Welcome to the ISOM webpage for schizophrenia. The purpose of this resource is to provide information on potential promoters and causes of schizophrenia that are related to nutrition, micronutrients, and metabolism. Understanding these factors can be an important and productive part of addressing and recovering from schizophrenia.

The information provided is not intended to be a substitute for medical advice from a licensed physician or other qualified healthcare professional.


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Page Contents

What is schizophrenia?

Schizophrenia is a chronic psychiatric condition that manifests as abnormalities of perception, thinking, and behaviour. It can arise suddenly or gradually, and be anywhere from mild to disabling.

Schizophrenia symptoms are classified as “positive” or “negative”. Positive symptoms include paranoia and hallucinations, and negative symptoms include dampening of emotions, cognitive impairments and social withdrawal.

Genetic, environmental and psychosocial factors are involved in the development and manifestation of schizophrenia (Gaby, 2011).

Further information

 What is schizophrenia?

American Psychiatric Association webpage



Gaby AR. (2011) Nutritional Medicine. Alan R. Gaby, VitalBook file.

The standard medical approach typically does not consider or address dietary, nutrient, and environmental contributors to schizophrenia.

Conventional treatment for schizophrenia mainly utilizes antipsychotic medications such as neuroleptics and tranquilizers

For many people, these medications are only partially effective and have a variety of negative side effects. Nonpharmacological treatments like psychotherapy are used in addition to medications.

Medical standard of care for schizophrenia

(Treating schizophrenia, n.d.): 

  • Assess symptoms and establish a diagnosis.
  • Formulate and implement a treatment plan.
  • Develop a therapeutic alliance and promote treatment adherence.
  • Provide patient and family education and therapies.
  • Treat comorbid conditions, especially major depression, substance use disorders, and posttraumatic stress disorder.
  • Attend to the patient’s social circumstances and functioning.
  • Integrate treatments from multiple clinicians.
  • Carefully document the treatment, since patients may have different practitioners over their course of illness.

Further information


Description of diagnosis, medications and psychosocial interventions

Schizophrenia Treatment and Self-Help

Schizophrenia Treatment and Self-Helphttps://www.nimh.nih.gov/health/topics/anxiety-disorders/index.shtml


Treating schizophrenia: A quick reference guide. (n.d.). American Psychiatric Association. Retrieved October 5, 2020, from https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/schizophrenia-guide.pdf

Schizophrenia has numerous biological and molecular causes and contributors that have been identified through research and clinical practice. Each individual may experience schizophrenia symptoms for different reasons.

The orthomolecular approach:

  • Identifies the drivers and causes of schizophrenia and focuses on understanding them
  • Works WITH the body to restore balance and normal function, and considers the person with the condition versus just the condition
  • Addresses nutrient depletions that promote anxiety whereas medications do not
  • Can be done SAFELY in conjunction with most medical treatments

Orthomolecular recovery

According to Dr. Abram Hoffer, a pioneer in orthomolecular schizophrenia treatment, if the person with schizophrenia is provided the basic elements of shelter, good food, and care for personal dignity and respect (Gaby, 2011):

  • The natural recovery rate is 50%
  • Adding nutritional therapy increases the recovery rate of acute schizophrenics to 90% (acute means sick less than 2 years or have had several remissions and relapses)
  • Chronic schizophrenics will be much improved or well within 10 years

Orthomolecular approach and nutritional therapy

  • A goal of nutritional therapy is to reduce medication dosing to low, non-toxic levels, or to discontinue them completely (Gaby, 2011)
  • For acute schizophrenia, it may take at least 2 months to see effects of supplementation
  • Progress with chronic schizophrenia is often slow, and it may take years to see significant improvement
  • Once supplementation has taken effect, schizophrenia symptoms rarely return as long as supplementation is continued.
  • Many patients, particularly chronic patients, continue to require antipsychotic medication, but at much lower doses than previously used (Gaby, 2011)


Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Contributing factors for schizophrenia

Contributing factors are substances, contexts or conditions that have roles in the causation or promotion of schizophrenia and psychosis.

Food, food components, and food additives

Diet and schizophrenia

  • Diet is commonly considered the most important mediator of health and disease. 
  • People with psychosis are more likely to eat quickly, skip breakfast and eat evening snacks (Aucoin, 2020).
  • Schizophrenia is more common in industrialized cultures than non-industrialized cultures, suggesting that diet, among other factors, have roles in schizophrenia. (Schizophrenia | Nutrition Guide for Clinicians, n.d.)
  • Diets of schizophrenia patients are often poor, and antipsychotic medications can promote weight gain, as well as blood-sugar and blood-lipid issues (Schizophrenia | Nutrition Guide for Clinicians, n.d.).

Psychosis is one aspect of schizophrenia. Several diet-mediated mechanisms have been tied to psychosis. These include (Aucoin, 2020):

  • vitamin and mineral insufficiency
  • blood sugar dysregulation
  • gut microbiome
  • oxidative stress
  • methylation cycle imbalances
  • inflammation
  • food sensitivities
  • essential amino acid deficiency
  • fatty acid deficiency

The Mediterranean diet

  • The Mediterranean diet is considered a good model for a healthy diet. It includes foods that are beneficial and reduces or elimates foods that promote mental health issues.
  • General components of the mediterranean diet include:
    • plenty of vegetables and fruit
    • healthy fats including olive oil
    • regular consumption of seafood
    • whole grains instead of refined grains
    • poultry, beans, and small amounts of red meat
    • small amounts of dairy (yogurt and cheeses)

Useful Information

Schizophrenia—Symptoms and causes. (n.d.). Mayo Clinic. Retrieved November 3, 2020, from https://www.mayoclinic.org/diseases-conditions/schizophrenia/symptoms-causes/syc-20354443

Mediterranean diet for heart health


Aucoin, M., LaChance, L., Cooley, K., & Kidd, S. (2020). Diet and Psychosis: A Scoping Review. Neuropsychobiology, 79(1–2), 20–42. https://doi.org/10.1159/000493399

Mediterranean diet for heart health. (n.d.). Mayo Clinic. Retrieved September 27, 2020, from https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/mediterranean-diet/art-20047801

Schizophrenia | Nutrition Guide for Clinicians. (n.d.). Retrieved November 5, 2020, from https://nutritionguide.pcrm.org/nutritionguide/view/Nutrition_Guide_for_Clinicians/1342091/all/Schizophrenia?refer=true

  • Gluten is a general name for proteins found in wheat and related grains. Although many people are not affected by gluten, for others it can cause problems, including schizophrenia.
  • 1 in 7 people experience negative effects from eating gluten-containing foods. (Specter, 2014).

Wheat allergy, celiac, and NCGS

  • gluten sensitivity (NCGS).
  • Only a small amount of people have an antibody-mediated allergy to wheat
  • Most people who have issues with wheat react to the gluten component of grains (Specter, 2014).

Some effects of gluten consumption are (Specter, 2014):

  • abdominal and muscle pain
  • nausea
  • diarrhea and constipation
  • brain fog
  • mood changes.

Other effects of gluten include:

  • decreased nutrient absorption
  • increased digestive tract and systemic inflammation
  • damage to digestive tract lining leading to leaky gut
  • dysregulation of immune system function (Aucoin et al., 2020).

Celiac disease and NCGS

  • Celiac and NCGS are different conditions, but both can affect brain and mental health.

Characteristics of celiac disease

  • Mediated by a genetic predisposition
  • Exposure to gluten provokes autoimmune reactions that damage absorptive structures in the digestive tract as well as different organs throughout the body.

Characteristics of NCGS

  • negative response to gliadin and other grain proteins
  • over-activated innate immune system
  • different antibodies from those tied to celiac disease
  • absence of intestinal damage seen in celiac disease

Onset of symptoms after consuming wheat (Schuppan et al., 2015):

  • Allergy – minutes to hours
  • NCGS – hours to days
  • Celiac – days to weeks

Gluten and schizophrenia

  • Epidemiological studies show an association between wheat and gluten consumption and schizophrenia (Aucoin et al., 2020).
  • Celiac patients have been estimated to be at five times greater risk for becoming schizophrenic (Eaton et al., 2004; Kelly, et al., 2019).
  • Leaky gut caused by celiac or NCGS can allow undigested food particles and microorganisms to get into the bloodstream, where they promote inflammation and autoimmune reactions throughout the body, including the brain.
  • Patients with celiac and NCGS share similar inflammatory markers with schizophrenics (Jeppesen & Benros, 2019).
  • Inflammation is a known promoter of schizophrenia. It affects neurotransmitters, synaptic plasticity, and cortisol levels, which results in alterations to mood, awareness, and behaviour (Khandaker et al., 2015).

Addressing gluten issues

  • Avoid all sources of gluten
  • Some sources of gluten (Sources of Gluten, n.d.) are: wheat, rye, barley, triticale, malt, brewer’s yeast, wheat starch, pastas, noodles, bread, crackers, baked goods, cereals, sauces and gravy, beer
  • “Gluten-free diets represent a potential safe adjunctive therapeutic strategy for a subset of patients with schizophrenia” (Aucoin et al., 2020).

Diagnostic tests to determine likelihood of benefiting from a gluten-free diet can include:

  • serum concentrations of IgA and IgG antibodies to glutaminase (AGA) 
  • tissue transglutaminase (tTG) 
  • Also see Schizophrenia and exorphins section for more effects of gluten.


Aucoin, M., LaChance, L., Cooley, K., & Kidd, S. (2020). Diet and Psychosis: A Scoping Review. Neuropsychobiology, 79(1–2), 20–42. https://doi.org/10.1159/000493399

Eaton, W., Mortensen, P. B., Agerbo, E., Byrne, M., Mors, O., & Ewald, H. (2004). Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers. BMJ, 328(7437), 438-439.

Jeppesen, R., & Benros, M. E. (2019). Autoimmune diseases and psychotic disorders. Frontiers in Psychiatry, 10, 131.

Kelly, D. L., Demyanovich, H. K., Rodriguez, K. M., Ciháková, D., Talor, M. V., McMahon, R. P., … & Fasano, A. (2019). Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study. Journal of Psychiatry & Neuroscience: JPN, 44(3), 1-9.

Khandaker, G. M., Cousins, L., Deakin, J., Lennox, B. R., Yolken, R., & Jones, P. B. (2015). Inflammation and immunity in schizophrenia: Implications for pathophysiology and treatment. The Lancet. Psychiatry, 2(3), 258–270. https://doi.org/10.1016/S2215-0366(14)00122-9

Schuppan, D., Pickert, G., Ashfaq-Khan, M., & Zevallos, V. (2015). Non-celiac wheat sensitivity: Differential diagnosis, triggers and implications. Best Practice & Research. Clinical Gastroenterology, 29(3), 469–476. https://doi.org/10.1016/j.bpg.2015.04.002

Sources of Gluten. (n.d.). Celiac Disease Foundation. Retrieved September 27, 2020, from https://celiac.org/gluten-free-living/what-is-gluten/sources-of-gluten/

Specter, M. (2014). Against the grain. New Yorker Magazine.

What are exorphins?

  • Exorphins are short strands of amino acids, absorbed from partially digested food, that bind to opiate receptors in the brain.
  • The exorphins gliadorphin and casomorphin are generated from normal digestive breakdown of gluten and casein. Gliadorphin is derived from the gluten component of grains, and casomorphin is derived from the casein component of dairy.
  • At normal levels, exorphins have roles in food-seeking and appetite regulation. 
  • At high levels, exorphins drive addictions and alter sensory perceptions (Pruimboom, & De Punder, 2015), and cause:
    • speech and hearing problems
    • spaciness and “brain fog”
    • near-constant fatigue
    • irritability; aggression and moodiness
    • anxiety and depression
    • sleep problems

Causes of increased brain exorphins

  • Leaky gut (increased intestinal permeability) can allow large amounts of exorphins to enter the bloodstream from the digestive track and access the brain.
  • The enzyme dipeptidyl peptidase-IV (DPP-IV) breaks down gliadorphin and casomorphin into harmless amino acids. However, DPP-IV function can be inhibited by the gliadin component of gluten. When DPP-IV is inhibited, less gliadorphin and casomorphin is broken down, so more of it reaches the brain.

Drivers of DPP-IV insufficiency include: 

  • overconsumption of wheat and milk
  • genetic susceptibility
  • antibiotics
  • gelatin from vaccines
  • candida
  • mercury and other heavy metals
  • pesticides
  • nutritional deficiencies

Exorphins and schizophrenia

  • Blood and urinary concentrations of exorphins from wheat and dairy have been reported to be higher in schizophrenics (Bressan & Kramer, 2016).
  • A diet that excluded grains and milk versus a standard diet, allowed relapsing schizophrenics to be released significantly faster from hospital (Gaby, 2011), implying gliadorphin and casomorphin played a role in the expression of schizophrenic symptoms.


Bressan, P., & Kramer, P. (2016). Bread and other edible agents of mental disease. Frontiers in human neuroscience, 10, 130.

