All About the Liver, and How to Support Your Favorite Detoxification Organ

The liver is incredible. Most people think of it as a filter, but filters are physical barriers that accumulate junk and have to be cleaned. The liver isn’t a filter. It’s a chemical processing plant. Rather than sit there, passively receiving, filtering out, and storing undesirable compounds, the liver encounters toxic chemicals and attempts to metabolize them into less-toxic metabolites that we can handle.

• It oxidizes the toxins, preparing them for further modification
• It converts the toxins to a less-toxic, water-soluble version that’s easier to excrete
• It excretes the toxins through feces or urine

Bam. It’s an elegant process, provided everything is working well back there. And it’s not the only process it controls.

The liver is the primary site of cholesterol synthesis and disposal. It creates cholesterol as needed and converts excess into bile salts for removal via the bile duct. The liver also plays a huge role in the burning of fat for energy, the storage of vitamin A, the metabolism of hormones, and the regulation of blood sugar. If you enjoy burning ketones, you can thank the liver because that’s where they’re produced.

The liver supports full-body health, in other words. If it isn’t working correctly, nothing is. Everything starts to fall apart.

How do we support the liver?

It’s not one thing we do. It’s many things. It’s nutrition, supplementation, lifestyle, sleep — everything. It’s also the things we don’t do. The stakes are high, you see. Whenever there’s a grand overarching orchestrator regulating dozens of different processes in the body, you must protect it from multiple angles. A lot can go wrong. Or right, depending on how you look at it.

Since the liver is “hidden away” and you can’t really “feel” it, you may not give it too much thought. When you’re overweight, you know it. When your fitness is suffering, you consciously experience it. When your liver is overburdened or suffering, you don’t necessarily know it. That’s where doing the right things for the sake of doing them comes in handy.

So, what should you do to maintain pristine liver health?

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11 Ways to Maintain a Healthy Liver

Liver health depends on steps you take toward a healthy lifestyle, and equally as important, the things you refrain from doing. Here are some things you can to to contribute to lifelong liver health:

• Reduce linoleic acid intake
• Reduce refined carb intake
• Reduce alcohol intake
• Stop overeating, and lose weight
• Practice time-restricted eating
• Eat fatty fish and get omega-3s
• Eat egg yolks and other choline sources
• Take NAC
• Take whey protein
• Regularly deplete your liver glycogen
• Get good, regular sleep

Reduce Linoleic Acid Intake

When a patient can’t eat, they get something called parenteral nutrition — a direct infusion of nutrients into the gut. The classic parenteral nutrition consists of an emulsion of olive oil and soybean oil. It’s very rich in linoleic acid and typically leads to elevated liver enzymes and fatty liver. That’s right: the medical establishment for whatever reason just accepts that people receiving parenteral nutrition have a high chance of developing fatty liver disease.

Okay, but what’s happening here? Is it really causal? Yes. The more linoleic acid you eat, the more oxidized metabolites of linoleic acid show up in your body. The more oxidized metabolites of linoleic acid you have, the higher your risk of fatty liver. These toxic metabolites of LA are actually full-fledged biomarkers of liver injury.¹

The bottom line: your liver prefers smart fats like avocado oil, butter, lard, fatty fish, and olive oil over industrial seed oils.

Reduce Refined Carb Intake

The real danger of refined carbs is that they tend to be nutrient-poor. They’re basically just pure starch (or sugar). All the energy, none of the micronutrients required to metabolize that energy.

Your liver works hard to convert carbs into glucose that your body can use. When you don’t use the glucose in your blood, it gets stored in the liver and skeletal muscle as glycogen, and if you have excess after that, it gets stored as body fat. With refined carbs, it’s easy to get there.

Studies show that carb overfeeding, especially with fructose, can lead to non-alcoholic fatty liver disease,² which affects how efficiently your liver works.

Of course, the combo of high linoleic acid and high refined carbohydrate is just about the worst thing possible.

Reduce Alcohol Intake

To detox alcohol, the liver converts it into the metabolite acetaldehyde. Acetaldehyde is far more toxic than ethanol itself, so the body then releases acetaldehyde dehydrogenase and glutathione to break down the acetaldehyde. If you stick to just a few drinks and space them out accordingly, your body’s natural antioxidant enzyme production can keep up. If you start binging, though, glutathione stores become overwhelmed and the liver must produce more. Meanwhile, acetaldehyde, which is between 10-30 times more toxic than ethanol, accrues in your body.³

Here’s where dosage matters. The more you drink in a given allotment of time, the higher the liver burden. Your liver doesn’t metabolize ethanol all at once. It’s an ongoing physical process. It takes time, and glutathione. Glutathione is also a physical material. You need more substrate, like glycine and cysteine, to produce it. Without enough glutathione (and there’s never enough if you drink too much), your liver will incur damage and develop fat.

If you’re going to drink, do so sparingly, choose healthier drinks, and practice good hangover prevention hygiene. High linoleic acid intake, for example, mixes terribly with alcohol; a much better choice is something saturated like beef fat or cocoa butter.

Stop Overeating, and Lose Weight

The number one risk factor for getting a fatty liver with impaired function is gaining excess body fat. Don’t get fat. If you are fat, lose it. Losing weight is the number one risk factor for losing a fatty liver.

Figure out what type of diet helps you eat normal amounts, and then go follow that diet. For most of my readers, it’s a low-carb Primal or keto approach. For others, it’s full-on carnivore. And yes, there are some for whom a moderate or even high carb diet works best. Whatever satiates you is the one that will improve your liver function.

Overeating fat especially can be bad, because the extra fat doesn’t need to waste any extra steps becoming available to your liver.

Practice Time-restricted Eating

In mice fed a typical soybean oil-fructose-based lab diet, the “high-fat” kind that reliably plumps up their livers, switching to a shortened eating window eliminates the metabolic fallout. They don’t get fat, they don’t get insulin resistant, and, most importantly, they don’t get fatty or dysfunctional liver.⁴

Eat Fatty Fish and Get Omega-3s

If you offset some of that olive oil and soybean oil with a blend of medium triglycerides and fish oil, liver enzymes may drop and overall integrity of the liver may improve.⁵ Amazing how that works.

Fish oil isn’t the only option. In fact, eating actual seafood is ideal because in addition to the omega-3s it also provides micronutrients and macronutrients that enhance liver function. If you’re not a fish eater, supplements can fill in the gaps.

