Today’s post is about treating a wide range of conditions that share neuroinflammation in common, by targeting the serotonin receptor 5-HT2A.
Severely disabling cluster headaches, that were seen as untreatable, have been resolved by monthly micro dosing with psilocybin.
Psilocybin is a naturally occurring prodrug compound produced by more than 200 species of fungus, including magic mushrooms. Psilocybin is quickly converted by the body into Psilocin.
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Psilocin Binding Profile |
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|
Target |
Affinity |
Species |
|
|
Ki (nM) |
|
||
|
3,801.0 |
Human |
|
|
|
567.4 |
Human |
|
|
|
219.6 |
Human |
|
|
|
36.4 |
Human |
|
|
|
52.2 |
Human |
|
|
|
107.2 |
Human |
|
|
|
4.6 |
Human |
|
|
|
97.3 |
Rat |
|
|
|
> 10,000 |
Human |
|
|
|
83.7 |
Human |
|
|
|
57.0 |
Human |
|
|
|
3.5 |
Human |
|
|
“The neurotransmitter serotonin is
structurally similar to psilocybin.
Psilocybin is rapidly dephosphorylated in the body
to psilocin, which is an agonist for several serotonin
receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors.
Psilocin binds with high affinity to 5-HT2A receptors and low
affinity to 5-HT1 receptors,
including 5-HT1A and 5-HT1D; effects are also mediated
via 5-HT2C receptors.
Various lines of evidence have shown that
interactions with non-5-HT2 receptors also contribute to the
subjective and behavioral effects of the drug. For example, psilocin
indirectly increases the concentration of the neurotransmitter dopamine in
the basal ganglia, and some psychotomimetic symptoms of psilocin are
reduced by haloperidol, a non-selective dopamine receptor antagonist.
Taken together, these suggest that there may be an
indirect dopaminergic contribution to psilocin's psychotomimetic
effects. Psilocybin and psilocin have no affinity for dopamine receptor
D2, unlike another common 5-HT receptor agonist, LSD. Psilocin
antagonizes H1 receptors with moderate affinity, compared to LSD
which has a lower affinity.”
A Canadian company, Pilz Bioscience,
is trialing its version of psilocybin to treat autism.
We already know that micro dosing of Lysergic acid diethylamide (LSD) promotes social behavior
via 5-HT2A/AMPA receptors and
mTOR signaling.
The FDA is
already onside
For those worrying about the law, the
FDA is well aware of the therapeutic potential of low dose psychedelics like Psilocybin, and indeed LSD.
FDA Grants
Psilocybin Second Breakthrough Therapy Designation for Resistant Depression
The US Food and Drug Administration (FDA) has granted the Usona
Institute breakthrough therapy designation for psilocybin for the treatment of
major depressive disorder (MDD).
For really motivated readers, click on
the link below to read the details of Psilocybin
https://www.usonainstitute.org/wp-content/uploads/2020/08/Usona_Psilocybin_IB_V3.0_08.31.2020_cc.pdf
Nova (Pilz Bioscience) Launches Preclinical Autism
Spectrum Disorder Therapeutic Study
A
treatment phase with its proprietary psilocybin compound is scheduled to begin
in February 2021.
PILZ
BIOSCIENCE
INNOVATION IN ASD
Though
ASD symptoms are diverse, underlying causes converge on common biological
mechanisms, priming development of a new approach to diagnostics and treatment.
Scientific studies suggest a strong association between ASD and inflammation,
as well as ASD and microbiota in the gut. Likewise, parallels exist between
social cognition in autism and some of the key behavioral elements already
being treated with psychedelic therapy.
Micro dose LSD
for Autism? via activation of 5-HT2A/AMPA/mTORC1
LSD may offer viable treatment
for certain mental disorders
Researchers from McGill University have discovered, for the first time, one of the possible mechanisms that contributes to the ability of lysergic acid diethylamide (LSD) to increase social interaction. The findings, which could help unlock potential therapeutic applications in treating certain psychiatric diseases, including anxiety and alcohol use disorders, are published in the journal PNAS.
Psychedelic drugs, including LSD, were popular in
the 1970s and have been gaining popularity over the past decade, with reports
of young professionals claiming to regularly take small non-hallucinogenic
micro-doses of LSD to boost their productivity and creativity and to increase
their empathy. The mechanism of action of LSD on the brain, however, has remained
a mystery.
The researchers note
that the main outcome of their study is the ability to describe, at least in
rodents, the underlying mechanism for the behavioural effect that results in
LSD increasing feelings of empathy, including a greater connection to the world
and sense of being part of a large community. "The fact that LSD binds the 5-HT2A receptor
was previously known. The novelty of this research is to have identified that
the prosocial effects of LSD activate the 5-HT2 receptors,
which in-turn activate the excitatory synapses of the AMPA receptor as well as
the protein complex mTORC1, which has been demonstrated to be dysregulated in
diseases with social deficits such as autism spectrum disorder,” as specified by Prof.
Nahum Sonenberg, Professor at the Department of Biochemistry of McGill
University, world renowned expert in the molecular biology of diseases and
co-lead author of the study.
