Search This Blog

Friday, 30 July 2021

Virta Health vs Seidelmann - of ketones and COVID-19

You would have seen this paper; senior author is Sara Seidelmann of the infamous "low carb kills" paper, the reviewers were one vegan propagandist David Jenkins (a friend of the family, so to speak) and an Iranian prof with a decent publications list in the plant-based area - neither with any infectious diseases expertise.

There were 568 COVID-19 cases and 2316 controls. Among the 568 cases, 138 individuals had moderate-to-severe COVID-19 severity whereas 430 individuals had very mild to mild COVID-19 severity. After adjusting for important confounders, participants who reported following ‘plant-based diets’ and ‘plant-based diets or pescatarian diets’ had 73% (OR 0.27, 95% CI 0.10 to 0.81) and 59% (OR 0.41, 95% CI 0.17 to 0.99) lower odds of moderate-to-severe COVID-19 severity, respectively, compared with participants who did not follow these diets. Compared with participants who reported following ‘plant-based diets’, those who reported following ‘low carbohydrate, high protein diets’ had greater odds of moderate-to-severe COVID-19 (OR 3.86, 95% CI 1.13 to 13.24). No association was observed between self-reported diets and COVID-19 infection or duration.

you'll find good criticisms in the rapid responses attached, and my PubPeer comment here.

 The methods state 
Lastly, we combined ‘low carbohydrate’ diets and ‘high protein’ diets into another category (‘low carbohydrate, high protein diet’, n=483) to evaluate whether these dietary patterns are associated with COVID-19 severity.

Why? No reason is given for combining these 2 categories. 

There was a keto option, so why didn't they add keto + low carb?

Methods state
Before analyses, we selected dietary patterns with sufficient ‘yes’ responses (‘yes’ response of at least 100 individuals). To increase precision, we analysed three dietary patterns after combining dietary patterns that are similar in terms of dietary intake.

Perhaps keto had less that 100 responses? But there was no registered protocol, those decisions were post-hoc - even if keto had fewer than 100 responses, adding it would have still increased numerical power, which was presumably the point of combining categories as they did. And there's nowhere it says how many responses, and we also have no way of knowing how similar low carb and high protein really were (everything was pretty similar really, these were for most respondents just the virtue-signaling labels they gave to their eating habits).

Anyway, there was no association once people with a negative or no PCR test were excluded.
That's not in the abstract.

But, you know, people are using the keto and LCHF diets to treat diabetes and reduce COVID19 mortality associated with type 2 diabetes, MetSyn, or obesity, so this is a nasty thing to say if it's not true. It's a bit like trying to get people to stop taking vaccines based on your bias and some shit you didn't understand.

Fortunately Vitra Health have ridden to the rescue with a survey of their own T2D population on a ketogenic diet. We know these people are actually following the diet, or adhering closely to it.

The abstract (presented at an ADA conference) is 
COVID-19 Severity in a Geographically Diverse, U.S.-based, Ambulatory Population with Type 2 Diabetes on a Medically Supervised Ketogenic Diet

Data were obtained from medical records and from surveys sent to T2D patients who self-reported COVID-19 diagnosis; 47.8% (294/614) responses and one known COVID-related death yielded a sample of 295 (50% male, 54±9 years, across 41 US states). We observed low reported rates of hospitalization (10.9%), ventilation (2.0%), and death (0.3%) relative to national reports.
Let's compare with the Seidelmann paper - 1) we know the diet is real. 2) COVID-19 is self-reported (some will have tests some not, as in Seidelmann) but - we do have people being hospitalised, unlike Seidelmann, and we even have one death, so Virta are able to capture events that people weren't able to report directly, because their model includes liaison with primary providers likely to report deaths to them. 3) the event rates are low for a population with type 2 diabetes, as shown by the comparison with this population. The populations, though much the same age, aren't identical, but the biggest difference seems to long term inclusion in the Virta Health population (note the "baseline" HbA1c data in Virta - before treatment with the ketogenic diet - is similar to the overall HbAic data in the comparator vs standard practice, but many of the Virta Health population have put their T2D in remission. At this stage, we have to say that the EFFECTS of the keto program are protective - weightloss and euglycaemia, etc. We don't have evidence that keto per se is protective apart from those factors. But that may well be hidden in the data, once the whole set is fully written up. But once again, it looks like Harvard is a bad actor, an ill informant in the nutrition-and-health space, interfering with effective treatments to preserve its own ill-gotten (by a process of bloviation if not graft) dietary hegemony.

Wednesday, 7 July 2021

The Carb-Fat Food Quality Gradient - a real metabolic advantage

This post was originally published as a subscriber-only post on Patreon. You don't have encourage the speculations of the likes of me, but if you want to try, please subscribe!

By now, we've all seen them - studies that purport to show equivalent effects of LCHF and HCLF diets once diet quality is addressed and people are Eating Whole Unprocessed Foods.
The latter is a good thing, the default to go for in terms of population health; macronutrient tweaking is next-level.
But here's a question - why were almost all the original studies that validated the efficacy of LCHF diets to a skeptical medical world comparisons of ad lib low carb vs energy-restricted low fat?
To make a really low carb high fat diet (unless you want to pretend a high-protein diet is that) you're going to be using some isolated fats (cream) or refined ones (coconut oil, olive oil). There may not be sugar in your chocolate bar, but there will be cocoa butter.
This only works if in some way those isolated fats are NOT equivalent to sugar and flour.
What is the evidence for a difference?

One of the more lasting concepts in carb nutrition is the glycemic index, the average speed at which a food appears as glucose in the system. It's not perfect because sugar is only half glucose so is lower GI, but you get the idea.
High GI is worse for you.

The PURE study is good for producing null results, which makes whatever it does throw up seem a bit more reliable than most nutritional epidemiology.[1]

"In the study population, 8780 deaths and 8252 major cardiovascular events occurred during the follow-up period. After performing extensive adjustments comparing the lowest and highest glycemic-index quintiles, we found that a diet with a high glycemic index was associated with an increased risk of a major cardiovascular event or death, both among participants with preexisting cardiovascular disease (hazard ratio, 1.51; 95% confidence interval [CI], 1.25 to 1.82) and among those without such disease (hazard ratio, 1.21; 95% CI, 1.11 to 1.34). Among the components of the primary outcome, a high glycemic index was also associated with an increased risk of death from cardiovascular causes. The results with respect to glycemic load were similar to the findings regarding the glycemic index among the participants with cardiovascular disease at baseline, but the association was not significant among those without preexisting cardiovascular disease."

As I've said before, everything in plants that is supposed to be good for you but isn't actually a real nutrient is probably lowering GI in some way. It's the glucose (glycemic load above) but the way it arrives in your bloodstream (GI) is more pointed.

Is there equivalency for fats? Do fats that are rapidly absorbed correlate with disease?
That would be the medium chain fatty acids, MCFA.

"In comparison to triglycerides containing LCFAs, those containing MCFAs are more rapidly hydrolyzed in the intestinal tract and do not become incorporated into chylomicrons. SCFAs and MCFAs are transported by portal bloodstream to the liver, where they are readily metabolized."[2]

And perhaps also the unsaturated fatty acids, UFA.

"Although pancreatic lipase hydrolyzes fat only in the 1 and 3 positions of the molecule, it is nevertheless possible for fatty acids in the 2 position of the triacylglycerol to be hydrolyzed. This apparent violation of the specificity of pancreatic lipase occurs because of the relative instability of both the 2-monoacylglycerol and the 1,2-diacylglycerol (Crossley et al., 1959). These molecules rearrange by migration of the fatty acid in the 2 position to the 1 or 3 position, which is readily hydrolyzed by lipase (Figure 18–3). This rearrangement is more rapid when the fatty acid is either a short-chain one or an unsaturated one, and a portion of the 2-position fatty acids may be absorbed as fatty acids rather than as monoacylglycerols (Benzonana et al., 1964)."[3]

We'll call this the fat index, FI.
Are fatty acids with a high FI worse than low-FI fats?
In epidemiological studies of individual fatty acids and their associations with disease risk, the MCFAs, which are SFAs, are always more benign than the longer-chain SFAs (see table 2).[4]

"Two recent studies from the Netherlands reported largely diverging findings. In the European Prospective Investigation into Cancer and Nutrition study, intakes of 4:0-10:0 and 12:0 were inversely associated with ischemic heart disease risk, but no associations were found for 14:0, 16:0, and 18:0. However, in the Rotterdam study, only 16:0 intake was associated with higher risk of coronary heart disease." [see also table 2]

In an overfeeding experiment, the benefits of MCFA were obvious.[5]

"In conclusion, substitution of a small amount of dietary LCFAs with MCFAs rescues insulin action in conditions of lipid-induced energy excess."

This is because high-FI fatty acids are metabolized more rapidly, and, in the case of MCFAs, oxidized with less metabolic and hormonal effort than LCFA.[2,6]

In conclusion - if you eat carbs in bulk you will need to pay some attention to the speed at which your body absorbs them; this rules out eating purified carbohydrates.

If you eat fats in bulk, you need pay little attention to the speed your body absorbs them; you may want more fast-absorbing fatty acids in your food, but this does not rule out eating purified fats.

