MOOD DISORDERS: SAFE, EFFECTIVE, AND NATURAL SOLUTIONS
Todd A. Born, ND, CNS Mood Disordersare mental health issues that primarily impact a person’s emotional state; an affected person may experience periods of extreme happiness, extreme sadness, or both, that lasts at least several weeks.1 In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition(DSM-5), the list of mood disorders and their diagnostic criteria is lengthy; however, the most common mood disorders include major depression; dysthymia; bipolar disorder; major depressive disorder with seasonal pattern [ie, seasonal affective disorder, or SAD]; and depression related to an illness, substance abuse, or medication.2 For simplicity in this article, I will refer to these issues collectively as mood disorders unless otherwise indicated.
The 2001 to 2003 National Comorbidity Survey Replication shows an estimated 9.7% of US adults (anyone over 18) having any mood disorder within the past year, with a higher prevalence among females (11.6%) than males (7.7%); the report also estimated that 21.4% of US adults will experience a mood disorder at some point during their lives.3 (Please note that these figures are a combination of mood disorders; frequently updated individual statistics may be found on the website of the National Institute of Mental Health.4)
Depression, alone, affects almost 300 million people worldwide.5 Bipolar disorder affects around 45 million worldwide.5 SAD is estimated to affect about 5% of the US population, depending on geographical location.6 The direct and indirect costs of these health issues are immense. For example, in 2008 the World Health Organization (WHO) found major depression to be the third leading cause of disease burden in high-income countries worldwide and predicted that major depression will rank as first by the year 2030.7 In 2015, it was estimated that the total global cost of treatment for Bipolar I Disorder (BDI) was $202.1 billion, an average of $81 559 USD per affected individual.8
Sadly, the aforementioned numbers of afflicted individuals, as well as a cost burden, are likely underestimates because many of the individuals that struggle with mood disorders go undiagnosed. At times, they may be reluctant to seek help due to the social stigma associated with these conditions. Due to the variety of patient presentations, the unpredictable course and prognosis of mood disorders, and the inconsistent responses to treatment, clinicians are also challenged in terms of diagnosis and management.9,10
Alternatives are Needed
There is an urgent need for safer and more efficacious alternatives to pharmaceuticals. Medications certainly have their role in mood disorders, but they must be used judiciously. For example, it has been well established that in mild-to-moderate depression, medications are probably no more effective than placebo.11 In manic and depressive states of bipolar disorder, the data is mixed on how efficacious medications really are.12
The extensive laundry list of side effects of mood disorder medications is so vast, it makes one’s head spin. In clinical practice, many patients find the side effects intolerable enough that they would rather suffer from their illness than deal with the negative consequences of the medications. Antidepressants, anxiolytics, stimulants, antipsychotics, and mood stabilizers are the medications typically used in mood disorders. A full discussion of their efficacy and potential side effects is beyond the scope of this article.
To better understand mood disorders and provide more effective treatment interventions, it is beneficial to look at underlying etiologies, risk factors, and genetics (encompassing family history). Each particular mood disorder has its own unique set of etiologies; however, commonalities among all of them include brain structural changes (not yet well understood) compared to those without mood disorders, neurotransmitter alterations, and hormonal imbalances. Risk factors include low self-esteem, a high degree of self-criticism, history of traumatic and stressful events (eg, physical or sexual abuse or loss of a loved one), comorbid mental disorders (eg, schizophrenia or anxiety disorders), alcohol and recreational drug abuse, and chronic illness and side effects of certain medications (eg, sleeping pills or anti-hypertensive drugs).13
An enormous risk factor is one’s genetics,14, and even epigenetics.15 Research into the role that single nucleotide polymorphisms (SNPs) play in mood disorders has exploded within the last 15 years or so and offers promise in helping to improve people’s lives through nutritional and botanical interventions.16,17 Indeed, even pharmacogenetic testing is finally becoming more mainstream in clinical practice, offering safer, more specific, and personalized pharmaceutical options.18-20
A comprehensive, integrative approach to mood disorders works very well in clinical practice.21 This may include all or most of the following: lifestyle and dietary modifications, constitutional homeopathy, botanical medicines, nutraceutical support, psychotherapy, and, occasionally, pharmaceutical interventions.
Studies consistently indicate that up to half of all individuals diagnosed with a mood disorder use 1 or more complementary and alternative medicine (CAM) therapies.22,23 It has been shown that a healthy diet,24 exercises,25 sleep, a strong supportive social network, and a low-stress environment reduce relapses in individuals with mood disorders.26 Even targeting the proverbial “gut microbiome” can have a tremendous positive impact!27,28 Given space limitations, this article will focus on evidence-based botanical and nutraceutical interventions.
Given all of the aforementioned information, it is clear that there is a dire need for safe and effective alternatives. But are there really any nutraceutical and/or botanical interventions that work? The answer is: yes, definitely.
