Can Bifidobacterium Probiotics Help With Depression? A New Study Says Yes

A recent study has just been published showing that probiotics can reduce depression in humans, providing further evidence that the bacteria in your gut can affect your mood. 

It is estimated that 500 to 1,000 species of bacteria live in the human gut. They help with digestion and the proper functioning of the gastrointestinal tract.

But an increasing amount of research suggests that they also communicate with your brain and affect your behaviour. 

In a new randomized, double-blind, placebo-controlled trial, Canadian researchers at McMaster University studied whether one specific strain of beneficial gut bacterium – bifidobacterium longum – would affect patients with depression.

The researchers took 44 adults with irritable bowel syndrome (IBS) and mild to moderate depression, and randomly assigned them to two groups. One group was given the probiotic bifidobacterium longum every day for 6 weeks. The other was given placebo for 6 weeks. 

Patients filled out a questionnaire at the beginning and end of the study, which allowed researchers to determine each participant’s level of depression and quality of life. 

What’s interesting about this study is that researchers also performaned a Functional Magnetic Resonance Imaging (fMRI) test before and after the study. This allowed them to assess how the probiotic affected brain activation patterns.  

What Were The Results?

At the end of the study, 64% of patients taking the probiotic bifidobacterium longum had a significant reduction in their depression, compared to just 32% of patients given placebo. Their quality of life score also increased

And the fMRI analysis showed that multiple brain areas that are associated with depression, including the amygdala and fronto-limbic regions, were less active. The probiotic bifidobacterium longum actually reduced their reaction to “negative emotional stimuli”. In other words, they weren't as negatively affected by sad experiences and images. 

“What we found was that the patients that were treated with this probiotic bacterium improved their gut symptoms but, also surprisingly, decreased their depression scores. That means their mood improved. And this was associated also with changes in the brain imaging.

This study shows that consumption of a specific probiotic can improve both gut symptoms and psychological issues in IBS. This opens new avenues not only for the treatment of patients with functional bowel disorders but also for patients with primary psychiatric diseases.”

— Dr. Premysl Bercik, Associate Professor of Medicine at McMaster University

Even four weeks after the study had concluded, depression scores were still reduced in the patients who had been given the probiotic bifidobacterium longum.

Researchers concluded that the probiotic bifidobacterium longum can reduce depression and increase quality of life. And these improvements were associated with changes in brain activation patterns.

So if you currently struggle with depression, I think supplementing with bifidobacterium longum is worth a try. 

Bifidobacterium longum is included in the Optimal Biotics supplement.

I created Optimal Biotics because I want to give my clients and readers the very best probiotic supplement so that they can experience superior results.

I have found that many probiotic supplements on the market fall short and even cause side effects.

But Optimal Biotics doesn't, and it contains the 8 most well-researched and beneficial probiotic strains for your mental health.

In the future, I imagine practitioners will be able to use genome sequencing techniques to determine the microbiome profiles of individuals, which could then be tweaked with probiotics. In other words, there may come a day when we can "biohack" our gut bacteria for optimal mental health.

In the meantime, you can try supplementing with bifidobacterium longum, and if you’re interested in learning more about this new study, you can read the entire abstract at the end of this post.

Other Research on Bifidobacterium Longum

This isn’t the first time that the probiotic bifidobacterium longum has been linked to reductions in depression and improvements in mental health.

Here are some other studies:

• In a double-blind, placebo-controlled, randomized study, participants with mild depression took a probiotic that contained bifidobacterium longum and lactobacillus helveticus for 30 days. At the end of the study, the participants had a significantly reduction in depression, cortisol, anger, self-blame, and overall psychological distress. They also displayed higher problem-solving skills.

• In another double-blind, placebo-controlled, randomized study, healthy volunteers took bifidobacterium longum and lactobacillus helveticus for 30 days, and the results showed a reduction in psychological stress and cortisol levels.

• In an animal study, bifidobacterium longum improved learning and memory during cognitive tests.

• In a study of mice under chronic psychological stress, bifidobacterium longum and lactobacillus helveticus reduced cell death in the emotion-processing parts of their brains. It did this by reducing stress hormones and increasing brain-derived neurotrophic factor (BDNF), a protein in the brain that can help reduce depression. Another animal study also found that bifidobacterium longum increases BDNF.

• In a study of mice, bifidobacterium longum reduced schizophrenic behaviour.

Conclusion 

Conventional medicine tries to correct depression by relying on medications. But unfortunately this often ends up creating new chemical imbalances and nutrient deficiencies. 

Supplementation with bifidobacterium longum is a more evidence-based approach.

Human and animal studies show that the probiotic causes favourable biochemical and behavioural changes, leading to significant decreases in symptoms of depression.

For anyone experiencing depression, supplementing with it seems worthwhile and may allow you to reduce your reliance on prescription medication.

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Jordan Fallis

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Probiotic Bifidobacterium longum Reduces Depression Scores and Alters Brain Activity: a Pilot Study in Patients With Irritable Bowel Syndrome.

Abstract

BACKGROUND & AIMS:

Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities. We performed a prospective study to evaluate the effects of Bifidobacterium longum (BL) on anxiety and depression in patients with IBS.

METHODS:

We performed a randomized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood samples were collected. Patients were then randomly assigned to groups and given daily BL (n=22) or placebo (n=22) for 6 weeks. At week 0, 6 and 10, we determined patients' levels of anxiety and depression, IBS symptoms, quality of life, and somatization using validated questionnaires. At week 0 and 6, stool, urine and blood samples were collected, and functional magnetic resonance imaging (fMRI) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters and neurotrophin levels.

RESULTS:

At week 6, 14/22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7/22 patients in the placebo group (P=.04). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto-limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo.

CONCLUSION:

In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity. 

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20 Nutrient Deficiencies Proven to Cause Depression

Being depressed doesn’t mean you’re weak.

It’s not a defect in your personality. 

As I’m sure you know, it’s often caused by physiological changes in your body and brain.

So you need to think of it like any other illness. 

If you have a broken bone, you need to wear a cast to stabilize the bone while it heals. 

And if you have depression, you need to be kind to yourself, as you seek and address the underlying root causes. 

The good news is that you’re not powerless. 

I used to think that I’d be depressed forever.

That my depression was simply genetic, and I couldn’t do anything about it. 

In fact, I accepted that notion for a while.

I felt defeated and hopeless, and thought I'd feel that way for my entire life.

I told myself I’d simply have to rely on drugs to survive because that’s just “how I’m wired”. 

But then one day, I changed my mind and decided that I’d had enough. 

And I was actually going to get to the bottom of it instead of just accepting it.

I took action and searched far and wide for safer and healthier solutions to deal with my depression.

I came across a lot of different research and therapies.

I wasn’t sure if they would work, but then they did.

And I overcome my depression for good. 

One of my most important discoveries was that nutrient deficiencies can make your depression worse. 

And they could even be the root cause of it. 

It made so much sense.

But why hadn’t anyone ever brought it up?

I delved deeper into the scientific literature, and I found MANY nutrient deficiencies that can contribute to depression.

I started increasing my intake of them.

And I got better.

Much better.

This new post includes 20 nutrient deficiencies that could be making you feel depressed.

Read on to learn more. 

Vitamin Deficiencies That Can Cause Depression

1. Vitamin B12

“Lack of understanding of B12 is one of the greatest tragedies of modern medicine.”

— Dr. James Greenblatt, Integrative Psychiatrist

Having sufficient levels of Vitamin B12 is necessary for optimal brain and mental health.  

Unfortunately, a deficiency is very common, especially in older individuals and vegetarians and vegans.

And even if you eat meat and you’re young, you may still have a deficiency. 

Poor gut health and even psychiatric medications can cause a deficiency.

In fact, it’s estimated that almost 40% of Americans are deficient today.

Numerous studies have shown that having a deficiency in Vitamin B12 leads to symptoms of depression (16-22). 

And B12 levels tend to be significantly lower in people who are depressed (13). 

In one study, subjects with Vitamin B12 deficiency were 2 times as likely to be severely depressed as non-deficient subjects (15). 

Even a mild decrease in B12 levels is associated with mood disturbances (14). 

Luckily, there are steps you can take if you’re deficient. 

Vitamin B12 is found primarily in animal foods, and beef liver is an excellent source. I take beef liver capsules because I don’t like the taste of liver.

You may also want to supplement with Vitamin B12 because studies show that B12 supplementation significantly lowers homocysteine levels and reduces depressive symptoms (23-24). 

If you decide to supplement, avoid the semisynthetic version of B12 (cyanocobalamin) and instead take the methylated form (methylcobalamin or methyl-B12). 

Methyl-B12 is better absorbed and more biologically active.

2. Vitamin D (and Vitamin K2)

Vitamin D is a fat-soluble vitamin that your skin synthesizes when exposed to the sun.

Every tissue in your body has Vitamin D receptors, including the brain, so a deficiency can lead to costly physiological and psychological consequences, including depression.

Researchers have found a very strong link between Vitamin D deficiency and depression (27-28). 

The lower your Vitamin D levels, the more symptoms of depression you are likely to have (35). 

Unfortunately, reports indicate that Vitamin D deficiency is widespread and a major health problem globally (25). 

