DEPRESSED? THESE EVIDENCE-BACKED SUPPLEMENTS CAN HELP!

7 SUPPS FOR DEPRESSION: TYROSINE, GLUTAMINE,

PEA, SAM-E, MUCUNA, ST. JOHN’S WORT, VITAMIN D

For those with low excitatory NTs and who are dealing with depression, I generally suggest they start by considering tyrosine and/or glutamine supplements, depending on the details of their lab results. If lab testing hasn’t been done but assessment results and symptoms strongly suggest low excitatory NTs, I usually suggest starting with tyrosine (a dopamine-booster) and then moving on to glutamine (a glutamate-booster) if needed.



TYROSINE: THE DOPAMINE-BOOSTER

Tyrosine, one of the 20 protein-building amino acids, is a precursor to the excitatory NT dopamine, which itself is a precursor to the excitatory NTs epinephrine and norepinephrine. Low levels of any of these 3 NTs can lead to symptoms of depression. [61-63]


Dozens of studies over the past several decades have demonstrated the positive effects of tyrosine supplementation on depression as well as cognitive performance when under stress. For those battling depression and low mood where low levels of dopamine, epinephrine and/or norepinephrine are suspected, I generally recommend starting at 1-3g/day of tyrosine, taken first thing in the morning. That said, many clinical studies use dosages of 7-14g/day, and doses of up to 20g/day have been used with good results and no adverse effects. [64-73]


GLUTAMINE: ELEVATING LEVELS OF GLUTAMATE

After tyrosine (with its dopamine, epinephrine and norepinephrine-boosting qualities), the next depression-combating supplement I generally look at is glutamine. Much of the clinical research on glutamine is focused on its ability to promote healthy intestinal barrier functioning. Intestinal hyperpermeability (aka “leaky gut”) is a common occurrence in digestive disorders, autoimmune conditions and arthritis (among other conditions). Glutamine, the most prevalent amino acid in the body, also plays a major role in reducing excess ammonia build up in the body’s soft tissues. [74-76]


As we already discussed, the amino acid glutamine can also increase the body’s supply of glutamate, one of the chief excitatory neurotransmitters. An increasing amount of scientific evidence is showing that, in many cases of depression, the glutamatergic system is a primary mediator of psychiatric pathology. A 2007 study in the journal Archives of General Psychiatry found depressed patients had reduced glutamine/glutamate levels in the prefrontal brain regions. [77-79]


And listen to the authors of a study in the December 2018 edition of the journal Neuropharmacology...


"Emerging evidence has shown the low levels of glutamate and glutamine hypoactivity in the cortex of patients with depression. Expectedly, glutamine supplementation showed antidepressant effects. Depressive behaviors evoked by chronic stress were due to hypoactive glutamatergic neurons in the medial prefrontal cortex, caused by low levels of glutamine. Exogenous (supplemental) glutamine can be used as an alternative antidepressant to increase glutamatergic neurotransmission." [80]


Dosage-wise, I generally recommend adults start at 5-10g of glutamine a day, taken in the morning. Clinical studies have shown that up to 40g/day have been safely tolerated, with good results.


PHENYLALANINE: THE DOPAMINE,

EPINEPHRINE & NOREPINEPHRINE BOOSTER

Your body naturally converts phenylalanine (an essential amino acid) into tyrosine (a conditionally essential amino acid), which is then converted into L-DOPA, which is then used to make the excitatory neurotransmitter dopamine. [81]


Phenylalanine is also used by the body to make phenylethylamine (PEA). PEA is a neurotransmitter itself and has also been shown to support the activity of excitatory NTs like dopamine, norepinephrine and epinephrine (as well as serotonin). Several scientific studies (many from the 1980s and 1990s) demonstrated the relationship between PEA and depression, including…


* A 1986 study found that low plasma and urinary PEA was associated with depression, and that phenylalanine supplementation elevated mood in 31 of 40 people with depression.

* A 1995 review found that PEA promotes energy and elevates mood, and that one of the main metabolites of PEA is decreased in the biological fluids of those with depression. Supplementation of phenylalanine improves mood in depressed patients.

* A 1996 study found that PEA increases attention and activity in animals and that supplementation of phenylalanine has been shown to relieve depression in 60% of depressed patients (indicating that PEA deficiency may be a common cause of depressive illness). [82-84]


Free form amino acid supplements (like phenylalanine) are sometimes available in both D and L forms. While L forms are generally more easily utilized by humans, phenylalanine is one of the few amino acids that can be utilized in its D form. Thus you will see both L-phenylalanine (LPA), D-phenylalanine (DPA) and DL-phenylalanine supplements available (DLPA). DL is usually a 50/50 combination of D and L forms of the amino acid.


For those dealing with depression I generally recommend starting with one 500-1000mg dose, taken first thing in the morning. Common dosages reach up to 2g/day, and doses as high as 6g/day have been used in clinical studies.