Vitamins & Minerals
Vitamin B12 (cobalamin) is involved in DNA synthesis, red blood cell (RBC) formation, homocysteine metabolism, and synthesis of S-adenosylmethionine (SAMe). B12 is also heavily involved in the proper functioning of the nervous and immune systems.29 Observational studies have shown that as many as 30% of patients hospitalized with depression are deficient in this vitamin.30 Depression can be induced by B12 deficiency, even with normal hematological and blood parameters,31 which has led to the recommendation of therapeutic intervention of 1000 µg (1 mg) of oral B12 daily.32 The forms of B12 in these studies have varied.
It has been shown that individuals with various neuropsychiatric conditions have impaired transport of vitamin B12 across the blood-brain barrier and/or accelerated catabolism of the vitamin, hence the need for increased requirements.29 Some studies have demonstrated clinical improvements in such patients when treated with B12.31
Folate is a generic term that refers to natural folates in food as well as folic acid (the synthetic form of folate used in many fortified foods and supplements). Folate is critical for the synthesis of DNA and RNA, several amino acids, methylation reactions, homocysteine, and B12 metabolism, and it assists in the proper functioning of the central nervous and immune systems.33
Like B12, low RBC folate levels have been found in 15-38% of adults diagnosed with depression.34 Efficacious doses of folic acid, given along with medication(s), have ranged from 500 µg to 3 mg, depending on the study and the mood disorder.35,36 Note that most trials have been conducted on folic acid, not its biologically active forms, ie, 5-methyltetrahydrofolate (5-MTHF, the major circulating form of folate in the body) and 5,10-methylenetetrahydrofolate. In individuals with methylenetetrahydrofolate reductase (MTHFR) SNPs and/or who are on medications that inhibit dihydrofolate reductase (by reducing interactions), as well as in individuals having compromised gastrointestinal function, folinic acid and 5-MTHF may be the preferred forms.37,38
Vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine) and its coenzyme form, pyridoxal 5′-phosphate (P5P), are essential to over 50 enzymes that are involved in the metabolism of lipids, amino acids, and carbohydrates; B6 is also involved in steroid hormone action.29 B6 cannot be synthesized in the body, so must be obtained from the diet. In the brain, P5P is necessary to metabolize serotonin from tryptophan, and dopamine from L-3,4-dihydroxyphenylalanine (L-Dopa). Other neurotransmitters and amino acids that are P5P-dependent include glycine, D-serine, glutamate, histamine, and gamma-aminobutyric acid (GABA).39 P5P also plays a role in the metabolism of homocysteine. Dosing of pyridoxine commonly ranges from 10 to 200 mg per day, though anyone taking more than 200 mg/day should be monitored for neurotoxic symptoms.29
Vitamin D3 (cholecalciferol) is a fat-soluble vitamin that functions as a hormone precursor. It is biologically inactive and must first be hydroxylated in the liver to 25-hydroxyvitamin D (25[OH]D), with further hydroxylation in the kidneys to its active form, 1,25-dihydroxyvitamin D – the form that acts as a steroid. In this form, it suppresses prostaglandin action; inhibits p38 stress kinase signaling, tumor angiogenesis, invasion and metastasis; and inhibits nuclear factor-kappa B (NF-κB) signaling.40
Many studies have demonstrated a correlation between low serum concentrations of 25(OH)D and mood disorders.41 While the exact mechanism(s) of action haven’t been fully elucidated, vitamin D supplementation has been shown to improve mood in both depression and SAD.42,43 It should be noted that the Endocrine Society has suggested that “optimal” serum levels of 25(OH)D are at least 30 ng/mL.44
Magnesium insufficiency and frank deficiency are both rampant in the United States and most industrialized nations. Almost half of the US population (ages ≥4 years) is considered to be under consuming this vital mineral.45 Medications, chronic diseases, diminishing magnesium content of food crops, and the plethora of refined and processed foods46 have all contributed to this epidemic.
Next to potassium, magnesium is the second most abundant cation in soft tissues and is a cofactor for at least 300 enzymes. It plays a role in adenosine triphosphate (ATP) production, neuronal activity, cardiac function, and electrical properties of cell membranes47; it also has antispasmodic effects and assists in glutathione synthesis.48 In addition to all of these accolades, magnesium has anxiolytic properties, increases stress tolerance, and has been shown in human and animal studies to be an effective antidepressant.49,50 The recommended daily allowance (RDA) varies by age and gender, ranging from 360 to 420 mg per day of elemental magnesium.
