug for the treatment of cognitive impairment?

 Roflumilast is the one and perhaps the only drug which shows a dose dependent occupancy of PED-4 in primate models and at doses proven to be very safe in humans, has shown its efficacy in enhancing memory and cognition.

 

An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients

This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 μg daily) with 14 days of washout between treatments.

Results

Verbal memory was significantly improved under 250 μg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03).

Conclusions

Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia.

 

Improvisation

I did recently write about Desmopressin nasal spray as a possible alternative to specially compounded vasopressin nasal spray.  I did actually order some, but what arrived was the tablet form of Desmopressin.

The advantage of Desmopressin over Vasopressin is that there already exists a nasal spray in your pharmacy. There is currently a worldwide availability issue. 

Fine tuning Social Behavior in Autism with an existing pediatric drug, Desmopressin?

Having recently been making Christmas Pudding and sweet mincemeat for mince pies, from raw ingredients and improvising for those not available, I think I can safely make my own Desmopressin nasal spray, and with the correct excipients. 

Due to Covid, we did not go to England at Christmas; setting Christmas Pudding on fire is something that Monty looks forward to.

Christmas pudding takes days to make and 8 hours to cook, then you leave it to mature.  You re-heat for Christmas lunch.

 

Sweet mincemeat is something that came to England with the returning crusaders.  Nowadays it is just made with dried fruit.  When the English established colonies in New England, they took the older version with them, which included actual meat.  Today in the US you have store-bought sweet mincemeat with ground beef in it, in the UK it has been meat-free for many decades. 

The fat in sweet mincemeat is suet.  In the UK and US, pre-packaged suet sold in supermarkets is dehydrated suet.

I had no idea what suet was, but I know it is not in my supermarket.  Suet is actually raw, hard fat of beef or mutton, found around the loins and kidneys.  Jewish people are not supposed to eat suet, but Muslim people apparently seek it out.  These days I think most is actually a vegetable substitute.  To follow the recipe, a friend helped out with some of this fat; I put a chunk of it in the freezer for a couple of hours and then grated it. You are supposed to coat with rice flour, if you want to store it for later use.

The recipe said 300g (10 oz) of suet but having grated half, I decided it was pretty disgusting and substituted butter for the remainder.

In the recipe are raisins, currants and sultanas, they are actually all slightly different.  In effect they are all dried grapes

 

Raisins, sultanas and currants

 

In the US, the term raisin is applied to both raisins and sultanas. To distinguish the two, sultanas are referred to as “golden” raisins.

Where we live, they are all just “dried grapes”.  The different types exist, but are called the same thing.

Candied peel and glace cherries were also a struggle to find, by this time I had decided to add dried blueberries and cranberries.

One day after the mincemeat jars were already full and maturing in the garage, candied peel and glace cherries turned up and got added.  There is a lot of brandy in the recipe and this is why you leave the jars to mature.

 

It was a lot of bother to make, but the resulting mince pies were really good.  The brandy carries the spices making it very fragrant, not at all like store-bought mince pies.

The Christmas pudding was set alight, in fact twice for good measure.

Compared to all that, how hard can it be to make desmopressin nasal spray?  It only has a handful of ingredients, after all. 

Sulforaphane

I first wrote about Sulforaphane from broccoli, back in 2014. Johns Hopkins have been researching this substance for decades.

What has happened to Sulforaphane for autism? Stuck as Complementary and Alternative Medicine (CAM) therapy forever?  Apparently so.

Sulforaphane has anti-cancer effects and is suggested for common cancers like that of the prostate.  A stable man-made version (an analog) was developed in the UK as drug to treat prostate cancer.  In France a modified broccoli-based OTC product is sold as another prostate therapy.

 

When it comes to autism, there have been a series of positive clinical trials.