Eat Yolks and Other Choline Sources

Choline protects against fatty liver by providing the backbone for VLDL—the particle the liver uses to transport fat out  into the body. Without adequate choline, you can’t make enough VLDL for transport and the fat tends to accumulate in the liver.

Egg yolks are the best source of choline.

Take NAC

In patients with non-alcoholic fatty liver disease, taking NAC every day for three months improved liver enzyme levels and overall liver function.⁶ Taking it with vitamin C may be even more effective.

NAC is well-known for boosting levels of glutathione, the primary antioxidant used by the liver to metabolize toxins and protect itself.

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Grab a bottle of Primal Damage Control, a source of NAC, choline, and other vital nutrients to support a strong liver.

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Take Whey Protein

Obese women with fatty liver who took 60 grams of whey protein per day reduced their liver fat by almost 21%.⁷

Whey boosts glutathione levels and provides methionine, which the body can convert to choline when deficient.

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Try Vanilla Coconut Primal Fuel, made with whey protein

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Regularly Deplete Your Liver Glycogen

De novo lipogenesis, or the creation of fat from carbohydrate, is a hallmark of fatty liver disease.⁸ When liver glycogen is full, it becomes far more likely that your liver will turn any subsequent carbohydrate it encounters into fat for storage. If you keep liver glycogen low, or regularly deplete it, you can avoid de novo lipogenesis because there’s usually a place to store the glucose.

Furthermore, keeping liver glycogen low increases fat utilization from all over the body, including the liver.⁹ A few of my favorite ways to deplete glycogen:

• Train hard. I like HIIT, higher volume lifting, and sprints. Or my personal favorite: Ultimate Frisbee. Not all at once.
• Fast. Fasting is a reliable way to burn through available liver glycogen.
• Reduce carbs. Going low-carb or keto is a reliable, if slightly slower way to burn through your liver glycogen.

Get Good, Regular Sleep

Certain molecules responsible for clearing liver fat operate according to a circadian schedule.¹⁰ If you don’t get to sleep at a normal, consistent time, your rhythm is disrupted and the molecules can’t do their jobs.

If you hadn’t already noticed, these are good health practices in general. We keep running into this phenomenon, don’t we?

What’s good for the liver is good for the brain is good for the cardiovascular system is good for your performance in the gym is good for the mirror.

It makes things easier and harder.

You know what to do.

Thanks for reading, everyone. Do you have any other recommendations for liver health? Which of these do you follow?

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578804/
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405421/#:~:text=This%20study%20suggests%20that%20human,patients%20with%20obesity%20(48).
3. https://www.springerlink.com/content/w307w62037125v33/
4. https://www.sciencedirect.com/science/article/pii/S1550413112001891
5. https://journals.lww.com/ejanaesthesiology/Fulltext/2009/12000/Hepatocellular_integrity_after_parenteral.17.aspx
6. https://pubmed.ncbi.nlm.nih.gov/22308119/
7. https://pubmed.ncbi.nlm.nih.gov/21288612/
8. https://pubmed.ncbi.nlm.nih.gov/24316260/
9. https://www.nature.com/articles/ncomms3316
10. https://www.eurekalert.org/pub_releases/2011-03/uops-mwt030311.php

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London Fog Drink – Earl Grey Tea Latte Recipe

Next time you want to sip on something warm and comforting, try a London Fog Latte. I’ve been hooked ever since a friend encouraged me to order one at a local coffee shop. As soon as I took my first sip, I was determined to figure out how to make them myself.

A London Fog Latte is now my go-to drink whenever I need a hug in a mug. Start-to-finish, it takes about as long as brewing a cup of coffee, and you probably have all of the ingredients on hand right now.

What Is In a London Fog Latte?

In its most basic form, a London Fog Latte is Earl Grey tea flavored with vanilla and lavender, topped with frothy milk, and softly sweetened. Recipes vary, but the predominant ingredients in a London Fog Latte include:

• Earl Grey tea (black tea flavored with bergamot)
• Vanilla
• Lavender (optional)
• Steamed and frothed milk
• Sweetener

How to Make a London Fog Drink at Home

Makes: 2 tea lattes

Time in the kitchen: 5 minutes

Ingredients

• 12 oz. hot water
• 2 Earl Grey tea bags
• 1/2 tsp. vanilla extract
• A few drops of liquid monk fruit sweetener or stevia, to taste
• 6-8 oz. milk of choice (I used a full-fat almond milk)
• 1 scoop collagen peptides (optional)
• Pinch of fresh lavender buds (optional)

Directions

Grab two mugs and place one tea bag in each. Top with hot water and allow to steep for three to five minutes – longer for a stronger tea, shorter for a weaker tea. For a more floral drink, you can throw a pinch of lavender into the water while the tea is steeping.

While the tea steeps, warm your milk in a saucepan. Add the vanilla extract. To froth your milk, you can use an immersion blender, froth wand, or a french press. To froth using a french press, pour warmed milk into the french press. Aggressively agitate the milk by moving the plunger halfway up the french press and then back down about 10 times or so. You will see the milk expand as it becomes foamy.

Remove the tea bags and strain out any lavender buds if you used them. If you are using collagen peptides and sweetener, mix them in now. Pour your frothed milk on top.

Just add a fluffy blanket of foam, plus an optional sprinkle of lavender buds if you’re feeling fancy. Enjoy!

How to Customize Your London Fog Latte

• Make it decaf: A typical London Fog Latte contains caffeine. Earl Grey tea has a moderate amount of caffeine, around 30 to 60 mg per cup depending on how you brew it. For comparison, an 8-ounce cup of coffee contains around 100 mg. If decaf is more your speed, look for decaffeinated Earl Grey tea bags.
• Make it dairy-free: London Fog Lattes are equally delicious whether you use full-fat milk or cream, nut milk, coconut milk, or other dairy-free options.
• Keep it keto-friendly by using monk fruit or stevia, or opt for honey or the sweetener of your choice.
• Serve it over ice: To make an iced London Fog Latte, brew the tea with 4 ounces of water per mug instead of 6 ounces. After it steeps, add the sweetener and collagen, then let it cool for a few minutes. Pour the tea into a cup of ice. Top with foam.

