Weekly Link Love — Edition 25

Research of the Week

Statins linked to diabetes, again.

A ketogenic diet helps relapsing MS patients lower fatigue, reduce depression, and lose weight.

Indigenous Australians traded pottery with Papua New Guineans for thousands of years.

A fatty liver epidemic in young people is bad news and simply shouldn’t be happening (but is).

Narcissists make better citizens.

New Primal Blueprint Podcasts

Episode 328: Dr. Loren Cordain: Host Elle Russ chats with the creator of the original Paleo Diet, Dr. Loren Cordain PhD.

Episode 329: Dr. Lindsay Taylor: Host Brad Kearns chats with Dr. Lindsay Taylor, PhD and co-author of the Keto Passport.

Health Coach Radio Episode 8: Kama Trudgen: Kama Trudgen runs health retreats for the indigenous Yolngu people of Northeast Arnhem Land, Australia, helping them reclaim health using traditional diets and lifestyle practices.

Each week, select Mark’s Daily Apple blog posts are prepared as Primal Blueprint Podcasts. Need to catch up on reading, but don’t have the time? Prefer to listen to articles while on the go? Check out the new blog post podcasts below, and subscribe to the Primal Blueprint Podcast here so you never miss an episode.

Media, Schmedia

Not grazing on junk all day long is “starving,” apparently.

Irish soil contains microbes that fight drug-resistant bacteria.

Interesting Blog Posts

Ancient animal urine could reveal the history of animal agriculture.

A sandwich with pickles instead of bread? Sure, why not.

Social Notes

Enter now to win a Cuisinart Airfryer, $200 in Primal Kitchen loot, and a $100 gift card to PrimalKitchen.com.

My quick, effective road workout when I’m traveling light without gym access.

Everything Else

This seems like a good use of GMO technology: blight-resistant American chestnut.

Google pulls the plug on its glucose-monitoring “smart lens” they’d been working on since 2014.

Raw eggs in milk, carrots, steak, lamb chops, liver, and the odd ice cream sundae: Marilyn Monroe’s diet.

Things I’m Up to and Interested In

Virtual health summit you should attend: Habits to Thrive, a 7-day summit hosted by Deanna Wilcox, Anya Perry, and 17 other Primal Health Coaches.

Study I found interesting: Drug and alcohol use and life satisfaction.

Positive side effect I’m hoping develops: Scientists are mad that T-rex bones are going for millions on eBay rather than remain in the public trust. But what if high prices and private sales spur more finds and more discoveries?

I think there are better ways to lose weight: Than swallowing 3-dimensional cellulose matrix tabs that expand in your stomach and take up space.

I can’t think of a better way to gain weight: “…eating behaviors of modern consumers may be guided by a predominant goal to attain the subjective experience of complete fullness.”

Question I’m Asking

Some high-end coffee places are banning milk, sugar, and cream, arguing that the extra additions detract from the true coffee experience. What do you think of food establishments with draconian policies like that—snobs or real artisans?

Recipe Corner

Time Capsule

One year ago (Apr 14– Apr 20)

Comment of the Week

“What about a half scoop of metagenics thermaphaseprotein detox powder in water? Will this break my fast?”

– Depends which ThermaPhase tier you’ve reached. Tier 2 and below you’d better go a quarter scoop if you want to maintain the fast. Tier 3 ThermaPhase or higher actually extracts calories from you.

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The post Weekly Link Love — Edition 25 appeared first on Mark's Daily Apple.

Keto and the Menstrual Cycle: Is There Reason To Worry?

It seems every “keto for women” forum abounds with stories about menstrual cycles gone wild in the first few months of keto. Irregular cycles, breakthrough bleeding, and periods lasting much longer than normal are common complaints. Sometimes these stories are cited as evidence that keto isn’t good for women, at least not premenopausal women, and that we need carbs for healthy hormones. Yet, many women don’t notice any changes in their menstrual cycles at all, while others report improvement in PMS symptoms and cycle regularity from the get-go.

What gives? Why do some women’s cycles apparently become wacky when they start keto, while others feel like keto is the key to period bliss? Can keto “mess up” the menstrual cycle?

We know that diet—what and how much we eat—can profoundly affect our hormones. This is true for both women and men. One of the reasons people are so excited about ketogenic diets is specifically because keto shows promise for helping to regulate hormones and improve cellular sensitivity to hormones such as insulin and leptin.

At the same time, women’s hormones are especially sensitive not only to dietary changes but also to downstream effects such as body fat loss. Furthermore, one of the ways women’s bodies respond to stressors is by turning down the dial on our reproductive systems. It’s reasonable to hypothesize, then, that women might have a tougher time adapting to or sustaining a ketogenic diet. Keto can be stressful depending on one’s approach, and that might negatively impact women’s reproductive health. But do the data actually bear that out, or is so-called “keto period” more misplaced hype than genuine fact?

Note that throughout this post, I’m going to use the term “reproductive health” to refer to all aspects of women’s menstrual cycle, reproductive hormones, and fertility. Even if you aren’t interested in reproducing right now, your body’s willingness to reproduce is an important indicator of overall health. When your reproductive health goes awry—irregular or absent periods (amenorrhea) or hormone imbalances—that’s a big red flag. Of course, post-menopausal women can also experience hormone imbalances that affect their health and quality of life (and low-carb and keto diets can be a great option for them).

Menstrual Cycle 101

Let’s briefly review what constitutes a normal, healthy menstrual cycle, understanding that everybody’s “normal” will be a little different. A typical cycle lasts from 21 to 24 days on the short end to 31 to 35 days on the long end, with 28 days being the median. Day 1 is the first day of your period and begins the follicular phase, which lasts until ovulation. Just before ovulation, levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (a form of estrogen) spike. Next comes the luteal phase covering the approximately 14 days from ovulation to menses. LH, FSH, and estradiol drop, while progesterone rises. Estradiol bumps up again in the middle of the luteal phase. If a fertilized egg is not implanted, menstruation commences, and the whole cycles starts over again. All this is regulated by a complex communication network under the hypothalamic–pituitary–gonadal (HPG) axis, which is closely tied to the actions of the adrenal (the A in HPA axis) and thyroid glands.

