How Sulfite Destroys Your Mental Health

The mechanistic support is strong, the empirical support is scattered, the potential yield of assessing and optimizing your sulfur metabolism is pure gold.

One in every eight people worldwide are estimated to live with a mental illness, while the prevalence is higher in certain areas. For example, this figure is one in five in the United States.

The fact that this is framed as “living with” in the statistics betrays that we understand almost nothing about how to deal with mental illness because we can’t shake it from a person’s identity by resolving it.

This means that there is great hope in considering new ideas about mental illness, since there is such enormous room for upside in getting to the bottom of what causes them and what can be done about it.

This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.

The Short Answer

Dysfunctional sulfur metabolism has very strong mechanistic support for a major contribution to a large number of mental health problems. Empirical support for this is scattered. Where it exists, it is supportive. Since the empirical research is so behind, looking at your personal sulfur metabolism is a goldmine to put your action plan way ahead of the game and open up doors of hope for far better outcomes.

Anyone with concern over their mental health should apply the screening and any relevant components of my Sulfur Protocol:

At the Intersection of Neurotransmitters and Energy Metabolism

Dr. Chris Palmer’s theory of Brain Energy is the best unifying theory of mental illness, and I would consider it highly aligned with my argument that Energy Metabolism Governs Everything.

Sulfur metabolism is a way of zooming in on one major part of this. Sulfur electrons are burned for energy with sulfate being released as the most oxidized product, similar to how carbs, fat, and protein are burned for energy and carbon dioxide is released as the most oxidized product.

Incompletely oxidized sulfur is used to make the neurotransmitter S-sulfocysteine, which can later reenter the sulfur oxidation process to be burned for energy and release sulfate.

This is much like how partially oxidized glucose is joined to ammonia released from branched-chain amino acids in the brain to make the neurotransmitter glutamate, which can be converted to the opposing neurotransmitter GABA, and this can later enter the citric acid cycle to be oxidized to carbon dioxide.

On the other hand, when the sulfur oxidation process is disrupted by genetic impairments or nutrient deficiencies rather than deliberately slowed to synthesize a purposeful neurotransmitter, sulfite can accumulate and act as a mitochondrial toxin. Impairment in mitochondrial energy metabolism will compromise the synthesis of myelin and all kinds of other brain functions, and will acutely disrupt the incredibly energy-intensive handling of all neurotransmitters.

While dysregulated sulfur metabolism can both cause and be caused by impaired energy metabolism, there is also a neurotransmitter-centric element to this discussion: sulfite can disrupt the conversion of phenylalanine to tyrosine, which causes gross dysregulation of a variety of neurotransmitters; S-sulfocysteine is an excitatory neurotransmitter that could be seen as glutamate’s sidekick, and this biases the effects of sulfur dysregulation toward excitatory states like anxiety, mania, pain, and hypersensation.

Sulfite Causes Anxiety in Rats

Let’s start with this.

Sulfite administration experimentally induces anxiety in rats.

There are no and will never be any randomized controlled trials testing whether sulfite administration causes anxiety in humans.

Mechanisms of Sulfite Damage

Here are the major mechanisms by which sulfite could damage mental health.

S-Sulfocysteine Is an Excitatory Neurotransmitter

Sulfite binds to cystine, which consists of two cysteine molecules in a disulfide bond, breaking it into a free cysteine and binding to the other cysteine, forming S-sulfocysteine. S-sulfocysteine activates NMDA receptors, leading to neural excitation.

As I covered in Maybe THIS Is Why You’re Hangry, S-sulfocysteine is found in everyone’s urine, and it varies 50-fold, suggesting it is a completely unappreciated normal neurotransmitter.

Based on what we know about NMDA function in various mental illnesses, S-sulfocystiene would be predicted to protect against schizophrenia and borderline personality disorder; have a poorly understood and possibly cyclical relationship to bipolar disorder, have a complicated relationship to ADHD; and to increase the risk of depression, anxiety, eating disorders, OCD, addiction, and PTSD.

Overactivation of NMDA receptors could also contribute to chronic pain, which is not a mental illness but increases the risk of mental illness. It likely would have a similar effect by increasing the risk of sleep disorders.

The well established effects of disorders of sulfite clearance in promoting seizures, tremors, tics, jerks, Parkinsonian movement disorders, gait disorders, and a wide variety of neurological problems probably also increase the risk of mental illness due to the difficulties of life they cause and the anxiety associated with chronic health problems. However, this is not well researched and will be covered further below.