[1] Jenkins DJA, Dehghan M, Mente A, Bangdiwala SI, Rangarajan S, Srichaikul K, Mohan V, Avezum A, Díaz R, Rosengren A, Lanas F, Lopez-Jaramillo P, Li W, Oguz A, Khatib R, Poirier P, Mohammadifard N, Pepe A, Alhabib KF, Chifamba J, Yusufali AH, Iqbal R, Yeates K, Yusoff K, Ismail N, Teo K, Swaminathan S, Liu X, Zatońska K, Yusuf R, Yusuf S; PURE Study Investigators. Glycemic Index, Glycemic Load, and Cardiovascular Disease and Mortality. N Engl J Med. 2021 Apr 8;384(14):1312-1322. doi: 10.1056/NEJMoa2007123. Epub 2021 Feb 24. PMID: 33626252.

[2] Schönfeld P, Wojtczak L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res. 2016;57(6):943-954. doi:10.1194/jlr.R067629

[3] Institute of Medicine (US) Committee on Military Nutrition Research; Marriott BM, editor. Food Components to Enhance Performance: An Evaluation of Potential Performance-Enhancing Food Components for Operational Rations. Washington (DC): National Academies Press (US); 1994. 18, Structured Lipids: An Overview and Comments on Performance Enhancement Potential. Available from:

[4] Zong G, Li Y, Wanders A J, Alssema M, Zock P L, Willett W C et al. Intake of individual saturated fatty acids and risk of coronary heart disease in US men and women: two prospective longitudinal cohort studies BMJ 2016; 355 :i5796 doi:10.1136/bmj.i5796

[5] Anne-Marie Lundsgaard, Andreas M. Fritzen, Kim A. Sjøberg, Maximilian Kleinert, Erik A. Richter, Bente Kiens. Small Amounts of Dietary Medium-Chain Fatty Acids Protect Against Insulin Resistance During Caloric Excess in Humans.
Diabetes Jan 2021, 70 (1) 91-98; DOI: 10.2337/db20-0582

[6] James P DeLany, Marlene M Windhauser, Catherine M Champagne, George A Bray, Differential oxidation of individual dietary fatty acids in humans, The American Journal of Clinical Nutrition, Volume 72, Issue 4, October 2000, Pages 905–911,

Sunday, 27 June 2021

Probiotic extracts for PTSD - proof of concept for the gut-brain axis?

It is with great pleasure that I can announce results from an experiment I was actually involved with, albeit long ago.

It happened like this - having noticed that probiotics were helping with my HCV symptoms, I was theorising about the reasons for this in a Hep C forum with nurse Silvia H, who supplied a lot of my early background on immunity; this attracted the notice of Elizabeth McKenna, who was working with Beth Jones, the senior author of the present paper. Dr Jones had invented a process for producing a cell wall lysate from bacteria that, or so it was claimed, preserved the probiotic immune function to a far greater extent than other lysates and heat-killed probiotic products then available.

I knew a bit about these products because a friend with HCV swore by a product called Del Immune V, which had corrected what seemed to be autoimmune symptoms. I tried this product but to be honest was already so saturated with effective herbs and other supps that I couldn't honestly say what it did, though it did appear to be something. But by looking on the interwebs, as they then were, I could deduce a bit about such things. 

My theory was, still is, that commensal bacteria - as well as herbs like astragalus and some mushroom sp. produce polysaccharides and other PAMP signaling molecules that mimic LPS in a benign way. An agonist-antagonist relationship with PAMP receptors could explain this modified version of the effect (this is why it can be useful having a druggie on the board, pharma execs). This summary minimizes the amount of reading I did on complement and alternative complement pathways, Tregs and Th17, retinoid metabolism and immune cell differentiation, dendrite cell translocation of LPS, and other things that mercifully I only faintly remember now. Anyway, it looked as if the toll-like receptors, a major PAMP recognition pathway, were important.

Elizabeth McKenna, by now the CEO of Labyrinth holdings overseeing the patent process for Dr Jones, had the realization that TLR activity was assayable - the tests were done and, as in the current paper, there was significant activity at several PAMP receptors.

Soon after I received some test samples of the product, now called ReseT. From Reset T cells - a good concept but as it turned out a very poor name when it came to finding the product in search engines!

Anyway, at the time I still had HCV, and that was one possible use for ReseT, so I thought I should try it. Even though at the time my symptoms were under control and I had no idea if I would notice, because that's how I roll, someone has to try things and I was already implicated, as it were.

We know know that the dose I took was about twice what's optimal. It's a sublingual lactose-based pill, or was, and the effect was rapid. The pattern on the carpet in front of me softened, life softened, and I felt something very similar to the effect of valium or some other GABA agonist. Well that's quite impressive I thought, but it left me fully functional and I was on my way to a Neil Young concert.
While on the way I smoked a couple of strong joints.
Then there I was, trapped indoors with thousands of strangers in a swirling mob. 
This sort of thing is of course a recipe for social anxiety, and it's normal to negotiate this effect, which can get quite harsh, if you're a stoner who wants to be really stoned for, you know, NEIL.

But this time things were completely different - I was immune to anxiety. And I remained immune to anxiety from this cause for a long time after I stopped taking ReseT, which I didn't take regularly for long, and it's never really been all that strong ever again.

Now, the experiential effects I've described haven't been described by anyone else - that is, no-one else who's benefitted from ReseT since seems to have observed the point at which it happened in the way I did. That's Okay, I'm used to being highly observant of such things, even though it gets me laughed at sometimes. I only noticed the strong GABA effects on the first two or three occasions I took ReseT, fading as I became less prone to anxiety.

Anyway I drifted away from the probiotic problem as other work came along, and though Elizabeth McKenna kept in touch I did think the proposed mechanism, that the effect can be explained by the manipulation of oxidative stress, was putting too much onus on the immune system. and too much responsibility on bacteria.

But obviously I didn't have all the facts that the people on the ground did, and as it happens there's nothing better than a highly simplistic hypothesis - IF the evidence supports it.
If the evidence supports a simple explanation, there is no immediate requirement for terms like complex and multifactorial. To paraphrase William of Occam.

In the first of two papers, A pilot study: Innate immune modulation reduces F2-Isoprostanes and improves psychological health in a chronically stressed cohort

Seven male participants (combat veterans aged between 28 and 47 years) with PTSD completed the 70-day study.

The study design was a single-arm treatment study, wherein the effects of treatment were assessed and compared to the baseline pretreatment values (Day 1). Once the baseline samples were collected, the study participants were requested to take two 12 mg tablets, sublingually, twice daily (48 mg daily dose) for the duration of the study, and maintain their normal daily routine. Treatment sample collection and the measurements were performed on Days 15 and 70.

The graphs demonstrate after 14 days of treatment, most of the participants experienced improved psychological health that were consistent with reduced urinary levels of F2-IsoP (Figure 1A). In case of depression profiles, there was significant improvement observed by Day 15 (Figure 1D). However, with further treatment, the participants continued to exhibit improvement, with significant improvement in the metrics of life satisfaction (Figure 1B) and daytime sleepiness (Figure 1C) by Day 70. The correlation coefficients between the F2-IsoP and mental health parameter values were −0.99, 0.99, 0.95, and 0.96 for life satisfaction, sleepiness, depression, and anxiety, respectively.

To be sure, the study wasn't controlled. But a placebo effect shouldn't lower F2-IsoP that much, and I think it very unlikely that placebo effects can be maintained this consistently for 55 days, especially given the very minimal interaction between participants and clinicians during the study. But note that the antianxiety effect I noticed is probably only being experienced by one or two participants.

Anyway, placebos shouldn't affect drosophila, and there's also a fruit fly study that corroborates that ReseT is bioactive (via NF-κβ).

Treatment with Bacterial Biologics Promotes Healthy Aging and Traumatic Brain Injury Responses in Adult Drosophila, Modeling the Gut–Brain Axis and Inflammation Responses

Here we get to compare ReseT with a well-tested live bacteria that is closely related to its source, LGG.

Here, we examine the response of adult Drosophila given an inactive bacteriologic (IAB; proprietary lysate preparation of Lactobacillus bulgaricus, ReseT®) and a probiotic (Lactobacillus rhamnosus, LGG). In vitro, the IAB activates a subset of conserved Toll-like receptor (TLR) and nucleotide-binding, oligomerization domain-containing protein (NOD) receptors in human cells, and oral administration slowed the age-related decline of adult Drosophila locomotor behaviors. On average, IAB-treated flies lived significantly longer (+23%) and had lower neural aggregate profiles. Different IAB dosages also improved locomotor function and longevity profiles after traumatic brain injury (TBI) exposure. Mechanistically, short-term IAB and LGG treatment altered baseline nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) signaling profiles in neural and abdominal tissues. Overall, at select dosages, IAB and LGG exposure has a positive impact on Drosophila longevity, neural aging, and mild traumatic brain injury (TBI)-related responses, with IAB showing greater benefit. This includes severe TBI (sTBI) responses, where IAB treatment was protective and LGG increased acute mortality profiles. 

Well. Interestingly there may be a "too much" point here with both interventions where they are no longer great, with a lower tolerance for the live probiotic. These are not placebos.  

Anyway L. Bulgaricus was the probiotic that Élie Metchnikoff predicted would extend life in 1907.

Just sayin'.

Tolstoy and Metchnikoff, 

Disclaimer - my work for Labyrinth in its early days was pro bono, and I've never been paid by anyone involved. I did receive two textbooks.

