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What are the Best Serotonin Supplements for Anxiety and Depression?

Top 9 Evidence-Based Serotonin Optimizers List

Serotonin, as a primary neurotransmitter, has always been the focus as a key regulator of our mood. In recent years, researchers have been finding the mood disorder role of serotonin a complex one, and not what we previously believed it to be as the sole cause of mood disorders such as depression.

Even still, some researchers believe any activity involving human behavior involves serotonin. Amongst the 7 major serotonin 5-HT receptors, we find 70% of their cells in the gastrointestinal system, producing 90% of all serotonin in the human body.

From mood to digestion to even blood vessel function, serotonin plays more roles than most seem to believe. Going beyond just mood, serotonin is a key manager of the gastrointestinal system and various gastrointestinal conditions.

This has led us to believe the roles of serotonin are much more complicated than once believed. Much like we believe serotonin activity can operate in dysfunction, it is also possible to increase serotonin to unsafe levels.

Serotonin syndrome is often the result of dangerous serotonin levels from serotonergic substances such as 5-HTP, or MDMA, also known as “Molly” or “ecstasy”. If an individual believes that they are experiencing serotonin syndrome, they should seek immediate medical attention, as this can be a serious condition.

It would be reckless to discuss serotonin, without analyzing the role of the gut, as this is where we produce serotonin. For this reason, we continue to reason optimal gut health can equate to better serotonin function.

#1 5-HTP

The human body directly synthesizes serotonin from 5-HTP, an amino acid produced by the body. 5-HTP crosses the blood-brain barrier creating serotonin in the brain, while serotonin itself, primarily produced in the gut, does not cross the blood-brain barrier.

And this is an important distinction. Despite synthesis from L-tryptophan, it remains unclear whether L-tryptophan, another amino acid, is an effective supplement for raising 5-HTP.

Some evidence exists to support using L-tryptophan, as with melatonin, for insomnia and sleep improvement. Overall, 5-HTP, we consider as the more effective serotonin supplement.

Some believe the use of 5-HTP should be limited to 3 days, and any use beyond the short-term is counterproductive. As 5-HTP can suppress dopamine function, others in the nootropics community believe that “stacking”, or combining 5-HTP, with dopamine enhancing substances such as mucuna pruriens or L-tyrosine, provides for the best “full-spectrum effect.”

#2 Agmatine

Matching its very strong anecdotal support within the nootropics community, the initial agmatine studies, while tiny, are promising. Agmatine, an amino acid derived from another amino acid, L-arginine, as its metabolite or byproduct, is a popular athletic performance enhancer.

We believe the antidepressant effect on serotonin is because of the inhibition or blocking of excess glutamate, which can be toxic to the brain. This means it has a neuroprotective action, protecting the brain from toxicity, as an N-methyl-D-aspartate receptor (NMDA antagonist).

Some studies show agmatine to, directly and indirectly, raise serotonin levels. We also see some initial and promising evidence for cardiovascular protection besides the neuroprotection, in the form of nitric oxide production, which relaxes and dilates blood vessels.

Neuropathic pain and drug addiction are newer indications of agmatine evaluation with some initial success. Some biohackers in the nootropics community are claiming to realize even better results with intranasal using agmatine in the way of stronger effects and longer duration of effects.

#3 Creatine

We find sound evidence of creatine supplements improving symptoms of depression by increasing phosphocreatine stores in the brain. This effect appears to be greater amongst females and likewise greater amongst those on plant-based diets, not deriving creatine from meat consumption.

We also believe creatine increases mitochondrial function and dopamine levels. Some nootropics and supplement users are now combining creatine with d-ribose, another mitochondria booster, and cardioprotective supplement.

We theorize creatine improves cognition, not only through increased energy but likewise via neuroprotection. More and more evidence continues to emerge supporting creatine for use as much more than just a popular workout supplement.

Finally, creatine appears to be an area of deficiency and supplement focus for vegans. Studies typically have used 5 grams for dosage and as well lead us to believe micronized creatine might offer better gut tolerance.

#4 Krill or Vegan Algal Oil

Emerging studies show that omega-3 fatty acids in algae or krill phospholipid form may be superior to fish oil or even cod liver-based omega-3’s, because of the differences in structural form. This means phospholipids have much greater bioavailability and absorption, as every cell membrane in the human body is made of phospholipids.

In this phospholipid form, omega-3’s, (DHA and EPA), are more shelf-stable than fish oil, allowing for significantly lower dosages. While we need more studies to confirm this, initial studies are promising, and also seen in other areas of research such as cardioprotective benefits.

Proven for serotonin and dopamine, Omega-3’s are being linked as most effective for individuals with depression in the absence of anxiety. As vitamin D helps produce serotonin as a key-cofactor, omega-3’s help serotonin work more efficiently.

Eicosapentaenoic acid, (EPA) within omega-3 fatty acids, lowers brain inflammation, enabling efficient serotonin release from our serotonin receptors.