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Pruimboom, L., & De Punder, K. (2015). The opioid effects of gluten exorphins: asymptomatic celiac disease. Journal of Health, Population and Nutrition, 33(1), 24.


  • Caffeine is a molecule that acts as a stimulant in the central nervous system. It is commonly found in coffee, black tea, energy drinks, soda drinks, chocolate, some medications, as well as guarana and yerba maté.

Effects of caffeine

  • Effects of excessive caffeine consumption can include nervousness, irritability, palpitations, insomnia as well as increased heart rate, body temperature, blood flow, and blood sugar levels.
  • Caffeine depletes nutrients that are important for mental health such as B vitamins, vitamin C, potassium, magnesium, calcium, zinc (Scott, 2011).
  • Caffeine increases adrenal production of epinephrine and norepinephrine, which over time, can weaken the adrenal glands (Levi, 1967)
  • Excess caffeine makes the way the body responds to hypoglycemia worse (hypoglycemia is a risk factor for schizophrenia).

Caffeine and schizophrenia

  • Excessive caffeine consumption has been associated with worsening of psychosis, mania, and unusual thought content (Lucas et al., 1990).
  • Restricting caffeine consumption can promote decreased hostility, suspiciousness, anxiety, and irritability in people with psychiatric conditions who drink excessive amounts of coffee (“Effects of Caffeine in Chronic Psychiatric Patients,” 1979).


Effects of caffeine in chronic psychiatric patients. (1979). American Journal of Psychiatry, 136(10), 1337–1338. https://doi.org/10.1176/ajp.136.10.1337

Levi L. (1967) The effect of coffee on the function of the sympatho-adrenomedullary system in man. Acta Medica Scandinavica, 181(4), 431–438. https://doi.org/10.1111/j.0954-6820.1967.tb07260.x

Lucas, P. B., Pickar, D., Kelsoe, J., Rapaport, M., Pato, C., & Hommer, D. (1990). Effects of the acute administration of caffeine in patients with schizophrenia. Biological Psychiatry, 28(1), 35–40. https://doi.org/10.1016/0006-3223(90)90429-6

Scott T. (2011). The Antianxiety Food Solution: How the Foods You Eat Can Help You Calm Your Anxious Mind, Improve Your Mood, and End Cravings (Illustrated edition). New Harbinger Publications.

  • Nicotine is a stimulant compound found in tobacco and has been shown to increase heart rate and blood pressure.

Smoking and mental health

  • Smoking increases dopamine activity in the brain by increasing its production and decreasing its breakdown (Sagud et al., 2009).
  • Smoking increases the risk of panic attacks and panic disorder (Goodwin, Lewinsohn, & Seeley, 2005)

Nicotine and schizophrenia

  • Although smoking can temporarily relieve immediate anxiety, chronic smoking can increase chronic nervousness and agitation.
  • Smoking is significantly more common in schizophrenics compared to the general population. More than 60% of schizophrenics smoke (Sagud et al., 2009).
  • Smoking can increase the amount of antipsychotic medication required by schizophrenics. Medication amounts may need to be reduced if discontinuing smoking (Sagud et al., 2009).


Goodwin RD, Lewinsohn PM & Seeley JR. (2005) Cigarette smoking and panic attacks among young adults in the community: The role of parental smoking and anxiety disorders. Biological Psychiatry, 58(9), 686–693. https://doi.org/10.1016/j.biopsych.2005.04.042

Sagud, M., Mihaljević-Peles, A., Mück-Seler, D., Pivac, N., Vuksan-Cusa, B., Brataljenović, T., & Jakovljević, M. (2009). Smoking and schizophrenia. Psychiatria Danubina, 21(3), 371–375.

Environmental factors

Toxic metals like mercury, lead, and cadmium are pervasive in the environment. 

Toxic metals and mental health

  • An abundance of research shows that the accumulation of these metals in the body have negative impacts on health.
  • Toxic metals bind tissues and interfere with the functions of essential minerals (Sears, 2018). 
  • The high level of metabolic activity of the brain and excessive oxidative stress caused by toxic metals, can promote free radical damage to important components and molecules in the brain.
  • Toxic metals compete with essential minerals for absorption and transportation, which means poor nutrition increases the risk for toxicity (Sears, 2018).
  • The brain is especially susceptible to accumulation and storage of fat-soluble toxic metals because of its high fatty-acid composition (Orisakwe, 2014).

Toxic metals and schizophrenia.

  • Toxic metals that have roles in the development or manifestation of schizophrenia include lead, aluminum, cadmium, copper, arsenic.

Addressing toxic metal accumulation

  • Environmental and dietary sources of toxic metal exposures need to be identified and removed as much as possible. 
  • Many patients will improve with a basic protocol of a healthy diet, supplementation of essential nutrients, exercise and rest. Sweating from exercise or sauna can also help remove toxic metals (Sears, 2018).
  • The best approach for brain detoxification is conservatively, “with repeated, modest treatments, using multiple agents” (Sears, 2018).
  • It is important to work with a practitioner that is trained in detoxification when addressing excessive or chronic heavy metal exposure or accumulation.


Orisakwe, O. E. (2014). The role of lead and cadmium in psychiatry. North American Journal of Medical Sciences, 6(8), 370. https://doi.org/10.4103/1947-2714.139283.

Sears M. E. (2013). Chelation: harnessing and enhanc- ing heavy metal detoxification – a review. The Scientific World Journal, 2013, 219840. https://doi.org/10.1155/2013/219840.


Medication-induced nutrient deficiencies and mental health

Many types of medications deplete essential nutrients that have roles in preventing mental health issues. For example:

  • Oral contraceptives, antidepressants, decongestants deplete vitamin B6 (Pelton, LaValle, & Hawkins, 2001)
  • Corticosteroids, ACE inhibitors and oral contraceptives deplete zinc.  (Scott, 2011)
  • The antipsychotic drug chlorpromazine may cause riboflavin deficiency in malnourished people (Pelliccione et al., 1983). Riboflavin deficiency can cause psychiatric symptoms (Zaslove et al., 1983)

Further information

An in-depth examination of common medications and nutrient depletions. (Mohn et al. 2018)



Bouchard, M., Bellinger, D. C., Weuve, J., Matthews-Bellinger, J., Gilman, S. E., Wright, R. O., Schwartz, J., & Weisskopf, M. G. (2009). Blood lead levels and major depressive disorder, panic disorder, and generalized anxiety disorder in U.S. young adults. Archives of General Psychiatry, 66(12), 1313–1319. https://doi.org/10.1001/archgenpsychiatry.2009.164

Mohn ES, Kern HJ, Saltzman E, Mitmesser SH & McKay DL. (2018) Evidence of drug–nutrient interactions with chronic use of commonly prescribed medications: An update. Pharmaceutics, 10(1). https://doi.org/10.3390/pharmaceutics10010036

Pelton, R., LaValle, J. B., & Hawkins, E. B. (2001). Drug-Induced Nutrient Depletion Handbook. Hudson OH. Lexi-Comp.

Scott T. (2011). The Antianxiety Food Solution: How the Foods You Eat Can Help You Calm Your Anxious Mind, Improve Your Mood, and End Cravings (Illustrated edition). New Harbinger Publications.

Pelliccione, N., Pinto, J., Huang, Y. P., & Rivlin, R. S. (1983). Accelerated development of riboflavin deficiency by treatment with chlorpromazine. Biochemical Pharmacology, 32(19), 2949–2953. https://doi.org/10.1016/0006-2952(83)90401-x

Zaslove, M., Silverio, Y., & Minenna, R. (1983). Severe Riboflavin Deficiency: A Previously Undescribed Side Effect of Phenothiazines. Journal of Orthomolecular Psychiatry, 12, 113–115.

Medications and Schizophrenia

Standard schizophrenia treatments use atypical psychotic drugs (APDs) which act primarily on dopamine receptors. These medications typically only partially reduce symptoms. 

Some APDs include:

  • Aripiprazole
  • Clozapine
  • Olanzapine
  • Quetiapine
  • Risperidone

Additional drugs are often required to address the extrapyramidal and parkinsonian symptoms caused by the APDs. These symptoms can include:

  • tremors
  • muscle spasms 
  • rigidity
  • slowness
  • involuntary movements

Schizophrenic patients taking one or more of the APDs can experience a state of unease or dissatisfaction (Horrobin, 2001), and are at higher risk for brain damage, heart arrhythmias, diabetes, weight gain, sexual dysfunction, and akathisia (uncontrollable urge to move).

Tranquilizer psychosis and tardive dyskenesia

  • The “tranquilizer psychosis” is a term used to describe the mental effects — lethargy, loss of interest, difficulty in concentration, loss of libido, tardive dyskinesia —which the antipsychotic drugs exert on the patient.
  • Tardive dyskinesia is an involuntary neurological disorder caused by dopamine-affecting medications, resulting in uncontrollable, erratic or repetitive muscular movements.

Orthomolecular support and medications

  • According to Dr. Hoffer, less than 10 percent of schizophrenic patients treated with drugs alone recover (Gaby, 2011). 
  • By combining both nutrients and drugs patients can take advantage of both therapies and minimize the disadvantages. Patients started on both will respond much more quickly.
  • The use of orthomolecular nutrients in conjunction with medications can reduce medication need, reduce side effects, and increase chances for a full recovery
  • Results of orthomolecular treatments may be seen after one to two months, but it can take 3 to 6 months to see clinical benefits. With chronic schizophrenia, results may take years to see benefits.

Decreasing medications

  • “Antipsychotic drugs convert a natural psychosis to a different type of psychosis. Consequently, any improvement resulting from the use of diet and nutritional supplements may not become evident until medication doses are decreased” (Gaby, 2011).
  • Medications should not be discontinued without the cooperation of the patient’s psychiatrist, and even then they may need to be reduced very slowly, over many months to several years.


Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Metabolic conditions

  • Schizophrenia symptoms can be caused or promoted by nutrient deficiencies or dependencies.


  • Nutrient deficiency is when the minimum amounts of nutrients needed for normal body function are not met by diet
  • A nutrient deficiency results in depletion of nutrients in body tissues, and changes to mental and physical functioning from diet, medications.


  • The metabolic need for a nutrient exceeds what can be supplied by diet and results in impaired biochemical processes and functions.
  • A nutrient dependency results from long-term environmental and genetic stressors.

Food allergies and the brain

  • Allergic reactions may play a major role in almost every psychiatric syndrome, including mood disorders, schizophrenia, the anxiety states, and children with learning and/or behavioral disorders.
  • Food allergies and sensitivities that affect the brain can be referred to as “cerebral allergies”. Cerebral allergies encompass more than antibody-antigen reactions.

Cerebral allergies are mediated by:

  • direct biochemical effects of substances found in food or drink, for example caffeine, alcohol, and sugar
  • hidden or delayed allergic reactions to food or drink, for example wheat, milk, corn, and egg

Foods commonly associated with allergies (Prousky, 2015):

  • dairy products
  • wheat, rye, barley
  • eggs
  • pork, beef, seafood
  • soy
  • corn, tomato
  • citrus fruits
  • nuts, peanuts
  • chocolate
  • coffee, tea
  • sugar
  • yeast

Food allergies and schizophrenia

  • Food allergy reactions that affect the brain may be a contributor to psychosis.
  • Schizophrenic patients have a high prevalence of food antibodies (Gaby, 2011)
  • A study by Kinnell et al. (1982) showed that 37% of schizophrenics, when tested for wheat, oats, gluten, chicken, beef, and milk protein, had antibodies for one or more of the foods.
  • Antibodies to certain foods may cross-react with brain tissue in susceptible people and negatively impact brain function (Gaby, 2011)
  • Anti-brain antibodies in a study by Pandey et al (1981) were absent in healthy controls, but were present in 48% of schizophrenics.

Foods that have been reported to frequently cause symptoms in people with schizophrenia include (Philpott, 1976):

  • wheat
  • dairy
  • corn
  • coffee
  • legumes

Identifying food allergies

  • Common symptoms include: a history of many colds, runny noses, earaches, and tubes in the ears. 
  • Allergic children may have red ears and allergic “shiners” (dark circles under the eyes caused by congestion)
  • Often allergic patients love what they are allergic to and have great difficulty in eliminating these foods from their diet.

Addressing food allergies

  • Food allergies can often be identified by following an elimination diet, then testing individual foods one at a time. 
  • Once identified, allergic foods need to be eliminated from the diet.
  • When allergic substances are eliminated, it may take one to six months to become free of the food-allergy effects.
  • Food allergies often point to leaky gut.
  • A digestive healing protocol should be considered as part of addressing food allergies in the context of schizophrenia.


Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Kinnell, H. G., Kirkwood, E., & Lewis, C. (1982). Food antibodies in schizophrenia. Psychological Medicine, 12(1), 85–89. https://doi.org/10.1017/s0033291700043312

Pandey, R. S., Gupta, A. K., & Chaturvedi, U. C. (1981). Autoimmune model of schizophrenia with special reference to antibrain antibodies. Biological Psychiatry, 16(12), 1123–1136.

