Mental Health Information – Depression

Vitamin B6 and anxiety

Vitamin B6 is required for:

• Conversion of the amino acid tryptophan into serotonin – Low levels of serotonin are associated with depression
• The synthesis of monoamine neurotransmitters, such as serotonin, dopamine, and γ-aminobutyrate. PLP, the active form of vitamin B6, is a cofactor in this synthesis process. (Food and Nutrition Board, Institute of Medicine, 1998) (Skarupski et al., 2010)

Vitamin B6 and Depression

• Vitamin B6 deficiency may be involved in both the onset and progression of depression (Skarupski et al., 2010) (Greenblatt & Brogan, 2016 pg 104).
• Humans developed feelings of depression and confusion when following a vitamin B6-free diet for 55 days. This was resolved with pyridoxine supplementation (Hawkins & Barsky, 1948).
• The ‘serotonin deficiency hypothesis’ suggests that depression is due to  serotonin deficiency in the brain. Therefore, depression may be associated with decreased transportation of L-tryptophan across the blood-brain barrier, since it is a serotonin precursor (Williams et al., 2005) (Greenblatt & Brogan, 2016) .
• Vitamin B6 is required for the metabolism of homocysteine. According to the ‘vascular hypothesis’ of depression, vitamin B6 deficiency will lead to increased homocysteine levels. High homocysteine levels are associated with cerebrovascular disease, which is a significant risk factor for depression (Almeida et al., 2010) (Ford et al., 2008).

Vitamin B6 Deficiency

Deficiency of vitamin B6 can be identified by:

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

Causes of deficiencies

• inadequate dietary intake
• medications, including anti-tuberculosis drugs, anti-parkinsonians, 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

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 20–6,000 mg a day in divided doses (Office of dietary supplements, 2020).
• “In women with laboratory evidence of vitamin B6 deficiency, apparently as a result of taking oral contraceptives, supplementation with 40 mg/day of vitamin B6 relieved anxiety and depression” (Bermond, 1982).
• Treatments of 150 mg/day of Vitamin B6 for one month was found to decrease patients’ symptoms of depression, shown through the use of the Hamilton Depression Rating Scale (Shiloh et al., 2001)
• A summary of studies found the use of Vitamin B6 beneficial for treating the mood symptoms of premenstrual syndrome (Wyatt et al., 1999).
• Vitamin B6 should be considered as treatment or adjunct therapy for people with depression, especially the elderly and/or patients not responding to traditional medications (Skarupski et al., 2010).
• 1.3 mg/day of Vitamin C is the recommended daily allowance for adults (Skarupski et al., 2010).

SAFETY, SIDE EFFECTS

• Vitamin B6 is considered a safe treatment for depressive symptoms (Almeida et al., 2010) (Wyatt et al., 1999).
• Vitamin B6 has been proposed as a safe adjunct therapy to antidepressant medications (Almeida et al., 2010) (Wyatt et al., 1999).
• 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). 

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).

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References

Bermond P. (1982). Therapy of side effects of oral contraceptive agents with vitamin B6. Acta Vitaminologica et Enzymologica, 4(1-2), 45–54.

McCarty M. F. (2000). High-dose pyridoxine as an ‘anti-stress’ strategy. Medical hypotheses, 54(5), 803–807. https://doi.org/10.1054/mehy.1999.0955

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

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

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

Food and Nutrition Board, Institute of Medicine. (1998). Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press, 196–305.

Skarupski, K. A., Tangney, C., Li, H., Ouyang, B., Evans, D. A., & Morris, M. C. (2010). Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. The American Journal of Clinical Nutrition, 92(2), 330–335. https://doi.org/10.3945/ajcn.2010.29413

Hawkins, W. W., & Barsky, J. (1948). An Experiment on Human Vitamin B6 Deprivation. Science, 108(2802), 284–286. https://doi.org/10.1126/science.108.2802.284

Almeida, O. P., Marsh, K., Alfonso, H., Flicker, L., Davis, T. M. E., & Hankey, G. J. (2010). B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Annals of Neurology, 68(4), 503–510. https://doi.org/10.1002/ana.22189

Ford, A. H., Flicker, L., Thomas, J., Norman, P., Jamrozik, K., & Almeida, O. P. (2008). Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: Results from a 2-year placebo-controlled randomized trial. The Journal of Clinical Psychiatry, 69(8), 1203–1209. https://doi.org/10.4088/jcp.v69n0801

Shiloh, R., Weizman, A., Weizer, N., Dorfman-Etrog, P., & Munitz, H. (2001). [Antidepressive effect of pyridoxine (vitamin B6) in neuroleptic-treated schizophrenic patients with co-morbid minor depression—Preliminary open-label trial]. Harefuah, 140(5), 369–373, 456.

Wyatt, K. M., Dimmock, P. W., Jones, P. W., & Shaughn O’Brien, P. M. (1999). Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: Systematic review. BMJ (Clinical Research Ed.), 318(7195), 1375–1381. https://doi.org/10.1136/bmj.318.7195.1375

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 and Depression

Depression is a symptom of vitamin B12 deficiency. (Hector & Burton, 1988) (Gaby).

• Vitamin B12 was found to be inversely correlated with depression scores in un-medicated depressed patients (Kapoor et al., 2017)

 Low levels of Vitamin  B12  are associated with:

• Higher scores on the Beck Depression Inventory (BDI) (Güzelcan & van Loon, 2009)
• Decreased efficacy of Fluoxetine for Depression (Mischoulon et al., 2000)
• Poorer responses to common depression treatment (Hintikka et al., 2003)

Vitamin B12 and Depression in 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
• Higher frequency of depression (31%) than omnivores (12%)

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)

Low serum Vitamin B12, with low folate and high homocysteine levels, predicted a higher risk of depression in older adults (Kim et al., 2008)

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

Vitamin B12 levels can be normal in blood tests but be deficient in the cerebral spinal fluid. (Prousky, 2015)

Top food sources of vitamin B12 by serving size:

• clams, mussels
• mackeral
• 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 establish due to low potential for toxicity.

