The central thesis of this paper is that low levels of dopamine and serotonin interfere with limbic system inhibitory circuits for controlling central noise, while high levels of free bivalent copper contribute to over-excitation of both the limbic system and the auditory cortex. All of these factors create a chronic state of hypervigilance and stress arousal, which complicates the tinnitus clinical picture. When this is the case, psychological therapies such as cognitive behavioral therapy, self-regulation therapy and neural feedback are more effective once the basic underlying biochemical imbalance has been corrected with individualized nutrient therapies.


Tinnitus is the experience of hearing a sound when there is no evidence of an external sound stimulus. In that sense, it is very much like phantom limb pain, where an individual experiences pain in a body part that has been amputated. Estimates of the prevalence of tinnitus in the American population range from 10 to 15 % (Crayton & Walsh, 2007). Many people have a mild experience of tinnitus that is not particularly disturbing or disabling. However, others describe the effect of tinnitus as severely impairing the quality of their lives or even disabling. In this paper, I shall present an integrative model of tinnitus and a nonpharmacological treatment protocol.

To date, there are no effective general pharmacological treatments for tinnitus (G. B. Parker et al., 2006). Recent guidelines recommend against the use of anxiolytics and antidepressants (Crayton & Walsh, 2007). Auditory masking and retraining strategies, however, have shown effectiveness for some but not all tinnitus patients (Oz et al., 2013) (Tyler, Noble, Coelho, & Ji, 2012).

Tinnitus is often comorbid with anxiety, depression, insomnia, irritability and/or stress intolerance. Psychological treatment including cognitive behavioral therapy, self-regulation therapy and neural feedback have all been used with some efficacy for decades (Hesser, Weise, Westin, & Andersson, 2011; McKenna, Handscomb, Hoare, & Hall, 2014; Milner et al., 2016). The treatment effect, however, may be more an acceptance of the tinnitus experience than actual reduction of tinnitus sensation (Moschen et al., 2015).

Until recently, it has been thought that tinnitus is caused by peripheral noise-induced hearing loss followed by changes in the central auditory pathways (Jastreboff, 1990). Some support for this explanation has been provided by animal studies (Irvine, Rajan, & Brown, 2001). Hyperactivity of certain auditory pathways has also been visualized by functional imaging studies in tinnitus patients (Arnold, Bartenstein, Oestreicher, Romer, & Schwaiger, 1996; Lanting, de Kleine, & van Dijk, 2009).

Limbic involvement in tinnitus has been explained as a reaction to the unpleasant experience of tinnitus (Jastreboff & Jastreboff, 2000).   More recently, a complex feedback system has been identified between the limbic system and the auditory cortex (Rauschecker, Leaver, & Muhlau, 2010). Rauschecker proposes that it is the failure of limbic and para-limbic structures to inhibit or cancel signals at the thalamic level that causes tinnitus to become chronic.

Tinnitus has also been associated with hypozincemia (Ochi, Kinoshita, Kenmochi, Nishino, & Ohashi, 2003; G. B. Parker et al., 2008). However, a recent large population study did not find significant correlation between low levels of zinc and tinnitus experience (G. Parker et al., 2011). This is likely due to the heterogeneity of the tinnitus population, making statistical significance of low zinc levels unlikely. Multiple causes are likely to be involved. Just as the diagnosis of mental health problems is often based upon symptoms rather than the multiplicity of underlying biochemical causal factors (Crayton & Walsh, 2007), tinnitus is likely to present as a constellation of causal factors with overlapping symptom presentation.

The comorbidities of tinnitus (anxiety, depression, insomnia, irritability and stress intolerance) are also symptoms associated with Kryptopyrrole disorder. Kryptopyrrole disorder is objectively identified through urinalysis. Elevations of urinary pyrrole molecules in excess of 10 mcg/dc is pathognomonic for a syndrome of mental health problems including anxiety, obsessive worry, insomnia, depressed mood, stress intolerance and irritability. Interestingly, tinnitus is frequently seen in this constellation of symptoms with Kryptopyrrole disorder.

The mechanism by which excessive pyrrole molecules cause this constellation of symptoms is very interesting. Pyrrole molecules are a byproduct of hemoglobin synthesis. Typically, pyrroles circulate through the bloodstream and are filtered out in the kidneys and excreted in the urine. While circulating in the bloodstream, pyrrole molecules have a high affinity for zinc and vitamin B6. Therefore, excessive pyrrole production causes the excretion of zinc and B6 in urine, creating functional deficiencies in zinc and B6.

Both zinc and B6 are critical for the synthesis of the calming catecholamines such as serotonin, dopamine and GABA. This suggests that pyrrole over-activity could interfere with the inhibitory capacity of the limbic system in controlling central auditory noise stimulation by reducing catecholamine production. In addition, low levels of zinc are often a cause of high levels of bivalent free copper. This is due to the fact that copper levels are regulated by a protein called ceruloplasmin, which is zinc dependent. Biochemically, these factors create a homeostatic balance between zinc and copper. Ideally, the ratio of copper to zinc is around 0.8 to 1.0, and free copper is below 25. Free copper is calculated as 100 x (serum copper – (3 x ceruloplasmin))/serum copper.

Free copper is neuro-excitatory, and at very high levels it is neurotoxic. In addition, free copper is a critical cofactor in the conversion of dopamine to norepinephrine. Low levels of zinc in combination with high levels of free copper can convert sufficient dopamine to norepinephrine to produce the symptom constellation described above. Low levels of dopamine will cause anhedonia, amotivation and a failure of the reward system. High levels of norepinephrine, which is a primary stress neurotransmitter, can cause hypervigilance, anxiety, obsessive rumination and insomnia. Patients often describe this syndrome as “tired body/racing mind.”

