Autism drug L1-79 and partial proxies available today, from ultra expensive to affordable - in search of a happier homeostasis

 

 

Click to enlarge (very detailed)

I was recently asked about the promising autism research drug L1-79 and the idea of using a similar drug called Demser as an immediately accessible alternative.

It is an interesting question, but I do wonder if that reader had checked out how much Demser costs. Even I was shocked, $100,000 to $500,000 per year in the US.

Demser is an old generic drug but with a tiny market, so it never became cheap. It was developed to treat a rare tumor of the adrenal glands that leads to the production of  excess catecholamines.

You can make the case that L1-79 is just a low-dose (about 1/10^th) re-packaged version of Demser, to be sufficiently different to be patentable as a new drug.

L1-79 has shown promise in a very small trial to improve social responsiveness in adolescents with autism, but no intellectual disability. This is great news, but realistically how much is that worth?

Clever drugs are great, but they have to be affordable.

 

L1-79 Clinical Trial

https://live-yamopharma.pantheonsite.io/wp-content/uploads/2024/11/CNS-Conference-Poster.pdf

The clinical trial suggests that reducing catecholamine “noise” (dopamine + noradrenaline) can improve social engagement in some people with autism.

 A Phase 2 randomized, double-blind, placebo-controlled crossover study tested L1-79 in adolescents and young adults with autism (IQ ≥ 70).

Key results:

• Significant improvement in socialization
• Vineland-3 Socialization score increased 8 points (clinically meaningful)
• Improvements also seen in:
• Play & leisure
• Clinician (CGI-S) and caregiver ratings
• Well tolerated
• No serious adverse events
• No withdrawals due to side effects

 The most interesting finding

The crossover phase failed due to:

• Carryover effect → benefits persisted after stopping
• Sequence effect → order of treatment influenced results

Only the first 12-week period was usable

The drug may create a temporary window for improved engagement, with some effects persisting after discontinuation. This is actually a good thing.

 

What L1-79 actually is

L1-79 is described as a racemic formulation of alpha-methyl-para-tyrosine (AMPT)

This is the same core compound used in Demser.

Alpha-methyl-para-tyrosine (AMPT) is a molecule with two mirror-image forms:

•          R-enantiomer

•          S-enantiomer

Consider it like a pair of gloves, one is right-handed and the other is left-handed.

 

Both L1-79  and Demser are essentially:

• 50% R-AMPT + 50% S-AMPT
• Same mechanism:
• inhibition of tyrosine hydroxylase
• ↓ dopamine
• ↓ noradrenaline

 

So are L1-79 and Demser identical?

Chemically, yes (or extremely close).

The pharmokinetics may have been improved to give a more stable effect.

 

The target phenotype for L1-79

Best described as:

“Too dysregulated to engage socially effectively”

Features:

• Over-aroused / “wired”
• Inconsistent engagement
• Easily overwhelmed
• Better in calm environments

Not lack of social interest — but loss of access

This autism treatment aims to reduce background neurochemical noise to improve signal-to-noise ratio.

 

Why not just use Demser?

This was the exact question posed to me. It is a great question, until you see the crazy price of Demser.

 

Are there any affordable alternatives today?

No direct equivalent

There is no cheap drug that safely and precisely reduces catecholamine synthesis for CNS use.

 

Partial proxies (available today)

1. Guanfacine

• ↓ noradrenergic tone
• improves regulation

 2. Clonidine

• stronger, more sedating

 3. Propranolol

• reduces adrenergic stress response

 

Does reducing catecholamine-driven dysregulation improve social engagement?

 Positive signs:

• more sustained interaction
• better back-and-forth
• increased shared attention

 

Negative signs:

• flat affect
• reduced motivation

 

Clonidine and guanfacine:

• have been trialed in autism
• improve:
• hyperactivity
• irritability

but do not consistently improve socialization.

 

Propranol

Propranolol helps when stress blocks performance.

It is good for social anxiety.

Propranolol can improve certain aspects of social and cognitive performance — especially under stress — but does not broadly change core autism symptoms.

