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.
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 1/5th
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.
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.
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.
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: -
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.
