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How to Free Yourself from Depression with Natural Antidepressant Supplements: Part 1

The Top 9 Science-Backed Supplements Which Outperform SSRI Drugs

[References to this Article]

Sadly, depression is a common mood disorder affecting 16.2 million Americans at least once.

Depression is the leading cause of disability, according to the World Health Organization (WHO), affecting over 320 million people worldwide.

More tragic is the number of depression cases increased by 20% over the past decade.

Sadly, depression is a common mood disorder affecting 16.2 million Americans at least once.

Depression is the leading cause of disability, according to the World Health Organization (WHO), affecting over 320 million people worldwide.

More tragic is the number of depression cases increased by 20% over the past decade.

Depression is difficult to treat with its subjective self-reporting, and likewise, their diagnoses having the same subjectivity by the attending physician.

Diagnosing and treating depression is contrary to the precision of taking a simple blood pressure reading in 60 seconds or fewer.

The stigma depressed individuals feel in not wanting to talk about their private thoughts, feelings, and emotions, makes depression even more difficult in diagnosis and treatment.

The difference between being down and depressed is when the depressed feelings interfere with managing day-to-day tasks, responsibilities, and participation in activities that were once pleasurable.

When one is experiencing this depressed state as severe and/or long-lasting, we diagnose it as a mood disorder.

And if one shows up for treatment, they will typically be prescribed medications for depression and anxiety, such as SSRIs, sometimes along with cognitive-behavioral therapy, (CBT).

The side effects of antidepressants can devastate some and sometimes last longer after termination of treatment.

While depression is more common in females, it affects all people across all demographics.

Types of Antidepressants: (Medications for Depression and Anxiety)


There are three basic types of antidepressants.

SSRIs are used as medications for depression and anxiety.

1. SSRIs

Selective Serotonin Reuptake Inhibitors

2. TCAs

Tricyclic Antidepressants

3. MAO-Is

Monoamine Oxidase Inhibitors

Side Effects of Antidepressants

  • Agitation
  • Anxiety
  • Blurry vision
  • Constipation
  • Dizziness
  • Drowsiness
  • Dry mouth
  • Fatigue
  • Insomnia
  • Irritability
  • Nausea
  • Sexual Dysfunction (Erectile Dysfunction, Loss of Libido, Orgasm Difficulty)
  • Weight Gain and Increased Appetite


What are the Best Antidepressants?

You might have noticed the title referenced, natural antidepressant supplements outperforming SSRI drugs?

Yes, you read this correctly.

This claim is well-supported by the referenced research studies about the types of antidepressants.

The supplements on this list are the best antidepressants in the natural supplement form.

They all perform equal to or superior to SSRI drugs, with little to none of the side effects of antidepressants.

And for the reason of safety, with no loss of effectiveness, we can legitimately call them these the best types of antidepressants.

#1 Saffron Extract: (Performs Equal to Prozac and Tofranil)

Known as the world’s most expensive spice, saffron is well-studied and shows up as effective against mild, moderate, and major depression.

Saffron performs equally effectively as the SSRI drugs, such as fluoxetine (Prozac) and a tricyclic antidepressant (TCA), imipramine.

We see an increase in mood, a reduction in anxiety, and stress management with no side effects.

Saffron has also been proven as effective as ADHD medication for children, appetite suppressants, and weight loss aid.


15 mg of standardized extract taken twice daily.

#2 Omega-3 (EPA) (Performs Equal to Prozac)

We find omega-3 supplements equal to SSRI drug, fluoxetine, Prozac in individuals with major depression.

For depression, EPA is the omega-3 compound delivering the therapeutic effect, with 15 studies showing products with 60% or more EPA is significantly more effective.

Omega-3’s appear to only be effective against major depression, and not milder types.

Omega-3 EPA might also benefit individuals with anxiety.

We also see a strong synergy between omega-3’s and curcumin for increasing cognitive boosting DHA brain-levels.

A few studies indicate phospholipid krill oil might deliver twice the bioavailability as triglyceride based fish oil.

There are several other meaningful benefits in choosing krill over fish oil, including its superior choline source, greater shelf-life, and substantially lower levels of mercury.

Vegans and vegetarians, who can use algae oil supplements, are at risk of omega-3 deficiency as chia, flax, and hemp seeds inefficiently and insufficiently convert into DHA and EPA.


