Stress and inflammations contribution to chronic disease

 

The Impact of Stress

Large bodies of research indicate that chronic stress, whether experienced in early life or as an adult, is linked to increased coronary heart disease risk.1,6 In particular, childhood adversity, including physical and sexual abuse in childhood, has been shown to relate to higher morbidity of cardiovascular events.7,8 Work-related stressors, poor sleep, and emotional disturbances have been correlated with adult-related cardiovascular disease.1 Racism and discrimination create additional daily stressors for Black, Indigenous, and People of Color (BIPOC) communities, impacting their increased cardiovascular disease risks.9-12

A 2018 finding using data from the Jackson Heart Study suggested that in African American adults, global stress (overall stress level) and major life events were associated with increased risk of metabolic syndrome (MetS) severity.13 Additionally, men and women’s MetS and stress responses varied in severity. For example, men significantly increased their MetS severity at medium levels of stress, whereas women significantly increased their MetS severity at high levels of stress.13

LEARN MORE ABOUT FUNCTIONAL MEDICINE

Chronic psychological stress and inflammation are also associated with a greater risk of depression, autoimmune diseases, upper respiratory infections, and poor wound healing.3 In a large study published in 2019 in the journal Molecular Psychiatry, a team of researchers from Cambridge examined the link between depression and coronary heart disease.14 Their findings suggest that the connection between these two conditions cannot be explained by a common genetic predisposition; rather, it is environmentally related. They used Mendelian randomization to investigate 15 biomarkers associated with the risk of coronary heart disease; of these biomarkers, they found that triglycerides and the inflammation-related proteins IL-6 and CRP were also risk factors for depression. What’s more, the authors note that with regard to shared environmental factors, the depression–coronary heart disease comorbidity could be linked with early-life factors influencing inflammatory regulation, such as impaired fetal development or childhood maltreatment/trauma. Low birth weight and childhood maltreatment were associated with increased levels of circulating inflammatory markers, depression, and coronary heart disease in adulthood.14

Similarly, researchers have for years speculated that disorders of the gastrointestinal tract, such as Crohn’s disease and ulcerative colitis, are related to stress and inflammation,15 but the underlying mechanism remained largely unresolved. An elegant 2018 study in mice suggests a clue, showing that chronic stress disturbs gut microbiota, triggering an immune system response and facilitating dextran sulfate sodium-induced colitis.16 Recently, a 2020 systematic review of 19 clinical prospective cohort studies also concluded that while evidence suggests that psychological factors have a weak to moderate causal involvement in inflammatory bowel disease symptom exacerbation, overall results remain inconclusive and additional studies are warranted.17

Managing Stress

With a wide range of stress-related chronic diseases on the rise, how can functional medicine clinicians target stress-related factors with interventions that improve the health of their patients? Accumulating evidence points to the beneficial effects of regular exercise in preventing or improving the metabolic and psychological comorbidities brought about by chronic stress.18 Recent meta-analyses indicate that physical exercise improves the inflammatory state in children with obesity19 and improves inflammatory biomarkers in middle-aged and older adults.20

In 2017, a first-of-its-kind study on yoga and meditation showed improvement in biomarkers of cellular aging, which are associated with oxidative stress and complex lifestyle diseases like depression, diabetes, and cardiovascular disease.21 The researchers suggested that the improvement in stress and inflammatory response was mediated by changes in cortisol, ?-endorphin, IL-6, and other factors, with regulation by changes in the brain through the hypothalamic-pituitary-adrenal (HPA) axis.21

Many diseases stemming from chronic stress and inflammation have early warning signs, meaning some cases may be prevented or improved with lifestyle changes that help manage stress. The functional medicine model focuses in on identifying stress as a cause of dysfunction and utilizing specific interventions like exercise, meditation, and yoga that work for the individual patient. Tools such as the functional medicine timeline can also help clinicians identify areas of life where stress may be problematic and design treatments that focus on improving stress management.Learn more about tools and strategies to help patients achieve sustainable lifestyle change and improve their well-being through IFM’s new course Lifestyle: The Foundations of Functional Medicine.