SAM-e: THE MASTER METHYL DONOR

THAT BOOSTS NEUROTRANSMITTER FUNCTION

S-adenosyl-methionine (aka SAM-e, pronounced "sammy") is a form of the sulfur containing amino acid methionine. SAM-e is a master methyl donor. What's a methyl donor you ask? A methyl donor is a chemical (or nutrient) that will readily donate a methyl group to another substance. SAM-e performs this essential process of delivering its methyl groups to substances like hormones, enzymes, DNA and neurotransmitters exceptionally well! Without this process (termed "the methylation cycle") substances like neurotransmitters wouldn't be able to carry out their function.


SAM-e, with its excellent methyl-donating properties, has been clinically shown to boost excitatory neurotransmitters like dopamine and norepinephrine (as well as serotonin). It shouldn't come as a surprise then that several studies have demonstrated SAM-e's ability to improve symptoms of depression, including a 2002 review from The American Journal of Clinical Nutrition that found that...


* "At doses of 200-1600mg/day, SAM-e is superior to placebo and is as effective as tricyclic antidepressants in alleviating depression"


* "SAM-e may have a faster onset of action than do conventional antidepressants"


* "SAM-e may also protect against the deleterious effects of Alzheimer's disease"


* "SAM-e is well tolerated and relatively free of adverse effects"


* "SAM-e appears to be safe and effective in the treatment of depression" [85-88]


A common dosage protocol for SAM-e for adults is 400-800mg in the morning and then the same dose in the evening. While many studies cap dosages at 1600mg/day, dosages as high as 3600mg/day have been taken with good results and no adverse effects.


MUCUNA PRURIENS/VELVET BEAN:

A NATURAL SOURCE OF L-DOPA

Mucuna pruriens (aka Velvet Bean) is a natural source of levodopa (L-dopa). Mature seeds usually contain anywhere from 3-6% L-dopa by volume. Mucuna supplements often use a standardized form that increases the L-dopa concentration to up to 20%.


What does the scientific data say on using L-dopa to combat depression and other mood and neurological issues? A 2014 animal study showed that L-dopa from mucuna pruriens extract had anti-depressant actions, which were likely caused by L-dopa’s positive effect on the dopaminergic system. A 2012 study showed that L-dopa (a precursor to the excitatory NT dopamine) can cross the blood-brain barrier, where it undergoes conversion to dopamine, which can improve neurotransmission and mood. And while not directly related to depression, a 2004 double blind study on humans with Parkinson’s disease showed that doses of 500-1,000mg/day of L-dopa were equally effective as standard pharmaceutical drugs in treating Parkinson’s.


Dosage-wise I generally most adults start at 200-400mg of L-dopa, taken first thing in the morning with food. Those with Parkinson’s disease have used up to 1500mg/day with good results. [89-91]


ST. JOHN’S WORT:

THE DOPAMINE & NORADRENALINE BOOSTER

St. John’s Wort (hypericum perforatum) is a plant with yellow flowers that grows in many parts of the world (including Europe and the United States). Often regarded as a weed in the U.S., its name is derived from the fact that it often blooms on the birthday of the biblical John the Baptist. The flowers of the plant have been used to treat mental health conditions for at least 1500 years, and modern scientific studies are validating its traditional use.


Research suggests that several active ingredients (including hypericin and hyperforin) may be primarily responsible for the antidepressant effects of St. John’s Wort. These ingredients appear to increase the levels of dopamine and noradrenaline in the brain.


For example, a 2000 review that looked at 27 trials with more than 2200 participants found that SJW preparations were as effective as standard pharma antidepressants with lower side effects (26% for SJW preparations versus 44% for standard pharma antidepressant drugs). A 2008 review of 29 trials and more than 5400 patients found the same thing- that SJW formulations were as effective as pharma drugs but led to fewer adverse effects. And two 2016 reviews that looked at dozens of studies and more than 7000 participants also came to similar conclusions, finding that SJW preparations were very effective in treating mild to moderate depression. [92-97]


As far as supplementation goes, I generally suggest looking for products that are standardized to contain 0.3% hypericin. Dosage-wise I suggest that adults battling depression use 300-1200mg, 1-3 times a day (usually starting on the lower end and titrating up as needed).


VITAMIN D: THE ESSENTIAL NUTRIENT

WHERE DEFICIENCY IS LINKED TO DEPRESSION

While the 6 supplements mentioned above all work to combat depression by improving excitatory neurotransmitter levels and functioning, researchers are still teasing out exactly how vitamin D improves symptoms of depression. What we DO know is that low levels of vitamin D are associated with depression, including Seasonal Affective Disorder (SAD), which affects more than 3 million Americans each year.


