Grape-Derived Compounds to Help Beat Depression

grape seed extract depression

Story at-a-glance

  • A polyphenol preparation made from Concord grape juice, grape seed extract and trans-resveratrol has shown promise for treating depression
  • Two phytochemicals in particular — dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc) — appeared to be responsible for the beneficial effects
  • The grape-derived compounds target cellular and molecular pathways associated with inflammation while modulating synaptic plasticity, disruptions of which have been linked to depression


This is an older article that may not reflect Dr. Mercola’s current view on this topic. Use our search engine to find Dr. Mercola’s latest position on any health topic.

By Dr. Mercola

A polyphenol preparation made from Concord grape juice, grape seed extract and trans-resveratrol has shown promise for treating depression, according to an animal study from the Icahn School of Medicine at Mount Sinai.1 Two phytochemicals in particular — dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc) — appeared to be responsible for the beneficial effects, which included modulating inflammation and synaptic plasticity, essentially increasing resilience against stress-induced depression in mice.2

Previous research has found that a single dose of resveratrol can improve blood flow to your brain and may enhance several aspects of brain function, including lowered inflammation that may extend to protection again depression.3 The featured study revealed that the grape-derived compounds target cellular and molecular pathways associated with inflammation while modulating synaptic plasticity, disruptions of which have been linked to depression.

DHCA was found to reduce a pro-inflammatory compound called interleukin 6 (IL-6) while Mal-gluc modulates synaptic plasticity, a fundamental brain function that controls your ability to sense and store complex information and respond to external stimuli.

With chronic stress (or acute traumatic stress) acting as the most significant factor in a person’s susceptibility to depression,4 the fact that the specialized grape preparation promoted resilience against stress in mice was also highly notable. Study author Giulio Maria Pasinetti, Ph.D., professor of neurology, said in a news release:5

"Our approach to use a combination treatment of DHCA and Mal-gluc to simultaneously inhibit peripheral inflammation and modulate synaptic plasticity in the brain works synergistically to optimize resilience against chronic stress-induced depression-like phenotypes …

The discovery of these new, natural grape-derived polyphenol compounds targeting cellular and molecular pathways associated with inflammation may provide an effective way to treat a subset of people with depression and anxiety, a condition that affects so many people."

Why Conventional Treatments for Depression Often Fail

Nearly 7 percent of U.S adults suffered from a depressive episode in the past year6 while, worldwide, 350 million people suffer from depression, making it a leading cause of disability.7 Despite this, only about one-third of Americans with depression get treated,8 which puts the remaining two-thirds left untreated at increased risk of suicide and with a lower quality of life.

Yet, major problems exist with conventional depression treatments, which typically center on antidepressants. For starters, the side effects can be serious. Antidepressant users have an increased risk of developing Type 2 diabetes,9 even after adjusting for other risk factors, like body mass index (BMI).10 Antidepressant use has also been linked to thicker arteries, which could contribute to the risk of heart disease and stroke,11 along with increased risk of heart attack12 and, ironically, suicidal thoughts.

The drugs are also linked to dementia, with researchers noting “treatment with SSRIs, MAOIs, heterocyclic antidepressants, and other antidepressants was associated with an increased risk of dementia,” and as the dose increased, so too did the risk.13 Importantly, the drugs are also known to deplete various nutrients from your body, including coenzyme Q10 and vitamin B12 — in the case of tricyclic antidepressants — which are needed for proper mitochondrial function. SSRIs may deplete iodine and folate.14

Importantly, studies have repeatedly shown antidepressants work no better than placebo for mild to moderate depression.15 In fact, Irving Kirsch, associate director of the Program in Placebo Studies at Harvard Medical School, has conducted meta-analyses of antidepressants in comparison to placebo and has concluded that there’s virtually no difference in their effectiveness, noting, “The difference is so small, it’s not of any clinical importance.”16

What is different, however, is the potential for side effects, which is far greater among antidepressants than placebos. Not to mention, the widely held belief that depression is due to low levels of serotonin or other chemicals in your brain is only a theory — one that’s been largely disproven. Antidepressants targeting the chemical imbalance theory remain the go-to treatment for this condition nonetheless. As the grape compound researchers wrote in Nature Communications:17

“Currently available treatments for major depressive disorder (MDD) mainly target neurochemical or neurobiological mechanisms. Conventional pharmacological treatments produce temporary remission in <50 percent of patients. Thus, there is an urgent need for a wider spectrum of novel therapeutics to target newly discovered underlying disease mechanisms.”

Nature May Be Home to a Number of Depression Busters

As mentioned, the grape compound resveratrol, also found in raspberries, mulberries and other dark berries, pomegranates, red wine and dark chocolate, has previously been shown to have antidepressant effects in mice and rats. In one study, resveratrol showed “antidepressant-like effect[s],” possibly due to activation of hippocampal brain-derived neurotrophic factor (BDNF).18 BDNF promotes healthy brain neurons and levels tend to be low in people with depression.

