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

Excitatory/Inhibitory (E/I) imbalances as a unifying, treatable, feature of severe autism that cause Cognitive Impairment, Self-Injurious Behavior (SIB) and ultimately seizures in some

 

Autism is a complex condition that manifests in a range of symptoms, from social and communication challenges to sensory sensitivities and repetitive behaviors. Researchers long ago identified a key neurobiological mechanism that underlies many of the core and associated features of autism: excitatory/inhibitory (E/I) imbalances in the brain.

These imbalances, where the delicate interplay between neuronal excitation and inhibition is disrupted, offers a unifying framework to explain certain severe manifestations of autism, including cognitive impairment, self-injurious behavior (SIB), and seizures. Understanding E/I imbalance not only sheds light on the biology of autism but also opens new avenues for targeted therapies.

 

The Role of E/I Balance in the Brain

Neuronal circuits rely on a finely tuned balance between excitatory and inhibitory signals to function properly. Excitatory neurons promote the firing of signals, enabling processes like learning, memory, and sensory integration. Inhibitory neurons, on the other hand, dampen excessive activity, ensuring stability and preventing overstimulation.

In individuals with autism, this balance is often disrupted. Overactive excitatory signaling or insufficient inhibitory control can lead to hyperexcitability in certain brain regions, contributing to behavioral and neurological symptoms. This imbalance is influenced by a range of factors, including:

• Genetic mutations in key synaptic proteins (e.g., SHANK3, SCN1A, GABA receptor subunits).
• Neuroinflammation and oxidative stress.
• Developmental disruptions in synaptic pruning or circuit formation.

 

How E/I imbalances drives severe autism symptoms

 

Cognitive Impairment

E/I imbalance affects the prefrontal cortex and hippocampus, regions critical for cognitive functions like problem-solving, memory, and attention. Disrupted neural signaling in these areas impairs synaptic plasticity—the brain’s ability to adapt and learn—which can manifest as intellectual disability in some individuals with autism.

Studies have shown that restoring E/I balance in animal models can improve cognitive deficits, highlighting its central role in intellectual development.

 

Self-Injurious Behavior (SIB)

Self-injurious behaviors, such as head-banging or skin-picking, are often linked to dysregulated sensory processing and impaired impulse control. Hyperexcitability in brain regions like the amygdala can heighten stress responses, while altered pain thresholds caused by E/I imbalance may make some individuals less sensitive to injury.

Addressing the underlying imbalance can reduce the neural hyperactivity driving these behaviors and improve emotional regulation.

 

Seizures

Seizures are a common comorbidity in autism, affecting up to 30% of individuals. They arise directly from hyperexcitability in neural networks, where excessive excitation leads to abnormal, synchronized firing of neurons. Genetic conditions like Dravet syndrome, linked to mutations in sodium channel genes (e.g., SCN1A), exemplify the connection between E/I imbalance and epilepsy.

Therapies that stabilize E/I balance, such as GABA-enhancing drugs or ion channel modulators, have shown promise in reducing seizure frequency and severity.

 

Targeting E/I Imbalance: A Path Toward Better Treatments

Given its central role in severe autism symptoms, E/I imbalance represents a promising target for therapeutic intervention. Approaches to restore balance include:

 

Pharmacological Therapies

Bumetanide

Bumetanide is a diuretic that also affects neuronal chloride homeostasis by inhibiting the NKCC1 transporter. In autism, elevated intracellular chloride levels impair the function of GABA, shifting its action from inhibitory to excitatory. Bumetanide lowers intracellular chloride, restoring GABA’s inhibitory effect and reducing hyperexcitability. Clinical trials have shown improvements in social behaviors and reduced severity of core autism symptoms in some individuals.

 

L-Type Calcium Channel Blockers

L-type calcium channels play a role in synaptic plasticity and neuronal excitability. Excessive calcium influx can contribute to hyperexcitability and oxidative stress. Blockers like nimodipine and verapamil may help stabilize neuronal activity and have shown potential in reducing seizures and hyperactivity in preclinical studies.

 

T-Type Calcium Channel Blockers

T-type calcium channels are involved in regulating burst firing and thalamocortical oscillations. Dysregulation of these channels can contribute to sensory processing abnormalities and seizures. Agents like zonisade, traditionally used for absence seizures, may also offer benefits in addressing E/I imbalances in autism.

