We can do better.

Autistic burnout is a prolonged state of physical, mental, and emotional exhaustion accompanied by a significant loss of daily functioning, increased executive dysfunction, and reduced tolerance for sensory, cognitive, or social demands. Current research suggests it develops when the chronic stress of living in environments that exceed an autistic person's capacity, including masking, sensory overload, and insufficient support, outpaces their ability to recover. Although autistic burnout is not yet a formal medical diagnosis, growing evidence indicates it is a distinct phenomenon that differs from depression and occupational burnout.

I believe that autistic burnout is more than the mental condition of experiencing chronic stress, but actual differences in our body that make our experience of stress something that is more complicated to recoup from. This is the map I built for my health based on studies of autism. There is not extensive research on Level 1 and even less research on burnout, so I found what most of us shared and addressed it as best I could.

We are all unique, but there are metabolic weaknesses found in most of autism. I'm putting this information forward so others like me, that lost their health and cognition, can start to understand what might support their return. No one told me that my body is just as different as my brain is. What I know now is that understanding what my neurodivergent body needs metabolically has made me physically healthier and my nervous system is calmer. I lived in survival mode, like many autistics, until it became overwhelming.

It would have been hard for me to understand that my body was under strain when I was doing well. I was athletic, quick thinking, and could manage stress like a pro, which is generally a sign of success in our society. Looking back, it was a sign that my body couldn't rest. I was always in low level fight or flight as a baseline with no awareness that there was another option. That momentum was the closest I came to calm. Eventually that caught up with me. For a lot of us, that's a traumatic event, perimenopause, an illness, or mold exposure. When it did, it turned into a high level fight or flight with no resolution. That's when my system started crashing on numerous levels.

Burnout was a regression in my ability to express myself verbally, emotional regression, and a distress that had become my entire internal world. I recognized its expression because I had grown up around two women with the same symptoms. They were brilliant, but they seemed trapped inside their selves in a very unique and childish way. It wasn't until I began deteriorating that I finally understood their behavior. That became the trigger that something was very wrong. I had already seen where that road could lead.

Looking back, I had signs of systemic inflammation, like waking up with ankle joints that had stopped flexing overnight, every night, and had to be worked back into mobility. I had histamine reactions I had never had, and my executive function had gone from independent to unable to get a dishwasher fixed. Most importantly, I wasn't me, but I couldn't remember who I had been. I was defensive, stuck internally, melting down numerous times a day, and losing my ability to live the life I had built. I couldn't hold unfamiliar processes in my head to learn new skills, and the skills I had were deteriorating. Because I had seen this growing up, my thought process was simply to figure out what the metabolic holes in autism were and support them. Back then the wording wasn't as precise. It was, "My autism is getting in the way of my autism." So the question became, what does autism look like in the body? It looked like chaos. My plan of attack became find what we all share and figure out how to support it. My nutritional journey turned into a somatic one and learning why they're both equally important.

Autism is full of subgroups except when it comes to redox markers, especially glutathione levels and SAMe to SAH balance. We generally have greater oxidative stress, lower glutathione, and reduced antioxidant capacity. That means we struggle to handle metabolic burdens on our body. Stress is a metabolic burden, not a psychological one, and it's a burden on top of a body that is already struggling with oxidative stress.

I look at my body as a kitchen, and everything entering it, including food, medication, or the byproducts your own metabolism makes every second, creates work. Every breath, every meal, every thought, every movement throws off compounds that have to be processed, recycled, or removed. That workload is normal. Most kitchens are built to handle it. Ideally you eat food, the nutrients go into our metabolic "pantry," and the body uses the nutrients when it needs it. However, each kitchen also has a different capacity than the next. Autistic kitchens have gut dysbiosis, meaning our gut throws off more byproducts that need to be handled. One way to look at the gut dysbiosis is to imagine gut bacteria as customers coming into a restaurant. Some customers are polite and tip, meaning they give back to the system. In the gut, some bacteria provide benefits, like producing certain B vitamins. Others leave a mess and don't tip the staff. We have more customers in our gut that leave a burden to be cleaned up by the body and don't give back to our system very well. Just like a normal kitchen, you need food in your pantry. We need nutrients in our body so enzymes can function optimally. If you don't digest food well, the nutrients don't go into the pantry to be stocked and the kitchen staff come up empty when they need to prep food for the restaurant (our bodies) to run smoothly. If you have a limited diet, you're also not stocking the pantry well. Calories may give us energy, but they do not complete the meal.

The problem is not that reactive compounds exist. The problem begins when the workload consistently exceeds what the kitchen can clear. That is what oxidative stress is: the accumulation of reactive molecules because they are being made faster than the body can effectively manage them. Or put another way, there's more mess than cleaning supplies and staff to clean it.

Every second, normal metabolism generates reactive oxygen species, damaged proteins, oxidized fats, worn-out neurotransmitters, sulfites, purine metabolites, reactive aldehydes, and spent cellular components that must be recycled. These are normal byproducts of living, and the body has systems to process each of them before they build up. When production outpaces cleanup, they accumulate. And remember, we carry a gut dysbiosis, so our own bodies make an unusual amount of the mess that needs cleaning. Each of our bodies is unique in its ability to handle the reactive compounds produced by our bodies, but with burnout, that tipping point got exceeded. I had to learn to support my body and reduce the burden, which is what I'm going to explain here.

The alarm itself is not the problem. You want your body recognizing danger when danger is present. The problem begins when the kitchen (our body) is always in a panic, even if we act calm on the outside.

Producing energy makes oxidative stress that has to be cleaned up. Nutrient shortages leave the kitchen understocked. Gut dysbiosis creates compounds that have to be processed. Each of those is another job before our bodies can relax.

If the stress being experienced is requiring energy, it is a metabolic burden. I never considered the cost stress had on my body because we think of it as a mental process, but any energy has a metabolic cost. The questions I started asking were is that cost greater in a group of people who are already in fight or flight and what else is impacting how we handle it.

