19 Things to Look For In a Seed Oil n=1 Experiment
tl;dr: Things I have no interest in doing myself. Thank Heavens for those who do.
Our Guinea Pig
Nick Norwitz is graduating from Harvard Medical School in a few weeks. He must be winding down pretty quickly, as he seems to be bored.
He’s announced that he is going to do an n=1 experiment on seed oils, and he has asked for some suggestions on what to do.
So here we go. Based on what I’ve read and experienced over the years, this is what I think he could do. I doubt he’ll be able to do them all (see the last two especially) but they’re all reasonable to do in a month-long experiment and don’t involve significant risk or permanent disfigurement.
Previous n=1s
These are the experiments that have already been done, so Nick should at least attempt to replicate these findings.
There are three I am aware of.
1. Stephen Phinney
First was Stephen Phinney’s attempt to discover why his subjects in an RCT he did (Phinney, 1983a; 1983b) felt unwell while on a ketogenic diet, discussed in his 2012 book, and which I discussed here:
At the time, Phinney reported: “There were no symptoms of nausea, persistent fullness, diarrhea, or flatulence,” (Phinney, 1983b); but in his book he explained:
“Within a week or two of starting the high fat diet, most of the subjects developed a strong distaste for the mayonnaise-based meals. Opening a new container and then switching brands of mayonnaise didn’t help. Nobody actually got sick eating these tuna salad or chicken salad entrees – they just said that they didn’t feel completely well after eating them.” (Phinney, 2012)
To try to determine what was going on, Phinney gets a gold star for n=1 experimentation:
“Out of curiosity, Steve put himself on a ketogenic diet for a month and fed himself most of his fat intake overnight via a tiny feeding tube in his stomach (so taste wasn’t an issue).
“Within 3 days of feeding himself 1500 Calories of either soybean or corn oil nightly, he developed quite prominent nausea and gastro-intestinal upset.” (Phinney, 2012)
Neither olive oil (through the tube) nor animal fats (between the tube experiments) caused the same distress.
This has been a common complaint through the decades.
“The prescribed dose of oil was 80 g./day. But many found the treatment burdensome: distaste, nausea, and diarrhoea were the commonest complaints.” (Rose, 1965)
Nausea is an indicator of acute toxicity, so that’s definitely something to track.
Nausea
2. Susan Allport
Second is that done by Susan Allport in 2010, covered here:
She increased her consumption of Ω-6 fats for a month, and measured the following factors:
Body weight
Resting metabolic rate (RMR)
Body composition (fat vs. lean)
Flow-mediated vasodilation (marker of CVD risk)
Fatty acids in red blood cells (Ω-3 vs Ω-6)
The RMR measurement was done by Jeff Volek, Steve Phinney’s co-author of (Phinney, 2012).
3. Anthony Hulbert
Third was that done by Tony Hulbert, and described in his 2023 book, discussed here:
“I had just over a month free from other commitments and set upon the following schedule; 11 days on high omega-6 diet, then 13 days on high omega-3 diet, followed by 12 days on the original high omega-6 diet.” (Hulbert, 2023)
Hulbert swabbed his cheek and did a membrane phospholipid analysis (nice to have your own lab!):
Membrane phospholipid Omega balance
Other Things to Track
Cholesterol
Of course. Lowering ‘cholesterol’ and Apo lipoproteins is thought to be a ‘benefit’ of increased seed oil consumption, and is the reason for the American Heart Association recommending their consumption since 1961 (Page, 1961).
“When the experimental group returned to a conventional diet, serum cholesterol rose promptly. Most of the change had occurred after one week, and the new level vas reached within two weeks (fig. 20). This rise, after an average of seven years on the experimental diet, was as rapid as that seen in short-term metabolic tests, and the magnitude of the change-about 30 mg/dl-was comparable to the drop at the start of the study. Apparently stored linoleic acid, in slow-turnover sites such as adipose tissue, has no influence upon serum cholesterol levels.” (Dayton, 1969)
Cholesterol
VLDL/LDL/ApoE
Oddly, the liver is reluctant to secrete rancid fats into the general circulation.
“The current results, taken with our recent report (4), show that ApoB100 production and degradation in hepatic cells are inversely and directly related, respectively, to the degree of polyunsaturation of the supplied fatty acids.
“Lipid peroxidation regulates the secretion of ApoE, but not its degradation.”
“Like marine ω-3 fatty acids, common dietary PUFAs from nonmarine sources are good substrates for lipid peroxidation and have long been known to lower plasma concentrations of ApoB-lipoproteins in vivo (reviewed in ref. 44).” (Pan, 2004)
This is likely why lowered cholesterol correlated with worse outcomes in the largest human RCTs. Oxidized lipids cause CVD.
