APPENDIX D: NUTRACEUTICALS THAT HELP ALLEVIATE WORRY AND ANXIETY

WHEN I’M TREATING PEOPLE, one question I always ask myself is What would I prescribe if this were my mother, my wife, or my child? More and more, after all my years as a psychiatrist, I find myself recommending natural treatments. I am not opposed to medications and I have prescribed them for a long time, but I want you to use all of the tools available, especially if they are effective, less expensive, and have fewer side effects than medications.

My interest in nutraceuticals (supplements with medicine-like health benefits) started after I began using brain SPECT imaging to help understand and treat my patients. One of the early lessons SPECT taught me was that some medications, especially those often prescribed for anxiety, had a negative effect we could see on the scans. Later I learned that some research suggested that a number of these medications increased the risk of dementia and strokes.[1] In medical school I was taught, “First, do no harm. Use the least toxic, most effective treatments.” As I looked for alternatives to these treatments to help the children and adults I was serving, I discovered that many natural supplements had strong scientific evidence behind them, with fewer side effects than prescription medications.[2]

Certain supplements are especially effective at calming and balancing the brain, which can lessen feelings of anxiety. Here are some of my favorites:

Magnesium

Magnesium has a calming effect on neuronal function, is involved in more than 300 biochemical reactions in your body, is vital for your body to make energy, and plays a key role in blood sugar regulation. Low magnesium is associated with seizures, inflammation, diabetes, anxiety, and depression.[3] With the standard American diet, 68 percent of Americans do not consume enough magnesium. Some researchers believe that supplementing magnesium can decrease seizure frequency,[4] and others have shown it is helpful for severe stress,[5] migraines, depression, chronic pain, anxiety, and strokes.[6] The mineral is found in green leafy vegetables, such as spinach, kale, and Swiss chard; legumes; nuts; and seeds. In general, foods that contain dietary fiber provide magnesium. The typical adult dose is 50–400 mg a day.

GABA

GABA (gamma-aminobutyric acid) is an amino acid that helps to regulate brain excitability and calms overfiring in the brain. GABA and GABA enhancers, such as the anticonvulsant gabapentin and L-theanine (found in green tea), function to inhibit the excessive firing of neurons, which results in a feeling of calmness and more self-control. Low levels of GABA have been found in many mental health disorders, including anxiety and some forms of depression. Rather than overeating or drinking or using drugs to calm your anxiety, natural ways to boost GABA may help. I often recommend GABA supplements. Researchers report that GABA does not cross the blood brain barrier (a network of blood vessels that protect the brain), but the studies are contradictory,[7] with some showing an increase in alpha brain waves (which indicate a relaxed state).[8] Nonetheless, GABA still has a calming influence on the brain imaging studies we have done. The typical recommended dosage ranges from 100 to 1,500 mg daily for adults and from 50 to 750 mg daily for children. For best effect, GABA should be taken in two or three doses a day.

Saffron

Saffron, one of the world’s most expensive spices, is grown mostly in Iran, Greece, Spain, and Italy and traditionally has been consumed to help digest spicy food and soothe irritated stomachs. It also has been used for hundreds of years as a folk medicine for a variety of health problems. In recent years there has been significant research showing that saffron can help boost serotonin and benefit mood,[9] memory,[10] and sexual function;[11] decrease the symptoms of PMS;[12] and, when combined with methadone, help alleviate withdrawal symptoms in patients undergoing treatment for opioid addiction.[13] The recommended adult dosage is 15 mg twice a day.