Sunday, 30 May 2021

Bernard Shaw goes to Samoa

I’ve been lucky enough to have worked as an extra on the latest fantasy series, and this means I have finally had the time and the freedom from digital poisoning to read some of the books I have wanted to finish.

Like Thomas Mann’s Doctor Faustus. A Thomas Mann book is long and its characters and ideas only really come into focus in the second half. But when they do, wow. Hitler – what were the Germans thinking? Mann describes not the rise of the Nazis but the fall of reason and cults of irrationality that preceded it. And which could precede any form of extreme collectivism anywhere. What he describes isn’t the Popper analysis everyone bandied about cack-handed back when we thought that any reinvigorated conservative critique of progressive radicalism was an impending fascist coup. It’s something more general, something latent in our own instinct to find the self-serving pattern of submission and permission to suit any uncertain times, and also latent in the instinct of intellectuals to make all times seem so uncertain that shit like that can be made to happen in them.
I also read four plays by Ibsen, all good and Ghosts and Hedda Gabbler being perfect marvels, the best plays I can remember having read. Seeing these plays as a bourgeoise in a Victorian theatre must have felt like finding a bomb under your seat.
I was also able to start part 2 (having already read parts 1 and 3) of Michael Holroyd’s biography of Bernard Shaw, covering the years 1898-1918. Shaw, a playwright (and disciple of Ibsen), is an unsympathetic character, with his vegetarianism, chastity, self-regard and urge to pontificate on everything, but he’s also the man who was a tireless cheerleader, inventor, and, behind the scenes, a diligent planner for much of what we call progress in the Western world. Everyone being paid the same amount, men and women being treated by society as if they were physiologically and psychologically identical – these were Shaw’s ideas, expressed frequently enough during an age when they only seemed outlandish and attention-seeking to become familiar, if still attention-seeking, concepts in our own times. And so much more (renewable energy, pacifism, animal rights, the list is quite possibly endless) – Shaw was the original SJW, with the important exception that he could and did laugh at himself, and was prepared to do the grinding political work needed to make civics work well – better schools, better drains, that sort of thing. And not a typical SJW either in that he courted and tolerated opposition in order to better spread his views. Thus he debated G.K. Chesterton, in debates chaired by Hilaire Belloc in a friendly but no-holds barred fashion, for many years. 

And most importantly for our purposes, Shaw was an antivaxxer who debated the most famous vaccinationist of his days, Sir Almroth Wright, regularly for decades. Wright, in fact, sought out Shaw first for publicity purposes.
Shaw’s opposition to vaccination was in part emotional (as an anti-vivisectionist), in part mystical (as a believer in a Life Force which trumped Darwinian evolution), in part envious of the prestige belonging to the freemasonry of Medicine over that of Art.
But he also sensed the role of bunkum in medicine, the unproven theories presented as fact, the faked experiments presented as proof, the corrupting influence of money, and the hollowness of appeal to authority (when the British government wanted to promote Wright’s serum they gave him a knighthood, then used his “Sir” as a selling point).    

“Shaw’s sense of vulnerability to the power of this medical elite, replacing his fear of death, gives his satire its edge…Behind these years of correspondence and controversy with Wright, and the play [The Doctor’s Dilemma] that resulted from their association, there lay a wish to take authority from the orthodoxly educated and give it to outsiders… the medical freemasonry was a closed circle of privileged people whose mesmeric power over other human beings angered Shaw.”

Most relevantly to the present day, he saw vaccination as a shameful cover-up for poverty. No need to fix the drains, supply decent housing, or feed the poor properly if you can stop a pandemic breeding in the slums, or at least the fear of one, or at least reduce the chances of it reaching the bourgeoisie, with a cheap jab. And this point – which perhaps acknowledges that vaccination can be effective, but highlights the social cost of its success – remains valid today.

Modern medical opinion, as reported by Holroyd, seems to be, that Sir Almroth Wright’s tuberculosis serum was worthless. There is even a theory that a similar vaccine technology gave the Spanish flu what it needed to get going. I don’t have the reading or expertise to comment on that. But I do know that Wright’s certainty that women were psychologically unfit to vote was misplaced (because, as Shaw noted, and as we can clearly see today, men are not any less prone to pseudoscientific reasoning) and that his repeated opinion that “the effect of hygiene is aesthetic” was positively dangerous, even if it always gave Shaw the opening to argue the case for Art.  

Which brings us to today. Diet is an arm of hygiene just as surely as hand-washing and the avoidance of crowded indoor spaces, both effective in reducing the spread of COVID19 and other infectious diseases. We can see from China and other places that an adequate selenium level of the diet alone quite possibly reduces the case fatality rate (CFR) for COVID-19 by a factor of 4. We can see that higher vitamin D levels (a sign of good diet quality overall, and not only sunlight exposure or vitamin D intake, because vitamin C, iron and magnesium are among the factors contributing to the serum vitamin D level) are associated with a greatly reduced CFR. And that higher levels of unsaturated fat in fat stores (as in the US population) increase the risk of lung damage and death when infected with SARS-CoV-2. Unsaturated fat is the main component of margarines and the cheap oils used to cook the food of the poor; white bread helps to keep it from being burned for fuel; meanwhile the wealthy eat butter and steak, and are not so prone to the storage of excess fat, despite needing to do less work.
Most of these risk factors, as I’ve said before, are actually the unintended consequences of earlier scientific error regarding the risk of skin cancer (which unsaturated oils also promote) and heart disease (which is mainly driven by the excessive insulin response to the modern diet).

A recent example of how the pro-vax narrative ignores the effects of poverty, and hygiene including diet, appeared in the blog of David Farrier. I’ve mentioned Farrier before in this blog because he’s quite a good bellwether of right-thinking opinion, and because he’s worth reading for his own sake. He’s the creator of an entertaining film, Tickled, about the human capacity for deception, and has a pretty good take on conspiracy theory and its psychology. But it depends whose conspiracy theory, because beneath all his quirkiness Farrier is a bog-standard PMC worrywart and always defers to the interests of his class, acting, on the blog at least, as a gatekeeper who's never met an expert he didn't agree with, or at least submit to meekly.

In this article on fake news written by Farrier’s friend Byron Coley, which is otherwise an intelligent and insightful guide to the current conspiracy theory and misinformation landscape inside NZ, we get an example of misinformation by omission, regarding the measles epidemic in Samoa, in a section on some Covid grifters who ran for parliament on the New Conservative platform.

In April on Talano Sa’o, Tildsley spent an episode interviewing a man she described as “an unsung hero in Samoa” Edwin Tamasese.

During the measles pandemic — which was devastating to our people, killed around seventy of our babies — he was right in the middle of it, and he was part of sharing vitamin D, vitamin A, vitamin C, and he did what he needed to do.

Tamasese, who has no medical training, spread the false claim during the measles outbreak that authorities were “seeding” the country with measles through the emergency mass immunisation program deployed to stem the epidemic."  

So far, so bad. But the story of the Samoan measles outbreak is being manipulated here. The outbreak happened after Samoa’s regular measles vaccination program was stopped, and it was stopped after two babies died from a botched vaccination. It was the deaths of these two babies, and not the activities of anti-vax grifters, that lead to the deaths of 70 children. The Samoan health service, for reasons that are still not clear, could not run a safe vaccination program. Understandably parents chose not to take further risks, until the cost of not having vaccinated their children became obvious. Samoa has a population of 202,506, and 83 people died in the measles epidemic, among 5,700 confirmed cases. New Zealand has a population of 5 million, the same epidemic was described as the worst since 1938, with 2,194 confirmed cases, and two unborn fetuses in the second trimester died as a result of the outbreak. New Zealand many have higher vaccination rates than Samoa, at least among children, but it also has a thriving population of privileged unvaccinated kids.

This is a huge difference in impact. It is the kind of inequality of outcomes that is usually attributed to systemic racism, colonization etc. But when we see a difference so extreme that it really can be interpreted as evidence of those things by anyone with eyes to see, everyone is strangely silent.
Because systemic racism and neo-colonial exploitation could be real features of life in Samoa, if New Zealand’s experience is anything to go by. What else do we call the replacement of traditional foods with imported rubbish, under a system that promotes Western dietary values? New Zealand has a large Samoan population, and
New Zealand’s dietary guidelines are dismissive of all the traditional Pacific energy foods in favour of grains. The use of coconut is confused with coconut oil and discouraged in patronising statements like “The Heart Foundation considers that when indigenous people consume coconut flesh and milk along with fish and vegetables, and they are also physically active, the coconut consumption is unlikely to put them at risk of cardiovascular disease. They are in a very different situation from people who consume coconut oil along with a typical western diet.”
Which if true (and the claim is still untested, as Shaw would have recognized, but
likely to be untrue) would be true of any food supplying energy. Is it also saying that coconut is unhealthy for a sedentary population? That’s also unlikely to be true.
Traditional diets, and decent diets aligned with them, have long been disrupted in the Islands by Western-trained medical freemasons and commercial traders of imported goods, often
working hand-in-hand. If you want to call it structural racism I won’t stop you. But weird how silent the usual suspects are.

