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. 

 

Out with the old and in with the new? Maybe for iPhones but not for Autism therapies

 

It is important to move with the times, but it is equally important to realize that some old ideas remain better than some new ideas.

I was both pleased and surprised that my new car came with a full sized spare wheel in the boot/trunk. Where we live you can expect at least one puncture a year. In theory you do not need a spare wheel because cars rarely have punctures and you can carry an aerosol spray that will temporarily inflate the tire and fill a small hole. Some cars have skinny space-saver spare wheels. Neither of these is actually a good alternative.  

Old vs new autism therapies

People definitely are interested in new and “cutting edge” therapies for autism.

I was recently contacted again by a reader of this blog who has been struggling to control self injurious behaviors in her child for years. I have provided many ideas that have each worked a sub-group of those with SIB. One idea I had not yet suggested was Memantine/Namenda.

Memantine is a cheap, old, and not very effective Alzheimer’s drug.

It blocks NMDA receptors in the brain to prevent excessive stimulation by glutamate. It does actually have many other modes of action.

It has weak inhibitory effects on L-type calcium channels that add to its neuroprotective profile. This secondary mechanism helps regulate calcium influx, protect neurons from excitotoxicity, and mitigate oxidative stress, making it beneficial for managing various neurodegenerative and excitotoxic conditions.

Memantine has mild inhibitory effects on AMPA receptors, reducing overall excitotoxicity.

Memantine may block certain sodium ion channels, which can reduce neuronal excitability and help prevent excitotoxicity.

Memantine has been found to interact with serotonin (5-HT3) receptors, modulating their activity, which might contribute to cognitive and mood improvements.

Memantine reduces microglial activation, which is associated with neuroinflammation. This anti-inflammatory action can protect against secondary neuronal damage in neurodegenerative conditions.

By preventing excessive calcium influx through NMDA receptors, memantine reduces the production of reactive oxygen species (ROS), protecting neurons from oxidative damage.

Memantine's ability to stabilize calcium homeostasis helps maintain mitochondrial function, reducing energy deficits and apoptosis (programmed cell death).

Memantine may enhance synaptic plasticity by reducing pathological over activation of glutamate receptors. This improves synaptic connectivity and cognitive function.

Some studies suggest that memantine may partially activate or modulate nicotinic acetylcholine receptors, which are important for attention and memory.

Memantine may increase brain-derived neurotrophic factor (BDNF) levels, promoting neuronal survival and plasticity.

Memantine as a treatment for SIB in some, but a cause of it in others

It is clear from the above summary of Memantine’s modes of action that it should indeed be effective for some people’s SIB (self injurious behavior). Unfortunately, all these changes in the excitatory-inhibitory balance can cause problems in some other people where Memantine actually causes SIB.

Too much glutamate can be very damaging

Glutamate excitotoxicity refers to the pathological process in which excessive activation of glutamate receptors, particularly NMDA and AMPA receptors, leads to over-excitation of neurons. This over-excitation can result in cellular dysfunction, oxidative stress, and ultimately neuron death. It is a common mechanism underlying many neurological and neurodegenerative conditions.

NMDA and AMPA receptors, over activated by the high levels of glutamate, trigger a massive influx of calcium (Ca²⁺) ions into neurons.

High intracellular Ca²⁺ levels disrupt cellular homeostasis. It activates enzymes that damage cellular structures it causes oxidative stress, mitochondrial dysfunction and eventually cell death.

Elevated intracellular Ca²⁺ from allergy causing elevated glutamate and SIB

As we know from this blog, some SIB is triggered by allergy. You can halt it via treating the allergy, blocking the L-type calcium channels or targeting other inflammatory pathways.

In this allergy-driven self injurious behavior (SIB), glutamate is likely a significant downstream effector. Allergic reactions and inflammation can disrupt calcium homeostasis and activate pathways that increase glutamate signaling, leading to heightened excitotoxicity and contributing to behaviors such as SIB.

Allergic reactions significantly impact calcium homeostasis, primarily through the activation of immune cells, release of inflammatory mediators, and systemic effects on calcium metabolism. These disruptions contribute to the symptoms and complications of allergic diseases and highlight potential therapeutic targets to restore calcium balance.

When allergens bind to IgE on mast cells or basophils, they activate receptors that trigger intracellular calcium release from the endoplasmic reticulum (via IP3 signaling). Recall Prof Gargus proposed IP3 signaling as a nexus point in autism.

Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?

This calcium influx promotes the degranulation of histamine, serotonin, and other inflammatory mediators.

Abnormal calcium levels may trigger unregulated, spontaneous release of glutamate, even in the absence of an action potential.

Elevated calcium levels can impair the function of glutamate transporters (e.g., EAATs), responsible for clearing excess glutamate from the synaptic cleft.

Dysfunctional transporters exacerbate extracellular glutamate accumulation, amplifying excitotoxicity.

Memantine in broader autism

Memantine was extensively studied in a large clinical trial in autism that concluded that it was no better than a placebo.

You might well conclude that the matter should end there.

Memantine for Aspies

While looking for information about Memantine for SIB I came across some very positive reviews from Aspies.