References

1. Liu YZ, Wang YX, Jiang CL. Inflammation: the common pathway of stress-related diseases. Front Hum Neurosci. 2017;11:316. doi:10.3389/fnhum.2017.00316
2. Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822-1832. doi:10.1038/s41591-019-0675-0
3. Cohen S, Janicki-Deverts D, Doyle WJ, et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci U S A. 2012;109(16):5995-5999. doi:10.1073/pnas.1118355109
4. Miller GE, Cohen S, Ritchey AK. Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol. 2002;21(6):531-541. doi:10.1037//0278-6133.21.6.531
5. Walsh CP, Bovbjerg DH, Marsland AL. Glucocorticoid resistance and ?2-adrenergic receptor signaling pathways promote peripheral pro-inflammatory conditions associated with chronic psychological stress: a systematic review across species. Neurosci Biobehav Rev. 2021;128:117-135. doi:10.1016/j.neubiorev.2021.06.013
6. Su S, Jimenez MP, Roberts CTF, Loucks EB. The role of adverse childhood experiences in cardiovascular disease risk: a review with emphasis on plausible mechanisms. Curr Cardiol Rep. 2015;17(10):88. doi:10.1007/s11886-015-0645-1
7. Rich-Edwards JW, Mason S, Rexrode K, et al. Physical and sexual abuse in childhood as predictors of early-onset cardiovascular events in women. Circulation. 2012;126(8):920-927. doi:10.1161/CIRCULATIONAHA.111.076877
8. Kreatsoulas C, Fleegler EW, Kubzansky LD, McGorrian CM, Subramanian SV. Young adults and adverse childhood events: a potent measure of cardiovascular risk. Am J Med. 2019;132(5):605-613. doi:10.1016/j.amjmed.2018.12.022
9. Acosta JN, Leasure AC, Both CP, et al. Cardiovascular health disparities in racial and other underrepresented groups: initial results from the All of Us research program. J Am Heart Assoc. 2021;10(17):e021724. doi:10.1161/JAHA.121.021724
10. Javed Z, Maqsood MH, Amin Z, Nasir K. Race and ethnicity and cardiometabolic risk profile: disparities across income and health insurance in a national sample of US adults. J Public Health Manag Pract. 2022;28(Suppl 1):S91-S100. doi:10.1097/PHH.0000000000001441
11.  Javed Z, Haisum Maqsood M, Yahya T, et al. Race, racism, and cardiovascular health: applying a social determinants of health framework to racial/ethnic disparities in cardiovascular disease. Circ Cardiovasc Qual Outcomes. 2022;15(1):e007917. doi:10.1161/CIRCOUTCOMES.121.007917
12.  Panza GA, Puhl RM, Taylor BA, Zaleski AL, Livingston J, Pescatello LS. Links between discrimination and cardiovascular health among socially stigmatized groups: a systematic review. PLoS One. 2019;14(6):e0217623. doi:10.1371/journal.pone.0217623
13.  Cardel MI, Min YI, Sims M, et al. Association of psychosocial stressors with metabolic syndrome severity among African Americans in the Jackson Heart Study. Psychoneuroendocrinology. 2018;90:141-147. doi:10.1016/j.psyneuen.2018.02.014
14.  Khandaker GM, Zuber V, Rees JMB, et al. Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort. Mol Psychiatry. 2020;25(7):1477-1486. doi:10.1038/s41380-019-0395-3
15.  Pereira C, Grácio D, Teixeira JP, Magro F. Oxidative stress and DNA damage: implications in inflammatory bowel disease. Inflamm Bowel Dis. 2015;21(10):2403-2417. doi:10.1097/MIB.0000000000000506
16.  Gao X, Cao Q, Cheng Y, et al. Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response. Proc Natl Acad Sci U S A. 2018;115(13):E2960-E2969. doi:10.1073/pnas.1720696115
17.  Schoultz M, Beattie M, Gorely T, Leung J. Assessment of causal link between psychological factors and symptom exacerbation in inflammatory bowel disease: a systematic review utilising Bradford Hill criteria and meta-analysis of prospective cohort studies. Syst Rev. 2020;9(1):169. doi:10.1186/s13643-020-01426-2
18.  Tsatsoulis A, Fountoulakis S. The protective role of exercise on stress system dysregulation and comorbidities. Ann N Y Acad Sci. 2006;1083:196-213. doi:10.1196/annals.1367.020
19.  Sirico F, Bianco A, D’Alicandro G, et al. Effects of physical exercise on adiponectin, leptin, and inflammatory markers in childhood obesity: systematic review and meta-analysis. Child Obes. 2018;14(4):207-217. doi:10.1089/chi.2017.0269
20.  Zheng G, Qiu P, Xia R, et al. Effect of aerobic exercise on inflammatory markers in healthy middle-aged and older adults: a systematic review and meta-analysis of randomized controlled trials. Front Aging Neurosci. 2019;11:98. doi:10.3389/fnagi.2019.00098
21.  Tolahunase M, Sagar R, Dada R. Impact of yoga and meditation on cellular aging in apparently healthy individuals: a prospective, open-label single-arm exploratory study. Oxid Med Cell Longev. 2017;2017:7928981. doi:10.1155/2017/7928981

Highly processed foods as Addictive as Tobacco

 Highly Processed Foods 'as Addictive' as Tobacco: <https://www.medscape.com/viewarticle/984600>

LONDON — Highly processed foods meet the same criteria as tobacco for addiction, and labeling them as such might benefit public health, according to a new US study that proposes a set of criteria to assess the addictive potential of some foods.

The research suggests that healthcare professionals are taking steps towards framing food addiction as a clinical entity in its own right; it currently lacks validated treatment protocols and recognition as a clinical diagnosis.

Meanwhile, other data, reported by researchers last week at the Diabetes Professional Care (DPC) 2022 conference in London, UK, also add support to the clinical recognition of food addiction.

Clinical psychologist Jen Unwin, PhD, from Southport, UK, showed that a 3-month online program of low carbohydrate diet together with psychoeducational support significantly reduced food addiction symptoms among a varied group of individuals, not all of whom were overweight or had obesity.

Unwin said her new data represent the first widescale clinical audit of its kind, other than a prior report of three patients with food addiction who were successfully treated with a ketogenic diet. 

"Food addiction explains so much of what we see in clinical practice, where intelligent people understand what we tell them about the physiology associated with a low-carb diet, and they follow it for a while, but then they relapse," said Unwin, explaining the difficulties faced by around 20% of her patients who are considered to have food addiction.