5-HTP

5-HTP (5-hydroxytryptophan), another amino acid, is a step further along in the serotonin production pathway. It is more widely available than L-tryptophan and more easily taken up in the brain—70 percent versus 3 percent of L-tryptophan. About 5 to 10 times more powerful than L-tryptophan, 5-HTP boosts serotonin levels in the brain and helps to calm ACG hyperactivity (greasing the cingulate, if you will, to improve shifting one’s attention). A number of double-blind studies have shown that it is also an effective mood enhancer[14] and appetite suppressor.[15] The recommended adult dose of 5-HTP is 50–300 mg a day. Children should start with a half dose. As with L-tryptophan, it is best to take 5-HTP on an empty stomach to help with absorption. The most common side effect is an upset stomach, which is usually very mild. Start with a low dose and work your way up slowly.

L-theanine

L-theanine is an amino acid uniquely found in green tea. It crosses the blood brain barrier and can increase dopamine. It also increases GABA and serotonin, so it tends to have a balancing effect on the brain. It helps with focus as well as mental and physical stress. The typical dose is 100–200 mg two to three times a day.

In addition to these supplements, I typically recommend the following three nutraceuticals to all my patients because they are critical to optimal brain function: a multivitamin/mineral, omega-3 fatty acids, and vitamin D.

Multivitamin/mineral

To feel better fast now and later, you need to give your brain the nutrition it requires. But there is evidence that many people are not getting it: More than 90 percent of Americans do not eat at least five servings of fruits and vegetables a day, the minimum required to get the nutrients you need, according to the Centers for Disease Control and Prevention (CDC).[16] An editorial in the Journal of the American Medical Association also asserted that most adults don’t get all the vitamins they need through diet alone and recommended a daily vitamin supplement for everyone because it helps prevent chronic illness.[17]

In the past 15 years, there have been more than 25 reports of mental health benefits from multivitamin/mineral formulas consisting of more than 20 minerals and vitamins.[18] In addition, studies show that multivitamin/mineral complexes can help with attentional issues,[19] mood,[20] and even aggression.[21] Two randomized, controlled trials were conducted after the 6.3-magnitude earthquake in February 2011 in Christchurch, New Zealand[22] and the devastating flooding in southern Alberta, Canada, in June 2013.[23] Both trials showed reduced acute stress and anxiety scores in those taking a multivitamin/mineral. In the New Zealand earthquake study, the incidence of post-traumatic stress disorder decreased from 65 percent to 19 percent after one month of treatment, while the control group showed little improvement. These two trials suggest that multivitamin/mineral complexes could be an inexpensive public health intervention for normal populations following natural disasters.

A 2010 study tested the effects of taking a multivitamin versus a placebo on 215 men ages 30 to 55. After a month, the multivitamin group reported improved moods and showed better mental performance, as well as having a greater sense of vigor, less stress, and less mental fatigue after completing mental tasks—essentially making them both happier and smarter.[24] Another placebo-controlled study looked at the effects of multivitamins on 81 healthy children and found that those who took multivitamins performed better on two out of three attention tasks.[25]

Omega-3 Fatty Acids

Omega-3 fatty acids are essential to well-being. Low levels are one of the leading preventable causes of death, according to researchers at the Harvard School of Public Health.[26] Studies have shown that 95 percent of Americans do not get enough dietary omega-3 fatty acids. Low levels of EPA and DHA, two of the most important omega-3s, are associated with:

• Inflammation[27]
• Heart disease[28]
• Depression and bipolar disorder[29]
• Suicidal behavior[30]
• ADHD[31]
• Cognitive impairment and dementia[32]
• Obesity[33]

Unfortunately, most people are low in EPA and DHA unless they are focused on eating fish (which can be high in mercury and other toxins) or they are taking an omega-3 supplement. We tested the omega-3 fatty acid levels of 50 consecutive patients not taking fish oil (the most commonly used source of EPA and DHA) who came into Amen Clinics and found that 49 had suboptimal levels. In another study, our research team correlated the SPECT scans of 166 patients with their EPA and DHA levels and found that those with the lowest levels had lower blood flow, the number one predictor of future brain problems, in the right hippocampus and posterior cingulate (one of the first areas to die in Alzheimer’s disease), among other areas.[34] On cognitive testing, we also found low omega-3s correlated with decreased scores in mood. Most adults should take between 1,000 and 2,000 milligrams of high-quality fish oil per day, balanced between EPA and DHA.