Philpott, W. (1976). Allergy and ecology in orthomolecular psychiatry. In L. Dickey  (Ed.) Clinical Ecology (pp. 729–737). Charles C. Thomas. Springfield, IL

Prousky J, (2015) Anxiety: Orthomolecular diagnosis and treatment, Kindle Edition. CCNM Press.

Adrenochrome and schizophrenia

  • Adrenochrome is a toxic derivative of adrenaline, which is thought to have a role in producing the psychotic features of schizophrenia.
  • People with schizophrenia can have a reduced capacity to degrade and remove adrenaline from their body, which makes them more susceptible to its negative effects

When healthy volunteers were given adrenochrome in a study, they experienced (Gaby, 2011):

  • changes in visual perception, thinking, and mood
  • hallucinations
  • psychotic reactions identical to schizophrenia

Adrenolutin, which is derived from adrenochrome, has also been shown to promote hallucinations.

Addressing adrenochrome

See vitamin B3 and vitamin C sections.


Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

The microbiome

  • The human microbiome is made up of 10-100 trillion microbial cells consisting of bacteria, fungi, and viruses, among many others.
  • The microbiome also includes the genes contained by these cells (Ursell et al., 2012).
  • The composition of the microbiome is influenced by changes in diet and health (Quigley, 2013).

The microbiome is affected by:

  • antibiotics
  • infections
  • dietary sucrose (sugar and starch consumption)
  • dietary chemicals – including pesticides, additives and preservatives
  • medications – NSAIDs, Prednisone, OCP
  • food intolerances 
  • location of birth
  • th birthing process 
  • formula feeding

The gut-brain axis and mental health

  • The gut-brain axis includes the brain, spinal cord, autonomic nervous system (sympathetic, parasympathetic and enteric nervous systems), and the hypothalamic-pituitary–adrenal (HPA) axis (Dinan et al., 2015).
  • Mental health conditions affected by the gut-brain axis include anxiety, depression, autism, obsessive compulsive disorder, and schizophrenia.

Assessment of the microbiome in the context of schizophrenia suggests that schizophrenia is associated with (Nguyen, Kosciolek, Eyler, Knight, & Jeste, 2018):

  • reduced microbial diversity
  • increased intestinal inflammation and permeability, and 
  • microbial populations that are associated with depressive and psychotic symptoms, compromised physical health and sleep.

The microbiome and schizophrenia

  • The microbiome may promote the production of the beneficial protein brain-derived neurotrophic factor (BDNF). BDNF is an important growth factor for neurons and has a role in the function of NMDA neurotransmitter receptors – both of which have a well-established relationship with schizophrenia pathology.

Candida and schizophrenia

Candida is a type of yeast and the most common cause of human fungal infections (Manolakaki et al., 2010).

Schizophrenia symptoms have been reported to be improved by antifungal medications and treatments (“Mold, Mycotoxins & Autoimmunity,” n.d.).

“Candidiasis should be considered as a possible contributing factor in schizophrenic patients who have had recurrent vaginal yeast infections or a history of treatment with antibiotics, oral contraceptives, or systemic glucocorticoids” (Gaby, 2011).


Dinan, T. G., Stilling, R. M., Stanton, C., & Cryan, J. F. (2015). Collective unconscious: How gut microbes shape human behavior. Journal of Psychiatric Research, 63, 1–9. https://doi.org/10.1016/j.jpsychires.2015.02.021

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Manolakaki, D., Velmahos, G., Kourkoumpetis, T., Chang, Y., Alam, H. B., De Moya, M. M., & Mylonakis, E. (2010). Candida infection and colonization among trauma patients. Virulence, 1(5), 367–375. https://doi.org/10.4161/viru.1.5.12796

Mold, Mycotoxins & Autoimmunity; Is There a Link? (n.d.). Naturopathic Doctor News and Review. Retrieved December 10, 2020, from https://ndnr.com/autoimmuneallergy-medicine/mold-mycotoxins-is-there-a-link/

Nguyen, T. T., Kosciolek, T., Eyler, L. T., Knight, R., & Jeste, D. V. (2018). Overview and systematic review of studies of microbiome in schizophrenia and bipolar disorder. Journal of Psychiatric Research, 99, 50–61. https://doi.org/10.1016/j.jpsychires.2018.01.013

Quigley, E. M. M. (2013). Gut Bacteria in Health and Disease. Gastroenterology & Hepatology, 9(9), 560–569. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983973/

Ursell, L. K., Metcalf, J. L., Parfrey, L. W., & Knight, R. (2012). Defining the Human Microbiome. Nutrition Reviews, 70(Suppl 1), S38–S44. https://doi.org/10.1111/j.1753-4887.2012.00493.x

Hypoglycemia is a condition of abnormally low levels of blood sugar.

Causes of hypoglycemia include (Hypoglycemia – Symptoms and Causes, n.d.):

  • diabetes
  • medications
  • excessive alcohol consumption
  • liver and/or kidney disorders
  • overproduction of insulin

Reactive hypoglycemia – overview

  • Consumption of a high-carbohydrate meal or drink causes a rapid rise in blood glucose. 
  • The high glucose causes the pancreas to release an abnormally high amount of insulin into the blood. This causes an abrupt drop in blood glucose.
  • The excessive drop in blood sugar triggers the release of the hormones epinephrine and norepinephrine, which in turn, trigger the “fight or flight” response.
  • The “fight or flight” response will show as hunger, irritability, sweating, palpitations, and anxiety.

Reactive hypoglycemia and schizophrenia

  • Reactive hypoglycemia can trigger or worsen symptoms such as anxiety, depression, fatigue, and paranoia (Gaby, 2011)

Identifying hypoglycemia

Signs of hypoglycemia:

  • tendency to crave sweets
  • consuming sugar or refined starches temporarily reduces hypoglycemia symptoms
  • symptoms worsen in the late morning or late afternoon
  • mental and anxiety symptoms occur after fasting, late at night, or first thing in the morning (Eaton & Konner, 1985)

Symptoms of hypoglycemia (Hypoglycemia – Symptoms and Causes, n.d.):

  • irregular or fast heartbeat
  • fatigue
  • pale skin
  • shakiness
  • anxiety
  • sweating
  • hunger
  • irritability
  • tingling or numbness of the lips, tongue or cheek

Typical medical tests to assess blood-sugar metabolism are:

  • fasting glucose
  • HbA1c, 
  • insulin, cortisol, ketone bodies, lactic acid, free fatty acids, and thyroid hormone may also be included (Mandal, 2019)


Eaton SB & Konner M. (1985) Paleolithic nutrition. New England Journal of Medicine, 312(5), 283–289. https://doi.org/10.1056/NEJM198501313120505

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Mandal D. (2019) Hypoglycemia diagnosis. Retrieved September 25, 2020, from https://www.news-medical.net/health/Hypoglycemia-Diagnosis.aspx

Hypoglycemia—Symptoms and causes. (n.d.). Mayo Clinic. Retrieved November 29, 2020, from https://www.mayoclinic.org/diseases-conditions/hypoglycemia/symptoms-causes/syc-20373685

  • Homocysteine is an amino acid that is made by the body and is also supplied by food.
  • Deficiencies of folate, vitamin B12, and vitamin B6 can result in increased homocysteine levels.

Homocysteine and schizophrenia

  • Many schizophrenia patients have elevated levels of homocysteine.
  • Elevated homocysteine levels are associated with mental issues including mild cognitive impairment, Alzheimer’s Disease, Parkinson’s Disease, depression, and schizophrenia (Kim & Moon, 2011)
  • Supplementation with vitamin B6, vitamin B12, and folic acid were shown to lower homocysteine levels and improve symptoms of schizophrenia compared with a placebo in a study by Levine et al. (2006)


Kim, T. H., & Moon, S. W. (2011). Serum Homocysteine and Folate Levels in Korean Schizophrenic Patients. Psychiatry Investigation, 8(2), 134–140. https://doi.org/10.4306/pi.2011.8.2.134

Levine, J., Stahl, Z., Sela, B.-A., Ruderman, V., Shumaico, O., Babushkin, I., Osher, Y., Bersudsky, Y., & Belmaker, R. H. (2006). Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biological Psychiatry, 60(3), 265–269. https://doi.org/10.1016/j.biopsych.2005.10.009

  • Histadelia is a clinical syndrome that is promoted by elevated histamine levels.

Histadelia and schizophrenia

  • Dr. Pfeiffer (1975) stated that around 20% of schizophrenics are estimated to have histadelia, and often suffer from suicidal depression.

Vitamin B3,vitamin C, and histadelia

  • The nicotinic acid form of vitamin B3, niacin, decreases tissue stores of histamine, which in turn helps to lower blood histamine levels. 
  • The nicotinamide form of vitamin B3, niacinamide,  helps with histadelia by inhibiting mast cell histamine release, which happens during an allergic response.
  • Both the nicotinic acid and the nicotinamide forms of vitamin B3 may be required to address the nicotinamide adenine dinucleotide (NAD) deficiency. NAD deficiency is considered to be the driver of histadelia.
  • Vitamin C has been shown to lower blood histamine levels. However people with schizophrenia may have impaired vitamin C metabolism, and a resulting increase in circulating histamine.


Pfeiffer CC, Bacchi D. Copper, zinc, manganese, niacin and pyridoxine in the schizophrenias. J Applied Nutr 1975;27(2,3):9–39

  • Histapenia is a clinical syndrome that is promoted by low histamine and high serum copper levels.
  • Histapenia is characterized by high blood copper and low histamine values. 

Histapenia and schizophrenia

  • Dr. Pfeiffer (1975) stated that around 50 percent of schizophrenics have histapenia, are usually over-stimulated, paranoid, and  suffer from hallucinations.

Addressing histapenia

When treated for histapenia by Dr. Pfeiffer, patients had the following time sequence of improvement:

  • In the first month, sweaty palms, racing thoughts, insomnia and hypomania tend to diminish. 
  • By one year, the hallucinations, obesity and paranoid ideas diminish.

Histapenic patients respond well to supplementation of Vitamin B3, folic acid, and Vitamin B12.

Take caution when supplementing vitamins while taking antipsychotic medications

  • Doses larger than 2 mg/day of folate, together with antipsychotic medications, can cause involuntary muscle twitching and seizures.
  • Excessive amounts of folic acid and vitamin B12 can increase histamine levels too much, increasing the risk of depression – so blood histamine levels should be monitored during this treatment. (Gaby, 2011)


Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Pfeiffer CC, Bacchi D. Copper, zinc, manganese, niacin and pyridoxine in the schizophrenias. J Applied Nutr 1975;27(2,3):9–39

  • Pyrroles are a by-product of hemoglobin production and are normally excreted in the urine.
  • Pyroluria is a condition of overproduction of pyrroles (McGinnis 2008a, 2008b). 
  • Excess pyrroles bind vitamin B6 (pyridoxine) and zinc, removing them from the bloodstream.

Signs of high amounts of kryptopyrrole are most prevalent in adolescents and children and include: 

  • white areas in their fingernails
  • fragile nails
  • pain in the joints often the knees
  • lack of pigment in the skin
  • skin infections and acne
  • sometimes morning nausea
  • poor dream recall
  • insomnia
  • psychiatric symptoms

Pyroluria and mental health

The mental symptoms of pyroluria are largely related to zinc and vitamin B6 deficiencies. 

Mental symptoms of these deficiencies include:

  • anxiety and depression
  • mood swings
  • poor stress control
  • severe inner tension
  • episodic anger
  • nervousness
  • poor short-term memory

Addressing pyroluria

  • Pyroluria can be objectively diagnosed by elevated levels of HPL (Hydroxyhemopyrrolin-2-one) when measured by the kryptopyrrole quantitative urine test.
  • The amount of kryptopyrrole can fluctuate dramatically. Stress, illness, and injury increase levels.
  • For optimal test results, the urine should be collected during a period of increased stress.

Supplementation support for addressing pyroluria (Greenblatt, 2018):

  • 200-800 mg of vitamin B6 in the pyridoxal-5-phosphate form
  • 25–100 mg of zinc

Dr. Jonathan Prousky (2006) stated, “Although I could test for this compound [HPL], I choose not to, since these nutrients are inexpensive and have minimal side effects. The daily dosages I routinely start with are 250 mg of pyridoxine and 50 mg of zinc”.


McGinnis WR, Audhya T, Walsh WJ, Jackson JA, McLaren-Howard J, Lewis A & Ho er A. (2008a) Discerning the mauve factor, Part 1. Alternative Therapies in Health and Medicine, 14(2), 40–50.

McGinnis WR, Audhya T, Walsh WJ, Jackson JA, McLaren-Howard J, Lewis A & Ho er A. (2008b) Discerning the mauve factor, Part 2. Alternative Therapies in Health and Medicine, 14(3), 56–62.

