High dose L-Serine to treat children under 7 with severe autism + ID ? It works in Korea

 

Source: Joon Kyu Park, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons

 

Today’s post is a follow up to the recent one that showed Memantine was beneficial to people with level 1 autism, normal IQ, with ADHD and anxiety/depression.

Our reader Hoang, highlighted a recent trial in Korea that used the OTC supplement L-serine, which has a biological effect that is the opposite of Memantine. The trial is part of series looking at treating those with severe autism with ID (intellectual disability). 

High-dose L-serine has been tested in children with severe autism and intellectual disability, and the main benefits were seen in those under 7 years old. While it may work by boosting NMDA receptor activity through conversion to D-serine, other brain-supporting roles of L-serine—like helping neuron membranes and reducing stress on brain cells—could also contribute. Older children may not respond as well, possibly because their brains are less plastic or they convert less L-serine to D-serine. Researchers should now explore whether direct D-serine dosing might help older kids, but safety must be considered.

 

The Trials and Target Group

The trials of AST-001, a syrup formulation of L-serine, focused on children with severe autism and intellectual disability (ID). The phase 2 study included children aged 2–11, but the most pronounced improvements were in those under 7 years old. The benefit did not entirely disappear after age 7, but it was smaller and harder to measure.

Dosing was weight-tiered:

Weight (kg)	Dose (g, twice a day)
10–13	2
14–20	4
21–34	6
35–49	10
>50	14

The outcomes measured were adaptive behavior (Vineland Adaptive Behavior Scales II) and clinical global impressions, with high-dose L-serine showing a statistically significant improvement over placebo.

 

How L-Serine Might Work

1. NMDA Receptor Modulation

L-serine can be converted in the brain to D-serine, a co-agonist of NMDA receptors, which are critical for learning, memory, and social behavior. This mechanism aligns with the idea that boosting NMDA signaling could help in some autism. This is the exact opposite of what Memantine does.

2. Other Neuroprotective Roles

However, L-serine also supports:

• Phospholipid and myelin synthesis, crucial for neuron structure
• One-carbon metabolism and methylation, which help maintain healthy brain chemistry
• Reducing cellular stress, oxidative damage, and excitotoxicity
• L-serine is the precursor to glycine. This matters because glycine is also an NMDA co-agonist (alongside D-serine). In some brain regions glycine—not D-serine—is the primary co-agonist.

So, the clinical effect might not be solely through NMDA receptor modulation.

 

Why Benefits Are Seen Mainly in Children Under 7

Several factors may explain the age effect:

1.     Brain Plasticity – Younger brains are more adaptable, so interventions may show stronger effects.

2.     Conversion to D-serine – L-serine is converted to D-serine by serine racemase, and this may be less efficient in older children.

3.     Ceiling Effects – In older children with long-standing autism and ID, neural circuits may have already stabilized in ways that make observable behavioral improvements harder.

It is unclear whether older children truly cannot benefit, or if the benefit is harder to measure with standard adaptive behavior scales.

 

Could D-Serine Directly Help Older Children?

A hypothesis is that older children might need higher levels of D-serine than their bodies can produce from L-serine. In theory:

• Direct D-serine supplementation might overcome this bottleneck.
• Safety is the main concern, as excessive D-serine can stress kidneys or neurotransmitter systems.

No large trials have tested this yet in older children with autism.

About the Researcher

Dr Yoo-Sook Joung led the AST-001 trials. She is a psychiatrist with an interest in autism interventions and has explored approaches like animal-assisted therapy. While not a basic science researcher, her clinical insights have helped design practical trials in children with severe autism and ID.

Takeaways

• High-dose L-serine shows promising results in children under 7 with severe autism and ID. The low dose was not effective.
• Benefits may involve NMDA receptor modulation, but other neuroprotective effects are likely relevant.
• Older children may require alternative approaches (e.g., D-serine), but evidence is lacking.
• Safety and careful dosing are essential; trials so far show good tolerability, with diarrhea being the most common side effect.

 

Here is the associated research leading up the recent trial

Population Pharmacokinetic Model of AST-001, L-Isomer of Serine, Combining Endogenous Production and Exogenous Administration in Healthy Subjects

AST-001 is an L-isomer of serine that has protective effects on neurological disorders. This study aimed to establish a population pharmacokinetic (PK) model of AST-001 in healthy Korean to further propose a fixed-dose regimen in pediatrics. The model was constructed using 648 plasma concentrations from 24 healthy subjects, including baseline endogenous levels during 24 h and concentrations after a single dose of 10, 20, and 30 g of AST-001. For the simulation, an empirical allometric power model was applied to the apparent clearance and volume of distribution with body weight. The PK characteristics of AST-001 after oral administration were well described by a two-compartment model with zero-order absorption and linear elimination. The endogenous production of AST-001 was well explained by continuous zero-order production at a rate of 0.287 g/h. The simulation results suggested that 2 g, 4 g, 7 g, 10 g, and 14 g twice-daily regimens for the respective groups of 10–14 kg, 15–24 kg, 25–37 kg, 38–51 kg, 52–60 kg were adequate to achieve sufficient exposure to AST-001. The current population PK model well described both observed endogenous production and exogenous administration of AST-001 in healthy subjects. Using the allometric scaling approach, we suggested an optimal fixed-dose regimen with five weight ranges in pediatrics for the upcoming phase 2 trial.