You may also like:

• Creamy Turmeric Tea
• Matcha Collagen Latte
• Savory Bone Broth Lattes, Two Ways
• Dairy-free Dirty Chai Latte

Print

London Fog Drink – Earl Grey Tea Latte Recipe

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• Author: Mark's Daily Apple
• Total Time: 5 minutes
• Yield: 2 servings
• Diet: Vegetarian

Print Recipe

Pin Recipe

Description

A London Fog Latte is made with Earl Grey tea, gently flavored with vanilla and lavender, and topped with warm frothed milk. It’s a delightful change from your usual coffee or tea that you can prepare in the same time it takes to brew a cuppa.

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Ingredients

12 oz. hot water

2 Earl Grey tea bags

1/2 tsp. vanilla extract

A few drops of liquid monk fruit sweetener or stevia, to taste

6–8 oz. dairy or non-dairy milk of choice

1 scoop collagen peptides (optional)

Pinch of fresh lavender buds (optional)

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Instructions

Grab two mugs and place one tea bag in each. Top with hot water and allow to steep for three to five minutes – longer for a stronger tea, shorter for a weaker tea. For a more floral drink, you can throw a pinch of lavender into the water while the tea is steeping.

While the tea steeps, warm your milk in a saucepan. Add the vanilla extract. To froth your milk, you can use an immersion blender, froth wand, or a french press. To froth using a french press, pour warmed milk into the french press. Aggressively agitate the milk by moving the plunger halfway up the french press and then back down about 10 times or so. You will see the milk expand as it becomes foamy.

Remove the tea bags and strain out any lavender buds if you used them. If you are using collagen peptides and sweetener, mix them in now.

Pour your frothed milk on top. Optionally top with a sprinkle of lavender buds. Enjoy!

Notes

Nutrition info calculated using Cronometer with 8 ounces almond milk and 1 scoop Primal Kitchen Unflavored Collagen Peptides.

• Cook Time: 5 minutes
• Category: Beverage

Nutrition

• Serving Size: 1 mug
• Calories: 40
• Fat: 1 gram
• Carbohydrates: 2 grams
• Protein: 6 grams

Keywords: London Fog Tea Latte Recipe, London Fog Drink, Earl Grey Tea Latte, Homemade London Fog

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How to Stop Drinking Coffee, and Why You Should Consider It

Thank you for reading past the title of this post. I wasn’t sure anyone would. After all, here I am offering advice on how to quit the world’s most beloved beverage. (“Hold my beer,” says Beer.)

The love of coffee transcends national and cultural borders. Around the world, most of us start our day with coffee. Folks take pride in sourcing the best beans and pairing them with the ideal grind and brewing method. We meet friends, clients, and first dates for coffee because coffee shops are comforting, safe spaces.

As good ol’ Anonymous observed, “Humanity runs on coffee.”

Yet here I am suggesting you might want to quit. Before I get into why, let me assure you that by and large, I still think coffee has more benefits than downsides. It improves workouts and memory, fights fatigue, and epidemiological evidence links coffee consumption to a host of health benefits. You can check out my Definitive Guide to Coffee to learn more.

There are downsides, though. In the pursuit of optimal health, it’s essential to examine our choices and behaviors and ask which of them might be undermining your health and longevity goals. That’s what I’m suggesting you do today.

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Why Would You Want to Quit Coffee?

Because you’re a masochist.

Kidding, of course. Really, if you think quitting coffee will be that painful, that’s a sure sign that you need to take a break. No substance aside from water or air should hold you so firmly in its grasp. I want to enjoy, not depend on, my morning coffee (and maybe a glass of red wine at dinner).

As to whether coffee is truly addictive, we clearly shouldn’t be talking about coffee in the same breath as something like heroin. However, there’s no question that it shares common features with other addictive substances. It stimulates dopamine release in the brain, creating a “feels good, want more” effect. With repeated exposure, you develop a tolerance such that caffeine no longer exerts the same effects. Plus, as many of you know if you’ve tried to kick the habit before, the withdrawal can be brutal.¹

Even if you don’t feel dependent on coffee, taking a break from coffee is akin to doing a 21-Day Primal Transformation or a Keto Reset. It’s a chance to shake things up and try something new. You might feel better, worse, or the same. In any case, you’ll have learned something about yourself. We should all strive to be curious and open-minded in the pursuit of health. For many people, coffee is a blind spot. They conveniently overlook the ways in which it’s not serving them and how they’re more dependent on it than they’d like.

Besides the philosophical, there are concrete reasons for taking a more honest look at your coffee habit.

Coffee: The Good, The Bad, and The Ugly

As I said, on the whole, I think that coffee consumption is beneficial for most people, assuming you drink it in reasonable quantities. Nobody needs a gallon of coffee per day, sorry. A “reasonable quantity” is up to four cups a day, or so say the experts. As a one-or-two-cup-a-day guy, that sounds like a lot to me.

Even at that level of consumption, some people can have adverse reactions to caffeine depending on their genetics and underlying health issues. Headaches, jitters, and racing heartbeat are common, and of course it can majorly mess with your sleep. It’s easy to slip into a vicious cycle where you’re sleeping poorly, so you drink coffee throughout the day to combat fatigue, which means you don’t get enough restorative sleep that night, and repeat ad infinitum.

Caffeine can also cause your adrenal glands to release cortisol, although this effect is tempered in habitual coffee drinkers.² For people dealing with a lot of stress—and who isn’t right now—drinking too much coffee may not be wise. It can interfere with your body’s ability to regulate cortisol and cope with the stressors.³ This is why practitioners often recommend that folks with HPA axis disorders limit or avoid coffee.

Caffeine consumption also worsens anxiety in some people and can even trigger panic attacks.^{4 5} People with certain psychiatric conditions are advised to limit or avoid caffeine consumption.⁶ On the other hand, two recent meta-analyses concluded that coffee actually helps with symptoms of depression.^{7 8}

If you’re a menopausal woman, think twice about drinking too much coffee. In two studies, caffeine intake was associated with increased vasomotor symptoms like hot flashes.^{9 10} Those were correlational studies, but in a separate experiment, researchers administered caffeine to pre- and perimenopausal women who were or were not on estrogen therapy. Perimenopausal women’s blood pressure rose significantly after taking 250 mg of caffeine (equivalent to two to three cups of coffee), regardless of estrogen status.¹¹

Need I go on? Okay, one more: caffeine can interact with prescription drugs, blocking absorption, increasing absorption rates to unsafe levels, or otherwise changing their effects.¹²

Many of these side effects are dose-dependent, meaning they get worse the more coffee you drink. For most people, modest coffee intake—two or four cups per day—is probably fine, maybe even desirable. Nevertheless, there’s always the possibility that you could quit coffee and feel better than you do today. Wouldn’t you want to know that?