Zinc, well known for its immune properties, also plays an important role in mood, as it is essential for over 300 enzyme-dependent reactions.51 The RDA for individuals 19 years and older is 11 mg daily for males and 8 mg daily for females. Therapeutically, trials have shown efficacy at much higher doses, although this depends on the condition being addressed. A meta-analysis of 9 studies found an inverse association between the risk of depression and zinc and iron intake.52 In many of the clinical trials conducted, a dose of 25 mg daily of elemental zinc has been utilized.53 Excessive zinc intake can have toxic effects and can also deplete copper; as a result, the US Food and Nutrition Board has set the tolerable upper limit for those 19 years or older at 40 mg/day.54
Omega-3 Fatty Acids
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well known for their anti-inflammatory effects,55 which are mediated by suppression of NF-κB, cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNFα), and interleukin-beta (IL-1β).56 These fatty acids also have a solid reputation for assisting those afflicted with mood disorders. Doses of 500 mg to 10 g of EPA and DHA (common dose of 1-2 g/day in clinical trials) have been shown to be effective in the prevention and treatment of depressive disorders.57-59 According to a meta-analysis, EPA appears to be more efficacious than DHA.60 In bipolar disorders, there is strong evidence that omega-3 fatty acids are helpful for attenuating depression but not mania.61
SAMe is produced in vivo from homocysteine and 5-MTHF and is also available as a supplement. It is the body’s major methyl-group donor and is vital for membrane function and neurotransmission.62 Depending on the study, total daily doses of SAMe ranging from 150 to 1600 mg have been shown to be as effective as tricyclic antidepressants, and with a lower side-effect profile.63 SAMe has also been shown to have a beneficial adjunctive effect in depressed individuals for whom medication was not fully resolving their symptoms.64 Note that SAMe should be used with caution in bipolar disorder, as it can trigger mania.65
5-Hydroxytryptophan (5-HTP) is the rate-limiting intermediary in the synthesis of serotonin from L-tryptophan. It is probably for this reason that the amino acid has been found to be superior to placebo for the treatment of depression in several studies,66 as well as an effective adjuvant to prescription antidepressant therapy.67 When used as a supplement, the dosage of 5-HTP depends on the condition being treated. In studies of mood disorders, dosages have frequently been 150 mg/day or higher.68,69 Commonly, 5-HTP is dosed at 50-100 mg, 1-3 times daily, with some of the best evidence at this dose seen in anxiety disorders.68,70 For depression, several clinical trials have used 150-400 mg per day in divided doses.71,72 Caution is advised for those on selective serotonin reuptake inhibitors (SSRIs), since 5-HTP supplementation will increase serotonin levels.
N-acetylcysteine (NAC) is a derivative of L-cysteine, but is more stable than the latter. NAC is well known for its function as an antioxidant and precursor to glutathione73; it also acts as a mucolytic,74 has anti-inflammatory properties,75, and is the treatment of choice for acetaminophen-induced hepatic necrosis.76,77 In dose ranges of 1200-3600 mg daily, this sulfhydryl molecule has also exhibited efficacy in numerous neuropsychiatric conditions.78-80 It appears to increase the uptake of cysteine, which activates a reverse transport of glutamate into the extracellular space.81 Restoring glutamate to the extracellular space inhibits more glutamate release, thereby improving some compulsive behaviors.
Taurine can be synthesized in vivofrom cysteine. It stabilizes cell membranes, is an osmoregulator, assists in bile acid conjugation, contributes to cardiac contractility, inhibits platelet aggregation, is an anti-arrhythmic and anticonvulsant, and, last but not least, also functions as a neurotransmitter.82,83 While direct clinical trials of taurine on mood disorders may not exist, taurine has been shown to inhibit the release of excitatory neurons like glutamate, act as a GABA agonist, inhibit TNFα, and increase ATP production.83,84
Hypericum perforatum (St John’s wort), is a highly revered botanical medicine with antibacterial, antiviral, anticancer (in vitro), antioxidant, neuroprotective, anti-inflammatory, and vulnerary (wound-healing) properties.85 It is probably most well known for its antidepressant effects and minimal side effects, often showing equal efficacy to tricyclic antidepressants and SSRIs but with higher tolerability.86-88 Animal studies suggest that St John’s wort’s constituents, hyperforin, and adhyperforin, appear to modulate the effects of serotonin, dopamine, and norepinephrine, as well as inhibit reuptake of these neurotransmitters.89,90 Many studies examining St John’s wort have shown clinical improvements in depression, anxiety, and SAD using a dosage of 300 mg 3 times daily.91,92 Caution should be used in individuals on medications that can induce certain cytochrome P450 enzymes (eg, CYP1A2, 2C9, 2C19, and 3A4), monoamine oxidase inhibitors (MAOIs), P-glycoprotein inducers, photosensitizers, and serotonergic agents.93
