Agmatine, again shown beneficial in some autism

 

Albrecht Kossel discovered Agmatine in 1910. That year he won the Nobel prize for medicine. The Albrecht Kossel Institute for Neuroregeneration, in Rostock Germany, is named after him.

 

For those people who keep an eye on the autism research, a recuring observation will have been how the same therapies keep on coming up, sometimes with a new twist. A good example that came up recently is Agmatine, a cheap supplement.

Agmatine is a naturally occurring compound in the body derived from the amino acid arginine, functioning as a neuromodulator and cellular regulator with benefits spanning neurological, cardiovascular, metabolic, and anti-inflammatory systems.

Monty, now aged 21 with autism, has been taking 750mg of Agmatine daily for eight years. In his case it reverses both mental and physical lethargy, like fitting a new set of alkaline batteries to an old toy.

Agmatine has many biological effects, the one that works in our case is its effect on nitric oxide (NO). Agmatine increase eNOS which improves vascular health, reduces blood pressure, enhances circulation. Agmatine can boost mitochondrial function, which also improves energy production and physical endurance.

Agmatine has many other effects, including:

1. Neurological Effects

Neuroprotection. Agmatine reduces oxidative stress and excitotoxicity by modulating glutamate and nitric oxide pathways.

Mood Enhancement. Agmatine acts as an antidepressant by interacting with serotonin and adrenergic receptors.

Cognitive Support. Agmatine may enhance memory and learning by promoting synaptic plasticity.

Pain Modulation. Agmatine offers analgesic effects by influencing opioid receptors and pain-related neurotransmission.

Seizure Protection. Agmatine demonstrates anticonvulsant properties in some animal studies.

 

2. Metabolic and Hormonal Effects

Insulin Sensitivity. Agmatine improves glucose uptake and reduces insulin resistance, aiding in blood sugar regulation.

Fat Metabolism. Agmatine may support weight management by modulating appetite and energy expenditure.

Stress Response: Agmatine regulates the hypothalamic-pituitary-adrenal (HPA) axis, improving the body’s response to stress.

 

3. Cardiovascular Effects

Blood Pressure Regulation. Agmatine enhances endothelial nitric oxide synthase (eNOS) activity, promoting vasodilation and lowering blood pressure.

Heart Protection. Agmatine may reduce the risk of atherosclerosis by improving endothelial function.

 

4. Anti-Inflammatory Effects

Cytokine Modulation. Agmatine reduces pro-inflammatory cytokines and markers like TNF-α and IL-6.

Oxidative Stress Reduction. Agmatine acts as an antioxidant, reducing damage from reactive oxygen species (ROS).

 

5. Musculoskeletal Effects

Bone Health: Agmatine supports bone remodeling by regulating osteoblast and osteoclast activity.

Muscle Recovery: Improves recovery after exercise by reducing inflammation and oxidative stress.

 

6. Gastrointestinal Effects

Gut Barrier Protection. Agmatine may enhance gut lining integrity and reduce inflammation.

Microbiota Interaction. Agmatine can indirectly influence gut microbiota through anti-inflammatory pathways.

 

7. Immune System Effects

Immunomodulation. Agmatine balances immune responses by reducing excessive inflammation.

Autoimmune Benefits. Agmatine shows potential in alleviating symptoms of autoimmune diseases by modulating iNOS activity.

 

Agmatine has been shown effective in various models of autism, including valproic acid-induced and Fragile X.

Agmatine signalling has been recently been shown to have a bidirectional interaction with the gut microbiome and its neuroprotective and anti-ageing functions have been suggested to depend on the resident microbes in that person’s gut. So it will not work for all.

Agmatine has even shown to have a benefit when given prenatally, to prevent autism.

The recent paper that I stumbled upon is this one below. There are two well-studied chemicals produced in the gut can induce autism, or just make existing autism worse. One is P-cresol and the other is propionic acid. Our reader Stephen is interested in ways to low P-cresol. A recent finding was that nutmeg lowers P-cresol and can indeed modulate colon cancer – no surprise to those who follow Chinese traditional medicine. Reducing propionic acid is the basis for the popular Nemechek Protocol for autism, which involves increasing fiber (inulin) in the gut, to favour butyric acid production over propionic acid. Butyric acid has many positive effects.

In the new paper the researchers looked at how propionic acid causes autism symptoms and they identified reduced agmatine as the problem.

Supplementing agmatine reversed the behavioral and biochemical alterations. Great!