Researchers estimate that 50 percent of the general population is at risk of Vitamin D deficiency (26). 

It’s best to get your Vitamin D by going outside and getting sunlight.

It’s especially important to make sure you get some sunlight in the morning to set your circadian rhythm. 

But most people still don’t get enough Vitamin D from the sun, especially during the winter.

That’s why I recommend taking a Vitamin D supplement. 

Research does show that taking a Vitamin D3 supplement is effective at reducing symptoms of depression and seasonal affective disorder (29-31). 

This is likely because Vitamin D increases the production of numerous neurotransmitters, including serotonin, dopamine, norepinephrine and epinephrine (32-34). 

It's important to test and monitor your Vitamin D levels before and after supplementing with it.

Lastly, if you decide to supplement with Vitamin D3, you should consider taking it with Vitamin K2. 

A recent study found that Vitamin K2 reduces depression in animals (36). 

And Vitamin K2 is known to improve brain function in humans (37-38). 

3. Vitamin B6

Having a deficiency in Vitamin B6 can also contribute to your depression.

It’s a key nutrient that supports your entire nervous system.

It can boost your mood because it plays a key role in the production of neurotransmitters in your brain, including serotonin and dopamine. It also lowers homocysteine. 

Research shows that people with depressive symptoms tend to have low levels of Vitamin B6 (85-87). 

A Vitamin B6 deficiency also contributes to chronic inflammation, which is one of the main underlying root causes of depression (88). 

Fortunately, consuming more Vitamin B6 can help. 

One study found that women that eat more foods containing Vitamin B6 have a lower risk of depression (89). 

Some of the best food sources of Vitamin B6 include potatoes, bananas and chicken. 

But supplementation is often necessary to see quick improvements. 

One study found that supplementing with Vitamin B6 can reduce depressive symptoms by lowering homocysteine levels (90). 

When I took antidepressants for depression, multiple functional and integrative doctors suggested I supplement with Vitamin B6.

This is because these medications can actually further deplete Vitamin B6, increasing depression in the long run. 

Vitamin B6 is included in the Optimal Zinc supplement.

4. Vitamin C

Having low levels of Vitamin C can also make you feel depressed.

Researchers have found that poor Vitamin C status is associated with increased symptoms of depression (105). 

Animal research also shows that a Vitamin C deficiency can lead to low levels of dopamine and serotonin in the brain, which causes mice to act depressed (106-107). 

As you probably know, Vitamin C can be found in foods such as peppers, citrus fruits, green leafy vegetables, broccoli, tomatoes, and berries. These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

In addition to getting Vitamin C from fruits and vegetables, I take at least 500 grams of this Vitamin C every day. 

I’ve experimented with taking up to 10 grams daily, and it definitely improved my mood and reduced my stress levels, especially when I was coming off antidepressants. 

Research backs this up, showing that supplementing with Vitamin C can actually improve mood in both unhealthy and healthy individuals (95, 102-103). 

Various other studies show that Vitamin C supplements reduce stress and anxiety and decrease the severity of depression (96-101, 104).

Studies even show that Vitamin C can increase the effectiveness of antidepressants (108-109). 

5. Folate

Folate (Vitamin B9) is an essential B vitamin that plays a key role in methylation, one of the most important processes in your body and brain for optimal energy and nervous system function.

Researchers have found that if you are depressed, you likely have lower levels of folate circulating in your blood, and people with low blood folate are at greater risk for developing depression (55-56). 

Good dietary sources of natural folate include: 

• Leafy greens

• Asparagus

• Broccoli

• Cauliflower

• Strawberries

• Avocado

• Beef liver

• Poultry

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health.

However, eating folate-rich foods sometimes isn’t enough. In fact, many people do not get enough folate from food because cooking and food processing destroy natural folates (54).

And supplementation is often needed. 

In one study, patients with depression took methylfolate for 6 months, and they witnessed a significant improvement in their depressive symptoms (57). 

Researchers have even suggested that folate supplementation should be a first-line treatment for depression (58). 

Methylfolate can be effective at treating depression because it helps lower homocysteine levels, helps produce serotonin and dopamine, and stimulates serotonin receptors in the brain (59-62). 

6. Thiamine

Thiamine, also known as Vitamin B1, is an essential water-soluble nutrient that cannot be made by the body. 

It’s used in nearly every cell in the body and especially important for supporting energy levels.

It’s also required by nerve cells and other supporting cells in the nervous system (167). 

Research shows that lower levels of Vitamin B1 are associated with a higher prevalence of depressive symptoms (168).

Vitamin B1 deficiency is also known to lead to irritability and symptoms of depression (170). 

Some doctors and researchers believe that postpartum depression is sometimes simply a Vitamin B1 deficiency (169). 

Luckily, consuming more Vitamin B1 can help.

A randomized, double-blind clinical trial found that Vitamin B1 supplementation reduces symptoms of depression within 6 weeks (171). 

And another concluded that Vitamin B1 supplementation improves mood, reduces brain fog, and speeds up reaction time (172).

In fact, researchers have even found that subjects’ mood improves if the amount of Vitamin B1 in their blood increases, and that the opposite occurs if the amount of Vitamin B1 in their blood decreases (173). 

Healthy food sources of Vitamin B1 include green peas, beef liver, asparagus, pecans, spinach, sunflower seeds, macadamia nuts, oranges, cantaloupe and eggs. 

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

7. Riboflavin

Riboflavin, also known as Vitamin B2, plays a key role in energy metabolism throughout your entire body.  

As a result, a Vitamin B2 deficiency can affect the entire body, leading to low energy, weight gain, and depression.

In fact, lower levels of Vitamin B2 have been found in people with depression (91). 

Researchers have also found that Vitamin B2 consumption decreases risk of postpartum depression (92). 

Healthy food sources of Vitamin B2 include pastured eggs, leafy vegetables, beef liver, mushrooms, sunflower seeds, and almonds. 

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

If you’d like, you can also supplement with Vitamin B2.

Studies show that supplementing with Vitamin B2 helps lower homocysteine and reduces depressive symptoms (93-94). 

Vitamin B2 is included in the Optimal Zinc supplement. 

8. Inositol

Inositol is a naturally-occurring molecule found in nearly all plants and animals. It plays a key role in various biological processes.

The brain has the highest concentration of inositol, where it plays an important role making neurotransmitters (124). 

Inositol can be found in many foods, particularly fruit, especially cantaloupe and oranges (125). 

It used to be considered a B Vitamin, called Vitamin B8. But it currently is no longer considered an essential nutrient because your body can produce inositol from glucose (126). 

But I’m including it in this list anyway because individuals with depression have very low levels of inositol in their brains (127-129). 

And inositol supplementation has been shown to increase inositol levels and help treat depression (130, 132). 

It can also reduce symptoms of depression in women with premenstrual syndrome and premenstrual dysphoric disorder (131, 133). 

It’s even been shown to help patients who have discontinued their antidepressant medication (134). 

I took high doses of inositol powder when weening off psychiatric medication.

Check out my full post about inositol to learn more about the benefits. 

Fun fact: Inositol is also used as a stand-in for cocaine in television shows and movies. 

9. Coenzyme Q10

Coenzyme Q10 (CoQ10) is a coenzyme and antioxidant located primarily in the mitochondria. It has numerous known health benefits and plays a critical role in producing energy for the body.

CoQ10 is produced within the body, but it’s also found within food and can be supplied to the body through food or supplementation. It resembles a fat-soluble vitamin.

Meat and fish are the richest sources of dietary CoQ10, including beef, pork, chicken heart, and chicken liver. Nuts and some oils also contain some CoQ10 (110). 

Research shows that CoQ10 levels are reduced in people with depression and chronic fatigue (111). 

One study also found that CoQ10 regulates serotonin levels and depressive symptoms in fibromyalgia patients (117). 

CoQ10 supplementation has also been shown to improve fatigue and reduce depression symptom severity (112-114). 

It also displays antidepressant-like activity in animals (115-116). 

Mineral Deficiencies That Can Cause Depression

10. Magnesium

Magnesium is a vital mineral that participates in more than 300 biochemical reactions in your body.

Unfortunately, a lot of people are deficient in magnesium today.  

This is a shame because magnesium is absolutely essential for the proper functioning of your nervous system and optimal neurotransmitter activity. 

Research shows that low magnesium levels contribute and worsen many neuropsychiatric problems, including depression (42). 

In fact, researchers have found that people with depression have lower magnesium levels than healthy people (49). 

They’ve also found a significant association between very low magnesium intake and depression (43). 

On top of this, animal research shows that removing magnesium from their diet results in depressive-like symptoms (50). 

So if you’re struggling with depression, it’s very important to make sure you’re getting enough magnesium so that you don’t have a deficiency.

Luckily, there are a number of ways to do this. 

First, make sure you’re eating magnesium-rich foods on a regular basis, including:

• Spinach

• Chard

• Pumpkin seeds

• Almonds

• Avocado

• Dark chocolate

• Bananas

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

Epsom salt baths are another great way to increase your body’s intake of magnesium. 

I also highly recommend a high-quality supplement that includes magnesium.

Magnesium is included in this supplement.