 

Memantine

Memantine is an NMDA receptor antagonist that modulates glutamatergic signaling. By dampening excessive excitatory activity, it can reduce hyperexcitability and improve cognitive and behavioral symptoms. Clinical studies have shown mixed results, with some individuals experiencing notable benefits in areas like communication and social interactions.

 

Low-Dose Clonazepam

Clonazepam, a benzodiazepine, enhances GABAergic inhibition by increasing the activity of GABA-A receptors. At low doses, it can stabilize neural circuits without causing significant sedation. It has been used off-label to manage anxiety, hyperactivity, and seizures in autism.

 

Valproate

Valproate is an anticonvulsant and mood stabilizer that enhances GABAergic signaling and reduces excessive excitation. It has shown efficacy in managing seizures and may also improve irritability and aggression in some individuals with autism.

 

Baclofen and R-Baclofen

Baclofen is a GABA-B receptor agonist that enhances inhibitory signaling. It can modulate overactive NMDA receptor activity, which may be beneficial in cases of excitatory dysfunction. Baclofen has been studied for its role in reducing repetitive behaviors and improving social interaction in preclinical models.

 

Taurine

Taurine is an amino acid with inhibitory properties that can enhance GABAergic activity and reduce excitatory signaling. It also acts as an antioxidant, mitigating oxidative stress linked to hyperexcitability.

 

Pioglitazone

Pioglitazone, a PPAR-gamma agonist, has anti-inflammatory effects that can indirectly stabilize neural circuits by reducing neuroinflammation associated with E/I imbalances. Preliminary studies suggest it may have benefits for behavioral symptoms in autism.

Other agents including

• Anti-inflammatory Drugs: Minocycline and mefenamic acid reduce neuroinflammation, which can exacerbate E/I imbalances.
• Ion Channel Modulators: Sodium channel blockers like lamotrigine and carbamazepine stabilize hyperexcitable neurons and may reduce both seizures and behavioral dysregulation.

 

Neuromodulation Techniques

• Transcranial Magnetic Stimulation (TMS): A non-invasive method to modulate cortical excitability.
• Transcranial Direct Current Stimulation (tDCS): Targets specific brain regions to enhance or suppress neural activity.

 

 

The Role of NMDA and GABA Receptors in E/I Imbalance

Excitatory NMDA receptors and inhibitory GABA receptors play central roles in maintaining E/I balance. NMDA receptor dysfunction, characterized by either hyperactivity or hypoactivity, is implicated in autism. Overactive NMDA receptors can amplify excitatory signaling, while underactive NMDA receptors can impair synaptic plasticity. Both scenarios disrupt neural communication and contribute to autism-related symptoms.

GABA receptors, particularly GABA-A and GABA-B subtypes, are essential for inhibitory control. Dysfunctional GABAergic signaling reduces the brain’s ability to counterbalance excitation, leading to hyperexcitability.

Baclofen’s modulation of GABA-B receptors exemplifies how targeting these systems can restore balance. By reducing NMDA receptor overactivation and enhancing GABAergic inhibition, baclofen addresses multiple aspects of E/I dysregulation.

 

NMDA receptor dysfunction

Addressing NMDA receptor dysfunction requires a nuanced approach because the receptor can be either hypoactive/underactive or hyperactive/overactive in autism, depending on the individual and the specific neural circuits involved. Treatments vary based on the direction of dysfunction:

 

Treating NMDA Hypofunction

In cases where NMDA receptors are underactive, excitatory signaling is insufficient, leading to impairments in synaptic plasticity, learning, and memory. Strategies to enhance NMDA receptor activity include:

1. D-Cycloserine
• Acts as a partial agonist at the glycine site of the NMDA receptor.
• Enhances receptor activity without overactivation, making it useful for improving social and cognitive functions in some individuals with autism.
2. Sarcosine
• A glycine transport inhibitor that increases synaptic glycine levels, promoting NMDA receptor activation.
• Preclinical studies suggest potential improvements in behavioral symptoms.
3. Glycine Supplements
• Directly increase the availability of a co-agonist required for NMDA receptor activation.
• May improve signaling in circuits where glycine levels are suboptimal.