If you believed social media you would think that people with level 1 autism are all anti-treatment and see autism as their superpower. In fact the majority of people contacting me about treating autism are actually those with level 1 autism and their parents.

I am really much more familiar with treatments for level 3 autism.

The symptoms may be slightly different, but the potential therapies are exactly the same.

 

https://www.drugs.com/comments/memantine/for-autism.html

"A life saver. I have autism. It is pretty bad autism. I saw help on day one. But it isn't a fix-it-all for me. Being able to understand nonverbal communication and verbal communication is huge improvements. This helps me with social interaction. This helps me with anxiety. Helps my expressive myself and respond better. Less meltdowns. Helps my cognitive functions. Helps me think. Helps my thought issue due to my autism and auditory processing disorder. Helps me slow down my mind to pay attention more and can respond to changes and sensory problems. Not a full fix for me but huge help. I am more polite. I can talk about others' interests not just my needs or wants or questions that I had trouble asking. Better behavior." 

"I was first prescribed this for Asperger's syndrome at the age of 24. I've been on numerous types of medications since I was a teenager, but this is the first one that I've been on that has significantly helped. My quality of life is much better. I don't have as many ruminating, obsessive thoughts that make me miserable." 

"I take 20 mg of memantine for my slight autism! And this has been a miracle drug! It helps me in social interactions, I can recognize social cues and skills that I couldn't before! It also helps with my obsessive and aggressive problems! Thank you to whoever made this drug." 

"I take 10 mg twice daily for autism spectrum disorder. It stops the intrusive thoughts, rumination, and repetitive thinking, which is a godsend. It also reduces repetitive behavior/stereotypes. I haven't noticed any side effects, maybe a little brain fog, but that has disappeared with continued use."

"Memantine has helped my social anxiety greatly, not through direct anxiolysis, but indirectly through dissociation from reality, albeit mild. It works perfectly for sensory overload as the autistic brain does not filter out unnecessary external stimuli due to NMDAR current blockade, similar to endogenous magnesium. Amazing, wonderful."

 

Conclusion

Don’t ignore all the therapies from the last 50 years and jump to the latest expensive therapy that is trending. You may after all find one of the oldies like Propranol, Pentoxifylline, Zoloft, Baclofen or Memantine is your Gamechanger. They each worked for some people.

Even though it failed in its phase 3 clinical trial, Memantine continues to have its believers. It is a cheap safe drug that clearly does provide a benefit to a sub group of autism that includes all levels of severity. It clearly does not work for all Aspies, but it certainly is worth trialing.

I think understanding glutamate excitotoxicity is very useful if you are trying to figure out a case of self injurious behavior.

In individuals where the GABA developmental switch has not occurred, oral GABA supplementation could potentially exacerbate glutamate excitotoxicity and trigger/worsen self injurious behavior. These are the people who react badly to benzodiazepine drugs and should respond very well to bumetanide.

Clonidine and Guanfacine for ADHD, mast cell activation, sleep disorders, tics and some self-injurious behavior (SIB)

 

Both clonidine and guanfacine were raised recently to me, they have been covered in various earlier posts and in my book. Here is a round-up of the information.

These two drugs are α2A-adrenergic receptor agonists originally used to treat high blood pressure. Subsequently many additional uses of these drugs have been discovered.

I was asked about its use to treat mast cell activation syndrome (MCAS) and the mechanism by which it achieves this effect is interesting.

Calming mast cells – the ones that release histamine during an allergic reaction

Clonidine/guanfacine, as alpha-2 adrenergic agonists, inhibit mast cells primarily by interacting with the central and peripheral nervous systems, leading to a decrease in the release of inflammatory mediators. Its mechanism involves stimulating alpha-2 adrenergic receptors, which in turn suppresses the release of norepinephrine and other neurotransmitters.

In terms of mast cell stabilization, clonidine/guanfacine is thought to reduce intracellular calcium levels and inhibit the degranulation process that releases histamine and other pro-inflammatory substances. Lower intracellular calcium prevents the activation of key signaling pathways that normally trigger mast cell activation and degranulation.

This stabilizing effect helps prevent excessive allergic and inflammatory responses, making clonidine/guanfacine beneficial in conditions where such inhibition is useful.

Clonidine/guanfacine have some calcium channel-blocking properties, though they are not classified as a traditional calcium channel blocker. By indirectly lowering intracellular calcium levels, clonidine/guanfacine inhibit the signaling pathways that lead to mast cell degranulation and the release of inflammatory mediators. The end result is a reduction in cellular excitability and a dampening of the inflammatory response, including mast cell stabilization.

Clearly, you could just go directly to a calcium channel blocker like verapamil.

Clonidine/guanfacine and indeed verapamil are not seen as first line treatments for MCAS but may well be beneficial.

Conventional First-Line Treatments for MCAS

Antihistamines

H1 blockers (e.g., cetirizine, loratadine) to manage allergic-type symptoms like itching, hives, and flushing.

H2 blockers (e.g., famotidine, ranitidine) to control gastrointestinal symptoms and histamine release in the stomach.

Mast Cell Stabilizers

Cromolyn sodium is often considered one of the most effective mast cell stabilizers for MCAS, especially for gastrointestinal symptoms.