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)
• Vitamin B12 supplementation may have the best clinical response when used in the context of anxiety and fatigue or depression (Prousky, 2015)

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

Arora, K., Sequeira, J. M., Hernández, A. I., Alarcon, J. M., & Quadros, E. V. (2017). Behavioral alterations are associated with vitamin B12 deficiency in the transcobalamin receptor/CD320 KO mouse. PLoS ONE, 12(5). https://doi.org/10.1371/journal.pone.0177156

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

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.

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

Hector, M., & Burton, J. R. (1988). What are the psychiatric manifestations of vitamin B12 deficiency? Journal of the American Geriatrics Society, 36(12), 1105–1112. https://doi.org/10.1111/j.1532-5415.1988.tb04397.x

Güzelcan, Y., & van Loon, P. (2009). Vitamin B12 status in patients of Turkish and Dutch descent with depression: A comparative cross-sectional study. Annals of General Psychiatry, 8(1), 18. https://doi.org/10.1186/1744-859X-8-18

Mischoulon, D., Burger, J. K., Spillmann, M. K., Worthington, J. J., Fava, M., & Alpert, J. E. (2000). Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression. Journal of Psychosomatic Research, 49(3), 183–187. https://doi.org/10.1016/S0022-3999(00)00158-6

Hintikka, J., Tolmunen, T., Tanskanen, A., & Viinamäki, H. (2003). High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. BMC Psychiatry, 3(1), 17. https://doi.org/10.1186/1471-244X-3-17

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

Kim, J.-M., Stewart, R., Kim, S., Yang, S.-J., Shin, I.-S., & Yoon, J.-S. (2008). Predictive value of folate, vitamin B-12 and homocysteine levels in late-life depression. The British Journal of Psychiatry : The Journal of Mental Science, 192, 268–274. https://doi.org/10.1192/bjp.bp.107.039511

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

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

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

Vitamin C (ascorbic acid) 

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 Depression

• Depression is a possible manifestation of severe vitamin C deficiency that can be resolved with correction of deficiency (Kinsman & Hood, 1971) (Dixit, 1979) (Gaby).
• Pharmacological doses of vitamin C may have an antidepressant effect (Gaby). 
• 3 g/day of vitamin C supplementation in healthy volunteers significantly decreased monoamine oxidase activity (MOA). MOA is responsible for metabolizing serotonin, norepinephrine, and dopamine. (Gaby)
• Healthy young men who were depleted of vitamin C frequently reported symptoms of fatigue and irritability (Schleicher et al., 2009) 
• When given a diet without any Vitamin C, participants experienced increased general malaise and fatigue over time.  After 30 days, symptoms of depression and suicidal ideations arose. This was hypothesized to be due to improper functioning of dopamine beta-hydroxylase enzyme, which catalyzes dopamine into norepinephrine, and requires ascorbic acid (vitamin C) to do so (Dixit, 1979)
• Vitamin C is a hormone that is responsible for excitement and  behavioral stimulation.  Decreased levels of Vitamin C can lead to depression. (Greenblatt & Brogan, 2016).

Vitamin C Deficiency

Causes of Vitamin C Deficiency include:

• 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.
• 1 g/day of vitamin C for three weeks was found to relieve depressive symptoms in a group of vitamin C-deficient chronic psychiatric inpatients. 1 g/day of vitamin C or placebo for 3 weeks. This resulted in significant improvements in depression, mania, and paranoia. (Milner, 1963) (Gaby).

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 depression medications.

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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.

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/

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

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

Kinsman, R., & Hood, J. (1971). Some behavioral effects of ascorbic acid deficiency. The American Journal of Clinical Nutrition, 24(4). https://doi.org/10.1093/ajcn/24.4.455

Dixit, V. M. (1979). Cause of depression in chronic scurvy. Lancet (London, England), 2(8151), 1077–1078. https://doi.org/10.1016/s0140-6736(79)92476-0

Schleicher, R. L., Carroll, M. D., Ford, E. S., & Lacher, D. A. (2009). Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES). The American Journal of Clinical Nutrition, 90(5), 1252–1263. https://doi.org/10.3945/ajcn.2008.27016

Milner, G. (1963). Ascorbic Acid in Chronic Psychiatric Patients—A Controlled Trial. The British Journal of Psychiatry, 109(459), 294–299. https://doi.org/10.1192/bjp.109.459.294

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 Depression

Roles of vitamin D in depression include reduction of pro-inflammatory cytokines and oxidative stress, and neurotransmitter synthesis & regulation in the brain and gut.

Vitamin D affects multiple brain regions that are linked to the development of depression. These regions include (Yue et al., 2014) (Bertone-Johnson, 2009) (Umhau et al., 2013):

• Prefrontal cortex 
• Hippocampus
• Cingulate gyrus 
• Thalamus
• Hypothalamus
• Substantia nigra

In a review of 14 studies, it was found that depressed individuals have a 65% greater likelihood of having lower 25(OH)D (a form of Vitamin D) concentrations (Parker et al., 2017).

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)
• Vitamin D supplements demonstrated statistically significant improvements in depression in multiple studies. The results from this supplementation was comparable to the effects of antidepressant medications (Spedding, 2014)  (Greenblatt & Brogan, 2016).

SAFETY, SIDE EFFECTS

• “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

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References

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.

