Mental Health Information – Bipolar Disorder

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)

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.

Folic acid supplementation

It has been suggested that supplementation with folic acid (synthetic form of folate) should be avoided in favour of folate, as folic acid impairs methylation by binding to and blocking receptors required for natural folate (Lynch, 2018).

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 in combination with medication has been shown to be safe and effective for addressing the acute stage of mania in bipolar disorder (Zheng et al., 2020).

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).

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References

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.

Lynch, B. (2018). Dirty Genes: A Breakthrough Program to Treat the Root Cause of Illness and Optimize Your Health (1st edition). HarperOne.

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

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

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.

1. Vitamin B12 Supplementation

• Amounts of vitamin B12 used in practice and research range from 1000–5000 IU/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).
• Vitamin B12 supplementation may have the best clinical response when used in the context of anxiety and fatigue or depression (Prousky, 2015).
• In the context of bipolar disorder, a therapeutic trial of intramuscular vitamin B12 would be reasonable to consider (1000 mcg, 1–2 times a week for four weeks), even in the absence of vitamin B12 deficiency (Gaby, 2011). Oral supplemented folate (1–5 mg/day) would be appropriate during the vitamin B12 trial (Gaby, 2011).

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).
• Many anxiety patients benefit from B12 injections even though they have no clinical evidence of deficiency (Prousky, 2015).

• Daily 5 mg B12 injections for two weeks in men and women with normal serum B12 were found to improve appetite, mood, energy, and sleep to the 4-week follow-up (Ellis & Nasser, 1973).

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).

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References

Andrès, E., Loukili, N. H., Noel, E., Kaltenbach, G., Abdelgheni, M. B., Perrin, A. E., Noblet-Dick, M., Maloisel, F., Schlienger, J.-L., & Blicklé, J.-F. (2004). Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ: Canadian Medical Association Journal = Journal de l’Association Medicale Canadienne, 171(3), 251–259. https://doi.org/10.1503/cmaj.1031155

Dommisse, J. (1991). Subtle vitamin-B12 deficiency and psychiatry: A largely unnoticed but devastating relationship? Medical Hypotheses, 34(2), 131–140. https://doi.org/10.1016/0306-9877(91)90181-w

Ellis, F. R., & Nasser, S. (1973). A pilot study of vitamin B12 in the treatment of tiredness. British Journal of Nutrition, 30(2), 277–283. https://doi.org/10.1079/BJN19730033

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

Greenblatt, J. M., & Brogan, K. (Eds.). (2016). Integrative Therapies for Depression: Redefining Models for Assessment, Treatment and Prevention (1st edition). CRC Press.

Kapoor, A., Baig, M., Tunio, S. A., Memon, A. S., & Karmani, H. (2017). Neuropsychiatric and neurological problems among Vitamin B12 deficient young vegetarians. Neurosciences (Riyadh, Saudi Arabia), 22(3), 228–232. https://doi.org/10.17712/nsj.2017.3.20160445

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). CCNM Press.

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

Wolters, M., Ströhle, A., & Hahn, A. (2004). Cobalamin: A critical vitamin in the elderly. Preventive Medicine, 39(6), 1256–1266. https://doi.org/10.1016/j.ypmed.2004.04.047

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.

Top sources of magnesium based on serving size

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

Comprehensive food 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).

Magnesium supplementation – beneficial forms and dosing (Greenblatt, 2018)

• Magnesium glycinate supplementation of 120-240 mg per meal and at bedtime has been shown to benefit mood
• Magnesium glycinate or citrate supplementation of 240-360 mg before bed supports sleep onset and sleeping through the night
• Some beneficial forms of magnesium include magnesium aspartate, magnesium glycinate, magnesium threonate
• The magnesium oxide form is less beneficial

Magnesium and bipolar disorder

• “Magnesium exerts biochemical effects similar to those of lithium, which raises the possibility that magnesium might be an effective mood stabilizer” (Gaby, 2011).
• Oral magnesium supplementation, by itself or in addition to medication has been shown beneficial in patients with bipolar disorder (Gaby, 2011).
• Bipolar patients who did not do well on combinations of lithium, haloperidol and clonazepam dramatically improved when magnesium was added to the regimen (Heiden et al., 1999).