Why rest isn't enough

That is why rest helps but does not stick. Rest lowers the load being created for a while. It does not support the pathways. It is a band-aid. What I ended up finding were studies that open the question to how much of a weakness we have around the ability to support stress, both nutritionally and metabolically.

When people say spoons, I hear ATP. ATP breaks down into purines, which then require nutrients to handle and recycle. So when rest or unmasking is offered as the cure for burnout, what I hear underneath is ATP conservation, which is lowering the purine load on the body. The idea that stress adds to the metabolic load is not something I came up with. Studies show that stress induces abnormal ATP release and dysregulates purinergic receptors, contributing to anxiety, depression, PTSD, etc.

Purines, however, are connected with autism in several ways outside of stress.

Purines are not a toxin to minimize. They are a currency. The same molecules become your energy (ATP), your signaling (adenosine), your DNA and RNA, and your antioxidants. Too low is an issue and too high is an issue. Both of those variables are found in autism. On top of that, purine pathways are commonly found to be metabolic issues in autism. When I hear low spoons, I think purine problem. Purines are vital in telling the body to begin the fight or flight signal. They also need sufficient nutrients to be handled correctly, including folate. They are the intersection of living a high stress life, insufficient folate and other nutrients, and commonly found pathway problems in autism.

The reason this pathway caught my attention is that ATP is usually described as our energy. What we don't hear is that ATP has another job.

ATP is both energy and a danger signal

When a cell senses danger, it shifts its metabolism away from growth and toward defense until the threat passes. This is ordinary, well-studied cell biology. One of the tools cells use to coordinate it is ATP, which we know as energy. What we don't hear is that it becomes a danger signal the instant it is pushed outside the cell. ATP gets broken down by the body into something called purines. That system, purinergic signaling, is ancient and conserved and known to be one of the necessary shifts that move the nervous system into fight or flight.

Purines as a molecule are the whole link to stress. Inside the cell, ATP is energy. The instant it is pushed outside the cell, it becomes a danger signal that is part of the start of a cascade of signaling in the body that we know as fight or flight. A depleted cell (so one struggling to perform normal functions) can still be loudly signaling danger, so low energy does not quiet the alarm, and the alarm can climb while energy falls.

Read again, you can be exhausted and panicking at the same time, which I have seen in others and experienced myself. Impaired clearance of this extracellular ATP keeps the signal going, which is where I felt nutrition became important to understand. We don't have standards for nutrition when the body is inflamed and in distress as a baseline.

The Cell Danger Response

Dr. Robert Naviaux named the sustained version of this the Cell Danger Response, and proposed that in some chronic conditions, including autism, it does not fully switch back off.

What interested me is the work he did that traced the cascade of metabolic events that happens when a body goes into fight or flight. His goal is to use an older medication called Suramin to block the purine receptors and allow the body to switch out of fight or flight.

His research did flag that there are numerous times in development that a human body is supposed to shift out of fight or flight and autism doesn't do that. It brings more evidence to our experience of our baseline being a higher level of stress.

He tested Suramin in mouse models, and then in a small placebo-controlled trial. Lowering the ATP danger signal temporarily eased core autism features like being nonverbal, which returned as the effect wore off.

The drug is not the point in me bringing this up.

The point is the principle underneath it: when the danger signal was lowered, features that looked fixed changed. That points toward a metabolic state that can move, not fixed wiring. What went down can come back up, which is what we need to heal burnout.

Note about Suramin: Suramin has toxicity issues with long-term use. Naviaux wants to use a low dose with autism, but I believe there are too many other factors at play to have that be effective longer than the medication is in the system. However, his studies were evidence to me that purines are having an impact on us.

The alarm and the brake live in the same pathway

One of the reasons I became so interested in purines is that the same pathway that starts the alarm also contains the brake.

Xanthine, a purine breakdown product, drives reactive oxygen species, fragments mitochondria, and runs high in adults with anxiety. The enzyme that makes uric acid also throws off ROS as it works, so purine breakdown is itself a direct source of oxidative stress that eats glutathione.

The pathway also has a brake called adenosine, which is an inhibitory signal that builds up when a cell has been working hard, promotes sleep, and lowers anxiety.

Nudging adenosine up, including through ordinary movement, is beneficial metabolically, not to mention movement's benefits on dopamine.

The alarm and the brake share one system depending on how you support it, which now makes sense when I look at those of us who stay regulated through heavy activity.

Why this changed how I viewed burnout

Purines got personal once I learned the fight-or-flight response starts with purine signaling, and anyone autistic knows how high our anxiety runs.

I have wondered how much my daily anxiety was producing purines that strained my nervous system, which fed more anxiety, which strained it further.

The friends I have known who were people-pleasers, myself included, struggled most with burnout or crashed even further. People-pleasing is a fear response that would add to our metabolic load.

My answer to lower purines leaned heavily on supporting the certain pathways and enzyme, breathwork to regulate (and reduce the load), and exercise.

If purines coordinate the body's response to stress, then where else do purines show up in autism?

Purines are all over autism. ADSL deficiency, which is part of the purine pathway, is the only genetic deficiency that presents as autism and not just autism as a feature. Genetic conditions involving purines have been connected with autism since the 1960s. However, for burnout, we don't have any of those genetic features. I'm coming at it from a different direction, but it still involves purines for a part of it.

When I looked, purine metabolism repeatedly appeared as one of the pathways most consistently disrupted in autism.

Purine metabolism is consistently altered in autism

One of the strongest findings across autism metabolomics is that purine metabolism is commonly disrupted.

A 2023 multi-omics study integrated metabolomics and transcriptomics to examine purine metabolism in autism spectrum disorder. The researchers found consistent evidence of dysregulated purine metabolic pathways, including altered levels of purine metabolites such as uric acid, inosine, and hypoxanthine, along with differential expression of purine metabolism-related genes. They concluded that purine pathway dysfunction is a common feature of ASD and suggested that blood uric acid may serve as a potential biomarker for autism while supporting purine signaling as an important biological pathway involved in ASD.