Meanwhile, the authors of the US study, led by Ashley N. Gearhardt, PhD, a psychologist from the University of Michigan, Ann Arbor, write that the ability of highly processed foods (HPFs) "to rapidly deliver high doses of refined carbohydrates and/or fat appear key to their addictive potential. Thus, we conclude that HPFs can be considered addictive substances based on scientifically established criteria."

They assert that the contribution to preventable deaths by a diet dominated by highly processed foods is comparable to that of tobacco products, and as such, like Unwin, the authors seek clinical recognition and a more formalized protocol to manage food addiction.

"Understanding whether addiction contributes to HPF intake may lead to new treatments, as preliminary research finds that behavioral and pharmacological interventions that target addictive mechanisms may reduce compulsive HPF intake," they state

The study led by Gearhardt was published this month in the journal Addiction, and the study led by Unwin was also recently published in Frontiers in Psychiatry.

Addiction Criteria Similar to Tobacco

HPFs can be associated with an eating phenotype "that reflects the hallmarks of addiction," say Gearhardt and co-authors; typically, loss of control over intake, intense cravings, inability to cut down, and continued use despite negative consequences.

Acknowledging the lack of a single addictive agent, they explain that food addiction reflects mechanisms implicated in other addictive disorders such as smoking.

As such, in their study, Gearhardt and colleagues propose a set of scientifically based criteria for the evaluation of whether certain foods are addictive. "Specifically, we propose the primary criteria used to resolve one of the last major controversies over whether a substance, tobacco products, was addictive."

They consider certain foods according to the primary criteria that have stood the test of time after being proposed in 1988 by the US Surgeon General to establish the addictive potential of tobacco: (1) they trigger compulsive use, (2) they have psychoactive effects, and (3) they are reinforcing.

They have updated these criteria to include the ability to trigger urges and cravings, and add that "both these products [tobacco and HPFs] are legal, easily accessible, inexpensive, lack an intoxication syndrome, and are major causes of preventable death."

For example, with compulsive use, tobacco meets this criterion because evidence suggests that most smokers would like to quit but are unable to do so.

Likewise, write Gearhardt and colleagues, even "in the face of significant diet-related health consequences (eg, diabetes and cardiovascular disease), the majority of patients are unable to adhere to medically recommended dietary plans that require a reduction in HPF intake.”

Reinforcement, through tobacco use, is demonstrated by its 'being sufficiently rewarding to maintain self-administration" due to its ability to deliver nicotine, they say, quoting the Surgeon General's report, and likewise, with food addiction, "both adults and children will self-administer HPFs (eg, potato chips, candy, and cookies) even when satiated."

Online Group Food Addiction Intervention Study

Unwin and co-authors want people with food addiction to be able to access a validated treatment protocol. Their study aimed to evaluate an online group intervention across multiple sites in the United States, Canada, and the UK, involving an abstinent, low-carbohydrate diet and biopsychosocial education focused on addiction and recovery in people self-identifying as having food addiction.

"Lots of people with food addiction go to GPs who don't clinically recognize this, or if they attend addiction services and psychiatry, then they tend to only specialize in drugs, alcohol, and gambling. Eating disorder services are linked but their programs mostly don't work for a food addict," Unwin remarked in an interview with Medscape Medical News.

"We feel running groups, as well as training professionals to run groups, is the best way to manage food addiction," she said, reflecting on the scale of the problem, with around 10% of adults in the UK general population considered to have food addiction. In Unwin's study, some people had type 2 diabetes and some overweight/obesity, but she added that some participants were underweight or of normal weight.

Initially, the 103 participants received weekly group (8-24 people) sessions for 10-14 weeks, and then monthly maintenance comprising follow-up that involved coaching participants on how to cope with relapse and get back on track.

Food addiction symptoms were assessed pre- and post-program using the modified Yale Food Addiction Scale (mYFAS) 2.0; ICD-10 symptoms of food-related substance use disorder (CRAVED); and mental health well-being measured using the short version of the Warwick Edinburgh Mental Wellbeing scale and body weight.

"The program eliminates processed foods with a personalized, abstinence food plan that involves education around mechanisms involved," said Unwin, who explained that processed foods deliver a dopamine high, and in response to this, the brain lowers the number of dopamine receptors to effectively counteract the increase in dopamine. This drop in dopamine receptors explains the depression often associated with food addiction.

Unwin reported that food addiction symptoms were significantly reduced, with the mYFAS dropping by 1.52, the CRAVED score by 1.53, and body weight by 2.34 kg (5.2 lb). Mental health, as measured by the Warwick Edinburgh Mental Wellbeing scale, improved by 2.37 points.

"We were very interested in mental health and well-being because it impacts so much across our lives, and we saw significant improvements here, but we were less interested in weight because food addicts come in all shapes and sizes with some people underweight," remarked Unwin. "Food addiction symptoms were significantly improved in the group, but we now need to look at the longer-term outcomes."

Unwin runs a low-carbohydrate program for type 2 diabetes with her husband David Unwin, MD, who is a GP in Southport, UK. She said that they ask patients if they think they have food addiction, and most say they do.

"I always try to explain to patients about the dopamine high, and how this starts the craving which makes people wonder when and where they can find the next sugar hit. Just thinking about the next chocolate bar gets the dopamine running for many people, and the more they tread this path then the worse it gets because the dopamine receptors keep reducing."

Lorraine Avery, RN, a diabetes nurse specialist for Solent NHS Trust, UK, who attended the DPC conference, welcomed Unwin's presentation.