Would the grifter’s supplements have saved lives? A silver bullet nutritional approach to systemic deprivation is rarely highly effective, but according to the
Cochrane Collaboration, the ultimate in evidence-based medicine “Vitamin A reduces the risk of death from measles by 87% for children younger than 2 years”.
Yet the Samoan authorities were telling parents to ignore the grifters. Did they throw the babies out with the bathwater, or were they also supplying the vitamins to the unvaccinated, preferably before they got measles?

I don’t know the answers. But I do read the papers, watch the TV news, and look at stories on the internet. If I don’t know then it’s likely that very few people know. They only know what they’re told, and the narrative is owned by people who won’t tell you these important things. It’s still owned by Sir Almroth Wright. There’s an alternative narrative, of course, but you certainly can’t trust the people who own that.

Which leaves it up to the people who claim to be investigative – including your David Farriers and Byron Coleys – to find out the truth for us, even if this does rattle their class interests.
Summary:  I'm always hopeful that my blog posts may attract people not familiar with my preoccupations and body-of-knowledge, such as it is. So to avoid confusion, here is a summing up:
Vaccines, which have been improved since Sir Almroth Wright's day, are a huge contributor to population health. You shouldn't have needed me to tell you that. However:  There was no Covid vax for a year and most people will still have no Covid vax this time next year. Over 3 million people have died. The drugs are not that effective at preventing this.  Look at environmental factors. The strong associations that exist - selenium, vitamin D and unsaturated/saturated fatty acid ratios - should have been exhaustively tested by now. But instead fuck all has happened. Why? Who is in charge of deciding what to test and how, and why have they not heard of Austin Bradford Hill?

There was no measles vax in Samoa due to a vaccine disaster. Such accidents are always possible, and antivaxers, paradoxically, will always be with us. Why were nutritional interventions - including those with known value - neglected and, indeed, scorned?
And were the other effective hygiene interventions - lockdown, masks, hand sanitizer, social distancing, quarantine - used to control spread, and if so, at what stage of the epidemic? They certainly weren't being used in the NZ outbreak.

The pertussis vax in DPT is also ineffective at preventing outbreaks and needs more frequent boosters than most people can manage. Again, 
lockdown, masks, hand sanitizer, social distancing, quarantine could be used to control spread, for which to work diagnostic criteria need to be more pragmatic and affordable, and environmental factors should be researched.

It's also relevant that the DPT vaccine is too dangerous to use in sub-Saharan Africa (due to local infectious disease risks that would not be at all relevant in the Pacific). Think of something else there. Why does the development of a vaccine prevent research into alternatives? They will often still be needed.

Saturday, 22 May 2021

Selenium reduces COVID-19 risk - a back-of-the-envelope Bradford Hill analysis [originally posted 28/09/20, updated 23/05/21]

Bradford Hill introduced a checklist for assessing the strength of epidemiological evidence for causality, which is useful in the current pandemic when nutritional factors have been insufficiently tested by experiment in favour of drugs with, so far, relatively weak effects.[1]
Remember, a long time has passed and a lot of people have died while Evidence-Based Medicine was facing the wrong way.
And asking the wrong question. "What new treatment will save more lives in the ICU?" is an important question, but one with few answers and no great ones - "What can stop people who catch SARS-CoV-2 coming to the ICU?" is a better one in a pandemic, and one that might also lead to better treatment protocols.

Selenium reduces COVID-19 mortality: A Bradford Hill analysis

1) Strength of association. Very Strong.

a) On inspection of the Hubei data, it is notable that the cure rate in Enshi city, at 36.4%, was much higher than that of other Hubei cities, where the overall cure rate was 13.1% (Supplemental Table 1); indeed, the Enshi cure rate was significantly different from that in the rest of Hubei (P < 0.0001). Enshi is renowned for its high selenium intake and status [mean ± SD: hair selenium: 3.13 ± 1.91 mg/kg for females and 2.21 ± 1.14 mg/kg for males]—compare typical levels in Hubei of 0.55 mg/kg (10)—so much so that selenium toxicity was observed there in the 1960s. Selenium intake in Enshi was reported as 550 µg/d in 2013.
Similar inspection of data from provinces outside Hubei shows that Heilongjiang Province in northeast China, a notoriously low-selenium region in which Keshan is located, had a much higher death rate, at 2.4%, than that of other provinces (0.5%; P < 0.0001). The selenium intake was recorded as only 16 µg/d in a 2018 publication, while hair selenium in the Songnen Plain of Heilongjiang was measured as only 0.26 mg/kg (Supplemental Table 2).

Finally, we found a significant association between cure rate and background selenium status in cities outside Hubei (R2 = 0.72, F test P < 0.0001; Figure 1, Supplemental Table 2).[2]

Correlation between COVID-19 cure rate in 17 cities outside Hubei, China, on 18 February, 2020 and city population selenium status (hair selenium concentration) analyzed using weighted linear regression (mean ± SD = 35.5 ± 11.1, R2 = 0.72, F test P < 0.0001). Each data point represents the cure rate, calculated as the number of cured patients divided by the number of confirmed cases, expressed as a percentage. The size of the marker is proportional to the number of cases.

b) Serum samples (n = 166) from COVID-19 patients (n = 33) were collected consecutively and analyzed for total Se by X-ray fluorescence and selenoprotein P (SELENOP) by a validated ELISA. Both biomarkers showed the expected strong correlation (r = 0.7758, p < 0.001), pointing to an insufficient Se availability for optimal selenoprotein expression. In comparison with reference data from a European cross-sectional analysis (EPIC, n = 1915), the patients showed a pronounced deficit in total serum Se (mean ± SD, 50.8 ± 15.7 vs. 84.4 ± 23.4 µg/L) and SELENOP (3.0 ± 1.4 vs. 4.3 ± 1.0 mg/L) concentrations. A Se status below the 2.5th percentile of the reference population, i.e., [Se] < 45.7 µg/L and [SELENOP] < 2.56 mg/L, was present in 43.4% and 39.2% of COVID samples, respectively.
The Se status was significantly higher in samples from surviving COVID patients as compared with non-survivors (Se; 53.3 ± 16.2 vs. 40.8 ± 8.1 µg/L, SELENOP; 3.3 ± 1.3 vs. 2.1 ± 0.9 mg/L), recovering with time in survivors while remaining low or even declining in non-survivors.[3]

c) Vitamins B1, B6, B12, D (25-hydroxyvitamin D), folate, selenium, and zinc levels were measured in 50 hospitalized patients with COVID-19. A total of 76% of the patients were vitamin D deficient and 42% were selenium deficient. No significant increase in the incidence of deficiency was found for vitamins B1, B6, and B12. folate, and zinc in patients with COVID-19. The COVID-19 group showed significantly lower vitamin D values than the healthy control group (150 people, age/sex matching). Severe vitamin D deficiency (based on 10 ng/dL) was found in 24% of the patients in the COVID-19 group and 7.3% of the control group. Among 12 patients with respiratory distress, 11 (91.7%) were deficient in at least one nutrient. However, patients without respiratory distress showed deficiency in 30/38 people (78.9%, P-value 0.425). These results suggest that a deficiency of vitamin D or selenium may decrease the immune defenses against COVID-19 and cause progression to severe disease; however, more precise and large-scale studies are needed.[18]

100% of the patients in this study with severe outcomes, including death, were selenium deficient; 75% were vitamin D deficient; none were zinc deficient.

d) In regression models, serum Se levels were inversely associated with lung damage independently of other markers of disease severity, anthropometric, biochemical, and hemostatic parameters.[23]

e) The association between soil Se level and the incidence of COVID-19 was observed in different cities of Hubei Province. The incidence of COVID-19 was more than 10 times lower in Se-enriched cities (Enshi, Shiyan, and Xiangyang) than in Se-deficient cities (Suizhou and Xiaogan).[25]

See also refs 19 and 22, discussed below.

2) Consistency - Very Strong

All epidemiological data about selenium and COVID-19 is consistent in direction and effect size. However, tests that could be done comparing COVID-19 risk in high and low selenium regions of Brazil, Scandinavia (selenium is supplemented in the food supply of Finland), and the USA would establish consistency further.

[edit 16/11/202o] - New study from South India is consistent with those from Germany, China, and South Korea:

We analysed the blood serum levels in apparently healthy (N=30) individuals and those with confirmed COVID -19 infection (N=30) in the southern part of India. Patients showed a significantly lower selenium level of 69.2 ±8.7 ng/ml than controls 79.1 ± 10.9 ng/ml, the difference was statistically significant (P=0.0003). Interestingly the controls showed a borderline level of selenium, suggesting that the level of this micronutrient is not optimum in the population studied.[19]

[edit 14/12/2020] letter from Finland in BJN compares death rate with Sweden's.

[edit 15/12/2020 deficiency of both zinc and selenium predicts COVID-19 severity in EPIC data]
"This combined deficit was observed in 0.15% of samples in the EPIC cohort of healthy subjects, in 19.7% of the samples collected from the surviving COVID-19 patients and in 50.0% of samples from the non-survivors."[22]

Statistically significant and often very strong associations between selenium intake, selenium status, and various COVID-19 outcomes have been reported from China, South Korea, Germany, South India, Russia and Europe. No null association has yet been reported.