Vitamin D: Optimize Your Level

Vitamin D’s best-known roles may be in building bones and boosting the immune system, but vitamin D is also an essential vitamin for brain health, mood, and memory. Low levels have been associated with depression, autism, psychosis, Alzheimer’s disease, multiple sclerosis, heart disease, diabetes, cancer, and obesity. Seventy percent of the population is low in vitamin D because we are spending more time indoors and using more sunscreen (the vitamin is absorbed through the skin). It is easy to remedy a low level: Get a blood test to check it, and if it is low (below 30 ng/mL), take between 2,000 and 10,000 IU a day. Recheck after two months to make sure your level is in the healthy range.

[1] A. Pariente et al., “The Benzodiazepine-Dementia Disorders Link: Current State of Knowledge,” CNS Drugs 30, no. 1 (January 2016): 1–7, doi: 10.1007/s40263-015-0305-4.

H. Taipale et al., “Use of Benzodiazepines and Related Drugs Is Associated with a Risk of Stroke among Persons with Alzheimer’s Disease,” International Clinical Psychopharmacology 32, no. 3 (May 2017): 135–41, doi: 10.1097/YIC.0000000000000161.

[2] Nutraceuticals do have drawbacks. Although they tend to be less expensive than medications, you may pay more for them because insurance usually doesn’t cover their cost. What’s more, they are not completely without side effects, and they can interact with medications. Also, some studies have shown that supplements don’t always contain what the label claims, which means they may not work or, alternatively, could be harmful. Don’t rely on the expertise of a health food store clerk for your supplement information. Instead, research brands online and develop a relationship with one or more, communicating your questions and issues to their technical and quality control staff.

Notwithstanding these issues, the benefits of nutraceuticals (and their relatively low risks compared to medications) make them worth considering, especially if you can get thoughtful, research-based information. I have witnessed targeted nutraceuticals make a positive difference in the lives of my patients, my family, and myself, which is why I take them every day and recommend them.

[3] J. Anjom-Shoae et al., “The Association between Dietary Intake of Magnesium and Psychiatric Disorders among Iranian Adults: A Cross-Sectional Study,” British Journal of Nutrition 120, no. 6 (September 2018): 693–702.

[4] A. W. Yuen and J. Sander, “Can Magnesium Supplementation Reduce Seizures in People with Epilepsy? A Hypothesis,” Epilepsy Research 100, nos. 1–2 (June 2012): 152–56.

[5] Etienne Pouteau et al., “Superiority of Magnesium and Vitamin B6 over Magnesium Alone on Severe Stress in Healthy Adults with Low Magnesemia: A Randomized, Single-Blind Clinical Trial,” PLOS One 13, no. 12 (December 18, 2018): e0208454.

[6] A. E. Kirkland, G. L. Sarlo, and K. F. Holton, “The Role of Magnesium in Neurological Disorders,” Nutrients 10, no. 6 (June 6, 2018): e730.

E. K. Tarleton et al., “Role of Magnesium Supplementation in the Treatment of Depression: A Randomized Clinical Trial,” PLoS One 12, no. 6 (June 27, 2017): e0180067.

[7] Evert Boonstra et al., “Neurotransmitters as Food Supplements: The Effects of GABA on Brain and Behavior,” Frontiers in Psychology 6 (2015): 1520.

[8] A. M. Abdou et al., “Relaxation and Immunity Enhancement Effects of Gamma-aminobutyric Acid (GABA) Administration in Humans,” BioFactors 26, no. 3 (2006): 201–8.

[9] “Saffron,” Examine.com, accessed April 16, 2018, https://examine.com/supplements/saffron/.

