And Nedley Health’s “Mood Balance”

The Role of Serotonin in Treating Mental Health Disorders

August 4, 2021

Stacey came to the residential Nedley Depression and Anxiety Recovery Program™ in her early 40s with a history of depression that had been going on since high school. After her first year of law school, her depression worsened, and she was put on medications. A traumatic biking accident in law school further deepened her depression, and she tried numerous new medications, but she still was not getting better. Instead, her condition caused her to have to take time away from law school. During this time, Stacey tried Zoloft (sertraline), Wellbutrin (bupropion), and Zyprexa (olanzapine), which caused her to have unwanted physical and facial movements, and Endep (amitriptyline), which caused weight gain.

“After a year, Stacey is feeling better than she ever remembers feeling.”

Since these more standard medications did not work, she was finally put on the most potent (and most dangerous) class of anti-depressants called monoamine oxidase inhibitor (MAOI). Stacey had to carefully watch her diet and lifestyle while taking the MAOI, Eldepryl (selegiline), with Wellbutrin. Thankfully, the combination of medications plus strict diet worked enough to allow Stacey to go back to law school and complete her course of studies. Due to her disabling depression and anxiety, the bar exam was allowed to be taken four times before she was able to pass. She finally landed a job with an important east coast law firm and married another attorney in the law firm.  

However, after an unsuccessful case that she took very personally, Stacey’s depression and anxiety worsened considerably despite the medications. She tried EMDR therapy, ketamine infusions (which did not work at all), and finally transcranial magnetic stimulation (TMS), which worked for a few months. However, after her third cycle of treatments, she felt worse off than before she had started TMS.

Stacey was taking three anti-depressants, including Abilify (aripiprazole) and Trintellix, and a potent medicine for ADHD, Vyvanse (lisdexamfetamine). Unable to work and living disabled by her conditions that continued to worsen with failing treatments, Stacey’s depression and anxiety were now classified as extreme. Although she was married to a good man, her marriage and family finances were under sizeable strain. Her psychiatrist had tried inpatient care but when that failed, he was ready to sign her permanent disability papers. That’s when her husband found the residential Nedley Depression & Anxiety Recovery Program™.  

When I met Stacey for the first time, she was experiencing deep sadness and cried through most of the interview. She had an increase in irritability, was constantly feeling on edge, had obsessive, negative thoughts, and was now starting to experience panic. She had become more impulsive with one of her signs of impulsivity being self-medicating with food, adding to her obesity. Many people who casually met her did not realize how much she was struggling because she looked calm on the outside but was actually quite tense on the inside. I quickly realized that every one of these presenting symptoms were signs of low brain serotonin.  

Traditional Treatment and Brain Serotonin

The problem is that no pharmaceutical agent or transcranial magnetic stimulation (TMS) can increase the brain’s ability to produce serotonin. In addition, no drug increases the amount of serotonin receptors. If giving serotonin in a pill or intravenously could increase the brain’s ability to produce serotonin neurotransmitter activity in the synapse, this therapy would likely be the most popular and effective therapy available for depression or anxiety, and it would be widely used to treat the symptoms Stacey suffered from. However, more serotonin in your blood does NOT equate to more serotonin in your brain. So how do these commonly prescribed medications work? They actually block the re-uptake channels for serotonin in the brain, preventing the releasing neurons from vacuuming up serotonin for later use. They might be more aptly called “serotonin vacuum cleaner pluggers.” These vacuum cleaners (re-uptake channels) are shown in the figure.

diagram of serotonin flow within the body

If any patient has a shortage of ability to make adequate serotonin in the brain (frequently due to a genetic mutation called under-methylation), inadequate light exposure, poor diet, or a shortage of nutrients necessary to produced adequate serotonin (such as tryptophan, folate, vitamin B6, vitamin B12, vitamin D, or magnesium), then serotonin synaptic activity will be reduced. Enter the most commonly prescribed pharmaceutical agents for depression and/or anxiety called an SSRI (selective serotonin re-uptake inhibitor), such as the one Stacey was taking called Trintellix (vortioxetine). Other commonly prescribed SSRIs include Prozac (fluoxetine), Zoloft (sertraline), Lexapro (escitalopram), or Paxil (paroxetine), along with others that in addition to their SSRI function are SNRI’s (selective norepinephrine reuptake inhibitors), such as Effexor or Pristiq (venlafaxine) or Cymbalta (duloxetine).  