Rigorous re-analysis of updated Chinese pandemic data published recently confirms the original observations, this time using the case-fatality rate:

A total of 147 cities each reporting over 20 cases were included in the current analysis. In these cities, 91% (14,045) of total cases and 85.8% (103) of total mortality from COVID-19 in China had been reported.
Totally, 14,045 COVID-19 cases were reported from 147 cities during 8 December 2019–13 December 2020 were included. Based on selenium content in crops, the case fatality rates (CFRs) gradually increased from 1.17% in non-selenium-deficient areas, to 1.28% in moderate-selenium-deficient areas, and further to 3.16% in severe-selenium-deficient areas (P = 0.002). Based on selenium content in topsoil, the CFRs gradually increased from 0.76% in non-selenium-deficient areas, to 1.70% in moderate-selenium-deficient areas, and further to 1.85% in severe-selenium-deficient areas (P < 0.001). The zero-inflated negative binomial regression model showed a significantly higher fatality risk in cities with severe-selenium-deficient selenium content in crops than non-selenium-deficient cities, with incidence rate ratio (IRR) of 3.88 (95% CIs: 1.21–12.52), which was further confirmed by regression fitting the association between CFR of COVID-19 and selenium content in topsoil, with the IRR of 2.38 (95% CIs: 1.14–4.98) for moderate-selenium-deficient cities and 3.06 (1.49–6.27) for severe-selenium-deficient cities

3) Specificity - Strong

Selenium has much weaker or less consistent associations with other diseases, except those caused by other RNA viruses, e.g. when risk of hepatocellular cancer in viral hepatitis patients is compared with risk of osteoporosis.[4, 5]

4) Temporality - Strong

Prospective ecological comparisons are temporal by design.[2] In the German study, the temporal association between low serum selenium levels and COVID-19 symptom severity was closely tracked.[3]

Nutrients 12 02098 g003 550

5) Dose-response gradient - Very Strong

A strong, consistent dose-response is seen, even at levels where the risk of selenium toxicity exists, and despite the fact that toxic levels of soil selenium are often a legacy of industrial pollution in China.[2]

6) Plausibility - Very Strong

Reading references 2 and 3, as well as this review of the evidence written before reference 2 was published, should be persuasive.[6] See also ref 17 for antiviral effects. The effects of selenium and selenite align to support the associational results across multiple mechanisms.

7) Coherence - Very Strong

Selenium is well-studied and nothing in its story seems to contradict the idea that higher intakes will protect against COVID-19 mortality and reduce the severity of disease.
Dexamethasone, a drug which can reduce COVID-19 mortality in the ICU, enhances 1α,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription.[7] 
Selenium sufficiency is essential for the function of vitamin D in peripheral blood monocytes.[8] Vitamin D status also correlates with COVID-19 survival.[9]

[Edit: 20/11/20] Two conditions which are associated with selenium depletion through effects on tubular mineral resorption, sickle cell disease (aOR, 1.73; 95% CI, 1.21-2.47), and chronic kidney disease (aOR, 1.32; 95% CI, 1.29-1.36), are the comorbidities most strongly associated with COVID-19 mortality in a large US MEDICARE patient analysis.[20] Selenium status in sickle cell disease is inversely associated with markers of hemolysis, a feature of severe COVID-19 pathology.[21]

8) Experiment - Weak (Neglected)

This is an area of sufficient neglect to make you despair about medical humanity, if you know that there have been thousands of trials of potentially useless drugs for COVID-19 already. However this criteria overlaps with the next section as there are several trials of selenium supplementation in other viral diseases, and animal experiments in analogous conditions, and many mechanistic experiments that are non-specific. The interaction between SARS-CoV-2 and selenoproteins has been confirmed by experiment.[10]

9) Analogy - Strong

Selenium intake is protective, and selenium supplementation has been useful, in other viral illnesses.
However, the protective effect of high selenium intakes before infection in epidemiology appears stronger than the protective effect of selenium as a late intervention in disease.[6, 11]

Those are the nine canonical Bradford Hill criteria. The discussion about selenium suggests that an ad hoc 10th criteria will also be useful:

10) Risk - Weak in short-term, Well-Established in long term.

We can add the most relevant of extra questions to any given set of criteria - "strength of the alternative hypothesis" would be a good one for any lipid hypothesis.
Bradford Hill stated that some interventions are easier to justify than others.

On fair evidence we might take action on what appears to be an occupational hazard, e.g. we might change from a probably carcinogenic oil to a non-carcinogenic oil in a limited environment and without too much injustice if we are wrong. But we should need very strong evidence before we made people burn a fuel in their homes that they do not like or stop smoking the cigarettes and eating the fats and sugar that they do like. In asking for very strong evidence I would, however, repeat emphatically that this does not imply crossing every ‘t’, and swords with every critic, before we act.[1]

With nutrient intakes there is often an identifiable risk, with a J-shaped curve. With selenium the risk is selenosis, which is a condition that requires chronic high exposure (I have given myself mild selenosis with around 900mcg selenium a day and it was not a terrible condition to experience and was reversible). There could be other risks. Luckily we have an experiment that tells us where the limit is.
In a low selenium country, like New Zealand or Denmark, you don't want to take more than 200mcg of extra selenium long term.[12] Pity the low dose arms here weren't retained in the intervention.


During 6871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis
the hazard ratio (95% confidence interval) for all-cause mortality comparing 300 µg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 µg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar.

Howsoever that may be, taking extra selenium above 200mcg per day may yet be advised if one becomes ill with COVID-19,  but an inorganic salt of selenium like sodium selenite (which is anyhow probably safer than the selenomethionine form long-term, as I'll discuss below) is preferable, according to the selenovirus expert, Ethan Will Taylor. 
(this video link does not show in the mobile version of this post but can be reached through the web view option at the bottom)

[Edit: 1/09/20] There is also very good evidence that intravenous high dose selenite is safe in the ICU setting.

Totally 19 RCTs involving 3341 critically ill patients were carried out in which 1694 participates were in the selenium supplementation group, and 1647 in the control. The aggregated results suggested that compared with the control, intravenous selenium supplement as a single therapy could decrease the total mortality (RR = 0.86, 95% CI: 0.78–0.95, P = .002, TSA-adjusted 95% CI = 0.77–0.96, RIS = 4108, n = 3297) and may shorten the length of stay in hospital (MD −2.30, 95% CI −4.03 to −0.57, P = .009), but had no significant treatment effect on 28-days mortality (RR = 0.96, 95% CI: 0.85–1.09, P = .54) and could not shorten the length of ICU stay (MD −0.15, 95% CI −1.68 to 1.38, P = .84) in critically ill patients.[13]

This, and an earlier analysis which found less benefit, did not single out viral illnesses as a subgroup - this is only evidence for safety - but the earlier analysis did find a) slightly lower mortality in trials without an initial bolus dose, b) no increased risk in patients with renal disease.[14]

I will hypothesize briefly on selenium increasing mortality at 300 mcg/day in the Danish intervention study, a dose far too low to cause selenosis.
(The conventional signs of selenosis result from selenocysteine replacing cysteine in proteins, and the relative weakness of the Se-Se bond compared with the S-S bond.)
[Edit - hypothesis improved, 23/09/20]
The question of selenium causing insulin resistance and increasing mortality in high-dose supplements, not mirrored as far as I can see in natural high-dose populations, may have a simple explanation - supplements allow us to consume micronutrients without protein.
If you have no cysteine or methionine coming in when you take Se (either because you're not eating protein, or perhaps it can happen naturally if the Se level is high in a low-protein food and diet) then the selenocysteine formed will be incorporated into all proteins, not just the ones that require it. Including the insulin receptors, which will suffer a relative loss of function.
(similarly, though for different reasons, pyridoxine toxicity can be triggered by supplementing on a low-protein diet)

If we think that insulin resistance causes CVD, then the increased risk from (mostly) natural high Se levels is not great, see fig 5 here [15], but the intervention studies have more alarming results, and I think the competition of selenium- vs sulphur-amino acids in protein fed vs unfed states can explain this. There is next to no evidence of Se toxicity from Brazil nuts, which are high in both Se and protein.

It makes sense to me that selenomethionine, very useful as it will increase selenoprotein levels quickly if you don't have much time, should be replaced with sodium selenite for long-term coverage.

Brazil nuts are a variable quantity, a sample of nuts sold in NZ in 2008 had an average of 19 mcg per nut and increased selenoprotein levels more than selenomethionine.[16]

Plasma selenium increased by 64.2%, 61.0%, and 7.6%; plasma GPx by 8.3%, 3.4%, and -1.2%; and whole blood GPx by 13.2%, 5.3%, and 1.9% in the Brazil nut, selenomethionine, and placebo groups, respectively. Change over time at 12 wk in plasma selenium (P < 0.0001 for both groups) and plasma GPx activity in the Brazil nut (P < 0.001) and selenomethionine (P = 0.014) groups differed significantly from the placebo group but not from each other. The change in whole blood GPx activity was greater in the Brazil nut group than in the placebo (P = 0.002) and selenomethionine (P = 0.032) groups.

[Edit 02/09/20] - thanks to Mike Angell for this link; while all selenium sources are probably protective against death and ongoing harm from COVID-19, only selenite is likely to have an additional antiviral effect, and has low toxicity.[17]

A rational protocol for using selenium in prevention and treatment of COVID-19, fully consistent with the evidence discussed here, is described at the end of this paper:

All scientific work is incomplete - whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time.

Austin Bradford Hill, 1965.


[1] Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58(5):295-300.