The Proposed Protocol

Identifying patients who are appropriate for this integrative treatment approach is relatively easy. First, they are likely to be tinnitus patients who describe their symptoms as “intolerable” and “emotionally disabling.” They will have a high incidence of comorbid symptoms such as anxiety, obsessive worry, reduced motivation, depression, anhedonia, and insomnia. They are likely to describe their quality of life as severely impacted by tinnitus, and they may be partially or totally disabled by the experience.

Second, laboratory testing confirms a diagnosis of Kryptopyrrole disorder. Laboratory tests to confirm Kryptopyrrole disorder would include blood test for whole blood histamine, plasma zinc, serum copper, and ceruloplasmin. These tests allow for the calculation of copper to zinc ratios and percent free copper. Urinalysis revealing excessive Kryptopyrrole concludes the laboratory testing.

Following a definitive diagnosis, treatment consists of patient education and nutritional supplementation to compensate for the loss of zinc and B6. Additional nutrients are needed for antioxidant support such as vitamin C and E, selenium and biotin. Dosing strategies are determined individually by body weight and symptomatology.

Improvement is often seen within 3 to 5 weeks with significant improvement after three months of compliance with the nutritional program. Concurrent with nutritional therapy, cognitive behavioral therapy, self-regulation therapy and stress management are often appropriate. In my experience, these psychotherapies are much more effective after the basic biochemical imbalances have been addressed.

Follow-up sessions are scheduled for six months and one year. At this time, fine-tuning of the nutritional protocol and a discussion of dietary or lifestyle changes to support continued recovery is appropriate. In one case, a patient who had successfully eliminated tinnitus as well as the comorbid emotional symptoms was found to have relapsed. An analysis of diet revealed high levels of consumption of high copper foods such as kale, shellfish and cashews. Continuing on the supplement protocol but eliminating high copper foods allowed this patient to return to a near symptom-free state. In another case, chronic caregiver stress caused periodic relapses requiring additional zinc and B6 as well as stress management and supportive psychotherapy.

This approach is not recommended for all tinnitus patients. For example, tinnitus patients who do not have some of the emotional comorbid features seen in Kryptopyrrole disorder are less likely to benefit. It is actually the patient who is suffering the most who is more likely to benefit. In my experience, the integration of biological and psychological intervention relieves patients of the stigma associated with addressing the psychological comorbidities of tinnitus alone. Once properly educated, patients often feel relief and hope, which helps motivate compliance with the treatment protocol. After initial symptom resolution they typically respond to psychotherapy quickly and effectively.

This paper presents the rationale for integrative treatment of a certain subset of tinnitus patients. It is my goal to evaluate this approach with a large enough sample size to allow statistical analysis. To date, I have had success with three of three initial patients. A sample size of 20 to 30 appropriate patients should be sufficient to draw conclusions about the efficacy of this approach.

Dr. Richard A. Wyckoff, PhD

Adult and Geriatric Behavioral Medicine

Diplomate, American Academy of Pain Management

Diplomate, American Board of Disability Analysts

Founder, The Alliance for Nutrition & Mental Health


Appletree Executive Suites

13606 NE. 20th St., Suite 205

Bellevue, WA 98005









Arnold, W., Bartenstein, P., Oestreicher, E., Romer, W., & Schwaiger, M. (1996). Focal metabolic activation in the predominant left auditory cortex in patients suffering from tinnitus: a PET study with [18F]deoxyglucose. ORL J Otorhinolaryngol Relat Spec, 58(4), 195-199.

Crayton, J. W., & Walsh, W. J. (2007). Elevated serum copper levels in women with a history of post-partum depression. J Trace Elem Med Biol, 21(1), 17-21. doi: 10.1016/j.jtemb.2006.10.001

Hesser, H., Weise, C., Westin, V. Z., & Andersson, G. (2011). A systematic review and meta-analysis of randomized controlled trials of cognitive-behavioral therapy for tinnitus distress. Clin Psychol Rev, 31(4), 545-553. doi: 10.1016/j.cpr.2010.12.006

Irvine, D. R., Rajan, R., & Brown, M. (2001). Injury- and use-related plasticity in adult auditory cortex. Audiol Neurootol, 6(4), 192-195. doi: 46831

Jastreboff, P. J. (1990). Phantom auditory perception (tinnitus): mechanisms of generation and perception. Neurosci Res, 8(4), 221-254.

Jastreboff, P. J., & Jastreboff, M. M. (2000). Tinnitus Retraining Therapy (TRT) as a method for treatment of tinnitus and hyperacusis patients. J Am Acad Audiol, 11(3), 162-177.