“Available RCT evidence demonstrates that replacement of SFA with LA-rich vegetable oil effectively lowers serum cholesterol, but does not support the hypothesis that this translates to lower risk of death from CHD or all-causes.” (Ramsden, 2016, Appendix A)
VLDL/LDL/ApoE
Liver Function/Fatty Liver
This is another well-demonstrated effect. If the liver won’t excrete those oxidized lipids they’re going to back up in the liver. Even Wikipedia is up on this!
It be interesting to see if the commonly-tracked liver function markers change (ALT and AST). We discussed this with the author of one of these studies.
ALT/AST
Susceptibility of Lipids in Circulation to Oxidation
This is critical, but so well-demonstrated in the literature that I wouldn’t bother to spend the money on testing it. See Reaven in 1994 for one example, there are many others.
Oxidized Lipids in Circulating Lipoproteins
There are a number of ways to track oxidized lipids in circulation. Mercodia has an oxLDL test which is not recommended, as it correlates highly with LDL (Tsouli, 2006). Conjugated dienes in lipoprotein are an early marker of LDL oxidation (Vasankari, 2005) as is electro-negative LDL (LDL(-)) (Demuth, 1996), and desialylated LDL (Takana, 1997). LDL(-) is a pretty generic test, and is well-demonstrated to occur outside of the atheroma, and to get to pretty high levels in sick people.
OxPL/ApoB (oxidized phospholipids per ApoB) is a hot marker for CVD risk—as there is a new drug to ‘treat’ it!, is a better test than Mercodia oxLDL, and is amenable to alteration by diet.
“Surprisingly, and seemingly paradoxically, several therapeutic interventions in relatively short-term studies, including low-fat diets, garlic supplements and most statins, have been shown to increase OxPL–apoB levels. Interestingly, these effects have been associated with concomitant increases in plasma Lp(a) levels. The Lp(a)–raising effects of statins and low-fat diets, have been generally underappreciated by the scientific and medical communities.” Yeang, 2016
LDL(-)
OxPL/ApoB
Direct Indicators of Oxidized Fats
Rancid fats are toxic, generally, and there are several tests of the presence of these rancid fats in vivo as a result of dietary changes.
4-HNE
Probably the easiest to measure is DHN-MA (1,4-Dihydroxynonane Mercapturic Acid), which is the urinary excretion pathway for the highly toxic Ω-6 metabolite 4-HNE (4-hydroxynonenal), discussed here:
The relevant paper from that post is: “New Marker of Colon Cancer Risk Associated with Heme Intake: 1,4-Dihydroxynonane Mercapturic Acid”, (Pierre, 2006).
If red meat has any impact on cancer risk, it’s via oxidizing Ω-6 fats in seed oils in the gut.
TBARS/MDA
TBARS (ThioBarbituric Acid Reactive Substances) gives me a headache, but it’s a common, if nonspecific, indicator of seed oil oxidation products (Devasgayam, 2003), and should be a readily-available test for blood samples. One of the primary things it reacts to is linoleic acid hydroperoxide, one of the immediate and immediately-toxic oxidation products of the primary fat in seed oils (Ohkawa, 1978).
DHN-MA
TBARS
C-Reactive Protein
CRP is a commonly-used risk marker for heart disease risk. A meta-analysis of linoleic acid consumption found that:
“However, in subjects with greater increase in LA intake, LA tends to increase the blood concentration of CRP.” (Su, 2017)
“Nonsignificant” in this next paper refers to p-value, which we ignore. It doesn’t meant clinically non-significant.
“For acute-phase proteins, there was a notable but nonsignificant increase in CRP, SAAt, SAA1t, and SAA2t after the [Ω]-6 supplementation (Table 1 and Fig. 2).” (Grytten, 2025)
This is because CRP binds to oxidized linoleic acid or related molecules (Chang, 2002).
“…The endogenous acute phase protein C-reactive protein (CRP), which is typically induced during infections such as pneumonia, binds to oxidized phosphorylcholine present in OxLDL and on apoptotic cells. This binding was found to promote the clearance of apoptotic cells and contribute to the resolution of inflammation.” (Matt, 2015)
CRP
DNA Damage
One of the odder, more ominous aspects of seed oil consumption is the ability to damage and mutate DNA. This can result in auto-immune reaction to DNA, for instance (Toyoda, 2007), as well as general dysfunction.
DNA damage is seen in a variety of diseases where it might not be expected, for instance in fatty liver, atherosclerosis, and of course in cancer.
8-OHdG (or 8-oxodG, 8-Hydroxydeoxyguanosine or 8-oxo-2′-deoxyguanosine) is a commonly used marker of DNA damage, and can be caused by oxidized linoleic acid in conjunction with iron.