A. L. Lopresti and P. D. Drummond, “Saffron (Crocus sativus) for Depression: A Systematic Review of Clinical Studies and Examination of Underlying Antidepressant Mechanisms of Action,” Human Psychopharmacology 29, no. 6 (November 2014): 517–27, doi: 10.1002/hup.2434.

[10] M. Tsolaki et al., “Efficacy and Safety of Crocus Sativus L. in Patients with Mild Cognitive Impairment,” Journal of Alzheimer’s Disease 54, no. 1 (July 27, 2016): 129–33, doi: 10.3233/JAD-160304.

[11] L. Kashani et al., “Saffron for Treatment of Fluoxetine-Induced Sexual Dysfunction in Women: Randomized Double-Blind Placebo-Controlled Study,” Human Psychopharmacology 28, no. 1 (January 2013): 54–60, doi: 10.1002/hup.2282.

[12] M. Agha-Hosseini et al., “Crocus sativus L. (Saffron) in the Treatment of Premenstrual Syndrome: A Double-Blind, Randomised and Placebo-Controlled Trial,” BJOG 115, no. 4 (March 2008): 515–19, doi: 10.1111/j.1471-0528.2007.01652.x.

[13] M. N. Shahi et al., “The Impact of Saffron on Symptoms of Withdrawal Syndrome in Patients Undergoing Maintenance Treatment for Opioid Addiction in Sabzevar Parish in 2017,” Advances in Medicine 2017 (2017): Article ID 1079132, doi: 10.1155/2017/1079132.

[14] P. Jangid et al., “Comparative Study of Efficacy of L-5-Hydroxytryptophan and Fluoxetine in Patients Presenting with First Depressive Episode,” Asian Journal of Psychiatry 6, no. 1 (February 2013): 29–34, doi: 10.1016/j.ajp.2012.05.011.

J. Angst et al., “The Treatment of Depression with L-5-Hydroxytryptophan versus Imipramine. Results of Two Open and One Double-Blind Study,” Archiv fur Psychiatrie und Nervenkrankheiten 224, no. 2 (October 11, 1977): 175–86.

[15] “5-HTP,” Examine.com, accessed April 16, 2018, https://examine.com/supplements/5-htp.

[16] Y. Steinbuch, “90 Percent of Americans Eat Garbage,” New York Post, November 17, 2017, https://nypost.com/2017/11/17/90-of-americans-eat-like-garbage/?utm_campaign=iosapp&utm_source=mail_app.

“Only 1 in 10 Adults Get Enough Fruits or Vegetables,” CDC website, November 16, 2017, https://www.cdc.gov/media/releases/2017/p1116-fruit-vegetable-consumption.html.

[17] R. H. Fletcher and K. M. Fairfield, “Vitamins for Chronic Disease Prevention in Adults: Clinical Applications,” JAMA 287, no. 23 (June 19, 2002): 3127–29.

[18] C. W. Popper, “Single-Micronutrient and Broad-Spectrum Micronutrient Approaches for Treating Mood Disorders in Youth and Adults,” Child and Adolescent Psychiatric Clinics of North America 23, no. 3 (July 2014): 591–672, doi: 10.1016/j.chc.2014.04.001.

[19] J. J. Rucklidge et al., “Vitamin-Mineral Treatment of Attention-Deficit Hyperactivity Disorder in Adults: Double-Blind Randomised Placebo-Controlled Trial,” British Journal of Psychiatry 204 (2014): 306–15, doi: 10.1192/bjp.bp.113.132126.

[20] J. J. Rucklidge and B. J. Kaplan, “Broad-Spectrum Micronutrient Formulas for the Treatment of Psychiatric Symptoms: A Systematic Review,” Expert Review of Neurotherapeutics 13, no. 1 (January 2013): 49–73, doi: 10.1586/ern.12.143.