Other Potential Benefits of Quitting Caffeine

Anecdotally, people notice all sorts of benefits once they significantly reduce or give up coffee. They promise glowing skin, whiter teeth, and better digestion.

They also promise you’ll save money, but in my experience, I just end up reinvesting those supposed savings into trying new teas, so that’s a wash. That said, I also don’t buy multiple frappe drinks from Starbucks every day. If you do, you might put some cash back in your pocket.

Who Should Take a Break from Coffee?

For the sake of self-experimentation, I’m going to go ahead and say: everybody.

It’s especially pressing if:

• Your inner voice is telling you that you have become dependent on caffeine
• Your sleep is anything other than deep and plentiful
• You have health issues that might be exacerbated by coffee

Also, if you’ve built up a tolerance—and you certainly have if coffee is a regular habit—taking a break means you should be able to return to your beloved coffee and actually feel the desirable effects of caffeine again when you use it strategically. That would be nice.

Anyway, aren’t you a little curious?

How to Stop Drinking Coffee

Time It Right

Unless you have an urgent health concern that means you should stop ASAP, consider waiting until a lower-stress period. Normally I’d say vacation is a perfect time, but we’re not taking many vacations right now. Perhaps a staycation is in order (for more reasons than one).

I wouldn’t advise ditching coffee the same week you have to deliver a big presentation at work, your kids are starting a new schedule at school, or you’ll otherwise be stretched thin enough as it is. Coffee withdrawal can lead to some pretty miserable symptoms—migraines, fatigue, irritability. Pick a week where you’ll have the mental capacity to deal with those, the ability to sneak away for naps, and ideally, fun distractions to keep your mind off the suck.

Pick Your Strategy

Some people have no problem quitting cold turkey, but tapering down your caffeine intake will probably be more pleasant. Start cutting your regular coffee with decaf, and slowly decrease the amount you consume altogether. Make your coffee weaker, and stop adding cream and sweeteners so it’s not as appealing. If you’re drinking coffee in the afternoon, cut that first.

Whatever you do, don’t compensate by adding caffeine back in the form of energy drinks or caffeine pills. Don’t drink energy drinks anyway, but definitely not now. That defeats the purpose entirely.

How Long Will it Take to Get off Coffee Completely?

The half-life of caffeine is about five hours, so within a day of quitting, your body should be free of it. However, withdrawal symptoms can last significantly longer—a week to ten days or more, though some lucky people don’t experience any noticeable withdrawal.

Beyond the chemical dependency, there is also a behavioral component to coffee. For most coffee drinkers, it is a habit, and habits are harder to break. You might find yourself headed to the coffee pot in the morning, or reaching for the mug that’s usually on your desk, well after the initial weaning period.

Worthy Alternatives to Coffee

For some people, coffee is merely a caffeine delivery system. Others enjoy the rituals around coffee—preparing it in the morning, breathing in the aroma, sipping a hot beverage while they work, and communing with coworkers and friends over a cup. You can still have all those things if you strategically replace coffee with an alternative that fills the hole coffee leaves.

The most obvious answer is switching to tea. There are so many different types of tea, each with its own benefits and flavor profile. If you were a snob about your coffee, you can easily channel that energy into tea. Brewing tea is an art unto itself. Just watch your caffeine intake. Teas vary considerably in caffeine content, though they are still lower than the average cup of joe.

You might also consider mushroom coffee, which has about half the caffeine of regular coffee, or chicory root coffee or dandelion tea, which offer some of the coffee flavor with none of the caffeine. Fans of these options swear they get a lift similar to the one they got from coffee without the jitters.

My go-to hot or iced option is Primal Kitchen’s Matcha and Chai Collagen Keto Lattes, and not just for the obvious reason. Caffeine can inhibit collagen synthesis in the body.¹³ I intentionally supplement collagen to combat this effect.

Finally, if it’s a calming morning routine you crave, consider alternatives like journaling, meditation or deep breathing exercises, yoga or tai chi, doing a crossword puzzle (my favorite), or reading. Just don’t read the news!

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Sip on a Matcha or Chai Collagen Keto Latte, or for a no caffeine option, mix up a soothing turmeric tea using Golden Milk Collagen Fuel 

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What if You Quit Coffee and Don’t Feel Better (Or Even Feel Worse)?

As with any big change, you’ll have an initial adjustment period after quitting coffee. After that, you should feel better. Still, some people don’t. Let’s go through the difference between the initial withdrawal and other reasons you might not have a great experience with the change.

Caffeine Withdrawal Symptoms

For a few days, you may experience caffeine withdrawal symptoms, like:

• Tiredness
• Headache
• Feeling anxious or “on edge”
• Irritabiliy
• Low mood

These should resolve within a few days. After about a week, you can truly assess how you feel without coffee.

If you don’t notice any differences once you quit coffee, then I’d say go back to drinking it in moderation to reap all the great benefits.

If you end up feeling worse, that doesn’t mean that you need coffee. It’s possible you were using coffee to mask the symptoms of an underlying health issue. Maybe you already suspect that’s the case, and you’re using coffee to push off having to deal with it? Before you go diving for your French press, take a health inventory, and see a doctor if necessary.

I’m not suggesting that you give up coffee for the rest of your life. I certainly don’t intend to. Coffee is one of life’s pleasures, as far as I’m concerned. However, it shouldn’t be a vice, and that can be a slippery slope. Periodically taking a break from coffee allows you to make sure you still have a handle on things and see more clearly where you need to be paying more attention to your health and stress management. Give it a try. There’s always a Starbucks on the next corner awaiting your return.

References

1. https://www.liebertpub.com/doi/10.1089/jcr.2013.0016
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2257922/
3. https://pubmed.ncbi.nlm.nih.gov/21346100/
4. https://jamanetwork.com/journals/jamapsychiatry/article-abstract/493529
5. https://www.ncbi.nlm.nih.gov/pubmed/12825092
6. https://pdfs.semanticscholar.org/ef8c/e1f994091de73049df7e08d71b6497fe86bf.pdf
7. https://www.ncbi.nlm.nih.gov/pubmed/26339067
8. https://www.ncbi.nlm.nih.gov/pubmed/26518745
9. https://pubmed.ncbi.nlm.nih.gov/25051286/
10. https://pdfs.semanticscholar.org/6be1/708f6629c6e67a23126688d31585b6d08791.pdf
11. https://www.ncbi.nlm.nih.gov/pubmed/8980163
12. https://pubmed.ncbi.nlm.nih.gov/12397877/
13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206198/

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Does Your Digestion Need a Tune-up?