 

Treating NMDA Hyperfunction

Excessive NMDA receptor activity can lead to excitotoxicity.  When there is too much glutamate or an overactive NMDA receptor, the influx of calcium ions into the neuron becomes excessive. This causes a series of harmful processes contributing to neuronal damage, increased oxidative stress, and seizures. Strategies to dampen NMDA receptor overactivity include:

1. Memantine
• An NMDA receptor antagonist that reduces overactivation without completely shutting down receptor function.
• Clinical trials in autism have reported mixed results but some individuals benefit in areas like hyperactivity and irritability.
2. Magnesium Supplements
• Magnesium acts as a natural blocker of the NMDA receptor under resting conditions.
• Supplementation can stabilize receptor activity and reduce hyperexcitability.
3. Low-Dose Ketamine
• At sub-anesthetic doses, ketamine modulates NMDA receptor activity and enhances synaptic plasticity.
• Emerging research suggests potential benefits for specific autism symptoms, although risks and side effects must be carefully managed.
4. Antioxidants (e.g., N-Acetylcysteine, Vitamin E)
• Reduce oxidative stress caused by NMDA receptor hyperactivity.
• Support neuronal health and may mitigate excitotoxicity.

 

Balancing NMDA Dysfunction

In some cases, the same individual may show hypoactivity in some circuits and hyperactivity in others.

Combining treatments tailored to the specific functional state of NMDA receptors in different brain regions. For example, Low-dose ketamine or memantine may help dampen excessive NMDA activity in the amygdala or basal ganglia, while D-cycloserine might be used to enhance NMDA function in areas like the prefrontal cortex.

  

Calcium, Sodium and Potassium Channels

Calcium signaling is critical for excitatory neurotransmission, as calcium ions mediate glutamate release and synaptic plasticity. Dysregulated calcium channels, such as overactive L-type or T-type channels, contribute to hyperexcitability and sensory abnormalities.

Sodium channelopathies, involving mutations in genes like SCN1A, directly impact neuronal firing rates. Excessive sodium influx leads to hyperactive neurons, causing seizures and other excitatory-driven symptoms. While calcium channels influence neurotransmitter release, sodium channel dysfunction primarily affects action potential generation.

Potassium channels, responsible for repolarizing neurons after firing, also play a key role in maintaining neural stability. Mutations in potassium channel genes can prolong neuronal firing and contribute to hyperexcitability.

 

Conclusion

While E/I imbalance is not the sole cause of autism, it is a key unifying feature that connects many severe symptoms. By targeting this imbalance, clinicians can develop more precise and effective treatments tailored to the individual’s needs. Early intervention, particularly during critical periods of brain development, holds the greatest potential for improving outcomes.

As we continue to unravel the complexities of autism, the concept of E/I imbalance serves as a key nexus to understand, and more importantly, treat the challenges faced by individuals with severe autism and their families. By restoring balance, to the extent possible, both in the brain and in daily life, we can empower those with severe autism to reach their full potential. 

People with mild autism are likely affected by less extreme E/I imbalances, but they may be more aware of them. They are likely easier to treat. The principles are the same. 

The issue of sound sensitivity can affect autism from level 0 (including self-diagnosed and ADHD) all the way to level 3; it is complex because it involves both an E/I imbalance and further issues. There will be a summary post on this subject. 

 

Low dose Clonazepam for MIA Autism, Ponstan and TRPM3 in Intellectual Disability, Clemastine to restore myelination in Pitt Hopkins, Improving Oxytocin therapy with Maca, Lamotrigine for some autism

 

Monty in Ginza, Tokyo

Today’s post comes from Tokyo and looks at 5 therapies already discussed in previous posts and follows up on recent coverage in the research. They all came up in recent conversations I have been having.

·      Low dose Clonazepam  – Maternal Immune Activation model of autism

·      Ponstan – TRPM3 causing intellectual disability  (ID/MR)

·      Clemastine – improving myelination in Pitt Hopkins syndrome model

·      Oxytocin – Maca supplement to boost effect

·      Lamotrigine (an anti-epilepsy drug) to moderate autism

The good news is that many of same therapies keep coming up.