A 2013 review of studies that included more than 30,000 participants found that “low vitamin D concentration is associated with depression.” A 2014 review of 15 randomized controlled trials found that vitamin D supplementation, even at a relatively low 800 IU/day, had a similar effect on depression as anti-depressant medication. A 2019 review of studies with more than 900 participants found that vitamin D supplementation positively impacted depression ratings with a moderate effect size. A 2020 review of more than 60 scientific articles found that “serum vitamin D levels inversely correlate with clinical depression.” And a 2020 analysis of 25 trials of more than 7,000 participants found that 4000 IU of vitamin D taken daily for 8 weeks had a positive effect on patients with major depressive disorder. [98-102]


Dosage-wise, I generally recommend most adults aim for around 10,000 IU/day of supplemental vitamin D3, in order to get blood serum levels to 40-90 ng/ml, which is the “sweet spot” according to most research.



DEPRESSED? CAREFUL WITH SUPPLEMENTS

THAT BOOST INHIBITORY NTs

Supplements like 5-HTP, GABA, taurine and glycine can cause an increase in inhibitory neurotransmitters like serotonin and GABA, which for those battling depression may exacerbate symptoms.


WHY AREN’T DOCTORS, PSYCHIATRISTS, PSYCHOLOGISTS AND THE MEDIA TALKING ABOUT THESE EVIDENCE-BASED ALTERNATIVES?!

So we’ve established that dozens and dozens of studies have highlighted the safety and efficacy of using therapeutic doses of various supplements to balance neurotransmitter levels and optimize their functioning in order to treat mood conditions like anxiety and depression. [103]


But why aren’t doctors, mental health professionals, government health organizations and the media talking about these natural, evidence-based alternatives?! I’ll let the authors of a 2008 study in the scientific periodical Nutrition Journal answer that question…


“Many of these studies were done in the 1970s and 1980s but were soon discontinued because they were underfunded. Nutritional therapies have now become a long-forgotten method of treatment because they were of no interest to pharmaceutical companies that could not patent or own them. Instead, the companies that funded most clinical research spent their dollars investigating synthetic drugs they could patent and sell- these drugs, however, usually caused adverse side effects.” [104]



5 OTHER SUPPLEMENTS FOR

MOOD & NEUROLOGICAL ISSUES


CHOLINE (GPC & CDP)

Choline is an essential micronutrient first identified by researchers in the mid-1800s. Choline is often categorized along with the B vitamins, although therapeutic doses of choline are so much greater than those of the other B vitamins that some have erroneously called it a macronutrient. Among its many roles includes its assistance in the emulsification of fats (i.e. breaking down dietary fat into its constituent parts) and protecting the liver from an abnormal accumulation of fat and cholesterol, such as is the case with conditions like Non-Alcoholic Fatty Liver Disease (NAFLD).


While choline is found in relatively high amounts in supplements like sunflower lecithin, other forms of choline are commonly used to improve brain performance (e.g. general cognition, memory, information recall, etc.) and are part of a class of nutraceuticals called nootropics. Supplements here include Alpha GPC (glyceryl-phosphoryl-choline), citicoline (i.e. CDP or cytidine-diphosphate-choline) and choline L-bitartrate (I prefer Alpha GPC or CDP personally). These supplements tend to work by optimizing the levels and functioning of acetylcholine, which was the first neurotransmitter ever discovered. Acetylcholine appears to act as a neuromodulator in the brain. While the exact definition of a neuromodulator is a bit murky, it generally describes any kind of neurotransmission that isn’t directly excitatory or inhibitory.


Dozens of scientific studies have highlighted the link between dietary choline intake, acetylcholine levels and functioning, and resulting cognitive performance. A 2019 study showed that supplementing the maternal diet with additional choline improved offspring cognition and neurodevelopment. A 2017 study came to similar conclusions, and even linked maternal choline intake with resistance to cognitive decline associated with aging and diseases like Alzheimer’s. Other studies have shown that adults who supplement with choline (including GPC and CDP choline supplementation) show improved cognition, memory, learning, and even protection against mood conditions like depression. [105-111]



In addition to GPC and CDP supplements, other nootropics that benefit the cholinergic system include bacopa and phosphatidylserine.


INOSITOL/MYO-INOSITOL

Inositol is actually a type of sugar that is found in high amounts in the brain. Sometimes called vitamin B8 (although it’s not technically an essential vitamin), myoinositol plays a major role in neurotransmitter functioning and mediates cell signaling in response to a variety of hormones.


Much of the clinical research surrounding inositol has looked at its effect on conditions such as PCOS and infertility, where it’s been found to be an incredibly safe and effective therapeutic agent, even at doses as low as 2-4g a day. [112- 117]


Other research has highlighted the effectiveness of inositol to stabilize unhealthy cholesterol levels and reduce liver fat and the risk of liver diseases such as liver cancer. [118-120]


As far as psychiatric conditions are concerned, research suggests that supplementation of inositol at doses of 12-18g a day (and up to 30g a day) is beneficial for a variety of mood issues, including depression and anxiety. [121-124]


OMEGA 3s (EPA & DHA)

Of the many fatty acids only two have been deemed essential fatty acids (EFAs)- an omega 6 fatty acid (linoleic acid) and an omega 3 fatty acid (alpha linolenic acid). Both of these EFAs are unsaturated fatty acids. Most of the research on EFAs focuses on omega 3s for a couple reasons- first, omega 3 deficiency is relatively common whereas omega 6 deficiency is not, and second, omega 3s tend to have more dramatic therapeutic effects on the body than omega 6s.


