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Health Protocols


Nutrients to Balance Brain Chemistry

Depression is a multifactorial condition, and efficient relief often requires addressing multiple neurochemical and metabolic imbalances that may underlie mood disturbances.

Many of the nutrients in this section may serve as adjuvants to conventional therapies for depression. Always consult a qualified healthcare professional before combining any supplements with an antidepressant medication.

The nutrients listed in this section are categorized according to their evidence-based mechanisms of action in brain health and mood regulation. The categories are:

Broad-Range Nervous System Effects

Omega-3 fatty acids. Omega-3 fatty acids are long-chain polyunsaturated fatty acids found in fish and various oils, such as flaxseed or canola oil.121 The brain has a high concentration of polyunsaturated fatty acids, which are found mostly in cell membranes. They affect adaptability of the nervous system, nerve cell conduction and function, and neurotransmitter synthesis.51,122 Several research models exhibit the influence of omega-3 fatty acids in depression including: (a) dietary studies123; (b) nutritional status studies showing positive effects associated with higher omega-3 to omega-6 fatty acid ratios124; and (c) intervention studies that look at both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) taken as a stand-alone treatment and as an adjunct to medication.91

One investigation showed that adding the omega-3 fatty acid EPA to conventional antidepressant treatment relieved depressive symptoms.125 Among children with depression, supplementation with omega-3 fatty acids demonstrated “highly significant” effects on symptom scores.126 In a review article from 2006, researchers analyzed results from six published studies and found that omega-3 fatty acids can reduce symptoms of depression among adults as well.127

Because they are anti-inflammatory, omega-3 fatty acids also reduce the risk of cardiovascular disease, which is highly associated with depression.128,129 In fact, the American Heart Association recommends fish oil for both preventing an initial heart attack and for preventing a second attack when one has already occurred.

Omega-3 fatty acids are counterbalanced with the inflammatory omega-6 fatty acids. Typically, Americans consume far too many omega-6's and not nearly enough omega-3's.

The ratio of omega-6 to omega-3 fatty acids is important. You can learn your ratio easily with the Omega-3 Index test. This test can help you assess your risk for depression, heart disease, and other age-related ailments. It can also help you evaluate whether you take enough fish oil or other omega-3 supplements. More information about the importance of maintaining an optimal omega-6 to omega-3 ratio of less than 4:1 can be found in the Life Extension Magazine article entitled “Optimize your Omega-3 Status.”

Magnesium. Magnesium is a cofactor for more than 300 enzymes in the body; it is important for blood-sugar regulation, and has a calming effect on the nervous system.130 Some evidence shows a link between magnesium deficiency and depression,131 and a recent, comprehensive review in the Journal of Medical Hypotheses suggests that magnesium supplementation is a viable approach for depressive symptoms.132

A major hurdle for supplemental magnesium historically has been delivery into the brain. This is a barrier that has limited the ability of typical magnesium supplements to target conditions that arise from within the central nervous system such as depression and anxiety. However, in a recent scientific breakthrough, researchers collaborating from Beijing, Ontario, the University of Texas, and the Massachusetts Institute of Technology have developed a highly advanced form of supplemental magnesium called magnesium-L-threonate.

Magnesium-L-threonate was shown in multiple animal models to not only effectively penetrate deep into the brain, but also to trigger enhancements in learning and memory by optimizing neuronal communication and reinforcing brain structure in key areas of the cortex, the most advanced aspect of the human brain.133,134 Since magnesium-L-threonate is readily able to diffuse across the blood brain barrier, while other forms of magnesium are not, it appears to be the ideal form of supplemental magnesium for those with depression of other mood disorders.