Ponstan and TRPM3 caused ID/MR

There is a lot in this blog about improving cognition, which is how I called treating ID/MR.  There are very many causes of ID and some of them are treatable.

ID/MR was always a part of classic autism and in the new jargon is part of what they want to call profound autism.

I was recently sent a paper showing how the cheap pain reliever Ponstan blocks the TRMP3 channel and that this channel when mutated can lead to intellectual disability and epilepsy.

Mefenamic acid selectively inhibits TRPM3-mediated calcium entry.

My own research has established that mefenamic acid seems to improve speech and cognition, as well as sound sensitivity.  The latter effect I am putting down to its effect on potassium channels. 

De novo substitutions of TRPM3 cause intellectual disability and epilepsy

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3’s S4–S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3’s flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.

 

Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3

This study reveals that mefenamic acid selectively inhibits TRPM3-mediated calcium entry. This selectivity was further confirmed using insulin-secreting cells. K_ATP channel-dependent increases in cytosolic Ca²⁺ and insulin secretion were not blocked by mefenamic acid, but the selective stimulation of TRPM3-dependent Ca²⁺ entry and insulin secretion induced by pregnenolone sulphate were inhibited. However, the physiological regulator of TRPM3 in insulin-secreting cells remains to be elucidated, as well as the conditions under which the inhibition of TRPM3 can impair pancreatic β-cell function. Our results strongly suggest mefenamic acid is the most selective fenamate to interfere with TRPM3 function. 

Here, we examined the inhibitory effect of several available fenamates (DCDPC, flufenamic acid, mefenamic acid, meclofenamic acid, niflumic acid, S645648, tolfenamic acid) on the TRPM3 and TRPV4 channels using fluorescence-based FLIPR Ca²⁺ measurements. To further substantiate the selectivity, we tested the potencies of these fenamates on two other TRP channels from different subfamilies, TRPC6 and TRPM2. In addition, single-cell Ca²⁺ imaging, whole-cell voltage clamp and insulin secretion experiments revealed mefenamic acid as a selective blocker of TRPM3.

  

Oxytocin

 Oxytocin does increase how emotional you feel; the difficulty is how to administer it in a way that provides a long lasting effect.  The half-life of oxytocin is a just minutes. The traditional method uses a nose spray.

I favour the use of a gut bacteria that stimulates the release of oxytocin in the brain.  The effect should be much longer lasting. Even then the effect is more cute than dramatic.

The supplement Maca does not itself produce oxytocin, but “it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways”.

So Maca looks like an interesting potential add-on therapy to boost the effect of oxytocin.

One reader wrote to me with a positive report on using Maca by itself, without any oxytocin.

 

Oral Supplementation with Maca Improves Social Recognition Deficits in the Valproic Acid Animal Model of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a congenital, lifelong neurodevelopmental disorder whose main symptom is impaired social communication and interaction. However, no drug can treat social deficits in patients with ASD, and treatments to alleviate social behavioral deficits are sorely needed. Here, we examined the effect of oral supplementation of maca (Lepidium meyenii) on social deficits of in utero-exposed valproic acid (VPA) mice, widely used as an ASD model. Although maca is widely consumed as a fertility enhancer and aphrodisiac, it possesses multiple beneficial activities. Additionally, it benefits learning and memory in experimental animal models. Therefore, the effect of maca supplementation on the social behavioral deficit of VPA mice was assessed using a social interaction test, a three-stage open field test, and a five-trial social memory test. The oral supplementation of maca attenuated social interaction behavior deficit and social memory impairment. The number of c-Fos-positive cells and the percentage of c-Fos-positive oxytocin neurons increased in supraoptic and paraventricular neurons of maca-treated VPA mice. These results reveal for the first time that maca is beneficial to social memory and that it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways, which play an essential role in diverse social behaviors.