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

Yue, W., Xiang, L., Zhang, Y.-J., Ji, Y., & Li, X. (2014). Association of serum 25-hydroxyvitamin D with symptoms of depression after 6 months in stroke patients. Neurochemical Research, 39(11), 2218–2224. https://doi.org/10.1007/s11064-014-1423-y

Bertone-Johnson, E. R. (2009). Vitamin D and the occurrence of depression: Causal association or circumstantial evidence? Nutrition Reviews, 67(8), 481–492. https://doi.org/10.1111/j.1753-4887.2009.00220.x

Umhau, J., George, D., Heaney, R., Lewis, M., Ursano, R., Heilig, M., Hibbeln, J., & Schwandt, M. (2013). Low Vitamin D Status and Suicide: A Case-Control Study of Active Duty Military Service Members. PloS One, 8, e51543. https://doi.org/10.1371/journal.pone.0051543

Parker, G. B., Brotchie, H., & Graham, R. K. (2017). Vitamin D and depression. Journal of Affective Disorders, 208, 56–61. https://doi.org/10.1016/j.jad.2016.08.082

Spedding, S. (2014). Vitamin D and Depression: A Systematic Review and Meta-Analysis Comparing Studies with and without Biological Flaws. Nutrients, 6(4), 1501–1518. https://doi.org/10.3390/nu6041501

Folate and Mental Health

• 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 is essential for brain development and function

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

Hundreds of studies have found that significant correlations between folate levels and depression risk (Gilbody et al., 2007). Low folate is associated with (Bottiglieri, 2005):

• Higher incidence of depression 
• Poorer response to antidepressants 
• Higher relapse rate
• Impaired synthesis and release of serotonin, dopamine, and norepinephrine

Folate and Depression

Depression is a psychiatric symptom of folate deficiency. The depression resulting from folate deficiency may be partially due to decreased serotonin levels in the brain. (Botez et al., 1979)

Folate deficiency can potentially (Fava et al., 1997):

• Perpetuate depression symptoms
• worsen clinical outcomes
• reduce response to traditional antidepressants (Coppen & Bailey, 2000)
• increase the risk of relapse in patients

Folate-deficient individuals showed 2.2 times greater likelihood of treatment resistance than healthy individuals (Greenblatt & Brogan, 2016, p.100)

Causes of folate deficiencies

• low dietary intake
• poor absorption
• gastrointestinal issues
• chronic alcoholism
• smoking
• oral contracetives (Gaby, 2011)
• drug interactions (Folate, 2014)
• genetic variations in folate metabolism, for example variations the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene  (“Folate”, 2014)

Top food sources of folate by serving size:

• lentils
• chickpeas
• asparagus
• spinach

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 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 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 100–5,000 mcg a day in divided doses (Office of Dietary Supplements, n.d.).
• A good quality mutlivitamin/mineral supplement typically contains 400 mcg folate.
• 500 μg/day of folic acid supplementation increased the efficacy of fluoxetine, and also reduced the side effects, in women with a new episode of major depression. (Coppen & Bailey, 2000).
• 200 μg/day of Folic acid has been demonstrated to increase the effectiveness of lithium prophylaxis in patients with unipolar depression (Coppen et al., 1986).
• Several relevant studies have shown positive effects of using Levomefolic acid (5-MTHF) for the treatment of depression. (Greenblatt & Brogan, 2016, p.100) 

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 1,000 μg (1 mg) daily (Folate, 2014).

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. 

Howard, J. S. III. (1975). Folate deficiency in psychiatric practice. Psychosomatics, 16.

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

Bottiglieri, T. (2005). Homocysteine and folate metabolism in depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 29(7), 1103–1112. https://doi.org/10.1016/j.pnpbp.2005.06.021

Gilbody, S., Lightfoot, T., & Sheldon, T. (2007). Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. Journal of Epidemiology & Community Health, 61(7), 631–637. https://doi.org/10.1136/jech.2006.050385

Botez, M. I., Young, S. N., Bachevalier, J., & Gauthier, S. (1979). Folate deficiency and decreased brain 5-hydroxytryptamine synthesis in man and rat. Nature, 278(5700), 182–183. https://doi.org/10.1038/278182a0

Coppen, A., & Bailey, J. (2000). Enhancement of the antidepressant action of fluoxetine by folic acid: A randomised, placebo controlled trial. Journal of Affective Disorders, 60(2). https://doi.org/10.1016/s0165-0327(00)00153-1

Fava, M., Borus, J. S., Alpert, J. E., Nierenberg, A. A., Rosenbaum, J. F., & Bottiglieri, T. (1997). Folate, vitamin B12, and homocysteine in major depressive disorder. The American Journal of Psychiatry, 154(3), 426–428. https://doi.org/10.1176/ajp.154.3.426

Coppen, A., Chaudhry, S., & Swade, C. (1986). Folic acid enhances lithium prophylaxis. Journal of Affective Disorders, 10(1), 9–13. https://doi.org/10.1016/0165-0327(86)90043-1

Chromium and Depression

• Chromium supplementation has been shown effective for addressing hypoglycemia, since (Anderson, 1986). Hypoglycemia is a  common contributing factor for depression. (See Hypoglycemia and Depression for more information)

Chromium improves blood glucose regulation and increases insulin sensitivity (Anderson, 1986) (Attenburrow et al., 2002). Improving insulin sensitivity may increase serotonin production in the brain by increasing uptake of tryptophan. It is also possible that chromium could improve depression by altering the sensitivity of central 5-HT2A receptors, and therefore modifying the actions of serotonin. (Attenburrow et al., 2002) 

Chromium has also been found to be effective for atypical depression, which is primarily treated with monoamine oxidase inhibitors (MOA). Atypical depression symptoms include:

• Mood reactivity
• Increased appetite
• weight gain
• Hypersomnia
• Leaden paralysis
• Sensitivity to interpersonal rejection

Atypical depression is often more chronic than other forms of depression, and is associated with increased disability and suicidal ideation. (Gaby 2011)

• Chromium has been demonstrated as an effective treatment for affective disorders. (Iovieno et al., 2011) (Greenblatt & Brogan, 2016, p.121) 

