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Mood-modulating nutraceuticals

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A number of nutraceuticals have shown promise when studied for potential use with depression and other mood disorders

Although many mood disorders exist, depression is among the most common. Characterized by changes in mood—as well as cognitive and physical symptoms—CDC’s National Center for Health Statistics noted depression is also associated with high societal costs and greater functional impairment than many other chronic diseases, including diabetes and arthritis.

In fact, CDC data indicate a substantial proportion of Americans reported suffering mild (15.6%), moderate (5.1%) or severe (2.9%) symptoms of depression. Combined, 8% of Americans indicated they have moderate to severe depression; and women are more likely to be depressed than men.

Although the best-known herbal medicine for depression is arguably St. John’s wort, it is also most associated with herb/drug interactions. However, a number of other nutraceuticals have shown significant efficacy in the treatment of depression—including mild-to-moderate depression—as well as other mood disorders. Many dietary supplement ingredients are worth considering, but three show particular promise.

Phosphatidylserine (PS)

PS is a “brain nutrient” phospholipid that functions as an integral component in the structure of the brain and spinal cord, and is active at cell membranes (including synaptic membranes, which transmit information from one neuron to the next). In a study conducted in 30 elderly outpatients with dementia, supplementation with PS was found to normalize hormones associated with stress in depressed patients.1 In another study, the effects of PS on cognitive, affective and behavioral symptoms were examined in a group of 10 elderly women with depressive disorders.2 Patients were treated with placebo for 15 days, followed by 300 mg/day PS for 30 days. To monitor changes in depression, memory and general behavior, the Hamilton Rating Scale for Depression, Gottfries-Bråne-Steen Rating Scale, Nurse's Observation Scale for Inpatient Evaluation and Buschke Selective Reminding Test were administered before and after placebo and after PS therapy. The results showed depressive symptoms in patients were marked before treatment, did not change after placebo, but were significantly reduced with PS therapy. In fact, PS significantly improved most psychological parameters studied. Remission of symptoms was clear-cut, both based on clinical observation and analysis of scores. In particular, drive, interests and socialization increased. The patients’ general neuropsychological improvement and better coping with requirements of daily life could be related to reduction of depressive symptoms. Additionally, recall and long-term memory were significantly improved. This correlated with attention and concentration, which can be compromised by depression. PS was found to induce consistent improvement of depressive symptoms, memory and behavior.

Saffron extract

Crocus sativus L, commonly known as saffron, has been used in a number of human clinical trials in the treatment of depression. Its compounds are interesting because they appear to have more than one mechanism of action. Hausenblas et al. proposed that saffron extract increases serotonin levels in the brain.3 Hosseinali et al. showed that saffron extract increased brain dopamine concentration in a dose-dependent manner and that, in addition to dopamine, saffron extract increased the production of brain glutamate levels in animal research.4 Other contributing beneficial effects on the brain include saffron’s activity against oxidative damages and neurotoxicity.5

The efficacy of the stigmas of saffron stigma extract was studied in the treatment of mild to moderate depression in a six-week, double-blind, placebo-controlled and randomized trial.6 Forty adult outpatients with major depression participated were randomly assigned to receive 30 mg/d of saffron stigma extract or a capsule of placebo. At six weeks, saffron stigma extract produced significantly better outcomes in depression relief than the placebo (P < 0.001), and no significant differences occurred in the two groups regarding observed side effects. Similar studies also demonstrated positive results,3 including studies in which saffron extract was compared to prescription antidepressant drugs.7,8,9

5-methyltetrahydrofolate (5-MTHF)

In the human body, folate/folic acid gets converted into its biologically active form, 5-MTHF. Several studies documented 5-MTHF promoted improvement in patients experiencing depression. In one study, elderly patients being treated with standard psychotropic medication were additionally given 5-MTHF.10 Patients with borderline or definite folate deficiency experienced improvements in mood, and patients with normal levels of folate experienced significant improvements in mood after three weeks of treatment. Similar beneficial results were seen with 5-MTHF supplementation in a double-blind, placebo-controlled trial.11 The authors of this particular study also commented that their findings contributed to the evidence implicating disturbances of methylation in the nervous system in the biology of mood disturbances. A six-week open-label trial using 5-MTHF noted that 81% of patients showed a markedly significant improvement in their depressive symptoms at endpoint.12


Depression is a common mood disorder. Approximately 1 in 12 Americans self-reported experiencing moderate to severe depression symptoms, and the true numbers are likely much higher. As clinically demonstrated in multiple studies, PS, saffron extract and 5-MTHF have a history of efficacy in the treatment of depression. Furthermore, these nutraceuticals offer an excellent safety margin.

To read other articles in the brain health category, check out the cognitive health digital magazine.

Gene Bruno, MS, MHS, RH(AHG) has 42 years of dietary supplement industry experience. With a master’s degree in nutrition and a second master’s degree in herbal medicine, he has a proven track record of formulating innovative, evidence-based dietary supplements. Bruno currently serves as both vice president of scientific and regulatory affairs at NutraScience Labs and professor of nutraceutical science at Huntington University of Health Sciences.


1 Rabboni M et al. “Neuroendocrine and behavioural effects of phosphatidylserine in elderly patients with abiotrophic or vascular dementia or mild depression. A preliminary trial.” Clin Trials J. 1990;27(3):230-240.

2 Maggioni M et al. “Effects of phosphatidylserine therapy in geriatric patients with depressive disorders.” Acta Psychiatr Scand. 1990;81(3):265-270.

3 Hausenblas HA et al. “Saffron (Crocus sativus L.) and major depressive disorder: a meta-analysis of randomized clinical trials.” J Integr Med. 2013;11(6):377-383.

4 Hosseinali E et al. “Aqueous Extract of Saffron (Crocus sativus) Increases Brain Dopamine and Glutamate Concentrations in Rats.” J Behav Brain Sci. 2013;3:315-319.

5 Lopresti AL, Drummond PD. “Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action.” Hum Psychopharmacol. 2014;29(6):517-527.

6 Akhondzadeh S 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.

7 Akhondzadeh S et al. “Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial [ISRCTN45683816].” BMC Complement Altern Med. 2004;4:12.

8 Shahmansouri N et al. “A randomized, double-blind, clinical trial comparing the efficacy and safety of Crocus sativus L. with fluoxetine for improving mild to moderate depression in post percutaneous coronary intervention patients.” J Affect Disord. 2014;155:216-222.

9 Noorbala AA et al. “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.

10 Passeri M et al. “Oral 5-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study.” Aging (Milano). 1993;5:63-71.

11 Godfrey PS et al. “Enhancement of recovery from psychiatric illness by methylfolate.” Lancet. 1990;336:392-395.

12 Guaraldi GP et al. “An open trial of methyltetrahydrofolate in elderly depressed patients.” Ann Clin Psychiatry. 1993;5:101-105.

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