Orthomolecular interventions include substances that have roles in promoting or addressing schizophrenia, depending on individual metabolic requirements and the amount present in the 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

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

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).

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)

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)

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

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)

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

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

• 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.

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).

• 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).

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).

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