Hey friend,

The depression epidemic is at an all-time high…

The pharmaceutical industry managed to get a staggering 10% of U.S. adults—about 25 million people—on antidepressants. [1]

But despite this, happiness and mental wellness remains elusive.

For many, the medications only add to the problem:

• Maxed-out doses with no relief—emotionally numb, just surviving, not thriving.
• Lexapro, Zoloft, Wellbutrin, Effexor, Prozac, Cymbalta—the meds stop working, you move to the next, and you’re back to square one.
• Side effects like sedation, weight gain, and heightened anxiety pile up... and then you’re handed another pill to manage those.

This vicious loop leaves you dependent on medications, only to realize that stopping them doesn’t bring you any closer to mental wellness than when you began…

But I'm NOT saying that they are ineffective for everyone.

They can be life-changing for some, but they fall short for many others!

And while a holistic approach to depression—addressing mind, body, and soul—is key, many just want a more natural alternative to pharmaceutical antidepressants to help them through the rough patches.

That’s exactly what I want to explore with you today.

Top 3 natural antidepressants for holistic mental health treatment

1) Psilocybin mushrooms

Ah, the humble psilocybin mushroom. After years of misinformation and propaganda, its healing power is finally being recognized!

I consider it one of the most effective, multi-faceted antidepressants—here's why.

• Psilocybin softens the Default Mode Network (DMN)—the brain’s "ego center"—breaking free from negative thought loops and boosting cognitive flexibility. In short, it helps you get out of your own way. [2]
• Psilocybin boosts neuroplasticity, enhancing neuron growth and repair, particularly in the prefrontal cortex (PFC)—a key area involved in depression and related disorders. [3]

And when you compare psilocybin to pharmaceutical antidepressants, the difference is clear:

• Antidepressants activate 5-HT1A receptors in the brain’s stress network, promoting passive coping. This leads to stress tolerance, emotional blunting, and a sense of patience, allowing you to endure without initiating change.
• Psilocybin activates 5-HT2A receptors [4] in the prefrontal cortex, promoting active coping and higher-level thinking. This sparks new ways of thinking, feeling, and being, breaks self-limiting patterns, and boosts brain plasticity—making change easier and longer lasting.

Just when you thought it couldn't get any better—psilocybin also helps reduce neural inflammation [5], an often overlooked factor in depression. [6]

AND it also promotes interconnectivity between brain regions, unlocking pathways and connections that may have never communicated before, tapping into the brain’s full potential! [7]

"Magic Mushroom" is right!!! 🍄

2) St. John's Wort

St. John's Wort (Hypericum perforatum) is a medicinal herb with roots dating back to ancient Greece, where it was used to treat nervous system conditions.

Known as "liquid sunshine," it lifts spirits and brings joy to those feeling gloomy. ☀️

It's a true herbal antidepressant powerhouse.

Meta-analyses have shown that St. John's Wort is as effective as pharmaceuticals for treating depression, but with fewer side effects. [8,9,10]

You might be thinking, how is St. John's Wort that effective for depression? Good question. Here's what we know:

• St. John's Wort supports depression primarily by influencing serotonin, dopamine, and norepinephrine levels in the brain. [11]
• It acts as a natural monoamine reuptake inhibitor (similar to some antidepressants), preventing the reuptake of these neurotransmitters. [12]
• St. John's Wort has anti-inflammatory and antioxidant properties. [13]
• It’s believed to also regulate the hypothalamic-pituitary-adrenal (HPA) axis, which is involved in the body’s stress response, further supporting emotional well-being. [14]

It’s a complex web of factors supporting depression, not just a single pathway.

*Caution: St. John's Wort is a wonderful natural antidepressant but should be used cautiously with other pharmaceuticals, especially antidepressants, as it can increase the risk of serotonin syndrome (a potentially life-threatening condition).

It's important to consult with a healthcare provider before using St. John's Wort!

3) Saffron

Saffron, the dried stigma of the Crocus sativus plant from the Middle East, is the most expensive culinary spice, costing between $500 and $5,000 per pound due to its labor-intensive hand harvesting.

Luckily, a little goes a long way—especially when compared to the astronomical costs of pharmaceutical drugs!

Saffron is rich in pharmacologically active compounds like crocin, safranal, flavonoids, vitamin C, and minerals [15]. It has been used medicinally for hundreds (if not thousands) of years to treat various ailments.

Talk about letting food be thy medicine!

Saffron is a time-tested herbal medicine, with modern research revealing its antidepressant efficacy comparable to pharmaceutical options like Prozac—without the side effects. [16]

Saffron works to support depression naturally by:

• Boosting serotonin levels
• Reducing oxidative stress and inflammation in the brain
• Protect brain cells from damage which supports overall brain function and mood
• And regulating the neuroendocrine system [17]

What's impressive is that numerous meta-analyses are consistently showing that saffron outperforms placebo in improving depressive symptoms, is as effective as synthetic antidepressants, and is safe!

[18,19,20]

If you're battling depression and feel overwhelmed, know that there is hope.

The path to healing is not easy, but it’s possible with the right support and protocol!

A natural approach can break the pharmaceutical cycle and address the root causes of emotional turmoil.

These natural antidepressants offer a broader spectrum of benefits, engaging in complex mechanisms beyond just boosting serotonin levels, which is the main action of SSRIs.