Saffron extract. Saffron and its constituents have multiple biochemical activities that help provide supporting evidence for saffron in the treatment of depression. These include serotonin modulation as well as neuroprotective, neuro-hormonal, anti-inflammatory, and oxidative stress reducing functions.135-137 In an advanced laboratory study, two saffron compounds, crocin and safranal, inhibited the activity of enzymes that lower levels of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine in brain synapses.138

Two randomized controlled trials found 30 mg per day of saffron extract to be as effective for mild-to-moderate depression as 20–40 mg per day of the antidepressant drug fluoxetine.139,140 In another randomized placebo-controlled trial, 40 patients hospitalized with major depressive disorder were given 15 mg of the saffron extract crocin, twice daily, in addition to antidepressant medication. Patients taking crocin had significantly greater improvement in anxiety and depression scores than those who received placebo plus antidepressant.141

In a controlled clinical trial, 60 individuals with depression and anxiety were treated with either 50 mg saffron twice daily or placebo for 12 weeks. The saffron group had significantly reduced depression and anxiety symptom scores on standardized questionnaires compared with placebo.142 In another controlled clinical trial in 40 patients with mild-to-moderate depression, six weeks of treatment with 15 mg saffron extract, twice daily, resulted in a more than 2.7-fold greater reduction in standardized depression symptom scores compared with placebo.143 A similar study also found treatment for six weeks with 30 mg per day saffron extract was significantly more effective than placebo at improving depression symptoms scores in individuals with mild-to-moderate depression.144

One relatively common side effect of SSRIs is sexual dysfunction in both men and women.145 Two controlled clinical trials, one in men and one in women, found saffron safely and effectively relieved some symptoms of antidepressant-induced sexual dysfunction.146,147 One study in women with premenstrual syndrome, a condition often treated with antidepressants, found saffron was significantly more effective than placebo for relieving symptoms, including depression, of this condition.148 In this randomized controlled trial, 50 women received either 15 mg saffron extract or placebo twice daily for two consecutive menstrual cycles. Sixty percent of the saffron group had a 50% or greater reduction in depression symptoms versus 4% in the placebo group. Seventy-six percent of the saffron group experienced a 50% or greater reduction in PMS symptoms versus 8% in the placebo group.149

Supporting Neurotransmitter Synthesis

Tryptophan. L-tryptophan is essential for the brain to synthesize serotonin, and several studies have shown that acute tryptophan depletion can cause depression in humans. In fact, some foreign countries license L-tryptophan as an antidepressant.150

In one study, healthy women given L-tryptophan for 14 days experienced increased recognition of happy faces and words, and decreased recognition of negative words. The research team concluded L-tryptophan had improved the study participants' supply of serotonin in a manner similar to that of SSRIs.150 In another study of the effects of acute tryptophan depletion on healthy women and on patients with bulimia nervosa, both groups were given amino acid mixtures to decrease their plasma L-tryptophan levels. Both groups experienced an increase in depression.151 Other studies have found L-tryptophan depletion can lead to recurrence of depression in those who are in remission from depression152 or in those with seasonal depression.153

Methylation is a process in which a molecule passes a methyl group to another molecule. Methylation is essential to multiple functions in the body, including the production of neurotransmitters. One can supply raw materials to support methylation reactions by supplementing with S-adenosyl-methionine (SAMe) or by providing metabolic cofactors such as folate, vitamin B12, and vitamin B6. These nutrients are necessary for neurotransmitter production and have other regulating effects.

S-adenosylmethionine (SAMe). SAMe, which can be found in almost every tissue in the body, assists with production of creatine, glutathione, taurine, L-carnitine, and melatonin.

Research shows SAMe can benefit depressed patients who do not respond to SSRIs. In a well-controlled, 6-week, double-blind trial, 73 subjects with treatment-resistant depression were treated with an SSRI plus placebo, or an SSRI plus 1,600 mg SAMe daily. The group receiving the SAMe experienced significantly better response rates and remission compared to the placebo control group.154 Intriguingly, the group that received SAMe also displayed improved memory function over those receiving placebo. A smaller 6-week study revealed a response rate of 50% and a remission rate of 43% in subjects taking 800–1,600 mg a day of SAMe as an adjunct to their antidepressants.155

Folate. Research shows that low blood levels of folate are associated with depression,156 and may also be predictive of poor response to antidepressant medication.157 Clinical trials have also demonstrated that folic acid both relieves depression on its own and enhances the effect of antidepressants. In one study, patients given 500 mcg folic acid daily in conjunction with fluoxetine experienced a significant improvement in depressive symptoms compared with patients receiving the antidepressant alone; women particularly benefited.158 Because relapse is associated with low serum folate, it is important to maintain folate supplementation for a year following a depressive episode.159

The form of supplemental folate is important since a considerable portion of Americans may have a genetic polymorphism that impairs folate metabolism.160 In fact, mutations in the gene (MTHFR) that converts folic acid into the active 5-methyltetrahydrofolate (5-MTHF) are associated with depression.161 Therefore, taking supplemental 5-MTHF directly, which can cross the blood-brain barrier, may be more effective in supporting healthy neurotransmission and decreasing potentially neurotoxic homocysteine levels.

Vitamin B12. Vitamin B12 should always be measured in the event of depression (or any other psychological problems) as a vitamin B12 deficiency can be a reversible cause of various neuropsychiatric disorders.162 One should also consider whether a vegetarian diet or malabsorption due to celiac disease or gluten enteropathy is a factor in B12 deficiency.

Weaker digestion, reduced absorption of nutrients, and hypochlorhydria (inadequate stomach acid needed to break down proteins that contain vitamin B12) are common in the aging population and associated with a B12 deficiency; B12 levels should be tested in an older person with symptoms of depression. Evidence suggests that the methylcobalamin form of B12 may have more beneficial metabolic effects than cyanocobalamin.163,164

Vitamin B6. Vitamin B6 is a cofactor for the production of most neurotransmitters, but it is particularly important for serotonin synthesis.165 B6 levels are often low in women taking oral contraceptives and research has shown that B6 supplementation in these women can improve mood. For example, one study showed 22 women who had depression associated with oral contraceptive use and a B6 deficiency saw significant improvement in their symptoms with B6 supplementation.166

A more recent study examined blood levels of pyridoxal-5-phosphate (P5P), a metabolically active form of B6, in the blood of 251 elderly individuals living is Massachusetts. The investigators found that deficient levels of P5P doubled the likelihood of depression in this population. Accordingly, when dietary composition was assessed, those with higher daily B6 intakes were less likely to be depressed.167

Blood Sugar Regulation and Insulin Resistance

Green coffee. Recent data link increasing consumption of coffee with decreased risk of depression.168 In fact, this relationship proved to be dose-dependent, meaning that the more coffee study participants drank, the less likely depression would strike them. These findings are corroborated by a similar study conducted in 2010, which supports the link between increasing coffee consumption and decreased depression risk.169 Interestingly, this last trial was unable to link caffeine with depression risk, suggesting that other compounds in coffee may be responsible for the mood-elevating effect.

Conventional coffee preparation, which involves roasting the green coffee beans at high temperatures to attain the desired flavor profile, dramatically lowers levels of health-promoting coffee constituents called chlorogenic acids.

Chlorogenic acids have been shown in several studies to aid in controlling blood sugar levels; especially those glucose spikes which occur after a high-carbohydrate meal.170,171 In a 12-week study, consumption of chlorogenic acid-fortified instant coffee led to a considerable reduction in the absorption of glucose when compared to regular instant coffee.172 As elevated glucose levels are common among depressives, chlorogenic acids may help combat some symptoms of depression tied to insulin resistance and irregularities in glucose metabolism.

Green coffee, the primary source of chlorogenic acids, cannot be consumed as a beverage due to its extremely bitter taste. Consuming a green coffee extract standardized to chlorogenic acids is an effective means of obtaining biologically active concentrations of chlorogenic acids.

The potential role of chlorogenic acids in mediating the mood boost associated with coffee consumption, and their thoroughly studied antihyperglycemic properties give rise to promising multimodal depression protection.

Chromium. Chromium has been studied for its role in regulating blood sugar by facilitating the uptake of glucose into cells, and some research indicates that it may be beneficial in depression as well.173

In one case series of five patients with minor depression, chromium supplementation led to remission.174 Two other pilot studies found chromium picolinate supplementation benefited atypical depression.175,176 Finally, although not studied for seasonal depression, chromium may help regulate blood sugar and cravings for sugar and carbohydrates in relation to seasonal depression.

Antioxidant Effects

N-acetyl cysteine (NAC). One of the best-researched antioxidants for depression is N-acetyl cysteine (NAC). NAC is a precursor to glutathione, one of the body's most powerful antioxidants. Research has found glutathione depletion and oxidative stress in people with bipolar depression. Two recent studies showed NAC is a safe and effective adjunctive treatment that improves depression in patients with bipolar disorder.177

Lipoic acid. Although lipoic acid has not been well studied for depression, it is one of the most effective supplemental antioxidants, since it helps recycle other antioxidants, such as vitamin C. It also may benefit blood sugar regulation and neurological function, as evidence shows it can help diabetic neuropathy.178

Vitamins C, E, and selenium. In general, antioxidants may help buffer nerve cell damage in cases of chronic or recurrent depression, although they also serve other roles in brain health. For example, the antioxidant vitamin C is an important cofactor in the synthesis of serotonin, norepinephrine, and adrenal hormones that mediate stress. Vitamin E helps protect nerve cell membranes, and low selenium levels are associated with depression.179

Additional Nutrients

Curcumin. Curcumin is a phytoceutical derived from turmeric, a spice used often in preparation of Indian cuisine. It belongs to a class of compounds called polyphenols, which have been extensively studied and shown to exert an array of health benefits. One of the most intriguing properties of polyphenols, and curcumin in particular, is the ability to positively influence mood.180 Indeed, mounting evidence suggests curcumin might represent an important novel modality for the treatment of depression.181

Curcumin appears to modulate several aspects of neurobiology involved in mood and behavior. Experimental evidence from an animal model of depression suggests curcumin can preserve levels of a protein important for healthy neuronal function (brain-derived neurotrophic factor [BDNF]) in a region of the brain called the amygdala, which is involved in mood regulation.182 Curcumin appears to manipulate neurotransmitter signaling as well. In another animal model, mice with neuropathy (who are prone to depression) were treated for three weeks with 45 mg/kg of curcumin twice daily (about 583 mg daily for an 80 kg adult human). While these mice normally exhibit depressive-like symptoms, curcumin treatment ameliorated this behavior. Interestingly, the researchers found that curcumin may have eased the rodent’s depression by altering serotonin and gamma-aminobutyric acid (GABA) signaling in their central nervous systems.183 Curcumin also helps relieve pain, which may be helpful for some individuals with depression because pain, especially of chronic nature, is closely—and potentially causally—associated with depression.183-186 Other studies show that curcumin’s powerful anti-inflammatory properties may also underlie its ability to elevate mood. In an experiment in which rats were exposed to chronic stress for 21 days to induce depressive-like behavior, curcumin administration was shown to significantly reduce signs of depression. This study also showed that curcumin considerably eased inflammation by suppressing activation of nuclear factor-kappaB (NF-κB), a master regulator of inflammation; the researchers concluded that curcumin’s antidepressant effects were due in part to its anti-inflammatory action.187

Evidence for a potent antidepressant effect of curcumin among animals has been partially confirmed in at least one human study. In a randomized, double-blind, placebo-controlled trial, 40 people with new-onset depression were treated with antidepressants (escitalopram [Lexapro] or venlafaxine [Effexor]) together with either curcumin (500 mg per day) or placebo for five weeks. Researchers then tracked subjects’ depression severity using several standardized assessments. Although subjects in both groups experienced comparable relief of their depression, those who received curcumin tended to achieve faster relief than those who received a placebo.188

A plethora of animal data indicate curcumin may be a powerful tool in the treatment of depression, and, as of the time of this writing, additional human studies are ongoing to assess its effects on mood (SHSC 2014). Lastly—and perhaps most importantly—curcumin, unlike conventional antidepressant medications, has an excellent safety and side-effect profile.189-193

St. John's wort. St. John's wort (Hypericum perforatum) is a medicinal herb used to treat neurological and psychiatric disorders, including depression.194 Compared to a placebo, H. perforatum extract is more effective at targeting mild to moderate depression, and reducing symptoms and recurrence rate.195 Its effectiveness is considered comparable to antidepressant medications, but its actions are more complex.196,197

St. John's wort's mechanism of action on depression is not entirely understood, even though it is one of the most researched herbs for depression. St. John's wort has been shown to inhibit serotonin and norepinephrine reuptake, thus increasing their availability at the synapse.194 Other investigators found it influences dopamine and GABA activity. Its antidepressant qualities also can be linked to its antioxidant and anti-inflammatory properties that normalize an overactive hypothalamus-pituitary-adrenal axis and stress response.198

While additional research is ongoing to identify all of the antidepressant mechanisms of action, experimental models and clinical trials alike have shown that treatment with St. John's wort delivers positive response rates for mild-to-moderate depression.199-201

Unfortunately, potential side effects associated with St. John's wort deprive many depressives of its benefits.

Vitamin D. Growing evidence suggests that vitamin D significantly affects depression. This is not surprising in seasonal depression, since the skin synthesizes vitamin D in response to sunlight, which is less available in the winter.202,203 However, vitamin D has been found to play other roles in depression. For example, in a study of 7,358 patients age 50 and over with a cardiovascular diagnosis and no history of depression, low vitamin D levels significantly increased the risk of developing depression.204

Studies also find that vitamin D3 (cholecalciferol) supplementation can improve symptoms of depression. One well-controlled study of 441 overweight and obese participants showed an association between low vitamin D levels and depression. High dose vitamin D supplementation (20,000–40,000 IUs per week or 2,800–6,000 IUs per day) for one year improved mood.205 Another pilot study noted significant improvement in depression in six of nine women with low levels of vitamin D upon supplementation.203

Vitamin D's effectiveness may be related to the high prevalence of vitamin-D deficiency in the general population, its importance in blood-sugar regulation, and its importance in overall regulation of genetic activity.

Zinc. Zinc is a trace element known to help regulate the nervous system206 and may be specifically related to depression.207 Increasing evidence shows that decreased blood levels of zinc are associated with depression,208-210 and, in depressed subjects, lower levels of zinc are associated with worse depression.211 One pilot study of 20 depressed patients also showed that 25 mg a day of zinc augmented benefits of antidepressant medication.212

Animal studies show that antidepressants and electroconvulsive shock treatments change zinc concentrations in areas of the brain associated with depression.211 In further animal research, zinc also was shown to enhance antidepressant effects of imipramine213 and influence serotonin levels and activity in several brain regions.214

Inositol. Inositol levels in the brain and cerebrospinal fluid were found to be lower in subjects with depression. One well-controlled trial showed that taking 12 grams a day of inositol helped relieve symptoms in 39 patients with depression.215

Further research on bipolar depression suggests beneficial influences of inositol.216 A well-controlled but small trial of 17 participants with bipolar depression showed varied responses. Four of nine patients experienced significant improvement with inositol supplementation compared to zero of eight who took a placebo.217

Inositol, a second-messenger precursor, has important cellular communication functions in the nervous system. Interestingly, inositol is also involved with insulin signaling and function. It therefore may have more of an effect on overweight or obese individuals, as well as those who are insulin resistant, such as those with metabolic syndrome or women with polycystic ovarian syndrome (PCOS). These findings require further research and replication.

Probiotics. Emerging research has revealed an important relationship between the gastrointestinal tract and its billions of resident organisms—often referred to as the microbiome—and the brain. This has been termed the “gut-microbiota-brain axis.”218-223 Probiotics are organisms which, when consumed in adequate doses, exert a beneficial effect on health.224 Probiotics, which are able to modulate the gut-brain axis, have been shown in preclinical and clinical trials to ameliorate behaviors and symptoms of stress, anxiety, and depression.225-227

Lactobacillus helveticus (L. helveticus) R0052 has been researched, in combination with another proprietary probiotic strain, Bifidobacterium longum (B. longum) R0175, as a probiotic for psychological health.227-229 Rats given a daily dose of a combination of L. helveticus R0052 and B. longum R0175 for two weeks had markedly reduced signs of anxiety compared to those treated with a placebo. In fact, the probiotics reduced anxious behaviors to a similar degree as diazepam (Valium), the prescription anti-anxiety medication.227,230

In a double-blind randomized clinical trial, 55 healthy volunteers took a supplement containing three billion colony-forming units (CFUs) of the combination of L. helveticus R0052 and B. longum R0175, or placebo, for 30 days. The probiotic treated group had significantly lower scores on anxiety, anger, and depression symptom scales, with particular improvement in symptoms of depression.227 Among a subset of 25 participants considered to have low levels of chronic stress based on low urinary cortisol levels, the combination of L. helveticus R0052 and B. longum R0175 appeared to act as a preventive, suggesting it may be able to protect against stress-related diseases.229

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.