Sulforaphane treatment for autism spectrum disorder: A systematic review

Autism Spectrum Disorder (ASD) is defined as a neurodevelopmental condition characterized by social communication impairment, delayed development, social function deficit, and repetitive behaviors. The Center for Disease Control reports an increase in ASD diagnosis rates every year. This systematic review evaluated the use of sulforaphane (SFN) therapy as a potential treatment option for individuals with ASD. PubMed.gov, PubMed Central, Natural Medicines, BoardVitals, Google Scholar and Medline were searched for studies measuring the effects of SFN on behavior and cognitive function. All five clinical trials included in this systematic review showed a significant positive correlation between SFN use and ASD behavior and cognitive function. The current evidence shows with minimal side effects observed, SFN appears to be a safe and effective treatment option for treating ASD.

 

The Johns Hopkins' researchers did spin off the idea to commercially exploit their findings.  The result is “True broc” from Brassica Protection Products.

 

https://truebroc.com/what-is-truebroc/ 

 

https://brassica.com/

 

Here you will find Avmacol and Thorne Crucera-SGS, among the products than include “True broc”.  

These products, along with Prostamol from France, are actually used in clinical trials.

The UK company Evgen is developing its stable analog of Sulforaphane for autism and other conditions.

https://evgen.com/technology/

I spoke to Evgen a few years ago and suggested their prostate drug might be used for autism.  You still cannot buy it, but there is a clinical trial for autism planned.

 

Do you need expensive broccoli supplements?

There are numerous cheap broccoli supplements and some moderately priced ones.

We know from the research that supplements generally are not reliable, because they often do not contain what is on the label.  This matters more with some products than others.  With broccoli products the big question is whether they really contain active myrosinase.  This is an enzyme that you need to make Sulforaphane when you eat broccoli.

Several years ago, when I started with Sulforaphane, I bought large tubs of Australian broccoli powder and one pack of Daikon radish powder.  Daikon radishes are rich in myrosinase and it is relative stable, so it can survive processing.  My idea was to start with just the broccoli powder and then, if not effective, add some Daikon radish powder for the extra myrosinase.  In the end I did not need to even open the Daikon radish powder.  A small scoop of this broccoli powder produced a profound effect, euphoria after minutes and then much more “speech”. Back then “speech” was more like babbling single words – but it was some kind of speech at least. 

Many people report broccoli powder improved speech, even parents of young Aspies report it. 

Some people found the effect on mood to be remarkable.

Long term users report that over time they have to increase the dose to maintain the effect.

It is important to note that for some people the benefit may not be from Sulforaphane, but rather from indole-3-carbinol (I3C).

 

Here I am quoting myself …

 

“PTEN is best known as a tumor suppressor affecting RAS-dependent cancer, like much prostate cancer. Activating PTEN is good for slowing cancer growth. As I mentioned in a recent comment to Roger, many substances are known to activate PTEN; a good example being I3C (indole-3-carbindol) which is found in those cruciferous vegetables (broccoli, Brussels sprouts, cabbage etc) that many people choose not to eat. PTEN is a well-known autism gene.” 

The research has now caught up: - 

Study hints at dietary chemical as therapy for type of autism

A compound derived from cruciferous vegetables, such as broccoli and kale, might limit the impact of certain mutations in a top autism gene, a new study suggests.

The compound, called indole-3-carbinol, or I3C, acts on the gene PTEN, a tumor suppressor. 

This does raise questions about the prostate cancer research.  A sulforaphane analog drug contains no indole-3-carbinol (I3C).

  

Does Broccomax “work” 

The easy to buy product is Broccomax.  In the research they do not seem to like it, but it does not include the True Broc product from the Johns Hopkins spin-off.

Anecdotally, Broccomax does “work” for autism, but less so than some expensive products.

My Australian broccoli powder is no longer made, but it was not expensive and it did “work”.

 

Spice up Broccoli with Wasabi?

In the original research from decades ago, the Johns Hopkins researchers combined Daikon radish sprouts with broccoli sprouts, the Daikon radish sprouts where there to provide myrosinase.  The product had to kept deep frozen.

Daikon radish is widely available and is a good source of myrosinase.