Lanting, C. P., de Kleine, E., & van Dijk, P. (2009). Neural activity underlying tinnitus generation: results from PET and fMRI. Hear Res, 255(1-2), 1-13. doi: 10.1016/j.heares.2009.06.009

McKenna, L., Handscomb, L., Hoare, D. J., & Hall, D. A. (2014). A scientific cognitive-behavioral model of tinnitus: novel conceptualizations of tinnitus distress. Front Neurol, 5, 196. doi: 10.3389/fneur.2014.00196

Milner, R., Lewandowska, M., Ganc, M., Ciesla, K., Niedzialek, I., & Skarzynski, H. (2016). Slow Cortical Potential Neurofeedback in Chronic Tinnitus Therapy: A Case Report. Appl Psychophysiol Biofeedback, 41(2), 225-249. doi: 10.1007/s10484-015-9318-5

Moschen, R., Riedl, D., Schmidt, A., Kumnig, M., Bliem, H. R., & Rumpold, G. (2015). The Development of Acceptance of Chronic Tinnitus in the Course of a Cognitive-Behavioral Group Therapy. Z Psychosom Med Psychother, 61(3), 238-246. doi: 10.13109/zptm.2015.61.3.238

Ochi, K., Kinoshita, H., Kenmochi, M., Nishino, H., & Ohashi, T. (2003). Zinc deficiency and tinnitus. Auris Nasus Larynx, 30 Suppl, S25-28.

Oz, I., Arslan, F., Hizal, E., Erbek, S. H., Eryaman, E., Senkal, O. A., . . . Ozluoglu, L. N. (2013). Effectiveness of the combined hearing and masking devices on the severity and perception of tinnitus: a randomized, controlled, double-blind study. ORL J Otorhinolaryngol Relat Spec, 75(4), 211-220. doi: 10.1159/000349979

Parker, G., Hyett, M., Walsh, W., Owen, C., Brotchie, H., & Hadzi-Pavlovic, D. (2011). Specificity of depression following an acute coronary syndrome to an adverse outcome extends over five years. Psychiatry Res, 185(3), 347-352. doi: 10.1016/j.psychres.2010.07.015

Parker, G. B., Heruc, G. A., Hilton, T. M., Olley, A., Brotchie, H., Hadzi-Pavlovic, D., . . . Stocker, R. (2006). Low levels of docosahexaenoic acid identified in acute coronary syndrome patients with depression. Psychiatry Res, 141(3), 279-286. doi: 10.1016/j.psychres.2005.08.005

Parker, G. B., Hilton, T. M., Walsh, W. F., Owen, C. A., Heruc, G. A., Olley, A., . . . Hadzi-Pavlovic, D. (2008). Timing is everything: the onset of depression and acute coronary syndrome outcome. Biol Psychiatry, 64(8), 660-666. doi: 10.1016/j.biopsych.2008.05.021

Rauschecker, J. P., Leaver, A. M., & Muhlau, M. (2010). Tuning out the noise: limbic-auditory interactions in tinnitus. Neuron, 66(6), 819-826. doi: 10.1016/j.neuron.2010.04.032

Tyler, R. S., Noble, W., Coelho, C. B., & Ji, H. (2012). Tinnitus retraining therapy: mixing point and total masking are equally effective. Ear Hear, 33(5), 588-594. doi: 10.1097/AUD.0b013e31824f2a6e



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Further thoughts on inflammation and depression

A search of the literature in Pub Med (3/29/2011), using the search terms depression and inflammation, reveals over 1700 documents published in the medical literature since 1922.  A tentative link between depression as a mental health issue and inflammation was first made in 1981 when Horrobin and Lieb suggested that inflammation and immune disorders could be thought of as “manic depression of the immune system.”[1]   It took another twenty years before it was noticed that elevated levels of inflammatory markers associated with heart disease were also seen in depressed patients who had no history of heart disease. [2]  But by the middle of the first decade of the new millennium, a burst of studies appear that note the link between inflammatory biomarkers and clinical depression [3-8] and dementia [9-11]. 

The role of the immune system was starting to be explored as a co-factor as well.  By 2010 links were reported between depression, inflammation and the immune system and a variety of disease states including depression[12-18], dementia [9-11], multiple sclerosis[19], heart disease [20-27], arthritis [28], and even dental diseases [29].  Also by 2010, the evidence base seemed clear that there was some link between inflammation, the immune system and depression, but it was not at all clear what the causal link was.  The evidence base exploded in the first quarter of 2011 with 24 articles compared to 34 articles in the entire year for 2010.  It could be concluded that the research community has found a new thread with a growing popularity.  But has any of this science been practically applied in the clinical trenches?

As we might expect, the pharmaceutical industry may be intrigued by the possibility of developing new psychiatric drugs based upon the underlying mechanisms of either inflammation or immunomodulation.[30]  There is even speculation that the actual benefit of current antidepressant medications may be due to their anti-inflammatory effects rather than their effects on catecholamines. [5, 31]  This opens up an area of speculation.  Since there are many foods with anti-inflammatory effects [32-43], could we eat our way out of depression?

Obviously whole natural food has limited amounts of anti-inflammatory flavonoids per kilo of food mass.  This limits the amount a person could be expected to consume.   If the effective flavonoids could be isolated and a nutraceutical could be prepared, we might have a way to test the hypothesis that depression can be reduced by ingestion of ant-inflammatory foods.  One nutraceutical preparation combines curcumin with scutellaria (a Chinese medicinal herb) and acacia derived from the bark of the boxwood tree. This combination was shown to reduce both COX and LOX enzymes to safe natural levels producing a corresponding reduction in systemic inflammation. [44]  This preparation was also found to be both safe and effective in double blind, placebo controlled trials, comparing the preparation to standard anti-inflammatory medications for arthritis.  [45-47]

To date I know of no research examining the effect of such natural anti-inflammatory foods on neurodegenerative conditions such as depression, anxiety and dementia.  In fact, despite the ample evidence of the negative effects of inflammation and oxidative stress on neurodegeneration, I have been unable to find any research on the therapeutic effects of anti-inflammatory or antioxidant diet or supplementation.   I have noticed anecdotally that a product containing anti-inflammatory flavonoids, anti-oxidants and a combination of other herbs and plant fractions has resulted in improved mood, mental energy, clarity and focus as well as stress resilience for many of my depressed patients.  This product, manufactured by the Univera company, has caused me to question whether it is time to try to obtain a formal research grant for a double blind human trial with clinically depressed individuals.