Top sources of chromium based on serving size

• broccoli
• green beans
• potatoes (mashed) 
• beef
• turkey breast

Comprehensive food list:
Table 2. Some Food Sources of Chromium (Chromium, 2014)
https://lpi.oregonstate.edu/mic/minerals/chromium

Referenced Dietary Intakes

Adequate Intakes for chromium (mcg/day)
Adolescents 14-18 years 35 (M) 24 (F)
Adults 19-50 years 35 (M) 25 (F)
Adults 51 years and older 30 (M) 20 (F)

Supplementing chromium

• Amounts of chromium used in practice and research range from 100–1,000 mcg a day in divided doses (Office of Dietary Supplements, n.d.).
• Case reports of patients with long-term depression (n=3) that had not responded to multiple interventions, experienced dramatic improvement after taking 400–600 μg/day of  chromium picolinate or chromium polynicotinate. (Gaby).

SAFETY, SIDE EFFECTS

• The Food and Nutrition Board concluded that no adverse effects have been linked to high intakes of chromium from food or supplements, so it did not establish a UL for chromium (Office of Dietary Supplements, n.d.).

CHROMIUM AND MEDICATIONS

Chromium can interact with medication interactions including (Office of Dietary Supplements, n.d):

• insulin
• metformin and other antidiabetes medications
• levothyroxine

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References 

Anderson, R. A. (1986). Chromium metabolism and its role in disease processes in man. Clinical Physiology and Biochemistry, 4(1), 31–41.

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

Attenburrow, M.-J., Odontiadis, J., Murray, B., Cowen, P., & Franklin, M. (2002). Chromium treatment decreases the sensitivity of 5-HT2A receptors. Psychopharmacology, 159(4), 432–436. https://doi.org/10.1007/s00213-001-0960-7

Iovieno, N., Dalton, E. D., Fava, M., & Mischoulon, D. (2011). Second-tier natural antidepressants: Review and critique. Journal of Affective Disorders, 130(3), 343–357. https://doi.org/10.1016/j.jad.2010.06.010

Iron is required for the synthesis of serotonin and norepinephrine (Gaby).

Iron and Depression

• Iron deficiency correction in teenage girls was found to improve mood and mental concentration, and decrease weariness and weakness. (Ballin et al., 1992) 
• “Iron deficiency should be considered as a possible contributing factor in selected patients with depression, particularly menstruating women, vegetarians, and people taking nonsteroidal antiinflammatory drugs”. (Gaby 2011) 
• Symptoms associated with low iron levels, such as depressed mood, can occur before blood levels would classify a person as iron-deficient  (Greenblatt & Brogan, 2016,p.122)
• Average serum levels of iron were significantly lower in patients with depression than in healthy individuals (Vahdat Shariatpanaahi et al., 2007)

Causes of Iron Deficiencies (Iron, 2014)

Chronic blood losses due to:

• Parasitic infestations
• Frequent blood donation 
• Regular intense exercise

Decreased iron absorption due to:

• Celiac disease 
• gastritis
• Helicobacter pylori infection
• Inflammatory bowel diseases (IBD)
• Gastric bypass surgery

Other causes of iron deficiency:

• Vegetarian diet with inadequate sources of iron
• Chronic kidney disease (CKD) 
• Pregnancy (due to increased need)
• Chronic inflammation

Deficiency of iron can be identified by (10 Signs and Symptoms of Iron Deficiency, 2020):

• Unusual tiredness
• Pale skin, inner eyelids, gums, or nails
• Cracks at the corners of the mouth
• Mouth ulcers
• Swollen, pale or smooth tongue
• Shortness of breath
• Headaches
• Dizziness, lightheadedness
• Heart palpitations
• Dry or damaged skin or hair

Top sources of iron based on typical serving size

• beef, beef liver
• chicken liver
• oysters, clams
• tuna
• raisins
• prunes

Comprehensive food list:

Table 2: some food sources of iron (Iron, 2014) 

Referenced Dietary Intakes

RDAs for iron (mg/day)

Adolescents (14-18 years): 11 (M) 15 (F)

Adults (19 years and older): 8 (M) 18 (F)

Tolerable upper intake: 45 mg/day 

(Office of Dietary Supplements – Iron, n.d.)

Supplementing Iron

• Amounts of iron used in practice and research range from 12–120 mg/day (Stoltzfus & Dreyfuss, 1999).

SAFETY, SIDE EFFECTS

• Supplementation  with more than 20 mg/kg can cause gastric upset, constipation, nausea, abdominal pain, vomiting, and faintness
• Doses of 60 mg/kg can lead to multisystem failure, convulsions, coma, and death (Office of Dietary Supplements – Iron, n.d.)

Iron and Medications

• Iron can reduce the absorption of levothyroxine; Levodopa, carbidopa, methyldopa; proton pump inhibitors such as lansoprazole (Prevacid) and omeprazole (Prilosec); cholestyramine and colestipol; penicillamine; quinolones; tetracyclines; and bisphosphonates. These medications should be taken two hours away from iron supplements ​​(Iron, 2014).

References

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

Murray, M. T. (1996). Encyclopedia of Nutritional Supplements: The Essential Guide for Improving Your Health Naturally (1st edition). Harmony.

Office of Dietary Supplements—Iron. (n.d.). Retrieved August 14, 2021, from https://ods.od.nih.gov/factsheets/Iron-HealthProfessional/

Stoltzfus, R. J., & Dreyfuss, M. L. (1999). Guidelines for the use of iron supplements to prevent and treat iron deficiency anemia. ILSI Pr.