I was re-reading old research and noted one researcher advocating putting Wasabi on your broccoli – the spicier the better apparently. Wasabi is Japanese horseradish and is widely available.  If it comes on a large bottle is likely fake wasabi - yes like they fake saffron, they fake wasabi.

Is it crazy to add wasabi to your broccoli capsules?

Look at what is in the expensive Avmacol supplement that they only sell in North America.

 

 

In the research they found that adding just 0.25% Daikon to frozen broccoli “brought it back to life” and sulforaphane was found in the person eating it. 

If you are using gelatine capsules with broccoli powder you can open them and, using a pointed knife, add a small amount of wasabi, re-seal and then swallow.  There is no taste or smell of wasabi.

It is bit fiddly to do this, but you soon master doing it.

 

Calcium Folinate (Leucovorin)

 

There is a lot in this blog already about Calcium Folinate.  It should give some benefit to the 75% of autism who have a problem with folate transport across the blood brain barrier. 

One of the most prominent effects in responders is improved speech. Just look at the tittle of the clinical trial

 

Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder

The only issue with Calcium Folinate (Leucovorin) are the side effects, but Professor Ramaekers assures me that if you gradually increase the dose over several weeks, there should not be any.

The summer before Covid, at 45mg a day of Calcium Folinate, my son had much more expressive language and it was also more complex language.  The problem was aggression.

 

Conclusion

As you can see the 2021 to do list is mainly tying up the loose ends remaining from previous ideas, so I anticipate success.

Broccoli powder does still have an effect, but much milder than a few years ago.  Does wasabi increase the effect?  This is very subjective, having bought the little jar of Wasabi, I will continue to adding it to two capsules of Broccomax before breakfast.

Calcium Folinate did increase speech significantly at the large dose (3 x 15mg a day) in my original trial.  At the lower dose of 15mg the effect is present, but is mild, and short-lived for the first few days.   I will very gradually increase from a starting dose of 15 mg a day and see if it possible to avoid the negative effects.

I do like the idea of the tiny dose of Roflumilast.  It has multiple potential benefits:-

1.     Improve sensory gating and reduce Misophonia

2.     Improve cognition

3.     Potentially reduce NKCC1/KCC2 expression and so make bumetanide more effective.

Can this be achieved without nausea? I think it is likely a matter of perseverance.  In COPD the starting dose of roflumilast is half the maintenance dose, but the likely “autism dose” of 100mcg in an adult is less than half the COPD starting dose of 250mcg. 

The research already tells us the effective dosage (for 1 & 2), 100mcg in an adult, and importantly that the effect is lost at higher dosage; indeed, the recent trial in Mild Cognitive Impairment (MCI) included a dose as low as 50mcg.

You would have to find the therapeutic window.  You are changing the intracellular level of cAMP, which will have numerous effects, not just on HCN channels, but also on things like pCREB and BDNF.

I think 80mcg will be a good place to start.

There may, or may not be, an equivalent dose of Pentoxifylline/Ibudilast that gives a similar effect.  Ideally you would want all 3 effects.

A dose higher than 100mcg might have a beneficial anti-inflammatory effect and so help reduce NKCC1/KCC2 expression which increases (3) but at the loss of (1) and (2).

It would be interesting to know if Maja’s daughter has/had Misophonia and what has been the effect of her Pentoxifylline use.

The next question is how to reliably measure such small doses of Roflumilast.  This drug does not dissolve in water, but is highly soluble in ethanol.  You have the choice of cutting a pill containing 500mcg into 5-6 pieces (fortunately, it is a large pill), or just crushing the pill and then using microscales to fill new capsules, or make a tincture.  The tincture should be the most accurate.  Tinctures are widely used for OTC remedies like propolis.  A tincture has the advantage that you can easily vary the dose. In phase 1, where I just try it on myself, I have opted for the tincture. One tablet dissolves in 2ml of vodka (dilute ethanol) to make a paste, but was much more fluid in 3 ml (the 3rd ml added probably could be just water).  One half of an old propolis pipette contains 100 mcg duly dissolved in 0.6 ml of vodka. It tastes exactly like the original propolis tincture, because all you really notice is the ethanol. Most commercial propolis tincture is made with alcohol and uses a much more concentrated ethanol than you will find in vodka. 