What doesn’t Curcuma longa (turmeric) do? Its benefits are endless, but one that you may not be aware of is its efficacy in depressive disorders. Studies have shown that just 1000 mg of the herb taken daily is as effective as 20 mg of fluoxetine, and when used in combination with the medication, response rates for those with major depression have been shown to rise from 65% to 78%.94 A 2017 meta-analysis also showed its efficacy in depression.95 In addition, it has been shown to reduce anxiety.95,96 It is postulated that turmeric inhibits the activity of both MAO-A and MAO-B, increases the levels of neurotrophic factors (particularly brain-derived neurotrophic factor [BDNF]), and modulates serotonin and dopamine neurotransmission in the brain.97
Rhodiola rosea (rhodiola) is a wonderful plant that thrives in cold regions and high altitudes and is notorious for its ability to increase resistance to physical, chemical, and biological stressors.98 In-vitro and animal studies have shown the constituents rhodioloside, salidroside, and tyrosol to regulate the activity of serotonin, dopamine, and norepinephrine as well as inhibit MAO-A.99-101 In depressed individuals, 340 mg taken 1-2 times daily has been shown to decrease overall depressive symptoms, emotional instability, insomnia, and somatization.102,103 Typically, dosages range from 200 to 600 mg daily, depending on the percentage of active constituents.104,105 Caution should be used in those with bipolar disorder, who are prone to manic episodes when given antidepressants or stimulants.104
Crocus sativus (saffron) is a well-known, brilliant, yellow-red, and precious spice that mostly grows in Greece, Iran, Morocco, and India; it is one of the most expensive botanicals in the world.106 It has a long history of traditional use and is considered to be an antispasmodic, thymoleptic, carminative, cognition enhancer, aphrodisiac, and emmenagogue.107 This revered spice has also been shown clinically to benefit attention-deficit/hyperactivity disorder (ADHD),108 Alzheimer’s disease,109,110 anxiety,111, and depression.112 It is theorized that safranal (a carotenoid found in saffron) interacts with the GABAergic system,113 modulates levels of serotonin (possibly by inhibiting reuptake),111 and alters levels of dopamine and norepinephrine.114 Standardized extracts containing 2% safranal, 2% crocin, and small amounts of picrocrocin (percentage in studies unspecified), dosed at 15 mg twice daily, have been shown to significantly reduce numerous parameters of depression.115-117 Saffron is very safe and has no known drug-herb interactions.118
The use of pharmaceutical hormone replacement therapies (estrogen, progesterone, and testosterone) will not be discussed in this article; however, the prudent use of dehydroepiandrosterone (DHEA) and pregnenolone will be.
Pregnenolone is a ubiquitously produced endogenous neurosteroid, mostly made in the brain and adrenal glands from cholesterol. It is known as the master steroid hormone, since all steroid hormones, including cortisol, aldosterone, allopregnanolone, DHEA, progesterone, and testosterone, are made from it.119 Pregnenolone is thought to interact with the cannabinoid receptor-1 (CB1), one of the mechanisms for pregnenolone’s antidepressant effects.120 Pregnenolone and its metabolites have also been shown to modulate GABAA; N-methyl-D-aspartate (NMDA); and cholinergic, dopaminergic, and neurotrophic systems, thus affecting neuronal excitability.121,122
While some studies have used a dosage of around 500 mg daily for individuals with mood disorders,120 I have personally found a dose range of 50-100 mg per day to be effective. Monitoring serum pregnenolone levels every 3 to 6 months is advisable. Studies have revealed lower CSF pregnenolone levels in both patients with bipolar disorder and depression.123,124
DHEA is the most abundant neurosteroid hormone in the human body, secreted by the adrenal gland and produced in the brain.125 As a precursor to male and female sex hormones, DHEA has been shown to be effective in many health conditions; for depression and dysthymia, specifically, doses of 30-450 mg daily have been used in studies, with greater benefit observed at the lower-dose end.126,127 DHEA-S, the major circulating metabolite of DHEA, is not subject to DHEA’s day-to-day and diurnal changes.128,129 For this reason, DHEA-S should be tested prior to administering the hormone to ensure it may be of benefit, as well as ideally monitored every 3-6 months. Excessive administration of DHEA can cause acne and hirsutism,130 and as a precursor to estrogen and testosterone, there is a theoretical risk that long-term use could lead to hormone-sensitive cancers, especially if DHEA-S becomes elevated.
The aforementioned text is not an exhaustive list of safe and effective interventions for mood disorders, but rather a consolidation of what has better evidence clinically, both from published human studies and this author’s personal experience with patients. As with any health condition, individuals should not self-treat, but rather seek out a qualified healthcare professional to discuss their health concerns and options.
This is a slightly revised version of an article by Dr. Born, published in the October 2019 issue (#435) of Townsend Letter.
- Cleveland Clinic. Mood Disorders. 2018. Available at: https://my.clevelandclinic.org/health/diseases/17843-mood-disorders. Accessed August 18, 2019.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5. Philadelphia, PA: American Psychiatric Publishing; 2013.
- National Institute of Mental Health. Any Mood Disorder. Last updated November 2017. Available at: https://www.nimh.nih.gov/health/statistics/any-mood-disorder.shtml. Accessed August 18, 2019.