[2] Jinsong Zhang, Ethan Will Taylor, Kate Bennett, Ramy Saad, Margaret P Rayman, Association between regional selenium status and reported outcome of COVID-19 cases in China, The American Journal of Clinical Nutrition, Volume 111, Issue 6, June 2020, Pages 1297–1299,

[3] Moghaddam, A.; Heller, R.A.; Sun, Q.; Seelig, J.; Cherkezov, A.; Seibert, L.; Hackler, J.; Seemann, P.; Diegmann, J.; Pilz, M.; Bachmann, M.; Minich, W.B.; Schomburg, L. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients 2020, 12, 2098.

[4] Yu MW, Horng IS, Hsu KH, Chiang YC, Liaw YF, Chen CJ. Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. Am J Epidemiol. 1999;150(4):367-374. doi:10.1093/oxfordjournals.aje.a010016

[5] Wang, Y., Xie, D., Li, J. et al. Association between dietary selenium intake and the prevalence of osteoporosis: a cross-sectional study. BMC Musculoskelet Disord 20, 585 (2019).

[6] Bermano, G., Méplan, C., Mercer, D., & Hesketh, J. (2020). Selenium and viral infection: Are there lessons for COVID-19? British Journal of Nutrition, 1-37. doi:10.1017/S0007114520003128

[7] Hidalgo AA, Deeb KK, Pike JW, Johnson CS, Trump DL. Dexamethasone enhances 1alpha,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription. J Biol Chem. 2011;286(42):36228-36237. doi:10.1074/jbc.M111.244061

[8] Schütze N, Fritsche J, Ebert-Dümig R, et al. The selenoprotein thioredoxin reductase is expressed in peripheral blood monocytes and THP1 human myeloid leukemia cells--regulation by 1,25-dihydroxyvitamin D3 and selenite. Biofactors. 1999;10(4):329-338. doi:10.1002/biof.5520100403

[9] Martín Giménez, V.M., Inserra, F., Ferder, L. et al. Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2. J Hum Hypertens (2020).

[10] Wang, Y et al. SARS-CoV-2 suppresses mRNA expression of selenoproteins associated with ferroptosis, ER stress and DNA synthesis. Preprint, 2020/07/31. 10.1101/2020.07.31.230243

[11] Steinbrenner H, Al-Quraishy S, Dkhil MA, Wunderlich F, Sies H. Dietary selenium in adjuvant therapy of viral and bacterial infections. Adv Nutr. 2015;6(1):73-82. Published 2015 Jan 15. doi:10.3945/an.114.007575

[12] Rayman MP, Winther KH, Pastor-Barriuso R, et al. Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial. Free Radic Biol Med. 2018;127:46-54. doi:10.1016/j.freeradbiomed.2018.02.015

[13] Zhao Y, Yang M, Mao Z, et al. The clinical outcomes of selenium supplementation on critically ill patients: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2019;98(20):e15473. doi:10.1097/MD.0000000000015473

[14] Manzanares W, Lemieux M, Elke G, Langlois PL, Bloos F, Heyland DK. High-dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis. Crit Care. 2016;20(1):356. Published 2016 Oct 28. doi:10.1186/s13054-016-1529-5

[15] Angelica Kuria, Hongdou Tian, Mei Li, Yinhe Wang, Jan Olav Aaseth, Jiajie Zang & Yang Cao (2020) Selenium status in the body and cardiovascular disease: a systematic review and meta-analysis, Critical Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2020.1803200

[16] Thomson CD, Chisholm A, McLachlan SK, Campbell JM. Brazil nuts: an effective way to improve selenium status. Am J Clin Nutr. 2008;87(2):379-384. doi:10.1093/ajcn/87.2.379

[17] Kieliszek M, Lipinski B. Selenium supplementation in the prevention of coronavirus infections (COVID-19) [published online ahead of print, 2020 May 24]. Med Hypotheses. 2020;143:109878. doi:10.1016/j.mehy.2020.109878

[18] Im, JH et al. Nutritional status of patients with coronavirus disease 2019 (COVID-19) Int J Infectious Diseases, August 11, 2020

[19] Majeed, M et al. An Exploratory Study of Selenium Status in Normal Subjects and COVID-19 Patients in South Indian population: Case for Adequate Selenium Status: Selenium Status in COVID-19 Patients. Nutrition. Available online 11 November 2020, 111053

Chen Dun, Christi M. Walsh, Sunjae Bae, Amesh Adalja, Eric Toner, Timothy A. Lash, Farah Hashim, Joseph Paturzo, Dorry L. Segev, Martin A. Makary. A Machine Learning Study of 534,023 Medicare Beneficiaries with COVID-19: Implications for Personalized Risk Prediction.
medRxiv 2020.10.27.20220970; doi:

[21] Delesderrier E, Cople-Rodrigues CS, Omena J, et al. Selenium Status and Hemolysis in Sickle Cell Disease Patients. Nutrients. 2019;11(9):2211. Published 2019 Sep 13. doi:10.3390/nu11092211

[22] Raban Arved Heller, Qian Sun, Julian Hackler, Julian Seelig, Linda Seibert, Asan Cherkezov, Waldemar B. Minich, Petra Seemann, Joachim Diegmann, Maximilian Pilz, Manuel Bachmann, Alireza Ranjbar, Arash Moghaddam, Lutz Schomburg,
Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker, Redox Biology, Volume 38, 2021101764,

[23] Skalny AV, Timashev PS, Aschner M, et al. Serum Zinc, Copper, and Other Biometals Are Associated with COVID-19 Severity Markers. Metabolites. 2021;11(4):244. Published 2021 Apr 15. doi:10.3390/metabo11040244

[24] Zhang, HY., Zhang, AR., Lu, QB. et al. Association between fatality rate of COVID-19 and selenium deficiency in China. BMC Infect Dis 21, 452 (2021).

[25] Liu Q, Zhao X, Ma J, et al. Selenium (Se) plays a key role in the biological effects of some viruses: Implications for COVID-19. Environ Res. 2021;196:110984. doi:10.1016/j.envres.2021.110984

Sunday, 16 May 2021

Is cannabis protective against an adverse effect of the modern diet? Cannabinoid signaling in the omega 3/6 hypothesis of obesity and mood disorders.

(this post originally appeared for subscribers on my Patreon blog in Dec 2020, and is now unlocked. If you want to support my blogging habit and see these posts before they happen, subscribe here!
The rest of you, enjoy.)

It’s pretty well accepted that cannabis is an appetite stimulant in the normal dose range. In fact, it’s pretty much been the unofficial standard-of-care drug for the treatment of appetite loss during illness or chemotherapy for a long time.
So we’d expect people smoking cannabis to have higher rates of obesity and type 2 diabetes, because of the munchies.
Yet it’s been a consistent epidemiological finding that the opposite is true – and the explanation that’s been proposed may give us an insight into why cannabis has become the modern panacea, a drug that has been proposed to treat almost everything and why its legalisation, especially for medical use, is being welcomed by such a large chunk of the population.

How consistent is the association between cannabis use and obesity? In a meta-analysis of BMI data:
“Nine studies were included that reported BMI of users and nonusers and met selection criteria, and an additional two studies were identified that reported lower BMI in Cannabis users, but did not provide numerical data. Of these studies, all reported lower values of BMI in Cannabis users, and only one of these did not reach statistical significance. A second study did not report statistical analysis of the BMI data. Of those studies reporting significant negative correlations, two reported that longer duration of Cannabis use was associated with reduced BMI.”(Clark 2018)

That’s a convincing association as far as it goes, but is there a mechanism that explains it?

In another paper, we read that “Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity.”(Alvheim 2012) The endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), promote both appetite and the growth and expansion of fat cells.(Naughton 2013, Banni 2010, Madsen 2012) This is a useful adaptation to store energy after a meal (or in the autumn, when linoleic acid, like sugar, is most easily found in nature) - but if it becomes a constant state can lead to obesity; with higher food (and especially carbohydrate) intake insulin levels also rise, ensuring more synthesis and storage of fat. When this fat exceeds the capacity of the body to store it, type 2 diabetes is one possible outcome, and at this stage it is very difficult to get the appetite to normalise; at which point removing carbohydrate from the diet seems to be the most effective way to reduce food intake without hunger.(van Zuuren 2018)

A drug that antagonises 2-AG and AEA, Rimbonabant, looked promising in animal studies but turned out to cause depression in humans.

Cannabis, of course, has similar effects to 2-AG and AEA, but the body’s response differs in an important way; we respond to the stimulation of endocannabinoid tone from THC and CBD by downregulating it, and this inhibition lasts longer than the effect of the drug does. In a sense, smoking pot inoculates us against excessive endocannabinoid signalling. This counter effect means that our cells burn more energy, rather than store it, and our appetite decreases, for quite a while after a session, even if we did have the munchies at some point.(Clark 2018) In a recent epidemiological study even historical cannabis use was associated with lower BMI and better insulin sensitivity. The rebound effect seems to last. Users probably don’t want to be saturated in cannabis all the time, but be using it intermittently to benefit.

But where does this excess endocannabinoid tone come from in the first place? 2-AG and AEA are made in the body from arachidonic acid, an omega-6 (ω-6 or n-6) fatty acid only found in animal foods – but the amount of AA in these foods is very low. Most AA in the body is synthesised from linoleic acid, the main polyunsaturated fatty acid in cheap vegetable oils (corn oil and soy oil, for example, are around 60% LA).

