Anxiety disorders and depression represent a considerable portion of the global burden of disease. Emerging brain-based research in psychiatry and neurology has focused on identifying fundamental metabolic disturbances within neurons and throughout the body involving insulin resistance, inflammation, oxidative stress, and alterations of the gut microbiome. Given the increasing popularity of low-carb diets, understanding their potential impact on mental health, particularly anxiety, is crucial. This article explores the existing research on the relationship between low-carbohydrate diets (LCDs) and anxiety, considering various factors and potential mechanisms.
The Body's Stress Response and Blood Sugar
The body's stress response involves a complex interaction of hormones and neurotransmitters controlled by the hypothalamic-pituitary-adrenal (HPA) axis. Acute stressors-like running from a life-threatening situation-and chronic stressors-like worry about work and fear about the future-both activate the HPA axis. When activated, the HPA axis triggers physiological changes, including increased heart rate, blood pressure, and the release of glucose into the bloodstream for energy. Glucose, derived from carbohydrates, is the body’s primary fuel source.
When blood sugar levels drop too low, the body initiates a stress response, releasing glucocorticoids to signal the need for glucose. This is why some individuals may experience anxiety-like symptoms when their blood sugar is unstable. Refined carbohydrates and sugars can lead to rapid spikes and subsequent drops in blood sugar, potentially exacerbating anxiety.
Examining the Impact of Low-Carb Diets on Mental Health
A cross-sectional study on 3362 adult men and women examined the association between adherence to low carbohydrate diet and psychological disorders. Dietary intakes were examined by the use of a validated semi-quantitative food frequency questionnaire. Low carbohydrate diet (LCD) score was computed for each participant based on deciles of percentages of energy from macronutrients. Then the scores of carbohydrate, protein and fat intake for each participant were summed up to achieve the overall LCD score, which ranged from 3 (highest carbohydrate intake and lowest fat and protein intakes) to 30 (lowest carbohydrate intake and highest fat and protein intakes). Prevalence of depression, anxiety and psychological distress in the whole population were 28.0, 13.3 and 22.6%, respectively. No significant differences were observed in the distribution of depression, anxiety and psychological distress across different quartiles of LCD score. After controlling for potential confounders, no significant association was seen between LCD score and prevalence of depression (OR for the highest vs. the lowest quartile of LCD score: (1.15; 95% CI: 0.93, 1.39). Consumption of LCD was not also associated with increased risk of anxiety (0.82; 95% CI: 0.59, 1.14) and psychological distress (0.92; 95% CI: 0.72, 1.16). Adherence to the low carbohydrate diet, which contains high amount of fat and proteins but low amounts of carbohydrates, was not associated with increased odds of psychological disorders including depression, anxiety and psychological distress.
However, it's important to note that some studies suggest that very restrictive low-carb diets, especially those that are also low in fat, could trigger the stress response due to the body's reduced efficiency in utilizing protein and fat for energy compared to glucose from carbohydrates.
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Ketogenic Diets: A Different Perspective
A ketogenic diet (KD) is a low carbohydrate, moderate-protein, high-fat diet that supports a fundamental metabolic shift from glucose to ketone bodies as the primary fuel source. Classic KMTs are formulated with strict macronutrient ratios, most commonly 4:1 and 3:1 (fat: protein + carbohydrates), and have demonstrated efficacy in intractable epilepsy and genetic disorders. More recently, modified classic KMTs with lower macronutrient ratios of 2.5:1, 2:1, and 1.5:1 have been utilized in research and clinical practice (15, 16). KMT exploits the body’s natural ability to produce ketone bodies (d-beta-hydroxybutyrate (BHB), acetoacetate, and acetone) in the liver from fatty acids by keeping carbohydrate consumption very low.
Recent research shows that a ketogenic diet (KD) reduces neuronal firing rates, modulates ion channels and cell signaling cascades, and stimulates the biochemical synthesis and neurotransmission of GABA by inhibiting glutamate decarboxylase, a major inhibitory neurotransmitter involved in neuronal firing and anxiogenesis (25, 26). BHB activates the transcription of antioxidant-related genes by inhibiting histone deacetylases, triggering long-term adaptive changes in gene expression. In addition, at physiologic concentrations, ketone bodies reduce neuroinflammation through direct action at G-protein coupled receptors (25). KD also favorably alters the gut microbiome (27). Perhaps most importantly, KD directly increases NAD+, which reduces reactive oxygen species and increases mitochondrial ATP production. It is also utilized as a substrate for sirtuins and PARP enzymes associated with DNA repair and longevity. A sustained increase in NAD+ may underlie the pleiomorphic benefits of KMT across multiple neuropsychiatric conditions (28). In terms of the frequent abnormal alarms set off in the amygdala during anxiety, nutritional ketosis may provide an acute and long-term intervention to reduce generalized anxiety, panic attacks, obsessive doubt, and symptoms of post-traumatic stress disorder (PTSD).