Lysergic
acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory
neurotransmission
Significance
Social behavior (SB) is a
fundamental hallmark of human interaction. Repeated administration of low doses
of the 5-HT2A agonist lysergic acid diethylamide (LSD) in mice
enhances SB by potentiating 5-HT2A and AMPA receptor
neurotransmission in the mPFC via an increasing phosphorylation of the mTORC1,
a protein involved in the modulation of SB. Moreover, the inactivation of mPFC
glutamate neurotransmission impairs SB and nullifies the prosocial effects of
LSD. Finally, LSD requires the integrity of mTORC1 in excitatory glutamatergic,
but not in inhibitory neurons, to produce prosocial effects. This study unveils
a mechanism contributing to the role of 5-HT2A agonism in the
modulation of SB.
Abstract
Clinical studies have reported that the psychedelic lysergic acid
diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its
mechanism of action remains elusive.
Using a multidisciplinary approach including in vivo electrophysiology,
optogenetics, behavioral paradigms, and molecular biology, the effects of LSD
on SB and glutamatergic neurotransmission in the medial prefrontal cortex
(mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase
SB. However, repeated LSD
(30 μg/kg, once a day, for 7 days) administration promotes SB, without
eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition
of mPFC excitatory neurons dramatically inhibits social interaction and
nullifies the prosocial effect of LSD. LSD potentiates the
α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A,
but not N-methyl-D-aspartate (NMDA) and 5-HT1A,
synaptic responses in the mPFC and increases the phosphorylation of the
serine-threonine protein kinases Akt and mTOR. In conditional knockout mice
lacking Raptor (one of the structural components of the mTORC1 complex) in
excitatory glutamatergic neurons (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the
potentiation of 5-HT2A/AMPA synaptic responses were nullified,
demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons
to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons
of the mPFC (Raptorf/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD
selectively enhances SB by potentiating mPFC excitatory transmission through
5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1
in the mPFC by psychedelic drugs should be explored for the treatment of mental
diseases with SB impairments such as autism spectrum disorder and social
anxiety disorder.
D-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis:
Mechanism of Action and Pharmacology
Figure 1. D-Lysergic Acid Diethylamide (LSD) acts at different brain regions with a pleiotropic mechanism of action involving serotonin 5-HT1A, 5-HT2A, 5-HT2C, and dopamine D2 receptors in the Dorsal Raphe (DR); dopamine D2 receptor and Trace Amine Associate (TAAR1) receptors in the Ventral Tegmental area (VTA); and 5-HT2A in the Locus Coerules (LC). These three nuclei project to the prefrontal cortex (PFC), enhancing or inhibiting the release of neurotransmitters and ultimately medicating the psychotic-like effects and cognitive changes. mPFC: medial prefrontal cortex (mPFC); NMDA(NR2B): N-methyl-D-aspartate (NMDA) receptor subunit NR2B.
LSD vs Psilocybin
LSD and psilocybin have effects that overlap, but they are not identical. Both are used by sufferers to treat cluster headaches.
Why does low dose psilocybin provide
long lasting protection from cluster headaches?
These headaches are often thought to be driven by ion channel
dysfunctions (channelopathic). Does psilocybin,
or indeed LSD, directly or indirectly affect ion channels? Nobody knows.
Regular readers will know that certain calcium/sodium channels are implicated in autism, epilepsy and MR/ID. Some of these same ion channels are also associated with headaches. So no surprise that some people with a mutation in one of these genes have additional problems to autism.
Are all types of migraine channelopathies?
Familial hemiplegic migraine (FHM) is characterized by migraine attacks, which is with transient, unilateral motor weakness as its episodic aura. FHM is an autosomal dominant migraine, three encoding protein genes have been identified: CACNA1A encodes α1 subunit of calcium channel Cav2.1, ATP1A2 encodes α2 subunit of Na+/ K+-ATPase pump, and SCN1A encodes α subunit of sodium channel Nav1.1. All these proteins are specially expressed on nervous system, and all the mutations mainly cause brain dysfunction. Series studies on FHM indicated that mutations on Cav2.1 and ATP1A2 increased the concentration of glutamate in synapses and disturbed the excitatory and inhibitory balance, which induced the brain dysfunction. Although the same result has not yet been concluded firmly enough from the functional studies on sodium channels (Nav1.1) owe to the more perplexed expression and structure of Nav1.1 and its encoding gene SCN1A, it firmly concluded that all the mutations of the three genes cause brain dysfunction. All above indicate that FHM is a definitely channelopathy. Are other types of migraine channelopathies?
Conclusion
Tiny doses of psilocybin (magic mushrooms) have been used for years by a small number of people with severe headaches. These headaches are not your typical migraine, they are totally disabling. Note that large doses of Psilocybin frequently cause headaches.
It appears that the same therapy has
an effect on other neurological conditions ranging from depression to autism. Take a look at all the trials to date:
https://clinicaltrials.gov/ct2/results?recrs=&cond=&term=psilocybin&cntry=&state=&city=&dist=
We know from anecdotes that many
Aspies feel better when they activate the serotonin receptor 5-HT2A,
but I suspect that may “overshoot” with dosing. It is a non-hallucinogenic effect that we are
looking for. The dose can be as little as
a micro dose once a month.
Genuinely effective micro dosing is
very attractive, because it is likely to be very safe and indeed very
cheap. Intermittent micro dosing, if
therapeutic, would be even better.
