Anxiety, Depression, and Insomnia: Treatment Using the Hippocratic Philosophy

CHRIS D. MELETIS, ND 

The philosophy of Hippocrates has been shown over the past 2400 years to not only have merit but also notable scientific veracity. Hippocrates advocated a natural approach to the treatment of diseases and emphasized the need for harmony between the individual and social and natural environments.1 His approach is especially relevant to mental disorders such as depression and anxiety. The Hippocratic philosophy centered around the belief that a healthy mind in a healthy body was the cornerstone of good health.1 Hippocrates emphasized that if the body and mind weren’t in harmony, an imbalance occurred that led to disease.1 In keeping with this body-mind philosophy, he encouraged the use of music and drama as a tool for helping patients with mental disorders.1 Hippocrates also advocated physical activity as a critical component of physical and mental health.1 Furthermore, he promoted eating a nutritious diet to enhance performance of athletes in the Olympic Games.1  

In treating patients with mental health problems such as depression, anxiety, and insomnia, the modern clinician can replicate this Hippocratic philosophy. Scientists have now identified aspects of these disorders that back up Hippocrates’ philosophy that the health of the mind is tied to the health of the body. For example, we now know that the gut is essentially a “second brain” that can influence our mood. This article will address the connection between the mind and body with respect to depression, anxiety, and insomnia. 

The Role of Neuroinflammation 

Individuals with major depressive disorder often have elevated levels of inflammatory biomarkers, such as C-reactive protein (CRP), and proinflammatory cytokines, such as IL-1β and IL-6.2 CRP and these cytokines can directly influence mood and emotion.3  

Furthermore, inflammation can indirectly impact mood by influencing tryptophan metabolism. The body can convert the amino acid tryptophan into the feel-good neurotransmitter serotonin and the sleep-inducing-hormone melatonin, or it can convert tryptophan to kynurenine.4 Chronic low-grade inflammation, such as can happen in patients with major depressive disorder (MDD),5 can activate the tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase (IDO), leading to decreased tryptophan levels and upregulation of the kynurenine-pathway (Figure 1).6 

Figure 1

(IDO = indoleamine 2,3-dioxygenase) 

When tryptophan is metabolized through the kynurenine pathway, the body has less access to serotonin and melatonin, which are both essential for mood and sleep. Furthermore, the kynurenine pathway generates potentially neurotoxic metabolites, such as such as 3-hydroxykynurenine and quinolinic acid.5,7  

The Link Between Sleep & Depression 

Insomnia is a risk factor for depression.8,9 It is thought that insomnia-exacerbated inflammation may be the mechanism of action by which chronic sleep loss can lead to depression.10-13 Conversely, depression can also lead to sleep loss, creating a vicious circle.  

Inflammation-induced alterations of kynurenine metabolism may explain the association between insomnia and depression. In a study of 68 currently depressed, 26 previously depressed, and 66 never-depressed subjects, only in the currently depressed group was sleep disturbance associated with alterations in kynurenine metabolites.7 Likewise, CRP levels were high only in the subjects with sleep disturbances who were currently depressed.7  

Obstructive sleep apnea (OSA) is a common sleep disorder that is linked to depression.14 OSA occurs when a patient temporarily stops breathing while sleeping, resulting in low oxygen levels. We can live without food for weeks and water for days, but we can only live without air for moments. OSA does not only occur in obese patients; I have diagnosed mild, moderate, and severe sleep apnea in people who are thin, young, and with no or few classical symptoms. My philosophy is always “test, don’t guess.” The standard treatment for OSA is for patients to use a continuous positive airway pressure (CPAP) machine. Resolving sleep apnea can result in a corresponding decrease in depression. Adults with OSA and coronary artery disease experienced reduced depression scores after 3 months of CPAP treatment, compared to participants not using CPAP.15  

The Body’s Second Brain 

An abundant array of research supports the existence of a gut-brain axis, which points to a strong connection between a healthy gut and optimal mental health and well-being. The fact that the gut microbiota produce or consume various neurotransmitters, including dopamine, norepinephrine, serotonin, and gamma-aminobutyric acid (GABA), is a strong indicator of the connection between the gut and the brain.16 In fact, 90% to 95% of serotonin is produced in the GI tract, mostly in epithelial enterochromaffin cells.16,17 Unfortunately, if tryptophan is metabolized via the kynurenine pathway, the resulting serotonin depletion may contribute to a number of adverse effects including depression and anxiety.18 

Animal research has established a direct association between the gut microbiota and many mental disorders, including chronic stress, anxiety, depression, and abnormal feeding behavior.19-21 This association is driven by molecules synthesized from bacteria, including short-chain fatty acids (SCFAs), secondary bile acids, and tryptophan metabolites such as 5-HTP (5-hydroxytryptophan) or serotonin that influence neurotransmitter synthesis in the central nervous system (CNS).22 Chemical signals produced in the gut may travel across the intestinal barrier, reaching the systemic circulation, and ultimately crossing the blood-brain barrier.23  