Across the cycle, fluctuations in body weight are common as fluid is retained and then released along with shifts in estrogen and progesterone. Changes in blood glucose are also normal, and insulin-dependent diabetics often find that they need to adjust their dose at different times of their cycles to keep their blood sugar in check. The most common pattern is higher blood glucose readings in the pre-menstrual period (the second half of the luteal phase), and lower readings after starting your period and before ovulation. This is generally attributed to the fact that progesterone, which is highest during the luteal phase, is known to reduce insulin sensitivity. However, different women experience different patterns, which can also be affected by other factors such as oral contraceptive use.

Normal fluctuations in insulin resistance and blood glucose can mean that women get lower ketone readings at certain times of the month than others. When these occur premenstrually—and so they tend to coincide with a period of (transient) weight gain and food/carbohydrate cravings—women often feel as though they are doing something wrong. Rest assured that these variations reflect normal physiology.

The many factors that affect your cycle and the levels of your sex hormones include: other hormones, gut health and microbiome, metabolic health (e.g., insulin sensitivity), environmental toxins, stress, sleep, immune health, nutrient deficiencies, activity level and energy expenditure, and age. Each affects the others, and all (except age of course) can be affected by diet. It’s no surprise, then, that it can be extremely difficult to pin down a root cause of menstrual changes or reproductive issues.

What the Research Tells Us About Keto and Menstruation

As I said at the outset, there are lots of anecdotes, both positive and negative. In my experience, most women whose cycles seem to go crazy when they start keto find that things get back to normal—and often a better version of normal—after a few months.

First, it’s tricky to determine the effects of keto per se, since many people combine a ketogenic diet with calorie restriction (intentionally to lose weight or unintentionally due to the appetite suppressing effects of keto) and with fasting (intermittent and/or extended). Each of these can independently impact the factors listed above, lead to weight loss, and affect the menstrual cycle and reproductive health.

So, is there any evidence that keto itself causes changes to menstruation?

The scientific evidence is scant….

The one statistic you’ll see floating around the interwebs is “45% of (adolescent) females experience irregular menstrual cycles on keto.” This statistic comes from one small study of adolescent girls using a therapeutic ketogenic diet to treat epilepsy. Six of the twenty girls reported amenorrhea (loss of period) and three were diagnosed with delayed puberty. However, the ketogenic diet used for epilepsy is different and usually much stricter than an “everyday” keto diet needs to be, and epilepsy is frequently associated with menstrual dysfunction regardless of diet.

To extrapolate the findings of this study and argue that nearly half of teenage girls (or women generally) are likely to experience menstrual problems from going keto is a huge leap.

The fact is, I’m unable to find any studies done in healthy human females (or mice for that matter) demonstrating that otherwise normal menstrual cycles are disturbed by going keto.

5 Ways Keto-Related Factors *Might* Affect Your Menstrual Cycle

With the limited amount of research looking directly at keto and menstruation, let’s look first at whether there are direct effects of carbohydrate restriction or elevated ketone production on the menstrual cycle. Those are the defining characteristics of keto and what differentiates keto from other ways of eating. Then we can examine indirect effects that occur due to factors such as weight loss. These are not unique to keto, though they might be more likely on a ketogenic diet compared to other ways of eating.

Carbohydrate Restriction

There is no real body of evidence that looks at ketogenic levels of carb restriction and menstruation, but there are some clues. In this small study, functional hypothalamic amenorrhea (FHA) was associated with dietary fat restriction; women with FHA actually ate non-significantly more carbs than matched controls and nearly identical total calories. Likewise, in this small study, FHA was associated with lower fat intake but no significant difference in carb intake.

This meta-analysis looked at the effect of low-carb (not keto) diets on markers of reproductive health among overweight women. The researchers found four studies that examined effects on menstruation; all showed improved menstrual regularity and/or ovulation rates. Of six studies that looked at levels of reproductive hormones, five reported significant improvements.

Carb restriction also results in decreased insulin production. Hyperinsulinemia and insulin resistance are frequently associated with polycystic ovarian syndrome (PCOS), one of the leading causes of female infertility and a frequent cause of menstrual irregularity. There is currently a lot of interest in using keto to treat PCOS, but only one small study has so far directly tested the effectiveness of a ketogenic diet to treat PCOS, with positive results.

Ketones

No studies have looked at the direct effects of ketones on menstruation.

Weight Loss

Of course weight loss is not unique to keto, but keto can be very effective for weight loss. Some women experience rapid weight loss when first starting a keto diet. Weight loss in and of itself can impact menstruation through a variety of pathways. A key way is by reducing the hormone leptin. Leptin’s main job is to communicate energy availability to the hypothalamus—high levels of leptin tell the hypothalamus that we have enough energy on board, which also means we can reproduce. Low leptin can disrupt the menstrual cycle and is linked to hypothalamic amenorrhea.

Body fat loss can also affect estrogen levels since estrogen is both stored and produced in adipocytes (fat cells). While fat loss in the long term will decrease estrogen production, it is possible that rapid fat loss might temporarily raise estrogen levels and can also affect estrogen-progesterone balance. These transient changes in estrogen levels might underlie some of the menstrual irregularities women report.

Stress

Stress can impact the menstrual cycle in myriad ways. Cortisol acts on the hypothalamus and pituitary glands, affecting hormone levels, sleep, immune function, and gut health, to name a few. Diets can be a source of stress, both at the physiological and psychological levels. Keto has a reputation for being especially stressful because it is more restrictive than other low-carb diets, but this can be mitigated by following the Keto Reset tips for women.

Thyroid Function

Thyroid dysregulation is another common cause of menstrual irregularities, and there remains a pervasive belief that keto is bad for thyroid health. Indeed, the thyroid is sensitive to nutrient deficiencies and caloric restriction, and thyroid hormones, especially T3, do frequently decline on keto. However, as Mark has discussed in a previous post, changes in T3 levels might not be a problem, especially in the absence of other problematic symptoms. Moreover, many practitioners now use keto as a cornerstone in their treatment of thyroid disorders.

What Should I Take From These Findings?

The first takeaway: there just isn’t much direct evidence about how keto might affect your menstrual cycle, positively or negatively. We have some studies suggesting that low-carb diets improve some aspects of menstruation and reproductive health, but keto is more than just another low-carb diet. Ketones themselves have important physiological properties, such as being directly anti-inflammatory, which might positively impact women’s reproductive health.

Second, the ways that keto is likely to (negatively) affect menstruation aren’t unique to keto, they’re common to any diet: hormone shifts mediated by energy balance, stress, and weight loss.