(Pathways for anandamide synthesis, from Naughton et al 2013)

So, what counters the obesogenic effect of anandamide and 2-AG naturally? The action of omega-6 endocannabinoids is opposed by omega 3 (ω-3, n-3) endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA), which have a weaker binding affinity to CB1 and CB2 receptors.(Naughton 2013, Watkins 2014) The omega-3 cannabinoids are synthesized from DHA and EPA, the fatty acids in oily fish (pastured lamb or mutton is also a pretty good source). EPA and DHA can also be synthesized from alpha-linolenic acid (ALA), the omega-3 fatty acid found in flaxseed, canola oil and hemp oil (and present in small amounts in most green veges). However, it looks as if too high an intake of ALA also suppresses blood levels of EPA and DHA.(Gibson 2018)
(There is also an omega-9 cannabinoid, made from the main monounsaturated fat oleic acid, which counters the effects of the omega-6 series, decreasing appetite and increasing fat-burning, but this does not seem to depend on dietary intake. Oleic acid is produced in the body as well as an item of diet; it is synthesised after meals from carbohydrate and other fats, so its cannabinoid probably acts as a fullness signal).

It’s been known for a while that a higher intake of LA drives synthesis of AA and inhibits the conversion of ALA to EPA and DHA.(Gibson 2018) This is probably why fish oil became popular as a supplement, but fish oil has had relatively disappointing results in human trials. The only fish oil product approved as a drug (for cardiovascular disease) is VASCEPA, a synthetic variant of EPA which is reliably able to raise the EPA level in the bloodstream.

However, research out of Australia and France shows that saturated fat, especially dairy fat, increases the level of EPA or DHA in the bloodstream, in people fed omega 3 fatty acids from fish oil or canola oil respectively, compared with people instructed to use vegetable oils as per common governmental health advice.(Dias 2016, Dabadie 2005)  The Australians achieved a doubling of the EPA level when the other fat in the diet was more saturated. Yet the LDL (so-called “bad cholesterol”) level also increased.(Dias 2016)

Why would this be? EPA and DHA trigger the burning of fat in the liver – this is a good thing, lowering triglycerides, but it means these omega-3 fatty acids are destroyed in the process so less will reach the bloodstream in the lipoprotein (“cholesterol”) particles. Some saturated fats, especially the longer medium-chain fatty acids in dairy and coconut, also trigger fat burning and lower triglycerides – and this tends to spare some of the EPA and DHA present, so that other cells in your body can use it.(Drouin 2018)  But removing triglycerides from lipoproteins in the liver means they come out with less fat, and therefore more cholesterol. This raises your LDL-cholesterol, yet these cholesterol-rich LDL particles are less likely to harm your blood vessels than cholesterol-depleted ones.(Hirayami 2012)

It’s noticeable that the true relationship between dietary saturated fat and omega-3 is thus the opposite of that described in influential early books about omega-3 fatty acids, such as Horrobin’s “The Madness of Adam and Eve” and Allport’s “The Queen of Fats”, which painted them as enemies, based on a priori assumptions.

Our diets used to be very low in omega 6 LA. This changed for two reasons – first we were told to replace animal fat with polyunsaturated vegetable oil for cooking because this would lower cholesterol and so reduce the risk of heart disease. But human experiments have never supported this idea. In particular, a meta-analysis of those trials replacing saturated fat with oils and foods high in LA (rather than omega 3 fats) found that the risk of heart disease and death was non-significantly increased in those trials that were properly controlled.(Hamley 2017)
The second reason is that more of our animal-based food today comes from animals fattened on grains. The fat of chickens and pigs fed on corn and soy waste can be very high in LA and higher in AA compared with the fat of the same animals in the past, and even ruminant fat gets higher in LA and AA, and lower in EPA and DHA, when sheep and cattle are fattened on grains.

Guyenet and Carlson analysed all the different studies done over the years measuring the fatty acid percentages of fat stores in samples from people in the USA and found “that adipose tissue LA has increased by 136% over the last half century and that this increase is highly correlated with an increase in dietary LA intake over the same period of time”.(Guyenet 2015)

Adipose LA in Sweden, for example, is significantly lower than in the USA – Scandinavians still eat plenty of meat and dairy fat, and when they do use plant oils prefer canola, which has 1/3 the LA content of soy or corn oil, or olive oil with 1/6 as much; they are also more likely to eat oily fish than Americans. The official recommended limit of saturated intake in some Scandinavian countries is significantly higher than the 10% of energy limit recommended in the USA, UK or NZ. The Swedes enjoy lower rates of obesity, type 2 diabetes, and heart disease than we do with a saturated fat limit which they seem to ignore.

As Clark et al stated in their hypothesis paper,

“…populations with diets characterized by a high omega-6/omega-3 ratio will see significantly larger health improvements from Cannabis use than those eating diets with more moderate ratios of omega-6/omega-3 FAs. This may explain some of the inconsistencies in the data on the metabolic impact of Cannabis use; for example, Cannabis use by Swedish populations may not have the same health impacts as Cannabis use by Americans due to the different dietary backgrounds and obesity rates of these populations.
Cannabis use in the United States appears to provide significant public health benefits due to partial or complete reversal of the metabolic dysregulation caused by the strongly elevated omega-6/omega-3 ratio of the American diet

(Note: If “cannabis use… appears to provide significant public health benefits” in a preventive sense, then the distinction between medicinal and recreational uses of the drug becomes a little blurred, as some medications, such as aspirin or statins, can be legally be prescribed to perfectly healthy people for their purported preventive effects, despite there not being strong evidence for such effects outweighing harms.)

Are governments blind to the possible harms of a high omega-6 intake? The New Zealand MOH is still recommending that high-omega 6 seed oils replace animal fats and coconut oil. Why?

Some public health experts still want us to have low cholesterol levels, despite a lack of evidence that the cholesterol effect of food (as opposed to genes or drugs) has any effect on disease risk.
Some also point to epidemiology in which higher linoleic acid intakes appear to be associated with benefit.
Unfortunately, this isn’t as reliable as it might be – the only foods that supply zero LA are sugar, alcohol, and highly refined flour. The less of these foods you consume, the better – and the higher your LA intake will be. None of these studies separates out the LA consumed from seed oils, as opposed to chicken or nuts and seeds, foods which might reasonably be expected to keep you healthy for other reasons than the type of fat they contain – there is no epidemiology of seed oils. How do you even measure cooking oil accurately in a questionnaire? Those takeaway chips you ate last week – do you remember what they were fried in?

But despite only weak evidence for benefit, plenty of negative evidence, and growing evidence of harm, the push continues. In 1987 the government of Mauritius introduced a raft of health measures, most of which were sensible (smoking, exercise, blood pressure control) but also ordered that soy oil replace palm oil in the cheap “ration” oil used for cooking by most people. 5 years later public health experts applauded a decrease in saturated fat intake, a large increase in polyunsaturated fat, and lower cholesterol levels.(Uusitalo 1996) But what was the outcome 10, 20 years later? Cardiovascular mortality increased a bit, BMI increased– and the prevalence of type 2 diabetes increased from 12.8% in 1987, to 15.2% in 1992, and 17.9% in 1998.(Morrell 2019, Söderberg 2005) Mauritius is now fighting the same type 2 diabetes epidemic seen in most other countries after seed oils were introduced. Yet the government of Fiji imposed a tax on palm oil in 2015 to try to get the same outcome, citing the Mauritius experiment as if it had been successful – because no-one involved had published anything suggesting that it wasn’t.(Coriakula 2018)
But while governments and establishment public health experts may appear to be blind to this problem, behind the scenes efforts to lower the amount of omega-6 in the food supply have been going on for decades. These initiatives include the development of canola and more recently the breeding of “high-oleic” oil seeds that are much lower in omega-6. For example, recently Pic’s peanut butter and peanut oil switched to using a high-oleic peanut, and these products now contain a far lower dose of linoleic acid than most other brands.
At present high-oleic oils and nut butters cost a bit more. The linoleic acid in the food supply, found in cheap oils, margarines and mayonnaise, and deep fried food, especially chicken (the cheapest meat), is tilted towards the diets of the poor, and alongside the similarly cheap refined carbohydrates is doing them no favours, whatever diet epidemiology, which is generally done in more privileged populations, might say.

Is this theory relevant to the psychotropic uses of cannabis in modern society?
I haven’t researched this question deeply, but here are some pointers -

The omega-3/6 balance also influences inflammation and pain perception; a high omega-3 and low omega-6 diet in people with chronic headache reduced pain. The control group restricting omega-6 alone, with no extra omega 3, had a lesser reduction in pain and saw some raising of EPA in the blood, but did not experience the drop in AA that was seen in the omega-3 arm.(Ramsden 2013, Taha 2014) Of course, pain relief is an important use of cannabis.