  

Population pharmacokinetic and pharmacodynamic model guided weight-tiered dose of AST-001 in pediatric patients with autism spectrum disorder

AST-001, a novel syrup formulation of L-serine, was developed for the treatment of autism spectrum disorders (ASD) in pediatric patients. This study aimed to establish a pharmacokinetic (PK)-pharmacodynamic (PD) model to elucidate the effect of AST-001 on adaptive behavior in children with ASD. Due to the absence of PK samples in pediatric patients, a previously published population PK model was used to link the PD model by applying an allometric scale to body weight. The time courses of Korean-Vineland Adaptive Behavior Scale-II Adaptive Behavior Composite (K-VABS-II-ABC) scores were best described by an effect compartment model with linear drug effects (Deff, 0.0022 L/μg) and linear progression, where an equilibration half-life to the effect compartment was approximately 15 weeks. Our findings indicated a positive correlation between the baseline K-VABS-II-ABC score (E0, 48.51) and the rate of natural progression (Kprog, 0.015 day⁻¹), suggesting enhanced natural behavioral improvements in patients with better baseline adaptive behavior. Moreover, age was identified as a significant covariate for E0 and was incorporated into the model using a power function. Based on our model, the recommended dosing regimens for phase III trials are 2, 4, 6, 10, and 14 g, administered twice daily for weight ranges of 10–13, 14–20, 21–34, 35–49, and >50 kg, respectively. These doses are expected to significantly improve ASD symptoms. This study not only proposes an optimized dosing strategy for AST-001 but also provides valuable insights into the PK-PD relationship in pediatric ASD treatment.

 

AST‐001 versus placebo for social communication in children with autism spectrum disorder: A randomized clinical trial

Aim

This study examined the efficacy of AST‐001 for the core symptoms of autism spectrum disorder (ASD) in children.

Methods

This phase 2 clinical trial consisted of a 12‐week placebo‐controlled main study, a 12‐week extension, and a 12‐week follow‐up in children aged 2 to 11 years with ASD. The participants were randomized in a 1:1:1 ratio to a high‐dose, low‐dose, or placebo‐to‐high‐dose control group during the main study. The placebo‐to‐high‐dose control group received placebo during the main study and high‐dose AST‐001 during the extension. The a priori primary outcome was the mean change in the Adaptive Behavior Composite (ABC) score of the Korean Vineland Adaptive Behavior Scales II (K‐VABS‐II) from baseline to week 12.

Results

Among 151 enrolled participants, 144 completed the main study, 140 completed the extension, and 135 completed the follow‐up. The mean K‐VABS‐II ABC score at the 12th week compared with baseline was significantly increased in the high‐dose group (P = 0.042) compared with the placebo‐to‐high‐dose control group. The mean CGI‐S scores were significantly decreased at the 12th week in the high‐dose (P = 0.046) and low‐dose (P = 0.017) groups compared with the placebo‐to‐high‐dose control group. During the extension, the K‐VABS‐II ABC and CGI‐S scores of the placebo‐to‐high‐dose control group changed rapidly after administration of high‐dose AST‐001 and caught up with those of the high‐dose group at the 24th week. AST‐001 was well tolerated with no safety concern. The most common adverse drug reaction was diarrhea.

Conclusions

Our results provide preliminary evidence for the efficacy of AST‐001 for the core symptoms of ASD.

 

The what, when and where of treating autism

The human brain is a work in progress up until your mid 20s.

It is near adult-sized at the age of 5, but many key developmental processes remain.

As brain development goes through it various steps, it requires certain genes to be activated to produce specific proteins. This is why in some single gene autisms babies are born appearing entirely typical, because at that point they are typical. Shortly thereafter when the gene cannot produce enough of its protein (haploinsufficiency) things start developing off-track. The human body is highly adaptable and the brain keeps on changing, but now on a different track.

Many dysfunctions in autism are localized to just one part of the brain and indeed you can have the opposite dysfunction in different parts of the brain at the same time. Some dysfunctions can be just transitory, or indeed just extreme in one particular developmental window.     

