A Root Cause Medicine Protocol for Patients With Generalized Anxiety: Comprehensive Lab Testing, Therapeutic Diet, and Supplements

Generalized anxiety disorder (GAD), a mental health disorder characterized by excessive anxiety and worry about various events or activities, affects nearly 6% of American adults at some point during their lives. One of the distinguishing features of GAD from normal, everyday stress is that anxiety impairs quality of life. According to one survey, 32% of adults report experiencing serious impairment attributed to their anxiety. (10) 

Fortunately, generalized anxiety is treatable, especially when utilizing an integrative treatment approach encompassing conventional and complementary therapeutic modalities. This article will discuss a functional medicine approach to treating GAD and provide a sample protocol that healthcare providers can use as a template in their clinical practices.

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What is Generalized Anxiety?

Generalized anxiety disorder (GAD) is a mental health condition characterized by excessive and uncontrollable worry or anxiety about various aspects of life, such as work, relationships, health, and everyday situations, that happens most days of the month for at least six months. While everyone experiences some level of anxiety in their lives, GAD goes beyond the normal occasional worry or stress, and people with GAD often find it challenging to control these feelings, so they interfere with their daily functioning, work, and relationships.

Generalized Anxiety Signs & Symptoms

The anxiety and worry associated with GAD last for at least six months. It is a chronic condition, and the symptoms persist over time. The symptoms can significantly impact a person's ability to function in their daily life, interfering with relationships, work, and social activities. Key features of GAD include:

• Excessive Worry: people with GAD experience persistent and excessive worry or fear about a wide range of issues, even without an apparent reason for the concern. 
• Individuals with GAD find it challenging to manage or suppress their anxious thoughts, and the excessive worry may be disproportionate to the actual situation.
• GAD can manifest with physical symptoms, such as restlessness, muscle tension, fatigue, irritability, difficulty concentrating, headache, stomachaches, chest pain, and sleep disturbances.

What Are the Possible Causes of Generalized Anxiety?

GAD is a complex disorder that arises from a combination of biological, genetic, psychological, and environmental factors. Not everyone with a predisposition or risk factor will develop GAD; some individuals may develop the disorder without a clearly identifiable cause. Here are some factors that may contribute to the development of GAD:

Biological Factors 

Neurochemical imbalances in the brain, specifically involving neurotransmitters, chemical messengers that transmit signals between neurons and allow for the proper functioning of brain processes, are thought to play a role in anxiety disorders. Lower levels of serotonin, often called the "happy hormone," or reduced sensitivity to its effects may contribute to increased anxiety and mood dysregulation. Norepinephrine is associated with the body's "fight or flight" response to stress. An imbalance in norepinephrine levels may lead to heightened stress responses and excessive worry associated with GAD. Increased norepinephrine activity can result in physical anxiety symptoms, such as increased heart rate, sweating, and restlessness. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that helps calm and regulate brain activity. It counterbalances the effects of excitatory neurotransmitters that promote arousal and stress responses. In GAD, there may be a deficiency in GABA, leading to an inability to dampen or regulate anxious thoughts and feelings effectively.

Hormones, vital chemical messengers produced by the body's endocrine glands, play a central role in regulating diverse bodily functions, including mood and stress responses. Various hormone imbalances have been linked to an elevated risk of GAD. These include thyroid hormone imbalances, where overactive (hyperthyroidism) or underactive (hypothyroidism) thyroid glands can disrupt mood regulation; cortisol imbalances, where chronic stress or excessive cortisol release from conditions like Cushing's syndrome can heighten anxiety; sex hormone imbalances, such as estrogen and testosterone fluctuations in women and men, contributing to mood changes; adrenal hormone imbalances, as observed in adrenal fatigue or Addison's disease, impacting stress management; and insulin and blood sugar imbalances, seen in diabetes or insulin resistance, potentially leading to irritability, nervousness, and concentration difficulties. (21)

