Marijuana

Marijuana is a very complex plant: many different strains with differing profiles of psychoactive, non-psychoactive, and peripherally-active compounds that impact metabolism.  Most have THC, which activates endogenous cannabinoid receptors and mimics many of the effects of smoked marijuana (eg, see studies by Hart, Wachtel, and Curran).

Do not underestimate the complexity of this plant.

 

"LOL"

“LOL”

 

I’m not ‘anti-pot’ as there are far worse drugs out there… however, some advocates make really bad “pro” arguments, like saying it’s actually healthy (or at least not harmful in any way)…
there are many independent lines of evidence which suggest otherwise, metabolically speaking.

 

MJ not crack

 

Rimonabant, the notorious pot-blocker, reduces appetite and is a fairly effective weight loss drug, but has the unfortunate side effect of doing the opposite of marijuana, psychologically speaking.  See any of the RIO studies, eg:

 

weight loss Rimonabant

 

All participants lost weight and experienced improved metabolic profiles, insulin sensitivity, etc., by blocking endogenous cannabinoid receptors.

Adverse effects?  Wellll, there’s a drug called Marinol (pure THC) that’s technically an anti-emetic (reduces the urge to vomit); it improves appetite in patients with conditions associated with anorexia or wasting.  It’s a cannabinoid agonist.  Blocking CB1 with Rimonabant induces nausea in some patients: no bueno, but not unexpected given the known effects of Marinol.  Rimonabant is also associated with depression and anxiety (in some patients); also not unexpected.

So, it’s not a good idea to block this receptor pharmacologically (for psychological reasons) or activate it recreationally (for metabolic reasons).  Obesity researchers (and big pharma no doubt) are still looking for a pot-blocker that doesn’t penetrate the brain  to avoid the negative psychological side effects (eg, Klumpers et al., 2013).

 

 

Best. Graph. Ever.  The effect of Rimonabant on how stoned participants felt after smoking pot.  Yes, “Stoned” was published in the Journal of the American Medical Association (Huestis et al., 2001).

 

Stoned

 

Indeed, Rimonabant effectively treats “cannabis intoxication” (Crippa et al., 2012).  Antagonist versus agonist 101.

 

Part II: the biological effects of cannabis, THC, marijuana, and antagonists, etc.

 

THC acts like insulin on adipocytes: increased adipogenesis, fatty acid uptake, and decreased lipolysis (eg, see studies by Teixeira and Cota).   Munchies, anyone?

Cannabinoids and mimetics/agonists induce hunger and repress satiety; cannabinoid blockers induce satiety and weight loss.  However, I actually don’t think marijuana is obesogenic aside from its anti-anorexic effects.  Cannabis use is not always associated with obesity, possibly due to confounding and/or the lack of good crossover studies (you can’t really do a proper study in healthy humans with MJ for ethical reasons).  But most rodent studies agree that cannabinoids, acting via cannabinoid receptors, induce metabolic syndrome-like effects in nearly every single tissue and on the whole-body level.

 

 

CB1 cannabinoid receptor deletion in mice leads to leanness, resistance to diet-induced obesity, and enhanced leptin sensitivity (Trillou et al., 2003).  For context, mice lacking CB1 is somewhat analogous to humans not smoking marijuana.

In liver, cannabinoid signaling induces fat accumulation and insulin resistance (Osei-Hyiaman et al., 2008).  This is absent in CB1 and liver-specific CB1 knockout models.   Mice overexpressing this receptor in liver exhibit increased insulin resistance (Liu et al., 2012).

Activating cannabinoid receptor-2 (CB2) causes insulin resistance and adipose tissue inflammation, and this is blunted in mice lacking CB2 (Deveaux et al., 2009).

 

Stoned

 

The knockouts & over-expressing rodent models, and pharmacological agonist & antagonist studies are all consistent.  That said, I still don’t think this is the worst recreational drug out there, even among “legal” ones.

 

calories proper

 

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Sunlight and the circadian rhythms in your skin

SUNLIGHT entrains circadian rhythms.  It gives us vitamin D and melanin; it can give us a sunburn, but some evidence suggests that it does NOT cause skin cancer.

“lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma” (Kennedy et al., 2003)

Anecdotally (or so I’ve heard), skin cancer frequently develops in places not regularly exposed to sunlight.  If true, this flies in the face of the dogma which goes something like this (Tl;dr): ultraviolet light from the sun penetrates into the nuclei of skin cells and damages DNA; if the right [wrong] genes are altered/mutated and the mutated cells proliferate, it can develop into a tumor (gross oversimplification).

So, what might explain the discord?

LIGHT entrains the circadian clock; this includes regulating cell cycle genes.  Aberrant cell cycling may lead to out-of-control proliferation in the wrong context, aka cancer.  Interestingly, some evidence suggests that part of the circadian regulation of cell cycle genes includes turning down proliferation when exposure to UV light is expected to be high (daytime); so DNA repair machinery has more time to fix any cell cycle genes that are mutated by UV light before the cell proliferates (Geyfman and Andersen, 2009) = lower chance of creating and propagating a potentially cancerous skin cell.

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Saturated fat, cholesterol, and carbohydrates

“You catch more flies with honey…”

^^^good policy in general, but especially for debating in the realm of nutritional sciences.

 

A short while back, Nina Teicholz discussed low carb ketogenic diets and plant-based diets with John Mackey.  Although I disagree with the dichotomy (keto vs. plant-based), it’s well-worth a watch:

 

 

Three topics that could not be avoided in such a discussion: saturated fat, cholesterol, and carbohydrates.

 

 

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Artificial light regulates fat mass: no bueno.

“despite not eating more or moving less”

We’ve seen this time and time again: LIGHT IS A DRUG.

 

above quote is extrapolated from this rodent study: “Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity.”

 

Artificial light impacts nearly every biological system, and it doesn’t even take very much to have an appreciable effect (think: checking your smart phone or watching a television show on your iPad in bed at night).  In this study, adding 4 hours to the usual 12 hours of light slammed the autonomic nervous system, disrupting sympathetic input into brown adipose leading to a significant increase in body fat  “despite not eating more or moving less.”

 

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Meal frequency, intermittent fasting, and dietary protein

Dietary protein “requirements” are some of the most context-dependent nutrient levels to decipher, and depend largely on energy balance and even meal frequency.

An objective look at intermittent fasting (Alan Aragon, 2007)

Meal frequency and energy balance (Lyle McDonald, 2008)

New study: “Increased meal frequency attenuates fat-free mass losses and some markers of health status with a portion-controlled weight loss diet” (Alencar et al., 2015)

This wasn’t well-received in social media because bro-science & many low carb advocates say grazing is no longer in vogue — “it’s much better/healthier/whatever to eat once or twice daily, because intermittent fasting and all that jazz” …however, this may be problematic when it comes to meeting overall protein needs, which is particularly important when you’re losing weight.

 

 

The study: 2 vs. 6 meals per day, crossover.  

Conclusion: “On average, fat-free mass (FFM) decreased by -3.3% following the 2 meals/d condition and, on average, and increased by 1.2% following the 6 meals/d condition (P<.05).”  

 

fat-free mass

 

In other words, 6 meals per day was better for body composition than 2 meals per day.  But context is everything, and this hypothesis has been tested from a variety of different angles, so what does it mean?  

The relevant context here: 1) big energy deficit (1200 kcal/d for obese women is a pretty low calorie intake); and 2) “adequateTM” protein intake (75 g/d).

The standard dogma says that in the context of an adequate protein hypocaloric diet, meal frequency matters a LOT, whereas with high protein, it doesn’t matter as much.  Theory being that with an “adequate” (read: too low?) overall protein intake, the fasting periods are simply too long with only two meals per day; you need either: 1) higher protein intake; 2) increased meal frequency; or 3) more calories (ie, smaller energy deficit).  

In this study, BOTH diets suppressed insulin and induced weight loss, but the increased protein feeding frequency skewed the weight loss to body fat while preserving fat-free mass.   I actually agree with a lot of the bro-science in this case, and also think that 75 grams of protein is not enough in the context of a big energy deficit (if body composition is a goal).    




 

Historical precedence?

 

Meal frequency and weight reduction of young women (Finkelstein et al., 1971)

Relevant context:  6 vs. 3 meals per day (3 meals per day may not seem like that many more than 2, but it significantly cuts down on the duration of time spent with no food or protein).