A 2024 metabolomic and metabolic network study compared blood samples from newborns who later developed autism with samples from 5-year-old children with autism. Among fifty biochemical pathways examined, purine metabolism showed the greatest developmental disruption, including altered regulation of xanthine and other purine metabolites. The authors concluded that abnormal purine metabolism is present before diagnosis and remains dysregulated throughout early childhood, supporting a role for purinergic signaling and mitochondrial metabolism in ASD.

A 2016 urinary metabolomics study also identified abnormal levels of multiple purine metabolites in autistic children and proposed that disturbances in purine metabolism contribute to the metabolic dysfunction observed in ASD, consistent with altered purinergic signaling and the Cell Danger Response.

This connection has existed for decades

The relationship between purines and autism isn't a recent discovery.

In 1964, researchers first described what became known as Lesch-Nyhan syndrome, a disorder later shown to result from deficiency of the purine salvage enzyme HGPRT. The discovery demonstrated that disruption of purine recycling can profoundly affect brain development and behavior, establishing one of the earliest links between purine metabolism and neurological disease.

In 1984, researchers described children with adenylosuccinate lyase (ADSL) deficiency, an inherited disorder of purine metabolism, who exhibited autistic features, developmental delay, and abnormal accumulation of succinylpurines. It provided one of the first direct demonstrations that disruption of purine metabolism can produce an autism-like neurodevelopmental phenotype. ADSL is part of the de novo purine synthesis pathway, meaning it obstructs the body's ability to create purines. Patients with it develop a spectrum of neurological presentations even though other pathways remain intact.

These disorders are rare and are not what I believe explains autistic burnout. What they demonstrate is something much simpler: when purine metabolism is disrupted, the nervous system can be profoundly affected. Purines are signaling molecules in addition to be energy molecules, regulating synapse formation, neuronal migration, axon growth, neurotransmitter release, microglial activation, sleep and wakefulness, seizure threshold, and neural excitability.

Low uric acid may be another clue

Purines eventually turn into uric acid, making uric acid one way to look at how this pathway is functioning.

Low uric acid is the more common autism finding and has been found low enough in studies to be proposed as a biomarker of autism. Low uric acid means the antioxidant end is thin and the buffer depleted.

A distinct subset runs high, a hyperuricosuric group, with sharply increased synthesis from scratch. So this is not everyone-is-low or everyone-is-high, and it is not the whole picture in autism, but I found it to be an incredibly helpful part of the picture in healing burnout.

What convinced me

The pathway that coordinates energy, danger signaling, antioxidant production, and stress recovery is also one of the pathways most consistently disrupted in autism. For my purposes of trying to heal, I moved forward with the idea that there was a chance that applied to me. To me, it meant supporting those pathways nutritionally were vital. Nutrient depletion on top of a disrupted pathway means even more disruption. I also put more weight on learning modalities like breathwork to give me tools to use in the moment.

It doesn't prove purines cause burnout. It does ask the question of if autistic people may begin with a system that is already less efficient at processing the metabolic demands of stress, and there is currently no research on burnout to know.

Purines are valuable molecules, so the body tries not to waste them.

The body gets purines two ways: salvaging old ones, which is easier on the body, and building new ones from scratch, which is expensive. Building new requires six enzymes and needs a folate-derived one-carbon unit at two steps, the amino acids glycine, glutamine, and aspartate, the starter PRPP, and a great deal of ATP.

When recycling works well, the body conserves both energy and nutrients.

When it doesn't, more purines have to be built from scratch. That requires additional ATP and folate, making the process metabolically expensive.

If recycling is slow, you cannot replenish ATP fast enough, and energy, methylation, and DNA building all suffer.

Too fast and you flood the system with breakdown products, which is where gout starts showing up. A small percentage of us have the too-fast issue that produces gout, but that is a subsection of autism. The more common finding is actually low uric acid, only adding to the question of how well we handle purines and, thus, stress.

Purines depend on folate

One of the things that surprised me was how closely purine metabolism and folate metabolism overlap. Two steps of the purine assembly line require folate.

What that means is a purine problem and a folate problem can look remarkably similar to the cell.

Geryk modeled exactly this: knocking out the purine genes produced nearly the same fingerprint as a simulated folate deficiency.

I'm not implying that a folate deficiency causes autism.

I'm saying that a folate deficiency can make our ability to handle stress through purine metabolism worse.

One pathway, many different jobs

Purines aren't simply one molecule.

As ATP is used, it moves through a series of different purine compounds, each with its own biological role.

ATP → ADP → AMP → adenosine → inosine → hypoxanthine → xanthine → uric acid

Most of us only learn that ATP is our energy.

What fascinated me is that each step along this pathway does something different.

ATP powers the cell.

Adenosine becomes one of the body's primary inhibitory signals, promoting sleep and helping calm the nervous system.

Uric acid becomes one of the body's major circulating antioxidants.

Looking at the pathway this way changed how I thought about burnout. Purines aren't simply producing energy. They are participating in nearly every phase of the stress response, from creating energy to signaling danger to supporting recovery afterward.

Before learning about purines, I thought burnout was mostly about running out of energy.

Now I think it is better understood as placing repeated demands on a metabolic system responsible for much more than energy production.

Purines help coordinate energy production, danger signaling, DNA and RNA synthesis, folate metabolism, antioxidant production, sleep, and recovery.

When that system is functioning well, the body can respond to stress and then return to normal physiology.

When it struggles, every stress response becomes metabolically more expensive.

That realization became one of the foundations of how I began thinking about autistic burnout, so not as a failure of willpower or resilience, but as a problem of metabolic capacity.

Rest is important.

Unmasking is important.

Reducing stress is important.

All of these lower the demands placed on the body.

But if burnout has a metabolic component, reducing demand is only one side of the equation.

The other side is increasing the body's ability to process the work that stress creates.

