Since AI is a trending tool in this blog, I decided to let ChatGPT rewrite today's post. It did rather strip out the science bits. It added the "don't wait for permission at the end"—a little cheeky, I think. It does like to use dashes.
Today’s post highlights a compelling new case study—one that turns theoretical research into a real therapy.
About time too! That was my reaction when a reader sent me the paper.
This case study reports on the repurposing of a cheap,
well-known drug—Nicardipine—to treat Pitt Hopkins syndrome
(PTHS). The drug had already shown promise in earlier mouse models.
So why aren’t we doing this more often? Because the system
misunderstands risk.
What About the Risk?
When it comes to trying new treatments, people often fixate
on the risk of the therapy itself. But that’s only half the equation.
The risk of doing nothing is often much greater—especially in autism.
Most conventional drug repurposing therapies pose minimal
long-term risk. Things change only when you start injecting compounds or
using untested chemicals. But even then, there’s surprisingly little harm on
record.
Only one death has ever been clearly attributed to a
therapy for autism:
A 5-year-old autistic boy from the UK died in the US while
undergoing chelation therapy. The wrong form of EDTA—disodium EDTA
instead of calcium EDTA—was used. The result was fatal hypocalcemia-induced
cardiac arrest. The doctor administering the therapy didn’t understand the
pharmacology.
Lesson: Always read the label.
Meanwhile, the risk of death from untreated autism is
well established:
- In severe
autism, common causes include drowning, accidents, and seizures.
- In milder
cases, the biggest risk is suicide.
Another overlooked danger, mentioned previously in this blog, is polydipsia—excessive
water drinking—which can cause hyponatremia (low blood sodium), leading
to seizures, coma, and even death.
Bottom line?
The risks from untreated autism far exceed the risks from science-based,
carefully applied therapies.
The Nicardipine Case Study
A newly published study builds on promising mouse results
and shows real benefit in a young child with PTHS. The drug used—Nicardipine—has
been around since 1988 and is commonly prescribed to older adults for high
blood pressure or angina.
🔗 Read the case study
Highlights:
- Pitt
Hopkins syndrome involves loss of function in the TCF4 gene,
leading to overactivity of Nav1.8 sodium channels in neurons.
- Nicardipine
inhibits Nav1.8, making it a logical therapy.
- In
this case study, the child received oral nicardipine for 7 months
(0.2–1.7 mg/kg/day).
- Result:
Mild to moderate improvement in all developmental areas, and reduced
restlessness.
- No
significant side effects reported.
It’s not a magic bullet—but it’s a start.
Used as part of polytherapy, this could become a powerful tool
for treating PTHS.
And there’s more coming: Vorinostat, another
potential therapy, is entering human trials.
Why Don’t More Therapies Get Adopted?
A recent paper by Antonio Hardan sheds light on this.
He’s the researcher who showed that the OTC antioxidant NAC benefits
many with autism, and later explored the hormone vasopressin.
This time, he tackled the placebo effect—a real
barrier in autism research.
🔗 Placebo Effect in Clinical Trials in Autism: Experience from a
Pregnenolone Treatment Study
What They Did:
- A two-week
placebo lead-in before the main trial.
- The
drug tested was pregnenolone, a neurosteroid.
- They
used parent-reported ABC-I scores to measure irritability.
What They Found:
- A 30%
reduction in irritability—just from placebo.
- Also
improvements in lethargy, hyperactivity, and repetitive speech.
- The placebo
effect was strongest in the first two weeks, then plateaued.
- Clinician-rated
scores (CGI) did not show this placebo response.
The Takeaway:
Parent expectations strongly shape trial results—at least in
the early stages.
A placebo lead-in is a clever way to measure and filter out this noise.
Early Adopters, Take Note
It pays to be ahead of the curve.
Some Pitt Hopkins parents are already trying nicardipine
at home based on this case study. Good luck to them—I hope they find the
right specialists and support.
Let’s not forget: the big autism trials of recent years—Bumetanide,
Memantine, Balovaptan, Oxytocin, Arbaclofen—all officially “failed.”
But the drugs didn’t fail—the trial designs
did.
Each of these drugs helped some individuals. The problem?
The trials weren’t structured to identify responder subgroups. We wasted
time, money, and hope by not tailoring inclusion criteria more carefully.