1,000 mg of EPA might be the optimal dose, as 2–4 grams is not more effective and instead might be counterproductive. The omega-3 supplement, preferably krill or vegan algae oil, should contain at least 60% EPA, whereas many will contain a much larger percentage.

#3 5-HTP: (Higher Levels than Paxil and Prozac)

Amino acid serotonin precursor, 5-HTP increased serotonin levels more than SSRI drugs Paxil, and exponentially more than Prozac.

5-HTP is also effective for insomnia, appetite, anxiety, weight loss, and possibly effective for opioid withdrawal.


While proven much safer than SSRIs, 5-HTP can have issues with its use, especially in higher dosages. Always start slowly at the lowest effective dose of 50 mg twice daily and increase in need. As with these, always double-check for interactions prior to use, and watch for side effects with this one.

#4 Creatine

Depression symptoms seem to improve noticeably with creatine.

Creatine seems to affect dopamine, norepinephrine, and serotonin while enhancing SSRI therapy.

There appears to be a greater benefit to females, which could be explained by females having lower phosphocreatine brain levels than men.

Vegans, and possibly even vegetarians, have been found to have lower phosphocreatine brain levels, and those with depression, should seriously consider creatine supplementation.

A popular combination is a creatine with D-Ribose, both of which act as mitochondria-stimulating ATP boosters.


5 grams per day. Creapure, micronized creatine could be possibly better tolerated and absorbed by some.

#5 St. John’s Wort (Equal to Prozac; More Effective than Zoloft)

The flower extract, St John’s Wort, performs as effectively as SSRI drugs, Prozac, and much more effectively than Zoloft in research studies.

We also find its performance on depression equal to tricyclic antidepressants, (TCA’s).

More Germans use St. John’s than use SSRI drug, Prozac, as St. John’s Wort remains popular throughout Europe.

St. John’s Wort contains both hypericin and hyperforin, in which researchers believe the hyperforin component to be more potent.

Bother hypericin and hyperforin are seen to inhibit COMT, MAO-A, and MAO-B, but likely much higher doses would be needed for this action to have a clinical effect.

This might not be the best option for major depression.

It also might be effective for menopause.


Like several on this list, St. John’s Wort is cautioned for interactions with an array of pharmaceutical drugs. Standardized extract of 0.3% hypericin with 300 mg taken three times daily.

#6 Curcumin: (Actions on Neuroinflammation)

Similar to Rhodiola, curcumin lowers major depression symptoms through believed powerful anti-inflammatory mechanisms.

Curcumin seems to be more effective than placebo in reducing symptoms of depression.

Overall, curcumin has tremendous value as an all-around supplement and remains arguably one of the very best options.

The challenge with curcumin is the general lack of bioavailability, in which researchers believe more bioavailable forms can help with increased effectiveness.


It may take 2–3 months for benefits. 1,000 to 1,500 mg in daily divided doses taken with a meal with fat and black pepper is the study dosages. Arthritis studies use 2,000 mg, and it is not clear whether this might be more effective. BCM-95 and C3 forms are used in studies with Longvida and Meriva reasoned to also be effective. Only use a high-absorption curcumin extract, as curcumin has a naturally low absorption rate. There appears to be a strong curcumin synergy with omega-3’s.

#7 Rhodiola Rosea: (Performs Equal to Zoloft)

This adaptogen acts as a cortisol blocker, with effects based on anti-inflammatory actions, as it blocks the three key cytokines involved in stress response and neuroinflammation, IL-1, IL-6, and TNF-alpha.

Rhodiola Rosea acts as a natural inhibitor of MAO-A and MAO-B, making it a unique plant medicine.

It performs equally to SSRI drug, Zoloft, even in low doses, with no side effects.

Rhodiola is effective for stress, and ADHD and possibly as a mild anti-anxiety supplement.


Rosavins not salidrosides are the more biologically active Rhodiola compounds. 200 mg of 5% rosavins taken twice daily.

#8 Kanna

Kanna is an African plant, also used for anxiety and depression.

In the Zembrin form, Kanna’s dual PDE4 and 5-HT activities proved effective for anxiety and depression.

We have seen it used culturally as an appetite suppressant, anti-nausea, and indigestion aid, and as a pain reliever.

Quality appears to carry a significant difference with Kanna, with users reporting the lack of effects with inferior quality Kanna.