Prousky J. (2006) The orthomolecular treatment of schizophrenia. Naturopathic Doctor News and Review. https://ndnr.com/neurology/the-orthomolecular-treatment-of-schizophrenia/

Greenblatt J. (2018, May 24) Integrative therapies for schizophrenia and psychosis, Module 1 [Webinar]. Retrieved from: https://isom.ca/schizophrenia-psychosis/

Thyroid hormones and the brain

  • Thyroid hormones have important roles in brain health and function. They are mediators of neuronal cell migration, differentiation, signalling, and brain maturation (Bernal, 2005). Thyroid hormones are also important for axonal outgrowth, dendritic branching and myelination (Calzà, Fernández & Giardino, 2015).
  • Thyroid hormones affect the amount of dopamine receptors that are made, as well as affecting the formation of dopamine, norepinephrine and epinephrine.
  • Thyroid hormones also have roles in regulating serotonin and glutamate levels. (Santos et al., 2012)

The hypothyroid state 

Hypothyroidism is a state of decreased effect of thyroid hormones on the body. Common symptoms of hypothyroid include: 

  • cold intolerance
  • low body temperature
  • weakness
  • low energy or fatigue
  • easy weight gain
  • hair loss
  • pain
  • headache
  • PMS
  • insomnia
  • indigestion and constipation
  • elevated cholesterol
  • frequent infections

Mental symptoms of hypothyroid include (Pataracchia, 2008; Hoffer, 2001a):

  • impaired cognition
  • anxiety or panic
  • depression
  • irritability
  • poor memory or concentration

Causes of hypothyroid

  • Insufficient precursor molecules for thyroid hormone, especially iodine and tyrosine.
  • Molecules like bromine and genistein can compete with iodine and tyrosine for absorption and incorporation into thyroid hormones.
  • Autoimmune action against thyroid enzymes and TSH receptors reduce thyroid function.
  • Decreased conversion of T4 to the more metabolically active form T3 can result from (Hoffer, 2001a) stress, oxidative stress, environmental toxin exposures, liver and kidney issues, calorie restriction, sleep deprivation, and excessive exercise.
  • Thyroid hormone receptors on target cells can become resistant to T3 due to environmental toxins, as well as autoimmune, genetic, and other factors.

Hypothyroid in the brain

  • Conversion of T4 to T3 can be inhibited in the brain by cortisol. Cortisol levels in schizophrenics are often elevated, especially when they are experiencing stress.

Hypothyroid and schizophrenia

  • Hypothyroidism affects systems involved in schizophrenia including:
    • metabolism of serotonin, dopamine, glutamate and GABA
    • myelination and regulation of inflammation (Santos et al., 2012).
  • Hypothyroidism is common in schizophrenia patients (Santos et al., 2012). Low thyroid symptoms are often seen in patients with psychosis, and schizophrenics can relapse when thyroid function is low (Pataracchia, 2008).
  • A study by Themeli, Aliko, & Hashorva (2011) showed that 25% of chronic schizophrenic patients had evidence of thyroid dysfunction. 
  • Thyroid function is often reduced as a result of taking psychiatric medications (Vickery, Mathews, & Vickery, 2019).


Bernal, J. (2005). Thyroid hormones and brain devel- opment. Vitamins & Hormones, 95–122. https://doi.org/10.1016/s0083-6729(05)71004-9.

Calzà, L., Fernández, M., & Giardino, L. (2015). Role of the thyroid system in myelination and neural connectivity. Comprehensive Physiology, 5(3), 1405–1421. https://doi.org/10.1002/cphy.c140035.

Hoffer, A. (2001a). Thyroid and schizophrenia. Journal of Orthomolecular Medicine, 16(4), 205–212.

Pataracchia, R. J. (2008). Orthomolecular treatment for schizophrenia: A review (Part Two). Journal of Orthomolecular Medicine, 23(2), 95–105.

Santos, N. C., Costa, P., Ruano, D., Macedo, A., Soares, M. J., Valente, J., … Palha, J. A. (2012). Revisiting thyroid hormones in schizophrenia. Journal of Thyroid Research, 2012, 1–15. https://doi.org/10.1155/2012/569147.

Themeli, Y., Aliko, I., & Hashorva, A. (2011). P03-345 – Thyroid dysfunction in chronic schizophrenia in Albania. European Psychiatry, 26(Suppl. 1), 1515.

Vickery, P. B., Mathews, A., & Vickery, S. B. (2019). E ects of psychotropic medications on thyroid function. Current Psychiatry, 18(1), 61-63.

Orthomolecular interventions for schizophrenia

Orthomolecular interventions are substances like vitamins and minerals that have roles in promoting or addressing anxiety, depending on the amount present inthe body.


There are two main forms of nicotinic acid known medically as Niacin and Nicotinamide. 

Vitamin B3 deficiency is known as Pellagra. Dr. Abram Hoffer reported that the earliest symptoms of subclinical (early, mild) pellagra appear as anxiety, depression, and fatigue (Prousky, 2015).

Psychosis and the neurological symptoms of pellagra are remarkably similar.

Actions of vitamin B3 in regards to schizophrenia

  • Helps correct subclinical pellagra
  • Increases serotonin production by diverting more tryptophan conversion to serotonin (Gedye, 2001)
  • Has sedative, benzodiazepine effects (Hoffer, 1962)
  • Can increase the effectiveness some sedatives, tranquilizers, and anticonvulsants (Hoffer, 1962)
  • Decreases production of adrenochrome (Hoffer, 1999)
  • Accepts methyl groups which would otherwise be used to produce adrenaline. As well, vitamin B3 acts as an antioxidant to prevent the oxidation of adrenalin to adrenochrome (Prousky, 2006).

Causes of vitamin B3 deficiencies (Niacin, 2014):

  • inadequate oral intake
  • poor bioavailability from grain sources
  • issues with absorption of tryptophan
  • some metabolic disorders
  • long-term chemotherapy treatments

Top food sources of vitamin B3 based on serving size:

  • chicken
  • tuna
  • turkey
  • salmon
  • beef

Comprehensive food list:

Table 2. Some Food Sources of Niacin (Niacin, 2014)


Referenced Dietary Intakes

Tolerable Upper Intake Level (UL) for Niacin and niacinamide (mg/day)

Children (9-13 years): 20 mg/day

Adolescents (14-18 years): 30 mg/day

Adults (19 years and older): 35 mg/day

The Food and Nutrition Board set the tolerable upper intake level (UL) for niacin (nicotinic acid and nicotinamide) at 35 mg/day in adults to avoid the adverse effect of flushing. (Niacin, 2014)

1. Vitamin B3 (niacin) Supplementation

  • Amounts of niacin/nicotinic acid used in practice and research range from 100–3000 mg/day in divided doses (Niacin, 2014).

The niacin flush

Niacin causes capillaries to dilate which results in increased blood flow to the skin. This effect is known as the “niacin flush”. It is harmless, but can be uncomfortable.

About the niacin flush:

  • Causes a“prickly heat” sensation
  • Causes the skin to feel warm and become red
  • The flush begins in the forehead and works its way down the body, rarely affecting the toes
  • The flush usually begins a few minutes after taking the niacin supplement
  • The flush may last for several hours
  • Each time that niacin is taken, the degree of flushing decreases
  • Most people will flush with 100 mg of niacin, some people will flush with less than 100 mg
  • The higher the initial niacin dose, the greater the initial flush
  • If the niacin supplementation is interrupted for several days, the flushing will resume as if starting for the first time, but not as strong as the original flush

Reducing the niacin flush

In a guide for patients, updated in 2018 by his long-time assistant Frances Fuller, Dr. Hoffer explained ways to mitigate the niacin flush. 

Actions to take include:

  • Taking 2 to 4 g of vitamin C at the beginning of a meal, and then taking niacin at the end of the meal. (Vitamin C decreases the flush by neutralizing histamine in the blood)
  • Taking the niacin with a cold beverage
  • Avoiding hot showers or baths immediately after taking niacin
  • Starting with a lower amount of niacin and gradually increasing the daily dose—for example starting with 125 mg, then doubling the amount every 4-5 days (flushing should stop shortly after reaching 1,000 mg per day

Chronic exposure to allergens, either food-based or environmental, can stimulate continuous production of histamine. This ongoing supply of histamine can be a reason why some people continue to flush, even after long-term niacin supplementation.


  • People who may be more susceptible to effects of excess niacin intake include those with abnormal liver function or liver disease, diabetes, active peptic ulcer disease, gout, cardiac arrhythmias, inflammatory bowel disease, migraine headaches, or alcoholism (Niacin, 2014).

Extended-release niacin has been associated with increased risk of serious adverse events (Anderson et al. 2014).

Although rare, serum aminotransferase levels should periodically be tested to monitor possible hepatotoxicity in patients who take large doses of vitamin B3 (Gaby, 2011).

2. Vitamin B3 (nicotinamide) Supplementation

  • Amounts of nicotinamide used in practice and research range from 300–3000 mg/day in divided doses (Niacin, 2014).
  • Dr. Abram Hoffer recommended 1500–6000 mg of niacinamide for all patients with psychiatric syndromes (Hoffer, 1995).
  • Most people need minimum 2000–4500 mg/day of niacinamide, and relief of symptoms can be seen within one month (Prousky, 2015).


  • Niacinamide supplementation doses of 1500-6000 mg have been used for extended amounts of time in children and adolescents without side effects or complications (Hoffer, 1971: Hoffer 1999).
  • Niacinamide does not generally cause flushing. The most common side effects of niacinamide supplementation are sedation (Werbach, 1997, p133-60).
  • At very high doses (≥10 g/day), nausea, vomiting, and signs of liver toxicity (elevated liver enzymes, jaundice) have been observed (Niacin, 2014).


Anderson, T. J., Boden, W. E., Desvigne-Nickens, P., Fleg, J. L., Kashyap, M. L., McBride, R., & Probstfield, J. L. (2014). Safety Profile of Extended-Release Niacin in the AIM-HIGH Trial. New England Journal of Medicine, 371(3), 288–290. https://doi.org/10.1056/NEJMc1311039

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Gedye, A. (2001). Hypothesized treatment for migraines using low doses of tryptophan, niacin, calcium, caffeine, and acetylsalicylic acid. Medical Hypotheses, 56(1), 91–94. https://doi.org/10.1054/mehy.2000.1117

Hoffer A. (1962). Nicotinic acid and niacinamide as sedatives. Niacin Therapy in Psychiatry. Springfield, IL: C.C. Thomas.

Hoffer, A.(1995). Vitamin B-3: Niacin and its amide. Townsend Letter for Doctors & Patients 147:30-39.

Hoffer, A. (1971). Vitamin B3 dependent child. Schizophrenia 3:107-13.

Hoffer. A. (1999). Dr. Hoffer’s ABC of Natural Nutrition for Children. CCNM Press.

Niacin. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/niacin

Prousky, J. (2006). The orthomolecular treatment of schizophrenia. Naturopathic Doctor News and Review.

Prousky J, (2015) Anxiety: Orthomolecular diagnosis and treatment. CCNM Press.

Werbach, M. R. (1997). Adverse effects of nutritional supplements. Foundations of Nutritional Medicine. Tarzanna, CA: Third Line Press, Inc,.

Vitamin B6 is required for:

  • The conversion of the amino acid tryptophan into serotonin, tyrosine to dopamine
  • The conversion of glutamate into GABA – improper glutamate metabolism is implicated in psychosis and schizophrenia (Kraal et al., 2020)
  • Reduction of homocysteine – elevated homocysteine has been implicated in schizophrenia symptoms
  • Synthesis of glutathione and metallothionein – molecules important for detoxification of toxic metals

Vitamin B6 and schizophrenia

  • Vitamin B6 may influence schizophrenia symptoms as it has roles in dopamine, serotonin, and glutamate metabolism.
  • Vitamin B6 can help address medication-induced symptoms of tardive dyskinesia.

Causes of vitamin B6 deficiencies

  • inadequate dietary intake
  • medications, including anti-tuberculosis drugs, antiparkinsonians, nonsteroidal anti-inflammatory drugs, and oral contraceptives, may interfere with vitamin B6 metabolism. (Vitamin B6, 2014)
  • alcoholism – due to low intake and impaired metabolism of vitamin B6

Deficiency of vitamin B6 can be identified by:

  • the absence of dreams, or the inability to remember dreams
  • having disturbing dreams or nightmares

Top sources of vitamin B6 based on serving size

  • salmon
  • potato
  • turkey
  • avocado

Comprehensive food list:

Table 2. Some Food Sources of vitamin B6 (Vitamin B6, 2014)


Referenced Dietary Intakes

RDAs for vitamin B6 (mg/day)
Adolescents (14-18 years): 1.3 (M) 1.2 (F)
Adults (19-50 years): 1.3 (M) 1.3 (F)
Adults (51 years and older): 1.7 (M) 1.5 (F)

Tolerable Upper Intake: 100 mg/day
(Office of dietary supplements, 2020)

Vitamin B6 Supplementation

  • Amounts of vitamin B6 used in practice and research range from 20–6000 mg/day in divided doses (Office of dietary supplements, 2020).
  • In a study, fifteen patients with schizophrenia and schizoaffective disorder were given 400 mg/day of vitamin B6 for 9 weeks. The supplementation significantly improved tardive dyskinesia and parkinsonian symptoms (Miodownik, Cohen, Kotler, & Lerner, 2003).