Alpha linolenic acid or ALA is a precursor to two other notable omega 3s- EPA and DHA. These two long-chain fatty acids are known for supporting neurological, eye, skin and cardiovascular health, and also have been shown to have notable anti-inflammatory effects on the body. While EPA and DHA can be synthesized from ALA by the body, due to a very low conversion efficiency it’s generally recommended that individuals consider utilizing supplements (such as concentrated fish oils high in EPA and DHA) in order to obtain therapeutic amounts. [125-126]


Aside from adipose tissue (i.e. body fat), the brain and nervous system has the highest concentration of lipids in the human body. Indeed, nearly 60% of the brain is made of lipids. Among these fatty acids, the brain is especially high in essential fatty acids such as omega 3s. For instance, DHA makes up 10-15% of the total fatty acids in the brain of both males and females. This means that essential fatty acids like EPA and DHA are indispensable for the normal development and functioning of the brain and nervous system. [127]


When it comes to using omega 3s to treat mood conditions such as anxiety and depression, there are conflicting reports in the scientific literature, although most of the data indicates that omega 3s have a positive effect on mood conditions. For instance, a 2019 review of 26 studies with more than 2000 participants found that consuming high EPA omega 3s at a dose of more than 1g a day has beneficial effects on depression. A 2018 review of 19 trials of more than 2200 participants from 11 countries showed that omega 3 treatment led to improvements in anxiety symptoms. A 2015 review of the clinical evidence found that "omega 3s preventive benefits on mood and anxiety disorders is supported by their regulatory effects on immuno-modulation, anti-inflammation, signal transduction, neurotransmission and neuroprotection." [128-130]


While many health researchers and organizations recommend 2-5g a day of EPA+DHA for optimal health benefits (including the European Food Safety Authority, who advises no more than 5g a day of EPA+DHA), other experts (ex. Barry Sears PhD) suggest a MINIMUM of 3g/day and see the greatest benefit at 5-15g of EPA+DHA/day. Up to 15g/day of EPA+DHA have been used in clinical studies.


THE 8 ESSENTIAL B VITAMINS (B COMPLEX SUPPLEMENTS)

There are 8 essential B vitamins: B1, B2, B3, B5, B6, B7, B9 and B12. While many people associate B vitamins with energy levels, much of the scientific research on B vitamins has to do with their vital role in nervous system functioning. An increasing amount of evidence suggests that adequate levels of all 8 members of this vitamin group are essential for optimal neurological health. [131]

When it comes to conditions such as anxiety and depression, the role that B vitamins play in cellular process such as the folate and methionine cycles have helped formed the basis for the B vitamin status-mood hypothesis. While the clinical data isn’t overwhelming, there is a decent amount of research that suggests that therapeutic doses of all 8 B vitamins can play a beneficial role in treating mood disorders like anxiety and depression. For example, a 2019 review of 18 articles found that 11 reported a positive effect of B vitamins on overall mood. A 2016 review of the literature highlighted findings that B1, B3, B6, B9 and B12 in particular are essential for neuronal functioning, and that deficiencies in these essential micronutrients have been linked to depression. A 2011 study showed that the effects of workplaces strain and stress were significantly decreased after 90 days of participants consuming a B complex supplement. [132-134]


As far as dosage goes, I generally suggest a B complex that uses activated forms of B vitamins at higher than normal doses, such as the product made by Pure Encapsulations. Note that I do NOT recommend supplementing with more than 100-200mg/day of vitamin B6, as higher doses may cause peripheral neuropathy.


LITHIUM OROTATE

Lithium is a mineral, and even though it’s not officially considered an essential micronutrient, there are many researchers who believe it meets the criteria for inclusion, as it may be required for normal neurological functioning. [135]


Lithium is a well-established option for mood conditions like bipolar disorder and major depression. Lithium is a neuroprotective agent and has also been used as a therapeutic agent for several neurodegenerative disorders, including Alzheimer’s, ALS and Parkinson’s disease. Lithium’s therapeutic effects are due, at least in part, from its role in autophagy, inflammation and oxidative stress reduction and mitochondrial functioning. [136]


Unfortunately, the prescription form of lithium, lithium carbonate (LC), has a science-backed reputation for causing a host of adverse effects, including kidney damage, liver damage, flat affect (i.e. dulled personality and reduced emotions), memory loss, tremors and weight gain. This is partly due to the fact the LC is relatively inefficient at crossing the blood-brain barrier, meaning that larger doses (which carry greater risk) are needed. Lithium orotate (LO) is a non-prescription form of lithium that research shows is a safer alternative than LC. Lithium orotate more easily crosses the blood-brain barrier and enters cells more readily than LC, which allows for reduced dosage requirements and a better safety profile. [137-138]


For conditions like bipolar disorder, a common dosage schedule of 5-10mg 1-3x a day (max of 40mg/day total) are usually recommended.