- National Institute of Mental Health. Statistics. Last updated January 2018. Available at: https://www.nimh.nih.gov/health/statistics/index.shtml. Accessed August 18, 2019.
- World Health Organization. Mental Disorders. 2018. Available at: https://www.who.int/news-room/fact-sheets/detail/mental-disorders. Accessed August 18, 2019.
- Kurlansik SL, Ibay AD. Seasonal affective disorder. Am Fam Physician. 2012;86(11):1037-1041.
- World Health Organization. The Global Burden of Disease: 2004 Update. 2008. Available at: https://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf?ua=1. Accessed August 18, 2019.
- Cloutier M, Greene M, Guerin A, et al. The economic burden of bipolar I disorder in the United States in 2015. J Affect Disord. 2018;226:45-51.
- Gregory C. Mood Disorders. Last updated October 21, 2019. Psycom. Available at: https://www.psycom.net/mood-disorders/. Accessed August 18, 2019.
- Malhi GS, Mann JJ. Depression. Lancet. 2018;392(10161):2299-2312.
- Pigott HE, Leventhal AM, Alter GS, Boren JJ. Efficacy and effectiveness of antidepressants: current status of research. Psychother Psychosom. 2010;79(5):267-279.
- Pompili M, Serafini G, Del Casale A, et al. Improving adherence in mood disorders: the struggle against relapse, recurrence and suicide risk. Expert Rev Neurother. 2009;9(7):985-1004.
- Mayo Clinic. Depression (major depressive disorder). February 3, 2018. Available at: https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-20356007. Accessed August 18, 2019.
- Lau JY, Eley TC. The genetics of mood disorders. Annu Rev Clin Psychol. 2010;6:313-337.
- Archer T, Oscar-Berman M, Blum K, Gold M. Epigenetic Modulation of Mood Disorders. J Genet Syndr Gene Ther. 2013;4(120). pii: 1000120.
- Detera-Wadleigh SD, McMahon FJ. Genetic association studies in mood disorders: issues and promise. Int Rev Psychiatry. 2004;16(4):301-310.
- Lynch B. Dirty Genes. New York, NY: Harper One; 2018.
- Amare AT, Schubert KO, Baune BT. Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry. EPMA J. 2017;8(3):211-227.
- Brennan FX, Gardner KR, Lombard J, et al. A Naturalistic Study of the Effectiveness of Pharmacogenetic Testing to Guide Treatment in Psychiatric Patients With Mood and Anxiety Disorders. Prim Care Companion CNS Disord. 2015;17(2). doi: 10.4088/PCC.14m01717.
- Pickar D, Rubinow K. Pharmacogenomics of psychiatric disorders. Trends Pharmacol Sci. 2001;22(2):75-83.
- Qureshi NA, Al-Bedeh AM. Mood disorders and complementary and alternative medicine: a literature review. Neuropsychiatr Dis Treat. 2013;9:639-658.
- Elkins G, Rajab MH, Marcus J. Complementary and alternative medicine use by psychiatric inpatients. Psychol Rep. 2005;96:163-166.
- Simon GE, Cherkin DC, Sherman KJ, et al. Mental health visits to complementary and alternative medicine providers. Gen Hosp Psychiatry. 2004;26(3):171-177.
- Davison KM, Kaplan BJ. Nutrient intakes are correlated with overall psychiatric functioning in adults with mood disorders. Can J Psychiatry. 2012;57(2):85-92.
- Byrne A, Byrne DG. The effect of exercise on depression, anxiety and other mood states: a review. J Psychosom Res. 1993;37(6):565-574.
- Lakhan SE, Vieira KF. Nutritional therapies for mental disorders. Nutr J. 2008;7:2.
- Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305-312.
- Sherwin E, Rea K, Dinan TG, Cryan JF. A gut (microbiome) feeling about the brain. Curr Opin Gastroenterol. 2016;32(2):96-102.
- Gaby A. Nutritional Medicine. 2nd ed. Concord, NH: Fritz Perlberg Publishing; 2017.
- Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry. 1997;38(6):305-314.
- Hector M, Burton JR. What are the psychiatric manifestations of vitamin B12 deficiency? J Am Geriatr Soc. 1988;36(12):1105-1112.
- Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol. 2005;19(1):59-65.
- Higdon J. Folate. 2014. Linus Pauling Institute, Oregon State University. Available at: https://lpi.oregonstate.edu/mic/vitamins/folate. Accessed August 18, 2019.
- Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55(5):145-149.
- Coppen AA, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Dis. 2000;60(2):121-131.
- Behzadi AH, Omrani Z, Chalian M, et al. Folic acid efficacy as an alternative drug added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: a double-blind randomized controlled trial. Acta Psychiatr Scand. 2009;120(6):441-445.
- Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010;49(8):535-548.
- Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488.
- Clayton PT. B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis. 2006;29(2-3):317-326.