Furthermore, since keto is so often combined with caloric restriction, time-restricted eating, and fasting, even the anecdotal evidence might not be able to tell us all that much. If a woman is eating ketogenically, in a big caloric deficit, and doing OMAD (one meal a day), and her leptin plummets, how are we to know what really caused it? We don’t have good evidence that otherwise healthy women start a well-executed ketogenic diet and end up messing up their menstrual cycles.

That said, women do need to be cognizant of the sum total of the signals they are sending their bodies when it comes to energy availability and stress. A lot of women come to the keto diet with a history of adrenal, thyroid, metabolic, and reproductive issues. It’s important that they’re extra careful about how they approach keto. Done correctly, it might be just what the doctor ordered. I encourage any woman who’s dealing with other hormonal issues to work with a medical practitioner to tailor a keto diet to her unique needs.

But I’m Telling You, Keto Made My Period Go Haywire!

Ok, I believe you, really! But changes do not necessarily equal dysfunction. It is normal to experience hormone fluctuations when you make a massive—or even a relatively small but important—shift in your nutrition. Sometimes those fluctuations are unpleasant or unwanted, such as a period that lasts 14 days or one that arrives a week before you planned while you’re on vacation. However, that doesn’t make them bad from a health perspective. We need to respect that our bodies are dynamic systems. Changing the input will invariably change the output, and the system might need a few months to adapt to a new normal.

If your cycle goes wonky but you’re otherwise feeling good, give it a few months to sort itself out. If after a few months it’s still all over the place (or definitely if you’re having other disruptive symptoms), enlist help. In the meantime, check to make sure you’re not short-changing yourself nutritionally or calorically. Scale back on fasting efforts, and consider shifting more toward a traditional Primal way of eating.

At the end of the day, if you go keto and experience negative effects, stop. Keto is super hyped right now, but if your body is sending you clear signals that keto is not a good approach for you at this time, don’t do it. You can always try again later. It might be that your first attempt at keto didn’t work, but with a few adjustments and some experimentation over time you can find a version of keto that works for you.

Thanks for reading, everyone. Do you have comments, questions, or feedback? Let me know below.

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References:

Comninos AN, Jayasena CN, Dhillo WS. The relationship between gut and adipose hormones, and reproduction. Human Reproduction Update 2014; 20(2): 153–174.

Fontana R, Della Torre S. The Deep Correlation between Energy Metabolism and Reproduction: A View on the Effects of Nutrition for Women Fertility. Nutrients. 2016;8(2):87.

Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obesity Reviews 2007;8(1):21-34.

Meczekalski B, Katulski K, Czyzyk A, Podfigurna-Stopa A, Maciejewska-Jeske M. Functional hypothalamic amenorrhea and its influence on women’s health. J Endocrinol Invest. 2014;37(11):1049–1056.  

Tena-Sempere M. Roles of Ghrelin and Leptin in the Control of Reproductive Function. Neuroendocrinology 2007;86:229-241.

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What Breaks a Fast: Supplement Edition

Last week, I explored the impact of all the various foods, beverages, and food-like substances people consume while fasting—and hoping to maintain a functionally fasted state in the post, “The Definitive Guide To What Breaks a Fast.” Does MCT oil break the fast? What about coffee, tea, or bone broth?

There were more than a dozen, and I even did a follow-up. Today I’m going to discuss whether commonly-consumed supplements break the fast.

Let’s go:

Fish Oil

Fish oil is pure fat. If you’re taking the average supplemental dose of 1-2 grams of fish oil, it’s not a problem. That’s not even a teaspoon. It’s about 9-18 calories.

You may burn slightly less fat than you would otherwise, but in the grand scheme of things, a few grams of fish oil won’t break the fast.

Cod Liver Oil

Cod liver oil is fish oil with extra vitamin D and vitamin A. As long as you keep the doses low enough, cod liver oil won’t break the fast.

Multivitamin/Multimineral

Multivitamins do not break a fast. They are usually non-caloric. However, not all of their components will be absorbed very well on an empty stomach, so keep that in mind.

If you’re still not on board, note that in the older studies with really overweight people who fasted for upwards of a year straight, they usually supplemented with a multivitamin.

Food-Based Multivitamin

A popular one I’ve seen around—Alive, made from kale and raspberries—has just 2 grams of carbs per dosing. It’s not ideal, but it’s not a deal breaker—or a fast-breaker.

Gummy Vitamins

Gummy vitamins have the potential to be about 5-6 grams of sugar, a gram of protein (from gelatin), and a gram of fat (if including omega-3s) per serving, so they’d arguably break the fast. Plus, they taste like candy and are likely to stimulate cravings and make fasting harder.

Gummy vitamins break the fast.

Potassium

Potassium is non-caloric and does not break the fast. In fact, it can help you handle the fast better by replenishing electrolytes.

Potassium doesn’t break the fast.

Creatine

Creatine contains no calories and has no effect on insulin secretion (or glucose in the absence of calories).

Creatine does not break the fast.

Protein Powder

Protein powder provokes an insulin response, which opposes autophagy, which means you’re breaking your fast. Plus, protein powder contains calories.

I’m going to say “yes, protein powder breaks the fast.

Collagen

If you’re strict and technical, then yes, collagen breaks a fast. There’s evidence that glycine—the most prominent amino acid in collagen—can inhibit autophagy, but it was a convoluted animal study where inhibiting autophagy with large doses of glycine after brain injury actually improved outcomes. It probably doesn’t apply to someone adding a scoop of collagen to their coffee. Besides, even if it slightly reduces autophagy, a little collagen won’t negatively impact ketosis, fat-burning, or energy intake.

I’m going to say “technically yes,” but “realistically no, collagen doesn’t break the fast.” Avoid if your main focus is autophagy, however.

Branch Chain Amino Acids (BCAAs)

BCAAs trigger an insulin response and thus stop autophagy…and the fast. That said, many proponents of fasted training recommend using BCAAs before a workout to help preserve muscle and improve the post-workout anabolic response.

I’m going to say “yes, BCAAs break the fast.”

Vitamin D

Vitamin D is fat soluble and thus comes packaged in an oil carrier, but the dosage is so small that it won’t affect your fast.

Unless you find that 1/8 teaspoon of olive oil ruins your fast, vitamin D won’t break a fast.