Clearly, a standardized drug like
PLZ-1013 from Pilz Bioscience is what many people will want. It is very encouraging that these researchers
and those at McGill University and the Usona Institute have engaged themselves. But, prepare to wait a decade or two.
It is a pity
we have to wait so long; LSD was first used as an autism therapy before I was
born. LSD was then made a banned substance.
Clearly back in the days that Professor Lovaas was giving LSD to people with
autism at UCLA in the 1960s, he was using the “wrong” dose, but he might have eventually
stumbled upon the micro dose. Here we are
almost 60 years later, still with anecdotes.
Roll on the clinical trial of PLZ-1013.
We have acquired microdosing-ready LSD (comes in form of tiny papers), and two members of my family use it, a third one is in the pipeline. They both find it frees them from unnecessary anxiety and enables more productive conflicts (both are very emotional and the microdose enables them to be less overwhelmed). We are on the way to acquire microdose psylocibin which is what we’d like to try for the most affected person in our family as well but, the mushrooms are still growing however.
ReplyDeleteTatjana, it will be interesting to compare the effects of the two types of microdose.
DeleteI also wonder if the Pilz Bioscience dose will be the same as the dose currently used by Techies and Aspies. There probably are multiple effects possible before you reach the hallucinogenic doses. Uniformity of the product/dose will also be an issue, not all mushrooms are going to be created equal, making a synthetic alternative attractive.
It amazes me that the headache dose is so small and is needed so rarely.
Tatjana,scuze ca te intreb dar proiectul cu malarone care era o speranta pentru noi ce sa intamplat la-i abandonat....
ReplyDeleteGeorge, please be so kind and use google translate for asking questions. Its really fair that you use it instead of me. My daughter is still on malarone, still gains every day, she is more or less going from addition via counting dots representing numbers to using numbers. 6 weeks ago the dots were unimaginable, now we are leaving them behind. Speech is more complex every day. However, we are in a Pandas flare, and its making thungs really hard. If i could pick just one which to remove, autism or pandas, it would be pandas. I am at my wits end with it.
ReplyDeleteWhenever I used to experiment with LSD often I found that the social effects were that I had the ability to see people more as to how they really are. I could see the individual human in the person as well as being able to much better read their body language and facial expressions, an ability that is still very much absent in my general functioning now. Usually I found this effect to occur after the peak of the trip and the majority of the time after experiencing a bad trip, which for me would essentially be a feeling of being intensely overwhelmed sensory wise. I believe this kind of "bad trip" is related to a type of glutamatergic storm. Even days after the trip I found it easier to have interactions and to socialize with people even without the acute increased cognitive empathy experienced seemingly from LSD's afterglow effects.
ReplyDeleteGiven the tolerance from LSD microdosing I am not as interesting in trialing it again even though I have the option to. I am currently more interested in taking Medical Marijuana after a recent similar experience, also I am currently in the process of seeking a MMJ consultation and will hopefully have a THC tincture bottle in my hands in the coming weeks. I was gifted with THC microdose mints months ago and when I finally tried 20mg of the "relaxant" edibles (Indica) I was able to experience "vibes" in the way that I believe neurotypical people do. I was now able to see that every object, place, house, and even people had their own "vibe" that was felt very much interrelated to LSD's ability for me to perceive body language/facial expressions. The THC edibles also had the effect of slowing the speed of my mind down to the point where I could actually take in and process information in a way comparable to when I used to take ADHD stimulants, back when they used to still work for me at least. If I'm able to maintain these social perceptive benefits with chronic MMJ microdosing (5 - 10mg) I believe there is potential to greatly increase my quality of life as I could actually be able to truly learn how to effectively navigate the social world.
Several months ago I asked if you knew of any way to upregulate the 5HT2A Serotonin receptor and you suggested the possibility of marijuana in doing so. Given the well documented poor 5HT2A receptor binding for Asperger's do you think CB2-induced upregulation could be beneficial if someone were to have poor binding or otherwise poor 5HT2A receptor functioning? Increased numbers of 5HT2A receptors are typically implicated in negative psychiatric outcomes but would there necessarily be negative implications in ASD or Asperger's?
Also I trialed Riluzole but the strong sedative effects were too much for me at 35mg, I will probably trial a lower does of perhaps 10mg sometime in the future though. And provided I am able to find therapeutic benefit from chronically taking Medical Marijuana I may add something like the PS128 probiotic to further compliment the increase in social effects. I may even add Intuniv as well if I feel there's more room for improvement with my ADHD symptoms and sensory gating.
-H
Some receptors react via feedback loops when you attempt to block them, or indeed to stimulate them. The attraction of intermittent dosing, using very low (non-hallucinogenic) doses, is that there is no effect from feedback loops and so you do not develop a tolerance to the therapy.
DeleteAs I said in my post above, I suspect most Aspies over-shoot the microdose and are taking a hallucinogenic dose. The initial effect and the side effects from long term use are completely different. It is like comparing THC to CBD, they are different.
THC does not look like a good choice for long term use, unless you are using it to treat something that is otherwise untreatable, like some rare kinds of epilepsy. It will just create new problems.
The Israeli research shows us that CBD does seem to help some types of autism.