- Krishnan AV, Feldman D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol. 2011;51:311-336.
- Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2(1):76-89.
- Spedding S. Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients. 2014;6(4):1501-1518.
- Gloth FM 3rd, Alam W, Hollis B. Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder. J Nutr Health Aging. 1999;3(1):5-7.
- Szabo L. The Man Who Sold America On Vitamin D – And Profited in the Process. August 24, 2018. Medscape. Available at: https://www.medscape.com/viewarticle/901146. Accessed August 18, 2019.
- Wallace TC, McBurney M, Fulgoni VL 3rd. Multivitamin/mineral supplement contribution to micronutrient intakes in the United States, 2007-2010. J Am Coll Nutr. 2014;33(2):94-102.
- DiNicolantonio JJ, O’Keefe JH, Wilson W. Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis. Open Heart. 2018;5(1):e000668.
- Wester PO. Magnesium. Am J Clin Nutr. 1987;45(5 Suppl):1305-1312.
- Altura BM. Basic biochemistry and physiology of magnesium: a brief review. Magnes Trace Elem. 1991-1992;10(2-4):167-171.
- Tarleton EK, Littenberg B, MacLean CD, et al. Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. PLoS One. 2017;12(6):e0180067.
- Serefko A, Szopa A, Poleszak E. Magnesium and depression. Magnes Res. 2016;29(3):112-119.
- McCall KA, Huang C, Fierke CA. Function and mechanism of zinc metalloenzymes. J Nutr. 2000;130(5S Suppl):1437S-1446S.
- Li Z, Li B, Song X, Zhang D. Dietary zinc and iron intake and risk of depression: A meta-analysis. Psychiatry Res. 2017;251:41-47.
- Nowak G, Siwek M, Dudek D, et al. Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. Pol J Pharmacol. 2003;55(6):1143-1147.
- Institute of Medicine (US) Panel on Micronutrients. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academies Press; 2001:442-501.
- Maroon JC, Bost JW. Omega-3 fatty acids (fish oil) as an anti-inflammatory: an alternative to nonsteroidal anti-inflammatory drugs for discogenic pain. Surg Neurol. 2006;65(4):326-331.
- Kang JX, Weylandt KH. Modulation of inflammatory cytokines by omega-3 fatty acids. Subcell Biochem. 2008;49:133-143.
- Su KP, Lai HC, Yang HT, et al. Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial. Biol Psychiatry. 2014;76(7):559-566.
- Grosso G, Pajak A, Marventano S, et al. Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. PLoS One. 2014;9(5):e96905.
- Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007;68(7):1056-1061.
- Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr. 2009;28(5):525-542.
- Sarris J, Mischoulon D, Schweitzer I. Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression. J Clin Psychiatry. 2012;73(1):81-86.
- Carney MW, Toone BK, Reynolds EH. S-Adenosylmethionine and affective disorder. Am J Med. 1987;83(5A):104-106.
- Sharma A, Gerbarg P, Bottiglieri T, et al. S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. J Clin Psychiatry. 2017;78(6):e656-e667.
- Papakostas GI, Mischoulon D, Shyu I, et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010;167(8):942-948.
- Carney MW, Chary TK, Bottiglieri T, Reynolds EH. The switch mechanism and the bipolar/unipolar dichotomy. Br J Psychiatry. 1989;154:48-51.
- Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.
- Kious BM, Sabic H, Sung YH, et al. An Open-Label Pilot Study of Combined Augmentation With Creatine Monohydrate and 5-Hydroxytryptophan for Selective Serotonin Reuptake Inhibitor- or Serotonin-Norepinephrine Reuptake Inhibitor-Resistant Depression in Adult Women. J Clin Psychopharmacol. 2017;37(5):578-583.
- Kahn RS, Westenberg HG. L-5-hydroxytryptophan in the treatment of anxiety disorders. J Affect Disord. 1985;8(2):197-200.
- van Praag HM, Korf J, Dols LC, Schut T. A pilot study of the predictive value of the probenecid test in application of 5-hydroxytryptophan as antidepressant. Psychopharmacologia. 1972;25(1):14-21.
- Kahn RS, Westenberg HG, Verhoeven WM, et al. Effect of a serotonin precursor and uptake inhibitor in anxiety disorders; a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. Int Clin Psychopharmacol. 1987;2(1):33-45.
- Nakajima T, Kudo Y, Kaneko Z. Clinical evaluation of 5-hydroxy-L-tryptophan as an antidepressant drug. Folia Psychiatr Neurol Jpn. 1978;32(2):223-230.
- Jangid P, Malik P, Singh P, et al. Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr. 2013;6(1):29-34.
- James SJ, Slikker W 3rd, Melnyk S, et al. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors. Neurotoxicology. 2005;26(1):1-8.
- Sadowska A, Verbraecken J, Darquennes K, De Backer WA. Role of N-acetylcysteine in the management of COPD. Int J Chron Obstruct Pulmon Dis. 2006;1(4):425-434.