“The formation of 8-oxodG by lipid hydroperoxides seems to be due to the generation of reactive species other than superoxide radicals and hydrogen peroxide. These results indicate that some species formed during the reaction of lipid hydroperoxides with ferric ion can cause oxidative damage to DNA.” (Kaneko, 2000)
8-OHdG/8-oxodG
Endogenous Antioxidants
Antioxidants produced by the body are critical defenses again lipid peroxidation from increased PUFA intake.
Checking glutathione (GSH) and the GSSG ratio would be an interesting indicator.
“During acute oxidative stress, GSH concentration decreases and the associated increase in GSSG concentration results in an increased turnover of the GSH/GSSG cycle.” (Jones, 2002)
GSH/GSSG
Insulin Resistance
4-HNE directly induces insulin resistance (Al-Jaber, 2025), and soybean oil can do the same, probably via oxidized PUFAs.
“This study shows that one single [oral] fat load decreases whole-body insulin sensitivity to an extent comparable to that induced by iv fat or low-dose endotoxin administration.” (Nowotny, 2013)
Shulman’s group is at Yale, but I’m sure they’d cooperate with Nick in doing a hyperinsulinemic-euglycemic clamp!
Insulin resistance test
Sunburn
This would be a fun experiment to run. I saw a quick alleviation of sunburn when I cut seed oils from my diet.
There is actually an RCT done showing that added Ω-3 fats from fish oil reduced susceptibility to sunburn (erythema) in as little as a month.
It would be great, since he’s running this experiment in the summer, if Nick would do a before-and-after sunburn test to see if adding Ω-6 increases sunburn susceptibility.
A decreased membrane phospholipid Omega Balance (#7) should correlate pretty well with increased sunburn, although with a lag in skin compared to that from a cheek swab.
Sunburn
Things to Avoid
The damage from seed oils is due to the damage from oxidized fats (primarily linoleic acid, but also from alpha-linolenic acid, especially in cooking).
Ω-3
Nick has a pretty healthy diet and eats a lot of Ω-3 fats, which are protective against many of the negative effects of excess Ω-6 fats. Excess Ω-6 fats reduce Ω-3 fats in vivo (Taha, 2014) as I discussed here:
So we may see smaller effects in Nick than in most people. I would suggest Nick avoid trying to increase his Ω-3 intake, as that would be an obvious confounder. Reducing it to a level more typical of an industrial diet would make for a better experiment, in my mind.
Antioxidants
Similarly, any sort of exogenous antioxidant should be avoided beyond what he consumes in his regular diet. Antioxidant consumption long-term is generally considered harmful, but short-term consumption of extra vitamin E or C could affect the results of this experiment.
Sesame Seed Oil
Nick posted this picture with his X post. I added the red emphasis.
Sesame has long been recognized as unhealthy.
“Sesame seed is hurtful to the stomach and causes a stinking breath in the mouth… Oil is made of it that the Egyptians use.” (Dioscorides, 60; Sandy, 1989)
But it is not a typical component of modern industrial diets. It contains unique antioxidants not found in other seed oils, and is not, therefore, representative of other seed oils. Nick likes it (I use it for flavoring, too) but it would be inappropriate to use it as a significant part of a seed oil experiment.
Conclusion
Aside from the acute nausea described above, I wouldn’t expect to see any short-term effects of an n=1 experiment. No cancer or heart disease, in other words. But diabetes (measured by insulin resistance) and sunburn are real possibilities, and there are plenty of interesting markers that would indicate increase risk for many of the chronic diseases.
So here’s the final list:
Nausea
Body weight
Resting metabolic rate (RMR)
Body composition (fat vs. lean)
Flow-mediated vasodilation (marker of CVD risk)
Fatty acids in red blood cells (Ω-3 vs Ω-6)
Membrane phospholipid Omega balance
Cholesterol
VLDL/LDL/ApoE
ALT/AST (Liver function)
LDL(-) (Oxidized LDL)
OxPL/ApoB (Lp(a) on LDL)
DHN-MA (4-HNE)
TBARS (MDA & Linoleic acid hydroperoxide)
CRP
8-OHdG/8-oxodG (DNA damage)
GSH/GSSG (Glutathione antioxidant)
Insulin resistance test
Sunburn
And a graphic version:
This should do!
References
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Nick can learn so much - also for the rest of us, who would not try this out. Also,
- no alcohol during the test. Or maybe a 5th "party " week. Heavy drinking and omega 6 do not go well together, if you are a mouse.
Rgds JR
My own personal experience since not eating seed oil (or even straight seeds) since 2012 is that very quickly I stopped getting sunburn and can tolerate any amount of sun exposure. I can be out all day even in the height of summer in shorts and vest and don't burn. I don't even sweat and stay cool to the touch. It's fascinating! Before ditching seeds and seed oil I was intolerant of the heat and burned very, very easily. It's so much easier now!