When it comes to NMDA activity we know that very often in autism and schizophrenia it is disturbed. But, it can be too much or too little (hyper/hypo) and very likely this changes over time and varies in different parts of the brain.

Viewed in this broader context, it is not odd to see an intervention that is most effective up to the age of seven.

  

Conclusion

If you know a child with severe autism and intellectual disability, who is under 7 years old, maybe suggest to the parents to investigate following our proactive reader Hoang and make a trial of the OTC supplement L-Serine. You can buy it inexpensively on-line, just search “L serine bulk powder.” In the US 1kg costs about $50. Just follow the dosage in the trials.

L-serine is very safe.

Using D-serine is more problematic. In clinical studies for schizophrenia and cognitive disorders, doses ranged from 30 mg/kg/day to 120 mg/kg/day in divided doses. D-serine is mostly safe at moderate doses, but very high doses carry risks of kidney stress and excitotoxicity.

Modest amounts of L-serine can be found in eggs, chicken, milk etc. The body then converts this to D-serine using an enzyme called serine racemase and vitamin B6. Once these are used up, no more D-serine can be produced “naturally.” This is why schizophrenia researchers use D-serine itself. D-serine is also sold as a bulk OTC supplement.

If the child was actually an undiagnosed Memantine-responder, you would expect to see the following if they took high dose L-serine:

·        ↑ irritability

·        ↑ sensory overload

·        ↑ hyperactivity

·        ↑ emotional volatility

·        ↑ stereotypy

·        ↑ anxiety

Because a memantine responder is a child whose biology is defined by NMDA receptor overactivity, where excessive glutamate signalling drives irritability, sensory overload, anxiety, and cognitive stress and memantine works precisely because it reduces this hyper-NMDA state.

L-serine does the opposite, it increases D-serine and so enhances NMDA activity and so in an L-serine responder it improves:

·        learning and cognitive processing

·        social attention and engagement

·        adaptive behaviour

·        overall developmental trajectory

 

In this group, the core bottleneck is not excessive glutamatergic activity but insufficient NMDA co-agonism, especially in early development when social circuits and sensory-integration networks are still forming.

 

What does “insufficient NMDA co-agonism” mean?

NMDA receptors do not work like simple on/off switches.

They need two keys to open:

·        Glutamate – the main excitatory neurotransmitter

·        A co-agonist – either D-serine or glycine

If glutamate is present but the co-agonist is missing or too low, the NMDA receptor cannot fully activate, even though the neuron is trying to fire normally.

This situation is called NMDA hypofunction caused by insufficient co-agonism

In plain terms, the glutamate system is not actually weak. The receptor is not working properly because the “second key” is missing.

 

Neural circuits needed for learning, plasticity, and social behaviour do not work properly, because the key is missing. Go find it!

   

Why does this matter in autism with ID?

Several studies (postmortem, CSF, MR spectroscopy) show that in many children with severe autism + language delay + ID, D-serine levels are reduced in key brain areas (prefrontal cortex, temporal cortex, hippocampus).

Possible reasons:

·        Low activity of serine racemase (the enzyme converting L-serine → D-serine)

·        Higher breakdown of D-serine by DAO (D-amino acid oxidase)

·        Developmentally immature astrocytes (which supply D-serine early in life)

·        Genetic factors affecting NMDA co-agonist pathways

When D-serine is low, NMDA receptors cannot activate normally even if glutamate levels are normal or high.

 

The result:

Cognitive delay, poor adaptive behaviour, weak learning reinforcement, sensory disturbances, and poor social reciprocity.

How does L-serine help?

·        L-serine is the precursor to D-serine.

 

By giving large doses of L-serine

·        The brain produces more D-serine

 

D-serine binds the NMDA co-agonist site

·        NMDA receptors can finally reach normal activation

·        Neural circuits can strengthen and rewire more effectively

·        Behaviour improves, especially in younger children where plasticity is high

 

This is why L-serine produces the opposite clinical effect of memantine:

 

• Memantine helps when NMDA activity is too high

• L-serine helps when NMDA activity is too low because of a missing co-agonist

ARBs and ACE inhibitors for Autism, an old Peter idea finally explored in a research model

 

 A home run? Certainly worth further consideration. 

When I was doing my review of unexplored potential autism therapies several years ago, I did look at two closely related classes of drugs. ARBs and ACE inhibitors.

I wrote about it in blog posts and set out why I thought the ARB telmisartan was the best one to trial first.

 

           Targeting Angiotensin in Schizophrenia and Some Autism          

Just when you thought we had run out hormones to connect to autism and schizophrenia, today we have Angiotensin.

Angiotensin is a hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs (ACE inhibitors) that lower blood pressure. Angiotensin also stimulates the release of aldosterone, a hormone that promotes sodium retention which also drives blood pressure up.