I have tried LSD microdosing in the past but concluded that the benefits were miniscule for myself. I used 5 mcg every day and didn't find much in terms of benefits. In recent months I've considered retrialing LSD mircodosing and I suppose I could trial the 25 mcg every three days strategy. I always considered this strategy ineffective given that you'd only be taking the microdose once every three days and not every day so what would be the point. If these 5HT2A related/MTORC1 effects can still remain at intermittent doses then I may very well be open to a retrial for myself.
DeleteIf I may ask why might long-term THC use be a bad choice? I'm familiar about the potential epigenetic changes from fathers to sons who use marijuana but I already do not intend on having any children given the seemingly quite troubling genetics that I have.
And given that I very much consider my condition untreatable I have minimum reservations with viewing THC treatment as a potential option. While classic Autism is undeniably debilitating to both those directly affected and for the parents as well comparatively mild autism isn't so comparatively mild compared to more normal, neurotypical people. Not every Aspie is able to successfully hold down a job or have "Sheldon" like mental capabilities to go through life with. Just being in a room with other people can become strongly uncomfortable when your sensory difficulties can be triggered just by looking at another person's face.
Also the only effect I really receive from CBD is a sense of mental calmness but this effect definitely isn't strong enough to be warranted as a monotherapy. If I am able to receive MMJ there will very likely be CBD in the tincture mixture as well as THC of course.
-H
To add to my last comment and me being on my wits end...I believe the culprit for our current exacarbation of anxiety to be histamine. Onset is literally spot on, on the day, for tree pollen activity. Also, red cheeks in the morning, and backs of hands very rough skin. I added back tavegyl in the evening to take a look and it all went down a bit. So - what should I do? Verapamil, ketotifen, change of antihistamine, azelastine spray? We only have antibiotics and diflucan and malarone to look for interactions and there shouldn’t be any.
ReplyDeleteWe used neuroprotek and quercetin but i think it maybe agitates her a bit.
Tatjana, people with autism for whom histamine causes flare-ups do seem to benefit from Verapamil. The effect is almost immediate, so you only need to try it for a day or two. Cut a 40 mg Verapamil tablet in half with a sharp knife and see if anxiety fades away in the next 20 minutes.
DeleteHello
DeleteI use propranolol for my daughter it solve a problem similar to yours
Tested doses 10 and 20mg age 8
we did use propranolol for a while. we went off it to try malarone (simply clearing all pathways for excretion). i wanted to at least gauge the effect of verapamil. i might go back to propranolo. we used 10mg 2x daily. propranolol wasn’t helping with pandas related rage though it possibly had some effects on sociability.
DeleteAllergies, both environmental and food related, are a constant problem for us. We take Allegra, fexofenadine, every single day, both myself and my son. I cut a 120mg tablet in half for him, crush it, and put into juice. He used to take liquid but the sweeteners caused some hyperactivity. Unless it is allergy season I do not give more than 60mg. Fexofenadine is the ONLY antihistamine that I have found that doesn't cause side effects in my son. Claritin (loratadine) is better at stopping the anxiety that often comes with allergic reactions but for daily use it is too sedating for my younger son. However, my older neurotypical son takes it daily with no problem. On days where histamine is even more of a issue, I give Allegra as well as a big dose of Bromelain glycerin tincture, about 700mg once or twice a day. It's sweet so makes dosing easy. We used to use high dose quercetin daily but again, after about a week, it caused side effects, though I still give occasionally for an emergency. When outside during pollen season or another high allergy situation, Singulair (montelukast) works really well for us, much the same as how Peter describes Verapamil working for his son. It has an immediate calming, stabilizing effect.
DeleteMkate
I will do exactly that tomorrow when we are all home and can react if blood pressure drops. We have a VERY practical marker - has refused to wash hair for the past 2 weeks. If she goes into the tub tomorrow its all clear.
ReplyDeleteIs she refusing to wash hair because of anxiety/phobia or is it some kind of sensory exacerbation?
Deleteanxiety. and I am not a pushover, so for her to not was her hair 2 weeks, means she really is panicking and tics appear if you try. you cant really force a child to bathe - its far to dangerous since rhey are slippery when wet.
ReplyDeleteHopefully, verapamil will do the trick. In my son allergy driven anxiety quickly ended up with aggression to self and others.
DeleteIf not, then I would look at the tics as a clue.
I think there will be several copies of this comment because my browser went crazy. Anyway, we tried verapamil, 20mg on her 25 kg, is that the right dose? An hour later we proposed a bath. There was still anxiety - i would say it was about 50-70 percent less than these past two weeks. After an hour of coaxing we managed to get a shower, where once she very reluctantly agreed, she even had fun, drowning the bathroom in the process. She is proud to be clean finally. We think we will give verapamil a bit of a try for a week, to see what comes out of it. At least we finally have a clean child. The anxiety that was leftover was not nearly as panicky as what we had all these days, it was just extremely stubborn refusal with some whining.
DeleteTatjana, Verapamil is used off-label for children and in clinical trials, but there is no recommended dose as such.
DeleteIn the trial in Dravet syndrome, these were the doses:-
Week 1: 1mg/kg/day divided BID Week 2: 2mg/kg/day divided BID or TID Week 3: 3mg/kg/day divided BID or TID Week 4: 4mg/kg/day divided TID
Verapamil has a short period of action, which is why the dosing is often 3 times a day, or uses extended release tablets.