Well, does it?

We’re all going to be putting food in our bodies just about every day for the rest of our lives. Most of us will do it several times a day. We’ll chew it, send it down the esophagus into our stomach, and expose it to gastric juices and digestive enzymes. We’ll strip it of nutrients and send the excess down to the colon for dismissal, feeding resident gut bacteria along the way. The whole process should go smoothly. There shouldn’t be any pain or discomfort, bloating or constipation. Oh sure, nobody’s perfect, and there will be slow-downs or speed-ups from time to time, but in general a vital, fundamental process like digestion shouldn’t even register in our waking, conscious lives.

But sometimes it does.

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Instantly download your Guide to Gut Health

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Symptoms of Digestion Problems

Sometimes digestion can be downright unpleasant, or even unproductive. The symptoms are familiar:

• Bloating. Distended belly. Feeling overly full and unwieldy. Same weight but the pants don’t fit.
• Excessive gas. No need to define it. You just know it when you see (hear) it.
• Diarrhea. Acute (occasional) diarrhea that goes away immediately doesn’t indicate poor digestion, but protracted or chronic diarrhea is a warning sign.
• Constipation. Same deal with constipation: acute normal, chronic not.
• Stomach pain. Persistent gut pain should never be ignored.
• Bleeding or pain on the toilet. Elimination should be painless.
• Heartburn, or acid reflux. Although most people assume heartburn and acid reflux are caused by too much stomach acid, it’s actually the opposite: inadequate stomach acid is usually the culprit.

The Digestive Process: Troubleshooting Top to Bottom

To get to the bottom of these symptoms and hopefully fix them, let’s look at the actual process of digestion. We’ll go step by step down the line to identify and offer solutions for various issues that can arise at each.

What happens when you eat something?

The stops along the digestive route involve:

1. Sensing and signaling
2. Oral digestion, or chewing
3. Mechanical digestion, in the stomach
4. Duodenum digestion
5. Small intestine digestion
6. Colon digestion

Here’s how it works.

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Sensing and Signaling

You start digesting before you’ve even taken your first bite. Have you ever smelled burgers grilling, and you mouth started to water? Certain aromas can signal to your body that food is coming, and you begin to salivate and secrete digestive enzymes.

Even thinking about food can trigger a response.

Oral Digestion, or Chewing

Now, you’ve taken a bite.

First, you chew your food. Chewing is the first step in digestion. You physically break it up with your teeth into smaller pieces, increasing the surface area for digestive enzymes to access. Most of those enzymes appear later in the gut, but some appear in the saliva and start working immediately in the mouth during the chewing process.

Your taste buds communicate what you’re eating so that your body starts getting the right digestive juices flowing. For example, if you ate something sweet, you’ll make insulin. If you’re eating a fatty food, you’ll start secreting bile and enzymes.

Salivary amylase begins converting starch into sugar for easier digestion. Chew a potato for long enough and it’ll start tasting sweet.

Lingual lipase begins digesting the fats you eat. This is more important in babies, who express very high levels of lingual lipase in order to optimize their calorie intake from breastmilk. It still has an effect in adult fat digestion.

How to optimize oral digestion

Chew more: The longer you chew, the better you digest your food. In one study, healthy adults who chewed 50 times for each bite ended up eating fewer calories than those who chewed 15 times per bite, a strong indication of more efficient digestion and nutrient extraction.¹ They were getting “more” out of their food simply by chewing it up more.

Heed your salivary amylase levels: How much salivary amylase you produce is determined by your genetics, with historically agricultural (and thus starch-consuming) populations tending to possess more copies of the salivary amylase gene than other populations. There’s no good way to test salivary amylase gene status because the commercial genetic analysis sites don’t cover it. You’d need a more specific (and expensive) test for that. Ancestry can be a rough proxy; try to match your carb intake with the carb intake (and thus amylase copies) of your recent ancestors. But whatever number of amylase copies you (might) carry, chewing more times per bite will increase the efficacy of the salivary amylase you do produce.

As for meat and other animal foods which salivary amylase doesn’t affect, chewing is still important because it breaks apart the fibers and makes the nutrients contained therein more accessible to protein-digesting enzymes (proteases) in the stomach.

Mechanical Digestion, in the Stomach

Leaving the mouth, the food travels down the esophagus on into the stomach, where hydrochloric acid and a protein-degrading enzyme called pepsin break the food down into a big semifluid mass of partially-digested food components, water, enzymes, and acid known as chyme. The stomach walls undulate (move up and down) and mix the chyme,

How to Optimize Stomach Digestion?

Get your thiamine. Thiamine is a B-vitamin involved in hydrochloric acid production. If you want optimal stomach acidity—and you definitely do want it—you need to be replete in thiamine. The best source of thiamine is pork.

Watch the antacids. While heartburn meds can make a person feel better in an acute case of heartburn, they do so by inhibiting production of hydrochloric acid, which makes the stomach more alkaline and worsens your digestion in the long run. Pepsin cannot work without adequate acidity.

Try bitters. Post-meal bitters stimulate production of hydrochloric acid and assist many of the digestive organs, making the whole operation run more smoothly. But they must be bitter. Covering up the bitter flavor with something sweet mitigates the beneficial effect on digestion.

Get enough sodium. Low sodium levels reduce hydrochloric acid production. Make sure you’re salting your food to taste, as our moment-to-moment desire for salt is a good marker for sodium requirements. As long as you’re not eating packaged junk food, you won’t crave too much salt.

Try supplemental hydrochloric acid. A little betaine HCl, especially with protein meals, can really help if your acid production is too low. If you take betaine HCl and you feel a burn, you probably don’t need it.

Duodenum Digestion

Since the stomach is too acidic for amylase to work, the chyme migrates down to the duodenum, the first section of the small intestine immediately after the stomach where the pH is more alkaline. The pancreas produces protein-digesting enzymes as well as amylase and delivers them to the duodenum, where the full range of digestive enzymes can get to work liberating nutrients for absorption down the line. This is also where bile is introduced to assist in fat digestion.