Please add your comments if you have personal or professional experience with this or other plant based natural anti-inflammatory products affecting the course of depression.

1.            Horrobin, D.F. and J. Lieb, A biochemical basis for the actions of lithium on behaviour and on immunity: relapsing and remitting disorders of inflammation and immunity such as multiple sclerosis or recurrent herpes as manic-depression of the immune system. Medical hypotheses, 1981. 7(7): p. 891-905.

2.            Kop, W.J., et al., Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia. The American journal of cardiology, 2002. 89(4): p. 419-24.

3.            Toker, S., et al., The association between burnout, depression, anxiety, and inflammation biomarkers: C-reactive protein and fibrinogen in men and women. Journal of occupational health psychology, 2005. 10(4): p. 344-62.

4.            Shimbo, D., et al., Role of depression and inflammation in incident coronary heart disease events. The American journal of cardiology, 2005. 96(7): p. 1016-21.

5.            Ozcakar, L., et al., Selective serotonin reuptake inhibitors in familial Mediterranean fever: are we treating depression or inflammation? Rheumatology international, 2005. 25(4): p. 319-20.

6.            Janszky, I., et al., Self-rated health and vital exhaustion, but not depression, is related to inflammation in women with coronary heart disease. Brain, behavior, and immunity, 2005. 19(6): p. 555-63.

7.            Huang, T.L. and J.F. Chen, Cholesterol and lipids in depression: stress, hypothalamo-pituitary-adrenocortical axis, and inflammation/immunity. Advances in clinical chemistry, 2005. 39: p. 81-105.

8.            Hestad, K.A., et al., Inflammation and depression: further studies are needed. The journal of ECT, 2005. 21(1): p. 52.

9.            Sundelof, J., et al., Systemic inflammation and the risk of Alzheimer’s disease and dementia: a prospective population-based study. J Alzheimers Dis, 2009. 18(1): p. 79-87.

10.          Leonard, B.E., Inflammation, depression and dementia: are they connected? Neurochemical research, 2007. 32(10): p. 1749-56.

11.          Leonard, B.E. and A. Myint, Inflammation and depression: is there a causal connection with dementia? Neurotoxicity research, 2006. 10(2): p. 149-60.

12.          Song, C. and H. Wang, Cytokines mediated inflammation and decreased neurogenesis in animal models of depression. Progress in neuro-psychopharmacology & biological psychiatry, 2010.

13.          Shelton, R.C. and A.H. Miller, Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Progress in neurobiology, 2010. 91(4): p. 275-99.

14.          Shelton, R.C., et al., Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Molecular psychiatry, 2010.

15.          Lucchina, L., et al., Evaluating the interaction between early postnatal inflammation and maternal care in the programming of adult anxiety and depression-related behaviors. Behavioural brain research, 2010. 213(1): p. 56-65.

16.          Lucassen, P.J., et al., Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2010. 20(1): p. 1-17.

17.          Glover, A.T., et al., Can inflammation be an independent predictor of depression? Brain, behavior, and immunity, 2010. 24(2): p. 173; author reply 174-5.

18.          Gardner, A. and R.G. Boles, Beyond the serotonin hypothesis: Mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Progress in neuro-psychopharmacology & biological psychiatry, 2010.

19.          Gold, S.M. and M.R. Irwin, Depression and immunity: inflammation and depressive symptoms in multiple sclerosis. Immunology and allergy clinics of North America, 2009. 29(2): p. 309-20.

20.          Davidson, K.W., et al., Relation of inflammation to depression and incident coronary heart disease (from the Canadian Nova Scotia Health Survey [NSHS95] Prospective Population Study). Am J Cardiol, 2009. 103(6): p. 755-61.

21.          Pizzi, C., et al., Analysis of potential predictors of depression among coronary heart disease risk factors including heart rate variability, markers of inflammation, and endothelial function. Eur Heart J, 2008. 29(9): p. 1110-7.

22.          Hannestad, J., Regarding “depression and inflammation in patients with coronary heart disease: findings from the heart and soul study”. Biol Psychiatry, 2008. 63(3): p. e27.

23.          Whooley, M.A., et al., Depression and inflammation in patients with coronary heart disease: findings from the Heart and Soul Study. Biol Psychiatry, 2007. 62(4): p. 314-20.

24.          Vaccarino, V., et al., Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study. J Am Coll Cardiol, 2007. 50(21): p. 2044-50.

25.          Buriachkovskaia, L.I., et al., [Platelet activation and inflammation markers in patients with coronary heart disease and depression]. Ter Arkh, 2006. 78(10): p. 9-14.

26.          Shimbo, D., et al., Role of depression and inflammation in incident coronary heart disease events. Am J Cardiol, 2005. 96(7): p. 1016-21.

27.          Janszky, I., et al., Self-rated health and vital exhaustion, but not depression, is related to inflammation in women with coronary heart disease. Brain Behav Immun, 2005. 19(6): p. 555-63.

28.          Kojima, M., et al., Depression, inflammation, and pain in patients with rheumatoid arthritis. Arthritis and rheumatism, 2009. 61(8): p. 1018-24.