The most I used was 40mg 3 times a day. That was back when we had really severe raging. One doctor reader uses much higher doses and found the effect very dose dependent
I am always keen to avoid side effects and so use the lowest dose I can.
Some people use Verapamil just for situations that are likely to be stressful or provoke anxiety. People use Propranolol in a similar way. Some people use both Verapamil and Propranolol, which you are not supposed to do, but they find does not cause a problem.
I remembered there was a reason we did not use verapamil before - its interaction with diflucan. we will be changing to itroconazole now but the same mechanjsm remains. Now, I can actually use them on alternating days, since that would most likely still keep fungi in check. Would using verapamil every two days give a benefit on the days off as well? obviously the effect would not last that long as such, but would the body be less ‘tired’ of the histamine that way?
DeleteTatjana, Verapamil has several secondary benefits and some might remain with intermittent dosing. In our case of allergy driven autism flare up, the effect of Verapamil fades away to nothing after about 4 hours.
Deleteregarding tics - obviously, the PANS is implicated but every single expert I know sees histamine as huge contributing factor in pans/pandas.
ReplyDeleteThere are some amazing testimonials from high functioning aspies on youtube on their experiences after going clubbing and taking MDMA.
ReplyDeleteLife-changing, highly emotional stuff.
My suspicion is that all this, as much as it is involved in the affects of psychoactive drugs on xyz pathways in the brain, has much to do with simply 'bootstrapping' the brain.
As in pointing the brain 'owner' towards an alternative, and more rewarding, way of working after being stuck at 'same old same old' ways.
Nicely illustrated in this article https://www.nature.com/articles/d41586-021-00187-9
Nat, I think we have to discriminate between Aspies and those with severe autism. Pretty clearly some Aspies are seeking the "extreme effect" of these substances. As with depression, it may just hit the reset button and get them to open up.
DeleteIt does seem that at low doses something very different may be happening.
I am supposed to undergo therapy for ptsd with mdma, will let you know what it feels like.
DeleteI find it funny that I was coincidentally watching YouTube videos of this same very topic earlier today. I have indeed tried MDMA a few times before and the effect for me was a strong increase in verbal interaction with others as well as a strong sense of social barriers being weaker when interacting with others. I personally did not find anything much similar to those experienced by other Aspie's in regards to MDMA use.
ReplyDeleteIt would be much nicer if we could go back to where the distinction between Asperger's and classis Autism were more recognized and acknowledged between the medical community and the general public. The ambiguity can be difficult for the more high-functioning among us like myself as well.
-H
Peter, I'm sorry to bother you, I want to start treatment with Intraconazolum, and I wanted to ask you, I administer Verapamil to my child for aggression 2 or 3 times a day, do you think I can administer intraconazolum without verapamil?
ReplyDeleteGeorge, Itraconazole increases the blood levels and effects of Verapamil. This means that the dose of Verapamil would have to be reduced, if you also give Itraconazole. Nobody can tell you how much to reduce the dose.
DeleteIn addition to being an anti-fungal drug, the reason Dr Sidney Baker prescribed it to his patient with autism, it inhibits Hedgehog pathway activity, making it a possible cancer therapy.
It would be safer to take Itraconazole without any Verapamil.
I have the same question. However, for now, I am sticking with Verapamil. Today, my child not only had a shower, she had a shower totally by herself. We are (positively) shocked. I helped her with her hair a bit since its literally the first time ever she attempted to wash it by herself but...its amazing. 3 days ago it was an hour of panic, not wanting to step into the bathroom. Today she got muddy playing outside, came in and went to have a shower. I am so flabbergasted that I am repeating myself here :-).
ReplyDeleteI got a pharmacokinetics textbook on Kindle to read up on it. I obviously need to understand the cyp3a4 and all its modalities, because verapamil, atorvastatin, itroconazole and malarone and diflucan all use it.
Hi, I have only recently discovered this blog, and have definitely not finished reading through it. However, I'm wondering if you have suggestions for tests to request to guide decisions about which medical interventions are more likely to be successful for a particular individual. My son is 4 years old and relatively recently diagnosed. It seems likely to me that there is a genetic component, as he has a family history of autism on one side (grandfather) and schizophrenia on the other (parent's sibling). We are based in the US and in the process of finding a doctor willing to work through this process with us; but our pediatrician is open to ordering most tests. We have already done whole exome testing (waiting on results to come in). I am planning on requesting cholesterol levels (to see if statins are contraindicated), serotonin, FRAT, Vitamin A/D/Bs, zinc, copper, and magnesium. Any other ideas? FWIW, my son definitely has some seasonal allergies & also eczema. He does not appear to present with fatigue or lethargy. His largest issues are expressive communication (some apraxia) and social engagement.
ReplyDeleteSara, for some people testing is highly beneficial and leads to an effective treatment, in other people no amount of testing really helps. Since your son is only 4, it makes sense to do testing, if you can afford it.
DeleteI would suggest you first choose your “autism doctor” and then do the tests that he/she suggests. Most such doctors have their own "pet therapies" which they apply to everyone, and so you may end up using more than one doctor.
I also suggest you talk to some parents of much older children, who went through the same process in the US that you are embarking on. One US mother recently told me how she wished she had done testing on spinal fluid when her now adult child was younger, but the doctor did not want to do this because it is invasive. Blood tests cannot tell you what is going on in the brain, whereas spinal fluid can tell you much more. The same is true for an MRI or fMRI and indeed EEG. The doctor does not want to upset the child (and hence the parents) and so invasive/difficult tests are avoided. If you are going to have full sedation, you can do all the difficult tests at once.