[21] S. J. Schoenthaler and I. D. Bier, “The Effect of Vitamin-Mineral Supplementation on Juvenile Delinquency among American Schoolchildren: A Randomized, Double-Blind Placebo-Controlled Trial,” Journal of Alternative and Complementary Medicine 6, no. 1 (February 2000): 7–17, doi: 10.1089/act.2000.6.7.

[22] J. J. Rucklidge et al., “Shaken but Unstirred? Effects of Micronutrients on Stress and Trauma after an Earthquake: RCT Evidence Comparing Formulas and Doses,” Human Psychopharmacology 27, no. 5 (September 2012): 440–54, doi: 10.1002/hup.2246.

[23] B. J. Kaplan et al., “A Randomised Trial of Nutrient Supplements to Minimise Psychological Stress after a Natural Disaster,” Psychiatry Research 228, no. 3 (August 30, 2015): 373–79, doi: 10.1016/j.psychres.2015.05.080.

[24] D. O. Kennedy et al., “Effects of High-Dose B Vitamin Complex with Vitamin C and Minerals on Subjective Mood and Performance in Healthy Males,” Psychopharmacology 211, no. 1 (July 2010): 55–68, doi: 10.1007/s00213-010-1870-3.

[25] C. Haskell et al., “Cognitive and Mood Effects in Healthy Children during 12 Weeks’ Supplementation with Multi-Vitamin/Minerals,” British Journal of Nutrition 100, no. 5 (November 2008): 1086–96, doi: 10.1017/S0007114508959213.

[26] “Smoking, High Blood Pressure and Being Overweight Top Three Preventable Causes of Death in the U.S.,” Harvard T. H. Chan School of Public Health website, April 27, 2009, https://www.hsph.harvard.edu/news/press-releases/smoking-high-blood-pressure-overweight-preventable-causes-death-us.

[27] T. A. Mori and L. J. Beilin, “Omega-3 Fatty Acids and Inflammation,” Current Atherosclerosis Reports 6, no. 6 (November 2004): 461–67.

D. Moertl et al., “Dose-Dependent Effects of Omega-3-Polyunsaturated Fatty Acids on Systolic Left Ventricular Function, Endothelial Function, and Markers of Inflammation in Chronic Heart Failure of Nonischemic Origin: A Double-Blind, Placebo-Controlled, 3-Arm Study,” American Heart Journal 161, no. 5 (May 2011): 915.e1-9, doi: 10.1016/j.ahj.2011.02.011.

J. G. Devassy et al., “Omega-3 Polyunsaturated Fatty Acids and Oxylipins in Neuroinflammation and Management of Alzheimer Disease,” Advances in Nutrition 7, no. 5 (September 15, 2016): 905–16, doi: 10.3945/an.116.012187.

[28] C. von Schacky, “The Omega-3 Index as a Risk Factor for Cardiovascular Diseases,” Prostaglandins and Other Lipid Mediators 96, nos. 1–4 (November 2011): 94–98, doi: 10.1016/j.prostaglandins.2011.06.008.

S. P. Whelton et al., “Meta-Analysis of Observational Studies on Fish Intake and Coronary Heart Disease,” American Journal of Cardiology 93, no. 9 (May 1, 2004): 1119–23, doi: 10.1016/j.amjcard.2004.01.038.

[29] E. Messamore et al., “Polyunsaturated Fatty Acids and Recurrent Mood Disorders: Phenomenology, Mechanisms, and Clinical Application,” Progress in Lipid Research 66 (April 2017): 1–13, doi: 10.1016/j.plipres.2017.01.001.

J. Sarris et al., “Omega-3 for Bipolar Disorder: Meta-Analyses of Use in Mania and Bipolar Depression,” Journal of Clinical Psychiatry 73, no. 1 (January 2012): 81–86, doi: 10.4088/JCP.10r06710.

R. J. Mocking et al., “Meta-Analysis and Meta-Regression of Omega-3 Polyunsaturated Fatty Acid Supplementation for Major Depressive Disorder,” Translational Psychiatry 6 (March 15, 2016): e756, doi: 10.1038/tp.2016.2.