I was asked by an autism Grandad at the 2019 Thinking Autism conference how his Grandson could be helped.  The young man is highly intelligent, but has a severe problem with sound sensitivity.  His family paid extra money for him to sit his final school exams in a room with no other students, but the invigilator was opening up candy to chew all through the exams and so the boy flunked the exams.   This young man has Misophonia and I bet would exhibit impaired P50 gating if given an EEG. Before exam time, he needs to block some of the HCN channels in his brain and reduce stress/anxiety.  He might well benefit from Roflumilast 100 mcg and Propranolol 20mg and then sail through his exams. 

I actually think that many people reading this post likely have Misophonia, that is if they are a relative of someone with polygenic autism.  In the literature Misophonia is claimed to affect more women than men, but I doubt that is actually true.  If you have autism, your doctor is highly unlikely to add a diagnosis of Misophonia. 

Is Desmopressin going to be helpful?  I had put Vasopressin down as a potential therapy more for Aspies, but our reader whose young child was prescribed Desmopressin nasal spray by her neurologist, noted a broad range of substantial improvements. Desmopressin is water soluble, so no vodka required.

Fine tuning Social Behavior in Autism with an existing pediatric drug, Desmopressin?

 

There are two closely related hormones, vasopressin and oxytocin, that have been extensively researched in autism. 

With oxytocin you can modify social-bonding behavior. You can increase oxytocin in the brain either via a nasal spray containing oxytocin, or you can add a specific bacterium to your gut that triggers a signal to the brain to produce more of its own oxytocin.  The latter is my preferred method, because you can produce a mild long-lasting effect throughout the day.

Oxytocin has a very short life and it does not cross the blood brain barrier.

There is even a new study in the works that will compare these two methods of treating autism.

 

Probiotics and oxytocin nasal spray as neuro-social-behavioral interventions for patients with autism spectrum disorders: a pilot randomized controlled trial protocol

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication. Oxytocin (OXT), as a neuropeptide, plays a role in emotional and social behaviors. Lactobacillus reuteri (L. reuteri) supplementation led to an OXT-dependent behavioral improvement in ASD mouse models. Despite some promising results from animal studies, little is known about the efficacy of supplementation with L. reuteri, alone or with exogenous OXT therapy, on social-behavioral functions in ASD patients. This paper presents a protocol for a pilot randomized controlled trial to evaluate the feasibility of conducting a full trial comparing oral supplementation of L. reuteri probiotics and intranasal OXT spray to placebo on the effect of social and behavioral functions in ASD patients. The study will also capture preliminary estimates of the efficacy of the proposed interventions in ASD patients.

Methods

This pilot trial is a two-staged, randomized, double-blind, placebo-controlled, parallel-group study. Throughout the study (0–24 weeks), 60 patients with ASD will be randomly assigned to receive either oral L. reuteri probiotics or placebo. In the second study stage (13–24 weeks), all participants will receive intranasal OXT spray. As primary outcomes, serum OXT levels will be assayed and social behaviors will be assessed via the Autism Behavior Checklist and the Social Responsiveness Scale which are validated questionnaires, an objective emotional facial matching test, and a new video-based eye-tracking test. Secondary outcomes include the GI-severity-index and Bristol Stool Chart to assess GI function and gut microbiome/short-chain fatty acids. All the outcomes will be assessed at baseline and weeks 12 and 24.

Discussion

This pilot study will provide important information on the feasibility of recruitment, blinding and concealment, treatment administration, tolerability and adherence, specimen collection, outcome assessment, potential adverse effects, and the preliminary efficacy on both primary and secondary outcomes. If successful, this pilot study will inform a larger randomized controlled trial fully powered to examine the efficacies of oral L. reuteri probiotics and/or intranasal OXT spray on social-behavioral improvement in ASD patients. 