"My concern as a diabetes nurse specialist is that I'm unsure all our patients recognize their food addiction, and there are often more drivers to eating than just the food in front of them," she told Medscape Medical News. "I think there's an emotional element, too. These people are often 'yo-yo' dieters, and they join lots of expert companies to help them lose weight, but these companies want them to regain and re-join their programs," she said.

"I think there is something about helping patients recognize they have a food addiction and they need to consider that other approaches might be helpful."

Addiction. Published online November 9, 2022. Full text

Front Psychiatry. Published online September 28, 2022. Full text

Unwin has reported no relevant financial relationships; some other authors have fee-paying clients with food addiction. Gearhardt and Avery have reported no relevant financial relationships.

Tucker Carlson interviews Dr Aseem Malhotra on the corruption of medicin...

Breath

 I breathe in and all dissolves. I breathe out and create anew.  Every breath is an opportunity to create.   I get to choose that creation as I am recreated with every breath. 

Why do I have hope?

Why do I have hope. 

In this time where there appears to be so much chaos. The oceans are dying, the farms are decreasing and things seem hopeless and I have hope.  

I have hope because I have love, because I can see the beauty in the world.  

I see beauty in the sunrise and i fall in love.

I feel the major shift in conscious awareness. 

So many working towards healing their wounds and finding their true selves. 

I see love in the eyes of babes and in the reflection in the mirror I finally see beauty and I see you. 

I have hope when I see the resilience of Humanity and the return to love of the earth. When I see so many rising up and speaking their truth, loud and proud. 

I have hope because I see that we are moving towards oneness. Never have there been so many opening up to truth.  From chaos comes order?

I believe that the world can shift in an instant if we all find our alignment and the beauty that we are and this gives me hope. It gives me a vision. 

“In all chaos there is a cosmos, in all disorder a secret order.” ~Carl Jung, CW 9i, Para 66

I HAVE HOPE. 

Numbers 3,4,8 and 9 in your food and regarding your health

 

What do the numbers 3,4, 8 and 9 have to do with your health and wellness?

Ronald Grisanti D.C., D.A.B.C.O., D.A.C.B.N, M.S., CFMP

You know those little stickers on fruits and veggies? They're called price look-up (PLU) codes and they contain numbers that cashiers use to ring you up. But you can also use them to make sure you're getting what you paid for. If you are interested in staying healthy, here's what to look for:

• A five-digit number that starts with a 9  means the item is organic. Eating organically—or better yet, biodynamically—grown produce is paramount. This can be identified at the grocery store by a five-digit bar code starting with the number "9," or purchased from your local biodynamic grower.

• A four-digit code beginning with a 3 or a 4 means the produce is probably conventionally grown. For example, regular small lemons sold in the U.S. are labeled 4033, large are 4053; small organic lemons are coded 94033, large are 94053. We cannot emphasize enough the importance of food quality when it comes to the prevention of disease. Sure, a conventionally grown bell pepper (identified by a sticker with a four-digit bar code starting with the number "4") will contain the healthy compound beta-cryptoxanthin, but it will also come with a whole host of cancer-causing chemicals on it. 

• A five-digit code that starts with an 8 means the item is genetically modified (it has genes from other organisms). You won't see many of those because only genetically modified versions of corn, soybeans, canola, cotton, papaya, and squash are now widely sold. And because PLU codes aren't mandatory, companies can label those items as conventional. 

Authenticity and I...

The meaning: genuineness, legitamacy...the quality of being believable or trustworthy

I had to face a shadow side to my authenticity. I found that deep dark, gnarly part of me called inauthentic and she was unrecognizable. I hid her so far and deep for so long that I couldn't recognize her. It was startling. How many times had I been inauthentic? Obviously many, many times, judging from the shadow I faced.

I desire to be authentic in all my dealings and to walk the path of that. However, can one truly always be authentic? Does society allow for this? Am I afraid?

The answer is yes, when we decide to chose that and no, society may not always be open to it and yes, I am afraid!

The dance of life and belonging is always interesting. We humans wish to belong and sometimes we compromise our own individuality and authenticity to do so. I am walking this path and watching myself. There are many days that I wonder who I am and what my purpose is and how am I supposed to show up in the world. I feel lost and unsure. I feel caught between who I chose to be and belonging.

I know on an intellectual level that I am love and divine and have even had real moments of feeling my divinity and the depth of love that I, and we all, are. I do however struggle to maintain that love and peace at all time and I guess that is the experience of life and what we are all here to learn and strive for?

AM I authentic? Do I always say what I mean and mean what I say? I know I am trust worthy. I have lost many friendships since moving to the USA and living in Minnesota, due to saying exactly what is on my mind and in my heart. People tell you that they want honesty but most cannot handle it. I do not say things to hurt anyone and most certainly do not wish anyone harm, however, saying too much has been taken in the wrong light by many.

It is interesting that most of us do not take a moment to check our own reactions to what is being offered in conversation as a gift. An opportunity to see what it is that is affecting us thusly. What is it showing us that needs to be healed, addressed and loved? A gift in the sense that we can shift, grow and change through the experience, through the emotions.

Holding space for each other to be authentic and honest without taking everything personally. I make a sincere effort to always look within when I feel an emotional response to another's comments or conversation. What is there to learn and see in all of this for me.

I also find that my circle is growing smaller and smaller and I tend to be quieter, more cautious and keep my opinion to myself. They are just opinions after all. 