29.          Johannsen, A., et al., Dental plaque, gingival inflammation, and elevated levels of interleukin-6 and cortisol in gingival crevicular fluid from women with stress-related depression and exhaustion. Journal of periodontology, 2006. 77(8): p. 1403-9.

30.          Maes, M., et al., Editorial: (Neuro)inflammation and neuroprogression as new pathways and drug targets in depression: From antioxidants to kinase inhibitors. Progress in neuro-psychopharmacology & biological psychiatry, 2011.

31.          Brustolim, D., et al., A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice. International immunopharmacology, 2006. 6(6): p. 903-7.

32.          Bhandare, A.M., et al., Potential analgesic, anti-inflammatory and antioxidant activities of hydroalcoholic extract of Areca catechu L. nut. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2010. 48(12): p. 3412-7.

33.          Zhou, H., C.S. Beevers, and S. Huang, The targets of curcumin. Current drug targets, 2011. 12(3): p. 332-47.

34.          Shukla, S., et al., Studies on anti-inflammatory, antipyretic and analgesic properties of Caesalpinia bonducella F. seed oil in experimental animal models. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2010. 48(1): p. 61-4.

35.          Palozza, P., et al., Tomato lycopene and inflammatory cascade: basic interactions and clinical implications. Current medicinal chemistry, 2010. 17(23): p. 2547-63.

36.          Choi, S.P., et al., Protective effects of black rice bran against chemically-induced inflammation of mouse skin. Journal of agricultural and food chemistry, 2010. 58(18): p. 10007-15.

37.          Thakur, G.S., et al., Momordica balsamina: a medicinal and neutraceutical plant for health care management. Current pharmaceutical biotechnology, 2009. 10(7): p. 667-82.

38.          Li, X., et al., Anti-inflammatory and analgesic activities of Chaenomeles speciosa fractions in laboratory animals. Journal of medicinal food, 2009. 12(5): p. 1016-22.

39.          Butt, M.S. and M.T. Sultan, Green tea: nature’s defense against malignancies. Critical reviews in food science and nutrition, 2009. 49(5): p. 463-73.

40.          Ban, J.O., et al., Anti-inflammatory and arthritic effects of thiacremonone, a novel sulfur compound isolated from garlic via inhibition of NF-kappaB. Arthritis research & therapy, 2009. 11(5): p. R145.

41.          Yoshioka, Y., et al., Orally administered apple procyanidins protect against experimental inflammatory bowel disease in mice. International immunopharmacology, 2008. 8(13-14): p. 1802-7.

42.          Takaki, I., et al., Anti-inflammatory and antinociceptive effects of Rosmarinus officinalis L. essential oil in experimental animal models. Journal of medicinal food, 2008. 11(4): p. 741-6.

43.          Kurtz, E.S. and W. Wallo, Colloidal oatmeal: history, chemistry and clinical properties. Journal of drugs in dermatology : JDD, 2007. 6(2): p. 167-70.

44.          Burnett, B.P., et al., A medicinal extract of Scutellaria baicalensis and Acacia catechu acts as a dual inhibitor of cyclooxygenase and 5-lipoxygenase to reduce inflammation. Journal of medicinal food, 2007. 10(3): p. 442-51.

45.          Pillai, L., B.P. Burnett, and R.M. Levy, GOAL: multicenter, open-label, post-marketing study of flavocoxid, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin. Current medical research and opinion, 2010. 26(5): p. 1055-63.

46.          Levy, R.M., et al., Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized, double-blind pilot study. Nutrition research, 2009. 29(5): p. 298-304.

47.          Altavilla, D., et al., Flavocoxid, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, blunts pro-inflammatory phenotype activation in endotoxin-stimulated macrophages. British journal of pharmacology, 2009. 157(8): p. 1410-8.

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Anxiety & Food

There may be a link between the western diet and anxiety. [1]  In a recent article published in the American Journal of Psychiatry, the authors conclude that a “traditional” dietary pattern characterized by vegetables, fruit, meat, fish and whole grains was associated with lower odds for major depression, dysthymia and anxiety disorders.  On the other hand, a “western” diet of processed or fried foods, refined grains, sugary products and beer was associated with a higher likelihood of such symptoms. 

Despite the abundant research linking systemic inflammation, oxidative stress and cortisol levels to psychiatric symptoms, little research is being carried out exploring the impact of functional foods on psychiatric malaise. [2]  One article suggests that foods that support mitochondrial efficiency may be useful. [3] Of course, caffeine consumption has been linked to anxiety. [4-7] But are we getting any closer to understanding the link between food and mood?

A recent study suggests that for certain individuals, stress may increase the hedonistic food appetite control mechanism. [8, 9]  High trait anxiety individuals, the study asserts, are more likely to respond to stress with the urge to consume sweet foods.  However, when these individuals consume alpha-lactalbumin (whey protein), the urge to eat sweet foods in response to stress is reduced. [10]  Apparently whey protein increases tryptophan levels, which in turn may modulate serotonin physiology. [10, 11]  Could this be a food to reduce emotional eating?