My conclusion was to add two drops of L.Reuteri DSM 17938 (Biogaia Protectis) into the liquid part of my son's Polypill therapy. That way there are no extra pills to swallow and in theory the bottle should last 50 days, so I am not forever looking to buy more.  If you want a bigger effect, just add more drops.  The producer suggests a daily dose of 5 drops for babies, to promote GI health - the original intended purpose.

When it comes to Vasopressin it looks like you cannot avoid a nasal inhaler, unless you want to try transcutaneous electrical acupoint stimulation (TEAS).  There is a debate as to whether Vasopressin and its analogs (man-made modified versions) can cross the blood brain barrier and to what extent. 

There are 4 previous posts that looked at Vasopressin. 

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

The Vasopressin showing good results in the trials at Stanford is the injectable pharmaceutical version of the hormone made into a nasal spray.  This kind of spray could be made easily at a compounding pharmacy.

It turns out that a synthetic analog of vasopressin, called desmopressin, has been widely used for over 40 years to treat nocturnal enuresis (night-time bed-wetting) among other more serious conditions.

 

Desmopressin in Autism 

“Nocturnal enuresis is common in individuals with but to our knowledge, there are no reports that desmopressin enhances social functioning in ASD (or in any other clinical population). This may be because desmopressin is typically administered at bedtime (so prosocial effects would be less evident) and orally (oral desmopressin does not cross the blood-brain barrier). The most likely explanation, however, is that desmopressin acts selectively on AVPR2, rather than on AVPR1A”

 

From:

A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism

 

Desmopressin N=1 example 

I was recently contacted by the father of a young boy with autism who has been prescribed Desmopressin nasal spray by his neurologist.

The father noted major positive behavioral changes from the first dose.

This is of course great news.

Desmopressin is a widely available drug, seen as safe, and that is why it is prescribed to children.

In the US the nasal spray version is no longer widely used for children and they use the oral version.

In some countries it is used for people with MS (Multiple Sclerosis) with nocturnal enuresis.

 

Desmopressin Shortage

Before readers get too excited, Ferring Pharmaceuticals, the big producer of Desmopressin nasal sprays did voluntarily withdraw its brands (Minirin, DDAVP Nasal Spray, Desmopressin Acetate Nasal Spray) from the market in August 2020 due to a quality problem. 

https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/ferring-us-issues-voluntary-nationwide-recall-ddavpr-nasal-spray-10-mcg01ml-desmopressin-acetate

  

There is now a shortage and so what was an easy to obtain drug, may be more difficult to get.  There is a Pfizer version called Presinex.  

From the above paper on vasopressin for autism:-

Vasopressin benefits 

“In conclusion, the present pilot study determined that 4-week intranasal AVP treatment compared to placebo enhanced social communication abilities, diminished anxiety symptoms, and reduced repetitive behaviors in children with ASD. On nearly all behavioral measures, participants with the highest pre-treatment blood AVP concentrations benefitted the most from AVP treatment, suggesting that pre-treatment blood AVP concentrations may be useful for setting dosing guidelines for this medication. Last, intranasal AVP treatment was well tolerated with minimal side effects in this pediatric study population. These preliminary findings suggest that intranasal AVP treatment has potential to enhance social abilities in an ASD patient population characterized by currently intractable social impairments” 

Transcutaneous electrical acupoint stimulation (TEAS) to raise vasopressin 

“there is evidence that nonpharmacological interventions may facilitate endogenous AVP release, for example, electroacupuncture stimulation increases brain AVP concentrations in rats. Transcutaneous electrical acupoint stimulation (TEAS) therapy improves social functioning and anxiety symptoms in children with ASD, particularly in those with the largest post-treatment increase in blood AVP concentrations. The authors of this prior report theorized that increased AVP signaling may be the mechanism by which the prosocial and anxiolytic benefits of TEAS treatment were achieved” 

 

Vasopressin with Bumetanide  - take great care

A while back, one reader did ask me about taking intranasal Vasopressin with Bumetanide.  His doctor in California thought this might not be wise since the two drugs have opposing effects.

·        Bumetanide (a diuretic) makes you pee more.