  • Doses above 100 mg/day may, in some people, cause side effects that include nausea, vomiting, stomach pain diarrhea, headache, tingling, and sleepiness. The risk of negative effects can be reduced by supplementing  magnesium 6.6–8.8 mg /kg as well as a B-complex vitamin (Prousky, 2015).
  • Monitoring for symptoms of sensory neuropathy should be considered with long-term supplementation of more than 200 mg/day of vitamin B6 (Gaby, 2011).


  • High doses of vitamin B6 have been found to decrease the efficacy of phenobarbital, phenytoin, and L-Dopa (Vitamin B6, 2014).


Kraal, A. Z., Arvanitis, N. R., Jaeger, A. P., & Ellingrod, V. L. (2020). Could Dietary Glutamate Play a Role in Psychiatric Distress? Neuropsychobiology, 79(1–2), 13–19. https://doi.org/10.1159/000496294

Miodownik, C., Cohen, H., Kotler, M., & Lerner, V. (2003). Vitamin B6 add-on therapy in treatment of schizophrenic patients with psychotic symptoms and movement disorders. Harefuah, 142(8-9), 592-6.

Office of Dietary Supplements—Vitamin B6. (n.d.). Retrieved October 28, 2020, from https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/

Prousky J, (2015) Anxiety: Orthomolecular diagnosis and treatment, Kindle Edition. CCNM Press.

Vitamin B6. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/vitamin-B6

Vitamin B12 and schizophrenia

  • A deficiency of vitamin B12 can affect mood, emotions, sleep, and can result in psychiatric disorders. (Valizadeh & Valizadeh, 2011)

Roles of vitamin B12 in the context of schizophrenia:

  • Required for the synthesis of neurotransmitters including serotonin and dopamine
  • Required for the preservation of protective myelin sheath around neurons
  • Important for homocysteine metabolism
  • Can help reduce, reverse, and normalize damaged neurons by decreasing homocysteine levels

Psychiatric manifestations of vitamin B12 deficiency include (Oh & Brown, 2003: Dommisse, 1991):

  • agitation, restlessness, irritability
  • dementia
  • depression, fatigue
  • mild memory impairment
  • negativism
  • panic/phobic disorders
  • personality changes
  • psychosis

Causes of deficiencies

The most common causes of vitamin B12 deficiency:

  • vitamin B12-deficient diet
  • vegetarianism or veganism
  • bacterial overgrowth in the small intestine
  • increased breakdown of vitamin B12 in brain tissue (Gaby, 2011)
  • poor absorption due to decreased stomach acid production, low intrinsic factor, celiac or Crohn’s Disease, alcohol consumption, antacids

Vitamin B12 levels can be normal in blood tests but be deficient in the cerebral spinal fluid (Prousky, 2015). However most clinicians do not consider vitamin B12 to be an issue unless serum B12 levels are below laboratory reference ranges.

More information:

Prousky, (2010). Understanding the serum vitamin B12 level and its implications for treating neuropsychiatric conditions: An Orthomolecular Perspective. Journal of Orthomolecular Medicine, 25(2).

Top food sources of vitamin B12 by serving size:

  • clams, mussels
  • mackerel
  • crab
  • beef

Comprehensive food list:

Table 2. Some Food Sources of vitamin B12 (Vitamin B12, 2014)


Referenced Dietary Intakes

RDAs for vitamin B12 (mcg/day)
Adolescents (14-18 years): 2.4 (M) 2.4 (F)
Adults (19-50 years): 2.4 (M) 2.4 (F)
Adults (51 years and older): 2.4 (M) 2.4 (F)

Tolerable Upper Intake
Not established due to low potential for toxicity.

Supplementing vitamin B12

1. Vitamin B12 Supplementation

  • Amounts of vitamin B12 used in practice and research range from 1,000–5,000 IU a day in divided doses.
  • The preferred form of vitamin B12 is methylcobalamin, due to its greater tissue retention (“Methylcobalamin”, 1998)
  • Vitamin B12 is best absorbed in sublingual form.
  • “Those strict vegetarians who eat no animal products (vegans) need supplemental vitamin B12 to meet their requirements” (Vitamin B12, 2014)

2. Vitamin B12 injections

  • A typical injection regimen is 1000 mcg every 2 weeks.
  • Patients who respond to vitamin B12 injections typically need ongoing injections to maintain symptom improvement (Gaby, 2011).


  • The Institute of Medicine states that “no adverse effects have been associated with excess vitamin B12 intake from food and supplements in healthy individuals” (Vitamin B12, 2014).


Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Methylcobalamin. (1998). Alternative Medicine Review: A Journal of Clinical Therapeutic, 3(6), 461–463.

Oh, R., & Brown, D. L. (2003). Vitamin B12 deficiency. American Family Physician, 67(5), 979–986.

Prousky J, (2015) Anxiety: Orthomolecular diagnosis and treatment, Kindle Edition. CCNM Press.

Prousky, J. (2010). Understanding the Serum Vitamin B12 Level and its Implications for Treating Neuropsychiatric Conditions: An Orthomolecular Perspective. Journal of Orthomolecular Medicine, 25(2).

Valizadeh, M., & Valizadeh, N. (2011). Obsessive Compulsive Disorder as Early Manifestation of B12 Deficiency. Indian Journal of Psychological Medicine, 33(2), 203–204. https://doi.org/10.4103/0253-7176.92051

Vitamin B12. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/vitamin-B12

Folate is a water-soluble vitamin. “Folate” is the form that is naturally occurring in foods. Since folate is unstable, the synthetic form “folic acid” is often used in supplements and food fortification.

Folate has important roles in maintaining mental health, including: 

  • biosynthesis of neurotransmitters
  • amino acid metabolism
  • myelination of neurons
  • DNA replication
  • regulation of gene expression
  • cell division
  • reduction of homocysteine

Folate and schizophrenia

  • Folate reduces homocysteine and negative schizophrenia symptoms.
  • Lower folate levels have been shown to correlate with higher homocysteine levels and negative schizophrenia symptoms, and higher homocysteine correlates with lower cognitive function (Saedisomeolia, Djalali, Mogh- adam, Ramezankhani, & Najmi, 2011).
  • Studies showed significantly lower folate levels in schizophrenia patients (Cao et al., 2016).

MTHFR polymorphisms and schizophrenia

  • The methylenetetrahydrofolate reductase (MTHFR) enzyme converts folate to 5-MTHF (methylfolate), the most bioavailable form of folate. Methylfolate is the form of folate that crosses the blood-brain barrier.
  • Polymorphisms in the genes that make the MTHFR enzyme result in decreased function of the enzymes and reduced conversion of folate to methylfolate.
  • Schizophrenics are more likely to have MTHFR polymorphisms than healthy subjects. They are also more likely to have lower amounts of circulating folate and higher levels of homocysteine (El-Hadidy, Abdeen, El-Aziz, Sherin, & Al- Harrass, 2014).
  • Negative effects of the MTHFR polymorphism can, to a degree, be compensated for by supplementing methylated folate.

Causes of folate deficiencies

  • low dietary intake
  • poor absorption
  • gastrointestinal issues
  • chronic alcoholism
  • smoking
  • oral contraceptives (Gaby, 2011)
  • drug interactions (Folate, 2014)
  • genetic variations in folate metabolism, for example variations the MTHFR gene  (“Folate”, 2014)

Top food sources of folate by serving size:

  • lentils
  • chickpeas
  • asparagus
  • spinach
  • lima beans

Comprehensive food list:

Table 2. Some Food Sources of folate and folic acid (Folate, 2014)


Referenced Dietary Intakes

RDAs for folate (mcg/day)
Adolescents (14-18 years): 400 (M) 400 (F)
Adults (19-50 years): 400 (M) 400 (F)
Adults (51 years and older): 400 (M) 400 (F)

Tolerable Upper Intake:
Not establish due to low potential for toxicity.

The Food and Nutrition Board of the US Institute of Medicine recommends a maximum intake of 1000 mcg of the folic acid form of folate – from supplements and fortified food.

Supplementing folate

Amounts of folate/folic acid used in practice and research range from 100–5000 mcg/day in divided doses (Office of Dietary Supplements, n.d.).

A good quality multivitamin/mineral supplement typically contains 400 mcg of folate.


  • Folate supplementation may mask an underlying vitamin B12 deficiency.
  • In order to be very sure of preventing irreversible neurological damage in vitamin B12-deficient individuals, the Food and Nutrition Board of the US Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1000 μg (1 mg) daily (Folate, 2014).


Cao, B., Wang, D. F., Xu, M. Y., Liu, Y. Q., Yan, L. L., Wang, J. Y., & Lu, Q. B. (2016). Lower folate levels in schizophrenia: a meta-analysis. Psychiatry Research, 245, 1-7.

El-Hadidy, M. A., Abdeen, H. M., El-Aziz, A., Sherin, M., & Al-Harrass, M. (2014). MTHFR gene polymorphism and age of onset of schizophrenia and bipolar disorder. BioMed Research International, 2014, 318483

Folate. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/folate

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Office of Dietary Supplements—Folate. (n.d.). Retrieved October 28, 2020, from https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

Saedisomeolia, A., Djalali, M., Moghadam, A. M., Ramezankhani, O., & Najmi, L. (2011). Folate and vitamin B12 status in schizophrenic patients. Journal of Research in Medical Sciences, 16(13), 437-441.

Vitamin C is required for the synthesis of many compounds important for normal mental health. Some of these are:

  • tyrosine
  • thyroxine
  • norepinephrine
  • epinephrine
  • serotonin
  • carnitine
  • corticosteroids.

Vitamin C has been show in research to (Meister, 1994):

  • reduce psychological stress
  • decrease blood pressure
  • lower cortisol levels

Functions of vitamin C in the brain (Smythies, 1996):

  • Prevents oxidation of dopamine into toxic derivatives (Baez, Segura-Aguilar, Widerslen, Johansson, & Mannervik, 1997)
  • Protects NMDA receptors from glutamate toxicity
  • Counteracts the effects of amphetamines
  • Enhances the effects of older antipsychotic medications like haloperidol

Vitamin C and schizophrenia

  • Vitamin C has anti-inflammatory properties. Inflammation has a role in the onset and manifestation of schizophrenia (Fond et al., 2020).
  • Vitamin C is an effective anti-stress nutrient that helps schizophrenic patients cope more effectively (Hoffer, 1977).
  • Vitamin C preserves intracellular glutathione (Pauling et al., 1973). Glutathione is important for the detoxification of toxic metabolites associated with schizophrenia – adrenochrome, adrenolutin, dopaminochrome and noradrenochrome (Suboticanec, Folnegović-Smalc, Korbar, M., Mestrović, & Buzina, 1990; Smythies, 1996; Hoffer, 1999).

Vitamin C low in schizophrenics

  • Vitamin C levels in schizophrenics have been shown to be low schizophrenics (Rv et al., 2010).
  • Schizophrenics receiving an adequate amount of dietary vitamin C had lower blood levels of vitamin C than people in good health (Horwitt, 1942). 
  • In a study of 106 recently-hospitalized schizophrenic patients given a loading dose of vitamin C, 76% of the patients were deficient versus 30% of the controls and 22% of the patients had significant deficiency versus 1% of controls (Pauling, 1974).

Causes of vitamin C deficiency

  • restrictive diets
  • diet lacking in sources of vitamin C especially fresh fruit and vegetables
  • digestive tract disorders, e.g. diarrhea, Crohn’s and colitis
  • smoking
  • alcoholism
  • chronic inflammatory conditions

Signs of vitamin C deficiency

  • bleeding or swollen gums
  • frequent nosebleeds
  • dry hair, split ends
  • easy bruising
  • slow wound healing
  • fatigue
  • moodiness
  • depression and cognitive impairment (Plevin & Galletly, 2020)

Top sources of vitamin C based on serving size

  • grapefruit and orange juice
  • strawberries
  • kiwifruit
  • orange
  • sweet pepper
  • broccoli

Comprehensive food list:

Table 3. Some Food Sources of vitamin C (Vitamin C, 2014)


Referenced Dietary Intakes

RDAs for vitamin C (mg/day)
Adolescents (14-18 years): 75 (M) 65 (F)
Adults (19-50 years): 90 (M) 75 (F)
Smokers: 125 (M) 110 (F)

Tolerable Upper Intake: 2000 mg /day
(Office of Dietary Supplements – Vitamin C, n.d.)

Vitamin C supplementation

  • Amounts of vitamin C used in practice and research range from 500–6000 mg/day in divided doses.
  • Studies have shown that schizophrenic patients require vitamin C supplementation in the high-gram range in order to saturate body tissue stores. (Pauling et al., 1973; Suboticanec, et al., 1990).”