I've tried to describe how purines are involved in energy production, danger signaling, folate metabolism, antioxidant production, sleep, and recovery. These aren't independent systems. They work together as part of the body's response to stress.

When that system is functioning well, stress is processed efficiently and the body returns to growth and repair.

When the system struggles, the same amount of stress requires more metabolic work, produces more oxidative stress, and becomes harder to recover from.

From this perspective, healing burnout isn't only about removing stressors. It's also about supporting the pathways responsible for responding to stress.

That doesn't mean there is a single pathway or nutrient responsible for recovery. Purine metabolism depends on many interconnected systems, including the enzymes, cofactors, and nutrients that support its synthesis, recycling, signaling, and breakdown. I did find benefit from focusing it, however, after learning about one certain compound a chunk of us have a down regulation of.

I ran across a small study that ended up carrying a tremendous amount of weight for removing the metabolic burden and pulling me out of cognitive decline. It had to do with the down regulation of something called MOCOS found in nasal stem cells from autistic adults. It was a small study looking at one gene. What caught my attention was the enzymes MOCOS was directly responsible for and the high percentage of us that were found to have the down regulation, especially for such a small study.

Note, and this is important: when I was doing this research in the early 2020s, the study below wasn't out yet. It wasn't until 2025 that it was found that this down regulation was linked to an ATP deficiency. It's a direct link to why supporting this enzyme supported my energy levels.

There is the molybdenum cofactor, which handles four enzymes. Three of those four enzymes deal with a large number of the toxic metabolites produced by our body, purines, aldehydes, sulfites, and the outsider is mARC. The last one has very little research on it, but it handles nitrogen and helps fix things that are broken. MoCo is short for molybdenum cofactor. MOCOS is underneath MoCo and what adds sulfur to the purine and aldehyde side. The sulfite and mARC do NOT need MOCOS. MOCOS is where the down regulation was found, which impacts purines and aldehydes.

In learning MoCo, I wasn't looking at one pathway anymore. I was looking at something that sat upstream of everything: Energy metabolism, ATP signaling (purinergic signaling), sulfur metabolism, purine metabolism, oxidative stress, antioxidant defenses, redox balance, mitochondrial function, aldehyde metabolism, nitric oxide metabolism, drug metabolism, xenobiotic detoxification, gut microbial metabolite processing, immune signaling, inflammatory signaling, neuroinflammation, nervous system signaling, sleep regulation, DNA and RNA synthesis, folate-dependent one-carbon metabolism, tissue repair and healing, cellular stress responses, exercise recovery, vascular function, cellular growth and maintenance. There are plenty of other systems involved, but this one touches a tremendous amount of the kitchen. And the kitchen in autism is chaotic and expansive, so the connection that this offered was impressive.

How the gut dysbiosis comes into play

What changed my thinking was realizing that my body, via the gut dysbiosis, was producing a tremendous workload. Every day I was producing purines through stress, sulfites via the gut dysbiosis, aldehydes through oxidative stress and the gut dysbiosis, and all of those compounds had to be processed. I couldn't change how much down regulation this enzyme system had, but I could try to reduce what it had to process. The amount of stress we carry as a baseline is incredibly underestimated by a population that hasn't experienced it, so the metabolic load being created is not the same as a population that has a regulated nervous system. It's so very important to keep that in mind.

And what's important to understand is that strain on this enzyme in one area strains the other areas. Purine overload? The aldehyde, sulfite, and mARC sides are going to suffer also. Considering the majority of participants had a down regulation of this enzyme, I took into consideration that I probably did also. There came a tipping point in my late 30s where I started to see sulfite and MCAS symptoms, and that's when my cognition started struggling. I view that as the point where this enzyme became totally overwhelmed, and it started impacting my cognition and health.

This enzyme wasn't the whole picture. It was simply the bridge I had to understand to cross. Instead of trying to force my body to work harder, I started looking for ways to reduce the burden I was placing on it. That became the philosophy behind everything that follows.

The study

The original study compared olfactory stem cells from eleven autistic adults with eleven neurotypical controls. Olfactory stem cells are unusual because they reflect very early development, which is the window where autism is thought to begin. Since you can't biopsy a developing brain, they're one of the closest windows researchers have into early neurodevelopment.

What they found was that MOCOS, the enzyme responsible for sulfurating the molybdenum cofactor, was downregulated in eight of the eleven autistic participants, roughly 80%. The gene itself wasn't mutated or missing. It was simply being expressed at lower levels. For a study this small, that stood out. Most autism-associated genes are found in relatively small subsets of people, so 8 out of 11 is hard to find.

Three out of 11 participants showed disruption of AOX1, the gene that encodes aldehyde oxidase, another MoCo-dependent enzyme. When the researchers combined the two findings, ten of the eleven autistic participants had either reduced MOCOS expression or disrupted AOX1. One participant had neither and one participant had both.

Different goals support different solutions

My goal was never to cure autism or repair a gene. It was to restore my health, which I began to realize meant to reduce the amount of work my body had to do every day metabolically. If stress increased purines, I reduced stress with habits like breathwork. If gut dysbiosis increased sulfites and aldehydes, I started figuring out what addressing my diet looked like with that purpose in mind. If nutrient deficiencies made those enzymes work less efficiently, I corrected the deficiencies. Instead of trying to force the kitchen to work harder, I tried to stop overwhelming it and provided resources so it could catch up.

A population whose most common metabolic snag sits on the body's energy pathways being prone to burnout makes sense to me. Whether those purine problems are from the MOCOS down regulation or independent of it, they exist for a chunk of us. More profound genetic conditions are often much more complex, and the research is looking for treatments that work across the entire spectrum, like Naviaux and Suramin. My goal was different. I was looking for what we all had in common to learn how to support my system as it was. When you ask a different question, you find a different solution.