Ballin, A., Berar, M., Rubinstein, U., Kleter, Y., Hershkovitz, A., & Meytes, D. (1992). Iron State in Female Adolescents. American Journal of Diseases of Children, 146(7), 803–805. https://doi.org/10.1001/archpedi.1992.02160190035015

Vahdat Shariatpanaahi, M., Vahdat Shariatpanaahi, Z., Moshtaaghi, M., Shahbaazi, S. H., & Abadi, A. (2007). The relationship between depression and serum ferritin level. European Journal of Clinical Nutrition, 61(4), 532–535. https://doi.org/10.1038/sj.ejcn.1602542

10 Signs and Symptoms of Iron Deficiency. (2020, October 26). Healthline. https://www.healthline.com/nutrition/iron-deficiency-signs-symptoms

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 depression 

• Depression is a symptom of magnesium deficiency (Enya et al., 2004, Vidal Freyre & Flichman, 1970).
• Blood levels of magnesium have been found to be lower in people with depression (Frizel et al., 1969).
• Some antidepressant actions of magnesium include inhibiting N-methyl-D- aspartate receptors and mediating stress by moderating the hypothalamic-pituitary-adrenal axis (HPA) (Jung et al., 2010).

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

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.psychol- ogytoday.com/blog/evolutionary-psychiatry/201106/ magnesium-and-the-brain-the-original-chill-pill

Enya, M., Kanoh, Y., Mune, T., Ishizawa, M., Sarui, H., Yamamoto, M., Takeda, N., Yasuda, K., Yasujima, M., Tsutaya, S., & Takeda, J. (2004). Depressive State and Paresthesia Dramatically Improved by Intravenous MgSO in Gitelman’s Syndrome. Internal Medicine, 43(5), 410–414. https://doi.org/10.2169/internalmedicine.43.410

Frizel, D., Coppen, A., & Marks, V. (1969). Plasma Magnesium and Calcium in Depression. The British Journal of Psychiatry, 115(529), 1375–1377. https://doi.org/10.1192/bjp.115.529.1375

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

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

Jung, K. I., Ock, S. M., Chung, J. H., & Song, C. H. (2010). Associations of serum Ca and Mg levels with mental health in adult women without psychiatric disorders. Biological Trace Element Research, 133(2), 153–161. https://doi.org/10.1007/s12011-009-8421-y

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

Vidal Freyre, A., & Flichman, J. C. (1970). Spasmophilia Caused by Magnesium Deficit. Psychosomatics, 11(5), 500–501. https://doi.org/10.1016/S0033-3182(70)71617-4

Zinc and Depression

• Zinc deficiency can manifest as depression (Aggett & Harries, 1979) (Kay et al., 1976)
• Zinc has anti-anxiety and antidepressant effects, and  is critical for regulating excitatory glutamate and NMDA receptor activity in the brain. (Andrews, 1990; Joshi, Akhtar, Najmi, Khuroo, & Goswami, 2012).

The hypothesis of a relationship between zinc and depression is based on how  (Greenblatt & Brogan, 2016) :

• • Serum zinc levels are lower in patients with depression than in their healthy individuals ​​(McLoughlin & Hodge, 1990)
  • Zinc supplementation has been found to reduce depressive symptoms
  •  Antidepressant treatments have been found to increase zinc levels over time. 
  • An inverse relationship between the severity of depression and zinc levels has been seen in several studies. (Swardfager et al., 2013), (Irmisch et al., 2010)

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).
• “Zinc supplements have been shown to improve the efficacy of antidepressant treatment, especially in treatment-resistant patients” (Warner-Schmidt & Duman, 2006)
• Supplementation with 25 mg/day of zinc increased antidepressant drug efficacy in clinical trial patients with major depression (Nowak et al., 2003) (Gaby).
• “Long-term zinc supplementation should be accompanied by a copper supplement (1–4 mg/day, depending on the zinc dose), in order to prevent zinc-induced copper deficiency” (Gaby)

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 UL (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).

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References

Andrews, R. R. (1990). Unification of the  findings in schizophrenia by reference to the effects of gestational zinc deficiency. Medical Hypotheses, 31(2), 141-153.

Institute of Medicine. (2006). Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. https://doi.org/10.17226/11537

Joshi, M., Akhtar, M., Najmi, A. K., Khuroo, A. H., & Goswami, D. (2012). Effect of zinc in animal models of anxiety, depression and psychosis. Human & Experimental Toxicology, 31(12), 1237-1243.

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

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

Aggett, P. J., & Harries, J. T. (1979). Current status of zinc in health and disease states. Archives of Disease in Childhood, 54(12), 909–917. https://doi.org/10.1136/adc.54.12.909

Kay, R. G., Tasman-Jones, C., Pybus, J., Whiting, R., & Black, H. (1976). A syndrome of acute zinc deficiency during total parenteral alimentation in man. Annals of Surgery, 183(4), 331–340. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1344200/

Swardfager, W., Herrmann, N., Mazereeuw, G., Goldberger, K., Harimoto, T., & Lanctôt, K. L. (2013). Zinc in depression: A meta-analysis. Biological Psychiatry, 74(12), 872–878. https://doi.org/10.1016/j.biopsych.2013.05.008

Irmisch, G., Schlaefke, D., & Richter, J. (2010). Zinc and fatty acids in depression. Neurochemical Research, 35(9), 1376–1383. https://doi.org/10.1007/s11064-010-0194-3

McLoughlin, I. J., & Hodge, J. S. (1990). Zinc in depressive disorder. Acta Psychiatrica Scandinavica, 82(6), 451–453. https://doi.org/10.1111/j.1600-0447.1990.tb03077.x

Nowak, G., Siwek, M., Dudek, D., Zieba, A., & Pilc, A. (2003). Effect of zinc supplementation on antidepressant therapy in unipolar depression: A preliminary placebo-controlled study. Polish Journal of Pharmacology, 55(6), 1143–1147.

Warner-Schmidt, J. L., & Duman, R. S. (2006). Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment. Hippocampus, 16(3), 239–249. https://doi.org/10.1002/hipo.20156

Polyunsaturated fatty acids (PUFAs) (omega 3 and 6 fatty acids) are necessary for normal development and function of the brain.