Ketogenic Diet Pilot Study
For people living with serious mental illness like schizophrenia or bipolar disorder, standard treatment with antipsychotic medications can be a double-edged sword. Now, a pilot study led by Stanford Medicine researchers has found that a ketogenic diet not only restores metabolic health in these patients as they continue their medications, but it further improves their psychiatric conditions.
In the four-month pilot trial, Sethi's team followed 21 adult participants who were diagnosed with schizophrenia or bipolar disorder, taking antipsychotic medications, and had a metabolic abnormality - such as weight gain, insulin resistance, hypertriglyceridemia, dyslipidemia or impaired glucose tolerance. The participants were instructed to follow a ketogenic diet, with approximately 10% of the calories from carbohydrates, 30% from protein and 60% from fat. "The focus of eating is on whole non-processed foods including protein and non-starchy vegetables, and not restricting fats," said Sethi, who shared keto-friendly meal ideas with the participants. The research team tracked how well the participants followed the diet through weekly measures of blood ketone levels.
Before the trial, 29% of the participants met the criteria for metabolic syndrome, defined as having at least three of five conditions: abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure and elevated fasting glucose levels. "We're seeing huge changes," Sethi said. "Even if you're on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, the insulin resistance. The psychiatric benefits were also striking. On average, the participants improved 31% on a psychiatrist rating of mental illness known as the clinical global impressions scale, with three-quarters of the group showing clinically meaningful improvement. "The participants reported improvements in their energy, sleep, mood and quality of life," Sethi said.
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Case Studies: Ketogenic Diet for Depression and Anxiety
The aim of this case series is to examine the response to the treatment of major depression and generalized anxiety with whole-food animal-based personalized KMT in adults with complex psychiatric comorbidity and varied metabolic status. We conducted a retrospective review of three cases from our Metabolic Psychiatry Registry that demonstrate a consistent response and remission of major depression and generalized anxiety among patients who are psychiatrically and metabolically complex, despite differences in the initiation and adoption of KMT, and varied metabolic dysfunction. We describe the evaluation process and prescription of KMT, baseline metabolic workup and monitoring, elements that fostered treatment engagement and adherence, and challenges encountered during 12 weeks of KMT. We correlated capillary BHB/GKI with time to the remission of major depression and GAD and the achievement of metabolic health. We present individual case descriptions with time to response and remission, clinical challenges during KMT, and metabolic outcomes. Response was assessed quantitatively using PHQ-9, GAD-7, and correlated with BHB drawn from capillary blood and glucose-ketone index (GKI) using Keto-Mojo® GK+ Blood Glucose and β-Ketone Dual Monitoring System (ketone/glucose correlation coefficients to serum of 0.9927/0.9974) to determine the length of time to response and remission. Improvement in quality of life was assessed by qualitative reports during clinical visits and quantitatively using Self-Compassion Scale (SCS) and Flourishing Scale.
It is important to stress that in our therapeutic intervention (see Supplementary Data). KMT was used as a medical prescription, with a properly formulated, individualized ketogenic diet offered in conjunction with multiple clinical supports and lifestyle therapies, including sleep, circadian rhythms, movement, community building, friends, and family supports provided by the program, small group nature walks and talks with other patients, and the registered dietitian and psychiatrist, psychiatric follow-up, and metabolic monitoring.
Case 1
Case 1 is a 32-year-old unemployed married man. He had a lifelong history of previously unrecognized and untreated recurrent major depression, as well as GAD, obsessive-compulsive disorder, trypanophobia, and binge eating disorder. He experienced prominent inattention and distractibility since childhood; an adequate prior trial of atomoxetine 100 mg po qd for 1.5 years was somewhat effective; and lisdexamfetamine 70 mg was somewhat effective. He had long declined consideration of SRIs, SNRIs, other antidepressants, and buspirone. He was unaware of the degree to which his complex symptoms had pervasively affected his functioning and quality of life, resulting in his inability to sustain employment, financial insecurity, and adverse interpersonal relationships.
At the initiation of KMT 1.5:1, Case 1 chose to incorporate time-restricted eating and consumed two meals per day within a 4-8 h eating window. He achieved therapeutic nutritional ketosis with a mean serum BHB of ≥0.8 mmol/L, GKI < 6 within a couple of days, and high average serum BHB levels of 4.6 mmol/L within 1 week (Figure 1), without adverse effects. He maintained adherence without the muscle cramping he had experienced with exercise before KMT, due to close attention to electrolyte needs and supplementation during KMT.
Generalized anxiety response (GAD-7 decreased from 16 to 8) within 1 week and completely remitted 6 weeks later. The initial PHQ-9 of 17 indicated moderately severe depression. Depressive symptoms completely remitted (PHQ-9 ≤ 4) within 5 weeks of consistent therapeutic nutritional ketosis. Binge eating ceased within days of KMT initiation, and he reported that he “no longer gets over hungry,” and that he “no longer eat[s] without realizing [he’s] eating.” The SCS increased from 3 to 4.6 over 4 weeks. The Flourishing Scale increased significantly from 44 to 53 at 14 weeks; the 12-week data were missing. He reported increased mental focus, increased energy, renewed confidence, and motivation to return to work.