Side quests

Because it was a small study, I had to go down side avenues to figure out how much weight I was going to give it. Initially that was seeing if the markers of each of those enzyme dysfunctions showed up in autism, which they did. Later on, I compared it with the wider literature. MoCo seemed to have its toe in numerous areas. That being said, it was not 100% of the participants that had the down regulation. There's several paths to Rome, but this one seems to be a common one. This is not every idea out there, but it was enough for me to take MOCOS seriously considering how small of a study it was. For funsies, here they are:

Oxidative stress

During inflammation, xanthine oxidase (XO) generates superoxide, sulfite oxidase (SUOX) converts toxic sulfite to sulfate, and aldehyde oxidase (AOX1) helps clear reactive aldehydes. Reduced MoCo availability can therefore increase reactive species while impairing detoxification, placing oxidative stress at the center of many downstream abnormalities.

BH4

The oxidative stress from a reduced MoCo enzyme capacity oxidizes BH4 to BH2. That uncouples the four BH4-dependent conversions, stalling dopamine, serotonin, and melatonin synthesis and flipping nitric oxide synthase into a superoxide source. Oxidative stress can come from multiple directions, but this is one of the large ones.

Immune activation

XO is upregulated in inflammation and is itself both a ROS source and an NLRP3 primer through urate, so immune activation increases MoCo substrate load and uses one of its enzymes as an effector. Inflammation and the cofactor node reinforce each other.

Microglia

Microglial activation runs on purinergic (ATP and adenosine) signaling and produces oxidative and aldehyde load, the same currencies the MoCo enzymes handle. Sustained XDH-linked purinergic tone keeps microglia primed, though this one is more associative than mechanistically locked.

Excitatory / inhibitory imbalance

Two routes converge: SUOX-limited sulfite forms S-sulfocysteine, an NMDA agonist that drives excitotoxicity and calpain-mediated gephyrin destruction (loss of the GABA and glycine brakes), and gephyrin's dual role links the MoCo build itself to inhibitory-synapse scaffolding. Gephyrin is the single protein where the cofactor system and E/I balance meet.

Aldehyde toxicity

AOX1, which needs MOCOS sulfuration, is a primary clearance route for reactive aldehydes, so reduced AOX1 leaves aldehydes to damage proteins, membranes, and DNA. This is one of the two airtight MOCOS-downstream branches, alongside purines.

Mast cell activation

A MoCo bottleneck reduces the body's ability to convert sulfites, and sulfite triggers non-IgE degranulation through NADPH-oxidase-driven ROS.

Essential fatty acids

Membrane PUFAs are especially vulnerable to oxidative lipid peroxidation, producing reactive aldehydes. Reduced AOX1 activity may increase the persistence of some aldehydes, linking membrane integrity indirectly to MoCo-dependent aldehyde metabolism.

Glyphosate

Stephanie Seneff's work connecting glyphosate (Roundup) to autism has received substantial criticism. One component of her proposed mechanism involves PIN1. PIN1 regulates gephyrin conformation at inhibitory synapses, and gephyrin is also the enzyme responsible for the final steps of molybdenum cofactor (MoCo) biosynthesis. Whether PIN1 also regulates gephyrin's MoCo function has not been investigated. The known biological links exist, but the proposed PIN1-MoCo connection has not yet been experimentally tested. She leans more on the glycine side, but this is a connection that could potentially exist. I'm not saying it is the cause of the MOCOS down regulation. I'm saying it could mimic a side of what is known to be happening already. There are multiple genetics and multiple paths to Rome in autism.

PANS, PANDAS, and post-viral

Infection and immune activation load all three MoCo queues at once. Xanthine oxidase is upregulated during inflammation, so purine substrate rises while the enzyme handling it also becomes a ROS source. Cell stress and immune cell turnover push ATP out as a danger signal, and immune cells responding to endotoxin generate sulfite. A system already running at its clearance ceiling has no reserve for that surge, which may be part of why the onset is abrupt and the resolution is slow. The overlap here is capacity, not cause. PANS and PANDAS involve anti-neuronal antibodies and basal ganglia targeting that this framework does not explain. What it may explain is why some of us flare harder and recover slower from the same infectious hit. The BH4 entry above compounds this, since PANDAS work implicates dopamine receptor antibodies and BH4 oxidation stalls dopamine synthesis from the other direction.

Candida

Candida produces acetaldehyde directly through its ethanol metabolism, placing it upstream of AOX1 and the aldehyde queue rather than merely alongside it. It also produces arabinose, which forms adducts on lysine residues, the same binding chemistry that makes aldehydes damaging. The loop runs both directions: purines feed candida, stress raises purine turnover, candida raises aldehyde load, and aldehyde load competes for the same sulfurated cofactor that clears purines. That is the mechanism behind the antifungal case reports easing autism features without any of those studies naming a cofactor.

Clostridia

Clostridia loads two MoCo queues at the same time. On the aldehyde side, clostridial fermentation generates acetaldehyde and related reactive aldehydes directly in the gut lumen, feeding the same AOX1 clearance route that candida burdens and that MOCOS downregulation limits. On the sulfur side, clostridial phenolic metabolites, p-cresol and HPHPA among them, are cleared by sulfation, and every molecule consumes sulfate, the exact pool a limited SUOX is already failing to replenish. So one overgrowth drains sulfate from the demand side while sulfite conversion underdelivers on the supply side, and simultaneously adds to the aldehyde queue that competes for the same sulfurated cofactor. It also competes for the sulfation capacity measured in the 90s paracetamol studies, which means the phenol findings and the clostridia findings may be one finding seen from two angles. Worth distinguishing sulfate-reducing gram-negatives like Desulfovibrio, which sit on the LPS side as well.

So here is where a loop seems to begin, but it's going to take me a moment to get there.

The exact issue with sulfites and autism is confusing. We lose significantly more sulfites than neurotypicals in our urine, but it's not clear if we simply flush it through our kidneys or have neurotoxic levels in our tissue. Both lead to a sulfate deficiency. I didn't know enough about sulfites to test at the time, but looking back, I do believe I had symptoms of high sulfites, unexplained nausea, my mental health changing drastically, and waking up with a swollen face after drinking something with sulfites like wine. I see other neurodivergents talking about the same symptoms, especially the nausea, without realizing that it may not be a fixed part of neurodivergence for all of us.