Nutrient deficiencies can contribute to GAD by affecting the functioning of the brain and the body's ability to regulate stress and mood. Various vitamins, minerals, and other nutrients are important in supporting brain health, neurotransmitter function, and hormone signaling. A lack of these essential nutrients can lead to physiological and chemical imbalances that may contribute to the development or exacerbation of GAD symptoms. B vitamins, particularly B6, B12, and folate, are critical for synthesizing and regulating neurotransmitters; deficiencies in these B vitamins can disrupt the delicate balance of neurotransmitters, potentially leading to heightened anxiety and other mood disturbances. Some nutrient deficiencies, such as low levels of antioxidants and omega-3 fatty acids, can increase oxidative stress and inflammation in the body. Chronic inflammation has been linked to changes in brain chemistry and function, which may contribute to anxiety and other mental health issues. Magnesium, zinc, and iron are involved in energy production and oxygen transport to the brain. Deficiencies in these nutrients can lead to reduced energy levels, cognitive impairments, and a decreased ability to cope with stress. (12) 

Dysbiosis, an imbalance in gut microbiota, may contribute to GAD by affecting neurotransmitter production, triggering inflammation and immune responses, disrupting hormonal regulation, altering gut-brain communication, influencing metabolites and brain function, and impacting the stress response system. The gut-brain connection plays a key role in mental health, and dysbiosis can potentially exacerbate anxiety symptoms through these mechanisms. (4)

Genetics 

Evidence suggests that a family history of anxiety disorders can increase the risk of developing GAD. Meta-analytical studies have concluded that GAD is a heritable condition with a moderate genetic risk (a calculated heritability of approximately 30%). Genetic variations that influence the body's ability to digest, methylate, modulate inflammation, and regulate metabolism can make one more prone to anxiety (4).  

Lifestyle & Environmental Factors

Lifestyle and environmental factors can significantly influence the development and course of GAD. 

High levels of chronic stress or significant life events can trigger or exacerbate GAD. Ongoing stressors, such as work pressure, relationship difficulties, or financial problems, can contribute to the development of anxiety symptoms. The modern work environment, characterized by high demands, tight deadlines, interpersonal challenges, and uncertainty, can contribute to developing and exacerbating anxiety symptoms. Excessive exposure to negative news, social media, and digital devices can contribute to heightened anxiety by fostering comparison, information overload, and a sense of constant connectivity.

Early life experiences, including childhood trauma, neglect, or adverse family environments, can increase vulnerability to GAD later in life. These experiences can shape cognitive patterns and coping mechanisms that influence anxiety.

The presence of an anxiety or substance abuse disorder is a risk factor for the presence of the other disorder. Substance abuse, including alcohol, drugs, and even excessive caffeine, can worsen anxiety symptoms or trigger panic attacks by disrupting brain chemistry. (26) 

The Western Diet, characterized by a high intake of processed foods, sugary snacks, and foods that lack essential nutrients, has been associated with a greater risk for anxiety and psychological symptoms (20). 

Sleep disturbances, such as insomnia or irregular sleep patterns, can increase the risk of GAD and exacerbate anxiety symptoms. Sleep plays a crucial role in mood regulation and overall mental well-being, and people with insomnia or poor sleep habits are 17 times more likely to experience anxiety. (12) 

Regular exercise has been shown to positively affect mental health, including reducing anxiety. Sedentary lifestyles and lack of physical activity can contribute to anxiety symptoms. (12) 

A lack of social support and meaningful relationships can contribute to feelings of isolation and increase the risk of GAD. Strong social connections and a supportive network can buffer against the impact of stressors. (34) 

Functional Medicine Labs to Test for the Root Cause of Generalized Anxiety

While a single test cannot be used to diagnose generalized anxiety, your functional medicine doctor likely will recommend specialty testing to uncover biological and physiologic imbalances related to anxiety and its associated symptoms.

Organic Acid Test

This test measures urinary metabolites to screen for intestinal dysbiosis, neurotransmitter imbalances, nutrient insufficiencies and deficiencies, and neuroinflammation. It can be an excellent testing option for complex patients, as it can act as a snapshot into metabolic health, and certain patterns in the results can highlight areas of primary concern and indicate the need for additional testing.