We have already seen that the propionic acid induced model of autism can be reversed by NAC. Later in this post you will see that quercetin is also effective.

 

Postnatal propionic acid exposure disrupts hippocampal agmatine homeostasis leading to social deficits and cognitive impairment in autism spectrum disorder-like phenotype in rats

·        PPA reduced sociability and social preference and impaired learning and memory.

·        PPA treatment decreased agmatine and increase agmatinase in hippocampus.

·        PPA altered the glutamate, GABA, TNF-α, IL-6, BDNF levels and GFAP expression.

·        Agmatine reversed the behavioral and biochemical alterations induced by PPA.

·        Study suggests the role for hippocampal agmatinergic pathway in the etiopathogenesis of ASD.

 

I did then look up the research that has been published since I first investigated Agmatine as a potential autism therapy in humans and indeed started using it. There is a lot of research now existing.

 

Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism

 ·        Single treatment of agmatine rescues social impairment in the VPA-induced animal model of autism.

·        Effect of agmatine in social improvement in the VPA model is induced from agmatine itself, not its metabolite.

·        Agmatine rescues repetitive and hyperactive behavior, and seizure susceptibility in the VPA model.

·        Overly activated ERK1/2 in the brain of the VPA model is relieved by agmatine.

 

Autistic-like behaviors are attenuated by agmatine consumption during pregnancy: Assessment of oxidative stress profile and histopathological changes in the prefrontal cortex and CA1 region of the hippocampus

Conclusion:

Overall, this investigation suggests that agmatine may be a potential candidate for the early treatment and even prevention of appearance of autism symptoms.

  

Agmatine relieves behavioral impairments in Fragile X mice model 

·        Fragile X syndrome showed an exaggerated NMDA receptor signaling, problems in synaptic transmission, and abnormal behaviors.

·        Agmatine is an endogenous polyamine and functions as a synaptic neurotransmitter.

·        Agmatine reversed these problems in the model of fragile X syndrome mice.

 

 

The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway

Results

The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway. 

Conclusion

Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.

  

The Prenatal Use of Agmatine Attenuates Social Behavior Deficits in VPA-Exposed Mice by Improving Neuron Loss

Results: Prenatal use of agmatine alleviated the anxiety behaviors of autistic mice in the marble burying test, open field test and three-chamber social interaction test. Prenatal use of agmatine blocked hippocampal neuronal damage and protected the maturity of neurons in autistic mice. 

Conclusions: The prenatal use of agmatine efficiently attenuated social interaction, learning and memory impairments in VPA-exposed mice by improving neuron loss. Agmatine is useful to block the occurrence of autism in offspring for the VPA-exposed pregnant women to an extent.

 

Neuroprotection by agmatine: Possible involvement of the gut microbiome?

·        Dysfunction of agmatinergic signalling is implicated in neuropathologies.

·        Agmatine is a multimodal neuroprotectant and a potential anti-ageing therapeutic.

·        Agmatinergic signalling elicits a bidirectional interaction with the gut microbiome.

·        Its neuroprotective and anti-ageing functions possibly depend on the resident microbes.

  

Effects of agmatine on radial-arm maze memory performance and autistic-like behaviors in a male rat model of autism

Conclusion

·        In a rat model of autism, spatial learning, and memory did not change. Agmatine rescued social and anxiety-like behavior in autistic animals.

 

Conclusion

I wrote extensively about Agmatine in my blog

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

and in my book.

I have used 750mg a day for the last eight years. For me, no further research is needed!

Agmatine is sold as a cheap fitness supplement and is available in many countries, but not all.

You do wonder why more children with autism have not trialed it.

 

A few other interesting papers appeared recently, repeating what has been covered earlier in this blog. 

Oxytocin Improves Autistic Behaviors by Positively Shifting GABA Reversal Potential via NKCC1 in Early-Postnatal-Stage  

Overall, the results demonstrate that the early postnatal stage may be the unique critical period for oxytocin signaling to regulate GABA reversal potential and promote brain development for prosocial behaviors. These findings suggest an earlier intervention window and strategy for the clinical oxytocin treatment of autism.

 

This fits with idea of giving all new-born babies, delivered by C-section, a dose of oxytocin just after birth. These babies missed out on the mother’s surge in oxytocin during birth. The lack of oxytocin means that the GABA developmental switch may never takes place and neurons cannot mature. The result is autism and intellectual disability.

The body does have fall-back mechanisms that can trigger this switch, so not every baby delivered by C-section is autistic. But, humans have evolved to expect a dose of oxytocin at birth – let them have it.