Maca (Lepidium meyenii) belongs to the cruciferous family and grows at high altitudes in Peru. In 2002, it was transplanted from Peru to the Yunnan Province of China. It is rich in dietary fiber; has many essential amino acids and nutrients including vitamin C, copper, and iron; and its root contains bioactive compounds. It is globally consumed and is popularly used as a fertility enhancer and aphrodisiac. On the other hand, with its potential to possess multi-nutritious components, it is reported to have diverse functions, including immunomodulation, antioxidant, antidepressant, antirheumatic, UV radiation protection, hepatoprotective, anti-fatigue, and neuroprotective effects. Interestingly, although the mechanism of the neuronal effect of maca is unclear, the uptake of maca extract improves learning and memory in memory-impaired model mice induced by either ethanol, ovariectomy, or scopolamine. However, the effects of maca on social memory impairment in neurodevelopmental disorders, including ASD, have not yet been tested.

In this study, the effects of maca on ASD animal models, in utero VPA-exposed mice, were investigated. The effect on social recognition by maca uptake with gavage was assessed using the social interaction test, a three-stage open field test, and the five-trail social recognition test. We also explored whether maca intake affects oxytocinergic signaling pathways, which play an important role in various social behaviors.

In this study, we showed that maca uptake rescues the deficits of social behavior and social recognition memory in VPA mice, a mouse model of autism. The c-Fos immunoreactivity of oxytocinergic neurons in SON and PVN increased significantly after maca treatment in VPA mice. Following previous studies indicating that OT administration ameliorates the impairment of social behavior in VPA mice, maca may also have improving effects on the deficit of social behavior and social recognition memory of VPA mice, probably by activating the OT neuronal pathway. Previous studies showed that maca could improve cognitive function in the mice model of impaired cognitive memory induced by either ovariectomy, ethanol, or scopolamine. Further studies are necessary to elucidate the potential link between maca and OT and to determine which components are involved in improving social recognition memory.

We have shown that maca improves the impairment of social memory and social behavioral deficits through oxytocinergic system modulation in this study. Although maca may not have an immediate effect on social behavioral deficits and takes days or weeks to demonstrate the effects, behavioral improvements, were visible regardless of the time of oral intake. The time between the very last oral intake of maca and the start of the social behavioral experiments in this study was more than 16 h. The duration of the maca’s effect on social behavioral deficits after the supplementation period is being investigated in our follow-up experiments. The possibility of the persistent effect of maca is very appealing, given that OT does not have a sustained effect due to its rapid metabolism, despite its immediate effects. Therefore, taking maca as a supplement while also receiving repeated OT treatment may have a synergistic, sustainable effect on improving social impairment in patients with ASD. Maca is already being used as a dietary supplement worldwide and has a high potential for practical applications.

 

This study showed for the first time that maca supplementation improves the impairment of social recognition memory in ASD model mice. We added the mechanism that social memory improvement may occur through the upregulation of oxytocinergic pathways. Maca highlights the possibility of treating social deficits sustainably in individuals with ASDs.

 

Low dose clonazepam

Professor Catterall was the brains behind low dose clonazepam for mice, I just translated it across to humans. It is one way to modify the E/I (excitatory/inhibitory) imbalance in autism.

I found that it gave a boost to cognition. Not as big as bumetanide, but worth having nonetheless.

I do not believe you have to be a bumetanide responder to respond well to low dose clonazepam.

Several people have written to me recently to say it works for their child.

Our reader Tanya is interested in the Maternal Immune Activation (MIA) trigger to autism. She highlighted a recent study showing how and why clonazepam can reverse autism in the MIA mouse model of autism. 

Clonazepam attenuates neurobehavioral abnormalities in offspring exposed to maternal immune activation by enhancing GABAergic neurotransmission

Ample evidence indicates that maternal immune activation (MIA) during gestation is linked to an increased risk for neurodevelopmental and psychiatric disorders, such as autism spectrum disorder (ASD), anxiety and depression, in offspring. However, the underlying mechanism for such a link remains largely elusive. Here, we performed RNA sequencing (RNA-seq) to examine the transcriptional profiles changes in mice in response to MIA and identified that the expression of Scn1a gene, encoding the pore-forming α-subunit of the brain voltage-gated sodium channel type-1 (Na_V1.1) primarily in fast-spiking inhibitory interneurons, was significantly decreased in the medial prefrontal cortex (mPFC) of juvenile offspring after MIA. Moreover, diminished excitatory drive onto interneurons causes reduction of spontaneous gamma-aminobutyric acid (GABA)ergic neurotransmission in the mPFC of MIA offspring, leading to hyperactivity in this brain region. Remarkably, treatment with low-dose benzodiazepines clonazepam, an agonist of GABA_A receptors, completely prevented the behavioral abnormalities, including stereotypies, social deficits, anxiety- and depression-like behavior, via increasing inhibitory neurotransmission as well as decreasing neural activity in the mPFC of MIA offspring. Our results demonstrate that decreased expression of Na_V1.1 in the mPFC leads to abnormalities in maternal inflammation-related behaviors and provides a potential therapeutic strategy for the abnormal behavioral phenotypes observed in the offspring exposed to MIA.