#5 Saffron

Saffron, we know as the bright red spice as the world’s most expensive herb. It proves itself as a notable booster of serotonin, equally effective to SSRI’s in several studies.

Showing effectiveness for PMS, SSRI alternative for those experiencing erectile dysfunction, and appetite suppression, saffron most recently has most famously surfaced in one study as equally effective to ADHD medication for children.

A potent antioxidant, saffron is under investigation for a wider array of serious conditions beyond mood and cognition studies. Studies use a standardized extract dosage of 15 mg two times daily in studies.

#6 Curcumin

Curcumin is turmeric’s primary active polyphenol compound, producing its bright yellow color. Several curcumin studies illustrate how we believe it to carry its effect through potent antioxidant and anti-inflammatory mechanisms along with other actions.

While evidence supports its role in increasing serotonin, it only increases dopamine with higher dosages, while maintaining no effect on norepinephrine. While researchers have questioned the low bioavailability of curcumin, one study has shown it in the form of BCM-95 to be effective for serotonin-related depression indications.

Curcumin problematically has very low bioavailability, which is addressed by recent patented high-absorption formulas. When taken with meals, fat will also increase the absorption of curcumin.

Other areas of ongoing curcumin research involve its effect on brain-derived neurotrophic factor (BDNF), working memory, NMDA, glutamate, attention, mood, and cortisol.

#7 Black Seed Oil

Black seed oil (Nigella Sativa), also known as black cumin seed, is one of the world’s oldest plants native to South Asia and has been used for a wide array of indications. Over the years it has been affectionately labeled, “the cure for all diseases except for death.”

While black seed oil, also known as black cumin oil, has lacked evidential support, recent anecdotes represent significant success with black seed oil in the opioid community, assisting those in recovery. Further research is now reviewing black seed oil in human studies raising acetylcholine, GABA, and serotonin levels.

We attribute the mechanism for its anxiolytic or relaxing effects to high levels of thymoquinone, its most crucial phytochemical compound.

#8 SAMe (S-adenosyl-L-methionine) or TMG (Trimethylglycine)

SAMe (S-adenosyl-L-methionine) performs equal to a variety of antidepressants, none of which outperformed placebo. SAMe appears to have the greatest effect on men and/or those with either excessive homocysteine levels or vitamin B12 and/or folate deficiencies, because of methylation dysfunction.

Besides mood and homocysteine, SAMe is indicated for those with joint pain related to osteoarthritis. TMG (Trimethylglycine), directly produces SAMe, and while we have not studied TMG like SAMe, it serves as an alternative that users might find more cost-effective.

#9 St. John’s Wort

St. John’s Wort, (Hypericum perforatum), is an ancient plant with yellow flowers, available as a supplement in many forms. It is a widely used and traditionally popular anti-depressant plant.

In studies, it performs as effectively as Prozac, and much more effectively than Zoloft. More Germans use St. John’s wort than Prozac.

Hypericin and hyperforin, its primary active biological compounds, produce effects on dopamine, serotonin, and norepinephrine. Dangerous and even possibly life-threatening serotonin syndrome interactions can occur with St. John’s Wort and prescription medications.

Top 9 Notables

Inositol, L-theanine, Kanna, MCT oil, probiotics, red clover extract, Rhodiola Rosea, soluble fiber, St. John’s Wort.

Essential Cofactors

Magnesium, Vitamin B6 Pyridoxal-5-Phosphate (P5P), Methylated Vitamin B9 (Folate), Methylated Vitamin B12, Selenium, Vitamin B3 (Niacin), Vitamin C (Ascorbic Acid), Vitamin D3, Zinc.





Lemon oil, ginger, L-lysine.


L-tryptophan => 5-HTP => serotonin — vitamin B3 => melatonin — vitamin B6.

Serotonin Receptors

5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, 5-HT7.


5-HTP, L-tryptophan.


Acetyl-L-carnitine, alpha-GPC, American ginseng, apigenin, ashwagandha, Asian ginseng, BPC-157, bacopa monnieri, berberine, bromantane, butyric acid, CDP-choline, CoQ10, cacao, cannabidiol (CBD), carvacrol, chocolate, clary sage, cocoa, coca leaf, cod liver oil, creatine, DHA, danshen, eleuthero (Siberian ginseng), fenugreek, fish oil, ginkgo Biloba, green tea, hibiscus, holy basil, inositol, insoluble fiber, iron, kratom (mitragyna speciosa), Korean ginseng (Panax ginseng), L-DOPA, tryptophan, lavender, lemon balm, lithium orotate, maca, magnolia bark, matcha tea, mucuna pruriens, Muira Pauma, Myo-inositol, niacin (vitamin B3), niacinamide, Oil of oregano, oregano, PQQ, pregnenolone, probiotics, protein, purple passionflower, resistant starch, resveratrol, rosemary, shilajit, sumac, THC, taurine, ubiquinol, valerian, white oolong tea.

Your Friend in Health,

Mark Stein



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