Ketotifen, another mast cell stabilizer with antihistamine properties, can also be helpful.

Rupatadine and azelastine are also potentially beneficial as mast cell stabilizers.

Leukotriene Inhibitors

Medications like montelukast can help manage symptoms related to leukotrienes, which are other mediators released by mast cells.

Aspirin

Aspirin can play a role in managing MCAS, particularly in controlling specific symptoms like flushing, hives, and inflammation. Its primary action in MCAS involves inhibiting prostaglandin D2 (PGD2), which is one of the inflammatory mediators released by mast cells and contributes to the vascular symptoms seen in MCAS.

Sleep disorders

Some people with autism do not sleep well.

Clonidine/guanfacine can help some individuals fall asleep faster and stay asleep longer by promoting relaxation and calming overactivity in the brain.

It is sometimes used in pediatric populations, such as children with autism or ADHD, to help with sleep initiation and minimize frequent nighttime awakenings.

Clonidine/guanfacine, being alpha-2 adrenergic agonists, lower the activity of the sympathetic nervous system (the fight-or-flight response).

Clonidine/guanfacine is typically prescribed at a low dose for sleep, as higher doses can lead to daytime drowsiness. Taking clonidine at night, about 30-60 minutes before bed, is common practice.

Guanfacine has a longer half-life than clonidine, which means it provides a more sustained effect throughout the night and may lead to fewer night-time awakenings. This can be particularly useful for individuals who need consistent support for sleep through the night.

Tics

Clonidine/guanfacine have long been used off-label to treat Tourette’s syndrome, which is a tic disorder.

Clonidine/guanfacine can help manage some stereotypical behaviors (repetitive, non-functional behaviors) in individuals with autism, when these behaviors are driven by hyperactivity, impulsivity, or anxiety.

Clonidine/guanfacine helps manage tics by calming the nervous system, modulating norepinephrine release, reducing stress, and helping with impulse control.

This effect has been noted by our reader AW.

Self-injurious behavior (SIB)

Self-injurious behavior (SIB) is usually considered the worst feature of autism. It becomes a learned behavior which can be very hard to extinguish.

Clonidine/guanfacine is on the long list of sometimes effective therapies. Take a note of this!

 

Clonidine as a Treatment of Behavioural Disturbances in Autism Spectrum Disorder: A Systematic Literature Review

Clonidine has a limited evidence base for use in the management of behavioural problems in patients with ASD. Most evidence originates from case reports. Given the paucity of pharmacological options for addressing challenging behaviours in ASD patients, a clonidine trial may be an appropriate and cost-effective pharmaceutical option for this population.

Beneficial Effects of Clonidine on Severe Self-Injurious Behavior in a 9-Year-Old Girl with Pervasive Developmental Disorder

ADHD

ADHD is very commonly diagnosed these days.

The genes involved in ADHD, autism, bipolar and schizophrenia are overlapping, so it is not surprising that many people are now being diagnosed with both ADHD and autism.

What I find very odd is that people with ADHD line up for medical treatment, but most people with comorbid autism think there cannot be a medical treatment for their autism because it is just how their brain is “wired-up differently.” It is hard to reconcile these views - both conditions are clearly treatable.

Most ADHD treatments are stimulants. Medications like methylphenidate (Ritalin, Concerta) and amphetamine-based drugs (Adderall, Vyvanse) are typically considered first-line treatments for ADHD. They work by increasing levels of dopamine and norepinephrine in the brain, which help improve focus, attention, and impulse control in people with ADHD.

Not all individuals with ADHD can tolerate stimulants, and in some cases, they may experience unwanted side effects like anxiety, sleep disturbances, or increased irritability.

The most common non-stimulant options are Clonidine and Guanfacine. They does not directly increase dopamine or norepinephrine but instead reduces norepinephrine release, promoting a calming effect.

Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor (NRI), which increases norepinephrine in the brain by blocking its reuptake.

After years of off-label use in by 2010 both clonidine and guanfacine were FDA approved for use in ADHD.

 

Conclusion

As I mentioned to one reader, we should take note that both clonidine and guanfacine are approved for use in children (with ADHD) and so there is plenty of safety information and dosage guidance.

The effective dose for MCAS, sleep disorders, tics and SIB may well vary from person to person but the safe boundaries are well established from ADHD.

In general, guanfacine tends to be better tolerated than clonidine.

AW might note that guanfacine can cause sleep problems, including insomnia or vivid dreams.

Here is a useful list I found:

Common Side Effects:

Sedation/Drowsiness: Like clonidine, guanfacine can cause drowsiness, especially during the initial stages of treatment or when the dose is increased.

Fatigue: Many people report feeling fatigued or tired when starting guanfacine, which can affect daytime functioning.

Low Blood Pressure (Hypotension): Guanfacine also lowers blood pressure, potentially leading to dizziness or light-headedness, particularly when standing up quickly.

Dry Mouth: This is another common side effect, similar to clonidine, and may cause discomfort.

Headache: Some people experience headaches, especially when starting treatment.

Stomach Problems (e.g., abdominal pain, constipation): Gastrointestinal side effects can occur in some individuals, such as constipation or stomach discomfort.