Clinical improvement of schizophrenia patients resulted from 

Doses of vitamin C ranging from 500–6,000 mg of vitamin C have resulted in clinical improvement in schizophrenic patients (Gaby, 2011).


  • Vitamin C has low toxicity and is not believed to cause serious adverse effects at high intakes (Office of Dietary Supplements – Vitamin C, n.d.).
  • Vitamin C at higher doses can, in some people, cause side effects such as nausea, abdominal cramps, and other digestive tract disturbances

Vitamin C and medications

  • Vitamin C has been shown beneficial and safe when used in conjunction with schizophrenia medications.
  • Adjunctive vitamin C has been shown to improve symptoms in schizophrenic patients (Beauclair, Vinogradov, Riney, Csernansky, & Hollister, 1987).
  • “The absence of any substantial side effects, cheaper cost, improvement in BPRS score, and the fact that plasma ascorbic acid levels are decreased in schizophrenia and increases after oral supplementation make it a particularly attractive therapeutic adjuvant in the treatment of schizophrenia.” (Dakhale, Khanzode, Khanzode, & Saoji, 2005).


Baez, S., Segura-Aguilar, J., Widersten, M., Johansson, A. S., & Mannervik, B. (1997). Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochemical Journal, 324(Pt 1), 25–28.

Beauclair, L., Vinogradov, S., Riney, S. J., Csernansky, J. G., & Hollister, L. E. (1987). An adjunctive role for ascor- bic acid in the treatment of schizophrenia?. Journal Of Clinical Psychopharmacology, 7(4), 282-283.

Dakhale, G. N., Khanzode, S. D., Khanzode, S. S., & Saoji, A. (2005). Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome of schizophrenia. Psychopharmacology, 182(4), 494-498.

Fond, G., Lançon, C., Korchia, T., Auquier, P., & Boyer, L. (2020). The Role of Inflammation in the Treatment of Schizophrenia. Frontiers in Psychiatry, 11. https://doi.org/10.3389/fpsyt.2020.00160

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Hoffer, A. (1977). Treatment of schizophrenia. In R. Williams, D. Kalita (Eds.), A Physician’s Handbook on Orthomolecular Medicine. Keats Publishing.

Hoffer A. (1999). The adrenochrome hypothesis and psychiatry. Journal of Orthomolecular Medicine, 14, 49-62.

Horwitt, M.K. (1942). Ascorbic acid requirements of indi- viduals in a large institution. Proceedings of the Society for Experimental Biology and Medicine, 49, 248-250.

Meister, A. (1994). Glutathione, ascorbate, and cellular protection. Cancer Research, 54(7 Supplement), 1969s–1975s

Office of Dietary Supplements—Vitamin C. (n.d.). Retrieved December 4, 2020, from https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/

Pauling, L., Robinson, A., Oxley, S., Bergeson, M., Harris, A., Cary, P., … Keaveny, I. (1973). Vitamin C: New Biochemical and functional insights. In D. Hawkins & L. Pauling (Eds.), Orthomolecular Psychiatry (W.H. Freeman, San Francisco 1973).

Pauling, L. (1974). On the orthomolecular environment of the mind: Orthomolecular theory. The American Journal of Psychiatry, 131(11), 1251-1257.

Plevin, D., & Galletly, C. (2020). The neuropsychiatric effects of vitamin C deficiency: A systematic review. BMC Psychiatry, 20(1), 315. https://doi.org/10.1186/s12888-020-02730-w

Rv, B., Np, R., & G, V. (2010). Biological investigations in Indian psychiatry. Indian Journal of Psychiatry, 52(Suppl 1), S136-8. https://doi.org/10.4103/0019-5545.69225

Smythies, J. (1996). Oxidative reactions and schizophrenia: A review-discussion. Schizophrenia Research, 24(3), 357–364. https://www.academia.edu/24021570/Oxidative_reactions_and_schizophrenia_A_review_discussion

Suboticanec, K., Folnegović-Smalc, V., Korbar, M., Mestrović, B., & Buzina, R. (1990). Vitamin C status in chronic schizophrenia. Biological Psychiatry, 28(11), 959-966

Vitamin C. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/vitamin-C

Vitamin D, which is made from cholesterol in the skin and UVB radiation, is a neurosteroid hormone that has roles in brain development and normal brain function.

Vitamin D and mental health

  • Vitamin D regulates the transcription of genes involved in pathways for synaptic plasticity, neuronal development and protection against oxidative stress (Graham et al., 2015).
  • Vitamin D-deficient cells produce higher levels of the inflammatory cytokines TNF-α and IL-6, while cells treated with vitamin D release significantly less.
  • In the adrenal glands, vitamin D regulates tyrosine hydroxylase, which is the rate-limiting enzyme for the synthesis of dopamine, epinephrine, and norepinephrine. 
  • In the brain, vitamin D regulates the synthesis, release, and function of serotonin. Serotonin modulates executive function, sensory gating, social behaviour, and impulsivity (Patrick & Ames, 2015).

Vitamin D and schizophrenia

  • Roles of vitamin D in schizophrenia include reduction of pro-inflammatory cytokines and oxidative stress, and neurotransmitter synthesis & regulation in the brain and gut.
  • Vitamin D deficiency is associated with more severe psychotic episodes, more severe symptoms, and therapy resistance (Bogers et al., 2015).
  • Individuals with schizophrenia have been shown to have low serum vitamin D levels (below 20ng/ml), and normalization of vitamin D levels lead to improvement of symptoms (Chiang et al., 2016: Valipour et al., 2014).

Causes of vitamin D deficiency

  • limited sun exposure
  • strict vegan diet (most sources of vitamin D are animal-based)
  • darker skin (the pigment melanin reduces the vitamin D production by the skin)
  • digestive tract and kidney issues
  • obesity (vitamin D is sequestered by fat cells)

Measuring vitamin D

The best indicator of vitamin D status is serum 25(OH)D, also known as 25-hydroxyvitamin D. 25(OH)D reflects the amount of vitamin D in the body that is produced by the skin and obtained from food and supplements.

Vitamin D levels and health status
Institute of Medicine, Food and Nutrition Board. (2010)

Serum (ng/ml)  and Health status
<20  deficient
20–39  generally considered adequate
40–50  adequate
>50–60   proposed optimum health level
>200  potentially toxic

Top sources of vitamin D based on serving size (Office of Dietary Supplements – Vitamin D, 2020)

  • cod liver oil
  • trout
  • pink salmon
  • sardines
  • fortified cereal, milk, and orange juice
  • fortified almond, soy, and oat milks
  • egg yolk

Comprehensive food list

Table 3: Vitamin D Content of Selected Foods https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

Referenced Dietary Intakes

RDAs for vitamin D (IU/day)
Adolescents (14-18 years): 600 (M) 600 (F)
Adults (19-50 years): 600 (M) 600 (F)
Adults (51 years and older): 800 (M) 800 (F)

Tolerable Upper Intake: 4000 IU/day
(Office of dietary supplements, 2020)

Vitamin D supplementation

  • Amounts of vitamin D used in practice and research range from 400-14 000 IU/day. (Vitamin D, 2014)

SAFETY, SIDE EFFECTS (Vitamin D, 2014)

  • “Research suggests that vitamin D toxicity is very unlikely in healthy people at intake levels lower than 10,000 IU/day” 
  • Vitamin D can increase risk of hypercalcemia with calcium-related medical conditions – including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma
  • Certain medical conditions can increase the risk of hypercalcemia in response to vitamin D, including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma

Some drugs that affect vitamin D absorption or metabolism include (Vitamin D, 2014):

  • cholestyramine 
  • colestipol 
  • orlistat 
  • mineral oil
  • phenytoin 
  • fosphenytoin 
  • phenobarbital 
  • carbamazepine 
  • rifampin 
  • cimetidine
  • ketoconazole
  • glucocorticoids 
  • HIV treatment drugs


Bogers, J., Bostoen, T., & Broekman, T. (2015). Low levels of vitamin D poorly responsive to daylight exposure in patients with therapy-resistant schizophrenia. Nordic Journal of Psychiatry, 70, 1–5. https://doi.org/10.3109/08039488.2015.1086023

Chiang, M., Natarajan, R., & Fan, X. (2016). Vitamin D in schizophrenia: A clinical review. Evidence-Based Mental Health, 19(1), 6–9. https://doi.org/10.1136/eb-2015-102117

Graham, K. A., Keefe, R. S., Lieberman, J. A., Calikoglu, A. S., Lansing, K. M., & Perkins, D. O. (2015). Relationship of low vitamin D status with positive, negative and cognitive symptom domains in people with first‐episode schizophrenia. Early Intervention in Psychiatry, 9(5), 397-405.

Institute of Medicine, Food and Nutrition Board. (2010). Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academy Press.

Office of Dietary Supplements—Vitamin D. (2020). https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

Patrick, R. P., & Ames, B. N. (2015). Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. The FASEB Journal, 29(6), 2207- 2222.

Valipour, G., Saneei, P., & Esmaillzadeh, A. (2014). Serum vitamin D levels in relation to schizophrenia: A systematic review and meta-analysis of observational studies. The Journal of Clinical Endocrinology and Metabolism, 99(10), 3863–3872. https://doi.org/10.1210/jc.2014-1887

Vitamin D. (2014, April 22). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/vitamins/vitamin-D


Magnesium in the context of mental health (Kirkland, Sarlo, & Holton, 2018)

  • calms neurotransmission by regulating glutamate and GABA
  • modulates the HPA axis
  • has roles in the synthesis of serotonin and dopamine
  • regulates cortisol levels
  • increases Brain-derived neurotrophic factor (BDNF)
  • is required for enzyme systems that use thiamine (vitamin B1) and pyridoxine (vitamin B6) – these vitamins are cofactors in the production of serotonin, GABA, and melatonin (Kanofsky, & Sandyk, 1991)
  • decreases activation of the NMDA receptor which in turn, decreases excitatory neurotransmission (Bartlik, Bijlani, & Music, 2014)

Magnesium and schizophrenia

  • Magnesium inhibits acetylcholine release. High acetylcholine and low serotonin are associated with negative schizophrenia symptoms (Kanofsky, & Sandyk, 1991).
  • Lower levels of magnesium have been found in schizophrenia patients versus controls (Bartlik et al., 2014). Psychiatric symptoms reported with magnesium deficiency include depression, agitation, disorientation, auditory and visual hallucinations (Kanofsky, & Sandyk, 1991).

Magnesium deficiency 

Causes of magnesium deficiency include: 

  • loss of soil magnesium due to farming practices
  • following the standard American diet pattern, as it is high in processed and nutrient-deficient foods,
  • decreased magnesium levels in foods, especially cereal grains (Guo, Nazim, Liang, & Yang, 2016)
  • low dietary protein (needed for magnesium absorption)
  • gastrointestinal disorders (e.g. Crohn’s disease, malabsorption syndromes, and prolonged diarrhea)
  • stress, which causes magnesium to be lost through urine (Deans, 2011), and
  • chronically elevated cortisol, which depletes magnesium (Cuciureanu, & Vink, 2011).
  • high doses of supplemental zinc (competes for absorption)
  • alcoholism
  • certain diuretic medications

Elderly adults tend to have lower dietary intake, absorption, and increased loss of magnesium.

Magnesium deficiency and schizophrenia

  • Deficiency can cause or worsen schizophrenia symptoms such as agitation and irritablility, depression, and hallucinations
  • Magnesium deficiency has been shown to be common in people with schizophrenia (Kanofsky & Sandyk, 1991).
  • Neuroleptic medications can deplete magnesium and promote deficiency in schizophrenics (Gaby, 2011)

Top food sources of magnesium by serving size

  • Brazil nuts
  • oat bran
  • brown rice (whole grain)
  • mackerel

Comprehensive list

Table 2. Some Food Sources of Magnesium
(Magnesium, 2014)

Referenced Dietary Intakes

RDAs for magnesium (mg/day)
Adolescents (14-18 years): 410 (M) 360 (F)
Adults (19-30 years): 400 (M) 310 (F)
Adults (31 years and older): 420 (M) 320 (F)

Supplementing magnesium

  • Amounts of magnesium used in practice and research range from 100–750 mg a day in divided doses (elemental magnesium dose).
  • Correction of magnesium deficiency with magnesium supplementation has resulted in significant improvement in psychiatric symptoms (Kanofsky & Sandyk, 1991).


  • Side effects of magnesium supplementation are rare, but can include a laxative effect, dizziness or faintness, sluggishness, cognitive impairment, and depression.
  • An effective strategy for dosing magnesium is to gradually increase the amount to bowel tolerance, then reduce slightly.
  • Magnesium is best taken in divided doses throughout the day. Caution is required for high doses of magnesium with existing kidney disease.