Smaller energy deficit: 1700 kcal/d in overweight patients is less of a deficit than 1200 kcal/d in obese patients.

Higher protein intake: 106 – 115g/d.

Result: nitrogen balance (a surrogate for the maintenance of muscle mass) and fat loss were similar in both groups.  This study fixed two problems in the abovementioned study: 1) 3 meals is better than 2 in the context of an energy deficit; and 2) protein intake was higher.

 

And again here, with 3 vs. 6 meals per day (Cameron et al., 2010), just to make the point that 3 meals per day is better than 2 for preserving lean mass in the context of an energy deficit.

 

The effect of meal frequency and protein concentration on the composition of the weight lost by obese subjects (Garrow et al., 1981)

This study tested the opposite extremes: super-low calorie intake (800 kcal/d), much lower protein intakes (20g – 30g/d), and 1 vs. 5 meals per day.

Result: “a diet with a high-protein concentration, fed as frequent small meals, is associated with better preservation of lean tissue than an isoenergetic diet with lower-protein concentration fed as fewer meals.”

It basically confirmed all of the above.

 

Protein feeding pattern does not affect protein retention in young women (Arnal et al., 2000)

1 vs. 4 meals per day; and 70 grams of protein but no energy deficit (~2000 kcal/d isn’t very hypocaloric for lean young women).  In this study, no effect of meal frequency was seen, likely because 70 grams of protein isn’t inadequate when energy intake isn’t restricted.

 

 

 

1. PROTEIN “NEEDS” ARE HIGHLY CONTEXT-DEPENDENT

2. NEED =/= OPTIMIZATION

3. MEAL FREQUENCY & meal timing and peripheral circadian clocks > “MACRONUTRIENTS”

 

If you’re losing weight (ie, in an energy deficit), then intermittent fasting is cool if protein intake is high (above “adequateTM“)… the bigger the energy deficit, the more protein is necessary to optimize changes in body composition.

 

How much is ‘enough?’  Sorry, can’t give you a gram or even gram per pound of body weight answer… but if you’re losing weight and seeing no discernible effect on body composition (muscle vs. fat mass), then it may be prudent to consider eating more protein-rich foods… and paying more attention to sleep quality (which also greatly impacts nutrient partitioning).

No amount of protein will help you if circadian rhythms aren’t intact!!!

 

 

further reading:

Yes, it’s a high protein diet (Tom Naughton, 2015)

Protein requirements, carbs, and nutrient partitioning

Dietary protein, ketosis, and appetite control 

 

 

calories proper

 

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Good calories

Nuts are good calories.

I’m not a big fan of the omega-6 fatty acid linoleate, but that’s largely in the context of processed foods and confectioneries, where it’s more than likely no longer in it’s native form (Dc9,1218:2n6)… but in the context of unprocessed whole foods (eg, nuts), a little n6 is fine imo.

What are good calories?  They’re nutrient-dense and don’t generally lead to overeating… like the opposite of soda and junk food.  Nuts are low carb and many are highly ketogenic (eg, Brazils, macadamias, and pecans are ~90%fat).  Mr. Ramsey may even approve of macadamias because they have virtually zero PUFAs.

BONUS: magnesium, copper, selenium, many trace minerals and micronutrients, etc., etc.

I’m not saying you should crack open a can of Deluxe Mixed Nuts and sit down with nothing to do other than NOM NOM NOM ALL THE NUTZ.  I’m talking about a few nuts with a meal.  Possibly earlier in the day (coinciding with LIGHT); nuts are tryptophan-rich and this may improve melatonin onset -> good for circadian rhythms:

 

nuts and melatonin

 

 

Appetitive, dietary, and health effects of almonds consumed with meals or as snacks: a randomized controlled trial (Tan and Mattes, 2013)

In this study, the participants were instructed to eat a serving of almonds (~43g, ~245 kcal) daily for four weeks, at different times of the day (with breakfast, midmorning snack, lunch, or afternoon snack).

Regardless of when the almonds were consumed, the calories were practically completely compensated for.  The participants unwittingly ate less other stuff.  And in 3 out of 4 of the conditions, the almonds were so satiating that the participants actually ended up eating fewer overall calories.