Consider Trofinetide, the first FDA-approved drug for
Rett syndrome (2023). It helps only 20% of patients, but was
still approved.
I’d argue that Bumetanide has an even higher response
rate in severe autism, particularly with intellectual disability—and
that the best outcome measure is IQ, not a generalized autism scale.
My Own Example: No Placebo Here
How do I know I wasn’t misled by the parental placebo
effect?
Simple. No one knew I was trialing treatments—not
even the teachers or therapists. That meant their feedback was objective and
uninfluenced by my hopes.
My son Monty went from being unable to do basic
subtraction at age 9, to later passing his externally graded IGCSE high
school math exam.
Not bad for a therapy that mainstream medicine still
ignores.
Final Thoughts
- Drug
repurposing is safe, smart, and often effective.
- The
placebo effect is real—but it’s measurable and manageable.
- If
we want progress in autism treatment, we need smarter trial designs, not
just more of them.
- Being
ahead of the curve isn’t risky—it’s essential.
💡 Stay informed, stay
curious, and don’t wait for permission.
Thanks for the guest post, ChatGPT !!
One point to add to the risk assessment: by my estimation, each year in the US, around 200 to 300 people die from drowning, seizures, accidents, and suicides related to autism. In living memory, only one person has died as a result of visiting an autism doctor in the US and that death was entirely preventable.
Vorinostat, a potent HDAC inhibitor trialed in several autism models, was mentioned in the above post. Interestingly, there is a recent comment from a reader who finds it resolves 80% of his autism but only for about 2 hours. The half-life of this drug is about 2 hours. There are discussions on Reddit by people using it for autism, anxiety, PTSD etc. It is about 1,000 times more potent than HDAC inhibitors people typically might try at home. Perhaps there should be trials of micro-dosing Vorinostat? I think daily use of high-dose Vorinostat may not work well, due to side effects. Human trials will soon inform us better. It is often older people who struggle with drug side effects, not children.
Vorinostat may not only correct Differentially Expressed Genes (DEGs) but also:
- Increase synaptic plasticity
- Improve synaptic morphology (the shape and function of neuronal connections)
- Improve memory and cognition
The main research interest is in single gene autisms, where one specific gene is under-expressed (eg Pitt Hopkins, Rett, Fragile-X etc) but the general ideas are equally applicable to broader autism.
Please don't use ChatGPT for your posts, tastes like canned food. Sincerely, an avid reader.
ReplyDeleteFear not, it is just to show people who do not use AI what it looks like.
DeleteIn other news, ChatGPT just released model 5. It promises "PhD Level" knowledge in every subject. Peter, I think you can do amazing things with this tool if this claim has any truth to it.
ReplyDeleteAI is already a great tool, but the more you use it to deal with complex issues you notice that it does make mistakes and sometimes "forgets" what it has told you earlier in the same conversation. It can exhibit some of the same weaknesses as humans. It is so fast and polished that users need to realize it may not be 100% perfect.
DeleteI wonder if it can somehow be trained with epiphanyasd.com DB data. And what knowledge can be extracted. I've tried prompting it to web crawl but it cannot read the comments from the "load more" threads.
DeleteI am intrigued because of the infamous Move 37 of AlphaGo AI. Lots of what ifs...
DeleteKonstantinos, another reader asked about adding some AI feature to interpret the blog. I think that is still in the future.
DeleteI see a different appoarch as more realistic my fellow greek. AI+Wearable Technology (glasses, watches, etc) = integrated personal assistant. Could help with safety, social responses, etc. Of course this would yet again help only a subset of individuals with autism.
DeleteYou could even go as far as saying that you don't even need a wearable technology to go with AIA and in the future this is highly possible with elon musk upcoming neuralink..
DeleteWhat can be done for insomnia in an autistic person? Being very tired all day and even falling asleep in public spaces like busses, trains, but at night in bed an wave of energy comes out of nowhere and mind is switched on being unable to fall asleep. Medication like seroquel, cyproheptadine, baclofen, gabapentin, melatonin nothing works..