If we include herbs as food in this discussion, many other options emerge.  Kava-kava has long been recognized for its anxiolytic effects.  However, adverse reactions such as kava-dermatitis, liver damage and drug interactions have been reported, suggesting that it is not appropriate for clinical use by non-medical providers.[12-14]  St. John’s Wort is another herb with a strong history of psychiatric uses. One recent study suggests it may help reduce age related memory loss by “increasing the levels of cyclic adenosine 3′, 5′-monophosphate response element binding protein (CREB) and phosphorylated CREB (pCREB) in the hippocampus.”  Of course this research was in rats and there is no data to support human use for this purpose.[15] 

Numerous other herbs are common place either due to CAM providers prescribing them or due to self-use. This brings us to the observation that it is wise to routinely ask our patients what they are taking to avoid inadvertent interaction effects.[16, 17

I am interested in an herb called Ashwagandha.  It is an ayurvedic herb that has recently been shown to have anxiolytic and stress tolerance benefits and is safe and effective.  Is anyone else using this with patients?
Phytonutrients, botanicals, herbs and functional foods are rapidly moving into our clinical landscape.  One report suggests that 67% of persons suffering depression or anxiety may be using such alternatives to psychoactive drugs. [16] The tone of such articles is generally worrisome in that the implied value appears to be to minimize the risk of pharmaceuticals and magnify the risk of nutraceuticals.  I think that it is our job to discuss such risks candidly in the spirit of informed consent and to make every effort to stay current with the avalanche of research in our fields.  What do you think?  Please comment below.

1.    Jacka, F.N., et al., Association of Western and traditional diets with depression and anxiety in women. Am J Psychiatry, 2010. 167(3): p. 305-11.

2.    Wattanathorn, J., et al., Piperine, the potential functional food for mood and cognitive disorders. Food Chem Toxicol, 2008. 46(9): p. 3106-10.

3.    Casucci, G., V. Villani, and C. Finocchi, Therapeutic strategies in migraine patients with mood and anxiety disorders: physiopathological basis. Neurol Sci, 2010. 31 Suppl 1: p. S99-101.

4.    Luebbe, A.M. and D.J. Bell, Mountain Dew or mountain don’t?: a pilot investigation of caffeine use parameters and relations to depression and anxiety symptoms in 5th- and 10th-grade students. J Sch Health, 2009. 79(8): p. 380-7.

5.    Bruce, M., et al., Anxiogenic effects of caffeine in patients with anxiety disorders. Arch Gen Psychiatry, 1992. 49(11): p. 867-9.

6.    Mino, Y., et al., Caffeine consumption and anxiety and depressive symptomatology among medical students. Arukoru Kenkyuto Yakubutsu Ison, 1990. 25(6): p. 486-96.

7.    Mathew, R.J. and W.H. Wilson, Behavioral and cerebrovascular effects of caffeine in patients with anxiety disorders. Acta Psychiatr Scand, 1990. 82(1): p. 17-22.

8.    Neary, M.T. and R.L. Batterham, Gaining new insights into food reward with functional neuroimaging. Forum Nutr, 2010. 63: p. 152-63.

9.    Jesudason, D. and G. Wittert, Endocannabinoid system in food intake and metabolic regulation. Curr Opin Lipidol, 2008. 19(4): p. 344-8.

10.    Verschoor, E., et al., Effects of an acute alpha-lactalbumin manipulation on mood and food hedonics in high- and low-trait anxiety individuals. Br J Nutr, 2010. 104(4): p. 595-602.

11.    Orosco, M., et al., Alpha-lactalbumin-enriched diets enhance serotonin release and induce anxiolytic and rewarding effects in the rat. Behav Brain Res, 2004. 148(1-2): p. 1-10.

12.    Zhou, P., et al., Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-{kappa}B and MAPK signaling pathways. FASEB J, 2010.

13.    Anke, J. and I. Ramzan, Pharmacokinetic and pharmacodynamic drug interactions with Kava (Piper methysticum Forst. f.). J Ethnopharmacol, 2004. 93(2-3): p. 153-60.

14.    Singh, Y.N. and N.N. Singh, Therapeutic potential of kava in the treatment of anxiety disorders. CNS Drugs, 2002. 16(11): p. 731-43.

15.    Trofimiuk, E., A. Holownia, and J.J. Braszko, Activation of CREB by St. John’s wort may diminish deletorious effects of aging on spatial memory. Arch Pharm Res, 2010. 33(3): p. 469-77.

16.    White, K.P., A crash course in Chinese herbology for the psychopharmocological prescriber. Exp Clin Psychopharmacol, 2009. 17(6): p. 384-95.

17.    Carrasco, M.C., et al., Interactions of Valeriana officinalis L. and Passiflora incarnata L. in a patient treated with lorazepam. Phytother Res, 2009. 23(12): p. 1795-6.

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Inflammation and Depression

I recently found 33 new studies published in 2010, exploring the relationship of chronic systemic inflammation and depression. The large number of studies suggest that there is a widening acceptance that inflammation may be a common factor for neuro-degeneration leading to depression. [1] It is interesting that the observation of a link between the biochemistry of depression, immune disorder and dementia should be levels of pro-inflammatory cytokines and DHEA/cortisol ratios. [2-5]  If overload of inflammation sets the stage for depression, it should come as no surprise that psychosocial experiences also generate pro-inflammatory cytokines.  Social rejection and the perception of an unjust work environment are just two of the social stressors that have been linked to production of cytokines. [6-8]  I expect that we will find that any chronic stressor creates inflammatory overload as the root cause of stress related disease. Naturally, the research community is starting to look at anti-inflammatory medications as a potential treatment for depression. [9]  Given their potentially lethal side effects, NSAIDS and Cox 2 inhibitors may be questionable additions to our psychological armamentarium.  But what if there were a safe and effective natural product that could reduce systemic inflammation?  Would that open the door for nutraceutical psychoactive foods in non-medical mental health practice?  There is a growing body of research that supports the fact that flavocoxid, a proprietary blend of Scutellaria, Acacia and Turmeric may drive down Cox 2 to healthy levels without stimulation lethal side effects. [10-19]

1.    Rook, G.A., 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: darwinian medicine and the ‘hygiene’ or ‘old friends’ hypothesis. Clin Exp Immunol, 2010. 160(1): p. 70-9.