Eat meals rather than graze. The human digestive system operates best when it encounters whole meals with plenty of time between subsequent meals, rather than a steady stream of incoming food. It even tries to enforce this; when a bolus of chyme enters the duodenum, the opening leading from the stomach to the duodenum tightens up to prevent more food from coming in. Overriding this with constant snacking will only impair your digestion and back things up.

Go for a walk. A short walk after eating speeds up the transition of food from the stomach through the duodenum into the small intestine. It “gets things moving,” in a good, beneficial way.

Small Intestine Digestion

After softening up in the duodenum, the chyme passes on into the small intestine where the bulk of nutrient absorption occurs. All along the intestinal walls lie villi — microscopic finger-like projections that increase the surface area of the intestinal lining and pluck nutrients from the passing slurry to be absorbed and assimilated. (You may have heard of villi in the context of gluten. Gluten can wipe out the villi in some people, leading to nutritional malabsorption.)

Optimize your serotonin. 95% of the serotonin in our body occurs in the gut; it’s one of the primary regulators of intestinal peristalsis — the muscular contractions that move and mix food through the digestive tract.² I’ll have a much more in-depth post in the near future on this topic.

Fix leaky gut: Leaky gut isn’t just about allowing in pathogens and unwanted, allergenic food components into your bloodstream. It also impairs nutrient absorption and digestion in the small intestine. Go through this post and make sure you’re practicing excellent tight junction hygiene.

Pay attention to FODMAPs: Not everyone with digestive issues has to do this, but anyone who gets bloating, belly pain, excessive gas, and many of the other symptoms of poor digestion after eating should analyze their diet for FODMAPs and do an elimination trial. FODMAP foods include a wide range of fermentable fibers, sugars, vegetables, and fruits that have been shown to provoke uncontrollable and uncomfortable gut issues. These are often foods we consider to be healthy. Read the posts I’ve done on FODMAPs and follow the advice listed therein if you suspect you may have a problem with them.

You can also get tested for SIBO to see whether eliminating FODMAPs will benefit you.

Colonic Digestion

You don’t actually “digest” anything in the colon. Rather, you gather and expel the waste — mostly fiber — that’s left over from digestion. Some of that “waste” is food for the gut bacteria who live in your colon. So someone’s digesting the stuff, just not you.

Eat some prebiotic fiber. Ironically, sometimes you need to eat stuff you can’t digest in order to improve your digestion over the longterm. Fermentable, prebiotic fibers like inulin and resistant starch are some of the best-studied examples. They feed the (mostly) good gut bacteria, who in turn produce short chain fatty acids that power your colonic cells and improve your metabolic health.

Take probiotics. Certain probiotics have been shown to reduce bloating and belly pain, improve GI symptoms, improve IBS symptoms, reduce leaky gut, and reduce antibiotic-related diarrhea.³⁴⁵⁶⁷ I created Primal Probiotics with precisely these probiotics to tip the balance in your favor.

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Get Primal Probiotics here

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Digestion must be approached as a single unit. You don’t just pick one of these tips to try. You do them all, together, if they apply to you.

References

1. https://pubmed.ncbi.nlm.nih.gov/29767425/
2. https://pubmed.ncbi.nlm.nih.gov/11051338/
3. https://www.ncbi.nlm.nih.gov/pubmed/19332970
4. https://www.ncbi.nlm.nih.gov/pubmed/19922649
5. https://www.ncbi.nlm.nih.gov/pubmed/21418261
6. https://www.ncbi.nlm.nih.gov/pubmed/3938349
7. https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2004.02274.x/abstract

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Ask a Health Coach: More of Your Cravings Questions Answered

Hi folks, we’re excited to have Board-Certified health and wellness coach Erin Power back to break down the emotional and psychological reasons we crave comfort foods. If you’ve vowed to stick to a Primal diet this year, you’ll definitely want to check out this week’s post. Got a question for our health coaches? Head over to our Mark’s Daily Apple Facebook group or ask it in the comments below.

 

Luke asked:
“I’m a few weeks into eating Primal and I can’t seem to shake my cravings for comfort food. You know, mac ‘n cheese, beer, ice cream. I really want to stick to healthy eating this time and can’t understand why it’s always such a struggle.”

You probably won’t be surprised to hear that sugar is highly addictive. And that includes foods that turn to sugar in the body, like mac ‘n cheese, beer, crackers, cereal…you get the picture. But what you may not realize is that when you consume those foods, you experience a temporary rise in serotonin levels and then a fairly drastic crash. That’s why sugar gives you such a high. And then leaves you craving more once you get those cranky, hangry withdrawal symptoms.

Do Fat and Carbs Cause Cravings?

The macronutrients fat and carbohydrates are two of the main components of comfort foods. Fat and carbs aren’t inherently bad, but when combined they tend to pack a punch, metabolically speaking. As I mentioned, carbohydrates raise the feel-good neurotransmitter, serotonin, while fat has the phenomenal ability to soothe. In fact, this study found that when participants consumed saturated fat, they became less emotionally affected while watching a sad movie or listening to sad music.

That’s why certain foods are so addictive. And the situation gets worse when you’re under stress.

Not only that, research shows that the areas of the brain triggered by cravings (the hippocampus, caudate, and insula) are the same as those implicated with drug and alcohol addiction. These are the parts of the brain associated with our reward system and the emotional connection we develop every time we repeat a behaviour.

Eat and Repeat: Creating Neural Pathways

Every time you repeat an action, whether it’s one you want to keep doing or not, you reinforce your neural pathways. These are pathways that send signals from one part of the brain to another. Eventually, those actions become automatic.

It’s like if you took the same route to work every day. After a handful of times, you wouldn’t have to think about it anymore. Your brain automatically knows where to go. The same thing happens with cravings. When you reach for a big ole bowl of mac ‘n cheese each time you feel low or stressed out, you engage in the process of continuous reinforcement. The emotion (feeling low or stressed) triggers the action (eating), which elicits the reward (feeling good). Basically, it’s not your fault that you have cravings. That doesn’t mean you’re stuck with them though.

Cravings can also be a sign that you aren’t supporting your body properly in other ways. Lack of protein, poor sleep quality, and chronic stress play a major role too. Listen, it’s not about willpower here. Cravings are often a purely physiological response. That means with the right changes, you won’t feel as tempted to dive headfirst into a pint of rocky road or bowl of grandma’s chocolate chip cookie recipe.