Feature	Propranolol	Guanfacine	Clonidine	L1-79	Demser (metyrosine)
Mechanism level	Downstream	Downstream	Downstream	Upstream	Upstream
Main effect	↓ stress response	↓ noradrenergic noise (PFC)	↓ global noradrenergic tone	↓ dopamine + noradrenaline (controlled)	↓ dopamine + noradrenaline (strong)
Dopamine effect	Minimal	Minimal	Minimal	Reduced	Reduced (more strongly)
Noradrenaline effect	↓ peripheral + some CNS	↓ targeted	↓ broader	↓ global, moderate	↓ global, strong
Best for	Anxiety / performance stress	Regulation, attention	Hyperarousal, sleep	“Noisy” dysregulated system	Extreme catecholamine excess
Effect on socialization	Situational	Indirect	Indirect	Direct (trial signal)	Not studied
Consistency	Context-dependent	Moderate	Moderate	More sustained	Variable
Sedation risk	Low–moderate	Low	Moderate–high	Low–moderate	High if overdosed
Precision	Medium	Good	Lower	High (goal)
ASD use	Sometimes	Common	Common	Experimental	Not used

Slide left-right

A broader perspective: not one direction, but a spectrum

One important takeaway from L1-79 is that it highlights a direction of treatment, not a universal solution. Catecholamine function (dopamine and noradrenaline) operates along a spectrum. Some individuals have excess or unstable signaling (too much noise), others have insufficient drive (too little signal), and many show poor regulation between the two states.

This pattern is seen across multiple conditions:

Attention Deficit Hyperactivity Disorder

·        often low dopamine / noradrenaline tone

·        stimulants increase them

Depression

·        can involve low catecholamine activity, classic antidepressants will not work

·        need the opposite of L1-79 which could be Bupropion (1,000 times cheaper than Demser)

Anxiety disorders

·        often high noradrenergic tone

Autism Spectrum Disorder

·        likely heterogeneous

o   some hyper (too much)

o   some hypo (too little)

o   many dysregulated

The key insight is that the goal is not simply “increase” or “decrease,” but restore optimal regulation — the point at which signal is strong enough to support engagement, but not so strong that it creates noise and instability.

This has important implications. If catecholamine dysregulation is common and cuts across multiple conditions, then treatments targeting this system are likely to have broad relevance, not niche application. In that context, affordability becomes critical. A highly priced, specialist drug risks restricting access to a mechanism that may benefit a large population.

The challenge is not discovering the mechanism — it is making it usable, scalable, and affordable in everyday clinical practice.

As with many aspects of autism, or indeed depression, anxiety, ADHD etc, all you are doing is fine-tuning an imbalanced system. Consider it like finding a happier homeostasis.

Conclusion

The effective dosage of L1-79 was not found to be weight based. People in the trial were aged 12 to 21 years old. The effective dose was 300-600mg split into 2 doses day.

L1-79 reduces synthesis of:

• dopamine
• norepinephrine
• These are not just "bad when high" they are essential for function 

Think of it as a narrow window

• Too high (overactive system):
• agitation
• irritability
• poor regulation

• Optimal zone:
• calmer
• more focused
• better engagement

• Too low (over-suppressed):
• low motivation
• emotional flattening
• fatigue / low energy

L1-79 pushes you downward on this curve, so overshooting is very possible

Even though trials used up to 600 mg/day. Some people likely responded best at lower doses (300–400 mg/day). Others may have improved initially but then lost drive or engagement at higher doses.

The standard dosage of Demser/Metyrosine for pheochromocytoma is 1,500–4,000 mg/day.

If someone was in the phase 2 trial and responded really well to L1-79 at 250mg twice a day, you could understand their interest to just switch to 250mg twice a day of Demser. 

That would cost €60–€150 per day in Europe and very much more in the US.

I did ask AI to guess the price of L1-179, if it gets approved.

 

Likely pricing strategy for L1-79

Even though it uses lower doses, expect:

·         US price:
👉 ~$30,000–$80,000 per year
(very typical for autism CNS drugs)

·         Europe:
👉 €10,000–€30,000 per year (after negotiation)

 

The original Demser drug was approved by the FDA in 1979.

Demser is cheap to produce, so if L1-79 gets approved in the US for autism maybe the Chinese will trial low-dose Demser. If successful, that would create a large market and the price should fall. There is no patent to worry about.

Drug producers do see a market in the US for autism drugs costing $50,000 a year. Unfortunately, many people with disabling autism will require multiple drugs, targeting different aspects of their condition. It is not a case of pay $50,000 and you are "done."

The idea is that if insurance in the US is currently paying $100,000 to $200,000 a year for therapy for a child with level 3 autism, they can afford $50,000 for our pills.

In Europe the spending on therapies outside of school is dramatically less, more like up to €10,000 a year. European countries frequently reject new drugs because they are too expensive, or they just severely restrict access to keep costs down. 

The good news is that there is no shortage today of affordable pharmaceutical interventions that can improve troubling aspects of many sub-types of autism. You likely will need to stack them together in a personalized polytherapy. Don't expect any single drug to be a silver bullet, no matter how expensive it might be. 