Probiotics

Probiotics contain no calories and will not break a fast. However, they are best absorbed in the presence of food—the food protects them as they travel through the digestive system, and most probiotics occur naturally in food—so taking them during a fast is probably, mostly useless.

Probiotics don’t break a fast, but why take them during one?

Prebiotics

Pure prebiotics will not break a fast, as they contain no digestible carbohydrates. Prebiotic-enriched foods will break a fast, as they do contain calories.

Adaptogens

Adaptogens are compounds, usually herbs or herb derivatives, that modulate your stress response. They improve your ability to tolerate and respond to stressful situations; they don’t blindly inhibit the stress response if the stress response is warranted. They keep you honest and counter unnecessary stress responses. They contain no calories, unless you’re chowing down on a big hunk of maca or ashwagandha root. In fact, most adaptogens have traditionally been consumed in tea form, extracting the active compounds and leaving behind any calories. Have at ’em.

Adaptogens do not break the fast.

Mushroom Extracts

Medicinal mushroom extracts come from mushrooms, which are technically food. But the amounts you take are so low—usually no more than a teaspoon—that they won’t impact your fast or provide any significant amount of caloric energy. Four Sigmatic has those “mushroom coffee” blends you add to hot water. They can get up to about 30 calories per serving, but even that’s going to let you maintain most of the fasting benefits.

Mushroom extracts don’t break the fast.

Melatonin

I used to keep the old Trader Joe’s melatonin on hand because it was half a milligram, whereas most other melatonin supplements are in the 3-5 mg range. It was also sweet, tasting like those white Valentine’s Day mint hearts you used to get back in the day. I haven’t come across any sweetened melatonin supplements since Trader Joe’s phased those out, but that’s the only thing I’d worry about on a fast.

Melatonin does not break a fast.

Final Note: Most supplements are okay to take on a fast, though the lack of food may make absorption more difficult. If you have any other questions about supplements on a fast, drop them down below. Thanks for reading, everybody.

On a related note, with supplements on my mind this week I thought it would be a good time to offer one of my favorite deals—just for the MDA community: 20% off my full supplement line, plus Primal Fuel and Collagen Fuel. It’s a great time to stock up on favorites or to try something new. Offer ends 4/24/19 midnight PDT. Use code WELLNESS20 at checkout. (Offer doesn’t apply for autoship orders.)

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Dear Mark: What Breaks a Fast Followup

For today’s edition of Dear Mark, I’m answering a round of questions drawn from the comment section of the “What Breaks a Fast” post. You folks had tons of follow-up questions about whether other types of foods or compounds break a fast. Does a teaspoon of honey? Does elevated insulin from BCAAs? Does coconut milk? Does pure prebiotic fiber? What about longer fasts—are they recommended? And how about unsweetened cocoa powder? What explains my ability to predict your questions? Do sausages break a fast? Does liquor? How should you exercise?

Let’s dig right in:

Hey, what about honey? 1 tsp in morning tea?

A teaspoon or less of honey is fine and won’t negate the benefits of fasting. I alternate between doing collagen coffee and coffee with cream and teaspoon of sugar (which was my typical morning coffee for over a decade). No reasonable person should fear a teaspoon of sugar or honey.

For what it’s worth, honey isn’t “just” sugar. It elicits a more beneficial (or less negative) metabolic response than other forms of sugar.

I’m shocked about the BCAA. I used to fast and take BCAA’s (yes, to continue dynamic exercise). I used to find it extremely difficult to fast compared to now when I fast without taking them. Does that mean that the insulin response made fastic more difficult?

It’s possible. Insulin impairs lipolysis—the release of stored body fat into circulation for energy usage—and the success of fasting depends on lipolysis. Without lipolysis, you can’t access all that stored energy.

Thank you very much for this info!! I am a butter-coffee-for-breakfast drinker, and I always worry about the ingredients breaking a fast. Could you please comment on coconut milk (in the can)? I love putting that in my coffee/breakfast.
Thanks.

Coconut milk is a less concentrated source of medium chain triglycerides, or MCTs (as in MCT oil). MCTs convert directly to ketones, making MCT oil and to a lesser extent coconut oil or coconut milk a potential “boost” for fasting. Still, energy is energy, and any energy you take in is energy you won’t be pulling from your body.

I find MCTs and coconut to be more useful when someone is just getting the hang of fasting or ketosis—as a nice boost to get things moving in the right direction.

Keep your coconut milk under a tablespoon and you’ll be fine.

Does prebiotic (resistant starch) fiber break a fast? Acacia senegal or potato starch? Thanks!

No. If you’re worried, test your postprandial blood sugar after eating the fiber.

Great input Mark as someone 3days into a 7day water fast with electrolytes of course what’s your view on longer fasts.

Check out the post I wrote on long fasts. Potentially beneficial but the risks accumulate the longer you go. You just have to be even more careful and methodical.

How about unsweetened cocoa?

A tablespoon runs just over 12 calories (depending on the brand; some cocoa powders contain more fat and thus more calories), with around a gram of net carbs and a gram of fat. Also a nice source of potassium and magnesium, along with a ton of polyphenols which can have fasting-mimicking effects on their own.

Eating enough unsweetened cocoa powder to knock you out of your fast would be incredibly repulsive. Probably impossible.

Cocoa is definitely a nice addition.

Okay it’s almost creepy the way Sisson answers my questions before I even ask them! I was wondering about this yesterday and then this post popped up in my inbox.

How does he do that…? ?

Kraft-Heinz has a strong relationship with Google and Amazon, and the Kraft acquisition gave me access to Alexa/Google Home datasets and the ability to predict what my readers are wondering about.

Just kidding, though it’s scarily not out of the realm of possibility anymore.

What about a small snack of paleo sausages, smoked or dried? So meat and fat (beef, pork or lamb), and some spices. Maybe 100g worth.

Well, that’s a legit snack bordering on a small meal. That will break the fast, but it’s not all for naught. There is the whole “fasting-mimicking diet,” where you eating very few calories for several days out of the week and retain many if not most of the benefits of full-on fasting.

Let’s just say if you ate a small snack of paleo sausages on your “fasting” days, you’d still be way ahead of 99% of people.

But do try a full-on fast at least once. You might surprise yourself.

Great post! What about alcohol? Specifically, a shot or 2 of liquor. I would assume beer and wine would break a fast, but what about whiskey or tequila?