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.

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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/

Carman, J. S., Post, R. M., Runkle, D. C., Bunney, W. E., & Wyatt, R. J. (1979). Increased serum calcium and phosphorus with the “switch” into manic or excited psychotic state. The British Journal of Psychiatry: The Journal of Mental Science, 135, 55–61. https://doi.org/10.1192/bjp.135.1.55

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 (VitalBook file).

Greenblatt, J. (2018). Orthomolecular Applications in Integrative Psychiatry, Depression [Pdf].

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

Heiden, A., Frey, R., Presslich, O., Blasbichler, T., Smetana, R., & Kasper, S. (1999). Treatment of severe mania with intravenous magnesium sulphate as a supplementary therapy. Psychiatry Research, 89(3), 239–246. https://doi.org/10.1016/s0165-1781(99)00107-9

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

Nechifor, M. (2011). Magnesium in psychoses (schizophrenia and bipolar disorders). In R. VINK & M. NECHIFOR (Eds.), Magnesium in the Central Nervous System (pp. 303–312). University of Adelaide Press. https://www.jstor.org/stable/10.20851/j.ctt1t3055m.26

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.

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References

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

Greenblatt, J. (2015, April 26). Low dose lithium for the treatment of mood, behavioural, and cognitive disorders. Orthomolecular Medicine Today Conference, Toronto, Canada.

Lithium: Drug Uses, Dosage and Side Effects. (n.d.). Drugs.Com. Retrieved December 27, 2021, from https://www.drugs.com/lithium.html

Ohgami, H., Terao, T., Shiotsuki, I., Ishii, N., & Iwata, N. (2009). Lithium levels in drinking water and risk of suicide. The British Journal of Psychiatry: The Journal of Mental Science, 194(5), 464–465; discussion 446. https://doi.org/10.1192/bjp.bp.108.055798

Schrauzer, G. N., & Shrestha, K. P. (1990). Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biological Trace Element Research, 25(2), 105–113. https://doi.org/10.1007/BF02990271

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

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

Top α-Linolenic Acid (omega 3) food sources by serving size

• flax seed oil
• chia seeds
• walnuts
• flax seeds ground

Comprehensive food list:

Table 3. Food Sources of α-Linolenic Acid (18:3n-3) (Office of Dietary Supplements, n.d.)

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

Top Linoleic Acid (omega-6) sources by serving size

• safflower oil
• sunflower seeds
• pine nuts
• sunflower oil

Comprehensive food list: Table 2. Food Sources of Linoleic Acid (18:2n-6) (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 and older):  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 mg/day (M+F)

Supplementing omega 3 fatty acids

• Supplementation of omega 3 fatty acids seems beneficial for addressing depression (Bruinsma & Taren, 2000).
• Amounts of omega 3 fatty acids used in practice and research range from 1–4 g/day of combined EPA and DHA, in divided doses.
• Fish oil and E-EPA are generally well tolerated, but may cause gastrointestinal side effects in some individuals (Gaby)
• Long-term supplementation with EPA and DHA should be accompanied by a vitamin E supplement (Gaby), as polyunsaturated fatty acids increase vitamin E requirements in the body.
• It takes at least 10 weeks to restore brain levels of EPA and DHA after chronic deficiency (Bourre et al., 1993).

Supplementing fatty acids in the context of bipolar disorder

Fish oil

• Doses used in the treatment of bipolar have ranged from 1,290–9,600 mg/day of omega 3 fatty acids in adults, and 1.3–4.3 g a day in children (Gaby, 2011).
• “fish oil is relatively safe and appears to produce substantial improvement in a significant proportion of patients. Fish oil should therefore be considered for primary or adjunctive therapy for patients with bipolar disorder” (Gaby, 2011).

Flaxseed oil

• Flaxseed oil has shown benefit in bipolar patients when used adjunctively (Stoll et al., 1999). However, flaxseed oil may promote, or fail to prevent mania or hypomania in some bipolar patients (Stoll et al., 1999).

Evening primrose oil

• Evening primrose oil is generally contraindicated with bipolar disorder due to its omega 6 fatty acid content (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).