It may serve us well to remember that we all have differing opinions and thoughts and beliefs and that they come from our own experiences and programming and maybe our reactions do too? Is our response coming from our true self or from communal programming? 

I am paying more attention to being authentic in all my days and ways, and I am being more compassionate and understanding when it is not received as intended. I am making sure  that I am  trustworthy in my own internal dialogue and promises. Too be trusted one must first trust one self and that builds when we do what we say we are going to do and act as we chose to act. (I am talking about those internal conversations and promises) I am training my brain and creating new programming. I am the master of my brain.

Rotten...Lawyers, Guns and Honey (EPISODE 1)

 An amazing documentary on Honey and current corruption from China... (Episode 1)

It was so interesting to learn about the adulteration by China of our Honey supplies in the past and how important it is to know exactly where your honey comes from...MORE and more, it is becoming crucial to follow the money and know where you food is coming from.

https://www.netflix.com/watch/80149706?trackId=255824129&tctx=0%2C0%2CNAPA%40%40%7Cd296bc2d-7844-4026-977f-d037c9195523-86137718_titles%2F1%2F%2FRotten%2F0%2F0%2CNAPA%40%40%7Cd296bc2d-7844-4026-977f-d037c9195523-86137718_titles%2F1%2F%2FRotten%2F0%2F0%2C%2C%2Cd296bc2d-7844-4026-977f-d037c9195523-86137718%7C1%2C%2C80146284&_kx=i2UJeKfvXOnY0_vmL-p6WDmIJrlD5Bo-FslGgCw7zjA%3D.HKMsXE

The following Episodes cover, peanuts, garlic, milk, cod

Folic Acid Tied to a 44% Reduction in Suicide Attempts

 

Folic Acid Tied to a 44% Reduction in Suicide Attempts

Folic acid/vitamin B9, may provide a safe and effective approach for decreasing suicidal ideation, new research suggests. After adjusting for multiple factors, results from a large pharmaco-epidemiological study showed taking folic acid was associated with a 44% reduction in suicide events.

"These results are really putting folic acid squarely on the map as a potential for large-scale, population-level prevention," lead author Robert D. Gibbons, PhD, professor of biostatistics, Center for Health Statistics, University of Chicago, Illinois, told Medscape Medical News.

"Folic acid is safe, inexpensive, and generally available, and if future randomized controlled trials show this association is beyond a shadow of a doubt causal, we have a new tool in the arsenal," Gibbons said.

Having such a tool would be extremely important given that suicide is such a significant public health crisis worldwide, he added.

The findings were published online September 28, 2022 in JAMA Psychiatry.

Previous Research "Fairly Thin"

Folate, the naturally occurring form of B9, is essential for neurogenesis, nucleotide synthesis, and methylation of homocysteine. Past research has suggested that taking folate can prevent neural tube and heart defects in the fetus during pregnancy — and may prevent strokes and reduce age-related hearing loss in adults.

In psychiatry, the role of folate has been recognized for more than a decade. It may enhance the effects of antidepressants; and folate deficiency can predict poorer response to selective serotonin reuptake inhibitors (SSRIs).

This has led to recommendations for folate augmentation in patients with low or normal levels at the start of depression treatment.

Although previous research has shown a link between folic acid and suicidality, the findings have been "fairly thin," with studies being "generally small, and many are case series," Gibbons said.

The current study follows an earlier analysis that used a novel statistical methodology for generating drug safety signals that was developed by Gibbons and colleagues. That study compared rates of suicide attempts before and after initiation of 922 drugs with at least 3000 prescriptions.

Its results showed 10 drugs were associated with increased risk of suicide attempts after exposure, with the strongest associations for alprazolam, butalbital, hydrocodone, and combination codeine/promethazine. In addition, 44 drugs were associated with decreased risk, many of which were antidepressants and antipsychotics.

"One of the most interesting findings in terms of the decreased risk was for folic acid," said Gibbons.

He and his colleagues initially thought this was because of women taking folic acid during pregnancy. But when restricting the analysis to men, they found the same effect. Their next step was to carry out the current large-scale pharmaco-epidemiological study.

Prescriptions for Pain

Researchers used a health claims database that included 164 million enrollees. The study cohort was comprised of 866,586 adults with private health insurance (81.3% women; 10.4% aged 60 years and older) who filled a folic acid prescription between 2012 and 2017.

More than half of the folic acid prescriptions were associated with pain disorders. About 48% were for a single agent at a dosage of 1 mg/d, which is the upper tolerable limit for adults — including in pregnancy and lactation.

Other single-agent daily dosages ranging from 0.4 mg to 5 mg accounted for 0.11% of prescriptions. The remainder were multivitamins.

The participants were followed for 24 months. The within-person analysis compared suicide attempts or self-harm events resulting in an outpatient visit or inpatient admission during periods of folic acid treatment vs during periods without treatment.

During the study period, the overall suicidal event rate was 133 per 100,000 population, which is one fourth the national rate reported by the National Institutes of Health of 600 per 100,000.

After adjusting for age, sex, diagnoses related to suicidal behavior and folic acid deficiency, history of folate-reducing medications, and history of suicidal events, the estimated hazard ratio (HR) for suicide events when taking folic acid was 0.56 (95% CI, 0.48 to 0.65) — which indicates a 44% reduction in suicide events.

"This is a very large decrease and is extremely significant and exciting," Gibbons said.