[30] J. R. Hibbeln and R. V. Gow, “The Potential for Military Diets to Reduce Depression, Suicide, and Impulsive Aggression: A Review of Current Evidence for Omega-3 and Omega-6 Fatty Acids,” Military Medicine 179, supplement 11 (November 2014): 117–28, doi: 10.7205/MILMED-D-14-00153.

M. Huan et al., “Suicide Attempt and n-3 Fatty Acid Levels in Red Blood Cells: A Case Control Study in China,” Biological Psychiatry 56, no. 7 (October 1, 2004): 490–96, doi: 10.1016/j.biopsych.2004.06.028.

M. E. Sublette et al., “Omega-3 Polyunsaturated Essential Fatty Acid Status as a Predictor of Future Suicide Risk,” American Journal of Psychiatry 163, no. 6 (June 2006): 1100–2, doi: 10.1176/ajp.2006.163.6.1100.

M. D. Lewis et al., “Suicide Deaths of Active-Duty US Military and Omega-3 Fatty-Acid Status: A Case-Control Comparison,” Journal of Clinical Psychiatry 72, no. 12 (December 2011): 1585–90, doi: 10.4088/JCP.11m06879.

[31] C. M. Milte et al., “Increased Erythrocyte Eicosapentaenoic Acid and Docosahexaenoic Acid Are Associated with Improved Attention and Behavior in Children with ADHD in a Randomized Controlled Three-Way Crossover Trial,” Journal of Attention Disorders 19, no. 11 (November 2015): 954–64, doi: 10.1177/1087054713510562.

M. H. Bloch and A. Qawasmi, “Omega-3 Fatty Acid Supplementation for the Treatment of Children with Attention-Deficit/Hyperactivity Disorder Symptomatology: Systematic Review and Meta-Analysis,” Journal of the American Academy of Child and Adolescent Psychiatry 50, no. 10 (October 2011): 991–1000, doi: 10.1016/j.jaac.2011.06.008.

[32] Y. Zhang et al., “Intakes of Fish and Polyunsaturated Fatty Acids and Mild-to-Severe Cognitive Impairment Risks: A Dose-Response Meta-Analysis of 21 Cohort Studies,” American Journal of Clinical Nutrition 103, no. 2 (February 2016): 330–40, doi: 10.3945/ajcn.115.124081.

T. A. D’Ascoli et al., “Association between Serum Long-Chain Omega-3 Polyunsaturated Fatty Acids and Cognitive Performance in Elderly Men and Women: The Kuopio Ischaemic Heart Disease Risk Factor Study,” European Journal of Clinical Nutrition 70, no. 8 (August 2016): 970–75, doi: 10.1038/ejcn.2016.59.

K. Lukaschek et al., “Cognitive Impairment Is Associated with a Low Omega-3 Index in the Elderly: Results from the KORA-Age Study,” Dementia and Geriatric Cognitive Disorders 42, nos. 3–4 (2016): 236–45, doi: 10.1159/000448805.

[33] C. Couet et al., “Effect of Dietary Fish Oil on Body Fat Mass and Basal Fat Oxidation in Healthy Adults,” International Journal of Obesity and Related Metabolic Disorders 21, no. 8 (August 1997): 637–43.

J. D. Buckley and P. R. Howe, “Anti-Obesity Effects of Long-Chain Omega-3 Polyunsaturated Fatty Acids,” Obesity Reviews 10, no. 6 (November 2009): 648–59, doi: 10.1111/j.1467-789X.2009.00584.x.

[34] D. G. Amen et al., “Quantitative Erythrocyte Omega-3 EPA Plus DHA Are Related to Higher Regional Cerebral Blood Flow on Brain SPECT,” Journal of Alzheimer’s Disease 58, no. 4 (2017): 1189–99, doi: 10.3233/JAD-170281.