Mental Health Information – Schizophrenia

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)

https://lpi.oregonstate.edu/mic/vitamins/niacin

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.

SAFETY, SIDE EFFECTS

• 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).

SAFETY, SIDE EFFECTS

• 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).

References

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.
https://ndnr.com/neurology/the-orthomolecular-treatment-of-schizophrenia/.

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)

https://lpi.oregonstate.edu/mic/vitamins/vitamin-B6

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).

SAFETY, SIDE EFFECTS

• 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).

VITAMIN B6 AND MEDICATIONS

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

References

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)

https://lpi.oregonstate.edu/mic/vitamins/vitamin-B12

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).

SAFETY, SIDE EFFECTS

• 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).

References

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)

https://lpi.oregonstate.edu/mic/vitamins/folate

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.

SAFETY, SIDE EFFECTS

• 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).

References

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)

https://lpi.oregonstate.edu/mic/vitamins/vitamin-C

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).

SAFETY, SIDE EFFECTS

• 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).

References

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

References

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)
https://lpi.oregonstate.edu/mic/minerals/magnesium

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).

SAFETY, SIDE EFFECTS

• 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.

References

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
https://lpi.oregonstate.edu/mic/minerals/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)

SAFETY, SIDE EFFECTS

• 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).

References

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

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.)
https://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids

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).

SAFETY, SIDE EFFECTS

• 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.).

OMEGA 3 FATTY ACIDS AND MEDICATIONS

• 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

References

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.

• 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.)
https://nutritiondata.self.com/foods-000094000000000000000.html

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)

SAFETY, SIDE EFFECTS

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

GLYCINE AND MEDICATIONS

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

References

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

• 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).

SAFETY, SIDE EFFECTS

• 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

References

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.

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).

References

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.

https://doi.org/10.1097/PSY.0b013e31827d5fbd

Reference

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