 

 

Repurposing Anti-parasite drugs to treat Cancer and Autism?

 

I should start this post by highlighting that generally cancer and autism are not caused by parasites.

I have to be a little careful because we now know that certain types of virus and bacteria are involved in the initial trigger to initiate some types of cancer. This is why many females are now offered human papillomavirus (HPV) vaccines to minimize the chance of several different cancers. I noticed recently that in the US this vaccine is advertised on TV.  I used to know a woman who like most people had the HPV virus as a child, but did not have this vaccine.  She developed a rare oral cancer that the vaccine would have protected against and died very young. We saw in a previous post how a specific gut bacteria blocks the initiation of childhood leukemia.

The pharmaceutical industry does not seem to like the idea of repurposing existing drugs to treat a different disease.  There are some exceptions; it is OK to treat females with acne, using the diuretic drug Spironolactone.  Nobody seems to object to the treatment of intractable headaches with drugs actually approved to lower blood pressure (Verapamil, Amlodipine etc).

When investigating cancers you have to look at the specific underlying mechanisms, just as you do with autism.

As we saw long ago in this blog, it has been suggested to classify autism as either over-active pro-growth signaling pathways, or under-active pro-growth signaling pathways. Most is the over-active type.

Cancer is very clearly another example of over-active pro-growth signaling pathways, so it is not surprising that there is an overlap between therapies for autism and cancer.  The difference is that they are far more likely to be effective in autism. 

So, a cheap anti-parasite drug for kids like Mebendazole, which just happens to also be a Wnt inhibitor,  may slow down the growth of some cancers, but it is sadly not curative.  In an autistic brain where Wnt signalling might be overactive, a lower dose of Mebendazole, might well provide a long-term benefit.   

My old posts that mention Wnt signaling are here:-

https://www.epiphanyasd.com/search/label/Wnt 

Wnt signaling interestingly plays a role in how your hair will go gray/grey. If you reduce Wnt signaling, your hair will go gray and so this is an inevitable side effect of a potent Wnt inhibitor. 

Premature graying might indeed indicate reduced Wnt activity.

 

Pyrantel pamoate

Our reader Dragos recently fined tuned his adult son’s anti-aggression therapy and he recently shared his latest innovation:-

 

"you have to give him 20mg of propranolol 2-3 times a day, pyrantel pamoate 750mg in the evening for 2-3 days, and you will see that his anger will disappear, stay on propranolol. After 3 weeks repeat with antiparasitic, you will see that I was right, you don't use psychotropic drugs"

 

Propranolol is a normally used to lower blood pressure, but it does this in a way that also reduces anxiety.  At the low doses used by Dragos, it has been used to treat actors with stage fright. It can be used before exams or driving tests, to calm the person down.

Propranolol has been trialed in autism. Some people use a low dose and some use a higher dose.

Pyrantel pamoate is used to treat hookworms and other parasites that can be picked up by young children. It works by paralyzing the worms. This is achieved by blocking certain acetylcholine receptors in the worm.

As is very often the case, pyrantel pamoate likely has other modes of action that are entirely different. Is it a Wnt inhibitor like the other hookworm treatment Mebendazole?

I did a  quick search on google and it gave me the wrong pamoate. 

Pyrvinium pamoate is able to kill various cancer cells, especially CSC. The drug functions through the reduction of WNT- and Hedgehog-dependent signaling pathways (Dattilo et al., 2020). 

Pyrvinium pamoate is yet another anti-parasitic drug, but not the one Dragos is using.

So pyrantel pamoate may not be a Wnt inhibitor, unlike many anthelmintic drugs, but it is used by the “anti-parasitic re-purposer in chief” Dr Simon Wu.  He publishes his findings/thoughts, which is good to see.  He likes to combine different anti-parasitic drugs.

I did look up the effect of pyrantel pamoate on gene expression.  There is data, but you really need to see the source material to know whether anything is valid.

Inhibiting GSTP1 (glutathione S-transferase pi 1) is suggested and that is a feature in common with an anti-parasite drug class called Thiazolides (e.g.  Nitazoxanide).  That would make pyrantel pamoate a potential therapy for triple-negative breast cancer, where the cancer cells rely on vigorous activity by the enzyme glutathione-S-transferase Pi1 (GSTP1).  Cancer cells are highly vulnerable to oxidative stress, and as we know glutathione is the main way the body extinguishes it. Glutathione S-transferases P1 protects breast cancer cell from cell death.  So you want to inhibit GSTP1.