ReplyDeleteAlprazolam put him away fast but the sleep on this drug is not restful at all he says
What you are describing — tired all day but suddenly alert at night — is common in autism and often comes from a dysregulated circadian rhythm combined with overactive arousal systems. In that state, sedatives like melatonin, cyproheptadine, baclofen, or gabapentin rarely work well because they do not address the cause of the night-time alertness.
DeleteAlprazolam can knock a person out quickly because it boosts GABA-A activity, but this suppresses deep slow-wave sleep and REM sleep. The result is “drugged” sleep that feels non-restorative. Over time, tolerance and dependence are almost inevitable.
Two medications sometimes used in autism when this pattern occurs are low-dose trazodone and low-dose mirtazapine.
Trazodone (typically 25–100 mg at night) blocks 5-HT2A/2C serotonin receptors, histamine H1 receptors, and alpha-1 adrenergic receptors. This combination quiets mental overactivity and reduces noradrenaline’s night-time “fight-or-flight” effect, while preserving or increasing deep sleep.
Mirtazapine at low doses (7.5–15 mg) is even more antihistaminic than trazodone and can also promote deep, consolidated sleep. At higher doses (>15 mg) the sedating effect is often weaker because its activating antidepressant actions become stronger.
In both cases, the sedation is greatest at low doses because the histamine-blocking effect dominates before the antidepressant effect takes over.
Non-drug measures can help reset the circadian rhythm:
Bright light soon after waking (10,000 lux for 20–30 minutes).
Avoid blue light after sunset (screen filters, amber glasses).
Fixed wake-up time every day, even after a poor night’s sleep.
No long daytime naps, which can delay night-time sleep pressure.
Melatonin (pediatric prolonged-release / Slenyto) has shown some improvement in asd with insomnia:
Deletehttps://pubmed.ncbi.nlm.nih.gov/29096777/
Xolair could help.
DeleteThis inhibits the release of inflammatory mediators, such as histamine, and reduces the hypersensitivity response associated with chronic urticaria. By targeting the underlying immune system dysregulation, omalizumab provides significant relief from symptoms, improves QoL, and therefore, may contribute to better sleep outcomes for patients [77]. A study investigating the impact of omalizumab on sleep‐related outcomes in patients with chronic idiopathic urticaria demonstrated a notable decrease in sleep problems with omalizumab treatment compared to placebo. Patients receiving a dosage of 300 mg of omalizumab exhibited the most substantial improvement in sleep quality compared to other treatment groups. The study observed the greatest reduction in sleep problems during the initial 4 weeks of therapy. However, sleep quality deteriorated upon discontinuation of treatment. The findings also indicated a strong correlation between sleep scores and changes in itch and hives, suggesting a relationship between improved sleep and alleviation of urticaria symptoms [12].
https://pmc.ncbi.nlm.nih.gov/articles/PMC12051439/#:~:text=This%20inhibits%20the%20release%20of,effect%20on%20sleep%20and%20urticaria.
https://pubmed.ncbi.nlm.nih.gov/37714684/#:~:text=However%2C%20a%20significant%20negative%20correlation,studies%20to%20confirm%20our%20findings.
Interesting! We are working a new allergist/gastroenterologist who’s convinced that my daughter’s sleep issues are parasite related. I told him that Desloratadine used to help but stopped being effective after a while. His reply was that some parasites make the skin itch at night and the antihistamine was probably stopping this reaction.
DeleteWe did do some subsequent testing which did find 4 different parasites. So he’s right about that. But so far treatment for these has not shown any results on the sleep side of things.
Pinworms are apparently a well-known cause of sleep problems. Once you have one parasite. they can modify the immune system to stop it attacking the parasite and this then makes also it easier for other parasites to get established. Even after killing the parasites the immune system takes time to go back to "normal".
DeleteThere are very many different causes of sleep disorders.
There is a new drug called Dayvigo, which some children with autism take. Dayvigo (lemborexant) is a medication approved for the treatment of insomnia in adults. It belongs to a new class of drugs called dual orexin receptor antagonists (DORAs). It works by blocking the activity of orexin, a neurotransmitter that helps keep people awake. By blocking these signals, Dayvigo helps reduce wakefulness and allows a person to fall asleep and stay asleep.
It is approved for 18+, so it would be off-label use in children.
Clonidine has produced effortless sedation.