Sulfite Depletes NADPH

Sulfite has been shown in numerous studies to deplete NADPH by activating NADPH oxidase, which converts molecular oxygen to superoxide while converting NADPH to NADP+. Studies in 1967 and 1975 showed that this is an alternative mechanism of oxidizing sulfite. More recent studies have shown that this oxidizes sulfite to a sulfite radical that leads to many dangerous compounds, that this occurs to much greater degrees when sulfite oxidase activity is deficient, and that this occurs in human cells as it does in other models.

NADPH is needed for both the synthesis and recycling of tetrahydrobiopterin (BH4), which is a cofactor for phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine.

Genetic defects in phenylalanine hydroxylase cause phenylketonuria (PKU). PKU decreases the synthesis of dopamine, norepinephrine, and melanin because it reduces the synthesis of tyrosine. However, the secondary effects of the imbalance in amino acid transport lead to deficient brain levels of methionine, and thus methylation, and of tryptophan, and thus serotonin and melatonin. The drop in brain serotonin is due partly to phenylalanine outcompeting transport of tryptophan to the brain, and partly to phenylalanine’s inhibition of tryptophan hydroxylase.

PKU is associated with a 4-fold higher risk of eating disorders, a 3.9-fold higher risk of OCD, a 3.7-fold higher risk of behavioral disorders, a 2-fold higher risk of personality disorders, an 80% higher risk of schizophrenia or other psychosis, a 70% higher risk of attention deficit disorder, anxiety, or phobia, a 60% higher risk of depression, and a 40% higher risk of bipolar.

Thus, sulfite depletion of NADPH could mimic PKU and would be expected to similarly contribute to these mental illness risks by distorting neurotransmitter metabolism.

Sulfite Depletes B Vitamins

Sulfite deactivates folate, thiamin, and vitamin B6.

Frank thiamin deficiency causes Korsakoff’s psychosis, which involves amnesia and the creation of fake memories, called confabulation.

Vitamin B6 is involved in the production and interconversion of all amino acid-derived neurotransmitters, and thus is likely to cause similar distortions as PKU that are even more expansive. Frank B6 deficiency causes irritability, depression, confusion, or anxiety, and insomnia.

Folate contributes to mental flexibility, and is protective against anxiety, depression, and especially against rumination and OCD. I covered this in much more detail in Methylate Your Way to Mental Health.

Sulfite Causes Mitochondrial Dysfunction

Sulfite disrupts mitochondrial function by opening up the mitochondrial permeability transition pore, which allows many substances to enter or exit the mitochondria that shouldn’t. It also inhibits glutamate and malate dehydrogenases, which disrupts the citric acid cycle and worsens energy status. This is over and above the impairment in respiratory chain activity that occurs in response to hydrogen sulfide accumulation.

The citric acid cycle is the main source of citrate, which is the primary building block of myelin through its conversion to cytosolic acetyl CoA.

Energy is required for all functions of the brain and all functions of the rest of the body, but it is especially critical to the acute control of neurotransmission and neurotransmitter function. Without the constant production of energy, the ion gradients that mediate neurotransmission, release neurotransmitters, and clear neurotransmitters from synapses, all collapse.

Disruption of mitochondrial energy metabolism is catastrophic to all aspects of mental health.

Common Polymorphisms and Mental Health

The very common rs1081975 polymorphism in the sulfite oxidase (SUOX) gene has been associated with anorexia.

The very common rs594445 polymorphism in the molybdenum cofactor sulfurase (MOCOS) gene is associated with a lower risk of methamphetamine addiction and the mania-dominant bipolar 1 disorder. This enzyme adds sulfur to to the activated molybdenum cofactor, allowing it to participate in xanthine metabolism instead of sulfite metabolism. This may reflect less effective driving of molybdenum into xanthine metabolism, allowing more to be available for sulfite clearance, thereby mediating a protective effect on the risk of addiction and mania.

There are no other data on common polymorphisms that are relatively specific to sulfite accumulation and their association with mental health that I can find.

Genetic Disorders of Sulfite Accumulation

The genetic disorder that is most specific to sulfite accumulation is sulfite oxidase deficiency.

A second set of disorders in activating molybdenum to its cofactor form is thought to be relatively but not completely specific to sulfite accumulation, since the activated molybdenum cofactor is needed for sulfite oxidase.