When alcohol enters the system, utilization of all other energy sources is suspended until the alcohol is burned. Back in 1999, researchers did a study where they gave fasting adult men the equivalent of a couple shots of liquor. They stopped releasing stored body fat, stopped burning body fat, and began burning way more acetate (a product of ethanol metabolism). They didn’t exactly “break” the fast, but all the metabolic trajectories we love about fasting took a big pause.

Good morning Mark,
How does one exercise in the morning while fasting? When to eat?

You can exercise any way you like, but I change how I train based on when I’m going to break the fast with food.

If I’m going to break the fast with a meal right after, I train any way I like. I’ll do sprints, HIIT, weights, anything.

If I’m going to keep fasting after the workout, I like to stick to strength training and low-intensity movement (walking, hiking, standup paddling). The strength training is essential during a fast because it’s an anabolic signal to your muscles—move it or lose it. Simply lifting heavy things during a fast can stave off muscle loss.

That’s it for today, folks. Stay tuned later this week for “What Breaks a Fast: Supplements Edition.”

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The Primal Blueprint Is For Life!

It’s Monday, everyone! And that means another Primal Blueprint Real Life Story from a Mark’s Daily Apple reader. If you have your own success story and would like to share it with me and the Mark’s Daily Apple community please contact me here. I’ll continue to publish these each Monday as long as they keep coming in. Thank you for reading!

Most of the people whose amazing and life-altering stories appear on MDA are submitted by people aged 50 or younger. Here is one to inspire not only you “young puppies” but hopefully “geezers” like Mark and me. I am the same age as our fearless leader Mark Sisson, and while my story and my life have gone totally differently than Mark’s [I was never a triathlete or even close], the end result is just as rewarding!

My name is Lloyd and I am 65, and in the best shape of my life – almost. In my late 20’s I smoked 2 packs a day and drank two or three mixed drinks every night – and I sported a 42 inch waist. A neighbor convinced me to start running [he ran marathons and weighed like 140 lbs.]. I started running 2 miles a day around a golf course in the neighborhood and ran a very slow 10 minute pace at first. I really liked the feel of the endorphins kicking in and I took to exercise for the first time in my life. Fast forward a few years and I was running 8 miles every day, rain or shine, in around 55 minutes. I had lost weight, but was still eating poorly, whatever my wife put on the table, and often second helpings.

Then we had a freak snow and ice storm, and running was out of the question – for weeks. I was used to doing something physical late in the afternoon so I bought a beginner set of weights and got hooked on bodybuilding. Even after the streets were passable, I kept lifting and soon joined a gym.

I didn’t realize this because I was a neophyte, but the gym I joined was very hardcore. Incandescent lights, bare floors, hard rock music, all guys, chalk flying, grunting and screaming everywhere, and lots of the members were on steroids. No, I never partook, but I did start lifting very heavy weights, and found I could. By two years later, I was very strong and about as big as a natural guy could be. I loved lifting heavy weights and having big muscles. I received a lot of encouragement from the other members and many gave me diet tips as they could see I was serious. The diet? Low fat, high protein and lots of carbs. Some days I ate almost 5-6,000 calories a day and had a 34 waist. At my peak I weighed about 250, with very low body fat. But I was in my 30s. As we age, a lot of things change.

Year after year, I trained the same way, and ate the same way, but by my mid 50s I could see changes happening – my weight was staying the same, but my waist was getting bigger. So I started doing a lot of cardio, all high-intensity, close to my max heart rate, big puddles of sweat under my exercise bike at the gym, and no weight loss!

I was really discouraged, began doing internet research, and I found MDA when it was pretty new. I bought Mark’s first edition of The Primal Blueprint, and it all made so much sense, I dove in 100%. No cheat days, no 80% 20%, I was all in. I started this new eating style at [you’ll love this] at a Thanksgiving Day buffet, lost 2 pounds the first day and about 25 pounds in a few months. Blood pressure went down, bad cholesterol down, good cholesterol up, my doc was amazed, as he was ready to put me on a statin.

I maintained the weight for years until Mark started talking about Keto. Once again, I went all in immediately [I had been eating Primally for so long that I passed Mark’s “test” with flying colors]. I also started using the myfitnesspal app to keep track of my food and nutrient intake. My goal was to lose another 10 pounds and get to 215, but it was so easy, I ended up as low as 204 and I have stayed within a few pounds of that for about 18 months now.

Like Mark, I stay right on the edge of ketosis, some days I might have 60g of carbs, but most of the time, under 40g. I also have found fasting for 24 hours easy to do with my travel schedule and about half of the time, with the exception of coffee and maybe a piece of cheese, I eat nothing until dinner. And I am NOT hungry!

Just one thing more I want to add. From all the years of heavy lifting, I have had back surgery, two total shoulder replacements, and one hip replacement. Yes, I am a poster child for getting rid of old joints that don’t work well anymore.

During each recovery period, I had to stop lifting and curtail cardio, which by the way is now mostly elliptical limited to 75% of my max heart rate. Because of my primal eating style, even sitting around with little to no exercise other than PT] while recovering from surgery, I never gained weight!

So am I a huge fan of Mr. Sisson and this lifestyle? Absolutely! It works, it’s not hard, and it’s for LIFE!

The readers featured in our success stories share their experiences in their own words. The Primal Blueprint and Keto Reset diets are not intended as medical intervention or diagnosis. Nor are they replacements for working with a qualified healthcare practitioner. It’s important to speak with your doctor before beginning any new dietary or lifestyle program, and please consult your physician before making any changes to medication or treatment protocols. Each individual’s results may vary.

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Giveaway: Cuisinart AirFryer + $300 in Primal Kitchen Products

I’ve got a success story coming up this morning, but first this….

We’ve teamed up with Cuisinart to offer an amazing giveaway…to two lucky winners.

Yup, two lucky winners will receive: 1 Cuisinart AirFryer, $200 of Primal Kitchen products, and a $100 gift card to Primalkitchen.com. All you have to do is enter by submitting your email address on this entry page.

The giveaway is open from April 15, 2019 to April 29, 2019.

Enter HERE FIRST and then get BONUS points/entries when you follow: @primalkitchenfoods, @marksdailyapple and @cuisinart on Instagram. Open to those who reside in the U.S. only. We’ll announce the winners April 30th!