I do like quercetin and it also popped up recently, again in respect to propionic acid induced autism.

 

Antioxidant-Effective Quercetin Through Modulation of Brain Interleukin-13 Mitigates Autistic-Like Behaviors in the Propionic Acid-Induced Autism Model in Rats

These findings, when interpreted together, suggest that quercetin exerts its neuroprotective effects by targeting oxidative stress and neuroinflammation, thereby preventing neuronal cell loss and alleviating behavioral deficits associated with autism spectrum disorders.

 

The final paper is about vagus nerve stimulation (VNS), which has also been extensively covered in this blog. VNS holds promise as a potential adjunctive therapy for autism, especially for symptoms related to autonomic dysregulation, anxiety, and epilepsy. The technology is getting fine-tuned.

 

Vagus Nerve Stimulation Erases PTSD

Prior research shows many PTSD patients fail to respond to standard treatments, making this approach especially promising. Future trials will explore the therapy further, aiming to offer new hope for those resistant to conventional methods.

Key Facts:

·         100% Remission: All participants were free from PTSD diagnosis six months after therapy paired with VNS.

·         Neuroplasticity Boost: VNS enhances brain rewiring, improving outcomes for therapy-resistant PTSD patients.

·         Next Steps: A double-blind Phase 2 trial is underway to confirm findings and move toward FDA approval.

 

Presume competence? Presume incompetence? Or just stretch boundaries?

I had a strange experience recently: for the very first time, a stranger asked me if my 21-year-old son has autism.

We were on holiday in Northern Spain, staying at a tiny hotel with just 6 rooms. The hotel was in a tiny village near San Sebastian that happened to be on the Camino del Norte, or Northern Way, which is a well known hiking route. The route was originally a pilgrimage to the city of Santiago de Compostella. The route seems to be popular with older Americans and British.

At breakfast there was one long table and so strangers were almost inevitably going to talk to each other. For Americans this is normal behaviour, but much less so for Europeans.

Monty was wearing a new replacement set of wireless headphones, which we had not quite figured out how to reliably connect to all his devices. As a result, he did look like the classic person with autism – wearing ear defenders and looking anxious.

“Excuse me, is he autistic?”, queried a guest who was walking the Camino del Norte with a friend.

It turned out that this fellow guest at the hotel had an adult son with autism, now in his 30s. His son is still doing ABA and does not get taken on holidays. “I'm impressed you take him with you,” he commented.

We felt it necessary to explain that Monty can do a lot: he completed mainstream school, passed his exams like the typical students, and now travels alone by public transport to “work” twice a week. He has been to China, Japan, South America and most of Europe. He can ski down black slopes, play the piano …

Our fellow guest told us how once his son had eloped and a police helicopter had been needed to find him, not surprisingly near an expanse of water. He did not attend school, due to his sensory issues.

This got me thinking about how we presume competence, or indeed incompetence.

These concepts have become quite a topic in the field of inclusive education. They have been rather stretched by the DEI people, but they are worth evaluating.

Most people assume that a person who behaves typically and is fully verbal must have full mental competence. We are surprised when that assumption proves false. For instance, Harvard University has introduced remedial math classes for some students; you wonder how that is possible. Similarly, some high school students in the U.S. cannot read analog clocks. Social media is awash with videos of young adults asking high school aged kids basic questions like "what is 33 divided by 3?" and having them unable to even make a reasonable guess. There is even a meme of teenage American girls being asked "in what country is Alaska?" and one answers Mississippi.

When we see a person who is not fully fluent verbally, most people tend to presume incompetence.

Last night, as Monty and I were completing our evening uphill “rucking” (fast walking with weights), I decided to check something. An out of breath Peter said “Mont, what is 33 divided by 3?” Without hesitation, he replied “eleven.” OK, I can use that example.   

   

Stretching boundaries

I did explain in Spain how we got to the point of travel independence. It was a step-by-step process and did not happen overnight, or by itself. I was asked how far away I was during this process. I did explain that with modern GPS tracking available on phones and air tags, it is now very much safer and easier. But things can and will go wrong – that is life. People learn by making mistakes – best make small ones, whilst you are still young!

I am a proponent of constantly stretching boundaries on the basis that taking many small steps forward can take you a long way. Just as it does for those older folk walking along the Camino del Norte.

Constantly stretching boundaries and gradually extending your comfort zone seems a good approach to autism. 