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References

Bruinsma, K. A., & Taren, D. L. (2000). Dieting, Essential Fatty Acid Intake, and Depression. Nutrition Reviews, 58(4), 98–108. https://doi.org/10.1111/j.1753-4887.2000.tb07539.x

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

Institute of Medicine. (2002). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. https://doi.org/10.17226/10490

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

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

McNamara, R. K., Li, W., Lei, D., Tallman, M. J., Welge, J. A., Strawn, J. R., Patino, L. R., & DelBello, M. P. (2021). Fish oil supplementation alters emotion-generated corticolimbic functional connectivity in depressed adolescents at high-risk for bipolar I disorder: A 12-week placebo-controlled fMRI trial. Bipolar Disorders, n/a(n/a). https://doi.org/10.1111/bdi.13110

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.

Stoll, A. L., Locke, C. A., Marangell, L. B., & Severus, W. E. (1999). Omega-3 fatty acids and bipolar disorder: A review. Prostaglandins, Leukotrienes and Essential Fatty Acids, 60(5), 329–337. https://doi.org/10.1016/S0952-3278(99)80008-8

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).

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).

Supplementing NAC in the context of bipolar disorder

• Doses of NAC commonly used in the context of bipolar disorder range between 1000 and 2000 mg/day (Hellerstein, 2013).
• In a double-blind trial, 2 g/day of NAC in conjunction with bipolar medications improved symptoms of depresssion in bipolar disorder patients (Gaby, 2011).

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

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References

Berk, M., Copolov, D. L., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M., & Bush, A. I. (2008). N-acetyl cysteine for depressive symptoms in bipolar disorder—A double-blind randomized placebo-controlled trial. Biological Psychiatry, 64(6), 468–475. https://doi.org/10.1016/j.biopsych.2008.04.022

Berk, M., Copolov, D., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M., Judd, F., Katz, F., Katz, P., Ording-Jespersen, S., Little, J., Conus, P., Cuenod, M., Do, K. Q., & Bush, A. I. (2008). N-acetyl cysteine as a glutathione precursor for schizophrenia—A double-blind, randomized, placebo-controlled trial. Biological Psychiatry, 64(5), 361–368. https://doi.org/10.1016/j.biopsych.2008.03.004

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.

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

Hellerstein, D. (2013, October 31). NAC: The Amino Acid That Turns Psychiatry on Its Head | Psychology Today. https://www.psychologytoday.com/us/blog/heal-your-brain/201810/nac-the-amino-acid-turns-psychiatry-its-head

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

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.

Pereira, C., Chavarria, V., Vian, J., Ashton, M. M., Berk, M., Marx, W., & Dean, O. M. (2018). Mitochondrial Agents for Bipolar Disorder. International Journal of Neuropsychopharmacology, 21(6), 550–569. https://doi.org/10.1093/ijnp/pyy018

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).

Food sources of tryptophan

Common sources of tryptophan (Richard et al. 2009):

• turkey
• chicken
• tuna
• oats
• peanuts

Referenced Dietary Intakes

The recommended daily allowance for tryptophan for adults is estimated to be between 250 mg/day and 425 mg/day (Richard et al. 2009).

1. Supplementing tryptophan

• Amounts of tryptophan used in practice and research range from 50–6000 mg/day in divided doses.
• Carbohydrate consumption increases the amount of TRP that crosses the Blood Brain Barrier (BBB) (Richard et al., 2009). Therefore tryptophan is best taken away from meals, but with a small amount of carbohydrate to facilitate absorption. 5-HTP transport across the Blood-Brain Barrier (BBB) is not affected by dietary protein consumption and can be taken with meals (Werbach, 1997).
• The optimal dose of tryptophan has been found in practice to be 2 g/day, taken with vitamin B6 (Prousky, 2015).

• L-tryptophan increases serotonin levels, suggesting that it is most likely to be effective in serotonin-deficient patients. This includes patients with a history of a positive response to SSRIs or other serotonergic drugs (Gaby).
• A dosage of 6 g/day or less  is recommended when L-tryptophan is used by itself, and 4 g/day or less is recommended when given in combination with 2 g/day of niacinamide. These should be given in two separate doses per day to minimize fluctuation of tryptophan concentration (Chouinard et al., 1977) (Chouinard et al., n.d.).
• The dose required can be reduced by administering L-tryptophan and niacinamide on an empty stomach along with carbohydrates. (Gaby)
• L-tryptophan may cause fatigue. When this is experienced, the addition of 500 mg of L-tyrosine twice a day in addition to the L-tryptophan dose can prevent the fatigue and potentially increase the antidepressant effect of L-tryptophan. (Gaby)
• For tryptophan-deficent individuals, L-tryptophan supplementation can provide a larger range of benefits than supplementation with 5-HTP.