Addressing underlying factors like inflammation, oxidative stress, neurotransmitter imbalances, and more, supports a more holistic and sustainable path to healing.

I'm curious—if you've battled depression, have you tried any of these natural antidepressants?

Hit reply and let me know.

See you next Saturday,

Onjae

References:

[1] Elgaddal, Nazik. "QuickStats: Age-Adjusted Percentage of Adults Aged ≥18 Years Who Take Prescription Medication for Depression, by Sex and Race and Hispanic Origin — National Health Interview Survey, United States, 2021." MMWR Morbidity and Mortality Weekly Report, vol. 72, no. 21, 26 May 2023, pp. 591. Centers for Disease Control and Prevention, www.cdc.gov/mmwr/volumes/72/wr/mm7221a5.htm. Accessed 15 Jan. 2025.

[2] Gattuso, James J et al. “Default Mode Network Modulation by Psychedelics: A Systematic Review.” The international journal of neuropsychopharmacology vol. 26,3 (2023): 155-188. doi:10.1093/ijnp/pyac074

[3] Zhao, Xiangting et al. “Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice.” Journal of psychopharmacology (Oxford, England) vol. 38,5 (2024): 489-499. doi:10.1177/02698811241249436

[4] Madsen, Martin K et al. “Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels.” Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 44,7 (2019): 1328-1334. doi:10.1038/s41386-019-0324-9

[5] Flanagan, Thomas W, and Charles D Nichols. “Psychedelics as anti-inflammatory agents.” International review of psychiatry (Abingdon, England) vol. 30,4 (2018): 363-375. doi:10.1080/09540261.2018.1481827

[6] Beurel, Eléonore et al. “The Bidirectional Relationship of Depression and Inflammation: Double Trouble.” Neuron vol. 107,2 (2020): 234-256. doi:10.1016/j.neuron.2020.06.002

[7] Petri, G et al. “Homological scaffolds of brain functional networks.” Journal of the Royal Society, Interface vol. 11,101 (2014): 20140873. doi:10.1098/rsif.2014.0873

[8] Zhao, Xin et al. “The efficacy and safety of St. John's wort extract in depression therapy compared to SSRIs in adults: A meta-analysis of randomized clinical trials.” Advances in clinical and experimental medicine : official organ Wroclaw Medical University vol. 32,2 (2023): 151-161. doi:10.17219/acem/152942

[9] Ng, Qin Xiang et al. “Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis.” Journal of affective disorders vol. 210 (2017): 211-221. doi:10.1016/j.jad.2016.12.048

[10] Linde, Klaus et al. “St John's wort for major depression.” The Cochrane database of systematic reviews vol. 2008,4 CD000448. 8 Oct. 2008, doi:10.1002/14651858.CD000448.pub3

[11] Müller, W E et al. “Hyperforin--antidepressant activity by a novel mechanism of action.” Pharmacopsychiatry vol. 34 Suppl 1 (2001): S98-102. doi:10.1055/s-2001-15512

[12] Butterweck, Veronika. “Mechanism of action of St John's wort in depression : what is known?.” CNS drugs vol. 17,8 (2003): 539-62. doi:10.2165/00023210-200317080-00001

[13] Tedeschi, Elisa et al. “Anti-inflammatory actions of St. John's wort: inhibition of human inducible nitric-oxide synthase expression by down-regulating signal transducer and activator of transcription-1alpha (STAT-1alpha) activation.” The Journal of pharmacology and experimental therapeutics vol. 307,1 (2003): 254-61. doi:10.1124/jpet.103.054460

[14] Butterweck, V et al. “Flavonoids of St. John's Wort reduce HPA axis function in the rat.” Planta medica vol. 70,10 (2004): 1008-11. doi:10.1055/s-2004-832631

[15] Srivastava, R, et al. "Crocus Sativus L.: A Comprehensive Review." Pharmacognosy Reviews, vol. 4, no. 8, 2010, p. 200, https://doi.org/10.4103/0973-7847.70919. Accessed 15 Jan. 2025.

[16] Khaksarian, Mojtaba et al. “The efficacy of Crocus sativus (Saffron) versus placebo and Fluoxetine in treating depression: a systematic review and meta-analysis.” Psychology research and behavior management vol. 12 297-305. 23 Apr. 2019, doi:10.2147/PRBM.S199343

[17] Matraszek-Gawron, Renata et al. “Current Knowledge of the Antidepressant Activity of Chemical Compounds from Crocus sativus L.” Pharmaceuticals (Basel, Switzerland) vol. 16,1 58. 30 Dec. 2022, doi:10.3390/ph16010058

[18] Tóth, Barbara et al. “The Efficacy of Saffron in the Treatment of Mild to Moderate Depression: A Meta-analysis.” Planta medica vol. 85,1 (2019): 24-31. doi:10.1055/a-0660-9565

[19] Dai, Lili et al. “Safety and Efficacy of Saffron (Crocus sativus L.) for Treating Mild to Moderate Depression: A Systematic Review and Meta-analysis.” The Journal of nervous and mental disease vol. 208,4 (2020): 269-276. doi:10.1097/NMD.0000000000001118

[20] Shafiee, Arman et al. “Effect of Saffron Versus Selective Serotonin Reuptake Inhibitors (SSRIs) in Treatment of Depression and Anxiety: A Meta-analysis of Randomized Controlled Trials.” Nutrition reviews, nuae076. 24 Jun. 2024, doi:10.1093/nutrit/nuae076