 

Mission Impossible in 4D

Monty’s big brother took me and Monty to see the new Mission Impossible film last week.  As we were about to buy the tickets, big brother said “Oh no, it's in 4D”. Watching movies in 4D is like being on a plane in severe turbulence. “No problem, he will enjoy it” was my response.

This was an example of presuming competence.

It was a great film to see in 4D, it really is a compelling experience. 100 times better than films in 3D.

Monty loved it.

 

What about those who are never competent?

For the DEI (i.e. not realistic) version of competence, here is a link to the TACA site.

 

Presuming Competence in Autism

Presuming competence means valuing all people, including those with autism, as whole individuals with the right to express their thoughts, feelings, and opinions. For individuals with autism, this includes the right to communicate, the right to be treated their age, to have their views and feelings respected, and to be involved in decisions about their lives, large or small. This article covers ways and things to consider when presuming competence in your loved one with autism. 

Speak Directly to the Person and in an Age-Appropriate Manner

Presume that everyone can understand what is being said.

Do not talk down to people with autism.

Do not use baby talk or a baby voice. 

Etc … 

The problem is that some people have impaired cognition, not just impaired verbal communications skills. They may never be able to safely cross a road independently, and some will grow up to be like a toddler in an adult’s body.

However, some young children diagnosed with level 3 autism have made such great strides in the early years that they have left their greatest challenges behind them. They should no longer be considered at level 3.

The Lancet Commission has wisely stated that you need to wait until the age of 8 before you can reliably diagnose profound autism. For these children, stretching boundaries seems a better and safer approach than presuming competence.

  

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. 

 

Update on Oxytocin and Vasopressin in Autism

A nebulizer as a better means of delivering vasopressin?

 

Previous posts: 

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

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

One key, often unaddressed feature of autism is hormonal dysfunction in the brain. Oxytocin and vasopressin are two closely related hormones that significantly affect social behavior, an area frequently disrupted in those with autism. Interestingly, this challenge is often most troubling in individuals with milder forms of autism, as they are more acutely aware of their differences in social interactions. While serotonin dysfunctions also play a key role, today’s post focuses on the impact of oxytocin and vasopressin.

 

 Today we are in the top right - central hormonal dysfunction

Here is a very recent article on a Vasopressin trial:

Vasopressin Boosts Social Skills Without Aggression in Autism

Summary: New research shows that supplementing vasopressin levels in low-social rhesus monkeys improves social behavior and facial recognition without triggering aggression. The findings suggest vasopressin deficiency may underlie social difficulties seen in autism spectrum disorder (ASD).

Monkeys given vasopressin became more responsive to prosocial cues and better at remembering faces, critical skills often impaired in ASD. This work opens new avenues for precision therapies aimed at addressing core social deficits in autism rather than just managing symptoms.

Key Facts:

·    Social Gains Without Aggression: Vasopressin improved prosocial behavior and facial memory without increasing aggression.

·    Biological Link to ASD: Low-social monkeys naturally mirror some social impairments seen in humans with autism.

·    Therapeutic Potential: Vasopressin supplementation could offer a future targeted treatment for core social deficits in ASD.

For years, Florida Tech’s Catherine Talbot, an assistant professor of psychology, has worked to understand the sociality of male rhesus monkeys and how low-social monkeys can serve as a model for humans with autism.

Her most recent findings show that replenishing a deficient hormone, vasopressin, helped the monkeys become more social without increasing their aggression—a discovery that could change autism treatment. 

In a research paper published in the journal PNAS, Talbot and researchers with Stanford, the University of California, Davis and the California National Primate Research Center explored vasopressin, a hormone that is known to contribute to mammalian social behavior, as a potential therapeutic treatment that may ultimately help people with autism better function in society.

Previous work from this research group had found that vasopressin levels are lower in their low-social rhesus monkey model, as well as in a select group of people with ASD.

Previous studies testing vasopressin in rodents had found that increased hormone levels caused more aggression. As a result, researchers warned against administering vasopressin as a treatment, Talbot said.

However, she argued that in those studies, vasopressin induced aggression in contexts where aggression is the socially appropriate response, such as guarding mates in their home territory, so the hormone may promote species-typical behavior.

She also noted that the previous studies tested vasopressin in “neurotypical” rodents, as opposed to animals with low-social tendencies.

“It may be that individuals with the lowest levels of vasopressin may benefit the most from it—that is the step forward toward precision medicine that we now need to study,” Talbot said.