2.    Zeugmann, S., et al., Inflammatory biomarkers in 70 depressed inpatients with and without the metabolic syndrome. J Clin Psychiatry, 2010. 71(8): p. 1007-16.

3.    Miller, A.H., Depression and immunity: a role for T cells? Brain Behav Immun, 2010. 24(1): p. 1-8.

4.    Maes, M., et al., Multiple aberrations in shared inflammatory and oxidative & nitrosative stress (IO&NS) pathways explain the co-association of depression and cardiovascular disorder (CVD), and the increased risk for CVD and due mortality in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry, 2010.

5.    Caraci, F., et al., Depression and Alzheimer’s disease: neurobiological links and common pharmacological targets. Eur J Pharmacol, 2010. 626(1): p. 64-71.

6.    Zaluska, M. and B. Janota, [Dehydroepiandrosteron (DHEA) in the mechanisms of stress and depression]. Psychiatr Pol, 2009. 43(3): p. 263-74.

7.    Elovainio, M., et al., Organisational justice and markers of inflammation: the Whitehall II study. Occup Environ Med, 2010. 67(2): p. 78-83.

8.    Slavich, G.M., et al., Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc Natl Acad Sci U S A, 2010. 107(33): p. 14817-22.

9.    Muller, N., COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr Opin Investig Drugs, 2010. 11(1): p. 31-42.

10.    Walton, S.M., G.T. Schumock, and D.A. McLain, Cost analysis of flavocoxid compared to naproxen for management of mild to moderate OA. Curr Med Res Opin, 2010. 26(9): p. 2253-61.

11.    Polito, F., et al., Flavocoxid, a dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase, reduces pancreatic damage in an experimental model of acute pancreatitis. Br J Pharmacol, 2010. 161(5): p. 1002-11.

12.    Pillai, L., et al., Flavocoxid, an anti-inflammatory agent of botanical origin, does not affect coagulation or interact with anticoagulation therapies. Adv Ther, 2010. 27(6): p. 400-11.

13.    Pillai, L., B.P. Burnett, and R.M. Levy, GOAL: multicenter, open-label, post-marketing study of flavocoxid, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin. Curr Med Res Opin, 2010. 26(5): p. 1055-63.

14.    Levy, R.M., et al., Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen: a randomized multicenter controlled trial in subjects with osteoarthritis of the knee. Adv Ther, 2010. 27(10): p. 731-42.

15.    Levy, R., et al., Efficacy and safety of flavocoxid compared with naproxen in subjects with osteoarthritis of the knee- a subset analysis. Adv Ther, 2010.

16.    Morgan, S.L., et al., The safety of flavocoxid, a medical food, in the dietary management of knee osteoarthritis. J Med Food, 2009. 12(5): p. 1143-8.

17.    Messina, S., et al., Flavocoxid counteracts muscle necrosis and improves functional properties in mdx mice: a comparison study with methylprednisolone. Exp Neurol, 2009. 220(2): p. 349-58.

18.    Levy, R.M., et al., Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized, double-blind pilot study. Nutr Res, 2009. 29(5): p. 298-304.

19.    Altavilla, D., et al., Flavocoxid, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, blunts pro-inflammatory phenotype activation in endotoxin-stimulated macrophages. Br J Pharmacol, 2009. 157(8): p. 1410-8.

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Update on DHEA and Mental Health

2010 has been an interesting year for DHEA research related to mental health issues. The role of DHEA in Alzheimer’s [1, 2], neurogenesis [3], depression [4], problem solving [5] PTSD / childhood abuse [6], drug seeking behavior [7], and neurocognitive deficits in schizophrenia [8] show that DHEA may become an alternative or adjunct to psychoactive medication for both medical and non-medical practitioners to consider.  Of course this raises the question of safety, and this year’s crop of research has also been interesting in that arena, suggesting that DHEA is a safe option for most people. [9]  My read is that DHEA supplementation can be safely considered on a case by case basis for a wide range of mental health concerns.

1.    Aldred, S. and P. Mecocci, Decreased dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) concentrations in plasma of Alzheimer’s disease (AD) patients. Arch Gerontol Geriatr, 2010. 51(1): p. e16-8.

2.    Sinha, M., et al., Aging and antioxidants modulate rat brain levels of homocysteine and dehydroepiandrosterone sulphate (DHEA-S): implications in the pathogenesis of Alzheimer’s disease. Neurosci Lett, 2010. 483(2): p. 123-6.

3.    Li, L., et al., DHEA prevents Abeta(25-35)-impaired survival of newborn neurons in the dentate gyrus through a modulation of PI3K-Akt-mTOR signaling. Neuropharmacology, 2010. 59(4-5): p. 323-33.

4.    Nakano, M., et al., Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser473-phosphorylation of Akt-1 in PC12 cells. Life Sci, 2010. 86(9-10): p. 309-14.

5.    Wemm, S., et al., The role of DHEA in relation to problem solving and academic performance. Biol Psychol, 2010. 85(1): p. 53-61.

6.    Kellner, M., et al., Increased DHEA and DHEA-S plasma levels in patients with post-traumatic stress disorder and a history of childhood abuse. J Psychiatr Res, 2010. 44(4): p. 215-9.