• Clinical trials and case reports indicate that 6–12 g/day of tryptophan may be benefical for bipolar patients, especially in the context of low plasma tryptophan (Gaby, 2011).

SAFETY, SIDE EFFECTS – Tryptophan

• Side effects of L-tryptophan supplementation can include heartburn, stomach pain, belching and gas, nausea, vomiting, diarrhea, and loss of appetite, headache, lightheadedness, drowsiness, dry mouth, visual blurring, muscle weakness, and sexual problems in some people (L-Tryptophan: Uses, Side Effects, n.d.).
• High doses of tryptophan can promote bronchial asthma aggravation and nausea.
• Tryptophan should not be used during pregnancy, with lupus, or with adrenal insufficiency (Prousky, 2015).
• Co-administering L-tryptophan and antidepressants that increase serotonergic activity (SSRIs, amitriptyline, monoamine oxidase inhibitors) may increase the efficacy and toxicity of the drugs (Gaby).

TRYPTOPHAN AND MEDICATIONS

• Supplementing tryptophan or 5-HTP while on SSRI or MAOI medications is not generally recommended as it may promote an excessive buildup of serotonin  (Birdsall, 1998).
• Do not supplement tryptophan if taking morphine (Prousky, 2015)
• Avoid taking tryptophan or 5-HTP (or limit to very low doses) if receiving electroconvulsive therapy (Gaby)

2. Supplementing 5-HTP

Referenced Dietary Intakes

RDAs/Upper intakes for 5-HTP
None established.

• Amounts of 5-HTP used in practice and research range from 100–900 mg/day in divided doses (Prousky, 2015; Rakel, 2012).
• 5-HTP can be taken with meals, as opposed to tryptophan, which needs to be taken away from meals.
• Common amounts of 5-HTP used for addressing anxiety range from 100 to 900 mg daily in divided doses  (Prousky, 2015; Rakel, 2012).

SAFETY, SIDE EFFECTS – 5-HTP

• Side effects of 5-HTP supplementation are typically minimal and can include heartburn, flatulence, rumbling sensations, feeling of fullness, mild, nausea, vomiting, and hypomania (Werbach 1999: Murray & Pizzorno, 1998, p. 391-93)
• Other possible side effects include, stomach pain, diarrhea, drowsiness, sexual problems, and muscle problems (5-Htp: Uses, Side Effects, n.d.).
• High-dose supplementation – from 6-10 grams daily – have been linked to severe stomach problems and muscle spasms (5-HTP: Uses, Side Effects, n.d.).

5-HTP AND MEDICATIONS

• Supplementing tryptophan or 5-HTP while on SSRI or MAOI medications is not generally recommended as it may cause an excessive buildup of serotonin (Birdsall, 1998).
• Avoid taking tryptophan or 5-HTP (or limit to very low doses) if receiving electroconvulsive therapy (Gaby)

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References

5-HTP: Uses, Side Effects, Interactions, Dosage, and Warning. (n.d.). Retrieved October 29, 2020, from https://www.webmd.com/vitamins/ai/ingredientmono-794/5-htp

Birdsall, T. C. (1998). 5-Hydroxytryptophan: A clinically-effective serotonin precursor. Alternative Medicine Review: A Journal of Clinical Therapeutic, 3(4), 271–280.