Essential fatty acids and Depression

• Omega 3 fatty acids and their metabolites have roles in regulating inflammation, neuroinflammation, and neurotransmission (Larrieu, & Layé, 2018) – all of which are factors in depression.
• Deficiency of essential fatty acids, or an imbalanced ratio of omega 6 to omega 3 fatty acids has been shown to correlate with anxiety and depression. (Rakel, 2012).
• Patients with depression have shown to have low levels of Omega-3 fatty acids, or low levels of Omega-3 relative to Omega-6 fatty acid levels (Gaby 2011)
  • This is especially true among women in the postpartum period
  • Depression or genetic factors may cause low omega-3 levels (Beydoun et al., 2013) (Bloch & Qawasmi, 2011)
  • Adequate intake and/or supplementation of EPA (and DPA) could improve mood during postpartum (Beydoun et al., 2013) (Bloch & Qawasmi, 2011)

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:  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

• 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) 
• A study found that 1 g/day of ethyl-EPA (E-EPA) improved depression, but higher doses were ineffective. This loss of efficacy with higher doses may be due to an imbalance between omega-3 and omega-6 fatty acids. (Peet & Horrobin, 2002) (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.

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 appears 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

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

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.

Beydoun, M. A., Fanelli Kuczmarski, M. T., Beydoun, H. A., Hibbeln, J. R., Evans, M. K., & Zonderman, A. B. (2013). ω-3 Fatty Acid Intakes Are Inversely Related to Elevated Depressive Symptoms among United States Women1234. The Journal of Nutrition, 143(11), 1743–1752. https://doi.org/10.3945/jn.113.179119

Bloch, M. H., & Qawasmi, A. (2011). Omega-3 fatty acid supplementation for the treatment of children with attention-deficit/hyperactivity disorder symptomatology: Systematic review and meta-analysis. Journal of the American Academy of Child and Adolescent Psychiatry, 50(10), 991–1000. https://doi.org/10.1016/j.jaac.2011.06.008

Peet, M., & Horrobin, D. (2002). A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Archives of General Psychiatry. https://doi.org/10.1001/ARCHPSYC.59.10.913

Tyrosine is a dietary amino acid that also functions as a neurotransmitter. The body can also make tyrosine from the amino acid phenylalanine.

Tyrosine is a precursor molecule for the neurotransmitters dopamine, noepinephrine, and epinephrine, and is also required for the production of thyroid hormones.

Tyrosine and Depression

• Tyrosine levels in plasma were found to be significantly lower in depressed patients than in healthy individuals. Tyrosine levels rose as patients recovered from depression (Gaby). 

Causes of deficiencies

• a low-protein diet

Top sources of tyrosine based on serving size (Top Foods High in Tyrosine, n.d.)

• sesame seeds
• cheese 
• soybeans 
• meat and Poultry
• fish

Supplementing tyrosine

• Amounts of tyrosine used in practice and research range from 100–1000 mg/day in divided doses (Mahoney et al., 2007).
• Tyrosine seems to be safe when used in doses up to 150 mg/kg per day for up to 3 months”  (Tyrosine, n.d.) (Gaby).
• As antidepressants: 500-1000 mg of Tyrosine can be given 2-3 times daily as an antidepressants (Haas & Levin, 2006) (Gaby)
• Since L-tyrosine may act as a mild stimulant, Tyrosine should not be taken near bedtime. L-tyrosine is likely most effective when it is taken with carbohydrates on an empty stomach (Gaby). 

 

SAFETY, SIDE EFFECTS

• Some people may experience side effects such as nausea, headache, fatigue, heartburn, and joint pain (Tyrosine, n.d.)
• People who have migraine headaches may need to avoid tyrosine, as it can trigger migraine headaches
• People with hyperthyroidism or Graves disease may need to avoid supplementing tyrosine as it may promote increased thyroid hormone production

TYROSINE AND MEDICATIONS

• Tyrosine may decrease how much levodopa the body absorbs (Tyrosine, n.d.)
• Tyrosine may increase how much thyroid hormone the body produces

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References

Tyrosine: Health Benefits, Side Effects, Uses, Dose & Precautions. (n.d.). RxList. Retrieved August 15, 2021, from https://www.rxlist.com/tyrosine/supplements.htm

Top Foods High in Tyrosine. (n.d.). WebMD. Retrieved August 15, 2021, from https://www.webmd.com/diet/foods-high-in-tyrosine

Mahoney, C. R., Castellani, J., Kramer, F. M., Young, A., & Lieberman, H. R. (2007). Tyrosine supplementation mitigates working memory decrements during cold exposure. Physiology & Behavior, 92(4), 575–582. https://doi.org/10.1016/j.physbeh.2007.05.003

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 depression

• Tryptophan levels in cerebrospinal fluid are significantly lower in depressed patients than in controls (Gaby). 

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/day5,12,13 and 425 mg/day (Richard et al. 2009).

1. Supplementing tryptophan

• Amounts of tryptophan used in practice and research range from 50–2,000 mg day in divided doses (Prousky, 2015).
• Carbohydrate consumption increases the amount of TRP that crosses the BBB (Richard et al., 2009). Therefore tryptophan is best taken away from meals, but with a small amount of carbohydrate to facilitate absortption. 5-HTP transport across the BBB is not affected by dietary protein consumptions and can be taken with meals (Werbach, 1997).
• The optimal dose of tryptophan has been found in practice to be 2 g a day, taken with  vitamin B6 (Prousky, 2015).
• 1g, 3 times/day of L-tryptophan was significantly more effective than placebo at treating depression, and showed similar efficacy to amitriptyline. The combination of L-tryptophan and amitriptyline was most effective ​​(Thomson et al., 1982).
• “L-Tryptophan has been reported to relieve depression in patients with low tryptophan levels due with Crohn’s disease (when given at a dose of 0.6–1.2 g/day),32 and in hospitalized alcoholics (when given at a dose of 3 g/day)”(Asheychik et al., 1989).
• 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.