Comprehensive Stool Test

Poor gut health can disrupt hormone and neurotransmitter balance, interfere with optimal digestion and nutrient absorption, and contribute to systemic inflammation. A comprehensive stool test measures various markers related to key areas of gastrointestinal health to screen for malabsorption, intestinal inflammation, and dysbiosis. 

Nutritional Assessment

The NutrEval by Genova Diagnostics is a panel that directly and indirectly assesses the nutritional status of organic acids, amino acids, fatty acids, micronutrients, and toxic elements. It evaluates over 125 biomarkers in blood and urine samples related to the body's function on a biochemical and metabolic level, diagnosing nutritional deficiencies, insufficiencies, and oxidative stress.

Comprehensive Hormone Panel

A comprehensive hormone panel, like the DUTCH Plus, measures reproductive hormones, cortisol, melatonin, and various organic acids for an in-depth endocrine and neurological assessment. Abnormal results can indicate imbalances in sex hormones, dysfunction in the stress response or sleep-wake cycle, and nutrient imbalances contributing to neurotransmitter imbalances.

A complete thyroid panel, including TSH, total T4 and T3, free T4 and T3, and thyroid antibodies, screens for thyroid autoimmunity, subclinical thyroid disease, and overt thyroid dysfunction. Ordering a comprehensive panel to assess thyroid function helps in the early detection of thyroid disease.

Other Diagnostic Tools for Generalized Anxiety

The GAD-7, or Generalized Anxiety Disorder 7-item scale, is a widely used self-assessment questionnaire designed to screen and assess the severity of generalized anxiety symptoms in adults. It consists of seven questions about the frequency and intensity of common anxiety symptoms over the past two weeks. Each question is scored on a scale from 0 to 3, with response options ranging from "not at all" to "nearly every day."

The GAD-7 is often used by healthcare professionals, mental health providers, and researchers to quickly assess the presence and severity of generalized anxiety symptoms and monitor patient response to therapy. It helps identify individuals who may be experiencing significant anxiety and may need further evaluation or treatment. The total score on the GAD-7 ranges from 0 to 21, with higher scores indicating a higher level of anxiety.

Conventional Treatment for Generalized Anxiety

Initial treatment options for patients with GAD include medication and psychotherapy. Some studies suggest combining both may be more effective for patients with moderate to severe symptoms. Selective serotonin reuptake inhibitors (SSRIs) are considered first-line pharmacotherapy for patients with GAD. Other effective drug classes include serotonin-norepinephrine reuptake inhibitors (SNRIs), azapriones, and tricyclic antidepressants (TCAs). (18) 

Functional Medicine Treatment Protocol for Generalized Anxiety

While a functional medicine treatment protocol may utilize conventional treatment options, it will also emphasize lifestyle modifications, healthy stress management rituals, mind-body therapies, food-as-medicine, and dietary supplements to target biological imbalances identified on testing. (12) 

Therapeutic Diet and Nutrition Considerations for Generalized Anxiety

A 2021 meta-analysis reviewing the link between diet and generalized anxiety concluded that dietary patterns that emphasize intake of vegetables, fruit, limited sugars and refined grains, and greater consumption of minimally processed foods are associated with lower anxiety levels. Based on this analysis, here are the top dietary tips to follow when using nutrition to reduce anxiety:

Eat a Plant-Based Diet

A plant-based diet ensures a wide variety of fruits, vegetables, and whole grains rich in vitamins, minerals, and phytochemicals required for synthesizing neurotransmitters and neurotropic factors and reducing systemic inflammation. Additionally, plant-based diets are rich in prebiotic fibers that influence the composition of the gut microbiome and the gut-brain axis. (1) 

Choose Carbohydrates Wisely

Eating highly-processed carbohydrates and refined sugars creates rapid spikes of insulin and blood sugar swings that the body remedies by releasing cortisol, which can trigger anxiety symptoms (29). Reducing sugar intake and eating lower glycemic index carbohydrates help stabilize blood sugar levels and are associated with reduced levels of anxiety (1). 