Image source: www.verywellhealth.com


OF COURSE SUPPLEMENTS MAY NOT

FULLY SOLVE YOUR MOOD ISSUES…

While balancing and optimizing neurotransmitter functioning and correcting other metabolic issues affecting mood with proper nutritional supplementation may prove sufficient for solving some people’s anxiety and depression issues, many will need to take a more holistic approach.


What does this mean? It simply means that there are a variety of factors that can influence mood, including spiritual, mental and emotional factors, social/relational factors, and more physically overt factors such as diet, exercise and physical activity, sleep, environmental factors, stress management, drug use, sexual health and different types of trauma (to name several).



WEBSITES FOR MORE READING

www.sanfordlevymd.com/anxiety-stress-depression-a-supplement-approach/


www.tangoherbs.com/protecting-your-brain.html (supplements for mood issues)


https://universityhealthnews.com/daily/depression/dopamine-supplements-for-improving-mood-and-motivation/


www.integrativepsychiatry.net/neurotransmitter.html


https://bouldernaturalhealth.com/blog/neurotransmitter-testing/ (benefits of NT testing & supplements to help mood)


www.primalbody-primalmind.com/the-whacky-wild-and-misleading-world-of-neurotransmitter-testing/


BOOKS

* Mood Cure (2003) by Julia Ross

* The Ultramind Solution (2008) by Dr. Mark Hyman


OTHER DOCTORS & EXPERTS

* Dr. Daniel Kalish, http://kalishwellness.com/

* Dr. Chad Oler, http://naturalpathhealthcenter.com/, http://amino-acid-therapy.com/

* Dr. Mark Millar, www.thelithiumdoctor.com/


SOURCES

61 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716179/ (2017; dopamine dysregulation in depression)

62 https://pubmed.ncbi.nlm.nih.gov/12813473/ (2003; epinephrine system impaired in depressed patients)

63 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131098/ (2011; low levels of norepinephrine linked to depression)

64 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020390/ (2016; l tyrosine for depression; animal study; positive results are likely attributed to restoring basal levels of cerebral noradrenaline)

65 www.ncbi.nlm.nih.gov/pubmed/27403851 (2016; tyrosine improves cognition in stressful environments; "tyrosine, the precursor of dopamine, has been shown to enhance facets of cognitive control in situations with high cognitive demands.")

66 www.ncbi.nlm.nih.gov/pubmed/26424423 (2015; tyrosine improves cognition in stressful environments; “TYR does seem to effectively enhance cognitive performance, particularly in short-term stressful and/or cognitively demanding situations. We conclude that TYR is an effective enhancer of cognition, but only when neurotransmitter function is intact and DA (dopamine) and/or NE (norepinephrine) is temporarily depleted.”)

67 www.ncbi.nlm.nih.gov/pubmed/18274206 (2007; study of 85 men and women working in Antarctica found high dose tyrosine superior to synthetic t3 & t4 for improving mood; “Administration of tyrosine (12g/day) leads to a significant reduction in serum TSH and improvement in mood in winter compared with placebo, while the combined T4-T3 supplement (synthetic) leads to a worsening of mood in summer and no improvement in winter.”)

68 www.ncbi.nlm.nih.gov/pmc/articles/PMC1863555/ (2007; tyrosine has robust amount of clinical data supporting its effectiveness for mitigating adverse effects of stress; L-Tyrosine is the precursor of the catecholamines; alterations in the availability of L-tyrosine to the brain can influence the synthesis of both dopamine and norepinephrine… Stress increases the release of catecholamines, which can result in the depletion of their levels, an effect that can be corrected by giving L-tyrosine… The main effects of L-tyrosine that have been reported are acute effects in preventing a decline in cognitive function in response to physical stress… Doses of L-tyrosine in these studies ranged up to 20g”)

69 www.ncbi.nlm.nih.gov/pubmed/14514507 (2003; PET scan showed effect of dietary manipulation of dopamine precursors tyrosine & phenylalanine; “This is the first demonstration of an effect of a dietary manipulation on brain dopamine release in humans. This result provides support for the further investigation of the role of dietary manipulations in the treatment of neuropsychiatric disorders.”)

70 www.ncbi.nlm.nih.gov/books/NBK28/ (2001; tyrosine necessary for production of thyroid hormones & epinephrine & norepinephrine; “Like the catecholamines epinephrine and norepinephrine, thyroid hormones are synthesized from the amino acid tyrosine.)

