Vis Medicatrix Naturae

Todd A. Born, ND, CNS

Mood disorders are 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 last 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 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 exercise,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 a 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 an 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 underconsuming 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 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 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  

S-Adenosylmethionine (SAMe)

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

Amino Acids

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 the 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

Botanicals

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

Hormones

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 GABA_A; 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.

Closing Comment

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.

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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 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.