DeleteI am uploading all of my son’s lab tests into a health file in ChatGPT that interprets all lab tests and answers questions about why certain values may relate to what symptoms we see and to his known SNP’s and how they might relate to folate receptor auto-antibodies. The results are so impressive. I'm not really very tech savvy but it’s exhilarating to be able to ask any question you can possibly think of and get a very helpful response based on a review of all labs we have ever run going back to when my son was a small child.
ReplyDeleteEDFW, AI is getting better every day and really empowers parents. The health file is a great idea to ensure each time AI goes back to the beginning and reviews all your data, otherwise it "forgets" things that you told it previously in earlier chats.
DeleteWith some AI you are starting to get "I am just an AI model and cannot give medical advice". This was always going to be a risk and I think it will grow. If you make the conversation more technical this problem does not occur.
Hi, as an avid reader of your blog, I'd invite you to remove the reference to vaccines from your "cause of classic autism" page as I am afraid it could discourage people who are oversensitive to potential misinformation. My autism is of the sardonic-inconsiderate variety described by Hans Asperger so I am open if not sympathetic to conspiracy theories but I believe individuals unfortunate enough to suffer from a frontocortical hyperexcitability (and/or their distressed parents) in the context of ASD could feel offended by the mentioning of mercury and they also, in my view, deserve help and/or satifaction of curiosity. I am also, parenthetically, of the view that the risks of immune-related insults are largely unrelated to any xenobiotics present (formerly or currently) in the vaccines. Regression is usually reported to follow a fever which is an inevitable possibility with an immunological intervention. But my remark applies whether or not we agree on this matter.
ReplyDeleteThank you in advance, and of course take my neuroanatomical digression with a grain of salt.
I am glad you enjoy reading my blog.
DeleteVaccines are indeed a very sensitive subject, and I am also surprised when they still come up in presentations by clinicians and researchers at conferences.
The very concept of treating autism is controversial — for some it feels abhorrent, while for others it becomes a lifelong pursuit. My intention here is simply to be as objective as possible. Most people already have strong views, one way or the other, and it is not my role to persuade them otherwise.
I often remind readers that there are likely thousands of different causes and contributors to autism, and that number keeps expanding as the diagnostic net widens. It is natural for parents to seek explanations, and vaccines are one of the areas people focus on.
So I try to tread a fine line, acknowledging different perspectives without taking a rigid stance. My goal is to encourage curiosity and open discussion rather than to close down debate.
I agree that the topic is 'divisive'. This, however, does not mean that there is robust evidence for both positions on the matter. Rather, there is overwhelming evidence for a balanced position: one which acknowledges the mechanical plausibility of a vaccine-regression link in some rare cases while denying immunization the leading role in the epidemiological trends known to the public under the name 'autism epidemic'. Because both parties disregard much of the relevant evidence, a bit of verbosity and diplomacy in place of the potentially misleading blunt remark on the causes of classic autism page could attract open-minded individuals, even if true believers are left unconvinced. I believe it is insufficient to note that vaccinations or whatever xenobiotic substances they might contain are only a minor factor as this strategy is not uncommon among antivaxxers these days. Notably, they insist on the role of the weedkiller glyphosate (never failing to note that it is allegedly a vaccine contaminant).
DeleteSince the page on causes of classic autism is, in any case, a bit speculative, I see no counterindications to provide information there that could be revised in light of further evidence. I am not the one to discourage discussing these matters, even if I believe the broad outlines of the case to be largely settled. I just think one should not yield to antivaxxers (nor to neurodiverse folk) in what is essentially an introductory resource. I find the reference to mercury (never had mechanical plausibility, not a vaccine ingredient these days so no relevance for prevention and never has been in the live virus MMR vaccine) in the very first paragraph problematic above all.
Those who want to help their children with severe ASD, who can't ask questions or demand anything, need full access to a scientific field unbiased by sensitivities or other forms of subjective censorship. We are blessed to live in an age when the field of medicine moves fastest than ever and new relevant, potentially helpful evidence is produced daily. It's good to keep an open mind even about the sensitive topic of the role of vaccines in autism, especially when we want to help kids whom the neurodiversity "scientists" have completely abandoned. Specific genetic mutations are already scientifically acknowledged as problematic and causative of autism when vaccination occurs. Vaccine injuries are facts, or else the USA gvt wouldn't pay millions in compensation. Our kids deserve the truth. There is no meaningful help for them without digging honest and deep for the cause of their affliction.