400 mg on average appears to be the dose. Due to its mixed alkaloids and their actions, lower doses of Kanna produce more stimulating and euphoric effects, while higher doses promote more serotonergic and calming effects.

#9 SAM-e (Equal to Tricyclic Antidepressants)

S-Adenosyl methionine is a key methyl-donor, in the methylation process, as it provides an array of other actions, such as lowering oxidative stress through master antioxidant, glutathione production.

Most SAM-e is produced by and used by the liver and is needed by the brain in the production of dopamine, norepinephrine, and serotonin.

SAM-e performs equally to a variety of antidepressants, none of which outperformed placebo.

It seems to have its greatest effect on men and/ or those with either high homocysteine levels or B-12 or folate deficiencies.

SAM-e also provides liver protection, while performing equal to anti-inflammatory drugs in the treatment of osteoarthritis, but after taking a longer time to work.

It appears to improve SSRI therapy, (as with creatine).

As a standalone treatment, SAMe performs equal to tricyclic antidepressants in multiple studies.


SAM-e might have interactions with an array of medications. Studies show SAM-e doses of 800 to 1600 mg taken for 6 weeks.

Rising Stars

The following four deserve a special mention despite a lack of thorough studies done on them.

We feel it is worth looking at what people are talking about, as we need to look at a problem as big as depression from all sides and angles.

We expect to see more with these rising stars as time goes on.

Vitamin B3 (Niacin/ Niacinamide) and Vitamin C

It seems silly to be discussing these two common micronutrients as heavy-weights as “rising stars.”

The reality is both vitamin B3 (niacin) and vitamin C have been heavily understudied for their use for depression.

We all need vitamin C as it provides neurotransmitter support.

Those with depression likely need larger doses, and we have studies showing initial support when using larger vitamin C doses for depression both with and without antidepressant medications.

As for vitamin B3, despite a lack of peer-reviewed studies available, there exist thousands of case studies involving the use of niacin/ niacinamide for mood disorders by Dr. Abraham Hoffer.

The legend has it, Dr. Hoffer besides treating OCD, PTSD, BPD, schizophrenia, depression, and other mood disorders with high doses of niacin, also treated Bill W. of Alcoholics Anonymous (AA), prior to receiving a cease and desist from the AMA, with seemingly outstanding results.


Some report niacinamide being more effective than niacin, and vice versa. Dr. Hoffer prescribed 3,000 mg in three divided doses. We are seeing more researchers suggesting 12 to 18 grams of vitamin C in at least 3 divided doses is worth consideration. Niacin causes a skin flushing sensation and the dose should be titrated upward, starting with 50 mg.

Mucuna Pruriens

Researchers continue to recognize dopamine has been needlessly overlooked in depression studies, and recent research is beginning to point to the role of “low dopamine” or dopamine dysfunction as an explanation.

It makes sense to reason dopamine, associated with motivation and reward feelings, is likely an equally important role player as norepinephrine and serotonin, which have previously received all the attention.

The issue is likely not so much an issue of low dopamine, rather low dopamine in specific parts of the brain, causing depression symptoms.

Low dopamine in the brain’s emotional (mesolimbic) center may trigger the inability to feel pleasure, while low dopamine in cognitive (mesocortical) areas may promote the lack of motivation we find common in depressed individuals.

We find studies supporting Mucuna’s dopamine-stimulating actions, promoting mood improvement and depression symptoms while lowering stress levels.

These studies are only rodent studies, so we will await future confirmation and replication in humans.

Mucuna is also being tested for ADHD, and various cognitive disorders such as Parkinson’s, to which it appears to be equally effective to medication.


Parkinson’s studies use much larger doses of up to 30 grams. For depression we believe using standardized extracts in divided doses of 1 to 2 grams of 15 to 30% L-DOPA, could be the target for dosing. We believe mucuna might be more effective than the L-DOPA extracted from the plant.

Kratom (Mitragyna Speciosa)

As a member of the coffee family, kratom, mitragyna speciosa, has extensive anecdotal anti-depressant evidence, when used in lower, more-stimulating doses.

While it’s larger, more sedating doses of 5 grams or more are common and widely used as an opioid withdrawal and pain medication alternative, we feel this plant should be researched for its lower dose use for depression and energy.

While we don’t have studies on the effects of kratom on depression, we believe kratom also positively affects dopamine, amongst other neurotransmitters, with the power to lift one out of major depression.