That, in a nutshell, is what I call “good calories,” and I don’t think it’s too far from Taubes’ original definition… especially because it was accompanied with [modest] reductions in body fat (NS).  To be clear, they were instructed to eat more (in the form of almonds), but ended up eating less, BECAUSE ALMONDS.  This wasn’t a cross-sectional study, so no healthy user bias or other obvious confounders.

Further, the participants clearly weren’t obesity resistant.  They were overweight, obese, or lean with a strong family history of type 2 diabetes.  Sam Feltham would’ve been excluded.

This is not an isolated finding: another study showed a dose-dependent response to almonds: 28g or 42g consumed in the morning resulted in a compensatory reduction of hunger and total energy intake at lunch and dinner (Hull et al., 2014).  This wouldn’t happen with soda or junk food.

 

 

Another study tested ~350 kcal almonds daily for 10 weeks and concluded: “Ten weeks of daily almond consumption did not cause a change in body weight. This was predominantly due to compensation for the energy contained in the almonds through reduced food intake from other sources” (Hollis and Mattes, 2007).

Almonds vs. complex carbs? Almonds, FTW.

1 Brazil nut daily: “After 6 months, improvements in verbal fluency and constructional praxis (two measures of cognitive performance) were significantly greater on the supplemented group when compared with the control group.”    ONE FRIGGIN’ NUT!

 

http://www.dreamstime.com/-image11630100

 

Walnuts protect against alcohol-induced liver damage (in rats) (Bati et al., 2015) and may improve brain health (in humans) (Poulose et al., 2014).

Pistachios improve metabolic and vascular parameters (Kasliwal et al., 2015).

Meta-analysis (not an intervention study): nut consumption is associated with lower risk of all-cause mortality (Grosso et al., 2015). Yeah yeah yeah, I know, correlation =/= causation.  Whatever.

Nuts are good calories.  That’s all I’m saying.

 

Tl;dr: buy these and one of these, not this.

 

 

calories proper

 

 

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Non-celiac gluten sensitivity

Gluten is protein, not carbs.  A gluten-free diet is frequently low-carb, because most dietary gluten comes in the form of bread (and wheaty foods).  But believe it or not, bread is an incredibly complex food… many different proteins, carbohydrates, and nutrients that could be problematic for some people (more on this later).

Gluten is not a FODMAP, but most gluten-containing foods are.  Gluten is actually very rich in the amino acid glutamine.  Gluten, not bread.

So we have three studies on purified “gluten,” asking if it’s the gluten, FODMAPs, or something else in wheaty food that is problematic.

Study #1. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of FODMAPs (Biesiekierski et al., 2013)

Strong study design; patient population was people who thought they were gluten sensitive (but definitely not celiac).

This is the study which led journalists to claim non-celiac gluten sensitivity doesn’t exist, and it’s really sensitivity to FODMAPs, in part, because of this:

 

 

low FODMAPs and gluten free

 

 

Baseline = low gluten diet
Run-in = low gluten and low FODMAPs

 

Here’s the fly in the ointment:

 

symptoms returned in all participants

 

After the run-in period, subjects still followed their gluten-free diets but also received either 16g relatively pure gluten/d (High gluten), 2g gluten + 14g whey protein (Low gluten), or 16g whey protein (placebo).  GI symptoms returned in all participants.  So, low FODMAPs worked for about a week, but then symptoms returned regardless of whether they were eating gluten or not.  In other words, neither low FODMAPs nor low/no gluten worked very well in this study.

But this study may have introduced a brilliant new confounder: food intake was strictly controlled — the experimental diets were different from their normal diets.  Restricting gluten and FODMAPs may have provided some transient benefit, but if the new experimental diet introduced something else that caused problems, then that may explain the gradual return of symptoms…

bollixed?

 

 

Study #2. Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial (Di Sabatino et al., 2015)

It was another high quality study design: “Randomized, Double-Blind, Placebo-Controlled, Cross-Over.”  And it was addressing a basic question: do people who strongly suspect they have non-celiac gluten sensitivity (NCGS) really have NCGS?  Alternatively, is NCGS real?