And be sure to check out these Primal AirFryer recipes also on the giveaway page:

Teriyaki Chicken Wings

Air Fried Guacamole

Good luck, everybody, and have a great week!

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Keto Zoodle Alfredo

People say they love pasta, but often what they really crave is the sauce. Not that pasta is merely a “filler,” however. Noodles offer a nice texture and lighter feel—putting the sauce in a proper proportion of taste and richness within the overall dish. That may be especially true with alfredo, one of the richest sauces around. Its creamy fullness is hard to resist, and with this low-carb zoodle recipe, you won’t have to.

Servings:6

Time in the Kitchen: 20 minutes

Ingredients:

  • 3 spiralized zucchinis
  • 1 tub (250 g) organic cream cheese
  • 1 cup macadamia milk
  • 1 cup grated Parmesan cheese
  • pinch of ground nutmeg
  • 1 tbsp. Italian parsley (optional for garnish)
  • salt and pepper to taste

Instructions:

Boil zoodles in sea-water-salty water for a few minutes and drain.

For sauce, heat cream cheese with 1 cup each milk and Parmesan in a nonstick pot. Bring to a soft boil.

Season with a dash of ground nutmeg, and salt and pepper to taste.

Put zoodles in serving dish or broil-safe dish if you wish to broil for a baked look as pictured.

Pour enough sauce on zoodles and broccoli to cover them. (Note: This recipe makes enough sauce to cover almost twice as many Zoodles as pictured. There will be plenty for leftovers!)

Top zoodle mixture with extra Parmesan, black pepper and chopped Italian parsley.

Broil if desired. Serve on its own or with baked chicken, and enjoy!

Nutritional Info (per serving):

  • Calories: 230
  • Carbs: 5.2 grams
  • Fat: 20 grams
  • Protein: 8.7 grams

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Weekly Link Love — Edition 24

Research of the Week

The common food additive TBHQ, a synthetic antioxidant used to preserve freshness, appears to impair the immune response to influenza.

Maori people have a greater insulin response to fructose than BMI-matched Europeans.

There’s a new DNA editing tool in town.

Good dog.

Dog owners tend to be more happy than cat owners.

New Primal Blueprint Podcasts

Episode 325: Gary John Bishop: Host Elle Russ chats with Gary John Bishop, personal development coach and author of Unf*ck Yourself and Stop Doing That Sh*t.

Episode 326: Dr. Lindsay Taylor: Host Brad Kearns chats with Dr. Lindsay Taylor about silly six-packs and going by how you feel rather than how you look.

Health Coach Radio Episode 7: Michael Rutherford: Michael Rutherford is a veteran health coach who focuses on an underserved population—truck drivers.

Each week, select Mark’s Daily Apple blog posts are prepared as Primal Blueprint Podcasts. Need to catch up on reading, but don’t have the time? Prefer to listen to articles while on the go? Check out the new blog post podcasts below, and subscribe to the Primal Blueprint Podcast here so you never miss an episode.

Media, Schmedia

Twitter CEO Jack Dorsey sounds like he’s been reading this blog.

Researchers find a new human species, a tree-climber with curved toes who lived in the Philippines 60 thousand years ago.

Interesting Blog Posts

Ancient methods for preserving olives.

Icing may not work, may hurt.

Social Notes

I had a good time on the Taste Radio podcast, talking about my history as a serial entrepreneur and how it made growing the blog and brand into what they are today possible.

I also had a blast with Aubrey Marcus on his podcast, talking about our shared vision for changing how the world eats and the importance of learning from failure.

Everything Else

Chinese scientists insert human brain genes into monkeys.

It’s possible to get too much vitamin D.

Norway hospitals offer forest therapy.

Cashews come with a price.

Things I’m Up to and Interested In

New study: Dietary saturated fat unrelated to heart disease risk.

Topic I found interesting: How Alzheimer’s patients usually have more going wrong in the brain than “just” Alzheimer’s, and what it means for treatments.

As someone who has experience with both, I can agree: Exercise makes you happier than money.

I hadn’t thought of this angle: Is work more fun than not working?

Seems likely: Will space colonization be fully automated?

Question I’m Asking

What’s your opinion on the “money vs. exercise for happiness” question?

Recipe Corner

Time Capsule

One year ago (Apr 7 – Apr 13)

Comment of the Week

“Now that you mention it in your Sunday with Sisson, I think I’ve always thought of the pushup more as a toe-as-fulcrum rotation rather than an up-and-down activity. I mean, this perspective naturally follows if you are already doing pushups with a ridged plank from head to toes and focus on only moving your arms to raise your body up and lower it back down slowly, as if you were a plank of wood a single person was lifting up and down from the floor while standing at one end of the plank. Visualization and imagery can provide key insights into form and technique.”

– Great description and apt point, Aaron.

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13 Keto-Friendly Fiber Foods

While some keto or low-carb proponents claim fiber is useless at best and actively harmful at worst, I come down on the side that says fiber is probably helpful for most people. Some folks have persistently better responses to low- or no-fiber keto diets, and I won’t argue with that—I’ve seen it happen and I’ve read the studies where de-emphasizing fiber can actually improve constipation, for example.

I’ll just say that I have an opposite reaction, and, most importantly, I love eating a variety of plant foods that also happen to contain a ton of great nutrients in addition to fiber.

Do I buy into the idea that fiber is important because it is every human being’s responsibility to produce as much colonic bulk as humanly possible? No.

Do I think we should be consistently pushing the limits of our digestive tracts, performing feats of bathroom heroism so momentous they border on Herculean, and making sure the toilet bowl buckles beneath us? No.

The real value of fiber lies not in its coarseness, its tendency to form colonic bulk, to keep us topped off. The true value lies in its fermentability. A fermentable fiber is a prebiotic fiber—fiber that feeds our gut bacteria.

I won’t get into the many roles our gut bacteria play in our health today (I’ve covered that before. 1, 2, 3).

I will, however, explain why we need to be feeding our gut bacteria. Our gut bacteria form a physical barrier against incursions and colonization by pathogenic bacteria; they take up room along the gut lining so pathogens can’t. If we don’t feed our gut bacteria with prebiotics, it won’t be around to protect us. After antibiotic treatment where both good and bad gut flora are indiscriminately targeted and wiped out, pathogenic obesity-promoting bacteria take advantage of the open space. That’s a worst-case scenario, but it shows what can happen when the harmony of the gut is disturbed by antibiotics or, to a less extent, a lack of fermentable prebiotic fibers.