Neonatal-onset disorders of these two types cause intractable seizures, low muscle tone, exaggerated startle reflex, poor feeding, and mild developmental distortions in the face and head. These then progress to spasticity (stiff, rigid, or tight muscles with exaggerated reflexes), profound psychomotor retardation (slowing down of thought and movement), and sometimes dislocation of the lenses in the eyes. In molybdenum cofactor deficiency, xanthine accumulates in addition to sulfite, and this causes kidney stones.

“Late-onset” cases are generally defined as onset in the period from five months of age to two years. Followups rarely make their way into the teenage years and usually are limited to early or mid-childhood. One exception is a girl who presented at age 23, who likely was only diagnosed because her older sister had identical genetics and presented at the age of one.

This presents a huge problem for looking at mental health. The median age of onset for mental disorders ranges from 8 in the case of phobias and separation anxiety to 31 in the case of mood disorders and 35 in the case of acute and transient psychotic disorders. About a third of all mental disorders onset by age 14, about half by age 18, and about three quarters by age 25.

Contrast this with PKU, which was the first inborn error of metabolism added to newborn screening and has been systematically tracked since the 1960s, and is now well tracked from birth throughout the entire world. Due to systematic, proactive screening and prospective followup, we have good data on its relation to mental illness. We have nothing of the sort for sulfite oxidase and molybdenum cofactor deficiency.

There are eight case reports of late-onset sulfite oxidase deficiency, with very few comments made that can be related to mental health:

• In one, did not report any mental health issues, although at the age of 17 months, episodes involving fevers would cause acute episodes of not recognizing his parents. He was only followed up until he was six and a half years old.

• In another, a girl was followed up to the age of seven, and the only note about her mental state was that she was mentally retarded but with good comprehension.

• In another, a girl was followed up to the age of 30 months, and had a developmental quotient under 50, indicating mild intellectual disability (mental retardation).

• In another, a boy was followed between the ages of 11 and 12 months and shown to have poor alertness.

• In the most recent, a 5-year-old girl had “mild delay in social-emotional responses.”

There are fewer than two dozen reports of late-onset molybdenum cofactor deficiency spread across fifteen reports. Few of them have insights into mental health.

Two reports taken together demonstrate how mental health is easily ignored in the presence of severe neurological problems, and how diverse the neurological presentations can be across individuals with very similar genetics. The two reports concern two sisters with identical molybdenum cofactor deficiency genetics, born three years apart in a family of five siblings.

The first report primarily concerns the older of the two sisters. She presented at one year of age with “intermittent jerks” due to “probable seizures,” regression of language skills, motor control problems making feeding difficult (such as choking on solids), irritability and rigid muscle tone upon attempts to comfort involving touch, and involuntary movements. The younger sister was affected biochemically, and suffered from lens dislocation, but her only neurological issue was poor attention span and distractibility, suggestive of an attention deficit disorder.

In the second report, the younger sister developed a cramped neck and bilateral arm jerks at the age of 23. This progressed to apathy and difficulty swallowing, speaking, and walking. Within five months, she became nearly mute with no facial expression, a distorted voice, a tilted head, rigid muscle tone, parkinsonian movement, mild scoliosis, and tightened knee joints.

In the second report, no comment was made about the attention deficit that appeared to be emerging at the age of six.

The two sisters had identical molybdenum cofactor genetics, yet marked neurological problems onsetted at the age of one in the older sister and at the age of 23 in the younger sister. When a snapshot is taken at an early age, it shows remarkable diversity of presentation with similar genetics.

The way the authors draw attention to the younger sister’s mental health when she had no overt neurological dysfunction yet ignore her mental health once her neurological catastrophe began shows how mental health is easily ignored when symptoms that are more severe and more disorder-specific are present.

When you are able to move and speak normally, parents and doctors notice that you get distracted too easily. When these basic functionalities fall apart, they take no notice of how easily you get distracted.

Other molybdenum cofactor deficiency reports mention autism and an IQ of 50, indicating mild intellectual disability (mental retardation) as consequences, though neither of these are mental illnesses.

In a cohort of patients with autism, seizures, or schizophrenia, rare deletions in the gephyrin gene (GPHN) were found in six individuals, which made them six times more common than in controls (6 out of 8,775 instead of 3 out of /=27,019). In a separate schizophrenia-only cohort where only one individual was found from among 3,391, the incidence was 2.7-fold greater than in controls.