Find your doctor and tell him you are not afraid to do invasive tests, but plan ahead to do them at the same time. Even keep some spinal fluid in the freezer, for further analysis later.
I think TACA has given up on “curing” autism, they changed the meaning of their name to reflect this. “Talk About Curing Autism” became “The Autism Community in Action”.
Many readers cannot afford testing, but they can still successfully treat their child with autism, if they are willing to make short trials of evidence based therapies. Many readers of this blog fall into this category.
totally agree with everything you said. best is to find out in front what the pet therapy of your doctor is so you know what he is just doing for everyone. a great fb group I can recommend is rogue recovery. Its a huge group and it contains both people of the spinal tap variety as well as the energy healing type. you can learn so much by simply searching it - by name
Deleteof doctor or test etc.
If money was not a question I would go to dr Frye.
I have to say that with a young child like that I would also go, without any testing, for at least one course of msc stem cells. So many children have so much improvement from it that it would be benefitial to check what you can, so to say, wipe off the board with it, and then use testing and other therapies for what was not improved by them.
Thanks to both of you. We are lucky to be in a city with a major children's developmental disability research institute, so I think we are likely to be able to find a neurologist there who will work with us on an EEG. I don't think they typically sedate for that, though. But yes--if there is anything where sedation is required, I will definitely ask to get a spinal tap done at the same time. I will admit to being slightly traumatized by the time that my son had a spinal tap as a newborn (for high fever), but that was an emergent situation and obviously no sedation was used.
DeleteI will get in touch with Dr. Frye's practice. We don't have unlimited resources, but money is not the primary concern right now. And we have excellent insurance, which will typically reimburse part of costs even for out of network treatment, and will cover any 'mainstream' labwork (not FRAT/OAT, I think, but most of the rest).
I am hesistant about stem cells because the papers I have read so far do not seem to show much evidence of benefit, and it's a more invasive intervention. But I will keep looking at the research.
In my short experience so far, TACA as an organization has changed their rhetoric, but many of the parents involved are still interested in cures. But I have not been hugely impressed with their knowledge of the science.
I believe that most people did get frat covered by insurance. This is also a situation where tfscebook groups are helpful / there are some dedicated exclusively to getting insurance to cover tests used in autism.
Deleteas far as stem cells go - most available research is focused on cord blood and suffers from a major flaw, I will comment on it later.
as far as types of cells go, we are in our knowledge very limited right now and there is no expert who could say that 1. a child would be a responder or 2. to which type of cells. the various types and subtypes all do a bit different things once they are in the body. However, their safety profile is vastly better than most drugs I use on my child.
Duke was focused on cord blood for years. The major flaw of their research, which Peter ahs pointed out as a problem in some other types of autism research as well, is that they were looking for certain improvements and those who did not bave them were labeled nonresponders. Most nonresponders I talked to including us personally had huge improbements in gross and fine motorics. These are the base foundations of the neurological system and any improvement there is guaranteed to yield improvement in overall autism down the road.
Despite the fact that Dr Kurtzberg personally told me that msc cells are less potent in lab settings than cord blood, Duke is now switching their research to msc (which circles back to me saying that even the experts are not sure). They also have the advantage of being more readily available, cheaper and safer.
I recommended them because I have talked to, and having tallied it in my head, I am a bit surprised by the number myself, to over 500 parents who had improvements from it.
The procedure takes 15 minutes and one needs to stay at the dr office for half an hour and in the city for 24h afterwards.
though I am not Peter, I will add my two cents on a few tests which might not be on the nose but I would definitely recomend them to someone starting out - a comprehensive microbiome dna analysis with professional guidance (like the gut club on FB, Keith Bell does interpretation of tests), the OAT test which shows some system issues that can be addressed and can balance things out. we used Shawn Bean for interpretation of the oat but that really just my choice. this doesn’t seem as ‘hard science’ as the FRAT for example but in my humble experience metabolic imabalances can prevent some good therapies from working though they actually would. so removing these, seemingly small, obstacles in my experience yields a lot of good.
ReplyDeleteThank you! I had seen the OAT test on the TACA website, but then their FB group is also full of folks recommending homeopathy, so I hadn't figured out yet where it fell in the range of evidence-based to wholly implausible.
DeleteI do know from the top of my head that dr Baker used the mycotoxin panel from the same company that does the Oat for his itroconazole research. Also, practitioners whom I talked to who are jn the game for 20ish years have learned to rely on it because it would often guve them the same info but for a lot less money than expensive and invasive blood tests covering the same topics. in the beginning they would do both, and now they use the oat to at least get pointers where to dig deeper.
DeleteHave you seen this book Peter
Deletehttps://www.intechopen.com/books/a-comprehensive-book-on-autism-spectrum-disorders
Apinke, I have not seen it. The chapter are open access (free) and many issues are covered. The only missing part is how to treat autism, which is the part people really want to know.
DeleteI agree with you, it has nothing on how to treat autism though covers a lot except treatments
DeletePeter, did you check out the new Allopregnanolone drug developed by Asarina? I stumbled upon it looking for a solution for my PMDD. It looks like a great tool to add to the autism toolbox. I will try and call them to get an idea of when and how this will be available to buy.