- Palacio JR, Markert UR, Martínez P. Anti-inflammatory properties of N-acetylcysteine on lipopolysaccharide-activated macrophages. Inflamm Res. 2011;60(7):695-704.
- Harrison PM, Wendon JA, Gimson AE, et al. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med. 1991;324(26):1852-1857.
- Ziment I. Acetylcysteine: a drug with an interesting past and a fascinating future. Respiration. 1986;50 Suppl 1:26-30.
- Ooi SL, Green R, Pak SC. N-Acetylcysteine for the Treatment of Psychiatric Disorders: A Review of Current Evidence. Biomed Res Int. 2018;2018:2469486.
- Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011;36(2):78-86.
- Minarini A, Ferrari S, Galletti M, et al. N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects. Expert Opin Drug Metab Toxicol. 2017;13(3):279-292.
- Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2009;66(7):756-763.
- Hayces KC. A review on the biological function of taurine. Nutr Rev. 1976;34(6):161-165.
- Ripps H, Shen W. Review: taurine: a “very essential” amino acid. Mol Vis. 2012;18:2673-2686.
- Schaffer S, Kim HW. Effects and Mechanisms of Taurine as a Therapeutic Agent. Biomol Ther (Seoul). 2018;26(3):225-241.
- Benzie IFF, Wachtel-Galor S, eds. Chapter 11: Medical Attributes of St. John’s Wort (Hypericum perforatum). In: Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. New York, NY: CRC Press/Taylor & Francis; 2011.
- Vorbach EU, Arnoldt KH, Hübner WD. Efficacy and tolerability of St. John’s wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry. 1997;30 Suppl 2:81-85.
- van Gurp G, Meterissian GB, Haiek LN, et al. St John’s wort or sertraline? Randomized controlled trial in primary care. Can Fam Physician. 2002;48:905-912.
- Gastpar M, Singer A, Zeller K. Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study. Pharmacopsychiatry. 2006;39(2):66-75.
- Müller WE, Singer A, Wonnemann M, et al. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract. Pharmacopsychiatry. 1998;31 Suppl 1:16-21.
- Calapai G, Crupi A, Firenzuoli F, et al. Serotonin, norepinephrine and dopamine involvement in the antidepressant action of hypericum perforatum. Pharmacopsychiatry. 2001;34(2):45-49.
- Linde K, Ramirez G, Mulrow CD, et al. St John’s wort for depression–an overview and meta-analysis of randomised clinical trials. BMJ. 1996;313(7052):253-258.
- Drugs.com. St. John’s Wort. 2000-2020. Available at: https://www.drugs.com/npp/st-john-s-wort.html. Accessed August 18, 2019.
- Wang Z, Gorski JC, Hamman MA, et al. The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther. 2001;70(4):317-326.
- Sanmukhani J, Satodia V, Trivedi J, et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res. 2014;28(4):579-585.
- Nq QX, Koh SSH, Chan HW, Ho CYX. Clinical Use of Curcumin in Depression: A Meta-Analysis. J Am Med Dir Assoc. 2017;18(6):503-508.
- Esmaily H, Sahebkar A, Iranshahi M, et al. An investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized controlled trial. Chin J Integr Med. 2015;21(5):332-338.
- Kulkarni SK, Dhir A. An Overview of Curcumin in Neurological Disorders. Indian J Pharm Sci. 2010;72(2):149-154.
- Kelly GS. Rhodiola rosea: a possible plant adaptogen. Altern Med Rev. 2001;6(3):293-302.
- Chen Q, Zeng YS, Qu ZQ, et al. The effects of Rhodiola rosea extract on 5-HT level, cell proliferation and quantity of neurons at cerebral hippocampus of depressive rats. Phytomedicine. 2009;16(9):830-838.
- Panossian A, Nikoyan N, Ohanyan N, et al. Comparative study of Rhodiola preparations on behavioral despair of rats. Phytomedicine. 2008;15(1-2):84-91.
- van Diermen D, Marston A, Bravo J, et al. Monoamine oxidase inhibition by Rhodiola rosea L. roots. J Ethnopharmacol. 2009;122(2):397-401.
- Darbinyan G, Aslanyan G, Amroyan E, et al. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J Psychiatry. 2007;61(5):343-348.
- Ross M. Rhodiola rosea (SHR-5), Part 2: A standardized extract of Rhodiola rosea is shown to be effective in the treatment of mild to moderate depression. Holist Nurs Pract. 2014;28(3):217-221.
- Brown RP, Gerbarg PL, Ramazanov Z. Rhodiola rosea: A Phytomedicinal Overview. HerbalGram. 2002;56:40-52. Available at: http://cms.herbalgram.org/herbalgram/issue56/article2333.html?ts=1578841493&signature=cc4d6dbf7169d10853eea0a63508a12f. Accessed August 18, 2019.