 

Pitt Hopkins – Clemastine and Sobetirome

Poor myelination is a feature of much autism and is a known problem in Pitt Hopkins syndrome.

I did cover a paper a while back where the Pitt Hopkins researchers showed that genes involved in myelination are down-regulated not only in Pitt Hopkins, but in several other popular models of autism.

From the multiple sclerosis (MS) research we have assembled a long list of therapies to improve different processes involved in myelination. Today we can add to that list sobetirome (and the related Sob-AM2). Sobetirome shares some of its effects with thyroid hormone (TH), it is a thyroid hormone receptor isoform beta-1 (THRβ-1) liver-selective analog.

Some people do use thyroid hormones to treat autism, and indeed US psychiatrists have long used T3 to treat depression.

The problem with giving T3 or T4 hormones is that it has body-wide effects and if you give too much the thyroid gland will just produce less.

One proposed mechanism I wrote about long ago is central hypothyroidism, that is a lack of the active T3 hormone just within the brain. One possible cause proposed was that oxidative stress reduces the enzyme D2 that is used to convert circulating prohormone T4 to T3. The result is that your blood test says your thyoid function is great, but in your brain you lack T3.

It looks like using sobetirome you can spice up myelination in the brain, without causing any negative effects to your thyroid gland.

Rather surprisingly, sobetirome is already sold as a supplement, but it is not cheap like Clemastine, the other drug used in the successful study below.

 

Promyelinating drugs promote functional recovery in an autism spectrum disorder mouse model of Pitt–Hopkins syndrome

Pitt–Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt–Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt–Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt–Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.

 

Sobetirome  (also called GC-1)

Sobetirome is a thyroid hormone receptor isoform beta-1 (THRβ-1) liver-selective analog.

In humans, sobetirome lowers plasma LDL cholesterol and reduced plasma triglycerides, while its liver-selective activity helped avoid the side effects seen with many other thyromimetic agents.

 

Myelin repair stimulated by CNS-selective thyroid hormone action

Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.

 

Compound protects myelin, nerve fibers

 

Research could be important in treating, preventing progression of multiple sclerosis, other neurodegenerative diseases

A compound appears to protect nerve fibers and the fatty sheath, called myelin, that covers nerve cells in the brain and spinal cord. The new research in a mouse model advances earlier work to develop the compound - known as sobetirome - that has already showed promise in stimulating the repair of myelin.

Lead author Priya Chaudhary, M.D., assistant professor of neurology in the OHSU School of Medicine who is focused on developing therapies for neurodegenerative diseases, said that the technique is a common step in drug discovery.

"It is important to show the effectiveness of potential drugs in a model that is most commonly used for developing new therapies," Chaudhary said.

The researchers discovered that they were able to prevent damage to myelin and nerve fibers from occurring, by stimulating a protective response in the cells that make and maintain myelin. They also reduced the activity of migroglia, a type of inflammatory cell in the brain and spinal cord that's involved in causing damage in multiple sclerosis and other diseases.

"The effects are impressive and are at least in part consistent with a neuroprotective effect with particular inhibition of myelin and axon degeneration, and oligodendrocyte loss," the authors write.

The discovery, if proven in clinical trials involving people, could be especially useful for people who are diagnosed with multiple sclerosis early in the disease's progression.

"The drug could protect the nervous system from damage and reduce the severity of the disease," Bourdette said.

 

Does Lamotrigine have the potential to 'cure' Autism?

Recently headlines appeared like this one:-

Scientists 'CURE autism' in mice using $3 epilepsy drug

It referred to the use of the epilepsy drug Lamotrigine to treat a mouse model of autism, caused by reduced expression of the gene MYT1L.