In her latest paper, Talbot and her co-authors tested how low-social monkeys with low vasopressin levels and high autistic-like trait burden responded to vasopressin supplementation to make up for their natural deficiency. They administered the hormone through a nebulizer, into which the monkeys could opt.

For a few minutes each week, the monkeys voluntarily held their faces up to a nebulizer to receive their dose while sipping white grape juice—a favorite among the monkeys, Talbot said.

After administering the hormone and verifying that it increased vasopressin levels in the central nervous system, the researchers wanted to see how the monkeys responded to both affiliative and aggressive stimuli by showing them videos depicting these behaviors.

They also compared their ability to recognize and remember new objects and faces, which is another important social skill.

They found that normally low-social monkeys do not respond to social communication and were better at recognizing and remembering objects compared to faces, similar to some humans diagnosed with ASD. When the monkeys were given vasopressin, they began reciprocating affiliative, pro-social behaviors, but not aggression.

It also improved their facial recognition memory, making it equivalent to their recognition memory of objects.

In other words, vasopressin “rescued” low-social monkeys’ ability to respond prosocially to others and to remember new faces. The treatment was successful—vasopressin selectively improved the social cognition of these low-social monkeys.

“It was really exciting to see this come to fruition after pouring so much work into this project and overcoming so many challenges,” Talbot said of her findings.

One of Talbot’s co-authors has already begun translating this work to cohorts of autism patients. She expects more clinical trials to follow.

 

The original paper: 

Nebulized vasopressin penetrates CSF and improves social cognition without inducing aggression in a rhesus monkey model of autism

  

  

A review/update of all the previous posts on vasopressin and oxytocin: 

Plasma vs CSF Levels of hormones

It is relatively straightforward to measure hormone levels in a blood sample. However, plasma levels of oxytocin and vasopressin do not reliably reflect the levels in the brain. Brain hormone levels are best measured via cerebrospinal fluid (CSF), which requires a lumbar puncture. Studies have consistently shown that both oxytocin and vasopressin levels are reduced in the CSF of individuals with autism. These reductions highlight potential deficiencies in the central signaling pathways of these hormones.

 

Dysfunctional Receptors

The dysfunction in autism may not only involve reduced hormone levels but also abnormalities in their receptors.

• Oxytocin Receptors (OXTR): Variations in the oxytocin receptor gene have been linked to autism, potentially leading to reduced receptor sensitivity or signaling efficiency. Dysfunctional oxytocin receptors can impair bonding, trust, and other social behaviors.
• Vasopressin Receptors: Vasopressin exerts its effects through several receptor subtypes:
• V1a Receptors: Involved in social behavior regulation.
• V1b (also known as V3) Receptors: Primarily located in the anterior pituitary, these receptors influence the release of adrenocorticotropic hormone (ACTH) and are implicated in stress responses.
• V2 Receptors: Regulate water retention in the kidneys.

Alterations in these receptors, especially V1a and V1b, may contribute to the social and stress-related symptoms observed in autism.

 

Therapeutic Options and Their Limitations

Addressing these hormonal and receptor dysfunctions offers promising avenues for therapeutic intervention, though challenges remain:

• Increasing Hormone Levels in the Brain. Enhancing oxytocin or vasopressin concentrations in the brain could improve social behaviors. Measuring the efficacy of these interventions is difficult because CSF sampling is invasive.
• Receptor Activation. Drugs designed to activate oxytocin or vasopressin receptors directly could bypass issues with hormone levels. However, such therapies need precise targeting to avoid side effects and ensure effectiveness.

 

Delivery Methods

Various delivery methods have been explored to introduce oxytocin or vasopressin into the body:

Intranasal Spray: Widely researched, intranasal delivery targets the brain directly via the nasal mucosa. However, this method is challenging because the drug is not meant to be inhaled into the lungs. Instead, it must cross the nasal membrane or travel along the olfactory or trigeminal nerves directly to the brain. Only specific molecules can effectively cross the blood-brain barrier, typically those that are small and lipophilic. Stanford University has conducted groundbreaking work using intranasal vasopressin in autism, demonstrating potential improvements in social behavior. However, many commercially available nasal sprays may lose their effectiveness because the active hormones degrade during transit if not properly chilled.

Nebulizer: Recent studies have investigated the use of nebulized vasopressin, delivering the hormone in aerosol form for inhalation. This method may offer more consistent dosing and better absorption while avoiding the challenges of nasal delivery.