Sulfite: a reactive form of sulfur

The SUOX enzyme converts sulfite, one of the body's most reactive sulfur compounds, into sulfate, a stable nutrient the body can use. Autism has been found to be consistently sulfate deficient in studies. (There are separate genetic reasons that add to this in some of us, but not for the majority of us. I do want to note that.) That conversion helps supply us with necessary sulfur to use for numerous processes, and without the conversion happening, it may be impacting areas we don't realize. I haven't found a good nutritional supply of sulfur that matches the conversion that happens in our body. The closest our body can use chemically is Epsom salt, which isn't meant to be ingested.

Sulfate is not just waste. It regulates dopamine, epinephrine, and norepinephrine through sulfation, maintains the gut's protective mucus lining, sulfates bile acids for fat digestion, and helps detoxify phenols. When sulfite is produced faster than SUOX can convert it, sulfite accumulates and sulfate falls: neurotransmitters linger, mast cells release more histamine, the gut barrier weakens, oxidative stress rises, and active B6 and thiamine get damaged. The autism literature consistently reports elevated urinary sulfite and reduced sulfate findings in autism.

I do want to note that no sulfite gene is directly linked to autism, whereas numerous purine and aldehyde genetics are. However, giving molybdenum improved sulfate levels in 1/3 of autistic children in one study, which does open the door to more questions.

Tylenol debacle

When I say detoxify phenols, this is where the research seemed to stop and I wish it hadn't. This was studied in the 90s over several studies that were wondering how well a subgroup of autistic children handled phenols in foods. When the whole Tylenol debacle came out, I was immediately reminded of those studies because they used paracetamol, aka Tylenol, because it has the same phenol ring that the foods the children were reacting to had. What they found was that those children did not handle paracetamol in the body the correct way. They didn't have sufficient sulfur to handle Tylenol with the appropriate pathway, so their body relied on alternate pathways that are much harder on the body. In short, they didn't process Tylenol properly, and thus also didn't handle foods with the same phenol amines properly. Does Tylenol cause autism? Absolutely not. Tylenol needs sulfur. The studies back then speculated it was possibly an issue with the PST enzyme (now renamed SULT enzyme). It would be real helpful to know if this is only an issue in a subgroup or if all of us share this, because there are common pain killers that don't require sulfur and this is where our general health would be impacted. When the people who did the study on Tylenol recently concluded that Tylenol could cause autism, they excluded all research that was not prenatal or natal. They never saw these studies done in the 90s. There are other studies that show that transsulfuration patterns are also present in the parents as well as the children.

It should not be a surprise that a drug requiring sulfur isn't handled well in a population that is consistently sulfur issues.

Endotoxin (LPS): not a problem until the barrier leaks

The down regulation was in MOCOS (aldehydes and purine side), so this is where I have to bridge why I'm bringing sulfites into the picture. That bridge is lipopolysaccharides.

LPS sits in the outer membrane of gram-negative gut bacteria. Behind an intact barrier, i.e. a healthy gut wall, it is normal physiology. The moment the barrier becomes permeable, LPS enters the bloodstream and becomes inflammatory.

LPS is one of the best-studied links between a leaky gut, behavior, and neuroinflammation. Everyone has it. The difference in autism is degree: autistic microbiomes consistently carry a higher proportion of gram-negative bacteria, so more LPS is produced to begin with, and the dysbiosis-related barrier damage means a more permeable wall for it to cross.

There are numerous studies showing that our gut is permeable, but they are often testing something like zonulin. There are also numerous studies finding we have an increased immune response when given LPS. There is only one study I found measuring LPS directly in profound autism, and found a direct correlation.

This is the gap that I used successfully, because it is a solid gap. The studies seem to come at LPS to see how our immune systems respond instead of measuring if it already exists, so we know our immune systems overreact to it. Nobody looked to see if it was present, but based on microbiome studies, it should be. The bacteria populations present are often LPS producers, and I know when I tested my gut in 2021, I was proteobacteria heavy.

Where this comes into burnout is that stress increases LPS, and LPS releases ATP. In fact, there is a study showing if you block two certain purinurgic receptors, LPS-created inflammation is reduced.

The biggest disruption to my decline was binding LPS specifically because it stopped a cycle that seemed to be happening. And why I'm pairing it with sulfites is because sulfites produce an immune response that produces more lipopolysaccharides. The solution I found here was to make sure I had the nutrients the MoCo enzyme needed and ate whole food so I reduced the sulfite load while supporting its conversion to sulfate as much as possible.

The stress loop

This is part of why burnout is hard to climb out of: the elements it produces in your body become what spirals you further. The HPA axis, the body's central stress system, directly compromises the gut barrier when it is chronically active. Cortisol loosens the tight junctions, the wall turns permeable, and LPS gets into the blood. That aggravates the HPA axis, which makes more cortisol, which opens the gut further, which lets in more LPS. Addressing LPS felt like interrupting a loop that stress had created and LPS was sustaining. I was not lowering inflammation in general. I was lowering the inflammation specific to what is found in autism.

MoCo is important because LPS doesn't just activate the immune system. It increases the metabolic work the body has to perform. LPS increases oxidative stress and stimulates nitric oxide production. In small amounts, nitric oxide is beneficial, helping regulate blood flow and support immune defense. During chronic inflammation, however, excess nitric oxide reacts with superoxide to form peroxynitrite, which damages mitochondria and oxidizes BH4. At the same time, LPS causes cells to release ATP as a danger signal, activating purinergic signaling. That ATP is eventually broken down through the purine degradation pathway, increasing demand on xanthine dehydrogenase, one of the body's molybdenum cofactor (MoCo)-dependent enzymes. LPS also promotes lipid peroxidation, generating reactive aldehydes that must be detoxified by aldehyde-metabolizing enzymes. In other words, one trigger is increasing the workload across several pathways that depend directly or indirectly on MoCo.