7.    Yadid, G., et al., The role of dehydroepiandrosterone (DHEA) in drug-seeking behavior. Neurosci Biobehav Rev, 2010. 35(2): p. 303-14.

8.    Ritsner, M.S. and R.D. Strous, Neurocognitive deficits in schizophrenia are associated with alterations in blood levels of neurosteroids: a multiple regression analysis of findings from a double-blind, randomized, placebo-controlled, crossover trial with DHEA. J Psychiatr Res, 2010. 44(2): p. 75-80.

9.    Labrie, F., DHEA, important source of sex steroids in men and even more in women. Prog Brain Res, 2010. 182: p. 97-148.

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Anti-oxidants and Suicide?

The effect if oxidative stress in the brain has been linked to dementia[1], depression[2, 3] and now suicide attempts[4]. According to a study published in Nutritional Neuroscience, a study of nearly 7000 individuals with mental health diagnoses, those who attempted suicide had significantly lower levels of critical antioxidants than those who did not.  Could this study be the beginning of an evidence base supporting the recommendation of anti-oxidant supplementation for depressed patients with suicidal ideation?

1.    Aliev, G., et al., Antioxidant therapy in Alzheimer’s disease: theory and practice. Mini Rev Med Chem, 2008. 8(13): p. 1395-406.

2.    Maes, M., et al., Multiple aberrations in shared inflammatory and oxidative & nitrosative stress (IO&NS) pathways explain the co-association of depression and cardiovascular disorder (CVD), and the increased risk for CVD and due mortality in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry, 2010.

3.    Maes, M., et al., A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry, 2010.

4.    Li, Y. and J. Zhang, Serum concentrations of antioxidant vitamins and carotenoids are low in individuals with a history of attempted suicide. Nutr Neurosci, 2007. 10(1-2): p. 51-8.

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Fat Cells and Inflammatory Overload

There is now substantial literature suggesting that fat cells contribute greatly to systemic inflammation.  This appears to be one of the mediating links between obesity and a number of chronic conditions including chronic pain, metabolic syndrome, type II diabetes, coronary artery disease, heart disease, stroke and dementia.  Modifying the body mass index (BMI) has long been linked to health benefits, but the new research gives us a way to understand why this is so important.  Eating a wide variety of antioxidant rich fruits and vegetables, along with concentrated and balanced antioxidant supplementation, appears to be wise and safe from the perspective of today’s science. [1-17]

1.    Zeyda, M., et al., Inflammation Correlates With Markers of T-Cell Subsets Including Regulatory T Cells in Adipose Tissue From Obese Patients. Obesity (Silver Spring), 2010.

2.    Yang, H., et al., Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J Immunol, 2010. 185(3): p. 1836-45.

3.    Tkacova, R., Systemic inflammation in chronic obstructive pulmonary disease: may adipose tissue play a role? Review of the literature and future perspectives. Mediators Inflamm, 2010. 2010: p. 585989.

4.    Sell, H. and J. Eckel, Adipose tissue inflammation: novel insight into the role of macrophages and lymphocytes. Curr Opin Clin Nutr Metab Care, 2010. 13(4): p. 366-70.

5.    Ostertag, A., et al., Control of adipose tissue inflammation through TRB1. Diabetes, 2010. 59(8): p. 1991-2000.

6.    Maury, E. and S.M. Brichard, Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol, 2010. 314(1): p. 1-16.

7.    Ikeoka, D., J.K. Mader, and T.R. Pieber, Adipose tissue, inflammation and cardiovascular disease. Rev Assoc Med Bras, 2010. 56(1): p. 116-21.

8.    Hauner, H., Adipose tissue inflammation: are small or large fat cells to blame? Diabetologia, 2010. 53(2): p. 223-5.

9.    Gustafson, B., Adipose tissue, inflammation and atherosclerosis. J Atheroscler Thromb, 2010. 17(4): p. 332-41.

10.    Gonzalez-Periz, A. and J. Claria, Resolution of adipose tissue inflammation. ScientificWorldJournal, 2010. 10: p. 832-56.

11.    Gauthier, M.S. and N.B. Ruderman, Adipose tissue inflammation and insulin resistance: all obese humans are not created equal. Biochem J, 2010. 430(2): p. e1-4.

12.    Wajchenberg, B.L., et al., Adipose tissue at the crossroads in the development of the metabolic syndrome, inflammation and atherosclerosis. Arq Bras Endocrinol Metabol, 2009. 53(2): p. 145-50.

13.    Vachharajani, V. and D.N. Granger, Adipose tissue: a motor for the inflammation associated with obesity. IUBMB Life, 2009. 61(4): p. 424-30.

14.    Shwarts, V., [Adipose tissue inflammation and atherosclerosis]. Kardiologiia, 2009. 49(12): p. 80-6.

15.    Sakurai, T., et al., Exercise training decreases expression of inflammation-related adipokines through reduction of oxidative stress in rat white adipose tissue. Biochem Biophys Res Commun, 2009. 379(2): p. 605-9.

16.    Qatanani, M., et al., Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J Clin Invest, 2009.

17.    Pasarica, M., et al., Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes, 2009. 58(3): p. 718-25.

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Hello World!

Dr. Rick Wyckoff, PhD


This Blog will focus on exploring new research in the field of nutrition and mental health.  I will attempt to annotate my comments with a representative bibliography.  Please feel free to comment.  I hope to generate informed conversation.  If you like this blog, let your friends and colleagues know about it.  If you don’t like it, please let me know.  —  Rick

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