Irritability and Mood Swings: In some cases, guanfacine may cause irritability or emotional instability.

Less Common but Serious Side Effects:

Bradycardia (slow heart rate): As with clonidine, guanfacine can cause a slow heart rate, which could be concerning for individuals with underlying heart issues.

Rebound Hypertension: Discontinuing guanfacine too abruptly can cause rebound hypertension (a sudden increase in blood pressure), so it should be tapered gradually under a healthcare provider’s guidance.

Sleep disturbances: In some cases, though less common than with clonidine, guanfacine can cause sleep problems, including insomnia or vivid dreams.

The role of the microbiome in aggression. Gut microbe imbalances that predict autism and ADHD. Biogaia trial for Autism.

 

By December 2020 7.3% of the Swedish cohort born in 1997-9 had been diagnosed with a Neurodevelopmental Disorder (ND). This can be predicted by samples previously collected.

Today’s post is all about the microbiome and covers three different areas covered recently in the research. Eight years after I wrote a post about our informal trial of Biogaia probiotics for autism, we now have a published paper.

Aggression and self injurious behavior (SIB) affects at least half of those diagnosed with level 3 autism at some point in their lives. SIB can become the overriding concern for care givers.

Our first paper looks at the role of the microbiome in aggression.

Gut-brain axis appears to play a critical role in aggression

A series of experiments on mice has found that they become more aggressive when their gut microbiome is depleted. Additionally, transplanting gut microbiota from human infants exposed to antibiotics led to heightened aggression in mice compared to those receiving microbiome transplants from non-exposed infants. The research was published in Brain, Behavior, and Immunity.

In the past decade, scientists have discovered a complex communication pathway linking gut microbiota—the trillions of microorganisms living in the human gut—with the brain. This pathway is called the microbiota-gut-brain axis. It regulates various physiological functions, including digestion and immunity, but also affects mood and behavior. The gut microbiota produces neurotransmitters and other metabolites that can influence brain function through neural, immune, and endocrine pathways.

Recent studies have demonstrated that symptoms of various disorders, once considered primarily psychological or neurological, can be transferred to rodents by transplanting gut microbiota from humans with these disorders. For example, researchers have shown that transplanting gut microorganisms from people with Alzheimer’s disease into mice (whose gut microbiota had been depleted to enhance transplant effectiveness) resulted in cognitive impairments in the mice. Similarly, symptoms of anxiety have been induced in mice by transplanting gut microbiota from humans with social anxiety.

For the humanized mice, the researchers obtained fecal samples from infants who had been exposed to antibiotics shortly after birth, as well as from unexposed infants. These samples were transplanted into five-week-old germ-free mice. The researchers then waited for four weeks before testing the mice for aggression.

To measure aggression, the researchers employed the resident-intruder test, a well-established behavioral assay in which a male mouse (the “resident”) is introduced to another unfamiliar male mouse (the “intruder”) in its home cage. Aggression was quantified based on the latency to the first attack (how quickly the resident mouse attacked the intruder) and the total number of attacks during a 10-minute period.

The results showed that mice raised without gut bacteria (germ-free) and those treated with antibiotics exhibited higher levels of aggression compared to the control group. These mice attacked more frequently and were quicker to initiate aggressive behavior in the resident-intruder test.

The researchers found that humanized mice receiving fecal microbiota from antibiotic-exposed infants were significantly more aggressive than those receiving transplants from non-exposed infants. Even though the infants’ microbiomes had a month to recover after antibiotic exposure, the aggressive behavior was still evident in the recipient mice.

Biochemical analyses revealed that aggressive mice (both germ-free and antibiotic-treated) had distinct metabolite profiles compared to control mice. Specifically, levels of tryptophan—a precursor to serotonin, a neurotransmitter associated with mood and behavior—were elevated in these mice. Additionally, the levels of certain metabolites associated with microbial activity, such as indole-3-lactic acid, were reduced in the aggressive mice, suggesting that the absence of a healthy microbiome might alter key biochemical pathways involved in aggression.

Here is the link to the original paper:

A gut reaction? The role of the microbiome in aggression

Recent research has unveiled conflicting evidence regarding the link between aggression and the gut microbiome. Here, we compared behavior profiles of control, germ-free (GF), and antibiotic-treated mice, as well as re-colonized GF mice to understand the impact of the gut microbiome on aggression using the resident-intruder paradigm. Our findings revealed a link between gut microbiome depletion and higher aggression, accompanied by notable changes in urine metabolite profiles and brain gene expression. This study extends beyond classical murine models to humanized mice to reveal the clinical relevance of early-life antibiotic use on aggression. Fecal microbiome transplant from infants exposed to antibiotics in early life (and sampled one month later) into mice led to increased aggression compared to mice receiving transplants from unexposed infants. This study sheds light on the role of the gut microbiome in modulating aggression and highlights its potential avenues of action, offering insights for development of therapeutic strategies for aggression-related disorders

Note the ABX means antibiotics

We include a study of humanized mice using unique fecal samples of 1-month-old infants, collected nearly a month after early-life ABX administration. In previous work (Uzan-Yulzari et al. 2021, Nat Comm), we have demonstrated that ABX in this critical period of life can have lasting effects of childhood growth. Here, we extend these findings using samples from the same cohort. Using fecal samples collected weeks after ABX administration also reduces the direct chemical effects of ABX on the host, highlighting the causative role of the dysbiotic host microbiome and associated metabolome in driving aggressive behavior. We demonstrate that infant microbiota, perturbed within the first 48 h of life, has a lasting signature through 1 month of age that, when transplanted into GF mice, results in increased aggression (3–5 weeks after transplant) when compared to effects of stools of infants not exposed to any early-life antibiotics. The findings are revolutionary as they show how ABX-altered microbiota during a critical development window can lead to persisting behavioral deficits.