Angiotensin I has no biological activity and exists solely as a precursor to angiotensin II.

Angiotensin I is converted to angiotensin II  by the enzyme angiotensin-converting enzyme (ACE).  ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of Angiotensin II production.  

It turns out that Angiotensin has some other properties very relevant to schizophrenia, some autism and quite likely many other inflammatory conditions. 

Blocking angiotensin-converting enzyme (ACE) induces those potent regulatory T cells that are lacking in autism and modulates Th1 and Th17 mediated autoimmunity.  See my last post on Th1,Th2 and Th17. 

In addition, Angiotensin II affects the function of the NKCC1/2 chloride cotransporters that are dysfunctional in much autism and at least some schizophrenia.

Then I wrote another post and made a trial of Telmisartan.

Angiotensin II in the Brain & Therapeutic Considerations

I was pleased to see that some researchers have recently published a paper on this subject. They chose an ACE inhibitor called Captopril.

 

Captopril restores microglial homeostasis and reverses ASD-like phenotype in a model of ASD induced by exposure in utero to anti-caspr2 IgG

Microglia play a crucial role in brain development, including synaptic pruning and neuronal circuit formation. Prenatal disruptions, such as exposure to maternal autoantibodies, can dysregulate microglial function and contribute to neurodevelopmental disorders like autism spectrum disorder (ASD). Maternal antibodies targeting the brain protein Caspr2, encoded by ASD risk gene Cntnap2, are found in a subset of mothers of children with ASD. In utero exposure to these antibodies in mice leads to an ASD-like phenotype in male but not in female mice, characterized by altered hippocampal microglial reactivity, reduced dendritic spine density, and impaired social behavior. Here, we studied the role of microglia in mediating the effect of in utero exposure to maternal anti-Caspr2 antibodies and whether we can ameliorate this phenotype. In this study we demonstrate that microglial reactivity emerges early in postnatal development and persists into adulthood following exposure in utero to maternal anti-Caspr2 IgG. Captopril, a blood-brain barrier permeable angiotensin-converting enzyme (ACE) inhibitor, but not enalapril (a non-BBB permeable ACE inhibitor) ameliorates these deficits. Captopril treatment reversed microglial activation, restored spine density and dendritic arborization in CA1 hippocampal pyramidal neurons, and improved social interaction. Single-cell RNA sequencing of hippocampal microglia identified a captopril-responsive subcluster exhibiting downregulated translation (eIF2 signaling) and metabolic pathways (mTOR and oxidative phosphorylation) in mice exposed in utero to anti-Caspr2 antibodies treated with saline compared to saline-treated controls. Captopril reversed these transcriptional alterations, restoring microglial homeostasis. Our findings suggest that exposure in utero to maternal anti-Caspr2 antibodies induces sustained neuronal alterations, microglial reactivity, and metabolic dysfunction, contributing to the social deficits in male offspring. BBB-permeable ACE inhibitors, such as captopril, warrant further investigation as a potential therapeutic strategy in a subset of ASD cases associated with microglial reactivity.

 

So here is an update that incorporates all these ideas and the new study.

 ___ 

Targeting the Brain Renin-Angiotensin System: From Schizophrenia to Autism (2025 Update)

By Peter Lloyd-Thomas, Epiphany ASD Blog

In 2017, I wrote about the idea that drugs targeting the renin–angiotensin system (RAS)—ACE inhibitors and ARBs—might have therapeutic effects beyond blood pressure, including in schizophrenia and autism. At that time, the discussion was mostly mechanistic. Today, new evidence strengthens the rationale and provides translational plausibility.

 

Why the Brain RAS Matters

While angiotensin II is best known for regulating blood pressure, the brain has its own RAS, which regulates:

·         AT₁ receptors → oxidative stress, neuroinflammation, microglial activation

·         AT₂ and Mas receptors → neuroprotection, mitochondrial function, anti-inflammatory signaling

·         ACE → converts Angiotensin I → II and degrades bradykinin, affecting cerebral blood flow

Shifting the balance from AT₁-dominated to AT₂/Mas signaling can normalize microglial function, improve neuronal energy metabolism, and support synaptic plasticity.

 

New Autism-Relevant Evidence (2025)

A recent study (Spielman et al., Molecular Psychiatry, 2025) used a mouse model of maternal anti-Caspr2 antibodies, a risk factor for some forms of autism. Male offspring showed:

·         Hyperactive microglia

·         Reduced hippocampal dendritic spines

·         Impaired social behavior

Captopril, a BBB-penetrant ACE inhibitor, reversed these deficits. In contrast, enalapril, which poorly crosses the BBB, was ineffective. Single-cell RNA sequencing revealed captopril restored microglial metabolic homeostasis (mTOR, oxidative phosphorylation, eIF2 signaling), linking microglial function directly to behavioral outcomes.