He noted the decrease in suicidal events may have been even greater considering the study captured only prescription folic acid, and participants may also have also taken over-the-counter products.

"The 44% reduction in suicide attempts may actually be an underestimate," said Gibbons.

Age and sex did not moderate the association between folic acid and suicide attempts, and a similar association was found in women of childbearing age.

Provocative Results?

The investigators also assessed a negative control group of 236,610 individuals using cyanocobalamin during the study period. Cyanocobalamin is a form of vitamin B12 that is essential for metabolism, blood cell synthesis, and the nervous system. It does not contain folic acid and is commonly used to treat anemia.

Results showed no association between cyanocobalamin and suicidal events in the adjusted analysis (HR, 1.01; 95% CI, 0.80 - 1.27) or unadjusted analysis (HR, 1.02; 95% CI, 0.80 - 1.28).

Gibbons noted this result boosts the argument that the association between folic acid and reduced suicidal attempts "isn't just about health-seeking behavior like taking vitamin supplements.”

Another sensitivity analysis showed every additional month of treatment was associated with a 5% reduction in the suicidal event rate.

"This means the longer you take folic acid, the greater the benefit, which is what you would expect to see if there was a real association between a treatment and an outcome," said Gibbons.

The new results "are so provocative that they really mandate the need for a well-controlled randomized controlled trial of folic acid and suicide events," possibly in a high-risk population such as veterans, he noted.

Such a study could use longitudinal assessments of suicidal events, such as the validated Computerized Adaptive Test Suicide Scale (CAT-SS), he added. This continuous scale of suicidality ranges from sub-clinical, signifying helplessness, hopelessness, and loss of pleasure, to suicide attempts and completion.

As for study limitations, the investigators note that this study was observational, so there could be selection effects. And using claims data likely underrepresented the number of suicidal events because of incomplete reporting. As the researchers point out, the rate of suicidal events in this study was much lower than the national rate.

Other limitations cited were that the association between folic acid and suicidal events may be explained by healthy user bias; and although the investigators conducted a sensitivity analysis in women of childbearing age, they did not have data on women actively planning for a pregnancy.

"Impressive, Encouraging"

Commenting for Medscape Medical News, Shirley Yen, PhD, associate professor of psychology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, described the new findings as "quite impressive" and "extremely encouraging.”

However, she noted "it's too premature" to suggest widespread use of folic acid in patients with depressive symptoms. Yen, who has researched suicide risks previously, was not involved with the current study.

She did agree with the investigators that the results call for "more robustly controlled studies. These could include double-blind randomized controlled trials that could "more formally assess" all folic acid usage as opposed to prescriptions only, Yen said.

The study was funded by the National Institutes of Health, the Agency for Healthcare Research and Quality, and the Center of Excellence for Suicide Prevention (US Department of Veterans Affairs). Gibbons reported serving as an expert witness in cases for the US Department of Justice; receiving expert witness fees from Merck, GlaxoSmithKline, Pfizer, and Wyeth; and having founded Adaptive Testing Technologies, which distributes the Computerized Adaptive Test Suicide Scale. Yen has reported no relevant financial relationships.

Reference: JAMA Psychiatry. Published online September 28, 2022. doi:10.1001/jamapsychiatry.2022.2990. Association Between Folic Acid Prescription Fills and Suicide Attempts and Intentional Self-harm Among Privately Insured US Adults <https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2796907?guestAccessKey=9b279b0a-926b-4561-8b55-e943fd904f8e&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jamapsychiatry&utm_content=olf&utm_term=092822>

Are you returning the favor?

 This was interesting for me to ponder recently. I was experiencing some emotional upheaval and dis-regulation. We sometimes go through these clearing phases where everything feels overwhelming and I could have cried at the drop of a hat.

I am always there for any friends or family that need a shoulder to cry on or needs to vent or just have someone to listen without judgement or need to fix anything. (women will understand this) and it occurred to me that I am not as readily open to allowing those friends to return the favor. I tend to seclude myself when I am going through some emotional struggles and I do not always reach out for that shoulder or loving ear.

That is why I ask, are you open to returning the favor.

Our friends and family wish to be there for us too. They will lovingly listen and offer kind words and friends will be ready with some hard hitting wisdom.

It made me think about what this resistance to open up says about me...why do I behave this way?

Could it be that I have some underlying beliefs around self worth? Do I not feel deserving? Is it fear of being vulnerable or do I not believe that anyone has earned the right to hear my deepest darkest fears, thoughts and challenges?

And if I think the last statement is true then why have I not cultivated such a tribe?

I am grateful for the friends that I can turn to (you know who you are) and for their wisdom and for never being afraid to tell me the truth even when it is uncomfortable to hear and to offer a change in perspective whenever I need it.

Thinking about all of this and looking deeper within has also helped me get out of my funk and given me new motivation to create the life and community I desire and to create more health, happiness and joy, not just for myself, for all whom I associate and commune with. It has also made me look at how i treat myself and ask the question, am I a friend to myself? am I gentle and nurturing to myself?

Am I returning the favor....I may not have been as open to doing so in the past and with greater awareness of this, I am choosing to be open to returning the favor when needed. I am open to receive.

 

The One Emotion that Extends Your Life

Ronald Grisanti D.C., D.A.B.C.O., DACBN, MS, CFMP

Based on progressive research we find that what we think about and what we feel have far-ranging effects on our immune system.