Gephyrin is a multi-functional protein that plays a role both in the anchoring of glycine and GABA receptors, and in the activation of molybdenum to its cofactor form. In molybdenum cofactor synthesis, it both performs two steps of the activation and also anchors the several other enzymes of the pathway to the cell membrane as a large complex, where the complex is coupled to the inward transport of molybdenum. Gephyrin is thus a global coordinator of neuroinhibition in the sense that its activation of molybdenum cofactor synthesis will indirectly reduce glutamate receptor activation by S-sulfocysteine while it also directly facilitates inhibitory neurotransmission by glycine and GABA.

Two cases were reported in that paper of individuals with schizophrenia, both onsetting in the early 20s, but neither case had evidence of seizures or movement disorders and no biochemical analysis was done to show anything related to sulfite accumulation. However, this brings to mind the younger sister in the previous reports who only had attention deficit when her sister had classical signs of sulfite oxidase deficiency, and who only 17 years later developed a severe non-classical neurological catastrophe. That is, the expectation of a “pathognomonic” set of signs is a distraction from the great diversity of neurological outcomes that can be expected from a particular error of biochemistry.

Associations with Blood Markers

A hypothesis paper from 2020 argued that dysregulation of sulfur catabolism drives treatment resistant schizophrenia. They cite research that schizophrenia is associated with low cysteine, glutathione, hydrogen sulfide, molybdenum, and uric acid. Since sulfur is needed in the activation of molybdenum to its cofactor form, they propose that a low rate of trans-sulfuration compromises molybdenum cofactor synthesis, and this increases sulfite accumulation, which degrades NMDA receptors. The paper they cite on NMDA receptor degradation actually suggests the NMDA receptor expression goes down as compensation for S-sulfocysteine activation.

Low levels of molybdenum seem related but distinct from the main hypothesis, and the findings do not seem consistent. The study they cite found schizophrenia associated with low manganese and molybdenum and high iron and nickel. On the other hand, one study found no relation between schizophrenia and molybdenum levels, while schizophrenia was associated with high manganese and low levels of calcium, magnesium, selenium, and sodium. Another study found schizophrenia associated with high manganese and low copper and selenium, but no relation to molybdenum. A 2020 systematic review concluded that alterations in trace minerals are likely often related to the onset or aggravation of schizophrenia, but the research on specific minerals is too inconsistent to make any conclusions.

Most likely alterations in trace minerals have profound influence on an individual’s risk of onset or aggravation, but the risk is highly idiosyncratic depending on the individual’s diet and nutritional status in interaction with their unique genetic makeup.

If trans-sulfuration is reduced in schizophrenia, it may be that they don’t have enough S-sulfocysteine, consistent with the widely supported hypothesis that NMDA function is decreased in schizophrenia.

There are many paths to sulfite accumulation, which is why my Sulfur Protocol is multi-layered with an “assemble your own unique protocol” approach that matches your protocol to your unique circumstances and risks.

It is interesting that the high manganese shows up as a risk factor in two studies, while low manganese shows up as a risk factor in the one study that identified high iron as a problem. This is very reminiscent of my writings in Manganese Toxicity Is a CoQ10 Deficiency, CoQ10 Deficiency is Sulfur Toxicity, and Iron Overload: Forget What You Thought You Knew. In these articles I outlined how elevated manganese compromises CoQ10 synthesis, which compromises sulfur clearance and leads to accumulation of hydrogen sulfide and sulfite, and how iron overload genes cause manganese overload, but cause it to accumulate in the brain at the expense of the blood. Thus, excess manganese in the brain might be a consistent risk factor for schizophrenia, but this may manifest as high levels in the blood when excess dietary or environmental exposure is the primary cause, but manifest as low levels in the blood when the genetics shifting manganese from the blood into the brain is the primary cause.

Nevertheless the role of sulfur in schizophrenia is clearly complicated and a lot needs to be untangled.

Molybdenum levels have no consistent relationship to depression, and there is little else on how its blood levels relate to mental health.

Stay Ahead of the Game

Overall, then, the relationship between sulfur catabolism and mental health is extremely under-researched. However, the mechanistic support for how sulfite and S-sulfocystiene accumulation could destroy mental health is so strong that it makes tremendous sense to be proactive and optimize your sulfur metabolism if you have any concerns about your mental health.

My Sulfur Protocol covers how to assess your sulfur metabolism using your experience of health issues and your lab work, and how to assemble your personal sulfur protocol using dietary and supplement strategies. You can get my Sulfur Protocol here: