Review  |   February 2020
Nutraceutical Augmentation Strategies for Depression: A Narrative Review
Author Notes
  • Financial Disclosures: None reported. 
  • Support: None reported. 
  •  *Address correspondence to R. Gregory Lande, DO, 14480 Sunbridge Cir, Winter Garden, FL 34787-4532. Email:
Article Information
Review   |   February 2020
Nutraceutical Augmentation Strategies for Depression: A Narrative Review
The Journal of the American Osteopathic Association, February 2020, Vol. 120, 100-106. doi:
The Journal of the American Osteopathic Association, February 2020, Vol. 120, 100-106. doi:

Context: Depression is one of the most commonly diagnosed psychiatric disorders, but antidepressant pharmacotherapy often fails to achieve remission, leading health care professionals and researchers to consider various augmentation strategies to improve clinical outcomes.

Objective: To assess the safety, tolerability, and efficacy of nutraceutical augmentation for depression.

Methods: Nutraceutical-focused systematic reviews and clinical practice guidelines identified the more commonly studied augmentation strategies for depression.

Results: S-adenosylmethionine, l-methylfolate, omega-3 fatty acids, and hydroxyvitamin D have sufficient scientific evidence to support their clinical consideration in the stepped care approach to the management of depression.

Conclusions: Clinical remission is the goal in the management of depression, and nutraceuticals may be part of an overall treatment approach to achieve that outcome.

Depression is one of the most common psychiatric disorders in the United States as indicated by the 2017 National Survey on Drug Use and Health,1 which reported that the prevalence of a major depressive episode among adults was 7.1%. The best treatment options for depression are medications and psychotherapy, but these interventions failed to achieve remission in at least one-third of patients with a major depressive disorder.2 Improving response and remission rates involves multiple factors, such as encouraging patient adherence, reevaluating differential diagnoses, and considering nontraditional augmentation strategies such as transcranial magnetic stimulation.3 
Nutraceuticals are an often neglected strategy used to reduce the morbidity of depression. They occupy a gray zone that overlaps food, food supplements, and traditional pharmaceuticals, but an emerging definition considers the category as an extension of dietary supplements that are concentrated and administered as tablets or liquids. Additionally, nutraceuticals must have physiologic effects that target discrete disorders.4 
Nutraceutical researchers are pushing the boundaries of this new frontier in clinical practice with a dizzying array of compounds that target both physical and emotional disorders.3,4 The researchers’ efforts are hampered with inconsistent or nonexistent regulatory guidelines and small sample sizes that inhibit generalizations and assessment of potential adverse effects.4 Despite these limitations, some nutraceuticals are showing promise as clinical adjuncts to standard treatments for patients with depression.3,5 
The author conducted a review of systematic reviews to identify the more commonly studied nutraceuticals. A PubMed search using the terms “adult,” “depression,” “nutraceutical,” and “systematic review” produced 15 articles published from 2005 to 2019. As a group, those systematic reviews primarily targeted S-adenosylmethionine (SAMe), L-methylfolate, omega-3 fatty acids, and vitamin D and provided the basis for a detailed focus of those substances using the same search terms through the Cochrane Database of Systematic Reviews and through reference searching. 
Fifteen systematic reviews were analyzed. In each, the authors tempered their findings by acknowledging the limited pool of published studies, their variable quality, and the need for further research. Newer publications were more likely to have favorable opinions of nutraceutical augmentation for depression, which may be due to the expanded research base. 
Authors of a 2018 systematic review and meta-analysis5 concluded that 4 nutraceuticals—SAMe, l-methylfolate, omega-3, and hydroxyvitamin D—had sufficient evidence to support their clinical role as an augmentation agent for depression. Health care professionals can either initiate therapy by combining a traditional antidepressant with one of these nutraceuticals or hold them in reserve for treatment-resistant cases.5 Vitamin C, tryptophan, zinc, and inositol lacked sufficient evidence to recommend their consideration based on the number and or quality of published research studies.5-7 
Although not exclusively focused on depression, the Agency for Healthcare Research and Quality conducted one of the earliest systematic analyses of published literature examining SAMe's role in the management of depression, osteoarthritis, and liver disease in 2003.8 When compared with placebo, researchers8 reported that SAMe reduced the core symptoms of depression, and when compared with typical antidepressants, there was no statistical difference in outcomes between the 2 treatments. The authors of a similar report9 conducted by the Cochrane Database of Systematic Reviews concluded that SAMe was “superior to placebo when used in combination with selective serotonin reuptake inhibitor (SSRI) antidepressants” but advised more rigorous study because of the low quality of evidence. 
S-adenosylmethionine has several putative mechanisms of action that may explain its role in alleviating the symptoms of depression. One of the more novel theories emphasizes the central role of SAMe in donating methyl groups within a cell's internal environment which in turn controls critical epigenetic functions. Methylation, or the lack thereof, determines which genes are expressed or silenced with abnormalities in the methylation process, potentially contributing to the development of mental disorders such as depression. Correcting a SAMe deficiency could restore the cell's homeostasis.10,11 
In vivo animal studies also suggest SAMe increases central nervous system monoamine neurotransmitters and improves cell signaling pathways.12 S-adenosylmethionine may also prove to be an effective intervention when remission remains elusive following an adequate trial of SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs).13,14 
When prescribing nutraceuticals, dose is among the many challenges health care professionals must consider. The author of a 2018 review15 suggested SAMe doses between 400 mg to 3200 mg per day but recognized that some patients may require higher doses. For mild depression, a dose of 400 mg per day may be sufficient, whereas major depression may require higher doses (800-1600 mg per day).15 Treatment-resistant depression may require even higher doses.15 S-adenosylmethionine should be taken without food and initiated at 200 mg twice daily to minimize adverse effects. The dose can be increased every 3 to 7 days by 200 mg to 400 mg. S-adenosylmethionine quickly oxidizes and degrades the product's effectiveness when it is exposed to air, which makes packaging an important consideration when buying the product.16 
Another promising nutraceutical for the management of depression is vitamin B9, or folate, which is an essential dietary nutrient. Folic acid is the synthetic form of vitamin B9 that is used in various nutritional supplements. L-methylfolate is the active form of both folate and folic acid that crosses the blood brain barrier. Research17 has demonstrated that low levels of folate correlate with depression and also reduce the effectiveness of traditional antidepressant pharmacotherapy. This relationship underpinned subsequent research supporting the use of l-methylfolate as an augmentation strategy for depression.17 
A systematic review published by The Cochrane Collaboration in 200318 concluded that the limited evidence available at that time suggested “folate may have a potential role as a supplement to other treatment for depression.” This conclusion was based on a mean 2.65-point reduction in the Hamilton Depression Rating Scale scores.18 In the years following that review, accumulating evidence suggested that l-methylfolate may be a useful adjunct for treatment-resistant depression. 
In a naturalistic study,19 67.9% of participants responded to l-methylfolate treatment with a 50% reduction in Patient Health Questionnaire-9 scores. The study found a self-reported adherence rate of 90% with either the 7.5-mg or 15-mg dose, which suggested that participants tolerated l-methylfolate well.19 For patients with no response or a partial response to an SSRI, researchers20 reported that adjunctive treatment with 15 mg of l-methylfolate reduced the mean Hamilton Depression Rating Scale score by 2.6 points. Another study21 confirmed the safety, tolerability, and efficacy of augmenting an SSRI with 15 mg of l-methylfolate during a 12-month period for patients with treatment-resistant depression. Authors of a comprehensive review22 exploring the pharmacologic management of treatment-resistant depression suggested both SAMe and l-methylfolate as reasonable augmentation choices. 
Omega-3 Fatty Acids
A systematic review23 conducted by the Cochrane Collaboration in 2015 examined omega-3 fatty acids for the management of a major depressive disorder vs a comparator. Based on insufficient high-quality research, the authors reached no conclusions. A 2008 study24 from the Cochrane Collaboration examined the evidence supporting the putative value of omega-3 fatty acids for the adjunctive treatment of bipolar disorder. Based on the limited studies available, the researchers24 concluded that augmentation with omega-3 fatty acids reduced depressive symptoms but not manic behavior. 
A 2018 systematic review and meta-analysis5 examined the augmenting role of omega-3 fatty acids for depression and “revealed a significant and moderate to strong effect” favoring its use. The authors attributed the positive results to omega-3 fatty acids, which were primarily eicosapentaenoic or ethyl-eicosapentaenoic. 
A considerable body of evidence links deficits in omega-3 fatty acids with depression.25 A comprehensive review25 found that some studies had positive results from augmentation and other studies reached the opposite conclusion. This disparity suggests that low levels of omega-3 fatty acids may constitute an etiologic subset of patients with clinical depression.25 
Researchers are actively exploring how omega-3 fatty acids modulate neurobiological processes, and current efforts are directed at 3 areas.26 The first line of research focuses on the cellular level and examines how omega-3 fatty acids help regulate inflammation, enhance interneuronal signaling, and interact with specific receptors, such as the retinoic acid receptor, which may improve mood and cognition. A second line of research recognizes the role that omega-3 fatty acids play in modulating the endocannabinoid system, which in turn regulates both excitatory and inhibitory neurotransmitters. The third line of research follows observations correlating low levels of omega-3 fatty acids with alterations in plasma cortisol that targets the hypothalamic-pituitary-adrenal axis. 
Dosage guidelines for omega-3 fatty acids remain an area that requires more research. Omega-3 fatty acids are prevalent in fish, which provides a source for the essential nutrient. A systematic review and meta-analysis27 concluded that dietary intake of omega-3 fatty acids lowers the risk of depression. Interestingly, dietary consumption may not follow a linear dose response, but instead it appears to be a U-shaped relationship with the greatest reduction in depression seen with moderate and not higher levels of fish ingestion.28 A systematic review from Derbyshire29 suggests that global dietary consumption as a source of omega-3 fatty acids is inadequate, and that omega-3 supplementation may be beneficial in supporting brain health and mood.29 A 2016 review30 examined various research studies and concluded that the effective augmentation dose of ethyl-eicosapentaenoic for depression ranged from 1 to 4 g per day. This dose was well tolerated, and the most common adverse effects reported were nausea and a fishy aftertaste.30 
Hydroxyvitamin D
Researchers hypothesize the potential adjunctive value of hydroxyvitamin D in part because of its presumed function in the nervous system. As a neurosteroid, hydroxyvitamin D plays an increasingly evident role in brain health through calcium regulation and anti-inflammatory actions. Hydroxyvitamin D also appears to reduce β-amyloid deposition with hydroxyvitamin D deficiencies, which may contribute to neurocognitive disorders. Hydroxyvitamin D's role in maintaining the brain's calcium homeostasis, the interaction with nerve growth factor, and the presence of the hydroxyvitamin D receptor in key brain structures all suggest it has a putative relationship with healthy mood and cognitive function.31,32 
Hydroxyvitamin D deficiency may constitute another subset of treatment-resistant depression as indicated by studies supporting both the association and the potential benefit from supplementation.33-35 Low levels of hydroxyvitamin D are associated with postpartum depression.36 Decreased hydroxyvitamin D levels help in the differential diagnosis of poststroke depression from patients who did not have depression before their stroke.37 Hydroxyvitamin D dose seems crucial to therapeutic outcomes. A meta-analysis38 reported improvement in depression scores among patients with baseline deficiencies in 25-hydroxyvitamin D levels who received hydroxyvitamin D supplementing doses of greater than or equal to 800 IU daily. 
The factors driving clinical and research interest in the nutraceutical augmentation of depression include treatment-resistant depression, safe and effective alternative interventions, and a preference by some patients for nonpharmacologic treatments. Because nutraceuticals require no prescription and are readily available to patients, it is advantageous for health care professionals to understand their potential risks and benefits in a way that both reconciles the patients’ clinical history and considers their potential adoption as part of an integrated treatment plan. 
Nutraceutical researchers are exploring dozens of possible compounds as alternative first-line treatments for depression or for augmentation when traditional antidepressants fall short.39 International clinical practice guidelines40 from the Royal Australian and New Zealand College of Psychiatrists suggest consideration of omega-3 fatty acids and SAMe as adjunctive agents in treatment-resistant depression. The Canadian Network for Mood and Anxiety Treatments recommends omega-3 fatty acids, SAMe, and folate as adjunctive treatments for mild to moderate depression.41 Other treatments recommended in the British Association for Psychopharmacology guidelines included L-methylfolate in combination with SSRIs, omega-3 fatty acids, and SAMe in combination with SSRI or SNRIs.42 In the United States, Florida Best Practice Psychotherapeutic Medication Guidelines for Adults43 recommends l-methylfolate and SAMe as level-3 interventions in combination with SSRI or SNRIs for treatment-resistant depression. 
Health care professionals prescribing any nutraceutical should carefully explain the treatment to prospective patients and include that it does not have a US Food and Drug Administration–approved indication for the treatment of depression. At the same time, health care professionals should discuss the benefits and risks. For example, SAMe is well tolerated and has not been shown to contribute to weight gain or sexual dysfunction.44 Common adverse effects are mild and include nausea, anxiety, dizziness, and insomnia.44 Like antidepressants, SAMe may destabilize a patient with bipolar disorder.44 There are no reported deaths from SAMe overdose. This medication has few drug interactions, and even though it may theoretically increase serotonin levels, to our knowledge, there has only been 1 reported case of serotonin syndrome when combined with SSRIs.44 
Omega-3 fatty acids are generally safe and well tolerated; however, concomitant use of vitamin A could result is excessive levels of the vitamin.45 Hydroxyvitamin D is also generally safe and well tolerated, with only rare reports of hypercalcemia and hypercalciuria resulting from excessively high self-administered doses taken for protracted periods. To avoid outcomes of hypercalcemia and hypercalciuria, health care professionals should consider variables such as the patient's diet, geographic location in terms of sun exposure, and use of sunscreens when prescribing dose to maintain the measured 25-hydroxyvitamin D level in the range of 30 to 50 ng/mL.46 
Cost should also be discussed with patients. It may be helpful to remind patients that any out-of-pocket expenses must be weighed against mandatory copays for prescription medications.44 Other factors to consider include product quality, possible adulteration, and decreased potency. 
There are limitations to this review. As with any narrative review, selection bias can be a potential limitation; however, this review relied on a broad mix of systematic reviews and meta-analyses guided by specific search terms to minimize this bias. Nutraceutical research is also an active area of exploration, and new findings may alter or suggest new clinical pathways. 
Converging lines of research show increasing support for clinical consideration of adjunctive nutraceuticals for the management of depression, including treatment-resistant depression. This recommendation finds further support from clinical practice guidelines. Health care professionals should consider common nutraceuticals for purposes of medication reconciliation and patient education. 
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