“If this is done, medication will rarely be necessary for more than six months.”

How do these drugs produce more serotonin activity in the synapse?

These drugs work by blocking the vacuuming up of serotonin, there is more time for the inadequate amount of serotonin in the synapse to bind onto a serotonin receptor and produce synaptic activity. But this comes at a cost. Since serotonin is not vacuumed back into the releasing neuron, that neuron will end up with an even greater shortage of serotonin. That means it will require even more energy and nutrients to produce all of the required steps for the neuron to produce more serotonin. These medications can help short term (months to a year), but then relapse is common, and the person has to continue to see the doctor to get higher doses and additional medication. Such a patient can end up becoming a “psychiatric cripple” needing to see a psychiatrist frequently and still having troubling symptoms of depression and anxiety. Side effects include an “I don’t care attitude” which helps crying spells but can worsen motivation and empathy. In addition, worsened impulsivity before the depression improves can increase the risk of suicide or foolish behavior, and weight gain can occur, not to mention frequent sexual side effects. This is why medications alone are not the answer to depression and anxiety. Non-medical therapies and lifestyle interventions can be far superior to medications in efficacy as well as avoiding these unwanted side effects. If medications are prescribed, nutritional and lifestyle therapies should be prescribed along with the medication to achieve the goal of getting the neurons to produce more serotonin or build up more receptors. If this is done, medication will rarely be necessary for more than six months.  

Getting Serotonin into the Brain

The diagram of the synapse reveals that serotonin is produced inside the brain. Tryptophan, the building block of serotonin, has to get into the brain first. As Dr. Simon states in his article published in Psychiatry Neuroscience entitled How to Increase Serotonin in the Human Brain without Drugs, “Tryptophan is transported into the brain by a transport system that is active toward all the large neutral amino acids and tryptophan is the least abundant amino acid in protein. There is competition between the various amino acids for the transport system, so after the ingestion of a meal containing protein, the rise in the plasma level of the other large neutral amino acids will prevent the rise in plasma tryptophan from increasing brain tryptophan. The idea, common in popular culture, that a high-protein food such as turkey will raise brain tryptophan and serotonin is, unfortunately, false.” [i] He goes on to explain that lower protein food that comes packaged with carbs (plant foods) are a far better way to increase brain tryptophan. To understand this more practically, the section on nutrition and the brain in Depression and Anxiety Recovery Program Online will explain the details and foods to best accomplish this.  

But even if there is enough tryptophan that gets into the brain, serotonin does not automatically result. Tryptophan has to be converted to 5-HTP which then has to be converted to serotonin. There are a number of cofactors and conditions necessary for these steps to occur that have to do with diet and lifestyle (such as light through the eyes). The most active genetic condition seen in over a third of patients that attend our residential program (where we test every patient epigenetically to see if the genetic mutations are not only present but also active) is “under-methylation.” Whole blood testing confirmed that Stacey had this precise genetic condition and had low serotonin activity. Because of this, Stacey had a hard time making enough S-adenosylmethionine (SAMe) that provides the final methyl group to make melatonin out of serotonin, dopamine, and norepinephrine. In addition, she was low in vitamin D, had high cholesterol, and had borderline metabolic syndrome which were also contributing to her treatment-resistant depression. She needed a plant-based diet, an aerobic exercise fitness plan, and, due to her genetics, SAMe supplementation. After five days she had only slight improvement, and testing revealed continued low serotonin activity so the SAMe was increased. After 10 days, with only modest improvement, saffron crocus was added to augment the serotonin activity.  