A number of studies have concluded that magnesium supplementation can reduce depressive symptoms in humans – sometimes within 7 days (44-48). 

Since most people are deficient, magnesium is one of the three supplements that I think everyone should be taking.

11. Zinc

Zinc is an essential mineral for mental health.

Like magnesium, it plays a key role in neurotransmission and nervous system functioning.

Mounting evidence suggests a link between zinc deficiency and the development and severity of depression (66-68, 76).  

Depressed patients tend to have lower levels of zinc. And as their zinc levels drop, their depressive symptoms get worse (81-84). 

Unfortunately, it’s estimated that 2 billion people in the world are deficient in zinc, and several studies show that even subclinical deficiency of zinc impairs brain function in children and adults (63-65). 

So, if you struggle with depression, it’s quite possible that you’re deficient, and you’ll definitely want to optimize your zinc levels. 

Some of the best food sources of zinc include:

• Oysters

• Grass-fed beef

• Pumpkin seeds

• Cashews

• Mushrooms

• Spinach

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health.

However, if you’re deficient like I was, I recommend taking a high-quality zinc supplement, at least for a short period of time. 

A meta-analysis and several studies have concluded that zinc supplementation has antidepressant effects and significantly reduces symptoms of depression. One way it improves mood is by significantly increasing BDNF levels (69-75, 77-80).

I created and take the Optimal Zinc supplement to make sure my zinc levels are optimal. 

Check out my previous post all about zinc if you’re interested in discovering more steps you can take to increase your zinc levels.

12. Iron

Iron is a trace mineral found in every living cell in our bodies.

It carries oxygen to all parts of your body, and low levels can leave you feeling tired, pale, irritable and foggy. 

Sounds like depression doesn’t it?

Several studies show that iron deficiency increases the risk of developing depression and increases the severity of depression (184-186, 188-190). 

Researchers have also conducted a meta-analysis and found that high iron intake reduces the chance of developing depression (183). 

In one study, iron supplementation resulted in a 25% improvement in depressive symptoms (187). 

Despite this, I don’t actually recommend supplementing with iron though because some research suggests that too much iron can cause health problems.

It’s definitely preferable to get your iron from food. 

I make sure I get enough iron simply by taking grass-fed beef liver capsules.

Beef liver is one of the best sources of iron, but I don’t like the taste, so I go with the capsules.

Other good sources of iron include:

• Spirulina

• Dark chocolate

• Spinach

• Sardines

• Pistachios

• Raisons

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

13. Selenium

Selenium is an essential trace mineral that is important for many bodily processes that affect your brain and mental health.

Researchers have found that depression is associated with low levels of selenium (191). 

But supplementing with selenium has been shown to significantly increase selenium levels and improve symptoms of depression (192). 

Other research shows that selenium intake is associated with a general elevation of mood (193). 

Brazil nuts are the richest dietary source of selenium, but it can also be found in wild-caught seafood, pastured chicken and eggs, and grass-fed meat.

I also make sure I’m not deficiency in selenium by supplementing with it.

Selenium is included in this supplement.

14. Manganese

Manganese is an important trace mineral for human health. It acts as a cofactor, helping many enzymes carry out their functions in the body.

Research shows that having low levels of manganese can contribute to the development of depression (135). 

One study found that depressed patients had significantly lower levels of “manganese superoxide dismutase”, which is a manganese-dependent enzyme (136). 

Researchers have also found that women with higher manganese intake had a lower prevalence of depressive symptoms (137). 

Hazelnuts and macadamia nuts contain high levels of manganese, while leafy green vegetables, tea, chocolate and some fruits contain moderate levels (139). 

However, it’s important to note that you shouldn’t consume too much manganese.

In excess, manganese is neurotoxic and can lead to manganism, a neurodegenerative disorder that causes dopaminergic neuronal death and symptoms similar to Parkinson's disease (138). 

So I definitely don’t recommend supplementing with large doses of manganese. 

The small amount of manganese in Optimal Antiox is fine though. It’s what I take. 

Fatty Acid Deficiencies That Can Cause Depression

15. Dihomo-Gamma-Linolenic Acid

Dihomo-Gamma-Linolenic Acid (DGLA) is an uncommon fatty acid.

It’s made in the body by the elongation of Gamma Linolenic Acid (GLA).

But small amounts can also be found in animal products (118). 

Last year, researchers found that people with depression are more likely to have low levels of DGLA levels (121). 

And increasing DGLA levels may lower the risk of developing depression (122). 

DGLA also has anti-inflammatory effects in the body (119). 

So it makes sense that levels would be low in depressed individuals because an increasing amount of evidence suggests that depression is a chronic inflammatory disease. 

DGLA can be increased by supplementing with dietary GLA (120). 

GLA can be found in Borage Oil, Evening Primrose Oil and Blackcurrant Seed Oil (123). 

16. Omega-3 Fatty Acids

Omega-3s fatty acids are the highest quality fats for the brain and increasing your intake of them is one of the most impactful actions you can take to fight depression.

Several studies have shown that depressive patients have lower levels of omega-3 fatty acids (1-3).

Researchers even conducted a meta-analysis of 14 studies, and they found that levels of omega-3 fatty acids were significantly lower in people with depression (4). 

They concluded that having a deficiency in omega-3 fatty acids is a “contributing factor to mood disorders” (5). 

It’s important to consume enough omega-3 fatty acids because they are essential fats that your body cannot produce itself.

Omega-3 fatty acids are found primarily in cold water fish, including:

• Salmon

• Black cod

• Sablefish

• Sardines

• Herring

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

Unfortunately, most people don't consume enough omega-3 fatty acids through their diet.

That’s why I recommend supplementing with krill oil, a special kind of fish oil that contains the essential omega-3 fatty acids. 

Plenty of research shows that omega-3 supplements are effective at treating clinical depression – just as effective as antidepressants drugs – because they lower inflammation in the brain (6-10). 

Amino Acid Deficiencies That Can Cause Depression

17. Carnitine

Carnitine is an amino acid found in nearly every cell of the body. It plays a vital role in the production of energy.

Researchers have found significantly lower levels of carnitine in patients with depression. And their low carnitine levels are associated with the severity of their depression (11-12, 174-175). 

Carnitine is mainly found in meat, fish and poultry.

But you can also supplement with it. 

I recommend Acetyl-L-Carnitine (ALCAR), an acetylated form of carnitine. It’s best supplemental form of carnitine. 

It’s often used as a natural brain booster because it increases alertness and provides support to brain cells.

But it’s also been shown to be very effective at quickly improving mood and treating depression (179-182). 

Six randomized clinical trials have demonstrated that ALCAR is better at treating depression than placebo (177). 

And two other studies found that ALCAR improved depressive symptoms in patients with chronic depression, and it was just as effective as antidepressant medications, but with less side effects (176, 178). 

ALCAR is included in the Optimal Brain supplement. 

Make sure you read this article to learn more about the remarkable benefits of ALCAR.

18. Glutamine

Glutamine is the most abundant amino acid in the body, suggesting that it’s very important.

It’s also one of the few amino acids that can directly cross the blood-brain barrier.

Glutamine is a conditionally essential amino acid, meaning the body can usually produce sufficient amounts of it. But sometimes the body uses up so much glutamine that it becomes necessary to obtain it from the diet or supplements, particularly during periods of illness, stress, inflammation and injuries (156-157). 

Researchers have found that depressed adults have reduced levels of glutamine (158). 

And glutamine deficiency has been shown to increase depressive-like behaviour in animals (159). 

But glutamine supplementation has “clear anti-depressive properties” and has been shown to improve mood (160-161). 

High levels of glutamine can be found in protein-rich foods such as beef, chicken, fish and eggs. Beets, cabbage, spinach, carrots, parsley, brussel sprouts, celery, kale and fermented foods like miso also contain some glutamine.

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.

Glutamine is also available in supplement form. 

Glutamine was one of the main supplements that helped me heal my leaky gut, but I no longer need to take it regularly. 

19. Tryptophan

Tryptophan is an essential amino acid that cannot be produced by the body. It must be consumed through diet or by taking supplements. 

Some healthy foods that contain tryptophan include bananas, chicken, turkey and dark chocolate (140). 

Tryptophan helps produce the neurotransmitter serotonin. It’s converted to 5-hydroxytryptophan (5-HTP) in the brain, which then produces serotonin (141-142). 

Researchers have found that depressed patients have significantly lower levels of tryptophan in their blood than healthy control subjects (143-144). 

Studies also show that depressed patients have a decreased ratio of tryptophan to neutral amino acids in their blood. This suggests that tryptophan availability to the brain is likely reduced in depressed patients (145-146). 

Personally, supplementing with tryptophan never helped me. In fact, it always seemed to make me worse. It gave me asthma and acne and increased my depression.  

This is because depressed patients sometimes have problems creating serotonin from tryptophan. Instead, they create other metabolites from tryptophan, such as quinolinic acid, which can be toxic. For depressed patients like me, tryptophan supplementation won’t help, and may actually make their depression worse (150-151). 

However, some people do see their mood improve when they increase their intake of tryptophan. So it shouldn’t be completely disregarded. 