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 adrenal insufficiency (Prousky, 2015).
• 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)
• 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 a 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.
• Supplementing 5-HTP has been shown to help address panic attacks (Maron, Tõru, Vasar, & Shlik, 2004): Lake, 2007) and generalized anxiety (Lake 2007)
• 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 heart burn, 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 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.

Jones, R. S. (1982). Tryptamine: A neuromodulator or neurotransmitter in mammalian brain? Progress in Neurobiology, 19(1–2), 117–139. https://doi.org/10.1016/0301-0082(82)90023-5

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

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

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,.

Thomson, J., Rankin, H., Ashcroft, G. W., Yates, C. M., McQueen, J. K., & Cummings, S. W. (1982). The treatment of depression in general practice: A comparison of L-tryptophan, amitriptyline, and a combination of L-tryptophan and amitriptyline with placebo. Psychological Medicine, 12(4), 741–751. https://doi.org/10.1017/s0033291700049047

Asheychik, R., Jackson, T., Baker, H., Ferraro, R., Ashton, T., & Kilgore, J. (1989). The efficacy of L-tryptophan in the reduction of sleep disturbance and depressive state in alcoholic patients. Journal of Studies on Alcohol, 50(6), 525–532. https://doi.org/10.15288/jsa.1989.50.525

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

Inositol (also called myo-inositol) has important roles in the function of norepinephrine, GABA and serotonin receptors (Benjamin, Agam, Levine, Bersudsky, Kofman, & Belmaker, 1995).

Inositol and Depression

• Inositol levels are lower in the cerebrospinal fluid and brain of patients with depression than in healthy patients(Benjamin et al., 1995) (Gaby)  (Greenblatt & Brogan, 2016). 
• Clinical studies have found inositol supplementation to be beneficial in the treatment of depression. (Greenblatt & Brogan, 2016, p.106).

Causes of deficiencies

• An inositol-deficient diet
• High amounts of dietary glucose – which decreases myo-inositol synthesis and absorption, and increases its degradation (Dinicola, Minini, Unfer, Verna, Cucina, & Bizzarri, 2017).

Good sources of inositol (Clements & Darnell, 1980)

• meat and eggs
• oranges, grapefruit, lime 
• peaches, pears
• whole grains
• beans and legumes
• rutabaga

Referenced Dietary Intakes

RDAs/Upper intakes for Inositol
Not established.

Inositol Supplementation

• Inositol supplementation can increase the increase inositol levels in the brain (Benjamin et al., 1995).
• Amounts of inositol used in practice and research range from 12–18 g a day in divided doses (Supplement sampler, 2020).
• The dose should be increased gradually over several weeks. Inositol powder can be added to juice.
• The mechanism of action of inositol is different from most depression treatment mechanisms. Because of this, the addition of inositol may increase the antidepressant effect of other treatments.(Gaby)

SAFETY, SIDE EFFECTS

• Inositol can cause nausea, fatigue, dizziness, and headaches.
• Use of inositol has not been associated with and substantial side effects (Benjamin et al., 1995)

INOSITOL AND MEDICATIONS

• There are no known adverse reactions with other medications and supplements (Supplement sampler, 2020).

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References

Benjamin, J., Agam, G., Levine, J., Bersudsky, Y., Kofman, O., & Belmaker, R. H. (1995). Inositol treatment in psychiatry. Psychopharmacology Bulletin, 31(1), 167–175.

Benjamin, J., Levine, J., Fux, M., Aviv, A., Levy, D., & Belmaker, R. H. (1995). Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. The American Journal of Psychiatry, 152(7), 1084–1086. https://doi.org/10.1176/ajp.152.7.1084

Clements, R. S., & Darnell, B. (1980). Myo-inositol content of common foods: Development of a high-myo-inositol diet. The American Journal of Clinical Nutrition, 33(9), 1954–1967. https://doi.org/10.1093/ajcn/33.9.1954

Dinicola, S., Minini, M., Unfer, V., Verna, R., Cucina, A., & Bizzarri, M. (2017). Nutritional and Acquired Deficiencies in Inositol Bioavailability. Correlations with Metabolic Disorders. International Journal of Molecular Sciences, 18(10). https://doi.org/10.3390/ijms18102187

“Supplement Sampler, Inositol”. University of Wisconsin Integrative Medicine. Retreived October 28, 2020, from https://www.fammed.wisc.edu/files/webfm-uploads/documents/outreach/im/ss_inositol.pdf

SAMe and Depression

Studies have found that S-adenosylmethionine (SAMe) is effective and often well tolerated in the treatment of depression (Criconia et al., 1994) (Alpert et al., 2004) (Rosenbaum et al., 1990) (Bell et al., 1994) (Potkin et al., 1988) (Salmaggi et al., 1993). The onset of action for SAMe is generally quicker than with conventional antidepressants (Gaby).

The exact mechanism that SAMe uses to relieve depression is unknown. SAMe is known to function as a methyl donor while also playing a role in neurotransmission, monoamine metabolism, and  membrane function (Carney et al., 1987).

Referenced Dietary Intake 

RDAs/Upper intakes for SAMe

Not established.

SAMe Supplementation

• Amounts of SAMe used in practice and research range from 200-3200 mg/day in divided doses.
• Recommended dose for treating depression: 200–400 mg/day via IV or subcutaneously for 15–20 days, or 400–1,600 mg/day orally (Friedel et al., 1989)
• Clinical trial data with 200-1600 mg/d doses of SAMe was found to be safe, well-tolerated, and effective. This was found to be equivalent or superior to antidepressants and placebo treatments (Mischoulon & Fava, 2002).
• SAMe (1600–3200 mg/daily) supplementation was found be superior to Escitalopram (10– 20 mg/daily), an SSRI. at 2, 4, and 6-week follow-up appointments (Sarris et al., 2014).