Pyrantel has many other suggested effects even reducing expression of the gene FXR2 (fragile X mental retardation,2) and increasing expression of the gene MTSS1 (metastasis suppressor 1).

Pyrantel is even suggested as an epilepsy drug.

 

Drug repositioning in epilepsy reveals novel antiseizure candidates

Epilepsy treatment falls short in ~30% of cases. A better understanding of epilepsy pathophysiology can guide rational drug development in this difficult to treat condition. We tested a low-cost, drug-repositioning strategy to identify candidate epilepsy drugs that are already FDA-approved and might be immediately tested in epilepsy patients who require new therapies.

Expanding on these analyses of epilepsy gene expression signatures, this study generated a list of 184 candidate anti-epilepsy compounds. This list of possible seizure suppressing compounds includes 129 drugs that have been previously studied in some model of seizures and 55 that have never been studied in the context of seizures. 91 of these 184 compounds are already FDA approved for human use, but not for treating seizures or epilepsy. We selected four of these drugs (doxycycline, metformin, nifedipine, and pyrantel tartrate) to test for seizure suppression in vivo.

Pyrantel tartrate is an antiparasitic agent that acts by inhibiting fumarate reductase, and by directly acting on acetylcholine receptors at the neuromuscular junction of infecting helminths. Pyrantel tartrate is FDA approved for use in domestic animals and has been used to treat human parasitic infections.73 Unlike nifedipine and metformin (for which some rodent studies and human reports relate to seizures), a March 2018 PubMed search for “pyrantel and epilepsy” and “pyrantel and seizure” found no manuscripts that studied pyrantel in seizures. Thus, pyrantel tartrate represents a truly novel antiseizure drug candidate yielded by our screen.

 

All in all it is not surprising that Dr Yu is prescribing pyrantel pamoate.

Digging any deeper is beyond the scope of a blog post.

What is clear is that pyrantel pamoate and mebendazole are unlikely to be equally effective in Dragos’ son.

Other anti-parasite drugs work very differently.

In the chart the mode of action of some common drugs  is presented.

 

Anthelminticsfor drug repurposing: Opportunities and challenges

 

Mode of action of albendazole (ABZ), ivermectin (IVM), levamisole (LV), mebendazole (MBZ), niclosamide (NIC), flubendazole (FLU), rafoxanide (RAF), nitazoxanide (NTZ), pyrvinium pamoate (PP), and eprinomectin (EP).

  

Suramin is now quite well known as a potential autism therapy and two different groups are trying to commercialize it.  Suramin is the original anti-purinergic drug (APD), it blocks purinergic receptors that have names like P2Y2.

When I looked at PAK1 a long time ago, which was put forward as a treatment pathway for neurofibromatosis, some schizophrenia and some autism I came across Ivermectin as an existing alternative to the research drug FRAX486, or the expensive BIO 30 propolis from New Zealand.

A decade later and the world goes crazy when the idea of using Ivermectin to treat COVID 19 gets well publicized.  The good news is that now we know that regular use of Ivermectin is not as dangerous as people thought it would be.  Many people have been using the veterinary version in the US, Brazil and elsewhere. 

The supporting research:- 

Effect of Pyrantel on gene expression.

 https://maayanlab.cloud/Harmonizome/gene_set/pyrantel-5513/CMAP+Signatures+of+Differentially+Expressed+Genes+for+Small+Molecules

 

decreases expression of:-

FXR2   fragile X mental retardation, autosomal homolog 2

(and many more)

 

Increases expression of

MTSS1 metastasis suppressor 1

BNIP1 BCL2/adenovirus E1B 19kDa interacting protein 1

BRAF B-Raf proto-oncogene, serine/threonine kinase

(and many more)

 

https://maayanlab.cloud/Harmonizome/gene_set/Pyrantel+Pamoate/CTD+Gene-Chemical+Interactions

Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.

Pyrantel Pamoate Gene Set

Dataset          CTD Gene-Chemical Interactions

2 genes/proteins interacting with the chemical Pyrantel Pamoate from the curated CTD Gene-Chemical Interactions dataset.

GPR35    G protein-coupled receptor 35

GSTP1   glutathione S-transferase pi 1

 

Triple-negative breast cancer target is found

They discovered that cells from triple-negative breast cancer cells rely on vigorous activity by an enzyme called glutathione-S-transferase Pi1 (GSTP1). They showed that in cancer cells, GSTP1 regulates a type of metabolism called glycolysis, and that inhibition of GSTP1 impairs glycolytic metabolism in triple-negative cancer cells, starving them of energy, nutrients and signaling capability. Normal cells do not rely as much on this particular metabolic pathway to obtain usable chemical energy, but cells within many tumors heavily favor glycolysis.