There are studies that show that consuming a high tryptophan diet and consuming additional dietary tryptophan can increase mood and lead to significantly less depressive symptoms (152-154). 

So supplementing with tryptophan is worth a shot if you’re struggling with depression and haven’t tried it yet. Just be aware of possible side effects. 

If you want, you can also try supplementing with 5-HTP instead of tryptophan. 5-HTP is the direct precursor to serotonin. 

5-HTP is included in this supplement. 

20. Glutathione

Glutathione is a small peptide made up of 3 important amino acids – glutamic acid, cysteine and glycine – each of which have several important roles in the human body.

Glutathione is found in the food supply and within the human body, where it acts as an antioxidant. It is used by every cell in the body.

It’s technically not an “essential nutrient” because the body can create it.

However, it’s still very important, and a glutathione deficiency leads to increased susceptibility to oxidative stress, which is thought to be involved in a number of diseases, including depression.

Studies show that patients with depression have significantly lower levels of glutathione. And the lower a person’s glutathione levels, the more depressed they are likely to be (162-164). 

Some practitioners and researchers have found that increasing glutathione intake and levels can successfully treat depression (165). 

Glutathione is also able to prevent behavioural depression in animals (166). 

It’s important to note that standard glutathione supplements are not very effective at increasing glutathione levels because they are not well absorbed by the body.

N-acetyl-cysteine (NAC) is a tried-and-true way of increasing glutathione levels because it’s the direct precursor to glutathione. 

Garlic, asparagus, and cruciferous vegetables, such as broccoli and kale, can also help boost glutathione levels, but NAC supplements are more powerful. 

Other supplements that have been shown to help increase and maintain optimal glutathione levels include Selenium, Alpha Lipoic Acid, and S-adenosyl-methionine (Sam-E). 

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Jordan Fallis

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The 25 Best Natural Supplements Proven to Reduce Depression

In this article, I want to share with you my favourite natural supplements for relieving depression.  

Research shows that there are many natural antidepressants that are just as effective as prescription antidepressants, but without adverse effects. 

After I came off medication, I relied on many of them to reduce depression and improve my mood and energy.  

Depression is complex, and there are often numerous underlying root causes.  

But these natural options will support you and prop you up while you seek and resolve the root causes of your depression.  

I’ve tried hundreds of natural supplements over the years, and these are the most effective ones for depression.  

They’ve really helped me, and I’ve seen other people get better with them as well. 

Read on to discover the best evidence-based supplements for treating depression. 

The Best Vitamin and Mineral Supplements For Depression

1. Magnesium

Magnesium is a vital mineral that participates in more than 300 biochemical reactions in your body.  

Unfortunately, a lot of people are deficient in magnesium.  

This is a shame because magnesium is absolutely essential for the proper functioning of your nervous system and optimal neurotransmitter activity. 

Research clearly shows there are links between low magnesium intake, magnesium deficiency, and depression and suicide (26-28, 34-35).  

Several studies also show that magnesium supplementation improves depressive symptoms in people with depression, including people with postpartum depression, premenstrual syndrome, and chronic fatigue syndrome (29-32).  

Sometimes even just one week of supplementing with magnesium can improve mood and reverse symptoms of depression (33).  

Since most people are deficient, magnesium is one of the three supplements that I think everyone should be taking every day. 

Epsom salt baths are another great way to increase your body’s intake of magnesium.  

You should also make sure you’re eating enough magnesium-rich foods on a regular basis, including: 

• Spinach  

• Chard  

• Pumpkin seeds  

• Almonds  

• Avocado  

• Dark chocolate  

• Bananas 

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.  

2. Vitamin D

Vitamin D is a fat-soluble vitamin that your skin synthesizes when exposed to the sun.  

Unfortunately, Vitamin D deficiency is widespread and has become a major global health problem. Researchers estimate that 50% of people are at risk of Vitamin D deficiency. 

This is a huge concern because every tissue in your body has Vitamin D receptors, including the brain, so a deficiency can lead to costly physiological and psychological consequences, including depression. 

Research shows that there is a strong link between Vitamin D deficiency and depression and suicide (36-37).  

Thankfully, several studies shown that Vitamin D3 supplementation reduces depressive symptoms, treats seasonal affective disorder, and lowers suicide risk (38-40).  

Vitamin D helps fight depression because it plays a key role in the production of dopamine and norepinephrine, and protects against the depletion of dopamine and serotonin in the brain (41).  

Ideally, you should get your Vitamin D by going outside and getting sun.  

I try to get sunlight every day during the spring and summer months.  

But most people still don’t get enough Vitamin D from the sun, especially during the winter.  

During the winter months, when there isn't enough sun, I take a Vitamin D3 supplement.

Vitamin D is so critical for optimal brain health, so make sure to check your levels regularly.

If you decide to take a Vitamin D3 supplement, it’s a good idea to take it along with Vitamin K2. They are synergistic and mix well together. 

3. Zinc

Zinc is an essential mineral for mental health, as it plays a key role in neurotransmission and nervous system functioning. 

Unfortunately, it’s estimated that 2 billion people in the world are deficient in zinc, and several studies show that even subclinical zinc deficiency impairs brain function (42-44). 

Researchers have also found that a zinc deficiency increases the likelihood of developing depression, as well as increasing the severity of depression (45).  

But zinc supplementation can definitely help.  

A meta-analysis concluded that taking a zinc supplement is an effective treatment for depression (46).  

In one study, 50 people took 30 mg of zinc for 12 weeks, and their mood significantly improved, and their BDNF levels increased as well (47-49).  

So if you struggle with depression, it’s quite possible you’re deficient, and you’ll want to consider taking a zinc supplement to optimize your levels. 

I created and take the Optimal Zinc supplement to make sure my zinc levels are optimal. I created it because I want to give my clients and readers the very best zinc supplement so that they can experience superior results. I have found that many zinc supplements on the market fall short. Optimal Zinc includes several other nutrients (co-factors) that increase the absorption of zinc. 

Some of the best foods you should eat to optimize your zinc levels include: 

• Oysters  

• Grass-fed beef  

• Pumpkin seeds

• Cashews  

• Mushrooms  

• Spinach 

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health. 

Check out my previous post all about zinc for more steps you can take to increase your zinc levels. 

4. Methylfolate

Folate (Vitamin B9) is an essential B vitamin that plays a key role in methylation, one of the most important processes in your body and brain for optimal energy and nervous system function.  

Researchers have found that if you are depressed, you likely have lower levels of folate circulating in your blood, and people with low blood folate are at greater risk for developing depression (88).  

Good dietary sources of natural folate include: 

• Leafy greens  

• Asparagus  

• Broccoli  

• Cauliflower  

• Strawberries  

• Avocado  

• Beef liver  

• Poultry

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health. 

However, eating folate-rich foods sometimes isn’t enough. In fact, many people don't get enough folate from food because cooking and food processing destroy natural folates (103). 

People with depression often need to supplement with methylfolate to get the full benefits.  

In one study, six months of methylfolate supplementation reduced symptoms of depression in patients with clinical depression and schizophrenia (92).  

Research also shows that taking methylfolate alongside an antidepressant makes the antidepressant more effective (93).  

Researchers have even suggested that folate supplementation should be a first-line treatment for depression (104). 

Methylfolate works because it lowers homocysteine levels, stimulates serotonin receptors in the brain, and plays a key role in the production of dopamine (94-102).  

5. Vitamin B12

“Lack of understanding of B12 is one of the greatest tragedies of modern medicine.”

— Dr. James Greenblatt, Integrative Psychiatrist

Having sufficient levels of Vitamin B12 is necessary for optimal brain and mental health.  

Unfortunately, a deficiency is very common, especially in older individuals and vegetarians and vegans.  

Even if you eat meat and you’re young, you may still have a deficiency.  

Poor gut health and even psychiatric medications can cause a deficiency. 

In fact, it’s estimated that almost 40% of Americans are deficient today. 

Numerous studies have shown that having a deficiency in Vitamin B12 leads to symptoms of depression (136-142). 

But supplementation can help. 

Research shows that supplementing with Vitamin B12 for six weeks can reduce depressive symptoms in depressed patients (143).  

In one study, Vitamin B12 supplementation lowered homocysteine levels and reduced depression in more than 200 people (144).  

If you decide to supplement, avoid the semisynthetic version of B12 (cyanocobalamin) and instead take the methylated form (methylcobalamin or methyl-B12).  

Methyl-B12 is better absorbed and more biologically active. 

Besides methyl-B12 and methylfolate, you should also consider supplementing with the rest of the B vitamins. 

There is evidence to suggest that many people with depression are also deficient in Vitamin B1, B2, B3 and B6, and supplementing with them can help reduce, prevent and lower the risk of depression (145-151).  

Vitamin B12 is also found in animal foods, and beef liver is a really good source. I take beef liver capsules because I don’t like the taste of liver. 

The Best Spices and Herbal Supplements For Depression

6. Rhodiola

Rhodiola, also known as golden root or arctic root, is a Traditional Chinese and Scandinavian herb.  

It’s one of the most popular adaptogens used to increase physical and mental stamina. 

It can also reduce depression (9).  

In one study, rhodiola significantly reduced symptoms of depression and emotional instability in people with mild and moderate depression (7).  