Animal models further support the role the GI tract plays in mood regulation through the influence of neurotransmitter levels. In these models, gut microbiota assisted with the regulation of serotonin levels as well as other neurotransmitters.16 Furthermore, research in germ-free animals (lacking a microbiome) determined that rodents without bacteria had significantly lower levels of norepinephrine in the cecal lumen and in the tissue compared with non-germ-free animals.24 The researchers were able to restore cecal levels of norepinephrine by colonizing the animals with a specific pathogen-free microbiota or a mixture of 46 Clostridia species. It was unclear whether the bacteria produced norepinephrine directly or influenced the animals’ production of it. When levels of the neurotransmitter, norepinephrine, are balanced, the body is better able to cope with stress. Imbalanced norepinephrine levels are associated with anxiety, depression, substance abuse, and post-traumatic stress disorder (PTSD).25 

Human research also indicates that the gut microbiota can influence levels of GABA,26 the major inhibitory neurotransmitter in the CNS. Evidence points to a link between altered GABAergic neurotransmission and CNS disorders, such as anxiety, depression, pain, and sleep.26,27  

In humans, dietary interventions can change the composition and function of the gut microbiome.28 For example, consuming a ketogenic diet was shown to increase GABA levels in the cerebrospinal fluid of children with refractory epilepsy and was associated with an improvement in symptoms.29 In addition, in obese people with metabolic syndrome receiving a fecal transplant from lean donors, GABA was the most altered metabolite and was associated with enhanced insulin metabolism.30 This supports the idea that the gut microbiota can affect neurotransmitters involved in mental health. 

How Diet Affects Mood & Mental Health 

The saying “you are what you eat” is never more true than in regards to mental health. A Western-style diet including excessive fats and sugar can change the composition of the gut microbiota.31 This type of diet is associated with chronic inflammation and obesity and corresponding mental disorders such as depression.31-33 Research in mice indicates that this becomes a vicious circle, whereby eating a Western-style diet can cause depression and anxiety, but withdrawing from this type of eating pattern also causes anxiety as well as a craving for more sweet foods.34 This leaves patients trapped in a pattern that will only cause them to become more depressed and anxious. Ongoing psychological stress only makes matters worse. This is because it impairs the function of the hypothalamic-pituitary-adrenal (HPA) axis, which often results in increased intake of food,33 especially unhealthy foods. This in turn leads to high cortisol levels, which contributes to obesity.33   

NO’s Role in Relieving Depression & Anxiety  

Imbalanced levels of the neurotransmitter, nitric oxide (NO), are associated with anxiety and depression, due to NO’s role as a regulator of neuroinflammation.35 NO is thought to influence the release of other neurotransmitters. In doing so, it is involved in brain cell function, such as plasticity and development, and may also increase blood flow to the brain due to its vasodilating actions.35 Abnormalities in NO signaling correlate with major depressive disorder, and certain polymorphisms in the neuronal nitric oxide synthase gene (NOS1) are linked to MDD.36  

Natural Support for Depression, Anxiety, & Insomnia  

First and foremost, I recommend a Hippocrates-style approach to my patients by prescribing a diet rich in vegetables to raise dietary nitrate, a precursor of NO. Exercise is also important to boost mood. Ideally, exercise should be practiced outdoors at least some of the time, as research indicates spending time in nature can benefit mental health.37 In addition to those foundational strategies, I recommend the following supplements to my patients who need to support their mental health. 

Amino Acids & B Vitamins 

Eating a healthy diet is only useful if it’s accompanied by proper absorption of nutrients. This is essential for fueling complex biochemical pathways including the citric acid cycle that is essential for manifesting the genetic potential and biochemical output of neurons to make neurotransmitters. For example, sufficient amino acids such as tyrosine, phenylalanine, and tryptophan are required for the body to produce neurotransmitters. Therefore, an amino acid supplement can be used to fuel neurotransmitter production. Likewise, B vitamins such as B6, B12, and folate are necessary for a sense of well-being.38,39 Therefore, a multivitamin or a B vitamin containing the active and bioavailable form of folate is also foundational. 

Beetroot Juice 

Beetroot juice supports healthy levels of nitric oxide. Beetroot juice as well as dietary nitrates can help maintain the endothelial lining of blood vessels.40 This supports healthy circulation and, in turn, healthy blood pressure and blood flow to the brain.40 In my clinical practice, I find that people who have depression, anxiety, insomnia, or PTSD often have elevated blood pressure, making beetroot juice useful in this group of patients. Additionally, circulation is vitally important for nutrient delivery to target tissues, and the enhancement in circulation through increasing NO can help deliver critical nutrients to the systemic circulation and the brain.   

As noted earlier in this article, imbalanced NO levels are associated with anxiety and depression. Consequently, normalizing NO levels may also benefit mental health. However, before beginning supplementation with beetroot juice, I recommend testing patients to establish their nitric oxide levels. The key is to achieve balanced levels of this important neurotransmitter and signaling molecule.   