SAFETY, SIDE EFFECTS

• Primary side effects include (Gaby 2011) : 
  • Anxiety
  • Headaches
  • Mild gastrointestinal disturbances
• SAMe supplementation has frequently resulted in a switch from depression to hypomania in patients with bipolar disorder (Gaby). This adverse effect has occurred only rarely in unipolar depression patients. (Carney et al., 1989) (De Vanna & Rigamonti, 1992)

SAMe AND MEDICATIONS

• SAMe may decrease the efficacy of levodopa (L-dopa), a drug used for Parkinson’s disease (S-Adenosyl-L-Methionine (SAMe), n.d.). 
• SAMe may interact with drugs or dietary supplements that increase serotonin levels. This includes antidepressants, L-tryptophan, and St. John’s wort (S-Adenosyl-L-Methionine (SAMe), n.d.).

References

S-Adenosyl-L-Methionine (SAMe): In Depth. (n.d.). NCCIH. Retrieved August 16, 2021, from https://www.nccih.nih.gov/health/sadenosyllmethionine-same-in-depth

Criconia, A. M., Araquistain, J. M., Daffinà, N., Navajas, F., & Bordino, M. (1994). Results of treatment with s-adenosyl-l-methionine in patients with major depression and internal illnesses. Current Therapeutic Research, 55(6), 666–674. https://doi.org/10.1016/S0011-393X(05)80801-X

Alpert, J. E., Papakostas, G., Mischoulon, D., Worthington, J. J., Petersen, T., Mahal, Y., Burns, A., Bottiglieri, T., Nierenberg, A. A., & Fava, M. (2004). S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: An open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. Journal of Clinical Psychopharmacology, 24(6), 661–664. https://doi.org/10.1097/01.jcp.0000145339.45794.cd

Rosenbaum, J. F., Fava, M., Falk, W. E., Pollack, M. H., Cohen, L. S., Cohen, B. M., & Zubenko, G. S. (1990). The antidepressant potential of oral S-adenosyl-l-methionine. Acta Psychiatrica Scandinavica, 81(5), 432–436. https://doi.org/10.1111/j.1600-0447.1990.tb05476.x

Bell, K. M., Potkin, S. G., Carreon, D., & Plon, L. (1994). S-adenosylmethionine blood levels in major depression: Changes with drug treatment. Acta Neurologica Scandinavica. Supplementum, 154, 15–18. https://doi.org/10.1111/j.1600-0404.1994.tb05404.x

Potkin, S. G., Bell, K., Plon, L., & Bunney, W. E. (1988). Rapid antidepressant response with SAMe. A double-blind study. The Alabama Journal of Medical Sciences, 25(3), 313–316.

Salmaggi, P., Bressa, G. M., Nicchia, G., Coniglio, M., La Greca, P., & Le Grazie, C. (1993). Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Psychotherapy and Psychosomatics, 59(1), 34–40. https://doi.org/10.1159/000288642

Carney, M. W., Toone, B. K., & Reynolds, E. H. (1987). S-adenosylmethionine and affective disorder. The American Journal of Medicine, 83(5A), 104–106. https://doi.org/10.1016/0002-9343(87)90861-8

Friedel, H. A., Goa, K. L., & Benfield, P. (1989). S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs, 38(3), 389–416. https://doi.org/10.2165/00003495-198938030-00004

Mischoulon, D., & Fava, M. (2002). Role of S-adenosyl-L-methionine in the treatment of depression: A review of the evidence. The American Journal of Clinical Nutrition, 76(5), 1158S-61S. https://doi.org/10.1093/ajcn/76/5.1158S

Sarris, J., Papakostas, G. I., Vitolo, O., Fava, M., & Mischoulon, D. (2014). S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: Efficacy and effects of histamine and carnitine as moderators of response. Journal of Affective Disorders, 164, 76–81. https://doi.org/10.1016/j.jad.2014.03.041

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

De Vanna, M., & Rigamonti, R. (1992). Oral S-adenosyl-L-methionine in depression. Current Therapeutic Research, 52(3), 478–485. https://doi.org/10.1016/S0011-393X(05)80424-2

B-complex Vitamins and Mental Health

• Conditions including stress, illness, poor diet and nutrient absorption, as well as cetain 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).

B-complex Vitamins and Depression

Deficiencies in Vitamins B1, B3, B6, B9 and B12 are linked to depression (Mikkelsen et al., 2016)

• B vitamins can reduce risk of depression, This was seen in 273 stroke patients that were given Vitamin B6, B12, and folate for 1 to 10.5 years and were found to have significantly lower risk of major depression (Almeida et al., 2010).

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

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References

Mikkelsen, K., Stojanovska, L., & Apostolopoulos, V. (2016). The Effects of Vitamin B in Depression. Current Medicinal Chemistry, 23(38), 4317–4337. https://doi.org/10.2174/0929867323666160920110810

Almeida, O. P., Marsh, K., Alfonso, H., Flicker, L., Davis, T. M. E., & Hankey, G. J. (2010). B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Annals of Neurology, 68(4), 503–510. https://doi.org/10.1002/ana.22189

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

Multivitamins and Depression

• Conditions including stress, illness, poor diet and nutrient absorption, as well as cetain 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 on multivitamins and depression:

Blampied, M., Bell, C., Gilbert, C., Boden, J., Nicholls, R., & Rucklidge, J. J. (2018). Study Protocol for a Randomized Double Blind, Placebo Controlled Trial Exploring the Effectiveness of a Micronutrient Formula in Improving Symptoms of Anxiety and Depression. Medicines, 5(2). https://doi.org/10.3390/medicines5020056