We expect to hear more about kratom and its antidepressant lower dose actions.


Users report using lower doses of kratom to achieve its antidepressant and cognitive stimulating effects in the 2 to the 3-gram range. While an overdose is virtually impossible, psychological addiction has been reported with daily kratom use in a smaller subset of daily users, at least equal to caffeine. Some argue it can be physically addictive with withdrawals when using higher daily doses.

Agmatine, (Arginine Amino Acid Metabolite)

Agmatine has only one very preliminary depression study.

In this “most famous tiny mood study ever,” we see remission in all three subjects with major depression.


This study used a dosage range of 2 to 3 grams of agmatine. Agmatine might be best absorbed on an empty stomach.

Depression-Related Micronutrient Cofactors

*Folate, vitamin D3, and zinc are the most key micronutrients.

  • B-complex (B2, B6, B9, B12 effective in depression with homocysteine)
  • Chromium
  • Folic Acid (Notably methyl-folate with strong effects, possibly for methylation.)
  • Iron (Effects are seen in anemia and iron deficiency)
  • Magnesium (The best effects seen with type 2 diabetes and PMS)
  • Vitamin C (Lowers cortisol and improves blood flow, with neurotransmitter support.)
  • Vitamin D3 (Strong synergy with Omega-3’s)
  • Vitamin E (Reductions seen in PMS-related depression)
  • Zinc (Notable effects when combined with antidepressants)

*DHEA and pregnenolone are effective for deficient individuals only.

*Dietary fiber still appears to be a critical macronutrient for the elimination of excess estrogen in men and women.

*Higher vitamin C doses might be needed to manage dopamine and norepinephrine during stress.

*The right amount of magnesium is needed for COMT, depending on whether it’s fast or slow.

Notable Other Antidepressant Supplements

Dietary Fiber [R], Ginkgo Biloba [R], Kava [R], L-theanine [R], Lavender [R], Melatonin, [R] Red Clover Extract [R], Valerian [R]


Other Antidepressant Supplements

Tianeptine, phenylpiracetam, sulbutiamine, caffeine, coffee, cacao, cocoa, black tea, green tea, berries, bananas, protein, Panax ginseng, bacopa monnieri, apigenin, chamomile, berberine, oleamide, acetyl-l-carnitine (ALCAR), N-acetyl-cysteine (NAC) inositol, ashwagandha, bacopa monnieri, maca, L-tyrosine, DLPA, hawthorn, purple passionflower, California poppy, hibiscus, sumac, holy basil (tulsi), lemon balm, uridine, tryptophan, CBD.

Conclusions on Depression Supplements

This topic is deeply personal to me, as I lived over half of my life with treatment-resistant major depression.

I recovered…finally.

If you are reading this, it means you too know how much depression can hurt.

If I can overcome depression after an endless struggle in total darkness and frustration, you can too.

I didn’t tell those around me about my depression struggles and instead kept it to myself.

And it’s this stigma of depression which makes us not want to discuss it.

This is part of the glue which keeps us stuck.

I only started talking about my past with the people closest to me when I finally broke free from it.

It was difficult at first to discuss and still is awkward to talk about a condition which no one would understand unless they experienced it themselves.

I only began talking about it because I felt it was selfish not to discuss it with others who are struggling with this hidden and most often irrational illness.

My one and only regret is not talking about my depression struggles earlier.

I truly believe this is the first step in the healing process, and I encourage you to start now.

I also strongly believe just taking supplements and/ or pharmaceuticals is not nearly enough, and your results will often find its limits.

The protocol I used to finally break free of depression has 4 parts to it, and all are equally important.

While I am free of depression today, I know if I stop practicing my depression-protocol, it can come back.

And who would want that to happen?

Hope is so important, and moreover the belief a better day is possible, and it absolutely is to the degree you allow yourself to believe it is possible.

In part two, we will discuss the latest research into theories and targets of depression, along with the winning strategies and lifestyle changes.

“Breathe and Believe.”

“From the Ashes, We Rise!”

[Related Article: The Top 9 Science-Backed Dopamine Supplements]

[Related Article: The Top 9 Science-Backed Norepinephrine Supplements]

What’s your favorite antidepressant supplement

Your Friend in Health

Mark Stein

[Get The Essential 3 Sugars and Fat for Every Health Optimizer]

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