Supplementation to Augment Serotonin Activity

Recent research has shown the saffron crocus has amazing anti-depressant properties, in part due to its brain serotonin production enhancing effects. [ii] Studies have shown saffron to be equivalent or superior to SSRIs in effectiveness in treating depression, but even more importantly, it does not have the unwanted sexual side effects nor the unwanted emotional side effects of apathy or impulsivity. In addition, saffron has been shown to help premenstrual dysphoria in women and even improve memory in those with memory loss. [iii] In a 2018 meta-analysis of seven randomized controlled trials (randomized trials provide higher levels of evidence), saffron had comparable efficacy to traditional antidepressants but without any serious adverse events reported. More recently, Khaksarian and colleagues concluded that saffron was as effective as fluoxetine in the treatment of major depression upon review of eight randomized controlled trials. [iv]

In my clinical practice in dealing with under-methylation, I have found that some people respond to low dose SAMe, but many need high doses to respond. If SAMe and saffron are both used, many respond even better than using one or the other, and we can often avoid the high cost of high doses of SAMe. Both of these supplements are very expensive, saffron being the most expensive spice known, and SAMe being one of the most expensive supplements, in part due to its documented high efficacy.  

No nutraceutical company as of yet has combined these two, despite their effectiveness together. So Nedley Health decided to put these together in our newest supplement Mood. And amazingly we were able to work the price down to lower than what you can find either supplement alone. Our patients who were taking both supplements were excited about the convenience of taking both in one capsule and thrilled with the significant cost savings. Mood is best absorbed without food with water on an empty stomach and can be taken first thing in the morning and can be repeated early or mid-afternoon. Some notice an improvement starting in three days, but it can take four to six weeks before noticing a big difference, although their families often notice the improvement before the patient does. It will take three months before maximum efficacy in most cases.  

What Happened to Stacey?

A few days after saffron was combined with the SAMe, Stacey began to notice significant improvement. By day 17, her depression and anxiety were almost gone, and within less then two months she was able to discontinue first the Abilify and then the Trintellix, and finally her other medications. Her husband said the change has been like the deepest, darkest night in contrast to the most beautiful, bright, and shiny day. Stacey’s tests one year later continue to show no depression or anxiety and she is now down to her ideal weight, feeling physically, mentally, socially, and spiritually better than she can ever remember.  

Stacey has commented that it is easier to empathize with others, and now she can easily focus on her daughter and husband. And yes, she is back to work. Her boss has noticed increased productivity plus a surprising practical increase in creativity. At home, her artistic and musical ability returned. Perhaps most importantly, she has improved greatly in the so called “executive functions” including proper analysis and wise planning for the future. These positive traits all symptoms of adequate serotonin activity in the brain. In short, those with a healthy abundance of serotonin production and activity make great neighbors, great workmates, and great family members, and that is exactly who Stacey has become.  

Stacey’s only regret is that she did not find this program in her late teens and 20s. She said the process of finding and treating the underlying cause through nutrition and lifestyle would have saved her years of academic, social, emotional, employment, and relational turmoil. The simple dietary changes plus Mood and physical exercise have made all the difference in the world to Stacey.  

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[i] Young S. N. (2007). How to increase serotonin in the human brain without drugs. Journal of psychiatry & neuroscience: JPN, 32(6), 394–399.

[ii] Wang, Y., Han, T., et al. (2010). Antidepressant properties of bioactive fractions from the extract of Crocus sativus L. Journal of natural medicines, 64(1), 24–30.

[iii] Akhondzadeh, S., Sabet, M. S., et al. (2010). Saffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebo-controlled trial. Journal of clinical pharmacy and therapeutics, 35(5), 581–588.

[iv] Yang, X., Chen, X., et al. (2018). Comparative efficacy and safety of Crocus sativus L. for treating mild to moderate major depressive disorder in adults: a meta-analysis of randomized controlled trials. Neuropsychiatric disease and treatment, 14, 1297–1305.

About the author

Neil Nedley, MD, is a practicing physician in internal medicine. He is the founder and medical director of the Nedley Depression and Anxiety Recovery Programs™. Dr. Nedley has presented and published numerous scientific studies in the medical literature and is well known internationally as a public speaker and teacher. He is author of Proof Positive, Depression—the Way Out, The Lost Art of Thinking, and Optimize Your Brain. Dr. Nedley and his wife Erica have four sons.