DeleteYeah… I tend to try at least to mix science and logic or common sense which ain’t very common whilst being fully consistent of the fact that science can and will never capture a satisfactorily measurable construct due to its vast limitations in design,reliability,funding,conflicts of interests,stubborn medical paradigms,blinding confirmation biased,interrelationships between parties which all gain to function from false?made up,lies that support a false narrative eg that the vaccines are proven as safe and effective, Anyone who now doesn’t know they were bioweappons designed to kill as part of a long planned depopulation agenda.A bunch of bored old sick elites have hidden all world knowledge and brain expanding spiritual hacks plus the vibrational frequencies that we have free will over to change ourselves and entire reality,But how do we motivate each other to fight this scourge of evil ?
ReplyDeleteBut let’s start back to science which also measures pointless objectives with no intent or capacity to translate the data for example “it was found that men tend to use the is that i pretends to be measuring something of use when anyone with a brain would find that so obtuse. As it would obviously dismally fail to measure snytjimg of meaning for example “a significant number of teenage girls tended to have a post card crash after lunch but future research should rule out confounds of mood disorders,thyroids ie hashimotos,dysbiosis and past vaccine exposure for example?In autism there are spectrums within spectrums,symptoms all paradoxical like i am the intense truther and my dad the nerdy awkward bill gates who doesn’t enjoy murder based on hoax theories and believing the population is overpopulated when it’s VASTLY UNDERPOPULATED! Then maybe 25 sungroips of commonality yet to be biologically and bio medically differentiated so that any study can hold meaning, Badically it totally fails to capture the wonderful, enigmatic ,multi causal,multi veneered brilliance of THE least understood and by far most heterogenous anomaly ever to face medicine and expose its dire faulty and money driven psychopathic treatment and psychologising of talents as pathologies.BUT LUCKILY people like myself and half brained doctors realised the obvious, People with autism are all firstly very physically sick involving stomach infections like candida which then pierces holes in your gut.Insteaf of food being digested and assimilated it stagnates and poisons the entire body and brain.I knew i was bloody dying but doctors still missed ninety nine serious ailments i magically was forced to diagnose whilst virtually dead and homeless.I used all my disability pension to pay for the complex tests medicare “didn’t cover”’I also survived Statileptus Epticus unconscious and having seizures for hours and hours maybe on twenty different occasions but Jesus won’t let me die,i’m only here to serve anyone who needs me
This post is a wonderful resource. I wanted to see if there were any suggestions for someone like me a 31 yo F trialed >20 meds, >10 therapists including SLP/EF/ADHD coaches with persistent EF/abstract thinking/direction, social cognition, mood regulation (frequent reactivity and overwhelm) defitics. I have formal diagnoses of ADHD, anxiety, depression, bipolar II (typically induced by anything that helps the attention). I have a CACN1AC mutation, ZNF804a and SCL6A4 short allele.
ReplyDeleteSucceeded in school with immense efforts, but relationships and cumulative adult goals are hard to achieve as day to day functioining is so hard, chores, relationships, everything requires immense effort. Tried all ADHD meds including memantine without sig enough benefit, though honestly they do help, but not nearly enough. Tegretol was dulling. Depakote could exacerbate my PCOS. LDN and agmatine also helpful, not enough. Currently on 28 mg memantine, 36 mg concerta, 800 mg seroquel (yes, that in itself is scary, I don't feel physically sedated, but can't rule out my brain being slower), lithium 900 mg, klonopin 1 mg. Zinc 100, vit d 5,000, p5p 80 mg, lamictal 125 mg (slowly titratng up). Lithium hadn't seemed to work previously, but retrialling at a higher dose.
CRP nl.
Labs showed dysbiosis, but nl gut inflamamation markers. Sensitivity to caprylic acid and completed six week course 3 g daily.
SAM-e and cysthatione low, but am waiting to trial SAM-E til I get back on a strong dose of a better mood stabilizer since it has induced hypomania in past.
My biochemistry is frustratingly off and it doesn't appear that there may be solutions.
CBD and MCT oil helps. Keto trialed for two months without sig benefit.