Another study found that it was almost as effective as Zoloft, a commonly prescribed antidepressant, but it was better tolerated and it didn’t cause nearly as many side effects (8).  

Plenty of animal research also shows that rhodiola has antidepressant effects by lowering cortisol, and restoring serotonin, dopamine and norepinephrine (10-16).  

I personally take a rhodiola supplement some of the time. I don't take it every day, only when I need a boost in mood and energy.  

Be sure to check out this post to learn more about the benefits of rhodiola, above and beyond just reducing depression. 

7. Ginseng

Ginseng is known for its anti-stress effects. 

But it also has antidepressant effects (70).  

More than one study has shown that ginseng reduces depression and increases quality of life (71-72).  

Ginseng has been shown to work because it reduces inflammation and increases dopamine, serotonin and BDNF in the brain (73-76).  

Ginseng is one of my favourite herbal supplements for brain function and depression.

8. St. John’s Wort

St. John’s Wort (Hypericum Perforatum) is a natural medicinal herb with antidepressant effects. It's often prescribed for depression in European countries.  

Researchers have concluded that it’s as effective as pharmaceutical antidepressants for treating depression but has fewer adverse effects (105-107). 

A double-blind, randomized control trial showed that St. John’s Wort can prevent depression from developing, and delay relapses in depression (108).  

It's been found to work by increasing dopamine signaling and increasing serotonin receptors (109-111). 

I took a St. John’s Wort supplement years ago for my depression. It helped me, but I eventually stopped taking it and working on fixing the true, underlying causes of my depression instead. 

In my experience, it’s best for people who are struggling with mild or moderate depression.  

It’s important to note that you shouldn’t take St. John’s Wort if you’re already taking antidepressant medication. They don’t mix well.  

9. Ginkgo Biloba

Ginkgo Biloba is a plant that has been used in China for thousands of years to treat a number of health problems. 

It’s one of the top-selling natural supplements in the world, and it’s even a prescription herb in Germany. 

It’s most commonly used to improve brain health because it increases brain blood flow and improves memory, mental energy and attention in both healthy and unhealthy individuals. It even reduces the risk of dementia and Alzheimer’s disease. 

But researchers have also found that Ginkgo Biloba reduces depression in elderly individuals (123-127).  

Ginkgo Biloba is included in the Optimal Brain supplement.

10. Saffron

Saffron is a spice derived from the Crocus sativus plant.  

It has a number of health benefits due to the medicinal compounds within it. 

Researchers have found that saffron is effective at reducing depression in people with mild to moderate depression (127-128).  

More than one study shows that saffron works just as well as SSRI antidepressants, reducing depression without side effects (129-131).  

Saffron has also been shown to inhibit the reuptake of serotonin, dopamine and norepinephrine, similar to pharmaceutical antidepressants (132). 

11. Curcumin

Curcumin is the most heavily researched compound within turmeric, the spice that gives curry its yellow colour.  

It’s one of my favourite natural compounds for the brain. 

Researchers have repeatedly found that curcumin reduces depressive symptoms in patients with major depression (84-86). 

In one study, curcumin reduced depression in more than 100 people after six weeks of supplementation (87).   

It also reduces inflammatory markers and cortisol levels, and increases BDNF levels, all of which are involved in depression (87). 

The Best Amino Acid Supplements For Depression

12. Acetyl-L-Carnitine (ALCAR)

Acetyl-L-carnitine (ALCAR) is an acetylated form of the amino acid carnitine. It’s been shown to have neuroprotective and cognitive-enhancing effects. 

It’s often used as a natural brain booster because it increases alertness and supports brain cells.  

Researchers have found that ALCAR is quite effective at alleviating chronic fatigue, improving mood and treating depression (17-18).  

In one study, supplementing with ALCAR for 1 to 2 months reduced depression in elderly individuals (19). 

And another study showed that ALCAR can reduce depression in people with chronic depression. Twelve weeks of supplementation reduced their depressive symptoms just as effectively as an antidepressant (20).  

It works because it supports mitochondrial function, and increases BDNF levels and serotonin levels in the brain (21-22).  

I find that ALCAR personally gives me a big boost in mood, motivation, mental energy and resilience. 

That’s why I included it in the Optimal Brain supplement. 

Make sure you read this article to learn more about the remarkable benefits of ALCAR.

13. Theanine

Theanine is a unique amino acid found in tea. It has a number of mental health benefits. 

I take theanine alongside my morning coffee. It definitely improves my mood. It also helps me focus and cancels out the jitters of caffeine. 

In one study, theanine supplementation reduced depressive symptoms and anxiety, and improved sleep and cognitive function in patients with major depression (23).  

Animal research also shows that theanine can alleviate depression in mice that are exposed to chronic stress (24).  

This mental health supplement contains theanine, along with several natural compounds that have helped me manage depression and anxiety over the years. 

Theanine can also be found in green tea, which has also been shown to help reduce depression (25). 

14. DL-Phenylalanine

Phenylalanine is an essential amino acid, meaning that your body cannot create it, and you must obtain it from your diet. 

It plays a key role in the production of dopamine, a critical neurotransmitter that can improve your mood (50).  

People struggling with depression have been shown to have low levels of phenylalanine in their blood and urine (55).  

You can find phenylalanine in from protein-rich foods, such as: 

• Chicken  

• Beef  

• Turkey  

• Seafood  

• Eggs  

• Bananas  

• Almonds  

• Avocados  

• Pumpkin seeds  

• Sesame seeds

These foods are included in my Free Grocery Shopping Guide for Optimal Brain and Mental Health. 

But I find that supplementing with DL-Phenylalanine (DLPA), a special supplemental form of phenylalanine, is much more effective than simply eating foods with phenylalanine. 

In one study, 23 depressed patients took DLPA every day for 15 days. At the end of the 15 days, 17 of them had completely overcame their depression, and they didn't experience adverse side effects (51).  

Another 3-week study found very similar results (52).  

Researchers have even concluded that DLPA is just as effective as prescription antidepressants. And people who don’t respond to pharmaceutical antidepressants often get significantly better when they take DLPA (53-54).  

Even if you take medication, research shows that combining DLPA with antidepressants leads to greater increases in mood than simply taking an antidepressant alone (56).  

Yet unlike antidepressants, you can feel the effects of DLPA quickly (within a few hours) and in some cases, it can “terminate depression within 2 to 3 days” (57). 

Not surprisingly, I absolutely love DL-Phenylalanine. It was probably the most important supplement that I took while I transitioned off of antidepressants. 

If you’d like to learn more about DLPA, read this post. 

15. N-Acetyl-Cysteine (NAC)

N-Acetyl-Cysteine (NAC) is a modified form of the amino acid cysteine.  

It’s also the precursor to glutathione, your body’s master antioxidant. 

Nowadays, we’re exposed to so many environmental toxins, which cause oxidative stress in the body and deplete our reserves of cysteine and glutathione.  

But supplementing with NAC can increase and normalize your cysteine and glutathione levels. 

This can combat and reduce oxidative stress in your brain, which can then help treat several mental illnesses, including depression.  

In one study, 149 people with moderate depression were given NAC or placebo for eight weeks. The individuals who received NAC experienced a significant reduction in their depression, as well as improvements in their overall functioning and quality of life (58).  

In another six-month study, NAC significantly reduced symptoms of depression in patients with bipolar disorder. It also significantly improved their social and occupational functioning. The researchers concluded that NAC is a safe and effective strategy for depressive symptoms (59).  

Several other studies have examined the effects of NAC on bipolar disorder and found that taking NAC daily can significantly improve and even cause a full remission of depressive symptoms (60-62).  

16. S-adenosyl-L-methionine

S-Adenosyl-l-methionine (SAM-e) is a compound that naturally occurs in the body.  

It’s also available as a supplement.  

It’s most commonly used for treating depression because lowered SAM-e levels are associated with depression. 

Researchers have concluded that SAM-e is an effective and safe option for the treatment of depression. It has beneficial effects similar to conventional antidepressants (77-78, 82-83).  

In one study, people who hadn't responded to SSRI antidepressants took SAM-e for six weeks, and it significantly reduced their symptoms of depression (79).  

In another study, 20 healthy individuals received infusions of SAM-e or a placebo for seven days. The researchers scanned and studied the brains of the participants during the study. And it was confirmed that SAM-e is an antidepressant because it targets and supports brain regions involved in depression (81).  

It has also been shown to increase serotonin and dopamine activity in the brain, and inhibit the reuptake of norepinephrine (80).  

The great thing about SAM-e is that it works fairly quickly, as people usually notice benefits within the first few days of taking it, and it doesn’t cause severe side effects like pharmaceutical antidepressants (83).  

I took a SAM-e supplement after coming off psychiatric medication and it significantly helped me by improving my mood and energy.

17. Sarcosine

Sarcosine is an amino acid derivative that is naturally found in egg yolks, turkey, ham, vegetables and legumes. 

Supplementing with sarcosine has been shown to significantly reduce symptoms of depression without side effects (116, 119).  

In one study, sarcosine was found to be significantly more effective at treating major depression than citalopram (a common SSRI antidepressant). 