 

Gut microbe imbalances could predict a child’s risk for autism, ADHD and speech disorders years before symptoms appear.

Study Identifies Gut Microbe Imbalances That Predict Autism And ADHD

We are researchers who study the role the microbiome plays in a variety of conditions, such as mental illness, autoimmunity, obesity, preterm birth and others. In our recently published research on Swedish children, we found that microbes and the metabolites they produce in the guts of infants – both found in poop and cord blood – could help screen for a child’s risk of neurodevelopmental conditions such as autism. And these differences can be detected as early as birth or within the first year of life. These markers were evident, on average, over a decade before the children were diagnosed. 

The imbalance in microbial composition – what microbiologists call dysbiosis – we observed suggests that incomplete recovery from repeated antibiotic use may greatly affect children during this vulnerable period. Similarly, we saw that repeated ear infections were linked to a twofold increased likelihood of developing autism.

Children who both repeatedly used antibiotics and had microbial imbalances were significantly more likely to develop autism. More specifically, children with an absence of Coprococcus comes, a bacterium linked to mental health and quality of life, and increased prevalence of Citrobacter, a bacterium known for antimicrobial resistance, along with repeated antibiotic use were two to four times more likely to develop a neurodevelopmental disorder.

Antibiotics are necessary for treating certain bacterial infections in children, and we emphasize that our findings do not suggest avoiding their use altogether. Parents should use antibiotics if they are prescribed and deemed necessary by their pediatrician. Rather, our study suggests that repeated antibiotic use during early childhood may signal underlying immune dysfunction or disrupted brain development, which can be influenced by the gut microbiome. In any case, it is important to consider whether children could benefit from treatments to restore their gut microbes after taking antibiotics, an area we are actively studying.

Another microbial imbalance in children who later were diagnosed with neurodevelopmental disorders was a decrease in Akkermansia muciniphila, a bacterium that reinforces the lining of the gut and is linked to neurotransmitters important to neurological health.

Even after we accounted for factors that could influence gut microbe composition, such as how the baby was delivered and breastfeeding, the relationship between imbalanced bacteria and future diagnosis persisted. And these imbalances preceded diagnosis of autism, ADHD or intellectual disability by 13 to 14 years on average, refuting the assumption that gut microbe imbalances arise from diet.

We found that lipids and bile acids were depleted in the cord blood of newborns with future autism. These compounds provide nutrients for beneficial bacteria, help maintain immune balance and influence neurotransmitter systems and signaling pathways in the brain.

The full paper is here: 

Infant microbes and metabolites point to childhood neurodevelopmental disorders 

Highlights

• Infant microbes and metabolites differentiate controls and future NDs

• Early-life otitis lowers Coprococcus and increases Citrobacter in future NDs

• Preterm birth, infection, stress, parental smoking, and HLA DR4-DQ8 increase ND risk

• Linolenic acid is lower and PFDA toxins higher in the cord serum of future ASD

Summary

This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early-life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immune-dysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment.

ABIS = All Babies in Southeast Sweden cohort

NDs = Neurodevelopmental disorders

Young children later diagnosed with ASD or exhibiting significant autistic traits tend to experience more ear and upper respiratory symptoms. In ABIS, infants who had otitis in their first year were found to be more prone to acquiring NDs if they lacked detectable levels of Coprococcus or harbored Citrobacter. The absence of Coprococcus, despite comparable levels in controls irrespective of otitis, raises questions about microbial community recovery. This potential failure of the microbiome to recover following such events may serve as a mechanism connecting otitis media to ND risk. Moreover, antibiotic-resistant Citrobacter was more prevalent in these infants. The presence of strains related  to Salmonella and Citrobacter, labeled in this investigation as SREB, was significantly higher in infants who later developed comorbid ASD/ADHD (21%), compared to controls (3%). This disruption may have consequences on neurodevelopment during a critical period. Salmonella and Citrobacter have shown the ability to upregulate the Wingless (Wnt) signaling. The Wnt pathway is vital for immune dysregulation and brain development, and its disruption has been implicated in ASD pathogenesis. 

Two fatty acid differences were notable in the stool of future ASD versus controls: omega-7 monounsaturated palmitoleic acid, (9Z)-hexadec-9-enoic acid (below the level of detection in 87.0% of future ASD but present in 43.5% of controls), and palmitic acid (elevated in future ASD). Palmitoleic acid has been associated with a decreased risk of islet and primary insulin autoimmunity. Conversely, palmitic acid, a saturated fatty acid, has been linked to neuronal homeostasis interference. Its effects are partially protected by oleic acid, which although approaching significance, was lower in the cord serum of future ASD.