  

"Inhibiting GSTP1 impairs glycolytic metabolism," Nomura said. "More broadly, this inhibition starves triple-negative breast cancer cells, preventing them from making the macromolecules they need, including the lipids they need to make membranes and the nucleic acids they need to make DNA. It also prevents these cells from making enough ATP, the molecule that is the basic energy fuel for cells." 

 

Anthelmintics for drug repurposing: Opportunities and challenges 

It has been demonstrated that some of the anthelmintics are able to inhibit critical oncogenic pathways, such as Wnt/β-catenin, signal transducer and activator of transcription proteins 3 (STAT3), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB; therefore, their application for cancer treatment has been considered.

 

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

 

Anthelmintics for drug repurposing: Opportunities and challenges

 

Mode of action of albendazole (ABZ), ivermectin (IVM), levamisole (LV), mebendazole (MBZ), niclosamide (NIC), flubendazole (FLU), rafoxanide (RAF), nitazoxanide (NTZ), pyrvinium pamoate (PP), and eprinomectin (EP).

 

Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells

More research on the repurposing anti-parasite drugs: 

Antiparasitic and Antifungal Medications for Targeting Cancer Cells Literature Review and Case Studies Frederick T. Guilford, MD; Simon Yu, MD

Chronic inflammation is a new catch phrase for the explanation of all chronic degenerative diseases, from asthma, arthritis, heart disease, auto-immune disease, and irritable bowel disease to cancer. Occult infections from oncovirus, bacterial, and fungal infections as well as from lesser known parasitic infections are driving forces in the cellular evolution and degeneration of cancer cells. An approach using currently available medications that target both fungal and parasitic metabolism appears to interfere with the metabolic synergy that is associated with tumor growth and aggressiveness 

 

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs 

 

Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent 

 

Anti-Parasite drug Ivermectin shows promise against cancer 

A Pinworm Medication Is Being Tested As A Potential Anti-Cancer Drug

 Conclusion

I did suggest long ago that Mebendazole, as a Wnt inhibitor, might be a cheap and effective treatment for some autism.  I had envisaged that it would need to be given daily, as it is in the cancer trials.

Dragos’ use of pyrantel pamoate, for an average of 4 days a month is interesting.  It is cheap, safe and practical.

One key issue with antiparasitic drugs is how much is absorbed into the blood stream.  If 100% of the drug stays in the gut, its benefit will be limited.

About 20% of Mebendazole ends up in the blood stream and if you take it often this figure is reported to increase.

The combo of propranolol + pyrantel pamoate is an interesting option to treat self-injury and aggressive behavior.  It works for Dragos and undoubtedly will for some others.

Is the inhibition of Wnt signalling the reason why pyrantel pamoate is effective for Dragos’ son?  There is no evidence to support that.

Are antiparasitic drugs going to be widely adopted to treat any unrelated conditions, cancer included, I very much doubt it.

Cancer is better avoided, than treated.  It is a much more achievable objective.

The Fragile X researcher Randi Hagerman takes metformin, as her chemoprevention therapy. She is the medical director of MIND Institute at the University of California, Davis.

You can raise IQ in people with Fragile X by 10-15% using Metformin.  I guess Randi had been reading up on Metformin and came across the anti-cancer effects.

If I had to suggest an anti-parasite drug for Randi to try in Fragile X, I would suggest the PAK inhibitor Ivermectin, made (in)famous by Donald Trump and Jair Bolsonaro during Covid. The research drug FRAX 486 is called FRAX for Fragile X. It is a PAK inhibitor that never made it to market.  Ivermectin is an existing drug that is also a PAK inhibitor.  Worth a try, Randi?

I expect Dr Yu might try and increases his chances and make a combo with a second anti-parasitic drug.

Metformin is one of several anti-cancer choices, it depends which type of cancer is of concern. For RAS-dependent cancer I think Atorvastatin is the best choice. 

If you read the research, like me and Randi, chemoprevention is the obvious choice for older adults. Dementia prevention is equally obvious.

Parkinson’s prevention may be achieved by blocking Cav1.3 (amlodipine etc)

Alzheimer’s prevention may be achieved using low dose fenamates (Ponstan etc).

For vascular dementia and Alzheimer’s prevention/treatment spermidine (in the form of modified wheatgerm) is promising.

Anti-parasite drugs for cancer and autism? Yes, it sounds mad. But is it?

What is for sure is that your pediatrician will think you have gone mad!

Our reader MG in Hong Kong will have got some new ideas to think about.