Patients who received sarcosine were much more likely to improve, improved much more quickly, and were less likely to drop out of the study than patients that received citalopram (117).  

Animal research also shows that sarcosine has antidepressant effects (118).  

You’ll have to supplement with sarcosine for it to improve your mood. The amount of sarcosine in food is too small to have a beneficial effect. 

It has impressive antidepressant and anti-anxiety effects, but without any of the nasty side effects that are common with pharmaceutical antidepressants and benzodiazepines.  

18. Phosphatidylserine

Phosphatidylserine is a fat-soluble amino acid that is known to support cognitive function.  

High amounts of phosphatidylserine are in the brain, and supplementation has been shown to improve attention, learning and memory. 

But researchers have also found that phosphatidylserine can also reduce depression. 

In one study, supplementing with phosphatidylserine induced consistent improvement of depressive symptoms, memory and behaviour in elderly individuals with depression (121).  

Animal research also shows that phosphatidylserine has antidepressant effects. In fact, the antidepressant effects are more prominent in rats than the cognitive-enhancing effects (122).  

I personally take phosphatidylserine every day. It's included in the Optimal Brain supplement. 

Make sure you read this article to learn more about the remarkable benefits of Phosphatidylserine.

The Best Food-Based Supplements For Depression

19. Omega-3 Fatty Acids

Omega-3s fatty acids are the highest quality fats for the brain and increasing your intake of them is one of the most impactful actions you can take to promote the normal functioning of your brain and nervous system. 

They have been shown in many studies to significantly reduce brain inflammation; improve memory, mood and cognition; and protect against mild cognitive impairment, dementia and Alzheimer's disease. 

Researchers have also found that levels of omega-3 fatty acids are significantly lower in individuals with depression (63-64).  

It’s important to consume enough omega-3 fatty acids because they are essential fats that your body cannot produce itself. 

Omega-3 fatty acids are found primarily in cold water fish, including: 

• Salmon  

• Black cod  

• Sablefish  

• Sardines  

• Herring 

These foods are included in my Free Grocery Shopping Guide for Optimal Mental Health.  

Unfortunately, most people don't consume enough omega-3 fatty acids through their diet. 

That’s why I recommend supplementing with krill oil, a special kind of fish oil that contains the essential omega-3 fatty acids.  

Studies show that omega-3 fatty acid supplements are effective at treating clinical depression. They also improve mood in people who haven’t been diagnosed with depression, but have depressive symptoms (65-66. 68-69).  

One way they work is by reducing inflammation in the brain, which is strongly linked to depression (67).

Make sure you also check out this article for 22 other effective ways to reduce inflammation in the brain.

20. Probiotics

As you probably already know, the health of your gut (and the bacteria within it) significantly influence your brain and mental health.  

In fact, people who have been diagnosed with gut diseases are more likely to be diagnosed with depression (1).  

But luckily, there’s a solution. 

High-quality research shows that probiotic supplements can significantly reduce depressive symptoms in both healthy and depressed individuals (2-4).  

Studies also show that the neurotransmitter serotonin is produced in the gut.  

By taking a probiotic supplement, you can enhance the diversity of the bacteria in your gut, create a better environment for the synthesis of serotonin, and therefore increase serotonin levels and activity in your brain (5).  

Probiotics also reduce inflammation, which tends to be elevated in people with depression (6).  

The best probiotics for depression are Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium bifidum, and Lactobacillus casei. 

All five of them are included in the Optimal Biotics supplement.  

Check out this post for five other ways to increase the good bacteria in your gut.  

And if you struggle with anxiety, here are 9 probiotic strains that can help. 

21. Uridine

Uridine is a natural compound commonly found in beer.  

I definitely don’t recommend drinking beer, but supplementing with pure uridine can protect the brain, enhance cognition, and increase mood and motivation. 

Uridine supplementation has been shown to reduce depression in young people with bipolar disorder (113).  

Animal studies also show that uridine supplements alleviate depression and increases dopamine in the brains of rats (114-115).  

It’s important to note that uridine in food is not bioavailable, and no food has been shown to increase blood levels of uridine (112). 

So you’ll need to supplement with it.

22. Lion’s Mane Mushroom

Hericium Erinaceus – better known as lion’s mane mushroom – is an edible mushroom with numerous health benefits.  

It’s another one of my favourite supplements for brain health because it reduces inflammation and has antioxidant effects. 

One study found that it reduced depression in 30 women after 4 weeks of supplementation (120).  

This lion’s mane mushroom supplement is the highest-quality that I could find. I spent a lot of time researching and looking into different sources because not all lion's mane supplements are high-quality and effective, and I settled on this one.  

The Best Hormonal Supplements For Depression

23. Melatonin

Melatonin is a hormone released by your pineal gland, a small gland in your brain. You can also take it as a supplement.  

It helps control your circadian rhythm, and adequate levels of melatonin are necessary to fall asleep quickly and sleep deeply throughout the night. 

Researchers have found that people with depression often have low levels of melatonin and a compromised circadian rhythm (257-259). 

Studies also show that supplementing with melatonin at bedtime can lower symptoms of depression. It can also improve the circadian rhythm of various neurotransmitters that are disturbed in people with depression (260-261).  

This sleep supplement contains magnesium and a number of other natural compounds that I’ve used over the years to promote the production of melatonin.

But I work with my clients so that they can naturally produce more melatonin and maximize the quality of their sleep without so many supplements. We have free online workshop that talks about how you can work with us. You can register for the workshop here.

24. Pregnenolone

Pregnenolone is a steroidal hormone naturally manufactured by the body, but it can also be taken as a supplement.  

It’s the precursor to almost all other steroid hormones, including DHEA, progesterone, testosterone, estrogens, and cortisol.  

It’s been shown to enhance memory and reduce fatigue. 

But researchers have found that it can also reduce depression.  

Depressed patients often have low pregnenolone levels, but replenishing pregnenolone levels with supplementation significantly reduces symptoms of depression (133-135).  

Whenever I take pregnenolone, it gives me a big boost in brain function and mental energy. It definitely has an effect. But it doesn’t really improve my mood. In fact, if I take it every day, it starts to make me irritable. So I save it and only take it when I need it.   

Plenty of other people have excellent, consistent results with it though. 

25. Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is one of the most abundant circulating steroid hormones in humans. It’s produced in the adrenal glands, the gonads, and the brain, and it’s a precursor to other hormones, including estrogen and testosterone. 

It's also available as a supplement. 

Research shows that low DHEA levels are significantly associated with increased depressive symptoms, and low DHEA levels are often found in depressed patients (270-271).  

And in multiple studies, supplementing with DHEA has been shown to improve mood and reduce depression (272-273).  

Researchers have found that it works because it impacts the activity of several neurotransmitters involved in depression, including dopamine, serotonin and GABA (274).  

26. BONUS: Other Natural Supplements That Can Reduce Depression

Here are numerous other natural supplements that have also been shown to reduce depression and improve mood in humans.

I didn’t include them in the main list because they aren’t my favourite “go-to” solutions for depression.

Plus, they can be “hit-and-miss” and don’t always work for everyone in every situation.

But research still shows they can be quite effective, so they’re worth considering and giving a shot.  

• Tryptophan and 5-HTP (264-269) 

• Valerian (152-155) 

• Lemon Balm (156-158) 

• Kava (159-165) 

• Inositol (166-173) 

• Creatine (174-184) 

• Lavender (185-189) 

• Apigenin, a flavonoid in Chamomile and Bacopa (190-201) 

• Berberine (202-205) 

• Holy Basil (206-207) 

• Coenzyme Q10 (208-209) 

• Lithium orotate (210-211) 

• Ashwagandha (212-213) 

• Agmatine (214-219) 

• Hops (220) 

• Borage Oil (221-222) 

• Vitamin C (223-226) 

• Maca (227)  

• Iron (228) 

• Selenium (229-230) 

• Glutamine (231-232) 

• Trimethylglycine (233-235)

Enjoy This Article? You Might Also Like My FREE Food Guide for Optimal Brain and Mental Health!

CLICK HERE TO DOWNLOAD THE FREE GUIDE

Live Optimally,

Jordan Fallis

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14 Remarkable Benefits of Alpha GPC + Dosage & How To Take It

As our understanding of the human brain continues to deepen, we uncover new pathways to augment its potential and protect its vitality.

One such groundbreaking discovery is Alpha GPC.

Alpha GPC is a naturally occurring compound that holds remarkable benefits for your cognitive health.

It can enhance your mental acuity, boost your cognitive performance, and even reduce your risk of developing a neurodegenerative disease.

Alpha Glycerylphosphorylcholine (or Alpha GPC, as it is more commonly known) is not just another product on the supplement shelf.

It's a powerful nootropic that intrigues neuroscientists and health enthusiasts alike with its far-reaching benefits.

Alpha GPC has something to offer everyone.

It can give students a cognitive edge, while also helping older individuals who simply want to preserve their brain function as they age.

In this article, we’ll embark on a journey to better understand Alpha GPC.

I’ll explore the compelling research behind it.

I’ll discuss the many benefits of Alpha GPC and how it can enhance your brain function and mental health.

I’ll then talk about how to take it and the optimal dosage of Alpha GPC.