Curcumin 

A number of randomized, double-blind, placebo-controlled trials have indicated that Curcuma longa (curcumin) can relieve depression. This may be due to its role in mitigating neuroinflammation. In one of those studies, 80 patients with diabetic polyneuropathy were given 80 mg of nano-curcumin or a placebo daily for 8 weeks.41 Researchers measured the subjects’ depression, anxiety, and stress levels using the Depression, Anxiety, Stress Scale questionnaire before and after the intervention. The curcumin group experienced a pronounced reduction in the mean depression and anxiety scores compared with placebo group. Curcumin had no significant effect on the stress scores. 

In another double-blind, placebo-controlled trial, 65 people with MDD randomly received either curcumin or a placebo together with their usual antidepressant medications for 12 weeks.42 The curcumin dose was progressively increased from 500 to 1500 mg per day. Curcumin was more effective than placebo in improving depression scores, especially in the male study participants.  

Another trial, this one a double-blind, crossover study of 30 obese individuals, found that 1 gram/day of curcumin for 30 days reduced anxiety compared to the placebo.43 In this study, curcumin had no effect on depression scores.  

It should be noted that curcumin can be poorly absorbed by the body. Therefore, it is best to use a form with enhanced bioavailability.   

Hemp Oil  

Hemp oil contains cannabidiol (CBD), which can support a restorative night’s sleep as well as reduce depression and anxiety. CBD may reduce REM sleep behavior disorder and excessive sleepiness during the day.44 Furthermore, it was shown that people with insomnia given 160 mg CBD slept more deeply and awakened less during the night compared with the placebo.45 A case report also found that CBD oil reduced anxiety and improved sleep in a child suffering from PTSD.46  

At high concentrations, CBD can directly activate the 5-HT1A serotonin receptor, which mediates antidepressant actions.47 CBD has been found in human research to reduce anxiety in individuals with generalized social anxiety disorder.47 In other human studies, CBD at doses of 300-600 mg reduced anxiety in subjects participating in a simulated public speaking test.48,49  

L-Theanine 

This green-tea-derived botanical promotes relaxation and a state of calm alertness. In a double-blind, randomized, placebo-controlled, crossover trial, researchers gave 200 mg/day L-theanine supplements or a placebo to 30 healthy adults.50 Four weeks of L-theanine administration led to falling asleep faster, staying asleep longer, and reduced use of sleep medication compared to the placebo. Moreover, verbal fluency and executive function scores improved after supplementing with L-theanine. In an open-label study, L-theanine supplements were given to patients with MDD along with their current medication.51 Eight weeks of L-theanine supplementation led to decreased depression and anxiety scores. L-theanine was also associated with improved sleep and cognition, including verbal memory and executive function.  

Rhodiola 

Rhodiola rosea is an adaptogen that helps the body cope with stress. Doses of 200 mg twice daily have been found to reduce anxiety, stress, anger, confusion, and depression.52 It is also effective in reducing stress-related fatigue.53,54 Rhodiola is a good choice for patients with obstructive sleep apnea, as it was shown in one study to reduce anxiety and depression in this group of patients through a mechanism that involved blocking oxygen free radicals and lipid peroxidation.55  

Probiotics 

Due to the existence of the gut-brain axis, the inclusion of a probiotic supplement will increase the effectiveness of a depression, anxiety, and insomnia regimen. Supplementing with probiotics has been shown to reduce depression and anxiety.56-59 Probiotics can also be used to normalize the kynurenine pathway. The probiotic bacteria Lactobacillus Plantarum 299v was shown to reduce kynurenine levels and improve cognitive function in patients with MDD.60 Eating a healthy, Mediterranean-style diet can also favorably impact the gut microbiota.61  

Conclusion 

Science is now validating the mind-body approach Hippocrates used thousands of years ago. The existence of the gut-brain axis, establishing a connection between the mind and GI tract, firmly points to a connection between the health of the gut and the condition of the mind. In fact, neurotransmitters such as serotonin are primarily produced in the gut. Depression and anxiety are influenced by gut health, as well as other factors such as neuroinflammation and imbalanced nitric oxide levels. Diet, exercise, restorative sleep, and supplementation with such botanicals and nutrients as amino acids, active B-vitamins, beetroot juice, curcumin, hemp oil, L-theanine, rhodiola, and probiotics can go a long way in promoting a sense of happiness and well-being.     

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Chris D. Meletis, ND is an educator, international author, and lecturer. He has authored 18 books and more than 200 scientific articles in prominent journals and magazines. Dr Meletis served as Dean of Naturopathic Medicine and CMO for 7 years at NUNM. He was recently awarded the NUNM Hall of Fame award by OANP, as well as the 2003 Physician of the Year by the AANP. Dr Meletis spearheaded the creation of 16 free natural medicine healthcare clinics in Portland, OR. Dr Meletis serves as an educational consultant for Fairhaven Health, Berkeley Life, TruGen3, US BioTek, and TruNiagen. He has practiced in Beaverton, OR, since 1992. 

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