- Hudson H. Rhodiola rosea: An overview of its versatility, effectiveness and indications. Sponsored by Gaia Herbs.
- Baraghani A. What Is Saffron, the World’s Most Legendary Spice? February 5, 2018. Available at: https://www.bonappetit.com/story/what-is-saffron. Accessed August 18, 2019.
- Rios JL, Recio MC, Giner RM, Máñez S. An update review of saﬀron and its active constituents. Phytother Res. 1996;10(3):189-193.
- Baziar S, Aqamolaei A, Khadem E, et al. Crocus sativus L. Versus Methylphenidate in Treatment of Children with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Pilot Study. J Child Adolesc Psychopharmacol. 2019;29(3):205-212.
- Akhondzadeh S, Sabet MS, Harirchian MH, et al. Saffron in the treatment of patients with mild to moderate Alzheimer’s disease: a 16-week, randomized and placebo-controlled trial. J Clin Pharm Ther. 2010;35(5):581-588.
- Akhondzadeh S, Shafiee Sabet M, Harirchian MH, et al. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology. 2010;207(4):637-643.
- Mazidi M, Shemshian M, Mousavi SH, et al. A double-blind, randomized and placebo-controlled trial of Saffron (Crocus sativus L.) in the treatment of anxiety and depression. J Complement Integr Med. 2016;13(2):195-199.
- Dwyer AV, Whitten DL, Hawrelak JA. Herbal Medicines, other than St. John’s Wort, in the Treatment of Depression: A Systematic Review. Altern Med Rev. 2011;16(1):40-49.
- Marañón JA, et al. GABA receptors mediates the activity of safranal from IRIDAFRAN saffron extract. Int Soc Nutraceutical Func Foods. 2012. [Poster presentation]
- Talaei A, Hassanpour Moghadam M, Sajadi Tabassi SA, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double-blind, placebo-controlled, pilot clinical trial. J Affect Disord. 2015;174:515-516.
- Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the Treatment of Mild to Moderate Depression: A Double-blind, Randomized and Placebo-controlled Trial. Phytother Res. 2005;19(2):148-151.
- Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi AH. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot trial. J Ethnopharmacol. 2005;97(2):281-284.
- Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: A pilot double-blind randomized trial. BMC Complement Altern Med. 2004;4:12.
- Stargrove MB, Treasure J, McKee DL. Herb, Nutrient and Drug Interactions. Maryland Heights, MO: Mosby; 2008.
- Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations. 3rd edition. New York, NY: Wiley-Liss Inc; 1992.
- Brown ES, Park J, Marx CE, et al. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014;39(12):2867-2873.
- Ritsner MS, Gibel A, Shleifer T, et al. Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial. J Clin Psychiatry. 2010;71(10):1351-1362.
- Marx CE, Keefe RS, Buchanan RW, et al. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology. 2009;34(8):1885-1903.
- Osuji IJ, Vera-Bolaños E, Carmody TJ, Brown ES. Pregnenolone for cognition and mood in dual diagnosis patients. Psychiatry Res. 2010;178(2):309-312.
- George MS, Guidotti A, Rubinow D, et al. CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol Psych. 1994;35(10):775-780.
- Kroboth PD, Salek FS, Pittenger AL, et al. DHEA and DHEA-S: A review. J Clin Pharmacol. 1999;39(4):327-348.
- Wolkowitz OM, Reus VI, Keebler A, et al. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry. 1999;156(4):646-649.
- Bloch M, Schmidt PJ, Danaceau MA, et al. Dehydroepiandrosterone treatment of midlife dysthymia. Biol Psychiatry. 1999;45(12):1533-1541.
- Kamin HS, Kertes DA. Cortisol and DHEA in Development and Psychopathology. Horm Behav. 2017;89:69-85.
- Starka L, Dušková M, Hill M. Dehydroepiandrosterone: a neuroactive steroid. J Steroid Biochem Mol Biol. 2015;145:254-260.
- Drugs.com. Dehydroepiandrosterone. Last updated November 1, 2019. Available at: https://www.drugs.com/npp/dehydroepiandrosterone.html. Accessed January 13, 2020.
Todd A. Born, ND, CNS, is a naturopathic doctor, certified nutrition specialist, co-owner, and medical director of Born Integrative Medicine Specialists, PLLC. He is also an Allergy Research Group’s Head of New Product Development, Product Manager, Scientific Advisor, and Editor-in-Chief of their science-based Focus Newsletter. Dr. Born graduated from Bastyr University and completed his residency at the Bastyr Center for Natural Health, its 13 teaching clinics, with rotations at Seattle-area hospitals. He uses a wide range of therapeutic modalities. Strong interests include difficult and refractory cases, GI issues, neurological disorders, endocrinology, CVD, diabetes, autoimmune disease, developmental and behavioral issues, HIV/AIDS, and geriatrics.