Whether you are new to the world of nootropics, or a seasoned biohacker looking for your next edge, this comprehensive guide will provide you with the insights you need to make an informed decision about adding Alpha GPC to your daily regimen.

Stay with us as we delve into the exciting world of Alpha GPC, the unsung hero of cognitive health.

Let's begin!

What Is Alpha GPC?

Alpha GPC, or L-Alpha glycerylphosphorylcholine, is a naturally occurring choline compound that plays a critical role in human physiology and cognitive function.

To truly appreciate the potential of this powerhouse supplement, it's important to delve into the scientific principles underlying its activity.

Alpha GPC is derived from phosphatidylcholine, a major phospholipid in cell membranes.

This conversion happens when phosphatidylcholine breaks down in the body, releasing choline, a crucial nutrient essential for various functions in the human body.

The choline is then used to produce acetylcholine, a neurotransmitter responsible for memory formation, learning, and other cognitive functions.

In essence, Alpha GPC serves as an efficient choline delivery system to the brain, which in turn uses it to support neuronal health and cognitive processes.

How Does Alpha GPC Work in the Brain?

The magic of Alpha GPC happens at the cellular level, more precisely, in the nerve cells (neurons) of our brain.

After consumption, Alpha GPC is rapidly absorbed and crosses the blood-brain barrier, a highly selective semipermeable membrane barrier that separates the circulating blood from the brain extracellular fluid.

Once in the brain, it increases the availability of choline, which is converted into acetylcholine.

Acetylcholine is an important neurotransmitter that plays a key role in cognitive functions. I previously wrote about it here.

Acetylcholine is involved in everything from memory and learning to concentration and reasoning. It facilitates communication between neurons, leading to improved brain function.

Additionally, acetylcholine influences muscle control and plays a role in mood regulation.

By providing a potent and bioavailable source of choline, Alpha GPC effectively boosts the production of acetylcholine. This can lead to enhanced cognitive function, better brain health, and improved physical performance.

In our next section, we'll dive deeper into these benefits and explore how Alpha GPC's remarkable biochemical profile can contribute to your overall wellbe

14 Proven Benefits of Alpha GPC (Glycerylphosphorylcholine)

1. Alpha GPC Enhances Memory and Learning

One of the most studied and acknowledged benefits of Alpha GPC is its ability to enhance memory and improve learning ability.

Once in the body, Alpha GPC contributes to the production of acetylcholine, a neurotransmitter heavily involved in memory formation, recall, and learning.

Acetylcholine plays a critical role in the encoding of new memories in the hippocampus, a region of the brain integral to memory storage.

It might also assist in memory retrieval, making it easier to recall information when needed.

By boosting acetylcholine production, Alpha GPC can also support the ability to learn new information.

Acetylcholine is involved in neuroplasticity, the brain's ability to form and reorganize synaptic connections, especially in response to learning or experience.

Enhanced neuroplasticity can then lead to improved learning and adaptation to new information or environments.

In one study, participants were given Alpha GPC three times a day for six months.

Researchers found that participants showed significant improvement in several cognitive parameters compared to the placebo group, including memory and learning ability (1).

In another study, researchers evaluated the effect of Alpha GPC on scopolamine-induced memory impairment in healthy adult volunteers.

Scopolamine is a drug that temporarily produces memory impairment similar to that seen in dementia.

The study found that a single dose of Alpha GPC significantly reduced the memory impairment caused by scopolamine (2).

2. Alpha GPC Improves Focus and Concentration

Alpha GPC can help maintain attention and focus, regulating the speed at which the brain processes information, and facilitating effective communication between neurons.

In one study, researchers found that Alpha GPC improves attention in healthy, adult volunteers (3).

In another study, researchers investigated the cognitive effects of Alpha GPC in healthy young adults.

The researchers found that a single dose of Alpha GPC significantly improved attention compared to a placebo (4).

Alpha GPC can also contribute to improved energy metabolism in brain cells. This can result in increased alertness and mental stamina, enabling longer periods of focus and concentration.

3. Alpha GPC Is Neuroprotective

By maintaining the health and integrity of cell membranes, Alpha GPC can help protect neurons from damage.

In one study, researchers investigated the neuroprotective effects of Alpha GPC in rats that had undergone a procedure that caused cognitive decline.

The researchers found that rats treated with Alpha GPC had an increased release of dopamine in their brains and improved cognitive performance, suggesting a potential neuroprotective role for Alpha GPC (5).

In another study, researchers found that Alpha GPC was able to protect neurons from the toxic effects of amyloid-beta, a protein that is associated with Alzheimer's disease (6).

4. Alpha GPC Helps With Stroke Recovery

Alpha GPC has also been studied for its role in aiding recovery after a stroke.

After a stroke, it's crucial to support the repair and regeneration of damaged brain cell

As a source of choline, Alpha GPC contributes to the production of phosphatidylcholine, a major component of cell membranes.

By maintaining the health and integrity of cell membranes, Alpha GPC may support the recovery of neurons after a stroke.

Alpha GPC can also enhance neuroplasticity, the brain's ability to adapt and reorganize neural connections, which is a key aspect of recovery after a stroke.

Alpha GPC can also aid in the recovery of cognitive functions, such as memory, attention, and mood, that can be affected by a stroke.

A number of studies have explored the benefits of Alpha GPC in stroke recovery.

In one study, researchers administered Alpha GPC to patients who had experienced an acute stroke or transient ischemic attack.

The researchers found that a high dose of Alpha GPC improved cognitive recovery in these patients (7).

Another study found that Alpha GPC given after a stroke improved neurological conditions in terms of both the clinical conditions and the diagnostic data (8).

5. Alpha GPC Helps With Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease

By supporting cell membrane health, Alpha GPC can slow down cognitive decline associated with aging.

Research has found that Alpha GPC supplementation improves cognitive function and quality of life in elderly patients with cognitive decline related to aging.

Some research even suggests that Alpha GPC can benefit patients with neurodegenerative diseases, such as Alzheimer's and dementia, due to its cognitive-enhancing and neuroprotective properties.

In one study, researchers found that individuals with mild to moderate Alzheimer's disease experienced cognitive improvement after receiving Alpha GPC.

Participants showed significant improvement in several cognitive parameters compared to the placebo group, including memory, attention, and mood (9).

6. Alpha GPC Improves Mood and Helps With Depression

Alpha GPC could also help improve mood and manage depressive symptoms.

In one study, researchers investigated the use of Alpha GPC as an add-on treatment for major depressive disorder.

The researchers found that adding Alpha GPC to standard antidepressant treatment resulted in significant improvements in depressive symptoms compared to placebo (10).

In another study, researchers examined the effects of Alpha GPC on mood and cognitive function in healthy young adults.

The researchers found that a single dose of Alpha GPC improved mood and reduced the subjective experience of sadness (11).

7. Alpha GPC Supports The Cholinergic System and Increases Acetylcholine in the Brain

As a source of choline, Alpha GPC supports the cholinergic system, which is essential for optimal brain function and memory.

Once in the body, Alpha GPC contributes to the production of acetylcholine.

Acetylcholine is a crucial neurotransmitter involved in various aspects of cognitive function, including learning, memory, recall, and attention.

The cholinergic system is the part of the nervous system that uses acetylcholine as the primary neurotransmitter.

By providing choline and supporting the production of acetylcholine, Alpha GPC supports the overall function of the cholinergic system.

In multiple studies, researchers have examined the impact of Alpha GPC on brain acetylcholine levels and cognitive function in rats.

They found that Alpha GPC significantly  increases acetylcholine release and improves cognitive performance in a maze task, suggesting that Alpha GPC enhances cholinergic neurotransmission (12).

Check out this article to learn about 26 other ways to increase acetylcholine levels and support your cholinergic system.

8. Alpha GPC Supports Cell Regeneration

Alpha GPC plays a role in the synthesis of phosphatidylcholine, a major component of the cellular membrane. 

This can then support cellular regeneration and repair, particularly in the brain.

Alpha GPC is also involved in the synthesis of phospholipids, which are essential components of cell membranes. 

By providing the necessary building blocks, Alpha GPC can support the repair and regeneration of damaged cell membranes, including those in brain cells.

Alpha GPC has also been shown to have neuroprotective properties. 

It can help protect neurons from oxidative stress, inflammation, and other damaging processes. 

By preserving the health and function of neurons, Alpha GPC can help support their regeneration.

Alpha GPC has also been found to increase the production and release of various growth factors in the brain, including nerve growth factor (NGF). 

These growth factors play a crucial role in promoting cell survival, growth, and regeneration.

Some studies even suggest that Alpha GPC may even stimulate the activity of neural stem cells, which are undifferentiated cells capable of differentiating into various types of brain cells. 

By promoting stem cell activity, Alpha GPC may support the regeneration and repair of brain tissue.

9. Alpha GPC Helps With Addiction and Substance Abuse Recovery

Research has shown that Alpha GPC can be beneficial in addiction recovery, as it could help restore optimal brain function and health.

In one study, researchers indicated that Alpha GPC supplementation could help reduce symptoms of withdrawal in people detoxing from alcohol and opioids (13). 

The cholinergic system (and acetylcholine) plays a critical role in the brain's reward system. 