When our gut bacteria eat prebiotics, they also give off metabolites like butyric acid—a short chain fatty acid that our colonic cells use as an energy source and which improves metabolic health.

Gut bacteria also convert antinutrients like phytic acid into nutrients like inositol. The almond meal-obsessed keto eater would do well to have a powerful gut biome set up to convert all that phytic acid to inositol.

Now, some writers will come up with specific blends of fibers, powders and gums to create the “optimal” prebiotic diet for your gut bacteria, but that’s pretty silly. The gut is a complicated place. We’ve barely begun to even identify all its inhabitants. To think we know the precise blend of isolated fiber that will make them flourish, and then act on that, is a mistake.

A better option is to eat foods that contain fiber. Some of the prebiotic fibrous foods with the best nutrient profiles also happen to be extremely keto-friendly.

1) Almonds and Pistachios

Nuts are usually favored in health-conscious circles for a few reasons. They like the monounsaturated fat. They like the mineral profile, or the complete protein, or their ability to dissemble into nut meals and form baked goods. But what gets short shrift is the fiber content. Now, I can’t speak for other nuts, but almonds and pistachios in particular contain fiber with potent prebiotic effects. People who eat almonds and to an even greater extent pistachios end up with improved gut bacteria profiles.

2) Green Bananas

Ripe bananas are difficult to squeeze into a ketogenic diet. The green banana—an unripe one—is mostly resistant starch, a type of starch that cannot be digested and travels untouched until colonic bacteria metabolize it. It’s one of the best stimulators we know of butyric acid production. And sure, you could do a spoonful of raw potato starch to get your resistant starch, but the beauty of the green banana is that it also provides potassium, another nutrient that some find difficult to obtain and stay keto.

3) Wild Blueberries

Blackberries, boysenberries, raspberries, and strawberries are all loaded with fiber, and you should eat them. They’re lower carb than you think, they’re loaded with polyphenols, and topped with some real whipped cream they make a fantastic dessert. But wild blueberries are special. They’re smaller than other berries, which increases the amount of skin per ounce you get, and skin is where all the polyphenols and fiber lie. Heck, even the blueberry’s polyphenols have prebiotic effects on the gut biome.

4) Mushrooms

A few years ago, I wrote a whole post on mushrooms. Suffice it to say, they’re quite wonderful, bordering on magical. I did not discuss the fiber they contain. It turns out that all the various mushroom polysaccharides/fibers, including beta-glucans, mannans, chitin, xylans, and galactans also act as potent prebiotics that improve the health of the host.

5) Avocado

Your standard avocado has about 12-15 grams of fiber, if you eat the whole thing. I

6) Jicama

Great with chili powder, salt, and lime juice, jicama is about 11 grams of carbs per cup, but half of those are inulin, a potent prebiotic fiber with a tendency to really ramp up butyrate production.

7) Onions

Onions are another fantastic source of inulin. They go into almost every dish of every cuisine, so there’s no excuse not to be eating onions.

8) Garlic

I’ve been known to treat garlic like a vegetable, roasting an entire cast iron pan full until brown and sweet and chewy. They’re another great source of prebiotic fiber.

9) Leeks

Leeks have more inulin than onions. Try them crispy in egg scrambles.

10) Broccoli

Broccolini is a major part of my favorite meal of the day—my Big-Ass Keto Salad. Broccoli (and cruciferous vegetables in general) has been shown to have modulatory effects on the gut biome.

11) Sauerkraut

Kraut gives you two in one. It’s a fermented food, which is great for the gut biome. And it’s cabbage, which is very fibrous. Even pasteurized kraut improves gut health.

12) Dark Chocolate

Dark chocolate, the good stuff with a high cacao content (85%+) and low sugar content, is an incredible source of prebiotic fiber. Eat more of it.

13) Animal Fiber

Obligate carnivores like cheetahs who don’t eat any plants (willingly) still have gut bacteria. These gut bacteria thrive on “animal fiber,” the gristle and cartilage and other bits of connective tissue that comprise a good 20-30% of the walking weight of a prey animal. Humans are not obligate carnivores, but eating the entire animal has been a mainstay of advanced hominid existence for millions of years. I find it very likely that something, someone, somewhere inside our guts is breaking down the animal fiber we eat—so you’d better be eating some!

Not so tough, is it? It’s not like I’m suggesting you load up on bran muffins, psyllium smoothies. I don’t want you dumping flax meal into everything or munching on those awful fiber gummies. Just eat some basic, healthy, low-carb plant matter—foods that don’t really scream “fiber”—and the rest will take care of itself.

What’s your favorite low-carb source of fiber? Let me know down below.

Thanks for reading, everyone.

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References: 

Hernández E, Bargiela R, Diez MS, et al. Functional consequences of microbial shifts in the human gastrointestinal tract linked to antibiotic treatment and obesity. Gut Microbes. 2013;4(4):306-15.

Ukhanova M, Wang X, Baer DJ, Novotny JA, Fredborg M, Mai V. Effects of almond and pistachio consumption on gut microbiota composition in a randomised cross-over human feeding study. Br J Nutr. 2014;111(12):2146-52.

Jiao X, Wang Y, Lin Y, et al. Blueberry polyphenols extract as a potential prebiotic with anti-obesity effects on C57BL/6 J mice by modulating the gut microbiota. J Nutr Biochem. 2019;64:88-100.

Jayachandran M, Xiao J, Xu B. A Critical Review on Health Promoting Benefits of Edible Mushrooms through Gut Microbiota. Int J Mol Sci. 2017;18(9)

Nielsen ES, Garnås E, Jensen KJ, et al. Lacto-fermented sauerkraut improves symptoms in IBS patients independent of product pasteurisation – a pilot study. Food Funct. 2018;9(10):5323-5335.

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CBD Hemp Oil: How Should You Take It?

The burgeoning CBD hemp oil scene has made finding a product easier than ever, but it’s also made choosing a product harder. If you recall my post from years ago on decision fatigue, you’ll know what I’m talking about: the paralysis of too many choices…. I know my readership, and I know you’re the type of people who will wonder about optimizing their CBD ingestion. This stuff isn’t cheap, and it’s perfectly rational to want to get your money’s worth.