4 Tips for Conquering Cravings

1. Notice what triggers you. Are you hungry, tired, stressed out? Become aware of what sets you off. Research even shows that seeing food on TV can make you eat more of it. And not the healthy kind.
2. Eat more protein. Things like beef, fish, eggs, and chicken can help you feel full and have fewer cravings. That’s because protein reduces the hunger hormone, ghrelin, and improves dopamine production – one of the hormones involved in cravings.
3. Get more sleep. Studies prove that skimping on sleep can make you crave sweets and other comfort foods.⁸ So make getting quality shut-eye a priority and follow Mark’s tips for manufacturing a great night’s sleep here.
4. Decrease your stress. Our friends over at myPrimalCoach are sharing simple ways to relieve your stress in this post — everything from breathing techniques to taking a quick walk.

Try these for a week and see what happens. Managing cravings is easier than you think when you have the right tools.

 

Mihir asked:
“How do I get rid of my food addiction (cravings for junk food and other tasty food)? I’m not looking for medical advice, but if you have any tips for beating cravings for good, can you let me know how to do it?”

The emotional reasons we crave food (and have food addictions) are often stronger than the physiological ones. Since you’re up to speed on the temporary hormone changes that occur when you eat hyper-palatable food, I’ll cut right to the chase.

I don’t think there’s a single person out there who doesn’t have some emotional connection to food. Mind you, it doesn’t need to be a negative experience to count. Were there certain foods you enjoyed growing up? Did your parents treat you to sweets when you got hurt? Or rewarded you with junk food for good grades? Maybe a certain dish reminds you of when things were simpler, without bills and jobs and adulting responsibilities. This is all normal and extremely common.

Mindfulness and Emotional Eating

Practicing the act of staying present (also known as mindfulness) can help you learn to hold your ground when faced with the urge to eat. Instead of avoiding the feeling or binging on processed junk, mindfulness allows you to acknowledge the emotion without judgment. And researchers agree. Sarah Bowen from the University of Washington teaches a method called Mindfulness-Based Relapse Prevention. It was designed to help those struggling with substance abuse; however, her method helps all types of people with addictions learn how to become aware of the emotional sensations of their cravings and meet the experience with compassion, rather than giving in to their craving. Being mindful also helps you put a name on the emotion you’re experiencing.

When you’re stressed out or sad or feel isolated, and not legitimately hungry, be aware of what you might really be craving. It could be that you have an unmet need in one or more areas of your life.

We all have basic human needs, including:

• Certainty
• Uncertainty
• Significance
• Connection
• Growth
• Contribution

Your junk food cravings might bring you a sense of security that makes you feel grounded and safe. Or, they might feel wildly exciting, proving a much-needed blast of uncertainty. You might be feeling socially isolated (and really, who isn’t right now) due to the pandemic and look to food to help you cope.⁹ Or you might feel stuck in your current situation use junk to self-sabotage.

Find Alternatives that Empower You

Once you’ve honed in on what you need, take steps to find more empowering ways to get that need met. This is a fantastic exercise I use with my own health coaching clients to help them get started: Jot down 5 non-food ways to meet each of these basic human needs.

List 5 ways to meet your need for certainty.
You might read your favorite book or listen to a song that brings back good memories.

List 5 ways to meet your need for uncertainty.
Why not make a recipe you’ve never tried before or style your hair in a new way?

List 5 ways to meet your need for significance.
Being a role model for your family is a great way to meet this need.

List 5 ways to meet your need for connection.
Call a friend or play ball with the kids at the park.

List 5 ways to meet your need for growth.
Consider taking a class, learning a language, or checking out a new yoga video.

List 5 ways to meet your need for contribution.
This could be supporting a local cause or just being present with your family.

Now, here’s the important part: Have this list ready before you need it. That way it’s just as easy to go for a walk or call a friend as it is to order a large deep dish with pepperoni. And if you want more hands-on advice, feel free to check out the new myPrimalCoach program. You can even work with your own health coach one-on-one.

Now it’s your turn. Have you struggled with cravings? If so, what’s worked for you?

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What Are the Best Probiotic Strains?

“You should take probiotics.”

“I heard probiotics are good for you.”

“Oh, probiotics are so, so important.”

Yes, yes. These are all true statements. But they are broad. Which probiotics? Which strains for what purpose? Simply saying “probiotics” tells us very little about what we’re supposed to be taking. It’s like saying “You should eat food.” Technically accurate yet operationally useless.

Today I’m going to rectify that. I’m going to describe the best probiotic strains for each desired purpose, because there is no single strain to rule them all. The probiotic strain that’s best for anxiety may not be the best probiotic strain for allergies, and so on.

Of course, these aren’t the final word. What follows is the best available evidence as it exists today. That may change tomorrow. And it will certainly change based on your individual makeup.

With all that in mind, let’s get right down to it.

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Best Probiotic for Anxiety

The existence of the gut-brain axis — that mysterious thoroughfare running from the gut to the brain and back again — and the presence and even production of neurotransmitters along the gut suggests that “gut feelings” describe real phenomena. Mental and gut health are strongly linked, and it’s most likely a bi-directional relationship where each affect the other. You know this already, though, don’t you?

We’ve all felt fear or discomfort in our guts.

We’ve all had instinctual responses to certain people that seemed to manifest in our stomachs (and later be proven).

These are real. They aren’t figments of our imagination.

For instance, we know that some strains of gut bacteria can produce GABA, the “chill-out” neurotransmitter responsible for sleep and relaxation. We know that feeding prebiotics (bacteria food) to people can lower their cortisol and induce them to focus on positive stimuli instead of negative stimuli. We know that the greater the intake of fermented food like yogurt, kefir, kimchi, or sauerkraut, the lower the incidence of social anxiety.

The best candidate for anxiety is Lactobacillus rhamnosus. Although no human anxiety studies for this strain exist (yet), there are plenty of animal studies that support it. One notable paper found that dosing mice with L. rhamnosus increased cortical expression of GABA genes and reduced cortisol and anxiety-like behaviors.¹

Best Probiotic for IBS

Irritable bowel syndrome is, well, irritating. Even more irritating is the fact that it describes a confluence of symptoms rather than a specific disease; two people, each with “IBS,” can have disorders with completely different etiologies. This complicates the probiotic you choose.