 

ACE Inhibitors vs ARBs: CNS and Immune Effects

Feature	ACE inhibitors (e.g., captopril)	ARBs (BBB-permeable, e.g., telmisartan)
↓ Ang II	Yes	No (blocks AT₁ receptor)
↑ Bradykinin / NO	Yes	No
BBB penetration	Variable — captopril high, enalapril low	Most low; telmisartan high
Microglial activation	↓ via less Ang II & more NO	↓ via AT₁ blockade
NKCC1/2 chloride cotransporters	Normalized via ↓ Ang II	Normalized via AT₁ blockade
Regulatory T cells (Tregs)	Strong ↑	Moderate ↑ (telmisartan strongest among ARBs)
Th1/Th17 autoimmunity	Modulated ↓	Modulated ↓
PPAR‑γ activation	No	Yes (telmisartan)
Evidence in ASD model	Captopril reversed phenotype (2025)	Mechanistically promising; anecdotal human benefit

Both classes modulate neuroinflammation, chloride signaling, and immune function, but ACE inhibitors and ARBs differ in mechanisms and potency.

 

Clinical Evidence in Schizophrenia

Telmisartan has been trialed in adults with schizophrenia (NCT00981526), primarily for metabolic side effects of antipsychotics (clozapine, olanzapine). Secondary observations included:

·         Improvement in negative symptoms

·         Modest cognitive benefits

·         Good tolerability over 12 weeks

This demonstrates CNS activity in humans, beyond metabolic effects, supporting translational plausibility for neuropsychiatric conditions.

 

Personal Observation in Autism

Years ago, I trialed telmisartan in my son. The effect was striking: he began singing spontaneously—something no other therapy had achieved. Singing engages emotion, motivation, and executive coordination, all dependent on healthy microglial and neuronal metabolism. While anecdotal, this observation aligns with mechanistic insights from both the mouse autism model and schizophrenia trials.

 

Safety and Accessibility

ACE inhibitors and ARBs are:

·         Widely prescribed globally for hypertension and heart protection

·         Generic, inexpensive, and safe in adults

·         Typically well-tolerated (ACE-i cough, hypotension, mild electrolyte changes)

This makes them practical candidates for drug repurposing in neurodevelopmental and neuropsychiatric disorders.

 

Mechanistic Summary

1.     Microglial hyperactivation contributes to synaptic and behavioral deficits in some autism subtypes.

2.     Brain RAS modulation (ACE-i or ARB) restores microglial homeostasis, improves energy metabolism, and supports synaptic plasticity.

3.     NKCC1/2 chloride cotransporter regulation: By reducing Ang II (ACE-i) or blocking AT₁ (ARB), these drugs normalize intracellular chloride, restoring proper GABAergic inhibition.

4.     Immune regulation: ACE inhibition induces regulatory T cells (Tregs) and modulates Th1/Th17 autoimmunity. BBB-penetrant ARBs like telmisartan also modulate these pathways, enhanced by PPAR‑γ activation.

5.     Behavioral outcomes: In mice, captopril reverses ASD-like phenotypes; anecdotal human reports suggest telmisartan may improve engagement, motivation, and communication.

 

Next Steps for Research

·         Carefully designed biomarker-driven pilot trials in humans, selecting individuals with evidence of neuroinflammation or maternal autoantibody exposure.

·         CNS-focused outcome measures (microglial imaging, inflammatory markers, synaptic function).

·         Behavioral endpoints relevant to autism (social interaction, expressive communication).

Or skip that and maybe make an n=1 trial?

 

Take-Home Message

Drugs long used for cardiovascular health may have untapped potential in neurodevelopmental and neuropsychiatric disorders. BBB-penetrant ACE inhibitors and ARBs, particularly telmisartan, can modulate:

·         Microglial activity

·         Neuronal chloride gradients

·         Immune regulation

Recent mouse data (Spielman et al., 2025) and human observations in schizophrenia support mechanistic plausibility and safety, making these drugs promising candidates for further study in selected autism subgroups.

 

References and Further Reading:

Spielman et al., Molecular Psychiatry, 2025: Captopril restores microglial homeostasis in anti-Caspr2 ASD model

NCT00981526, Telmisartan in schizophrenia (Fan X, 2018)

Lloyd-Thomas, 2017: Angiotensin II in the Brain

Lloyd-Thomas, 2017: Targeting Angiotensin in Schizophrenia and Some Autism

From Conception to Early Childhood: Managing pain, fever, and neurodevelopmental risk. Time to apply some common sense? Time for NAC?