The range of effects

The documented effects are not small. LPS depletes zinc, which matters because zinc runs the enzyme that disarms LPS at the gut barrier, so it strips the body's defense when we need it most. It depletes that enzyme directly. It hits the liver first, since gut blood drains there. It crosses the blood-brain barrier. It suppresses oxytocin, a source of pleasure that we're known to be depleted of. It depletes serotonin by diverting tryptophan into quinolinic acid, an excitotoxin that overstimulates NMDA receptors. It is linked to depression, metabolic and cardiovascular disease, and endocrine disease, and it can trigger autoimmune-looking responses through molecular mimicry, where anti-LPS antibodies cross-react with human tissue. It also is connected with temperature regulation issues, which is one of the first symptoms I noticed changing. I stopped "running hot" to the touch while simultaneously wearing pants in 90 degree weather. A few years down the road and I'm wearing shorts in hot weather for the first time in decades.

The symptoms of chronic LPS activation are similar to burnout symptoms: lethargy and fatigue, brain fog and cognitive dulling, social withdrawal, reduced motivation and anhedonia, and altered thermoregulation, where you stop sensing temperature correctly.

Chronic LPS exposure causes neuroinflammation.

Activated charcoal was where I dipped my toe in the water to see if addressing LPS made a difference, and I did notice changes. In addition to temperature regulation changing, my muscles felt less heavy and my hand-eye reaction time sped up closer to what I had been used to for most of my life. It wasn't until a couple years into researching that I took LPS as seriously as it deserved and got more specific in how I approached it.

How it gets through

Two routes besides a leaky wall.

The chylomicron route: when fat is digested it is packaged into chylomicrons, and any LPS present hitchhikes across the epithelium with them, bypassing the barrier entirely. A single high-fat meal spikes plasma LPS even in healthy people; and on a dysbiotic, already-permeable gut, the effect multiplies.

The bacterial route: high-sugar and high-fructose diets preferentially feed the gram-negative bacteria that make LPS, and processed-food additives directly increase permeability. A four-week Western-style diet raised plasma LPS by 71 percent.

The IAP firewall and the zinc loop

Intestinal alkaline phosphatase (IAP) is the gut lining's built-in firewall: it dephosphorylates LPS, defusing it right at the wall. The catch is that IAP needs two zinc ions per active site, and LPS depletes zinc. Less zinc means less IAP, less IAP means more LPS through, more LPS means more zinc lost. A Western diet alone cut IAP activity by about 75 percent in mice with a fourfold rise in plasma LPS. Restoring zinc, fiber, butyrate, and vitamin D all raise IAP.

Why the two travel together

The link is direct. A heavy LPS burden produces sulfite. More specifically, immune cells responding to LPS produce sulfite. LPS and sulfite drain the same supplies, zinc and glutathione among them, and the zinc loss is its own trap through IAP. Focusing on reducing the LPS burden was a dramatic shift in my comfort level because it impacted the other areas simultaneously. That reduced my stress further, and it became a positive cycle.

Aldehydes took the longest for me to start to appreciate. The genetics back the importance. 7 of the 19 genes that handle aldehydes are connected to autism or speculated to be, and the same small MOCOS study that started me on this path found 3 of 11 participants with an AOX1 disruption independent of the MOCOS finding. So 8 of 11 had a MOCOS down regulation, 3 had AOX1 disruption, one overlapped, and one had none. 10 out of 11 was the final number for either a MOCOS or AOX1 disruption, which is incredibly unified for an autism study.

Aldehydes have the potential to be one of the bridges between chemical sensitivities and candida commonly found with autism. They also gave a potential reason for why I saw studies that seemed to be conflicting but maybe aren't. Early on, I remember seeing studies that claimed to fix autism with antifungals, a separate one saying that clostridia was probably a contributing issue, and then candida speculation was all over the place.

It was confusing to see studies covering elements that seemed so unrelated until I learned that all of those produce aldehydes. Chemical sensitivities are a sensitivity to the aldehydes emitted from perfume, smoke, or cleaning products that can trigger neurological or respiratory responses such as migraines, nausea, and asthma. If we have a down regulation of what is needed to handle aldehydes, anything producing them in our body or externally is going to be a problem because we won't be able to process them as well. If we have deficiencies further encumbering the enzyme that's already down regulated, we're going to have even more problems.

Aldehydes

Aldehydes bind rather than float past. They form irreversible adducts with proteins, inactivating them, and with DNA, causing strand breaks and mutations. The AOX1 enzyme (part of MoCo) helps clear them. One hypothesis paper made the strong claim that the many symptoms and divergent theories of autism are consistent with aldehyde toxicity, and laid out four ways they damage us: micronutrient depletion, oxidative stress, protein inactivation, and DNA damage. Whether they explain all of autism or not wasn't my concern. I looked at them like another burden to make sure I wasn't adding to my system any more than necessary.

Where they come from

• Outside the body: vehicle exhaust, smoke, cooking fumes, browned and fried food (especially reused oil, like fast food), off-gassing from furniture, carpet, and cosmetics, and many foods and natural flavorings such as vanilla, cinnamon, and citrus. Indoor levels run four to ten times outdoor. Alcohol and smoking produce them too. But this wasn't my biggest concern because the studies suggest that the larger problem might be internal production, or at least that was my read of it. All the same, I don't want to work at a factory breathing in paint fumes all day.
• Inside the body: reactive oxygen species hitting fats, lipid peroxidation, throws off more than 200 different reactive aldehydes such as 4-HNE, 4-HHE, and MDA. ROS are unstable oxygen molecules from normal metabolism; in small amounts antioxidants handle them, but when they outpace defenses you get oxidative stress, one of the most consistently replicated findings in autism.
• The gut: yeast and bacteria, Candida especially, generate them directly.