Few metabolites were higher in stool of infants with future ASD, but there are a few notable examples: α-d-glucose, pyruvate, and 3-isopropylmalate. Coprococcus inversely correlated with 3-isopropylmalate, suggesting gut-brain connections and a possible imbalance in branched-chain amino acid (BCAA) pathways given the role of 3-isopropylmalate dehydrogenase in leucine and isoleucine biosynthesis. An increase in dehydroascorbate suggests potential disruptions in vitamin C metabolism, crucial for neurotransmitter synthesis and antioxidant defense, while elevated pyruvate suggests disturbance of neurotransmitter synthesis or energy production early in life. Pimelic acid elevation, found in disorders of fatty acid oxidation, suggests disruption of mitochondrial pathways for fatty acid oxidation.

Akkermansia and Coprococcus, absent or reduced in infants with future NDs, positively correlated with signals in stool representing neurotransmitter precursors and essential vitamins in stool. Specifically, Akkermansia correlated with tyrosine and tryptophan (i.e., catecholamine and serotonin precursors, respectively) and Coprococcus with riboflavin. Disruption of BCAA metabolism in ASD has been documented, involving coding variants in large amino acid transporters (LATs) and reduced utilization of trypotphan and large aromatic amino acids along with increased glutamate and decreases in tyrosine, isoleucine, phenylalanine, and tryptophan in children with ASD. Oxidative stress, a diminished capacity for efficient energy transport, and deficiencies in vitamins (like vitamin B2) essential for neurotransmitter synthesis and nerve cell maintenance have been implicated. Riboflavin as an antioxidant reduces oxidative stress and inflammation, demonstrating neuroprotective benefits in neurological disorders, possibly through maintenance of vitamin B6, which is necessary for glutamate conversion to glutamine and 5-hydroxytryptophan to serotonin.

Together, these findings support a hypothesis of early-life origins of NDs, mediated by gut microbiota. This provides a foundation for research and for developing early interventions for NDs.

 

Today’s final paper was highlighted recently in a comment on a post I wrote eight years ago, when we were trialing Biogaia probiotics. This original interest was prompted by a reader sharing her successful experiences of treating her son with severe autism. Perhaps she left the recent comment?

The two bacteria involved are both types of L. reuteri.

L. reuteri 6475 is sold as Biogaia Osfortis

L. reuteri 17938 is sold Biogaia Protectis

The combination of L. reuteri 17938 and L. reuteri 6475 is sold as Biogaia Gastrus.

My old post from 2016:-

Epiphany: Biogaia Trial for Inflammatory Autism Subtypes

The recently published trial:

Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial -

Highlights

• L. reuteri (6475 + 17938) improves social functioning in children with autism

• L. reuteri does not improve overall autism severity or repetitive behaviors

• L. reuteri does not significantly alter microbiome composition or immune profile

•  Only the 6475 strain reverses the social deficits in a mouse model for autism

we performed a double-blind, randomized, placebo-controlled, parallel-design pilot trial in children with ASD. Importantly, we found that L. reuteri, compared with placebo, significantly improved social functioning, both in terms of reducing social deficits, as measured by the social responsiveness scale (SRS^31,32), and increasing adaptive social functioning, as measured by the social adaptive composite score of the Adaptive Behavior Assessment System, Second Edition (ABAS-2³³). L. reuteri did not improve overall autism severity, restricted and repetitive behaviors, and co-occurring psychiatric and behavioral problems, nor did it significantly modulate the microbiome or immune response. Thus, this safe microbial manipulation has the potential for improving social deficits associated with ASD in children.

I had to amend my old post with a warning long ago.

UPDATE: A significant minority of parents report negative reaction to Bio Gaia, this seems to relate to histamine; but more than 50% report very positive effects without any side effects; so best to try a very small dose initially to see if it is not well tolerated. 

Histamine Reaction to BioGaia gastrus

Conclusion

The gut microbiota does indeed play a key role in how your brain functions, but the gut-brain axis works in both directions. What goes on in your brain can affect your gut and not just the other way around. It is called bidirectional signaling.

Antibiotics taken during pregnancy, or during early childhood, will have unintended consequences. Often there is no choice, like for those readers whose baby experienced sepsis at birth (bacterial blood stream infection); you have to give antibiotics to avoid death.

In today’s second paper we see that the researchers are thinking about therapeutical implications. Perhaps the newborn’s gut flora should be repopulated during the weeks after the antibiotic treatment?

I receive many questions about how to treat self injurious behavior that does not respond to anything the doctor has prescribed. Rifaximin, an antibiotic used to treat irritable bowel syndrome with diarrhea, is one therapy that does help some types of SIB (and SIBO, small intestinal bacterial overgrowth, of course). This probably would not surprise the authors of today’s first paper.

Biogaia Gastrus (L. reuteri 6475 + 17938) from today’s third paper worked wonders for the SIB of one reader’s child.

Not surprisingly fecal microbiota transplantation (FMT) can improve SIB in some people.