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Case 2
Case 2 was a 36-year-old married man with a lifelong history of mood dysregulation, irritability, and trauma from adverse childhood experiences and recent work experiences. He had a history of childhood-onset generalized anxiety, panic disorder, and PTSD, as well as recurrent major depression, which was moderately severe and persistent. His anxiety was unrecognized and untreated. Although he did not have a history of mania, hypomania, or mixed states, he had been treated throughout childhood and adolescence with sertraline 50 mg (ineffective), duloxetine 60 mg (agitation), escitalopram 20 mg (diaphoresis), lamotrigine 300 mg (poor school performance), divalproex ER 1,500 mg (tremor, sluggishness, and weight gain), oxcarbazepine 1,200 mg (fatigue), olanzapine (hunger and weight gain), methylphenidate (ineffective), amphetamine-dextroamphetamine mixed salts 20 mg, and lisdexamfetamine (tachycardia). He discontinued all psychiatric treatment at age 19, but remained symptomatic for 15 years. Recent work-related trauma was unresponsive to psychotherapy and prompted him to present for evaluation and treatment; in addition to major depression and three concurrent anxiety disorders, he met DSM-V criteria for ADHD, a combined type, which had not been previously recognized.
He adopted KMT within less than a week, increased vitamin D3/K2 to 5,000 IU po qd, added magnesium glycinate 250-350 mg po qd, and replaced his sugar-containing electrolyte drink with one free of added sugars. However, he initially struggled to meet his daily goals for fat consistently, exercised heavily, and reported new-onset fatigue during exercise.
Despite inconsistent capillary BHB and GKI early in treatment, GAD-7 decreased from 8 to 4 within 2 weeks of KMT initiation and to 0 after an additional 4 weeks and remained at 0. Major depression was moderately severe at the initiation of KMT (PHQ-9 = 16), responded at 5.5 weeks (PHQ-9 = 8), and fully remitted at 9 weeks, coinciding with the first week in which he achieved consistent BHB ≥ 0.8 mmol/L/GKI 6.5 and had added acetyl-L-carnitine 1,500 mg po bid. Self-compassion increased from 2.7 to 4 over 12 weeks. Case 2 achieved optimal metabolic health in 12 weeks.
Case 3
Case 3 was a 34-year-old single woman with a history of childhood adversity and trauma, PTSD, childhood-onset GAD, and recurrent severe major depressive disorder. She developed anorexia in adolescence and later binge eating disorder with weight fluctuations up to 100 lbs. and reported a long history of dietary attempts at weight loss, including the use of low-carb diets. She had been previously prescribed long trials of citalopram, risperidone, and ziprasidone, all of which were ineffective. ADHD, the inattentive subtype, was treated with a long-acting methylphenidate with intermittent compliance.
She began KMT as adjunctive treatment to medication, which remained unchanged throughout 12 weeks. Initial mild transient fatigue resolved rapidly with no other adverse effects. Adherence to KMT was initially variable, affected by travel, holiday events, and family pressure to eat processed carbohydrates and desserts. She realized quickly that her lack of preparation for these events contributed to difficulties adhering to KMT and adopted simple strategies to prepare ahead.
Initially, GAD-7 decreased from 12 to 6 within 2 weeks, even before consistent adherence to KMT. By week 3, when she achieved consistent therapeutic ketosis, the mean BHB was 1.4 mmol/L/GKI 4.2, and GAD-7 dropped to 4 for the first time (Figure 3). One week later, the mean BHB wa…
The Gut-Brain Axis
The gut-brain axis, the biochemical pathway that allows communication between the gastrointestinal tract and the brain, may play a role in the relationship between high-fat diets and anxiety. A study on rats found that a diet consisting almost exclusively of saturated fats led to a marked drop in the diversity of their gut microbiomes. They also gained weight and exhibited behaviors associated with increased anxiety. Fecal analysis found an increase in microbes associated with obesity. In addition, the rats underwent metabolic changes that are associated with the rise of a subset of serotonin. However, it's important to note that the rats ate a diet high in fat, but they were not in a metabolic state of ketosis.
Choosing the Right Carbs
Instead of labeling foods as good or bad, it's more helpful to optimize carb intake for the desired outcome. Complex carbohydrates like whole grains take the longest to digest and produce a steady stream of glucose to support a balanced blood sugar level. Refined carbs and sweets can still be enjoyed as part of a balanced diet, but they should make up a smaller portion of the total carbohydrates consumed. It’s especially important to have refined carbs and sweets with other foods, particularly protein and/or healthy fat, to help slow their absorption, minimize their impact on your stress hormones, and improve your mood overall.
Additional Strategies for Managing Anxiety
Besides diet, several other strategies can help manage anxiety:
- Eat balanced meals: This helps stabilize blood sugar levels.
- Stick to a regular eating schedule: This can prevent blood sugar crashes.
- Eat mindfully: Pay attention to how what you eat makes you feel.
- Stay hydrated: Dehydration can increase cortisol levels.