Meet Protein Goals

Protein malnutrition is associated with a worsening of anxiety symptoms. Protein is broken down into amino acids, which serve as the precursor building blocks for the various neurotransmitters. In particular, inadequate intake of tryptophan, the amino acid precursor of serotonin, is associated with generalized anxiety. The recommended dietary allowance (RDA) for protein to prevent deficiency is 0.8 grams of protein per kilogram, or 0.36 grams per pound, bodyweight per day; however, protein intake should be modified based on physical activity levels to ensure you meet the body's functional needs. (1) 

Eat Healthy Fats

A diet predominantly consisting of omega-6 fatty acids can promote gastrointestinal and neurologic inflammation (29). Research shows that shifting food choices that favor a higher intake of omega-3 fatty acids has an anxiolytic effect, resulting in lower anxiety levels (1). 

Supplements Protocol for Generalized Anxiety

The literature supports various nutraceuticals to supplement a holistic treatment plan. Below is a sample protocol that can be recommended for patients with GAD.

L-Theanine

L-theanine is an amino acid found primarily in tea leaves, especially green tea. It is known for its potential calming and relaxing effects, and some research suggests that it may positively impact anxiety. L-theanine is believed to influence brain function by modulating neurotransmitters and increasing alpha-brain wave activity, leading to improved focus, reduced stress, and a sense of calm. A systematic review of nine studies found that L-theanine doses ranging from 200-400 mg daily decreased stress and anxiety in people exposed to stressful conditions.

Dose: 200-400 mg daily

Duration: 4 weeks

Magnesium

Exposure to stress has been shown to increase renal excretion of magnesium; furthermore, magnesium modulates the stress response by reducing cortisol secretion (2). Patients with anxiety and magnesium deficiency experience improved anxiety, as indicated by reductions in scores on the Depression Anxiety Stress Scales, with magnesium supplementation (23).  

Dose: 300 mg daily

Duration: 8 weeks

Lavender Oil

Lavender oil has been shown to modulate the autonomic nervous system, inhibiting sympathetic nerves while stimulating the parasympathetic, or "rest and digest," division of the nervous system. Lavender oil, administered orally or via aromatherapy, is a safe treatment option, as effective as the medication lorazepam, for patients with GAD.

Dose: 80 mg daily by mouth

Duration: 6-10 weeks

Ashwagandha

Ashwagandha is an adaptogenic herb that modulates the hypothalamic-pituitary-adrenal (HPA) axis in response to perceived stressors. Supplementing with ashwagandha has been shown to reduce morning cortisol levels and Hamilton-Anxiety Rating Scale scores. Additionally, using ashwagandha in conjunction with psychotherapy appears to augment positive treatment outcomes, including anxiety scores, fatigue, and overall quality of life.

Dose: 300 mg twice daily

Duration: 6-8 weeks

When To Retest Labs

Therapies should be initiated for at least 4-8 weeks before assessing their therapeutic effects. Treatment can be easily monitored by having the patient complete the GAD-7 and tracking changes in the questionnaire's score. The decision to reorder labs should be made by considering the medical necessity and the doctor's and patient's preferences. Most functional medicine labs are retested 3-6 months after baseline to assess the patient's response to treatment accurately. 

Learning More About Generalized Anxiety

• Magazine Article: Top Labs To Run Bi-Annually On Your Generalized Anxiety Disorder (GAD) Patients
• Case Study: Functional Medicine Approach to Generalized Anxiety Disorder
• Podcast: How Gas, Bloating, Indigestion, Anxiety, and Frequent Illness Are All Connected With Julie Davey, NP
• Podcast: Beyond Medications: Holistic Strategies for Managing Anxiety, Chronic Panic, and Depression with Dr. Kate Henry and Dr. Rachael Bevilacqua 

Summary

In conclusion, embracing a functional medicine approach offers a holistic and personalized strategy for addressing generalized anxiety disorder (GAD). By recognizing the intricate interplay of genetics, lifestyle, environment, and physiological factors, functional medicine empowers individuals and healthcare practitioners to explore innovative avenues for GAD management. Individuals can foster a comprehensive and sustainable path to anxiety relief through targeted interventions, such as optimizing nutrition, addressing gut health, balancing hormones, and incorporating mind-body practices.