·        Vasopressin (the anti-diuretic hormone) makes you pee less.

The real problem is the risk of low sodium, hyponatremia.  This is always a risk with vasopressin and the risk might well increase if you took Bumetanide.  The risk is going to be dose dependent.

If you take Vasopressin and then drink large amounts of water this will disturb the volume of fluids in your body and in particular it will lower the level of sodium.  This may lead to seizures and ultimately worse.

Bumetanide does disturb the level of electrolytes, but nearly all the change usually occurs in Potassium, this is why you need to add back potassium via diet and add a supplement.  Sodium is not normally a problem, but always check all electrolytes when taking a blood draw.

If someone adds vasopressin to their existing bumetanide therapy, the doctor should definitely monitor the level of sodium.

In most people’s diet, sodium is one thing you are likely to have too much of and it is very easy to add a bit more sodium if the blood test suggests it is necessary.  In extreme cases of low sodium you need to use a special re-hydration drink, or an intravenous saline solution.  Monty has a relative who keeps going to hospital for the latter.

The diuretic action of Bumetanide is a side effect of the "autism effect" and so if you can reduce the diuresis of bumetanide that would be good thing.  Researchers are trying to find a better-bumetanide and their goal is to have no diuresis.

If combining vasopressin with Bumetanide is accompanied by both reduced diuresis and a matching reduction in fluid intake, this might actually work well.  Clearly, extra care needs to be taken and what might be perfectly safe in one person may not be safe in another person.

  

Conclusion

I do have to give a big thank-you to our reader who shared his experience with Desmopressin and to the neurologist for suggesting it.

Desmopressin looks like one of those autism therapies that needs only a very short trial to determine whether it is beneficial.  This is a big advantage.

You would hope the Stanford vasopressin researchers make a short trial of Desmopressin, just to compare the effect.  They probably will not.

All you have to decide is whether it is going to be the left nostril, or the right nostril.  With intranasal insulin there was a problem with irritation inside the nose, so alternating left and right sides might be best.  You hold your breath and then squirt the spray; the objective is not to breath the spray into your lungs.  An easy mistake to make.

Note that I am referring to the 10 mcg/0.1mL Desmopressin nasal spray.  The one used to treat kids that wet their bed at night.

There is also a much more potent 1.5 mg/mL version, called Stimate in the US.  This is used to treat von Willebrand’s Disease (Type I) and hemophilia/haemophilia.  You do not want that version.  This version is 15 times more potent than the anti bed-wetting variant. 

I have been suggesting to Aspies living in the US that they give Vasopressin a trial to counter the social deficits that some find troubling.  I think they are able to obtain this via a compounding pharmacy, with a helpful doctor’s prescription.

I think outside the US your doctor will think you are mad if you ask for a specially compounded vasopressin nasal spray, or indeed a compounded  oxytocin spray.

For people unable to get the intranasal vasopressin prescribed/compounded, Desmopressin is on option to discuss with your doctor. Maybe time to develop a bed wetting problem?

The Aspies in the Netherlands have the legal option of a tiny non-hallucinogenic dose of Psilocybin once a month, which seems an effective way to target Serotonin 5-HT_2A receptor-mediated pathways and so improve social behavior. What caught my attention was that the effect of this tiny dose lasts a month and it can also be used to treat severe, otherwise untreatable, cluster headaches.

Psilocybin is the fancy name for magic mushrooms.

Psilocybin is also legal in Brazil and not surprisingly in Jamaica.  It looks like the US is moving in the same direction - medicinal magic mushrooms!

FDA grants Breakthrough Therapy Designation to Usona Institute's psilocybin program for major depressive disorder

The “medical” dose of Psilocybin is a tiny fraction of the “recreational” dose and is only taken when the effect of previous dose fades to zero.  It is not a crazy idea at all, just not currently a legal therapy in most countries.  More than half a century ago Lovaas was researching something very similar at UCLA, but using LSD.

All told, there are several potential ways to fine-tune social behavior in autism. Sulforaphane is yet another option.