Intervention was strong:

1) 4.375 grams of gluten or placebo (rice starch) daily for a week.  This is roughly equivalent to two slices of bread (note: this is way more than enough gluten to destroy the intestines of a patient with bona fide celiac disease).

2) important: they defined the what they would classify as NCGS prior to starting the trial.  A priori.

61 patients strongly suspected of NCGS started the trial, and one withdrew due to gluten-related symptoms in both the gluten and placebo groups.

 

Results:  regardless of whether they were assigned to gluten or placebo FIRST (prior to the crossover), most patients reported gluten-related symptoms.  More importantly, 3 of the 59 patients exhibited significantly worse symptoms on gluten relative to placebo according to the endpoint they defined prior starting the trial.  In one sense, this could be interpreted to mean 5% of people who strongly believe they have NCGS actually have NCGS.

 

gluten sensitive patients

 

Two patients reacted just as selectively strongly to the placebo as the three “real” NCGS patients did to gluten.  Rice-starch sensitivity?

 

See here for a more detailed description of the statistics involved in this study.  I’m willing to accept the “5%” rate, despite the strength of the placebo-responders, whereas the author of that blog post is not.  That’s fair, imo.

And here is another article which questions the legitimacy of NCGS based on this study.  I don’t think that’s totally fair.

And Raphael’s post, where he humorously concludes: “[Gluten-free] does not include advice to sport a gas mask when walking past bakeries.”

 

 

Study #3. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity (Hollon et al., 2015)

 

 

gluten increases intestinal permeability

 

 

“Delta TEER” is basically the amount of intestinal permeability in intestinal explants exposed to media + gluten (experimental condition) minus those exposed to plain media (control condition).  A better control condition, imo, would’ve been something like they did above: substitute gluten with another protein like whey protein.

 

NC: healthy people
RCD: celiac patients in remission
ACD: celiac patients with active disease
GS: non-celiac gluten sensitivity

 

Active celiac samples responded significantly worse than those in remission, which is good as it functions as a positive control for the experimental protocol.

 

However, gluten sensitive samples responded significantly worse than celiac remission samples; actually, they responded just as badly as celiac samples with active disease.  Celiac disease is supposed to be a million times worse than non-celiac gluten sensitivity… and statistically speaking, even permeability the normal samples declined as much as NCGS samples.

 

This led some to conclude that gluten is bad for EVERYONE.  I’d say it means the assay is bollixed.  Occam’s razor?

 

 

My advice: don’t be anti-science, but don’t use bad science to justify diet choices.  We simply need better studies on non-celiac gluten sensitivity and FODMAPs.

If bread doesn’t work for you, don’t eat bread.  You’re not missing much.

 

calories proper

 

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Carbs: Low vs. Lower

 

 

This was met with much backlash from the low carb cavalry, because, well, if low is good then lower must be better

I’m not anti-keto; but I’m not anti-science.  FACT.  

 

“…some people are not genetically equipped to thrive in prolonged nutritional ketosis.” –Peter Attia

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LIGHT, Leptin, and Environmental Mismatch

For a long time, the melanocortin system was basically thought to control the color of skin and hair.  It still does, and many redheads are redheaded due to polymorphisms in one of the melanocortin receptors.

Fast forward to 2015: to make a long story short, melanocortins are HUGE players in circadian biology.

 

POMC ACTH a-MSH

 

Brief background (also see figure above):

Fed state -> high leptin -> a-MSH -> MC4R (the receptor for a-MSH) = satiety, energy production, fertility, etc.

Fasted state -> low leptin -> AgRP blocks MC4R = hunger, energy conservation, etc.

MC4R polymorphisms in humans are associated with obesity.  Melanotan II causes skin darkening (marketed as “photoprotection” [no bueno, imo]), enhanced libido, and appetite suppression.

 

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Dark Skies and Light Pollution

The mission of the International Dark-Sky Association is “to preserve and protect the night time environment and our heritage of dark skies through quality outdoor lighting.”  They’re all about stressing the importance of lighting on health, light pollution, and some really interesting stuff.

For more on the topic, check out their website, darksky.org, and Paul Bogard’s book, The End of Night: Searching for Natural Darkness in an Age of Artificial Light.

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