Tablet by Mouth: Oral administration faces challenges because these hormones can degrade in the digestive system and may not cross the blood-brain barrier effectively. Vasopressin, for instance, cannot be taken orally due to rapid degradation. However, desmopressin, a synthetic analog of vasopressin, is orally bioavailable and can be used to treat conditions like diabetes insipidus.

Interestingly, desmopressin appears to help some individuals with autism, possibly due to its effects on water retention and central nervous system signaling. The nasal spray form of desmopressin offers rapid absorption compared to tablets, but tablets provide more convenient and consistent dosing.

Probiotic by Mouth. Human research suggests that specific strains of Lactobacillus reuteri can stimulate oxytocin production. These probiotics may offer a novel and non-invasive therapeutic option to enhance oxytocin levels naturally. Biogaia Protectis is one such oxytocin-stimulating probiotic.

 

Recent Advances: Nebulized Vasopressin for Social Deficits in Autism

Research conducted by scientists from Florida Institute of Technology, Stanford, and other institutions has revealed that supplementing vasopressin in low-social rhesus monkeys improves social behaviors and facial recognition without increasing aggression. These findings highlight the potential of vasopressin as a precision therapy for addressing core social deficits in autism.

The study focused on low-social rhesus monkeys, which exhibit behaviors similar to certain social impairments observed in humans with autism. The researchers used a nebulizer to administer vasopressin, a non-invasive and targeted delivery method. The monkeys voluntarily inhaled the hormone while drinking grape juice, ensuring an effective and stress-free administration. The point to note is that monkeys need to breath through their nose for the therapy to work, hence the drink.

Key findings include:

• Improved Prosocial Behavior. Vasopressin enhanced affiliative behaviors and facial recognition memory in low-social monkeys without increasing aggression, addressing a common concern from earlier studies in neurotypical animals.
• Precision Medicine Potential. Researchers observed that individuals with the lowest vasopressin levels derived the greatest benefit, suggesting the importance of tailoring treatments to specific biological deficiencies.
• Successful Central Nervous System Targeting. The study verified that nebulized vasopressin reached the central nervous system, a critical factor for its efficacy in enhancing social cognition.

These results offer a promising path forward, especially since one of the study’s co-authors is already working on translating these findings to human trials. If successful, this approach could modernize autism treatment by targeting an underlying hormonal deficiencies.

 

Why approved therapies remain elusive

Despite the promising science, no therapies targeting oxytocin or vasopressin have yet gained widespread approval for treating autism. The reasons for this include:-

• Challenges in Delivery Systems. Ensuring that sufficient amounts of oxytocin or vasopressin reach the brain remains a significant hurdle. Many delivery systems, such as nasal sprays, face degradation of the active hormone during transit or storage, limiting their effectiveness.
• Variable Responses. Hormonal therapies may yield inconsistent results due to genetic differences, baseline hormone levels, or receptor functionality among individuals.
• Complexity of ASD. Autism is a highly heterogeneous condition with diverse underlying causes, making it challenging to develop a one-size-fits-all treatment.

 

Over-the-counter (OTC) therapies also face criticism for their lack of rigorous testing and quality control. Many users report limited or no benefits, likely due to suboptimal dosing, poor bioavailability, or degraded products. These failures underscore the need for precision medicine approaches and robust clinical evidence to guide treatment.

 

Conclusion

While hormonal and receptor dysfunctions involving oxytocin and vasopressin present significant hurdles, they also offer unique opportunities for targeted interventions. Current therapies and delivery methods are promising but require further refinement to maximize their effectiveness. Recent advances, such as the use of nebulized vasopressin, demonstrate the potential for precision therapies to address core social deficits in autism. Future research into the relationship between these hormones and autism may unlock more personalized and effective treatments, bringing hope to those affected by these challenges. 

Many people have a nebulizer at home - we have had one for 15 years. They are very simple to use, even with a young child with severe autism. If the vasopressin, or oxytocin therapy was once a week for 5 minutes it would be a simple process. The trick would be ensuring breathing through the nose, rather than mouth, which you would normally be encouraging for drugs to reach the lungs. With the monkeys they added a straw and a favourite drink.

Vasopressin has to be kept between 2 and 8 celsius (36-46F). So you would get it from the local pharmacy, measure the dose, add saline solution and turn on the nebulizer. Do not try to buy it online, it will not work! It looks they have already started using this method at Stanford.  

If it works on a rhesus monkey, there is a good chance it will work on your own little monkey—and, of course, for our many adult Aspie readers.