 

Donald Trump recently reignited debate about Tylenol (paracetamol/acetaminophen) in pregnancy. His comments drew attention to research linking prenatal use to higher rates of autism and ADHD.

A large review of 46 studies, including work from Harvard, found consistent associations between paracetamol in pregnancy and neurodevelopmental risks. The FDA now advises caution: use the lowest dose for the shortest time.

 

Tylenol in pregnancy linked to higher autism risk, Harvard scientists report

Researchers reviewing 46 studies found evidence linking prenatal acetaminophen (Tylenol) exposure with higher risks of autism and ADHD. The FDA has since urged caution, echoing scientists’ advice that the drug be used only at the lowest effective dose and shortest duration. While important for managing fever and pain in pregnancy, prolonged use may pose risks to fetal development. Experts stress careful medical oversight and further investigation.

 Why the concern?

• Paracetamol depletes glutathione (GSH), the body’s main antioxidant.
• This raises oxidative stress in both mother and fetus.
• The fetus has weak antioxidant defences, so damage may occur during critical brain development.

But here is the dilemma: the fever, pain, or inflammation that drives a mother to take paracetamol is itself risky. We have long known from maternal immune activation models that fever and cytokine surges in pregnancy can disturb fetal brain development and cause autism or schizophrenia. There is also evidence linking maternal immune activation to ADHD in the offspring.

So, what is the solution? Pair paracetamol with NAC.

Why NAC?

• NAC (N-acetylcysteine) is a precursor to glutathione.
• It’s used worldwide in emergency rooms to save lives after paracetamol/ acetaminophen overdose.
• In pregnancy, NAC has been shown to reduce miscarriage risk by 50%,

N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss

• Increased pregnancy continuation: Women receiving NAC and folic acid were 2.9 times more likely to continue their pregnancies beyond 20 weeks compared to those receiving folic acid alone
• Higher take-home baby rate: The NAC group had a 1.98 times higher rate of delivering a live baby.
• These findings suggest that NAC, an antioxidant, may help mitigate oxidative stress, a factor implicated in pregnancy loss.

  

A combined Paracetamol/acetaminophen + NAC pill would:

• Prevent liver toxicity,
• Buffer oxidative stress in the fetus,
• Eliminate the overdose suicide risk that haunts current paracetamol use.

So far, no company has produced it. Perhaps the “rotten egg” smell of NAC is a barrier—but solid sustained-release tablets avoid this.

 

Why Paracetamol/acetaminophen use is problematic in under 5s

Paracetamol depletes glutathione (GSH), the body’s primary antioxidant, increasing oxidative stress. A fetus with some genetic predispositions might already be in a state of oxidative stress, as might the mother

Paracetamol is mainly metabolized in the liver. A small fraction is metabolized into NAPQI — a reactive toxic metabolite. Glutathione (GSH) neutralizes NAPQI by forming a harmless conjugate.

If GSH stores are low (or paracetamol is taken in high doses), NAPQI accumulates, causing liver toxicity and GSH is exhausted raising oxidative stress.

Acute oxidative stress can be very damaging to developing brains. The risk after 5 years old fades away, other than in those who have already exhibited a profound metabolic/mitochondrial condition.

Why Oxidative Stress Rises in Pregnancy

Placental development: Early pregnancy is low-oxygen; as blood flow increases, oxygen surges and generates reactive oxygen species (ROS).

High metabolic demand: The mother and placenta require much more energy, leading to increased mitochondrial ROS.

Immune adaptations: Pregnancy involves a shift in maternal immunity, with inflammatory cytokines contributing to oxidative stress.

Fetal growth: Rapid cell division and organ development naturally produce oxidative byproducts, while the fetus’s antioxidant defenses are immature.

Limited antioxidant reserves: Maternal antioxidants (glutathione, vitamins C & E, enzymes) are partly depleted as pregnancy progresses.

 

Compounding Risk Factors

Polycystic Ovary Syndrome (PCOS): Associated with high androgens, insulin resistance, and chronic inflammation. These increase oxidative stress and are linked to higher autism risk in offspring.

Gestational Diabetes: Maternal hyperglycemia and insulin resistance increase ROS, damage the placenta, and expose the fetus to oxidative and metabolic stress.

Other amplifiers: Obesity, infection, fever, or poor nutrition further elevate oxidative stress.

 

How Oxidative Stress Affects the Fetus

Neurodevelopmental disruption: ROS can damage neural stem cells, impair migration, and disturb synapse formation.

Epigenetic reprogramming: Oxidative stress alters DNA methylation and gene expression, shaping long-term brain function.

Immune activation: Inflammatory cytokines cross the placenta and disturb fetal brain development.

Mitochondrial dysfunction: ROS damage fetal mitochondria, reducing energy for developing neurons.