Yet, grapes are just one natural source of compounds that may give your mental health a boost. The psychedelic drug psilocybin, also known as magic mushrooms, is another that continues to show promise for treating depression. In a small study of 19 patients with treatment-resistant depression, all of them experienced improvements in symptoms one week after receiving a single dose of psilocybin, and half of them were no longer depressed five weeks post-treatment.19

Brain scans showed actual brain changes occurred in areas involved in depression, including less activity in the amygdala, which is involved in processing emotions, and more stable activity in the default-mode network (links between activity in the network and depression have been found).20 The researchers suggested the participants’ brains may have been “reset” in a sense, helping them to overcome depression.

Unfortunately, psilocybin is a Schedule 1 drug, like marijuana, so trials cost about 10 times that for other legal drugs, and in order to take the research to the level where it could potentially be turned into a psychiatric treatment, phase 3 clinical trials are needed with thousands of participants. For that to occur, psilocybin would need to be rescheduled. Light exposure is another way nature provides for your mental health.

Exposure to sunlight will help optimize your vitamin D levels (another factor linked to depression21) as well as influence your mental state via other mechanisms, like regulating your circadian rhythm and production of serotonin, which is released in response to sunlight exposure. If you don’t have access to regular sunlight, full-spectrum light therapy can be a useful alternative. Light therapy alone and placebo were both more effective than Prozac for the treatment of moderate to severe depression in an eight-week-long study.22

Supplements Useful for Depression

Other proven mood boosters are readily available via the food you eat or, alternatively, in the supplement aisle. These include:

  • Magnesium: Magnesium supplements led to improvements in mild-to-moderate depression in adults, with beneficial effects occurring within two weeks of treatment.23
  • Omega-3 fats, which have been shown to lead to improvements in major depressive disorder.24 Make sure you're getting enough omega-3s in your diet, either from wild Alaskan salmon, sardines, herring, mackerel and anchovies, or a high-quality animal-based omega-3 supplement.
  • B vitamins. Low levels of B vitamins are common in patients with depression, while vitamin B supplements have been shown to improve symptoms.25
  • Folate. Folate helps your body produce mood-regulating neurotransmitters, including serotonin and dopamine. One 2012 study found people who consumed the most folate had a lower risk of depression than those who ate the least.26
  • Probiotics. A small study involving adults diagnosed with IBS (irritable bowel syndrome) and depression found the probiotic Bifidobacterium longum provided depression relief. At six weeks, 64 percent of the treatment group had reduced depression scores compared to 32 percent of the control group that received a placebo.27 Eating fermented foods regularly is an excellent way to supply your body with an ongoing source of probiotics.

Other options include SAMe, an amino acid derivative that occurs naturally in all cells. It plays a role in many biological reactions by transferring its methyl group to DNA, proteins, phospholipids and biogenic amines. Several scientific studies indicate that SAMe may be useful in the treatment of depression.28

5-Hydroxytryptophan (5-HTP), a serotonin precursor, is another natural alternative that outperforms a placebo when it comes to alleviating depression29 — more than can be said about antidepressants. St. John's Wort has also been shown to provide similar relief to mild or moderate depression as antidepressants but with fewer side effects.30

Treating Depression Requires a Holistic Approach

Depression is a complex condition with varied causes that requires a similarly varied approach in treatment. What works to cure your depression may be different from what works for your neighbor’s. However, in addition to the supplements above, one strategy that will benefit most everyone is regular exercise.

Even a minimal amount of exercise may be enough to combat depression in some people — as minimal as one hour a week, according to an 11-year study in which people who engaged in regular leisure-time exercise for one hour a week were less likely to become depressed. On the flipside, those who didn’t exercise were 44 percent more likely to become depressed compared to those who did so for at least one to two hours a week.31

Please keep in mind that physical activity should include not just “exercise” but also plenty of nonexercise daily movements, such that you’re in motion more so than not (except while you’re sleeping). Spending time in nature — gardening, hiking or visiting a park — may also help to relieve anxiety and depressive symptoms, as can practicing mindfulness meditation32 and the Emotional Freedom Techniques (EFT).33 Attention to your diet is also crucial, particularly in limiting the amount of processed foods and sugars you’re eating.

On the other hand, foods that are good for your mood include dark chocolate, bananas, turmeric and even organic black coffee. Taking care of yourself by leading a healthy lifestyle (eating right, getting high-quality sleep, exercising and relieving stress regularly) is a crucial element to fighting and recovering from depression. However, if you’re in the throes of a depressive episode, it’s difficult to focus on making long-term plans or lifestyle changes.

In this case, reach out for help from a health care provider, close friend or family member, and if you are feeling desperate or having thoughts of suicide, please call the National Suicide Prevention Lifeline, a toll-free number: 1-800-273-TALK (8255), call 911 or go to your nearest hospital emergency department.


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