One important part of our immune system includes the natural killer cell or NK cells. These are a type of lymphocyte and an important player in the war on invading bad microbes and mounting an immune attack to combat these bad microbes. NK cells are known to be protective against cancer. Some studies have documented that the less active your NK cells are the more rapid cancer progression and the more it spreads throughout the body.

And guess what?

These important NK cells actually respond to your mood.

The most important emotion to boost these NK cells is laughter.

When you are feeling good, optimistic and happy your NK cells multiply exponentially!

If you are known pessimist, there is still hope for you.

A study done at the University of California showed that actors who spent time performing depressing movie scenes had a decreased immune responsiveness. On the other hand actors who performed roles where they were uplifting, had an increased immune responsiveness. So the moral of the story is something called, Fake it till you make it. Yes, even if you don't feel happy, at least act like you do! Your body's immune system will reward you for it.

Here is a good punch list to improve your mood and of course boost your NK cells: These include: watching funny movies, making music or listening to uplifting music, coloring in books, walking in the woods, going to a comedy show, spending time with good uplifting friends to something as simple as taking a soaking bath with relaxing herbs.

(Functional Medicine University)

References:

https://pubmed.ncbi.nlm.nih.gov/12652882

https://pubmed.ncbi.nlm.nih.gov/11712080

https://www.sciencedaily.com/releases/2010/04/100426113058.htm

The information on this website is not intended to replace a one-on-one relationship with a qualified health care professional and is not intended as medical advice. It is intended as a sharing of knowledge and information from the research and experience of Dr. Grisanti and his functional medicine community. Dr. Grisanti encourages you to make your own health care decisions based upon your research and in partnership with a qualified health care professional.

Antiviral Lactoferrin Now pitted against COVID-19

Antiviral Lactoferrin Now Pitted Against COVID-19

 by Noelle Patno, PhD

Lactoferrin (LF) has been advocated by researchers1–3 as a potential method to prevent or treat COVID-19. These recent reviews promote a hypothesis that the natural, endogenous compound which has shown antiviral capabilities for other viruses including SARS-CoV may be effective against the SARS-CoV-2 virus as well. With over 70 years since the discovery of this glycoprotein, this iron-scavenging milk protein now deserves greater attention. The current literature demonstrates that LF has many anti-inflammatory, immunomodulatory, and even anticarcinogenic effects; what remains to be discovered is its specific activity against the pandemic virus of our times, SARS-CoV-2. A large body of in vitroevidence suggests that lactoferrin may have efficacy because of its ability to inhibit viruses and bind to viral surface receptors, which are related to SARS-CoV-2 mechanisms. Now is the time to discover more about this glycoprotein and its potential against SARS-CoV-2.

Mechanism of binding to heparan sulfate

A recent paper (published in Cell, November 2020) demonstrated that SARS-CoV-2 infection depends on attachment to cellular heparan sulfate (HS) and ACE2.4 While ACE2’s role was predicted in January5 and subsequently demonstrated in March,6 this revelation in November reveals the importance of HS as an essential factor in the virus’s attachment and entry to infect the cell. Heparan sulfate, a complex carbohydrate on almost every cell’s surface, is useful to the host to determine the cell’s response to stimuli such as metabolic or inflammatory stimuli and critically as part of immune functions.7 However, many viruses hijack HS to bind and depend on it for their infection. In vitro evidence supports this mechanism for other viruses including the Nipah and Hendra viruses;8 entrovirus 71, which is associated with hand foot mouth disease;9 enteroaggregative E. coli, which is a significant cause of diarrhea and foodborne outbreaks;10 rift valley fever virus;11 and human papillomavirus.12 This list overlaps with the list of pathogenic viruses that lactoferrin inhibits in vitro, which includes but is not limited to the following: herpes simplex virus, hepatitis B virus, hepatitis C virus (HCV), avian flu, enterovirus 71, Japanese encephalitis virus, respiratory syncytial virus, influenza A virus, parainfluenza virus, cytomegalovirus, poliovirus, rotavirus, and human immunodeficiency virus (HIV), with clinical evidence for enterovirus 71, HCV, norovirus, and rotavirus.2 With lactoferrin’s previous ability demonstrated to prevent the Japanese encephalitis virus,13 alphavirus,14 Toscana virus,15 dengue virus,16 and the SARS pseudovirus17 from entering cells through HS receptors and infecting the cells, then LF has the possibility of preventing SARS-CoV2 from entering cells as well.

Potential mechanisms by which LF might help against SARS-CoV-2 are therefore the following:1

Prevent attachment to heparan sulfate receptors on the cell and inhibit viral entry4,13
Prevent attachment to ACE2 and inhibit viral entry/infection of the cell18

Prevent attachment to DC-SIGN, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin receptor and thereby prevent infection of the cell3
Prevent attachment and viral entry via other receptors17

Inhibit viral replication15,19
Decrease IL-6,20 which is part of the cytokine storm

Current clinical trials evaluating lactoferrin in COVID-19

The table below lists the current clinical trials on clinicaltrials.gov evaluating lactoferrin in COVID-19.