Chouinard, G., Young, S. N., Annable, L., & Sourkes, T. L. (1977). Tryptophan-nicotinamide combination in depression. Lancet (London, England), 1(8005), 249. https://doi.org/10.1016/s0140-6736(77)91036-4

Chouinard, G., Young, S. N., Annable, L., & Sourkes, T. L. (n.d.). Tryptophan-nicotinamide, imipramine and their combination in depression. Acta Psychiatrica Scandinavica, 59(4), 395–414. Retrieved August 26, 2021, from https://www.academia.edu/24627244/Tryptophan_nicotinamide_imipramine_and_their_combination_in_depression

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

L-Tryptophan: Uses, Side Effects, Interactions, Dosage, and Warning. (n.d.). Retrieved October 29, 2020, from https://www.webmd.com/vitamins/ai/ingredientmono-326/l-tryptophan

Moller, S. E., Kirk, L., & Fremming, K. H. (1976). Plasma amino acids as an index for subgroups in manic depressive psychosis: Correlation to effect of tryptophan. Psychopharmacology, 49(2), 205–213. https://doi.org/10.1007/BF00427292

Murray, M., & Pizzorno J. (1998). Encyclopedia of Natural Medicine. Revised 2nd ed. Rocklin, CA: Prima Publishing.

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

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

Richard, D. M., Dawes, M. A., Mathias, C. W., Acheson, A., Hill-Kapturczak, N., & Dougherty, D. M. (2009). L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications. International Journal of Tryptophan Research : IJTR, 2, 45–60.

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

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.

Top sources of choline (based on mg/serving)

• beef liver
• eggs
• beef
• soybeans
• chicken
• cod
• potatoes

Comprehensive food list

Table 2: Choline Content of Selected Foods

https://ods.od.nih.gov/factsheets/Choline-HealthProfessional/

Referenced Dietary Intakes

Adequate intakes for choline (mg/day) (Choline Fact Sheet for Health Professionals, n.d.)

Adolescents (14-18 years): 550  (M) 400 (F)
Adults (19+ years): 550 (M) 425 (F)

Choline supplementation

Amounts of choline used in practice and research range from 750–6000 mg/day in divided doses (Choline, 2014).

Sources of supplemental choline include:

• choline
• citicholine
• betaine 
• phosphatidyl choline
• lecithin

Supplementing choline in the context of bipolar disorder

• Choline or lecithin supplementation has shown in clinical trials to result in a substantial improvement in manic patients with bipolar disorder (Gaby, 2011)
• Phosphatidylcholine supplementation of 15 g to 30 g/day has been shown in case reports and open trials to reduce mania and depression in bipolar patients. Symptoms reoccurred upon discontinuation of supplementation (Lake, 2018).

SAFETY/SIDE EFFECTS

High intakes of choline (10,000–16,000 mg/day) have been associated with vomiting, excessive sweating and salivation, fishy body odour, low blood pressure, and liver toxicity (Choline Fact Sheet for Health Professionals, n.d.)

CHOLINE AND MEDICATIONS

Choline is not known to interact with any medications (Choline Fact Sheet for Health Professionals, n.d.).

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References

Choline. (2014, April 28). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/other-nutrients/choline

Choline Fact Sheet for Health Professionals. (n.d.). Office of Dietary Supplements. Retrieved January 5, 2022, from https://ods.od.nih.gov/factsheets/Choline-HealthProfessional/

Choline. (2014, April 28). Linus Pauling Institute. https://lpi.oregonstate.edu/mic/other-nutrients/choline

Lake, J. (2018, July 3). Choline Supplementation for Bipolar Disorder | Psychology Today. https://www.psychologytoday.com/us/blog/integrative-mental-health-care/201807/choline-supplementation-bipolar-disorder

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.

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References

Carney, M. W., Chary, T. K., Bottiglieri, T., & Reynolds, E. H. (1989). The switch mechanism and the bipolar/unipolar dichotomy. The British Journal of Psychiatry: The Journal of Mental Science, 154, 48–51. https://doi.org/10.1192/bjp.154.1.48

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

References

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

Mitchell, E. S., Conus, N., & Kaput, J. (2014). B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neuroscience & Biobehavioral Reviews, 47, 307–320. https://doi.org/10.1016/j.neubiorev.2014.08.006

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.

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

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References

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

Kaplan, B. J., Simpson, J. S., Ferre, R. C., Gorman, C. P., McMullen, D. M., & Crawford, S. G. (2001). Effective mood stabilization with a chelated mineral supplement: An open-label trial in bipolar disorder. The Journal of Clinical Psychiatry, 62(12), 936–944. https://doi.org/10.4088/jcp.v62n1204