ReplyDeleteTatjana, Asarina does indeed look interesting, but they are extremely slow, like other drug developers.
DeleteI like the idea of low dose sertraline as a potential alternative, that you use today. Some people have tried it.
https://epiphanyasd.blogspot.com/2018/11/when-is-ssri-not-ssri-low-dose-ssris-as.html
I emailed them today. They have abandonded the product for PMDD and pursuing it for menstrual migraine, proposed to come out in 2026. I have finally found a compounding pharmacy in my city, Galena, which will give me so many options for the future. Next week I will ask my very openminded gynecologist to give me a prescription for microdosing ssri for PMDD and the pharmacy will make it for me. Then I can also try it for my daughter.
DeleteHello, did anyone take intraconazole or want to start an experiment, I would like someone to tell us more about the recovered child, if he had food deficiencies, mast cell allergy to certain foods and how he reacted throughout the post-recovery period, excuse me if I stress you I am not a medical professional but I really want to recover my son from this disease ....
ReplyDeleteGeorge, the full case study has not yet been published, all we have is this:-
DeleteCase Study: Rapid Complete Recovery From An Autism Spectrum Disorder After Treatment of Aspergillus With The Antifungal Drugs Itraconazole And Sporanox
https://pubmed.ncbi.nlm.nih.gov/33132781/
There are many such examples of unusual things causing autism. What we need to know is how common they are, so parents know where to focus their attention.
In the case above the problem was a mold/fungus, how did this mold end up inside the child? Did it come from home or school etc? Was it from contaminated food? Did they check other family members for this mold/fungus?
Peter, here is the full case study:
Deletehttps://static1.squarespace.com/static/560ac814e4b067a33438ecea/t/602c48ade63b5208c80c3e0a/1613514925243/Baker+shaw+IMCJ+article+2020+-+Rapid+Recovery+ASD+Treatment+of+Aspergillus+with+Antifungal+Drugs.pdf
Further exploring itraconazole and the Sonic HedgeHog Pathway, I discovered this, I am not very scientific but yes I am really good at keywords and seo, perhaps you can shed some light on this, and how this might be related to bumetanide ? Did baker treat the fungus or the GABA balance ?
DeleteSonic Hedgehog Signaling (Shh) regulates the developmental shift of GABA polarity in rat somatosensory cortex
https://www.biorxiv.org/content/10.1101/799015v1.full
"Sonic Hedgehog (Shh) and its patched-smoothened receptor complex control a variety of functions in the early developing central nervous system (CNS) such as neural cell proliferation and differentiation. Recently, Shh signaling components have been found to be expressed at the synaptic level in the postnatal and adult brain, suggesting a potential role in the regulation of synaptic transmission. Here, using in utero electroporation of constitutively active and dominant-negative forms of the Shh co-receptor smoothened (Smo), we studied the role of Shh signaling in the development and maturation of GABAergic transmission in rat somatosensory cortex. Our results show that enhancing Smo activity during development accelerates, the shift from depolarizing to hyperpolarizing GABA, in a KCC2-dependent manner, rendering GABA inhibitory in immature tissues. On the other hand, blocking Smo activity maintains GABA response in a depolarizing state in mature cortical neurons resulting in altered chloride homeostasis and increased seizure susceptibility. Altogether, our study reveals an unexpected function of Shh signaling on the regulation of chloride homeostasis through the control of KCC2 trafficking and, in particular, on the timing of the GABA inhibitory/excitatory shift in brain maturation."
Sorry for so many comments, but I am eagerly waiting for your comments on this:
DeleteIn conclusion, these data uncovering an unexpected role of Shh components during early postnatal development in the regulation of the E/I balance through the control of chloride homeostasis. Thus Shh signaling will tune up or down GABA inhibitory transmission by acting on chloride homeostasis and trafficking of KCC2 at the cell membrane. Although the molecular links between Shh and KCC2 require further studies, our observations suggest that Shh is able to set the cursor of GABAergic inhibitory switch during this critical maturational period where developmental pathogenesis takes place.
Salman, many anti-parasite and anti-fungal drugs have effects that can be beneficial to very different conditions, everything from cancer to lupus to autism.
DeleteDr Baker clearly thinks he was treating some kind of fungus/mold. He seems to give anti-fungal drugs to most of his patients, which is in itself rather unusual.
As you point out, and as I have written in other posts, Sonic Hedgehog signaling may well be relevant to some people's autism.
There is a long list of anti-fungal and anti-parasite drugs that are potential autism drugs, due to these secondary effects.
The take home point is that you do not need to have a fungus/parasite to potentially benefit from one of these drugs. It does however remain a case of trial and error, or just luck.
Seems like Dr. Ben Ari was also involved in some way in the above study.
Delete"We thank Drs. Y Ben Ari and J.L. Gaiarsa for critical reading of the manuscript; F. Michel at InMAGIC (INMED Imaging Centre) for technical assistance"
Anyways, I will be trying out Bumetanide soon so I was trying to research more on NKCC1 and KCC2 pathways.