While the compound itself—cannabidiol, or CBD—doesn’t change from product to product, the way it’s administered does.

(Just a reminder that we’re talking here about CBD oil or “hemp extract,” a legal form of cannabis with extremely low levels of psychoactive THC: there’s no “high” with CBD hemp oil, but CBD hemp oil does contain cannabidiol, a component with big physiological impacts for health. Read more on those impacts here.)

Let’s look at the forms of available CBD oil….

There are oral CBD oil supplements—gummies, capsules, infused teas, chocolates. Things you eat and drink and digest.

There are sublingual CBD oil supplements—sprays, tinctures, lozenges. Things you swish and swirl around your mouth.

There are topical CBD—creams, lotions, and balms.

There are patches—things you rub and attach to your skin.

There is high-CBD cannabis and CBD-only vape juice. Things you can vaporize and inhale.

But how do you choose? What are the differences between the various routes of administration?

What To Consider When Choosing A CBD Product

Speed of absorption. How quickly do you want the CBD to take effect?

Intensity. How powerful do you want your CBD “experience” to be?

Duration. How long do you want it to last?

Effects. Where do you want it to take effect?

CBD Product Choices: The Rundown

Oral

Oral CBD is the most common method of administration. It’s simple, easy, and intuitive. Everyone swallows pills, eats food, and drinks fluids. There’s almost no way to mess it up (choking aside).

Oral CBD is readily absorbed. Like most everything else that travels through the digestive system, it goes to the liver to be metabolized and converted into different metabolites. The liver is so central to oral CBD that people with poor liver function actually end up with higher serum CBD after taking it orally, since their livers aren’t as good at metabolizing it into different compounds. This liver route also means it takes longer for oral CBD to take effect, but it lasts longer.

Taking an acute oral dose every once in awhile is less effective than consistent dosing because of the liver’s tendency to regulate its bioavailability. When you take it on a regular basis, CBD—being fat soluble like other cannabinoids—gathers in your adipose tissue where your endocannabinoid system can theoretically utilize it on an ongoing basis.

  • Speed: Slow
  • Intensity: Low to moderate (depending on dosage)
  • Duration: Long
  • Effects: Systemic

Sublingual

Sublingual CBD goes under the tongue for absorption via the mucosal membranes in the mouth, which are highly permeable. From there, it bypasses the portal vein—the passage that leads from the digestive tract to the liver—and heads straight for the blood. And then whatever’s left over and not absorbed sublingually gets swallowed and makes it into the digestive tract, so nothing’s wasted.

You have several sublingual options….

Tinctures: Little dropper bottles.

Sprays: AKA oromucosal spray; think CBD-infused Binaca (anyone remember Binaca?).

Lozenges: CBD lozenges that slowly dissolve in your mouth and enter through the mucosa.

The longer you let the CBD sit in your mouth, the more you’ll absorb. 60-90 seconds appears to be the most commonly recommended period of time.

  • Speed: Fast
  • Intensity: Low to high (depending on dosage)
  • Duration: Moderate
  • Effects: Systemic

Inhaled

The original way to get CBD, inhaling CBD, is the fastest-acting and the most intense (with intensity meaning “effectiveness,” not “this will get you messed up, man,” since CBD is not psychoactive). The vapor or smoke enters the lungs, whose alveoli act as a direct conduit to the bloodstream. Inhalation is also the most legally precarious (depending on where you live) because many inhalation CBD products also contain THC, which remains illegal in most places.

You can smoke cannabis bred to be very high in CBD and low in THC, but there will always be some THC present. You couldn’t exactly call this non-psychoactive (or legal in most places) either due to the THC.

There’s also CBD-only vape juice/E-liquid that you can vaporize and inhale.

It’s certainly effective, though if you’re going for efficiency it’s not “optimal.” Your lungs can’t absorb all the CBD in the smoke or vapor; a significant portion is exhaled and lost to the atmosphere. Plus, there’s the whole fact that filling your lungs with smoke is a major stressor. Vapor might be safer, but I’m skeptical.

  • Speed: Fast
  • Intensity: Low to high (depending on dosage)
  • Duration: Shorter
  • Effects: Systemic

Topical

Like other cannabinoids, the CBD molecule is highly hydrophobic and thus cannot pass through the aqueous layer of the skin to reach general circulation. However, if you lather enough of it on to an isolated patch of injured rat skin, it can interact with peripheral cannabinoid receptors that reduce pain and inflammation at a local level. This hasn’t been confirmed in live humans, but anecdotal reports are positive.

  • Speed: Fast
  • Intensity: Unknown
  • Duration: Unknown
  • Effects: Local

Which One Should You Choose?

I don’t have a dog in this fight. I don’t use CBD myself (though I’m not opposed to it and am open to incorporating it in the future if it proves to be uniquely helpful). As a result, I don’t have any strong personally motivated opinion about specific products. What I can give is my objective take on the available evidence, which is fairly light and preliminary:

The best-studied CBD administration methods are oral and sublingual. The majority of human studies have utilized those two routes. There are quite a few positive studies on smoked or inhaled CBD, too, but those often include THC and fail to isolate CBD. If you’re only interested in CBD and not in THC (or it’s illegal where you live), those studies probably don’t apply to you.

In the large set of case studies that found CBD helped patients improve their sleep, the subjects took CBD capsules.

In a study on CBD and pain, the subjects used an oromucosal spray.

In epilepsy patients, oral CBD capsules were incredibly effective.

For general use, whether it’s for anxiety, inflammation, pain, or “general wellness,” oral and/or sublingual use seems to be the real ticket. You know how much you’re consuming. You get a long lasting, fairly fast-acting duration of action. You get the quick absorption into the bloodstream of inhaled CBD without losing any due to exhalation. And if you don’t absorb it all through your oral mucous membranes, you’ll simply swallow and digest the rest. Nothing is lost.

What about you, folks? I know there are some experienced CBD users out there reading this. What’s your favorite method of administration, and why?

Take care everyone.

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References:

Taylor L, Crockett J, Tayo B, Morrison G. A Phase 1, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics and Safety of Cannabidiol (CBD) in Subjects With Mild to Severe Hepatic Impairment. J Clin Pharmacol. 2019;

Lattanzi S, Brigo F, Trinka E, et al. Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis. Drugs. 2018;78(17):1791-1804.

Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain. 1998;75(1):111-9.

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