Bartlik, B., Bijlani, V., & Music, D. (2014, July 22). Magnesium: An essential supplement for psychiatric patients—Psychiatry Advisor. Psychiatry Advisor. https://www.psychiatryadvisor.com/home/therapies/magnesium-an-essential-supplement-for-psychiatric-patients/

Cuciureanu, M. D., & Vink, R. (2011). Magnesium and stress. In R. Vink & M. Nechifor (Eds.), Magnesium in the Central Nervous System. University of Adelaide Press. http://www.ncbi.nlm.nih.gov/books/NBK507250/

Deans, E. (2011, June 12). Magnesium and the brain: The original chill pill. Psychology Today. http://www.psychologytoday.com/blog/evolutionary-psychiatry/201106/magnesium-and-the-brain-the-original-chill-pill

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Guo, W., Nazim, H., Liang, Z., & Yang, D. (2016). Magnesium deficiency in plants: An urgent problem. The Crop Journal, 4(2), 83–91. https://doi.org/10.1016/j. cj.2015.11.003

Kanofsky, J. D., & Sandyk, R. (1991). Magnesium Deficiency in Chronic Schizophrenia. International Journal of Neuroscience, 61(1–2), 87–90. https://doi.org/10.3109/00207459108986275

Kirkland, A. E., Sarlo, G. L., & Holton, K. F. (2018). The Role of Magnesium in Neurological Disorders. Nutrients, 10(6). https://doi.org/10.3390/nu10060730

Magnesium. (2014, April 23). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/minerals/magnesium

Zinc and the brain

  • Zinc regulates the storage and release of neurotransmitters (Zinc Regulates, 2017)
  • Zinc has critical roles in axonal and synaptic transmission development and brain cell growth and metabolism (Pfeiffer & Braverman, 1982).

Zinc and schizophrenia
(Richardson Andrews, 1990; Joshi et al., 2012)

  • Zinc is critical for regulating glutamate and NMDA receptor activity
  • Zinc has anti-anxiety and antidepressant effects
  • Zinc deficiency (and copper excess) are common with schizophrenia
  • Postmortem schizophrenic brain samples have shown 50% lower zinc levels in the hippocampus than normal
  • Kryptopyrroles can bind zinc (and vitamin B6) causing it to be depleted.
  • Impaired release of zinc in the hippocampus is associated with psychotic symptoms

Top sources of zinc based on serving size

  • oyster, cooked
  • beef, chuck, blade roast, cooked
  • beef, ground, 90% lean meat, cooked
  • crab, Dungeness, cooked
  • fortified, whole-grain toasted oat cereal

Comprehensive food list:
Table 2. Some Food Sources of Zinc

Referenced Dietary Intakes

RDAs for zinc (mg/day)
Adolescents (14-18 years): 11 (M) 9 (F)
Adults (19 years and older): 11 (M) 8 (F)

Supplementing zinc

  • Amounts of zinc used in practice and research range from 10–200 mg a day in divided doses (Zinc, 2014).
  • Adjunctive supplementation of zinc with antipsychotic medications can  reduce extrapyramidal symptoms of schizophrenia (Richardson Andrews, 1990, Joshi et al., 2012)


  • High zinc intakes can inhibit copper absorption, sometimes producing copper deficiency and associated anemia (Office of Dietary Supplements, 2014).
  • Intakes of zinc should not exceed the Upper Limit (40 mg/day for adults) in order to limit the risk of copper deficiency in particular
  • Milder gastrointestinal distress has been reported at doses of 50 to 150 mg/day of supplemental zinc (Zinc, 2014).


Joshi, M., Akhtar, M., Najmi, A., Khuroo, A., & Goswami, D. (2012). Effect of zinc in animal models of anxiety, depression and psychosis. Human & Experimental Toxicology, 31(12), 1237–1243. https://doi.org/10.1177/0960327112444938

Office of Dietary Supplements—Zinc. (n.d.). Retrieved October 29, 2020, from https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Pfeiffer, C. C., & Braverman, E. R. (1982). Zinc, the brain and behavior. Biological Psychiatry, 17(4), 513–532.

Richardson Andrews, R. C. (1990). Unification of the findings in schizophrenia by reference to the effects of gestational zinc deficiency. Medical Hypotheses, 31(2), 141–153. https://doi.org/10.1016/0306-9877(90)90010-C

Zinc. (2014, April 23). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/minerals/zinc

Zinc regulates the storage and release of neurotransmitters. (2017, March). Phys.Org. https://phys.org/news/2017-03-zinc-storage-neurotransmitters.html

Fatty acids and lipids

Polyunsaturated fatty acids (PUFAs) are classified as either omega-6 or omega-3 fatty acids.

Common omega-6 fatty acids include:

  • Linoleic acid (LA)
  • Gamma linolenic acid (GLA)

Common omega-3 fatty acids include:

  • Eicosapentaenoic acid
  • Docosahexaenoic acid

Polyunsaturated Fatty Acids and the brain

  • Polyunsaturated fatty acids (PUFAs) (omega 3 and 6 fatty acids) are necessary for normal development and function of the brain.
  • Fatty acids are required for neurotransmitter synthesis, release, binding, re-uptake, and degradation.
  • Approximately sixty percent of the dry weight of the brain is fat, and around 30 percent of fatty acids must be obtained through diet because they cannot be made by the body.
  • Low levels of the fatty acids EPA and DHA are associated with brain alterations that result in motor and visual impairments, attention and behaviour problems, and psychiatric disorders (Greenblatt, 2018).

Omega-3 deficiency manifestations
(Greenblatt, 2018)

  • motor & visual impairments
  • attention and behavior problems
  • psychiatric disorders
  • digestive issues
  • allergies

Essential fatty acids and schizophrenia

  • Omega 3 fatty acids and their metabolites have roles in regulating inflammation, neuroinflammation, and neurotransmission (Larrieu, & Layé, 2018) – all of which are factors in schizophrenia.
  • Omega-3 fatty acids have been found to be abnormally low in schizophrenia patients, when measured by red blood cell concentration (Laugharne et al., 1996).
  • “In most case reports, uncontrolled trials, and double-blind trials, supplementation with fish oil or with omega-3 fatty acids present in fish oil EPA, with or without DHA, was beneficial for patients with schizophrenia” (Gaby, 2011).

In a double-blind trial by Amminger et al (2010), young adults at high risk for schizophrenia were given 1.2 g/day fish oil for 12 weeks. When followed up at 40 weeks, only 5% of those taking the fish oil transitioned to full psychosis vs 27.5% of those who took the placebo.

EPA has been shown to improve positive symptoms (e.g. hallucinations and delusions) and negative symptoms (e.g. flat effect and depression) (Emsley, Oosthuizen, & van Rensburg, 2003).

Reasons for EFA deficiencies

  • inadequate dietary intake
  • poor absorption
  • deficiencies of nutrients required for EFA metabolism
  • issues with metabolism that cause decreased incorporation of, or increased removal of, fatty acids from cell membranes

Top EPA and DHA (omega 3) food sources by serving size

  • herring, pacific
  • salmon, chinook
  • sardines, pacific
  • salmon, atlantic
  • oysters, pacific

Comprehensive food list:
Table 4. Food Sources of EPA (20:5n-3) and DHA (22:6n-3) (Office of Dietary Supplements, n.d.)

Commonly suggested amounts for dietary fatty acid consumption:

  • cold water fish – 2 to 3 times a week, or
  • flaxseed oil – 2 to 6 tbsp daily, or
  • ground flax seed –  2 tbsp daily

Flaxseed oil may have negative effects in about 3% people, including: hypomania, mania, behaviour changes. (Prousky, 2015)

Referenced Dietary Intakes

Adequate Intakes for Alpha linolenic acid (Omega 3) (g/day) (Institute of Medicine, 2002)
Adolescents (14–18 years): 1.6 (M) 1.1 (F)
Adults (≥ 19 years): 1.6 (M) 1.1 (F)

Recommendations for long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (mg/day) (European Food Safety Authority, 2009)
Adults:  250 (M+F)

Supplementating omega 3 fatty acids

  • Amounts of omega 3 fatty acids used in practice and research range from 1–4 g a day of combined EPA and DHA, in divided doses.
  • Fish oils, which are sources of EPA and DHA, are considered preferable for addressing schizophrenia, have been shown to have a wide range of neurobehavioural effects (Logan, 2003)
  • Prudent dosing levels for omega-3 fatty acids in the context of schizophrenia would be 1–2 g/day of EPA (around 3–10 g/day of fish oil, for at least 3 months (Gaby, 2011).


  • Common side effects of high dose EPA and DHA supplementation include heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat
  • The European Food Safety Authority considers long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day to be safe.
  • The FDA recommends not exceeding 3 g/day EPA and DHA combined, with up to 2 g/day from dietary supplements (Office of Dietary Supplements, n.d.).


  • Use caution when supplementing omega 3 fatty acids while taking blood-thinning medications, or blood-sugar issues (Essential fatty acids, 2014).

Clinical Trials with Omega-3s
(Akter et al., 2012)

  • More than 20 placebo-controlled trials with high-dose EPA/DHA demonstrate symptom improvements for multiple psychiatric conditions
  • The strongest study support is for utilizing EPA and DHA in addition to conventional treatments
  • EPA/DHA treatments appear to be most effective in the early stages of disease


Akter, K., Gallo, D. A., Martin, S. A., Myronyuk, N., Roberts, R. T., Stercula, K., & Raffa, R. B. (2012). A review of the possible role of the essential fatty acids and fish oils in the aetiology, prevention or pharmacotherapy of schizophrenia. Journal of Clinical Pharmacy and Therapeutics, 37(2), 132–139. https://doi.org/10.1111/j.1365-2710.2011.01265.x

Amminger, G. P., Schäfer, M. R., Papageorgiou, K., Klier, C. M., Cotton, S. M., Harrigan, S. M., Mackinnon, A., McGorry, P. D., & Berger, G. E. (2010). Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial. Archives of General Psychiatry, 67(2), 146–154. https://doi.org/10.1001/archgenpsychiatry.2009.192

Emsley, R., Oosthuizen, P., & van Rensburg, S. J. (2003). Clinical potential of omega-3 fatty acids in the treatment of schizophrenia. CNS Drugs, 17(15), 1081-1091.

Essential Fatty Acids. (2014, April 28). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids

European Food Safety Authority. Labelling reference intake values for n-3 and n-6 polyunsaturated fatty acids. (2009, July 10). https://www.efsa.europa.eu/en/efsajournal/pub/1176

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Greenblatt, J. (2018, May 24). Integrative therapies for schizophrenia and psychosis, Module 1 [Webinar. https://isom.ca/schizophrenia-psychosis/

Larrieu, T., & Layé, S. (2018). Food for Mood: Relevance of Nutritional Omega-3 Fatty Acids for Depression and Anxiety. Frontiers in Physiology, 9. https://doi.org/10.3389/fphys.2018.01047

Laugharne, J. D. E., Mellor, J. E., & Peet, M. (1996). Fatty acids and Schizophrenia. Lipids, 31(1Part2), S163–S165. https://doi.org/10.1007/BF02637070

Logan, A. C. (2003). Neurobehavioral aspects of omega-3 fatty acids: Possible mechanisms and therapeutic value in major depression. Alternative Medicine Review: A Journal of Clinical Therapeutic, 8(4), 410–425.

Rakel, D., (2012). Integrative Medicine (3rd ed.). Elsiver.

Office of Dietary Supplements—Omega-3 Fatty Acids. (n.d.). Retrieved October 29, 2020, from https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/

Prousky J, (2015) Anxiety: Orthomolecular diagnosis and treatment, Kindle Edition. CCNM Press.

Amino acids

  • Glycine is an amino acid that is acquired from food and also made by the body
  • Glycine is an inhibitory neurotransmitter in the brainstem and spinal cord (Kawai et al., 2015), that prevents excessive neuronal firing.

Glycine and schizophrenia

Glycine promotes regular functioning of the NMDA receptor. Underfunctioning of the NMDA receptor has been identified as a key contributing factor for schizophrenia.

Top sources of glycine based on serving size

  • gelatin
  • pork skins, hocks
  • beef
  • chicken breast

Comprehensive food list: Foods highest in Glycine (Foods highest in Glycine, n.d.)

Referenced Dietary Intakes

RDAs/Upper intakes for glycine
Not established.

Supplementing glycine

  • Amounts of glycine used in practice and research range from 3–60 g/day in divided doses.
  • Glycine enhances neurotransmission that is mediated by the NMDA receptor, which me be useful for schizophrenia patients (Gaby, 2011) 
  • Glycine is usually started at 4 grams daily and increased by 4 grams per day until the effective dose is reached (Glycine: Uses, Side Effects, n.d.).
  • Taking glycine sublingually is considered the most effective method of dosing.
  • Two to ten grams taken sublingually has been shown in practice to a stop panic attack.
  • In double-blind trials glycine supplementation for 6–12 weeks in addition to regular antipsychotic medications, resulted in an improvement of  negative symptoms by 15–30%, without worsening positive symptoms (Carpenter, 1999; Heresco-Levy et al., 1999; Javitt et al., 1994)


  • There have be rare reports of nausea and vomiting from glycine supplementation (Glycine: Uses and Risks, n.d.).