In one study, IBS patients who took a combo of Saccharomyces boulardii, Bifidobacterium lactis, Lactobacillus acidophilus, and Lactobacillus plantarum saw a 73% improvement in symptoms—but only if they also had small intestinal bacterial overgrowth (SIBO). IBS patients without SIBO only had a 10% improvement.²

(Side note: since gastro-esophageal reflux disease, or GERD, usually presents with SIBO, there’s a good chance that this lineup of strains could also help there)

Another paper, a meta-analysis from 2019, sought to determine which strains were best for IBS patients. While they didn’t come up with one prevailing strain, they did find that multi-strain probiotics generally worked better than single-strain probiotics, and that Lactobacillus acidophilus appeared in all the successful multi-strain studies.³

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Get Primal Probiotics, which includes 4 of my favorite strains plus a prebiotic blend (food for friendly bacteria) to help them take root – all in one convenient capsule

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Best Probiotic for Leaky Gut

The intestinal lining is not a passive, inert barrier but rather a dynamic, selective filter. Lining the gut are epithelial cells whose cell membranes fuse together to form protein complexes called tight junctions. The tight junctions serve as doormen: their job is to discern between what belongs inside and what doesn’t. In a perfect world, these tight junctions keep out pathogens, antigens, and toxins while admitting nutrients and water. But it’s not a perfect world, and sometimes the intestinal tight junctions are asleep at the post. Sometimes the gut is leaky.

Addressing leaky gut isn’t as simple as popping a few pills. Defeating it requires a multi-pronged approach, including sleep, diet, exercise, sun, and all the other regular lifestyle pieces I’ve covered in previous posts. But certain probiotic strains really do seem to help. In children with atopic dermatitis, for example, L. rhamnosus and L. reuteri supplements reduce leaky gut and improve symptoms.⁴ L. rhamnosus also helps restore the gut barrier in kids with acute gastroenteritis.⁵ And in rats with leaky gut, yogurt improves gut barrier function.⁶ We aren’t rats, but yogurt is a safe bet (as is the Lactobacillus acidophilus that appears in most yogurts).

Best Probiotic for Diarrhea

Diarrhea after a round of antibiotics is a common side effect, especially in kids. A 2016 analysis of 23 studies of almost 4000 total pediatric subjects concluded that probiotics are effective at reducing the risk of antibiotic-related diarrhea, with L. rhamnosus and Saccharomyces boulardii as the safest bets.⁷

In adults coming off antibiotics, a combo of Lactobacillus acidophilus NCFM, Lactobacillus rhamnosus Lr-32, Bifidobacterium breve M-16V, Bifidobacterum longum BB536, Bifidobacterium lactis BL-04 and Bifidobacterium bifidum BB-02 was effective at reducing diarrhea.⁸

Best Probiotic for Constipation

Among young college-aged women with constipation, a combo of Bifidobacterium lactis BL 04, Bifidobacterium bifidum Bb-06, Lactobacillus acidophilus, Lactobacillus casei, and Lactococcus lactis improved symptoms and quality of life.⁹ Another study found that B. lactis reduced symptoms in constipated adults.¹⁰

Other than that, the rest of the constipation/probiotic literature is pretty inconclusive and meager. What does seem to help is combining probiotics with prebiotics—ie, food for the gut bugs.¹¹ Probiotic-enhanced artichokes are probably my favorite incarnation of this concept.¹²

Best Probiotic for Allergies

Probably the best anti-allergy probiotic strain is Lactobacillus paracasei.

L. paracasei has been shown to improve symptoms in subjects with hay fever across a number of studies. In adults with grass pollen hay fever, a fermented milk made using L. paracasei reduced nasal itching and congestion.¹³ In kids with hay fever, L. paracasei reduced nasal itching, sneezing, and eye swelling.¹⁴

L. paracasei also reduces eczema, probably by strengthening the skin barrier and improving water retention.¹⁵¹⁶

Best Probiotic for Immunity

The gut is in many ways the first line of our immune system. Some of the infectious diseases you don’t typically think of as gut-related can gain entry and spread via the gut. COVID-19, for example, often presents with gastrointestinal symptoms and researchers are examining whether probiotic supplementation can help reduce your risk of developing severe COVID.¹⁷

A meta-analysis of studies in elite athletes found a number of probiotic strains to be helpful in preserving immune function during extreme training. Athletes are a great population to study because their training places incredible stress on their immune systems; I remember back when I was running hundreds of miles a week, I’d constantly be coming down with something or getting over something else. So, which probiotics help?

Once again, the big names of the Lactobacillus and Bifidobacterium genera reign:¹⁸

Lactobacillus paracasei

Lactobacillus acidophilus 

Lactobacillus rhamnosus

Lactobacillus reuteri

Lactobacillus fermentum

Bifidobacterium lactis

Bifidobacterium bifidum

Overall, these strains from the Lactobacillus and Bifidobacterium genera are the best-studied for most applications. They’re often what appear in human guts and the fermented foods we’ve eaten for many thousands of years. It’s safe to assume that we’re well-adapted hosts to them.

There are so many more exotic strains out there. There are soil-based bacteria. There are strains unique to the Hadza hunter-gatherers of Tanzania. There are probably some interesting strains living in other traditional peoples in other regions. And I imagine many of them have potential to do us all a lot of good. But they may also have unwanted, unexpected effects.

The thing about probiotics is that you never really know which one will work best until you try. It’s a very personal thing. Each strain is going to react different to your unique intestinal ecosystem and genome. What we can say with fairly strong confidence is that probiotics are generally very safe. Not every strain recommended here will work for everyone, but luckily there’s not much harm in trying.

Which strains are your favorites? What have you tried? What hasn’t worked?

Let me know down below. Thanks for reading!

References

1. https://pubmed.ncbi.nlm.nih.gov/21876150/
2. https://pubmed.ncbi.nlm.nih.gov/29508268/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769995/
4. https://www.ncbi.nlm.nih.gov/pubmed/15520759
5. https://www.ncbi.nlm.nih.gov/pubmed/24501384
6. https://www.ncbi.nlm.nih.gov/pubmed/18427990
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5140692/
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609938/
9. https://pubmed.ncbi.nlm.nih.gov/31657615/
10. https://pubmed.ncbi.nlm.nih.gov/22284965/
11. https://pubmed.ncbi.nlm.nih.gov/30402873/
12. https://pubmed.ncbi.nlm.nih.gov/22225544/
13. https://www.ncbi.nlm.nih.gov/pubmed/21395878
14. https://www.ncbi.nlm.nih.gov/pubmed/24269033
15. https://www.ncbi.nlm.nih.gov/pubmed/21269308
16. https://www.ncbi.nlm.nih.gov/pubmed/24322880
17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357989/
18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888046/

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