Omega-3 fatty acids supress some effects of PTSD in animals, and Hibbeln and Gow, writing in the journal of Military Medicine, proposed that improving the omega-3/6 ratio in military rations would reduce depression, suicide, and impulsive aggression among US troops.(Hibbeln 2014) In a case-control study, low DHA status was more strongly associated with suicide in US troops than having witnessed the death or wounding of colleagues in combat (OR 1.62 vs 1.54).(Lewis 2011)

There’s an interesting study on the effect of cannabis use during CBT therapy for PTSD and substance use disorders – “results revealed a crossover lagged effect, whereby higher cannabis use was associated with greater PTSD symptom severity early in treatment, but lower weekly PTSD symptom severity later in treatment. Cross-lagged models revealed that as cannabis use increased, subsequent primary substance use decreased and vice versa”.(Ruglass 2017)

A high-dose EPA supplement in children with ADHD aged 6-18 significantly improved measures of attention and vigilance in those subjects with low EPA at baseline.(Chang) A trial of Sativex in adults with ADHD found “nominally significant” improvement in some measures tested, not contradicting the anecdotal reports from this population of cannabis users.(Cooper)

Acetaminophen (paracetamol) is a painkiller that enhances cannabinoid signalling through CB1 receptors in the pain centre of the brain.(Klinger-Gratz 2018) Paracetamol also reduces the pain of social rejection, empathy for the pain of others, and the experience of existential angst after exposure to material that provokes what psychologists call a “meaning threat”, defined as “whenever one is assaulted by thoughts and experiences that are at odds with one’s expectations and values” - represented in the experiment by the films of David Lynch played to people who hadn’t seen them before!(Mischkowski 2016, Slavich 2019, Randles 2013)

And now we’re getting into deep psychological and sociological territory indeed. Has the remodelling of diets (and reformulation of infant formulas) since the 1970s altered our social functioning? Should it join the long queue of factors proposed to account for our current malaise? Or has David Lynch just made too many films?

More research is needed.
But one thing does seem clear – for good or bad, cannabis probably is an appropriate medication for our times, and the widespread modern awareness of its efficacy may have complex roots in the recent history of our society.


Alvheim, A. R., Malde, M. K., Osei‐Hyiaman, D. , Hong, Y. H., Pawlosky, R. J., Madsen, L. , Kristiansen, K. , Frøyland, L. and Hibbeln, J. R. (2012), Dietary Linoleic Acid Elevates Endogenous 2‐AG and Anandamide and Induces Obesity. Obesity, 20: 1984-1994. doi:10.1038/oby.2012.38

Banni, S. and Di Marzo, V. (2010), Effect of dietary fat on endocannabinoids and related mediators: Consequences on energy homeostasis, inflammation and mood. Mol. Nutr. Food Res., 54: 82-92. doi:10.1002/mnfr.200900516

Chang, J.P., Su, K., Mondelli, V. et al. High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels. Transl Psychiatry 9, 303 (2019) doi:10.1038/s41398-019-0633-0

Clark TM, Jones JM, Hall AG, Tabner SA, Kmiec RL. Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in Cannabis Users. Cannabis Cannabinoid Res. 2018;3(1):259–271. Published 2018 Dec 21. doi:10.1089/can.2018.0045

Cooper RE, Williams E, Seegobin S, Tye C, Kuntsi J, Asherson P. Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial. Eur Neuropsychopharmacol. 2017 Aug;27(8):795-808. doi: 10.1016/j.euroneuro.2017.05.005. Epub 2017 May 30.

Coriakula J, Moodie M, Waqa G, Latu C, Snowdon W, Bell C. The development and implementation of a new import duty on palm oil to reduce non-communicable disease in Fiji. Global Health. 2018;14(1):91. Published 2018 Aug 29. doi:10.1186/s12992-018-0407-0

Dabadie H, Peuchant E, Bernard M, LeRuyet P, Mendy F. Moderate intake of myristic acid in sn-2 position has beneficial lipidic effects and enhances DHA of cholesteryl esters in an interventional study. J Nutr Biochem. 2005 Jun;16(6):375-82

Dias, C., Wood, L. & Garg, M. Effects of dietary saturated and n-6 polyunsaturated fatty acids on the incorporation of long-chain n-3 polyunsaturated fatty acids into blood lipids. Eur J Clin Nutr 70, 812–818 (2016) doi:10.1038/ejcn.2015.213

Drouin G, Catheline D, Sinquin A, et al. Incorporation of Dairy Lipids in the Diet Increased Long-Chain Omega-3 Fatty Acids Status in Post-weaning Rats. Front Nutr. 2018;5:42. Published 2018 May 23. doi:10.3389/fnut.2018.00042

Garg ML, Wierzbicki AA, Thomson ABR, Clandinin MT. Dietary saturated fat level alters the competition between α-linolenic and linoleic acid. Lipids 1989; 24: 334–339

Gibson RA, Musings about the role dietary fats after 40 years of fatty acid research. Prostaglandins Leukot Essent Fatty Acids. 2018 Apr;131:1-5. doi: 10.1016/j.plefa.2018.01.003. Epub 2018 Jan 6.

Guyenet SJ, Carlson SE. Increase in adipose tissue linoleic acid of US adults in the last half century. Adv Nutr. 2015;6(6):660–664. Published 2015 Nov 13. doi:10.3945/an.115.009944

Hamley, S. The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials. Nutr J 16, 30 (2017) doi:10.1186/s12937-017-0254-5

Hibbeln JR, Gow RV. The Potential for Military Diets to Reduce Depression, Suicide, and Impulsive Aggression: A Review of Current Evidence for Omega-3 and Omega-6 Fatty Acids, Military Medicine, Volume 179, Issue suppl_11, November 2014, Pages 117–128,

Hirayama S, Miida T. Small dense LDL: an emerging risk factor for cardiovascular disease. Clin Chim Acta 2012; 414: 215–224.

Klinger-Gratz PP, Ralvenius WT, Neumann E, et al. Acetaminophen Relieves Inflammatory Pain through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla. J Neurosci. 2018;38(2):322–334. doi:10.1523/JNEUROSCI.1945-17.2017

Lewis MD, Hibbeln JR, Johnson JE, Lin YH, Hyun DY, Loewke JD. Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison. J Clin Psychiatry. 2011;72(12):1585–1590. doi:10.4088/JCP.11m06879

Madsen L, Kristiansen K. Of mice and men: Factors abrogating the antiobesity effect of omega-3 fatty acids. Adipocyte. 2012;1(3):173–176. doi:10.4161/adip.20689

Mischkowski D, Crocker J, Way BM. From painkiller to empathy killer: acetaminophen (paracetamol) reduces empathy for pain. Soc Cogn Affect Neurosci. 2016;11(9):1345–1353. doi:10.1093/scan/nsw057

Morrell, S., Taylor, R., Nand, D. et al. Changes in proportional mortality from diabetes and circulatory disease in Mauritius and Fiji: possible effects of coding and certification. BMC Public Health 19, 481 (2019) doi:10.1186/s12889-019-6748-7

Naughton SS, Mathai ML, Hryciw DH, McAinch AJ. Fatty Acid modulation of the endocannabinoid system and the effect on food intake and metabolism. Int J Endocrinol. 2013; 2013:361895. doi:10.1155/2013/361895

Ramsden CE, Faurot KR, Zamora D, et al. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Pain. 2013;154(11):2441–2451. doi:10.1016/j.pain.2013.07.028

Randles D, Heine SJ, Santos N. The common pain of surrealism and death: acetaminophen reduces compensatory affirmation following meaning threats. Psychol Sci. 2013 Jun;24(6):966-73. doi: 10.1177/0956797612464786. Epub 2013 Apr 11.

Ruglass LM, Shevorykin A, Radoncic V, et al. Impact of Cannabis Use on Treatment Outcomes among Adults Receiving Cognitive-Behavioral Treatment for PTSD and Substance Use Disorders. J Clin Med. 2017;6(2):14. Published 2017 Feb 7. doi:10.3390/jcm6020014

Simopoulos AP. Dietary omega-3 fatty acid deficiency and high fructose intake in the development of metabolic syndrome, brain metabolic abnormalities, and non-alcoholic fatty liver disease. Nutrients. 2013;5(8):2901–2923. Published 2013 Jul 26. doi:10.3390/nu5082901

Slavich GM, Shields GS, Deal BD et al. Alleviating Social Pain: A Double-Blind, Randomized, Placebo-Controlled Trial of Forgiveness and Acetaminophen. Ann Behav Med. 2019 Dec; 53(12): 1045–1054.

Söderberg S, Zimmet P, Tuomilehto J, de Courten M, Dowse GK, Chitson P, Gareeboo H, Alberti KG, Shaw JE. Increasing prevalence of Type 2 diabetes mellitus in all ethnic groups in Mauritius. Diabet Med. 2005 Jan;22(1):61-8.

Taha AY, Cheon Y, Faurot KF, et al. Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools. Prostaglandins Leukot Essent Fatty Acids. 2014;90(5):151–157. doi:10.1016/j.plefa.2014.02.003

Uusitalo U, Feskens EJM, Tuomilehto J, Dowse G, Haw U, Fareed D, et al. Fall in total cholesterol concentration over five years in association with changes in fatty acid composition of cooking oil in Mauritius: cross sectional survey. BMJ 1996;313:1044­6.

van Zuuren EJ, Fedorowicz Z, Kuijpers T, Pijl H, Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments, The American Journal of Clinical Nutrition, Volume 108, Issue 2, August 2018, Pages 300–331

Watkins BA, Kim J. The endocannabinoid system: directing eating behavior and macronutrient metabolism. Front Psychol. 2015;5:1506. Published 2015 Jan 6. doi:10.3389/fpsyg.2014.01506