  • Supplementing glycine along with clozapine (Clozaril) may decrease the effectiveness of the medication (Glycine: Uses, Side Effects, n.d.).


Carpenter, W. T. (1999). New style clinical trials in schizophrenia. Current Psychiatry Reports, 1(1), 11–12. https://doi.org/10.1007/s11920-999-0004-2

Foods highest in Glycine. (n.d.). Retrieved October 29, 2020, from https://nutritiondata.self.com/foods-000094000000000000000.html

Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Glycine: Uses and Risks. (n.d.). Retrieved October 29, 2020, from https://www.webmd.com/vitamins-and-supplements/glycine-uses-and-risks#2-4

Glycine: Uses, Side Effects, Interactions, Dosage, and Warning. (n.d.). Retrieved October 29, 2020, from https://www.webmd.com/vitamins/ai/ingredientmono-1072/glycine

Kawai, N., Sakai, N., Okuro, M., Karakawa, S., Tsuneyoshi, Y., Kawasaki, N., Takeda, T., Bannai, M., & Nishino, S. (2015). The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus. Neuropsychopharmacology, 40(6), 1405–1416. https://doi.org/10.1038/npp.2014.326

Heresco-Levy, U., Javitt, D. C., Ermilov, M., Mordel, C., Silipo, G., & Lichtenstein, M. (1999). Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Archives of General Psychiatry, 56(1), 29–36. https://doi.org/10.1001/archpsyc.56.1.29

Javitt, D. C., Zylberman, I., Zukin, S. R., Heresco-Levy, U., & Lindenmayer, J. P. (1994). Amelioration of negative symptoms in schizophrenia by glycine. The American Journal of Psychiatry, 151(8), 1234–1236. https://doi.org/10.1176/ajp.151.8.1234

Theanine in the contextof mental health:

  • is a calming amino acid. The L-theanine is the form of theanine that is extracted from green tea
  • crosses the blood-brain barrier where it increases serotonin and dopamine production, helps with GABA production, and protects against glutamate toxicity.
  • protects cells from damage from oxidative stress by maintaining cellular glutathione levels (L-theanine. Monograph, 2005), and promotes relaxation by stimulating alpha waves
  • promotes the release of nerve growth factor
  • modulates brain-derived-growth factor (BDNF)
  • has antioxidant activity

Theanine and schizophrenia

  • L-theanine supplementation has been shown to improve anxiety, positive, and general psychopathology symptoms, sleep quality, and stabilize glutamate concentration in the brain (Ritsner et al., 2011).

Referenced Dietary Intakes

RDAs/Upper intakes for theanine
Not established.

Supplementing theanine

  • Amounts of theanine used in practice and research range from 100–400 mg/day in divided doses (L-Theanine Uses, Benefits, n.d.).
  • L-theanine helps reduce anxiety by enhancing alpha brain wave activity and increasing GABA synthesis. Increased GABA levels promote feelings of calm and well-being by raising brain serotonin and dopamine levels (Mason, 2001).
  • Daily supplementation of L-theanine of 200 to 400 mg for up to 8 weeks has been shown in published research to decrease anxiety symptoms and decrease stress, with both acute and chronic anxiety (Lopes Sakamoto, F., Metzker Pereira Ribeiro, R., Amador Bueno, A., & Oliveira Santos, 2019).
  • A 50 to 200 mg dose of L-theanine usually results in a calming effect within 30 to 40 minutes.
  • For severe anxiety, supplementing up to 800 mg daily, in 100 to 200 mg doses, spread throughout the day, has been shown to be effective.


  • Side effects of high-dose theanine supplementation may include headache or sleepiness (Theanine: Uses, Side Effects, n.d.).
  • Taking L-theanine does not increase drowsiness, reduce the ability to concentrate, or lead to the development of tolerance or dependence.


  • Taking theanine along with medications for high blood pressure may cause blood pressure to go too low (Theanine: Uses, Side Effects, n.d.).


L-theanine. Monograph. (2005). Alternative Medicine Review: A Journal of Clinical Therapeutic, 10(2), 136–138.

L-Theanine Uses, Benefits & Dosage—Drugs.com Herbal Database. (n.d.). Drugs.Com. Retrieved October 29, 2020, from https://www.drugs.com/npp/l-theanine.html

Lopes Sakamoto F, Metzker Pereira Ribeiro R, Amador Bueno A & Oliveira Santos H. (2019) Psychotropic effects of L-theanine and its clinical properties: From the management of anxiety and stress to a potential use in schizophrenia. Pharmacological Research, 147, 104395. https://doi.org/10.1016/j.phrs.2019.104395

Mason R. (2001) 200 mg of zen: L-Theanine boosts alpha waves, promotes alert relaxation. Alternative and Complementary Therapies, 7(2), 91–95. https://doi.org/10.1089/10762800151125092

Ritsner, M., Miodownik, C., Ratner, Y., Shleifer, T., Mar, M., Pintov, L., & Lerner, V. (2011). L-theanine relieves posi- tive, activation, and anxiety symptoms in patients with schizophrenia and schizoa ective disorder: An 8-week, randomized, double-blind, placebo-controlled, 2-center study. The Journal of Clinical Psychiatry, 72(1), 34-42.

Theanine: Uses, Side Effects, Interactions, Dosage, and Warning. (n.d.). Retrieved October 29, 2020, from https://www.webmd.com/vitamins/ai/ingredientmono-1053/theanine

  • N-acetylcysteine, more commonly known as NAC, is a derivative of the amino acid cysteine.

NAC in the context of mental health:

  • has roles in inflammation regulation and antioxidant production, and is required for the production of glutathione
  • modulates neurotransmitters including glutamate and dopamine, supports mitochondrial energy production, and provides neurotrophic support (Dean, Giorlando, & Berk, 2011)
  • regulates inflammation
  • supports mitochondrial energy production
  • supports neurotransmitter metabolism

NAC, glutathione and schizophrenia

  • NAC supports the production of glutathione.
  • Glutathione deficiency is linked with multiple psychiatric and other physiological disorders (Durieux, et al., 2015).
  • As brain glutathione levels decrease, cognitive and negative schizophrenia symptoms increase (Berk, et al., 2008).
  • Glutathione has been found to be decreased in the brains of those with schizophrenia (Arroll et al., 2014).
  • NAC supplementation has been shown to raise plasma glutathione in schizophrenic patients (Arroll et al., 2014).

Food sources of NAC

  • NAC is not found in food, but can be made by the body from the amino acid cysteine.

Food sources high in cysteine include (Foods Highest in Cystine, n.d.):

  • beef, lamb, pork
  • poultry
  • fish

Supplementing NAC

  • Amounts of NAC used in practice and research range from 600 to 3600 mg a day in divided doses.
  • NAC needs to be taken away from food for maximum therapeutic effect.
  • NAC supplementation has been shown to increase blood glutathione levels (Lavoie et al., 2007), and regulate metabolism of glutamate and GABA (Dean, Giorlando, & Berk, 2011).
  • In a clinical trial, chronic schizophrenia patients were given 1000 mg of NAC twice a day for 24 weeks, which resulted in improvements in their negative symptoms, global function, and akathisia (a feeling of inner restlessness and inability to stay still) (Berk et al., 2008).


  • NAC can be safely combined with atypical antipsychotic medication and can be combined with all classes of psychiatric medication. 

Side effects of NAC can include:

  • mild nausea
  • upset stomach and indigestion
  • diarrhea
  • tiredness or weakness
  • sweating
  • skin rash


Arroll, M., Wilder, L., & Neil, J. (2014). Nutritional interventions for the adjunctive treatment of schizophrenia: A brief review. – Abstract—Europe PMC. Nutrition Journal, 13(1), 91. https://europepmc.org/article/MED/25228271

Berk, M., Copolov, D., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., … & Ording-Jespersen, S. (2008). N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biological Psychiatry, 64(5), 361-368.

Dean, O., Giorlando, F., & Berk, M. (2011). N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. Journal of Psychiatry and Neuroscience, 36(2), 78.

Durieux, A., Fernandes, C., Murphy, D., Labouesse, M. A., Giovanoli, S., Meyer, U., … & McAlonan, G. (2015). Targeting glia with N-acetylcysteine modulates brain glutamate and behaviors relevant to neurodevelopmental disorders in C57BL/6J mice. Frontiers in Behavioral Neuroscience, 9, 343.

Foods highest in Cystine. (n.d.). Retrieved December 8, 2020, from https://nutritiondata.self.com/foods-000085000000000000000-10.html?

Lavoie, S., Murray, M. M., Deppen, P., Knyazeva, M. G., Berk, M., Boulat, O., . . . Do, K. Q. (2007). Glutathione pre- cursor, N-Acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology, 33(9), 2187-2199.

Multinutrient formulas

B-complex vitamins and mental health

  • Conditions including stress, illness, poor diet and nutrient absorption, as well as certain medications can increase needs for B-vitamins.
  • A good quality B-complex can address the minimum nutrient requirements for the important B-vitamins including vitamins B1, B3, B6, B12, and folate.
  • “A trial of B-complex supplement seems advisable, especially in older persons and in persons taking medications that may deplete this vitamin” (Rakel, 2012).


Gaby, A. R. (2011). Nutritional Medicine. Alan R. Gaby, VitalBook file.

Rakel, D., (2012). Integrative Medicine (3rd ed.). Elsiver.

Multivitamins and mental health

Conditions including stress, illness, poor diet and nutrient absorption, as well as certain medications can increase needs for many different vitamins and minerals.

A good quality multivitamin/mineral formula can address the minimum nutrient requirements for the important vitamins and minerals.

Further reading:

Effects of vitamin and mineral supplementation on stress, mild psychiatric symptoms, and mood in nonclinical samples: A meta-analysis.



Long, S.-J., & Benton, D. (2013). Effects of vitamin and mineral supplementation on stress, mild psychiatric symptoms, and mood in nonclinical samples: A meta-analysis. Psychosomatic Medicine, 75(2), 144–153. https://doi.org/10.1097/PSY.0b013e31827d5fbd


This section contains useful information and tools for getting started as well as exploring further the orthomolecular approach to addressing schizophrenia.

Basic first steps


  • Follow a mediterranean-type diet with adequate protein and good fat to stabilize blood sugar
  • Reduce or remove refined sugar and starches
  • Reduce or remove foods that contain additives
  • Consider as a trial, removing gluten and dairy for 4 to 10 days

Substances to address:

  • Incrementally reduce alcohol, caffeine, and nicotine
  • An appropriate approach is to reduce and eliminate only one substance at a time

Nutrients to supplement daily:

  • multivitamin/mineral or B-complex
  • vitamin C
  • magnesium
  • niacin or niacinamide
  • vitamin B6
  • omega 3 fatty acids
  • zinc

Further steps

  • Identify potential food allergies and avoid suspect foods
  • Identify and address reactive hypoglycemia if relevant
  • Research any associated nutrient depletions and consider supplementing those nutrients. Do not discontinue taking medications without consulting with your doctor.
  • Consider working with an orthomolecular health professional
Abram Hoffer, MD, PhD
With contributions from: James Greenblatt, MD; Jonathan Prousky, MSC, ND; Paul Demeda, CNP
It is well documented that nutrient deficiencies, nutrient dependencies, and environmental toxins such as heavy metals, contribute to the pathogenesis of mental health disorders. Ignoring this reality means missing out on the opportunity to make the lives of people with schizophrenia better. Conventional treatments for schizophrenia may not help or may even make things worse. Many patients and caregivers want more than just medications. They want to understand WHY things are the way they are.
Light on Schizophrenia clearly lays out the causes and contributors to schizophrenia from the Orthomolecular perspective, and it offers solutions. ‘Orthomolecular’ refers to the roles of vitamins, minerals and other essential molecules in the body.
This book is an update to Dr. Abram Hoffer’s 2007 book, Orthomolecular Treatment for Schizophrenia and Other Mental Illnesses: A Guide for Practitioners. It contains Dr. Hoffer’s chronicles of his 57 years of experience and success in treating schizophrenia patients; it also integrates current knowledge on the causes and moderators of schizophrenia.
Light on Schizophrenia contains valuable new contributions from James Greenblatt, MD, and Jonathan Prousky, ND. Both doctors have decades of clinical experience working with patients with schizophrenia and other mental illnesses.
This is the only book to provide a comprehensive look at the Orthomolecular approach to schizophrenia. Published by the International Society for Orthomolecular Medicine, October 2020
Paperback, Kindle, and Kobo formats available – purchase online

Schizophrenia & Psychosis (Online course for health care professionals)
Presenter: James Greenblatt, MD

Healing Schizophrenia
Author: Abram Hoffer, MD, PhD – CCNM Press, August 2011

Orthomolecular Treatment for Schizophrenia and Other Mental Illnesses: A Guide for Practitioners
Author: Abram Hoffer, MD, PhD – ISOM, 2007

Journal of Orthomolecular Medicine (Full text search of archives)