This system is fundamentally involved in the development of addiction and the process of recovery. 

Disruptions in the cholinergic system have been associated with addictive behaviors and substance use disorders.

Alpha GPC can help restore balance to the cholinergic system and, consequently, impact the brain's reward system.

10. Alpha GPC Supports Healthy Sleep Patterns

Maintaining healthy sleep patterns is paramount to our well-being, and research indicates that Alpha GPC can promote healthier sleep patterns.

Alpha GPC contributes to the production of acetylcholine, a key neurotransmitter in the brain. 

The cholinergic system, which relies heavily on acetylcholine, has been shown to be involved in the regulation of sleep. 

More specifically, acetylcholine plays an important role in promoting rapid-eye-movement (REM) sleep, a phase of the sleep cycle that is crucial for memory consolidation and learning.

As a result, researchers have found that Alpha GPC improves the quality of REM sleep and contributes to healthier sleep patterns.

11. Alpha GPC Reduces Inflammation in the Brain

Inflammation is a normal immune system response to injury or infection. 

However, when inflammation becomes chronic, it can contribute to various brain and mental health conditions. 

Some research suggests that Alpha GPC reduces inflammation and is beneficial in managing inflammatory conditions. 

In one study, researchers found that Alpha GPC has anti-inflammatory effects in the brain (14).

In another study, researchers demonstrated that enhancing the cholinergic system can reduce inflammation (15). 

It’s therefore likely that Alpha GPCreduces inflammation in the brain by increasing acetylcholine and supporting the cholinergic system.

12. Alpha GPC Increases Dopamine and Motivation

Motivation fuels our drive to achieve goals and tackle everyday tasks. 

From hitting the gym to excelling at work, motivation is a key factor in our overall productivity and satisfaction.

Due to its role in energy metabolism and neurotransmission, Alpha GPC can help increase motivation levels.

Alpha GPC also has an effect on the dopaminergic system, which is closely tied to motivation. 

Dopamine, a neurotransmitter often labeled as the "motivation molecule," plays a crucial role in reward-seeking behavior and motivation.

Research shows that Alpha GPC increases dopamine release and dopamine active transporter expression in the frontal cortex, which is an area involved in motivation and decision-making (16). 

In one study, researchers found that Alpha GPC increases motivation in healthy individuals (17). 

13. Alpha GPC Improves Reaction Time

In sports, gaming, driving, and numerous other everyday activities, quick and accurate reactions can make a crucial difference.

Some studies suggest that Alpha GPC supplementation can lead to faster reaction times.

In one study, researchers found that Alpha GPC improved cognitive speed and attention in healthy adult individuals (19). 

Another study found that it improved reaction time in athletes (18). 

14. Alpha GPC Helps With Autism Spectrum Disorders

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by difficulties with social interaction, communication, and repetitive behaviors.

Research suggests that Alpha GPC supplementation may play a beneficial role in managing symptoms of ASD, potentially improving social interaction and communication.

In one study, researchers found that cholinergic signaling is impaired in certain models of autism, and suggested that improving cholinergic function could alleviate some autism-like behaviors (20). 

Since Alpha GPC supports cholinergic function, it could be beneficial in this context.

Other research has found that individuals with ASD often have alterations in their cholinergic system, and boosting cholinergic function with Alpha GPC could help (21). 

Who Can Benefit from Alpha GPC?

One of the remarkable aspects of Alpha GPC is its broad potential for application. 

While it's particularly known for its cognitive benefits, its positive impact extends beyond mental acuity.

Below are various groups who could find Alpha GPC beneficial.

Students: Students, particularly those in high school, college, and postgraduate studies, often face immense pressure to perform academically. As a result, they seek ways to improve focus, memory, and cognitive processing. Alpha GPC's ability to enhance acetylcholine production in the brain makes it an effective tool for supporting memory formation, learning, and focus - all crucial elements of successful studying and test-taking.

Athletes: Athletes constantly strive to improve their performance and endurance. Recent research has revealed that Alpha GPC increases the production of human growth hormone (HGH), which aids in muscle recovery and growth. Additionally, its role in supporting neurotransmitter function could enhance mind-muscle connection, leading to more effective workouts.

Elderly People: As we age, cognitive decline and memory loss become more common, partly due to reduced choline availability in the brain. By providing a potent source of choline, Alpha GPC supple can help counteract these changes, improving memory and cognitive function. Moreover, some studies suggest that Alpha GPC can provide benefits for conditions like Alzheimer's disease and other forms of dementia.

Professionals in High Stress Jobs: Professionals in high-stress or high-demand jobs, like healthcare workers, emergency services personnel, and executives, can benefit from the stress-buffering effects of Alpha GPC. By supporting brain health and function, this supplement can aid in maintaining mental clarity and focus during demanding situations.

Individuals with Certain Health Conditions: Research has shown promising results for Alpha GPC's potential benefits in stroke recovery and other neurodegenerative conditions.

The Best Alpha GPC Supplement and How To Take It

Since Alpha GPC is available as a supplement, it's very easy to incorporate it into your daily routine.

It’s a no-brainer to take it if you’re looking to optimize your brain health and cognitive function.

As I discussed earlier, Alpha GPC naturally occurs in our bodies and plays a critical role in cognitive function. 

So, why is there a need for it as a supplement? 

The answer lies in optimization. 

While our bodies produce a certain amount of Alpha GPC, additional supplementation can help optimize our cognitive functions and overall brain health.

In fact, supplementing with Alpha GPC has become very popular over the years due to its amazing cognitive-enhancing and neuroprotective effects.

Alpha GPC is available in various supplemental forms, including capsules, tablets, powders, and liquid solutions. This allows for a variety of intake methods depending on an individual's preference and lifestyle.

Alpha GPC is typically derived from soy or sunflower lecithin. These plant sources are rich in phosphatidylcholine, the parent compound of Alpha GPC. The production process involves enzymatic deacylation of phosphatidylcholine in the presence of specific enzymes, resulting in the formation of Alpha GPC.

Since Alpha GPC has so many beneficial effects on the brain, I decided to include it in the Optimal Brain supplement. 

You can get Optimal Brain here.

Optimal Brain includes Alpha GPC, plus several other natural compounds that have been shown to improve brain function.

Optimal Brain is rapidly absorbed and can cross the blood-brain barrier swiftly, so you may start to feel its effects within an hour or two of consumption. 

Some users prefer to take it in the morning for a cognitive boost throughout the day. 

Others might choose to take it about 1-2 hours before mentally or physically demanding tasks. 

Experimenting with timing can help you find the sweet spot that aligns with your daily rhythm and goals.

Recommended Dosage For Alpha GPC

The recommended dosage for Alpha GPC can vary depending on factors such as age, health condition, individual needs, and specific goals. 

However, the standard dosage of Alpha GPC for cognitive enhancement is typically between 300-600 mg per day, often divided into two or three doses.

The Optimal Brain supplement includes just 200 mg of Alpha GPC. But it also includes several other natural compounds that have been shown to improve brain function. These ingredients work synergistically with Alpha GPC. Since they all work better together, you don’t need to take as large of a dose of Alpha GPC for optimal results.

You can get Optimal Brain here.

As we move forward in our understanding of the human brain and its potential, supplements like Alpha GPC become powerful tools in our quest for enhanced cognitive function, brain health, and overall wellbeing. 

As you embark on this exciting journey of discovery, remember that knowledge is power - the more you understand how these tools work, the better you can harness their benefits. 

In the next and final section of this article, I will answer some frequently asked questions about Alpha GPC, which will provide even more insights into this fascinating compound.

Frequently Asked Questions about Alpha GPC

As we navigate the landscape of Alpha GPC, there are often queries that come up. 

Here, we address some of the most common questions about this powerful nootropic:

1. How long does it take to feel the effects of Alpha GPC?

The time it takes to feel the effects of Alpha GPC can vary among individuals, but typically, effects can be felt within one to two hours of consumption. 

Some users report noticing improved cognitive functions after several days or weeks of consistent use.

2. Can I take Alpha GPC every day?

Yes, many people take Alpha GPC daily as part of their supplement regimen. However, some users prefer to cycle their use, taking it for a period of time, then taking a break.

3. Is it better to take Alpha GPC with or without food?

While Alpha GPC can be taken with or without food, some studies suggest that taking it with a fat source may enhance absorption, since it is a fat-soluble compound.

4. Can I take Alpha GPC if I am pregnant or breastfeeding?

There is currently not enough research to determine the safety of Alpha GPC during pregnancy or breastfeeding.

Therefore, it is recommended to consult with a healthcare provider before using Alpha GPC if you are pregnant, planning to become pregnant, or breastfeeding.

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Live Optimally,

Jordan Fallis

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(12) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235064/ 

(13) https://pubmed.ncbi.nlm.nih.gov/4116781/ 

(14) https://pubmed.ncbi.nlm.nih.gov/24682350/ 

(15) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651192/ 

(16) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235064/ 

(17) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235064/ 

(18) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650143 

(19) https://pubmed.ncbi.nlm.nih.gov/21156078/ 

(20) https://pubmed.ncbi.nlm.nih.gov/24096295/ 

(21) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8858939/

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