Neurotransmitter imbalance: Antioxidant depletion disrupts glutamate/GABA balance and monoamine systems.

 

Consequences for the Unborn Child

Most pregnancies manage oxidative stress without harm, thanks to maternal–fetal antioxidant defences.

When oxidative stress overwhelms these defences—especially in mothers with PCOS, GDM, or infections—the risk of complications rises:

Preterm birth, growth restriction, or preeclampsia

Higher vulnerability to neurodevelopmental disorders, including autism spectrum disorder (ASD) and ADHD.

Genetic predispositions in antioxidant or mitochondrial pathways may make some fetuses especially sensitive to these oxidative challenges.

Pregnancy naturally involves a controlled increase in oxidative stress, but when combined with maternal conditions like PCOS, gestational diabetes, or acute infections, the oxidative burden can exceed protective capacity. This imbalance may impair placental function and fetal brain development, increasing the risk of adverse outcomes, including autism. 

 

Pregnancy: Choosing safer options for pain and fever

• Paracetamol → Remains the best option if pain relief is absolutely needed, but should be paired with NAC.
• NSAIDs (ibuprofen, mefenamic acid) → Unsafe in later pregnancy due to fetal kidney damage and premature closure of the ductus arteriosus. Premature closure of the ductus arteriosus is a serious condition that occurs when the fetal blood vessel connecting the pulmonary artery to the aorta closes before birth. Do not use NSAIDs!
• NAC supplementation → Low-cost, safe, and evidence-backed for reducing oxidative stress.

 

Infancy and Early Childhood

• Paracetamol
• Licensed from birth.
• Effective for pain and fever, but still depletes glutathione.
• In at-risk infants (metabolic or mitochondrial issues), consider pairing with NAC.
• NSAIDs (ibuprofen, Ponstan)
• Suitable from 3–6 months (depending on guidelines).
• Do not deplete glutathione, making them safer for oxidative stress.
• Hydration matters to protect kidneys.

 

Vaccinations, Fever, and Oxidative Stress

Vaccines work by briefly activating the immune system. This triggers a short burst of oxidative stress—far smaller than that caused by actual infections.

• Healthy children clear this easily.
• At-risk children (mitochondrial disease, metabolic errors, weak antioxidant systems) may struggle, leading to fatigue, regression-like symptoms, or metabolic instability.

Medication choices around vaccines

• NSAIDs → Good for post-vaccine fever. Avoid routine pre-dosing to prevent dampening immunity, unless the child is in the at-risk group.
• Paracetamol → Pre-vaccine dosing can reduce antibody production and reduce GSH. Post vaccine should be paired with NAC.
• Montelukast → Anti-inflammatory, theoretically helpful in at-risk children, but not tested in trials, but is used at metabolic/mitochondrial clinics treating children.
• NAC → Biologically plausible support for antioxidant status, though not studied formally in this setting.

Mainstream pediatrics avoids routine prophylactic anti-inflammatories, but some specialists (e.g., Dr. Kelley, Johns Hopkins) do use them selectively in fragile children. Using paracetamol without NAC is a bad idea.

 

Metabolic Decompensation: The Hidden Risk

Some children with mitochondrial or metabolic disorders cannot handle stress from fever or illness. This can trigger:

• Energy failure (low ATP)
• Accumulation of toxic metabolites (lactate, ammonia)
• Seizures or regression

In developing brains, these crises can leave permanent autism-like features and/or intellectual disability. These symptoms are secondary to brain injury. Prevention is key:

• Hydration, glucose support
• Early fever control
• Antioxidant support (NAC, vitamins C & E)

 

Key Takeaways

• Pregnancy: If pain relief is needed, paracetamol + NAC is safer than paracetamol alone. Avoid NSAIDs.
• Infancy: Paracetamol is widely used, but NSAIDs are safer from 3 months onward when oxidative stress is a concern.
• Vaccination: Vaccines prevent far greater oxidative stress from infections. At-risk children may benefit from antioxidant or anti-inflammatory support, but this should be individualized.
• Metabolic decompensation: Recognize and prevent crises in vulnerable children—this reduces risk of secondary neurodevelopmental injury.

 

Conclusion

Paracetamol has been trusted for decades, but its link with oxidative stress and neurodevelopmental risk is becoming harder to ignore. A Paracetamol + NAC pill makes both medical and common sense—safer for mothers, safer for children, and suicide-proof.

Until then, thoughtful use of NAC, NSAIDs, and tailored fever management could make a real difference in protecting brain development from conception through early childhood.

 

My original draft post was rather long, so here is the “optional” part 2, for any avid readers out there!