I gave low dose clonazepam a try for 2 days, today is the 3rd day and seems to have more like magnified his behaviours, I can see more frequent use of words that he has, but also more frequent other behaviours that we dont need. The little speech/words he has seem more frequent but the behaviours we don't want also seem frequent, after 3 days I will be doing a lower dose for another 3 days and see if the effect remains.
I wonder what the effect will be if it's tried after he turns out to be a responder to bumetanide ?
Seems I will try out bumetanide and see if it has a positive effect and possibly then magnify that response with low dose clonazepam, if its a case of magnification we might see more magnification of bumetanides positives.
Also I wonder what kind of effect intraconazole would have in light of the above studies. Yes, its a case of trial and error and more importantly patience and very careful observation for every intervention.
Btw, hes more in the regressive subtype with typical development for 2 years but I think could be a case of a double tap, (no effect of kelly's cocktail) hence I lean towards a shift of GABA I/E imbalance.
Thank you fore replying. Appreciate your wisdom.
sorry, not the double tap exactly but more towards a defective GABA shift in early brain development, does that make any sense ?
DeleteSalman, it looks like even in adults their neurons can shift back to an immature state, with high chloride due to increase in NKCC1 and reduction in KCC2 expression. So kids that develop normally for two years might indeed then shift back to immature neuron state and then become bumetanide-responders.
DeleteWith low dose clonazepam, if you get a bad reaction you likely have dosage slightly too high, but you are a responder. In a non-responder there is no reaction, good or bad. Some people do respond to both low dose clonazepam and bumetanide, but the mechanism is not the same, but both do relate broadly to E/I imbalance.
Yes, I am reading more on it and trying to get hold of the science. Here's a latest consolidated research paper on the subject from February 2021.
DeleteThe postnatal GABA shift: A developmental perspective
https://www.sciencedirect.com/science/article/pii/S0149763421000506
Thank you for the swift response.
This para is from another blog post of yours:
DeleteGABA A Receptors in Autism – How and Why to Modulate Them
"It also answers somebody else’s question about starting with Clonazepam before the Bumetanide. If you did that you might well make things much worse, you would magnify the unwanted excess brain cell firing. Once you added bumetanide things would then reverse and brain cell firing would be inhibited."
There is a definite respond to LD clonazepam at 0.015mg (but something I dont need becuase he became x2 on that with speech x2, other unwanted behaviours also x2)
Do you think if this is the reason I saw a magnification of his autistm because I tried low dose clonazepam first, if I tried bumetanide first and hes a responder and then try LD clonazepam I would then see an x2 with the good effects from the therapeutic benefits of bumetanide ?
Salman, it turns out that Bumetanide may be only a partial solution for those with immature neurons. So taking bumetanide does shift GABA in the direction of inhibitory, but perhaps not as far as you might want. So things do not entirely "reverse" when you add bumetanide.
DeleteYou are fine-tuning the alpha 3 subunit of GABAa receptors with LD clonazepam and I think we should expect people to react differently. I was surprised that multiple people did respond well to bumetanide + LD clonazepam, but that was what happened.
In reality it probably does not matter which of the 2 drugs you start first. You might want to vary the dosage of Clonazepam, both more and less, and observe the result. The fact that you have a response at all is very relevant.
The alpha 5 sub-unit is another target of interest for fine-tuning autism. This will be covered again in the next post.
Malarone update: she is still on the treatment dose. Every day better than the last. My family and her assistant share a Google Sheets spreadsheet to fill out a daily diary of behaviour, meds, food, bowel movements, events, so that we have a history of behaviours and can connect them to events, food, medication etc. Right now that document is becoming terribly unwieldy because in order to write down in very short form all the amazing things that happen in one day takes about 600 characters which deforms the spreadsheet totally.
ReplyDeleteWe sent some blood to Armin Labs yesterday and should have the results in 2 weeks to see if any parasites pop up. But I will hold on to Malarone for at least 4 more weeks.
We got hold of Oxytocin spray...What dose should we start with? I think its 4 IU per spray.
In this paper they discuss dosage.
Deletehttps://link.springer.com/article/10.1186/s40814-020-0557-8
Because patients with sensory difficulties need additional training, we will instruct the patient and family members to the use of spray, which begins with 1 puff of 4 IU daily, as well as provide training for MRI taking. After 1 week, the dose will increase to 1 puff per nostril for both nostrils daily (8 IU/day). After the second week, the dose will increase to 1 puff per nostril for both nostrils twice a day (16 IU/day). After the third week, the dose will titrate up to the maximum dose 24 IU daily, which is 2 puffs per nostril for both nostrils in the morning, and 1 puff per nostril for both nostrils in the afternoon. The dosage of 24 IU per day has been approved safe and adequate in even younger patients (ages 3–8 years old) by previous publications [23, 24].
Hi Peter
ReplyDeletePlease what is the dosage for vermox for a 7 year old weighing 25kg.
Thanks
Apinke, I would use the standard dose for Roundworm which is 1 tablet morning and evening for 3 consecutive days. This drug affects both Hh signaling and Wnt signaling, both of which are implicated in some autism. Then you decide after 3 days if there was an effect in your specific type of autism.
DeleteAbout 5-HTA pathway somebody in Reddit had made a long scientific post recently, what deserves to be stored into here too. https://www.reddit.com/r/NooTopics/comments/1fe5do7/5ht2a_chosen_to_be_the_best_cognitive_therapeutic/
ReplyDelete