Why aldehydes are a problem

They consume the body's defenses as they go, depleting sulfur antioxidants (glutathione, cysteine, taurine) and locking up B1, B6, folate, zinc, and magnesium, and they strip zinc out of proteins, including the very enzymes meant to clear aldehydes and ROS. The lipid-peroxidation ones travel across membranes and damage neighboring cells far from where they formed. The paper described the result as a downward spiral: aldehydes deplete the local antioxidants, which lets more survive, which disables protection further out, until repair machinery goes offline and DNA damage starts to stick. The study suggests earlier intervention rather than later.

A kitchen running hot burns through supplies faster than a quiet one, and folate is one of the starting places because it sits under more than people realize.

The 98 percent figure I saw on blogs when I started this journey I didn't actually see supported by the research, and MTHFR may be less universal in autism than the supplement world suggests. No study I found gives a clean prevalence number. What does show up consistently is a folate deficiency, which appears more common than the mutation itself and is often tied to restricted eating. Whether the root is a gene variant or a dietary gap, the downstream effects are the same. The deficiency is what I care about more than MTHFR.

I also had to unlearn the assumption that because I ate well, I got enough nutrition. I assumed my whole life that I had enough folate, yet every time I supplemented I improved. Our food is depleted and getting more so, and the RDA does not account for a body that is healing, a dysbiotic gut, living in fight or flight, chronic inflammation, or struggling digestion. I test where I can, but symptom improvement is often king for me now. My budget limits the testing I can do. I did test along this journey where I thought it was important.

Folate feeds two systems we cannot afford to lose

The common narrative is MTHFR does not cause autism but we all have it so take methylfolate, it improves neurotransmitters, anxiety, and move on. I started there, then went deeper. Once folate is in a usable form, it can be used in two directions, and both are commonly depleted in autism.

• Toward SAMe, the body's primary methyl donor, used in hundreds of reactions: neurotransmitter synthesis, gene expression, inflammation control. Without enough SAMe, methylation falters and a lot of downstream processes feel it.
• Toward glutathione, the master antioxidant and detox molecule that handles oxidative stress, supports immunity, and is critical for repair.

One way to hold it: SAMe helps the body run its processes, and glutathione helps it survive the damage done while running them. Supporting them takes more than folate. SAMe in full needs folate, B2, B6, B12, zinc, and magnesium. Glutathione needs glutamine, cysteine, glycine, B6, B2, and selenium. It was never as simple as one pill, though multivitamins alone have shown improvement in autism, and it did untangle with patience.

Folinic acid versus methylfolate

Both bypass the MTHFR variant, so they are equal there, but not elsewhere. In one comparison, people with the 677CT genotype lowered homocysteine more on folinic acid than on methylfolate, and folinic acid may support DNA synthesis and rapidly dividing tissues differently because of where it enters the cycle.

The critical detail: folinic acid alone did not meaningfully improve methylation or glutathione markers. It only moved them when combined with methylcobalamin, a specific form of B12. If you are taking folinic acid hoping to feel better, the combination is what moves the needle, not folinic acid by itself.

Folate for energy

When it comes to burnout, folate is necessary to handle purines. So like I went over in the beginning, spoons are ATP and ATP gets broken down into purines. Purines are our energy, and they can either be recycled or produced de novo (produced new). Folate is necessary for this process to happen, so I view having adequate folate as necessary for burnout. Recycling purines is easier on the body than producing them anew.

Stress is not something that only lives in your mind. It is a metabolic event, and it pulls on nearly every system this site is about.

The fight-or-flight response runs on purine signaling. Under stress, cells release ATP into the extracellular space where it acts as a danger signal before eventually being broken down through the purine pathway. During an acute stressor, this system activates and then returns to baseline. Chronic stress means it is recruited over and over again.

At the same time, the HPA axis begins affecting the gut itself. Chronically elevated cortisol weakens the intestinal barrier, allowing lipopolysaccharide (LPS) from gut bacteria to enter the bloodstream. LPS activates the immune system, stimulates the release of even more extracellular ATP, and further amplifies purinergic signaling. The alarm is now being reinforced from two directions: psychological stress and immune activation.

This creates a self-reinforcing loop. Stress increases gut permeability. LPS enters the circulation. LPS sustains purinergic signaling and inflammation, which further activates the stress response. Instead of resolving, the alarm continues to recruit itself.

Stress raises demand while draining capacity

Chronic stress doesn't simply consume energy. It increases the amount of metabolic work the body has to perform.

Repeated ATP release increases purine turnover, increasing demand on xanthine dehydrogenase and the molybdenum cofactor system. LPS increases oxidative stress and stimulates nitric oxide production. While nitric oxide is beneficial in normal amounts, chronic inflammation can generate excess peroxynitrite, damaging mitochondria and oxidizing BH4. LPS also promotes lipid peroxidation, increasing production of reactive aldehydes that must be cleared through aldehyde metabolism. Rebuilding purines requires folate through one-carbon metabolism, increasing folate demand. Chronic stress increases magnesium and zinc losses, while those same minerals are required for many of the pathways responsible for restoring metabolic balance.

Stress therefore widens the supply-and-demand gap from both directions. It increases the workload while simultaneously making it harder to meet that workload.

Why this matters

Everything else on this site focuses on increasing metabolic capacity. Stress management reduces the amount of work those pathways have to perform. Nutrition and nervous system regulation are therefore not separate strategies, they solve opposite sides of the same equation.

Why this is the other half of the work

Everything else on this site raises your supply, your capacity to meet the load. Stress is the clearest lever on the demand side. Lowering it through boundaries, finding a good work atmosphere, having quality friendships, and nervous system practices like breathwork, is the same equation worked from the other direction. The metabolic work and the life changes are not separate projects. They are both essential. At the beginning, I carried my stress nutritionally. As I figured things out more, I realized that the somatic work was quite possibly just as important as the nutritional work and focused on both equally.