I will trial NAC, retrial luteolin/EGCG.
The potential list of potent options (w/o clear sense of who would benefit:
-Folinic acid
-Bumetanide
-Statin (prescribed will not likely prescribe)
--Oxytocin-given trauma hx likely to have bad reaction
PDE4-i-though from available research the effect size would seem to be small.
-MERT /TMS seems unlikely to yield sig benefits, I was told it's just "enhancement" The stray few people that seem to have sig benefits from any of these tx seem to have fewer underlying abnormalities, rather than a whole network of hardwired brain structural differences
All the novel/emerging therapies seem to have small effect sizes at most. I'm really at a loss of what to say or do. My processing is too uneven to be able to craft a meaningful adult life with a partner and a family, the deficits make every hour painful and challenging. I just need a new brain,
I know these posts are common among those with family members wtih similar tx resistant sx. I'm at truly a dead end, I don't see a future life worth living--it's too riddled by stress and struggle not couterbalanced by the ability to be directed and engaging. At this rate, it would be better if I could just disappear.
Some say that the darkest night is just before the dawn. This is a frequent occurrence on this blog. Things can get pretty awful and then a solution is found. The worst kind of awful is recurring self-injury, which can be soul destroying to those dealing with it.
DeleteOn a brighter note, in your case you should be able to treat the calcium channel mutation successfully.
The ZNF804A transcription factor needs a multimodal treatment to tackle the down-stream effects. For example, NAC, Taurine plus Atorvastatin might work well. You would need to experiment.
For SLC6A4 some people resort to recreational drugs (psilocybin, MDMA etc). If SSRIs fail then try SNRIs (venlafaxine, duloxetine). Exercise is a therapy most people tend not to like to hear about, but for SLC6A4 it might be the best/safest one.
Here is the detail:
For your calcium channel mutation (CACNA1C) I suggest you try Verapamil, which will directly block Cav1.2. In the research they also used a T channel blocker to treat this ion channel, which is an indirect approach. An example would be ethosuximide, an anti-epileptic. Many readers of this blog have had good results from Verapamil. It has been trialed in bipolar. It is usually well very well tolerated, some people get gum inflammation.
ZNF804A encodes a transcription factor (a zinc finger protein). That means it influences the expression of many downstream genes rather than having a direct receptor or channel to block.
ZNF804A variants seem to alter dopamine regulation and glutamate–GABA balance.
This is why some studies find differential responses to antipsychotics (dopamine D2 blockers) and NMDA modulators.
Memantine, glycine, D-serine, or sarcosine trials in schizophrenia/cognitive impairment have had modest benefit.
ZNF804A influences synaptic plasticity and dendritic growth.
Supporting BDNF signaling may help - exercise, SSRIs, omega-3 fatty acids, lithium and statins
Anti-inflammatory strategies (NAC, minocycline, luteolin, EGCG) have been tested in schizophrenia spectrum conditions and may counteract downstream effects.
Chantix (varenicline) is not a specific treatment for ZNF804A, but it does sit in the category of nicotinic pro-cognitive therapies, which seem promising for people with genetic risk affecting connectivity, cognition, and attention. Some individuals with schizophrenia/bipolar + cognitive symptoms have benefitted. It is sold to aid people stop smoking. It works well sometimes in autism.
SLC6A4 is the serotonin transporter gene, and it’s one of the most studied psychiatric genes because of its common polymorphism, the 5-HTTLPR short allele.
The short allele leads to reduced transcription so fewer transporters and less serotonin reuptake.
The consequences:
• Increased emotional reactivity (especially to negative stimuli).
• Greater risk of anxiety and depression under stress.
• Stronger amygdala activation, weaker prefrontal top-down control.
• Social sensitivity. Some people may struggle under stress but flourish with strong social support.
With SSRI drugs there are mixed results in short-allele carriers. Some respond well, others get blunted or paradoxical effects.
Some people respond better to SNRIs (venlafaxine, duloxetine)
Because the S-allele amplifies sensitivity to environment, stress management is crucial:
• Consistent exercise (especially aerobic) increases serotonin release and receptor sensitivity.
• Sleep optimization. Short-allele carriers show worse mood instability with disrupted circadian rhythms.
• Stable social support → protective effect against depression risk.