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

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 bipolar disorder

• An inverse relationship exists between homocysteine and both folate and vitamin B12 levels (Moustafa et al., 2014). As folate and/or vitamin B12 levels drop, homocysteine levels increase.
• Homocysteine promotes (Moustafa et al., 2014; Mitchell et al., 2014):
  • inappropriate activation of NMDA receptors
  • oxidative stress
  • mitochondrial dysfunction
  • neuronal apoptosis (cell death)

• Elevated levels of homocysteine are shown to promote mental issues that include cognitive impairment, and depression in patients with affective disorders including bipolar (Moustafa et al., 2014).
• Having high homocysteine and low folate and vitamin B12 levels may be a risk factor for developing bipolar disorder (Ozbek et al., 2008).

MTHFR polymorphisms and mental health

• 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.
• 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 B12 and mental health

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 brain

• Required for the synthesis of neurotransmitters including serotonin and dopamine
• Required for the preservation of protective myelin sheath around neurons
• Important for homocysteine metabolism

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

Vitamin B12 deficiency

• 40% of Americans have low levels of vitamin B12, and 20% of elderly people have severe vitamin B12 deficiencies. This is due to a decreased ability to absorb B12 with older age (Wolters et al., 2004) (Andrès et al., 2004) (Greenblatt & Brogan, 2016).
• People with depression may have higher needs due to decreased vitamin B12 transport across the blood-brain barrier (Arora, Sequeira, Hernández, Alarcon, & Quadros, 2017), or because of increased breakdown of vitamin B12 in brain tissue (Gaby, 2011).
• Vitamin B12 levels can be normal in blood tests but be deficient in the cerebral spinal fluid. (Prousky, 2015).

Vitamin B12 and Vegetarians

When comparing omnivores and vegetarians, it was found that vegetarians had (Kapoor et al., 2017):

• significantly lower serum B12 levels
• significantly higher methylmalonic acid (MMA) levels

The most common causes of vitamin B12 deficiency:

• vitamin B12-deficient diet
• vegetarianism or veganism
• decreased stomach acid production
• bacterial overgrowth in the small intestine

Magnesium and mental health

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 bipolar disorder

• Significantly decreased intracellular magnesium levels have been found in patients with untreated bipolar disorder during the manic episode (Nechifor, 2011).
• Manic agitation has been correlated with a higher calcium to magnesium ratio (Carman et al., 1979). 
• Medications used in bipolar therapy significantly increase intracellular magnesium (in addition to lithium)  (Nechifor, 2011)

Causes of magnesium deficiencies 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.

Lithium and mental health

Lithium (Greenblatt, 2018):

• protects neurons from damage
• stimulates growth of new neurons
• has anti-inflammatory properties
• inhibits glutamate synthesis and release
• modulates dopamine by decreasing its release
• stimulates production of GABA and GABA receptors
• increases levels of brain serotonin

Nutritional lithium

Lithium orotate (Kling et al., 1978): 

• has been used to treat stress, manic depression, alcoholism, ADD, ADHD, PTSD, and Alzhiemer’s disease
• can be used at much lower doses and has fewer side effects than medical lithium

Lithium dosing

• Nutritional lithium (orotate or aspartate) dosing ranges from 2–30 mg a day. (Greenblatt, 2015)
• Prescription lithium (carbonate) is used to prevent the manic episode of bipolar disorder. Doses range from 900 to 1800 mg a day (Lithium, n.d.).
• Important: prescription lithium (carbonate) should not be reduced or discontinued without the supervision of a medical professional.

Essential fatty acids and mental health

• Polyunsaturated fatty acids (PUFAs) (omega 3 and 6 fatty acids) are necessary for normal development and function of the brain.
• Omega 3 fatty acids and their metabolites have roles in regulating inflammation, neuroinflammation, and neurotransmission (Larrieu, & Layé, 2018).

Essential fatty acids and bipolar disorder

• Deficiencies in red blood cell membranes of the omega 3 fatty acids EPA and DHA are associated with, and may precede the onset of mania in bipolar disorder (McNamara et al., 2021).
• Omega 3 fatty acids have been shown to have mood stabilzing properties in both the manic and depressive phases of bipolar disorder, and increase duration of remission (Stoll et al., 1999).

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

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 and bipolar disorder

Levels of the protective molecule glutathione are low in patients with bipolar disorder (Berk, Copolov, Dean, Lu, Jeavons, Schapkaitz, Anderson-Hunt, & Judd, 2008). NAC is a precursor molecule in the production of glutathione.

NAC has been shown beneficial when used adjunctively with bipolar medications (Pereira et al., 2018).