Three recent publications further suggest that lactoferrin may help against SARS-CoV-2:

1. In vitro, bovine lactoferrin was able to decrease significantly the numbers of SARS-CoV-2-infected bronchial epithelial cell mimetics, the single compound mentioned in the abstract of the preprinted paper, and one of 17 dose-responsive compounds from a 1,425 library in a drug-repurposing high throughput screen19

2. The completed randomized clinical study listed above, in 32 patients with confirmed COVID-19 by RT-PCR, showed an early clearance of the virus, recovery from symptoms, and statistically significant reduction in IL-6 , with additional in vitro and in silico support for lactoferrin’s ability to prevent cells from infection through preincubation as well as simulated binding of lactoferrin to the ACE2 receptor.18

3. A 10-day study evaluating the effect of a liposomal bovine lactoferrin syrup that included vitamin C alone or with zinc (for a total of 256 to 384 mg of lactoferrin per day) and additional nasal and mouth spray or aerosol application for additional symptoms. IgM/IgG antibody rapid test in whole blood was used for confirmed COVID-19 diagnosis in 75 people. Symptoms were scored on a scale of 0 to 3 in severity twice a day for 10 days and then a follow-up after one month. By the fifth day, all patients recovered from respiratory distress and headache symptoms. The percentage of patients without symptoms of coughing, muscular pain, nasal congestion, tiredness, and diarrhea all increased by 48 hours and 5 days after study start.21

There are many limitations to the above three studies. The first two preprinted articles have not been peer-reviewed. The third lacked clear dosing instructions, did not use the more accurate SARS-CoV-2 diagnostic tests; did not follow-up test for the virus after-treatment; used additional interventions for subsets of patients; lacked more rigorous, randomized, and controlled design and more objective and validated methodology; and was not the complete data set for the study, among other limitations. Clinical studies on the effects of lactoferrin supplementation in COVID-19 patients is a promising and interesting research advancement to watch.

Citations

1. Campione E et al. Lactoferrin as protective natural barrier of respiratory and intestinal mucosa against coronavirus infection and inflammation. Int J Mol Sci. 2020;21(14):4903.

2. Chang R et al. Lactoferrin as potential preventative and adjunct treatment for COVID-19. Int J Antimicrob Agents. 2020;56(3):106118.

3. Wang Y et al. Lactoferrin for the treatment of COVID-19 (Review). Exp Ther Med. 2020;20(6).

4. Clausen TM et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell. 2020;183(4):1043-1057.e15.

5. Wan Y et al. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94(7).

6. Hoffmann M et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.e8.

7. Simon Davis DA et al. Heparan sulfate: a ubiquitous glycosaminoglycan with multiple roles in immunity. Front Immunol. 2013;4.

8. Mathieu C et al. Heparan sulfate-dependent enhancement of henipavirus infection. mBio. 2015;6(2).

9. Kobayashi K et al. Heparan sulfate attachment receptor is a major selection factor for attenuated enterovirus 71 mutants during cell culture adaptation. PLOS Pathogens. 2020;16(3):e1008428.

10. Rajan A et al. Enteroaggregative E. coli adherence to human heparan sulfate proteoglycans drives segment and host specific tesponses to infection. PLOS Pathogens. 2020;16(9):e1008851.

11. de Boer SM et al. Heparan sulfate facilitates Rift Valley fever virus entry into the cell. J Virol. 2012;86(24):13767-13771.

12. Selinka H-C et al. Inhibition of transfer to secondary receptors by heparan sulfate-binding drug or antibody induces noninfectious uptake of human papillomavirus. J Virol. 2007;81(20):10970-10980.

13. Chien Y-J et al. Bovine lactoferrin inhibits Japanese encephalitis virus by binding to heparan sulfate and receptor for low density lipoprotein. Virology. 2008;379(1):143-151.

14. Waarts B-L et al. Antiviral activity of human lactoferrin: inhibition of alphavirus interaction with heparan sulfate. Virology. 2005;333(2):284-292.

15. Pietrantoni A et al. Bovine lactoferrin inhibits Toscana virus infection by binding to heparan sulphate. Viruses. 2015;7(2):480-495.

16. Chen J-M et al. Bovine lactoferrin inhibits dengue virus infectivity by interacting with heparan sulfate, low-density lipoprotein receptor, and DC-SIGN. Int J Mol Sci. 2017;18(9).

17. Lang J et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS One. 2011;6(8). doi:10.1371/journal.pone.0023710

18. Campione E et al. Pleiotropic effect of Lactoferrin in the prevention and treatment of COVID-19 infection: randomized clinical trial, in vitro and in silico preliminary evidences. bioRxiv. Published online August 17, 2020:2020.08.11.244996.

19. Mirabelli C et al. Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19. bioRxiv. Published online September 28, 2020.

20. Lepanto MS et al. Efficacy of lactoferrin oral administration in the treatment of anemia and anemia of inflammation in pregnant and non-pregnant women: an interventional study. Front Immunol. 2018;9.

21. Serrano G et al. Liposomal lactoferrin as potential preventative and cure for COVID-19. Int J Res Health Sci. 2020;8(1):8.

Noelle Patno, PhD is the Nutrition Scientist for Digestive Health at Metagenics. Dr. Patno received her PhD in Molecular Metabolism and Nutrition and Masters in Translational Science from the University of Chicago, studying the role of microbial components in intestinal epithelial cell survival related to inflammatory bowel disease. Prior to her graduate studies, Dr. Patno received a chemical engineering degree from Stanford University and worked as an engineer. She has personal experience and interest in preventive nutrition and nutritional therapies for chronic disease, and her current role involves researching and developing probiotics, prebiotics, and other nutritional programs for the promotion of digestive and overall health.