What the tabloid journalists failed to notice was that there has already been a human trial of Lamotrigine in autism.  That trial was viewed as unsuccessful by the clinicians, although the parents did not agree.

There were many comments in the media from parents whose child already takes this drug for their epilepsy and they saw no reduction in autism. There were some who found it made autism worse.

 

MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention

 

Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo-controlled trial

In autism, glutamate may be increased or its receptors up-regulated as part of an excitotoxic process that damages neural networks and subsequently contributes to behavioral and cognitive deficits seen in the disorder. This was a double-blind, placebo-controlled, parallel group study of lamotrigine, an agent that modulates glutamate release. Twenty-eight children (27 boys) ages 3 to 11 years (M = 5.8) with a primary diagnosis of autistic disorder received either placebo or lamotrigine twice daily. In children on lamotrigine, the drug was titrated upward over 8 weeks to reach a mean maintenance dose of 5.0 mg/kg per day. This dose was then maintained for 4 weeks. Following maintenance evaluations, the drug was tapered down over 2 weeks. The trial ended with a 4-week drug-free period. Outcome measures included improvements in severity and behavioral features of autistic disorder (stereotypies, lethargy, irritability, hyperactivity, emotional reciprocity, sharing pleasures) and improvements in language and communication, socialization, and daily living skills noted after 12 weeks (the end of a 4-week maintenance phase). We did not find any significant differences in improvements between lamotrigine or placebo groups on the Autism Behavior Checklist, the Aberrant Behavior Checklist, the Vineland Adaptive Behavior scales, the PL-ADOS, or the CARS. Parent rating scales showed marked improvements, presumably due to expectations of benefits.

One reader of this blog who heard all about the news and was sceptical, since after all it is a mouse model. Her 8 year old non-verbal child was not happy taking the drug Keppra and was already scheduled to try Lamotrigine. 

“Within a week his teacher called to say he was saying his ABCs, the next week he was counting out loud, the following month he’s attempting to repeat words of interest and this week he’s spelling animals by memory, dolphin, duck, wolf, chicken, pig, etc.

We are 2 months in and at 50mg, our target dose is 100mg bid. Obviously with our success, I’ve been working with his doctor and will continue to.”

 

Conclusion

Even though every day new autism research is published, there is so much already in this blog that not much appearing is totally new to regular readers.

We saw several years ago that low dose clonazepam should be beneficial to some people with autism, in particular Dravet syndrome. Today we learnt a little more about why Nav1.1 might be disturbed beyond those with Dravet syndrome. In the maternal immune activation model it seems to be a winner. It seems to benefit many of those who have trialed it.

Treating myelination deficits has been well covered in this blog. In previous posts we saw how Pitt Hopkins syndrome researchers showed how myelination gene expression was disturbed in a wide range of autisms. Today we saw evidence to support such therapy and we discovered a new drug.

Oxytocin does help some people with autism, but not as much as you might expect. Today we learnt of a potential add on therapy, a supplement called Maca.

The idea that anti-epilepsy drugs might help some autism has been well covered. From low dose valproate to low dose phenytoin from Dr Philip Bird in Australia.

Treatment of Autism with low-dose Phenytoin, yet another AED

Recent research suggested that Lamotrigine should help some with autism and today you learned that it really does help in one case. The fact that a tiny study a few years ago suggested no responders just tells us that only a small subgroup are likely to benefit.

We already know that some people's autism is made worse by their epilepsy therapy. This is just what you would expect. Time to find a different epilepsy therapy.

My favorite new therapy, low dose mefenemic acid / ponstan has numerous effects. One reader without autism, but with an unusual visual dysfunction (visual snow syndrome) and a sound sensitivity problem contacted me a while to see if NKCC1 might be the root of his problem. I suggested he try Ponstan, which did actually work for him and is easy to buy where he lives. Now he sends me research into all its possible modes of action. One mode of action relates to a cause of intellectual disability (ID/MR). Is this a factor in why Ponstan seems to improve speech and cognition in some autism? I really don't mind why it works - I just got lucky again, that is how I look at it. The more I read the luckier I seem to get.