“NAC doesn’t always work, but when it does, troubling irrational thoughts gradually decrease in intensity and frequency and often fade away. Negative thoughts (e.g., “I’m a bad person,” or “Nobody likes me”) or ruminations about other people (“Will that girl like me?”) or about health issues (“Do I have AIDS?’) that can’t be quieted by reasonable evidence to the contrary, and that keep intruding on one’s awareness hour after hour, day after day despite all rational efforts to control, seem to diminish. Or, if they continue to occur, they are less distressing, and can be observed from more of a distance, with less worry or fear, and are less likely to trigger depression or other negative effects” (Hellerstein, 2013).

Tryptophan and 5-HTP and mental health

• Serotonin, regarded as the happy, feel good neurotransmitter, is synthesized from the amino acid tryptophan. Tryptophan is converted in the body to 5-HTP, which is then converted into the neurotransmitter serotonin.

Tryptophan and 5-HTP and bipolar disorder

• Supplementation of tryptophan has shown benefit in both the manic and depressive phases of bipolar disorder (Gaby, 2011).
• Patients with deficiency of plasma tryptophan had improved symptoms with supplementation of 100–200 mg/kg of body weight per day (Moller et al., 1976).

Choline is a water-soluble nutrient that is similar to B vitamins.

Choline has roles in (Choline Fact Sheet for Health Professionals, n.d.):

• the synthesis of the neurotransmitter acetylcholine
• the synthesis of the cell membrane components phosphatidylcholine and sphingomyelin
• methylation reactions needed for many aspects of metabolism

Choline and bipolar disorder

• Choline deficiency may be a factor in some cases of mania (Lake, 2018).
• Acetylcholine-promoting agents are known to have anti-manic effects. Supplementing choline or lecithin (which contains choline) may be helpful for people with bipolar disorder.

Causes of choline defiencies

• Since some choline is synthesized by the body, overt choline deficiency is rare. However people with variations in genes involved with metabolism of folate, methionine, and choline may have an increased demand for additional dietary choline (Choline Fact Sheet for Health Professionals, n.d.).
• Demands for choline increase during pregnancy.

Although SAMe has been shown useful in the treatment of depression, SAMe supplementation has been reported to cause hypomania, mania, and euphoria in a large portion of patients with bipolar disorder (Carney et al., 1989).

SAMe supplementation should be avoided in bipolar disorder.

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.
• People with variations in genes involved with metabolism of folate, methionine, and other B-vitamins may have an increased demand for additional 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.
• Deficiencies of B-vitamins are factor in psychiatric disorders (Mitchell et al., 2014).

“A trial of B-complex supplement seems advisable, especially in older persons and in persons taking medications that may deplete this vitamin” (Rakel, 2012).

“In my experience, supplementation with a high-potency B-complex vitamin sometimes improves chronic anxiety in patients who have no clinical evidence of B-vitamin deficiency” (Gaby, 2011).

Further reading

Lewis, J. E., Tiozzo, E., Melillo, A. B., Leonard, S., Chen, L., Mendez, A., Woolger, J. M., & Konefal, J. (2013). The effect of methylated vitamin B complex on depressive and anxiety symptoms and quality of life in adults with depression. ISRN Psychiatry, 2013, 621453. https://doi.org/10.1155/2013/621453

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.

Hardy-Stephan regimen

The Hardy-Stephan regimen is a multi-vitamin, mineral and amino acid supplement that may be of benefit in the context of bipolar disorder. The supplement is sold under the name EMPowerPlus (Synergy Group of Canada).

• In several uncontrolled trials, use of the supplement resulted in notable clinical improvement in bipolar patients (Gaby, 2011).
• In one trial, medicated patients with bipolar disorder, treatment for 6 months resulted in improvements in symptoms, and reduction or elimination of the need for psychotropic medicatons (Kaplan et al., 2001).

If implementing the Hardy-Stephan regimen with the intention of reducing bipolar medications it is advisable to work with qualified professional guidance. It has been observed that increasing the supplement dosing too quickly, and/or decreasing the medications too quickly, can result in an increase in bipolar symptoms.

Additional research with the Hardy-Stephan regimen:

Database analysis of children and adolescents with Bipolar Disorder consuming a micronutrient formula
Julia J Rucklidge, Dermot Gately & Bonnie J Kaplan
https://doi.org/10.1186/1471-244X-10-74

Nutritional and Safety Outcomes from an Open-Label Micronutrient Intervention for Pediatric Bipolar Spectrum Disorders
Elisabeth A. Frazier, Barbara Gracious, L. Eugene Arnold, Mark Failla, Chureeporn Chitchumroonchokchai, Diane Habash, and Mary A. Fristad
https://doi.org/10.1089/cap.2012.0098

Effective Mood Stabilization With a Chelated Mineral Supplement: An Open-Label Trial in Bipolar Disorder
Bonnie J. Kaplan, J. Steven A. Simpson, Richard C. Ferre, Chris P. Gorman, David M. McMullen, and Susan G. Crawford
https://doi.org/10.4088/jcp.v62n1204