71 www.ncbi.nlm.nih.gov/pubmed/10230711 (1999; 2g/day tyrosine improve cognitive functioning vs placebo; “Over 5 days, the group supplied with the tyrosine-rich drink (2g) performed better on a memory and a tracking task than the group supplied with the carbohydrate-rich drink… These findings suggest that supplementation with tyrosine may, under operational circumstances characterized by psychosocial and physical stress, reduce the effects of stress and fatigue on cognitive task performance.”)

72 www.ncbi.nlm.nih.gov/pubmed/7794222 (1995; high dose tyrosine improves cognitive performance when under stress; “Tyrosine administration (150mg per kg body wt or 10.5g for 155lb person) was associated with a significant amelioration of the usual performance decline on a psycho-motor task.”)

73 www.ncbi.nlm.nih.gov/pubmed/2736402 (1989; “We investigated whether tyrosine (100 mg per kg body wt per day, or ~7g/day for 155lb person) would protect humans from some of the adverse consequences of a 4.5 hour exposure to cold and hypoxia. Tyrosine significantly decreased symptoms, adverse moods, and performance impairments in subjects.”)

74 www.ncbi.nlm.nih.gov/pmc/articles/PMC5454963/ (2017; the role of glutamine in the intestines)

75 www.ncbi.nlm.nih.gov/pmc/articles/PMC4369670/ (2012; glutamine promotes gut health in intestine’s tight junctions)

76 https://pubmed.ncbi.nlm.nih.gov/17984189/ (2008; glutamine supplementation protects against excess ammonia in the body’s soft tissues)

77 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205453/ (2012; “the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents.”)

78 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439647/ (2012; “growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of Major Depressive Disorder”)

79 https://pubmed.ncbi.nlm.nih.gov/17283286/ (2007; Depressed patients had reduced glutamine/glutamate levels in prefrontal brain regions)

80 https://pubmed.ncbi.nlm.nih.gov/30266598/ (2018; “Emerging evidence has shown the low levels of glutamate and glutamine (along with) hypoactivity in the cortex of patients with depression. Expectedly, glutamine supplementation showed antidepressant effects. Depressive behaviors evoked by chronic stress were due to hypoactive glutamatergic neurons in the medial prefrontal cortex, caused by low levels of glutamine. Exogenous (supplemental) glutamine can be used as an alternative antidepressant to increase glutamatergic neurotransmission.”)

81 https://pubs.rsc.org/en/content/articlelanding/2014/ra/c3ra47364c/unauth

82 https://pubmed.ncbi.nlm.nih.gov/3944066/ (1986; “The results suggest that low plasma and urinary PAA may be state markers for depression and are compatible with the PEA hypothesis. In further support, phenylalanine elevated mood in 31 of 40 depressives.”)

83 https://pubmed.ncbi.nlm.nih.gov/7711493/ (1995; “A review of the literature indicates that brain phenylethylamine (PEA) … promotes energy (and) elevates mood... Phenylacetic acid, the main metabolite of PEA, is decreased in the biological fluids of depressed subjects… The administration of PEA or of its precursor L-phenylalanine improves mood in depressed patients”)

84 https://pubmed.ncbi.nlm.nih.gov/9081552/ (1996; “Phenylethylamine (PEA), an endogenous neuroamine, increases attention and activity in animals and has been shown to relieve depression in 60% of depressed patients. It has been proposed that PEA deficit may be the cause of a common form of depressive illness.”)

85 https://academic.oup.com/ajcn/article/76/5/1158S/4824264 (2002; review of the data on SAM-e)

86 https://pubmed.ncbi.nlm.nih.gov/18950248/ (2008; SAM-e, plus 5-MTHF, are essential for healthy NT levels in the cerebrospinal fluid; SAM-e improved depressive symptoms)

87 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247995/ (2017; S-adenosyl-L-methionine (SAMe) acts as a methyl donor, with dopamine, norepinephrine, and serotonin elevating properties)

88 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501081/ (2017; 132 studies; “this review of SAMe in the treatment of major depressive disorder found promising but limited evidence of efficacy and safety”)

89 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213977/ 2014; animal study; “The results of this study indicate that hydroalcoholic extract of MPE have antidepressant action, which may be mediated by an interaction with the dopaminergic system.”)

90 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942911/ (2012; L-Dopa, the precursor of dopamine, can cross the blood-brain barrier and undergo conversion to dopamine, restoring neurotransmission)

91 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1738871/ (2004 double blind study on mucuna and Parkinson’s; 500-1000mg/day of l dopa as effective as pharma drugs for Parkinson’s)

92 https://www.healthline.com/nutrition/st-johns-wort

93 https://pubmed.ncbi.nlm.nih.gov/10796719/ (2000; review of 27 trials and 2291 ppl; Hypericum preparations were similarly effective as standard antidepressants with lower side effects; those reporting side effects were 26.3% for hypericum single preparations vs. 44.7% for standard antidepressants)

94 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032678/ (2008; review of 29 trials and 5489 patients)

The available evidence suggests that the hypericum extracts tested in the included trials are similarly effective as standard antidepressants and have fewer side effects than standard antidepressants.)