The Swedish data shows interesting insights such as that lipids and bile acids were depleted in the cord blood of newborns with future autism. The researchers think they can predict the diagnosis of autism or ADHD. The question is and then what? Even when there is a diagnosis of autism, not much changes for most children.

Is it safe to treat autism in very young children? Plus, the impact of impaired autophagy on cognition and treating SIB

This blog is full of clinical trials that use existing drugs that are repurposed to treat autism. One constant issue is whether the trial drug is free from side effects. Generally speaking side effects tend not to be a problem, but there always can be exceptions.

I was recently contacted by the parents of a two year old with a single gene (monogenic) type of autism and they want to treat their child to improve his outcome.  This is the youngest case I have encountered.

With monogenic autisms you often have clear indications from a very early age that something unusual is present. Once you have a diagnosis you quickly discover what issues the child is going to face. You therefore have a good idea of what will happen if you do nothing. Some other two year olds have delayed speech and other signs of autism, but within a couple of years develop normally – it was a case of delayed maturation.

I noted long ago that American autism doctors tend to want to treat younger patients with supplements rather than drugs.

The reality is that the sooner you start to correct a severe biological dysfunction the better the outcome will be. We even see that some treatments are only effective if given to toddlers. This makes perfect sense although it may be uncomfortable to accept.

I was looking for supporting evidence for very early intervention. I found a glowing report of the treatment of a 2 year old with Fragile X syndrome using Metformin. I am amazed Fragile X still remains untreated in most cases.

On examination at age 2 years, typical physical features of FXS were observed, and baseline laboratory findings were normal (see Table Table1).1). He was started on metformin at 25 mg of the liquid form that is 100 mg/ml at dinner, and his dose was gradually increased to 200 mg twice a day (bid) over 1 year (see Table Table1).1). After initiation of metformin, his sleep disturbance resolved, only occasionally awakening once for roughly 30 min. Two weeks after initiation, he went from stacking 3–4 blocks to stacking a tower of 11 or more blocks; within a few more weeks, he began building more complex structures comprised of different size blocks. He showed marked improvement in self‐help and motor activities, including toilet training, clearing the table and loading the dishwasher, brushing his own teeth, dressing independently, and learning how to make toast. His preschool teachers, who were unaware of metformin treatment, told his mother that “it's like something just clicked or he just woke up. He's a whole different kid.”

Source: Metformin treatment in young children with fragile X syndrome

Some drugs including bumetanide are already safely given to babies.

Nonetheless, it is a brave step to start treatment in a two year old. I did connect the parents to a reader of this blog whose child has the same syndrome but is a few years older.

Today’s post was prompted by the news that the child is already showing improvements from the first therapy, which is a small dose of clemastine. In this syndrome there is a mutation in TCF4 and there is impaired myelination and very likely activated microglia (the brain’s immune cells). The near immediate beneficial effect cannot be on myelination, but it could be resetting microglia to the resting state.

Other genes very recently raised have been TRIT1 and PSMB9; neither of these are classed as autism genes, but evidently can cause it. Mutations in TRIT1 cause a problem in the mitochondria and PSMB9 mutations cause the immune system to misbehave.  It looks like both can lead to an autism diagnosis.

A common issue parents encounter is that often the interest shown by researchers and clinicians stops at the point of diagnosis. What really matters is what to do next. Only very rarely will such “experts” suggest what to do next. 

It looks like there nearly always are therapeutic avenues to pursue after such a diagnosis. It should be noted that even in single gene (monogenic) autisms there are varying levels of response to the same therapy. We saw this a while back with the new FDA approved therapy for Rett syndrome – it works for some, but not for others.

 

Treating self injurious behavior (SIB) in idiopathic autism

I recently received feedback from several parents who have had success in treating SIB based on ideas in this blog.

Verapamil came up again as successful.

Pioglitazone, at a low dose of 7.5mg, was the game changer for one child.

Ibuprofen worked in another case, but this cannot be used long term. Celecoxib should be better tolerated and in theory should be as effective. Time will tell.

More people are trying the add-on therapy of a small dose of taurine.

 

Macroautophagy as a cause of impaired cognition

Impaired autophagy came up recently in two people’s genetic testing results. There is a lot in this blog about autophagy and dementia/mild cognitive impairment.

Today we have a paper that links impaired autophagy with impaired cognition.

Twenty years ago severe autism generally also meant impaired cognition. Nowadays it does not; you can have severe autism with normal cognition.

There are various different types of autophagy but in general it is all about collecting bits of cellular garbage that might clog things up. As we get older this intracellular garbage collection process works less well and then diseases like Alzheimer’s follow decades later.

Impaired autophagy may contribute to impaired cognition at any age. Most research concerns dementia treatment, or other conditions affecting older people like Huntington’s disease.

There is little focus on younger populations, even though we know that children with Down syndrome are prone to get early onset Alzheimer’s. Treating young people with Down syndrome to improve autophagy might bring both short and long term benefits. 

Here is the recent paper on this subject. 

Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders

Autism spectrum disorder (ASD) represents a complex of neurological and developmental disabilities characterized by clinical and genetic heterogeneity. While the causes of ASD are still unknown, many ASD risk factors are found to converge on intracellular quality control mechanisms that are essential for cellular homeostasis, including the autophagy-lysosomal degradation pathway. Studies have reported impaired autophagy in ASD human brain and ASD-like synapse pathology and behaviors in mouse models of brain autophagy deficiency, highlighting an essential role for defective autophagy in ASD pathogenesis. To determine whether altered autophagy in the brain may also occur in peripheral cells that might provide useful biomarkers, we assessed activities of autophagy in lymphoblasts from ASD and control subjects. We find that lymphoblast autophagy is compromised in a subset of ASD participants due to impaired autophagy induction. Similar changes in autophagy are detected in postmortem human brains from ASD individuals and in brain and peripheral blood mononuclear cells from syndromic ASD mouse models. Remarkably, we find a strong correlation between impaired autophagy and intellectual disability in ASD participants. By depleting the key autophagy gene Atg7 from different brain cells, we provide further evidence that autophagy deficiency causes cognitive impairment in mice. Together, our findings suggest autophagy dysfunction as a convergent mechanism that can be detected in peripheral blood cells from a subset of autistic individuals, and that lymphoblast autophagy may serve as a biomarker to stratify ASD patients for the development of targeted interventions.

 

There are different types of autophagy and there are some overlaps. 

·      mTOR dependent (Fasting or Rapamycin)

·      AMPK dependent (Spermidine)

·      P53 dependent (no simple therapies)

·      Calcium signalling dependent (Verapamil)

The OTC way to increase autophagy is to use Spermidine, which is made from wheat germ or rice germ. Studies in humans are rather mixed and I think the dose is likely far too low. Supplements tend to contain about 1mg; I suspect you need much more to have an impact. You can indeed grow your own wheat sprouts which are highly nutritious and a rich source of spermidine. You can eat them raw or even in smoothies. 100 g of sprouts contains 10-15mg of spermidine.

The most researched calcium channel drug to induce autophagy is Verapamil, from my son’s original autism Polypill.

My takeaway continues to be to look for convergent mechanisms, like impaired autophagy, myelination, microglial activation etc that commonly occur in severe autism, of any origin. You then try and treat these likely dysfunctions rather than getting overly focused on individual genes.

 

Taurine – a cheap Autism intervention worth a trial

 

I did recently write a post all about Taurine and the many effects it has on the body, some of which really should affect autism. 

Taurine for subgroups of Autism? Plus, vitamin B5 and L Carnitine for KAT6A syndrome?

 

Having read the literature, it looked to me that anyone over 50 years old is likely to benefit from a little extra Taurine, but it certainly was not clear whether it would make my 21 year old’s autism better or worse. I went ahead and ordered some to investigate.

In theory one of the many effects of Taurine is negative. Taurine does affect the KCC2 transporter that takes chloride out of neurons the “wrong” way. The other effects include on calcium homeostasis, which we know is disturbed in most autism.

 

N = 2 Trial

Subject #1 (Peter)

I took 2g a day for a month and noticed no effect at all, other than some mild GI irritation.

In adults the long-term effects are numerous and varied throughout the body. Even the cells that remodel your bones (osteoblasts and osteoclasts) have special taurine transporters, whose sole role is to let taurine inside – taurine makes the osteoblasts work harder, while encouraging osteoclasts to take a break. The net effect should be stronger bones.  As you get older your natural levels of taurine fall substantially. There are taurine-rich foods you can eat and if you engage in strenuous exercise your liver starts making more taurine.

 

Subject #2 (Monty)

There is a clear contradiction when it comes to Taurine and sleep. Many energy drinks contain Taurine to keep you alert, but in theory Taurine should be calming and many people take it add bedtime to improve sleep.

Monty, aged 21 with ASD, likes getting up early and going to bed early.

Adding 2g a day of Taurine at breakfast shifted his circadian rhythms, so that he now goes to bed at a time typical for a 21 year old, but still wants to get up at 7am. Monty even fell asleep on the sofa watching TV late one night, something big brother often does. Indeed, Monty received a nod of approval when big brother discovered him in the early hours. 

The most beneficial change has been on his spring and summertime aggression. This has been controlled for years using an L-type calcium channel blocker. This does not resolve the allergy at all, but it “switches off” the consequential anxiety/aggression. With the addition of allergy therapies and the immunomodulation of Pioglitazone (in peak allergy season) the problem behaviors are controlled.

It appears that Taurine has a similar anti-anxiety/aggression effect. Maybe its effect on calcium channels and broader calcium homeostasis is the reason why. Anyway, it works – simple, cheap, OTC and effective.  It has no effect on allergy, in case you are wondering.

  

Conclusion

Taurine can be bought as a bulk powder for very little money. It is not like those numerous expensive supplements that would cost you several hundred dollars/euros/pounds a year.

If you have your own “healthspan polytherapy”, to ward off high blood pressure, high cholesterol, type 2 diabetes, dementia, arthritis, osteoporosis etc, consider spending a few pennies more and add a scoop of taurine.

The people who write to me and tell me how Verapamil has transformed life at home, by banishing aggression and self-injurious behaviors, should seriously consider a trial of Taurine.