 

 

Part 2: Vaccines, Oxidative Stress, and Children at Risk

Why some kids may react differently — and what parents and clinicians can do

Vaccines are one of the greatest public health achievements, protecting children from infections that would otherwise cause significant illness, hospitalization, or death. But for children with mitochondrial disorders, metabolic diseases, or weak antioxidant systems, even routine vaccination can temporarily stress the body.

How Vaccines Trigger Oxidative Stress

• Vaccination works by activating the immune system, prompting cytokine release, mild inflammation, and reactive oxygen species (ROS) production.
• In healthy children, this burst is short-lived. Antioxidant defences like glutathione, superoxide dismutase, and dietary vitamins C & E neutralize ROS quickly.
• In children with mitochondrial or metabolic vulnerabilities, baseline ROS is already elevated, and antioxidant defences may be limited. A small extra load from vaccination can feel disproportionately stressful.

 

Why Some Children React Differently

Mitochondrial Disorders

• Mitochondria produce ATP and ROS. Dysfunction means higher baseline oxidative stress and lower energy reserves.
• A vaccine-induced oxidative spike can linger longer, leading to fatigue, metabolic stress, or regression-like symptoms.

Metabolic Disorders

• Children with amino acid, fatty acid, or urea cycle defects have limited antioxidant capacity.
• ROS accumulation may overwhelm defences, causing secondary mitochondrial stress or toxic metabolite build-up.

Genetic Variants

• Some children carry variants that reduce glutathione production or antioxidant enzyme activity (e.g., GSTM1/GSTT1 deletions, MTHFR variants, impaired SOD/catalase).
• Even minor oxidative challenges can temporarily disturb synapse formation, neurotransmitter balance, and myelination in the developing brain.

 

Medications Around Vaccination

NSAIDs

• Symptom-driven use for fever or pain post-vaccine is generally safe.
• Routine prophylactic use is usually avoided because it can reduce antibody responses, but specialists consider this is likely minimal

Paracetamol

• Pre-vaccine dosing can modestly blunt antibody formation in some vaccines and is unwise because it reduces GSH just before it will be needed most.
• Post-vaccine, symptom-driven use is often considered safe, but is unwise due to the ruction in GSH when needed most
• High-risk children should always avoid paracetamol unless paired with NAC to protect glutathione and limit oxidative stress.

NAC (N-acetylcysteine)

• Biologically plausible support for antioxidant status in at-risk children.
• Safely used during pregnancy and by babies
• Not yet studied in formal vaccine trials, but safe and used in clinical settings for other oxidative stress conditions.

Montelukast

• Anti-inflammatory, may reduce oxidative stress, but not proven for vaccine prophylaxis.
• Used by children at vaccination time when already prescribed it for asthma/allergic disease.

 

Managing Vaccination in At-Risk Children

1.     Ensure good hydration, feeding, and metabolic stability before vaccination.

2.     Monitor closely for post-vaccine fever, fatigue, or regression-like symptoms.

3.     Have supportive measures ready:

o    NAC or other antioxidant support

o    Symptom-driven NSAIDs

o    Avoid paracetamol unless paired with NAC

o    Quick access to a specialist if metabolic stress occurs

 

Takeaways for Parents and Clinicians

• Vaccines do cause a small, transient oxidative stress, but it is far less than the oxidative burden from infections.
• Children with mitochondrial or metabolic vulnerabilities may need extra care before and after vaccination.
• NAC, hydration, symptom-driven NSAIDs, and careful monitoring can reduce risk without compromising immunity.
• Always coordinate with a metabolic or mitochondrial specialist when planning vaccination for high-risk children.

By understanding oxidative stress, supporting antioxidant defences, and tailoring care, parents and clinicians can protect both immunity and neurodevelopment.

Since most parents, in reality, do not have access a mitochondrial specialist it pays to do your homework in advance. All the needed resources are in plain view.

You do wonder why nobody makes a combined Paracetamol/acetaminophen + NAC pill.

Such a pill is perfect for pregnant women.

Nobody would be able to commit suicide with this pill. This pill blocks the harmful effect on the liver that ultimately can lead to death.

NAC does smell of rotten eggs. One argument against such a pill is that it would stink and pregnant women are often feeling nausea. If the pill is solid (like NAC Sustain) there is no smell of rotten eggs. So you certainly can have a combined pill.

Personally, I would ban all liquid formulations of Paracetamol, other than for babies under 3 months. Many countries have long used exclusively Ibuprofen or Ponstan for children. Once a child is 5 years old the potential for paracetamol to do neurodevelopmental harm should have faded.

You can give babies NAC, it is sold in a liquid form for this purpose. NAC acts as a mucolytic, meaning it thins mucus in the airways.

How common is Metabolic Decompensation as a cause of severe autism? We know it exists, but I think we will never know how common it is. Hannah Poling is the best-known example. Evidence of an inconvenient truth.