95 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010734/ (2016; review of 35 studies and 6993 ppl; Compared to antidepressants, SJW participants were less likely to experience adverse events with no difference in treatment effectiveness in mild and moderate depression.

96 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946846/ (2016; review of 27 studies and 3,126 patients found SJW supplements as effective as antidepressant meds with fewer side effects)

97 https://pubmed.ncbi.nlm.nih.gov/28064110/ (2017; review of studies; studies ranged from 4 to 12 weeks; For patients with mild-to-moderate depression, St John's wort has comparable efficacy and safety when compared to SSRIs.)

98 https://pubmed.ncbi.nlm.nih.gov/23377209/ (2013; review of studies with 31,000 participants; “Our analyses are consistent with the hypothesis that low vitamin D concentration is associated with depression”)

99 www.ncbi.nlm.nih.gov/pmc/articles/PMC4011048/ (2014 review of 15 RCTs found that “Vitamin D supplementation (≥800 I.U. daily) was somewhat favorable in the management of depression in studies that demonstrate a change in vitamin levels, and the effect size was comparable to that of anti-depressant medication.”)

100 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515787/ (2019; review of 4 trials involving 948 participants; Vitamin D supplementation favorably impacted depression ratings in major depression with a moderate effect size.)

101 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970300/ (2020 review of 61 scientific articles found “Serum vitamin D levels inversely correlate with clinical depression”)

102 https://pubmed.ncbi.nlm.nih.gov/32365423/ (2020 analysis of 25 trials with a total of 7,534 participants; 4000 IU of vitamin D taken for 8 weeks had a positive effect on patients with major depressive disorder and on subjects with serum D levels of less than 50 nmol/L)

103 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315550/ (2020; “The present study suggests that lowered serum methionine (SAM-e), phenylalanine (PEA), tryptophan (serotonin precursor), tyrosine (dopamine), and non-enzymatic antioxidants are associated with depression.”)

104 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248201/ (2008 article touching on why nutritional therapies haven’t been as widely used as pharma therapies for mood issues)

105 www.ncbi.nlm.nih.gov/pmc/articles/PMC6722688/ (2019; Supplementing the maternal diet with additional choline has been shown to improve offspring cognition, neurodevelopment, and placental functioning, and to protect against neural and metabolic insults)

106 www.ncbi.nlm.nih.gov/pmc/articles/PMC5579609/ (2017; Choline is an essential nutrient for humans; taken together, the available evidence strongly supports the notion that adequate choline intake during pregnancy, and throughout life, is an important determinant of brain development, cognitive performance in the adult, and resistance to cognitive decline associated with aging and neurodegenerative disease.)

107 www.ncbi.nlm.nih.gov/pmc/articles/PMC4536529/ (2015; improved visual motor & memory performance with choline bitartrate, CDP & GPC choline supplementation; “significant enhancements in a wide variety of memory and executive control functions, including working memory (e.g., n-back task), verbal memory and learning (e.g., recall a list of words), and maze pathway learning after CDP-choline (citicoline) and alpha-GPC (choline alfoscerate) administration in populations that have relatively low baseline memory performance”)

108 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327365/ (2013; supplemental dietary choline, at least when given during development, may inoculate an individual against stress and major psychological disorders, like depression.)

109 www.ncbi.nlm.nih.gov/pmc/articles/PMC5612430/ (2012; “a recent study performed on 1391 normal adult and elderly people (average age 61 years) showed that verbal and visual memory function correlated positively with the amount of dietary choline consumption, with poorest performance in individuals with lowest choline intake and best performance in those who were consuming the highest amounts of choline. These data further support the notion that adequate choline nutrition is essential for the maintenance of cognitive function in people.”)

110 www.ncbi.nlm.nih.gov/pmc/articles/PMC3466476/ (2012; acetylcholine appears to act as a neuromodulator in the brain, despite its role as the primary excitatory neurotransmitter in the periphery. The definition of a neuromodulator is flexible but has evolved to describe any kind of neurotransmission that is not directly excitatory (mediated through ionotropic glutamate receptors) or inhibitory (mediated through ionotropic GABA receptors))

111 https://pubmed.ncbi.nlm.nih.gov/6754453/ (1982; “administration of choline or lecithin might alleviate some neurological disturbances, prevent hypercholesteremia and atherosclerosis, and restore memory and cognition”)

112 www.ncbi.nlm.nih.gov/pmc/articles/PMC5728865/ (2017; inositol improving fertility rate)

113 www.ncbi.nlm.nih.gov/pmc/articles/PMC5554611/ (2017; inositol for PCOS)

114 www.ncbi.nlm.nih.gov/pmc/articles/PMC5097808/ (2016; inositol, PCOS and improving fertility; review of 12 RCTs)

115 www.rbmojournal.com/article/S1472-6483(16)30508-9/fulltext (2016; inositol & PCOS)

116 www.ncbi.nlm.nih.gov/pmc/articles/PMC5011528/ (2016; inositol & PCOS; 4g a day)

117 www.ncbi.nlm.nih.gov/pubmed/22612517 (2012; inositol at 2g/day has positive effects on insulin markers in obese PCOS individuals)

118 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968598/ 2018; review of 14 RCTs showing that “inositol supplementation may result in reduction in triglycerides, total- and LDL-cholesterol levels”)

119 www.ncbi.nlm.nih.gov/pubmed/29241575 (2017; inositol reduces liver fat accumulation in rats fed a high fructose diet)

120 www.ncbi.nlm.nih.gov/pubmed/15780031 (2005; rat study; inositol is liver cancer preventative)

121 https://pubmed.ncbi.nlm.nih.gov/24424706/ (2014; review of 7 RCTs found that inositol may be beneficial for depressed patients)

122 https://pubmed.ncbi.nlm.nih.gov/12001182/ (2002; rat study; inositol as effective anti depressant)

123 https://pubmed.ncbi.nlm.nih.gov/11386498/ (2001; small study of 20 ppl found that 1 month of inositol (up to 20g/day) was more effective for panic attacks than fluvoxamine (up to 150mg/day))

124 www.ncbi.nlm.nih.gov/pubmed/9169302 (1997; use of inositol in psychiatry)

125 www.ncbi.nlm.nih.gov/pmc/articles/PMC4730128/ (2015; EPA & DHA have positive effect on body fat accumulation, body fat metabolism and decreasing inflammation)

126 www.ncbi.nlm.nih.gov/pmc/articles/PMC4538411/ (2015; omega 3s reduce inflammation in fat tissue & systemically)

127 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087749/ (2018; the role of essential fatty acids in brain & nervous system health)

128 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683166/ (2019 review of 26 studies, which included 2160 participants, found that evidence supports the finding that omega-3 PUFAs with EPA ≥ 60% at a dosage of ≤1 g/d would have beneficial effects on depression.”)

129 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324500/ (2018 meta-analysis of 19 clinical trials including 2240 participants from 11 countries found that “improvement in anxiety symptoms was associated with omega-3 polyunsaturated fatty acid treatment”)

130 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540034/ (2015 review “the clinical evidence about omega-3 PUFAs’ preventive benefits on mood and anxiety disorders is supported by their regulatory effects on immuno-modulation, anti-inflammation, signal transduction, neurotransmission and neuroprotection.”)

131 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772032/ (2016; B vitamins and the brain)

132 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770181/ (2019 review of data on B vitamins and mood; 11 of 18 articles reported a positive effect for B vitamins over a placebo for overall mood or a facet of mood.)

133 https://pubmed.ncbi.nlm.nih.gov/27655070/ (2016 review; vitamins B1, B3, B6, B9 and B12 are essential for neuronal function and deficiencies have been linked to depression)

134 https://pubmed.ncbi.nlm.nih.gov/21905094/ (2011; workplace stress/strain reduced after 90 days of taking a B complex supplement)

135 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443601/ (2019; lithium may be an essential micronutrient, as it may be required for normal neurological functioning)

136 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063497/ (2014; Lithium is a well-established therapeutic option for bipolar disorder and major depression. Lithium also regarded as a neuroprotective agent in certain neurodegenerative disorders, namely Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). The neuroprotective effects of lithium rely on the fact that it modulates several mechanisms involved in neurotrophic response, autophagy, oxidative stress, inflammation and mitochondrial function)

137 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248201/ (2008; Rx lithium carbonate with doses as high as 180mg; high dose Rx lithium responsible for most of its adverse effects, including dulled personality, reduced emotions, memory loss, tremors & weight gain. Lithium orotate is preferred because the orotate ion crosses the blood-brain barrier more easily than the carbonate ion of lithium carbonate. Therefore, lithium orotate can be used in much lower doses (e.g. 5 mg) with remarkable results and no side effects. Clinical trials involving 150 mg daily doses of lithium orotate administered 4-5x/week showed a reduction of manic and depressive symptoms in bipolar patients)

138 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413749/ (2021; Bipolar disorder (BD) is characterized by manic and depressive mood cycles, the recurrence of which can be effectively curtailed through lithium therapy. Unfortunately, the most frequently employed lithium salt, lithium carbonate (Li2CO3), is associated with a host of adverse health outcomes following chronic use: these unwanted effects range from relatively minor inconveniences (e.g., polydipsia/abnormal thirst and polyuria/abnormal urination) to potentially major complications (e.g., hypothyroidism and/or renal impairment). Lithium orotate (LiOr), a compound largely abandoned since the late 1970s, may represent a more attractive alternative. LiOr is proposed to cross the blood–brain barrier and enter cells more readily than Li2CO3, which will theoretically allow for reduced dosage requirements and ameliorated toxicity concerns.)