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Artificial Sweeteners
The Not-So-Sweet Truth About Zero-Calorie Sweeteners

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There’s been debate over whether “you can have your cake and eat it too,” i.e. whether zero-calorie sweeteners are safe to eat or, in the long-term, are detrimental to health.

The short answer is “no,” and here are three reasons why. Many artificial sweeteners:

  • (I) spike your blood sugar just like real sugar, setting you on the “insulin roller coaster”
  • (II) screw up your microbiome to cause glucose intolerance
  • (III) mess directly with your neurochemistry and brain function!

If you prefer to watch a video explaining this in detail, click here.

Artificial Sweeteners: The Not-So-Sweet Truth About Zero-Calorie Sweeteners

1. Do Artificial Sweeteners Drive Hormonal Hunger?

Let’s start with blood sugar spikes and the insulin roller coaster. When it comes to your body’s hormones, insulin is like your blood glucose’s shadow. When you blood sugar goes up, insulin tends to follow. The problem is that many sweeteners spike your blood sugar, which then comes crashing down.

The insulin roller coaster refers to the hormonal shifts that pattern this rise and fall in blood sugar, which research reveals activates the reward center of the brain, the nucleus accumbens, and drives the sensation of hunger ( 1).

The punch line is that most artificial sweeteners drive hormonal hunger (which is different from when your body is truly hungry for nutrients), compelling you to eat every few hours, constantly spike your insulin, and remain on the sickening coaster.

Most artificial sweeteners drive hormonal hunger, compelling you to eat every few hours, constantly spike your insulin, and remain on the sickening coaster.

2. How Do Artificial Sweeteners Affect the Microbiome?

But, in my opinion, an even scary facet of artificial sweeteners is their potential impact on the gut microbiome — the community of microorganisms that live in our gastrointestinal systems and govern almost every aspect of our health.

Artificial Sweeteners in Mice

And paper published in the journal Nature ( 2) reveals a shocking truth that is anything but sweet. The researchers behind this paper began by examining what happened to different groups of mice fed any of three different artificial sweeteners (saccharin, sucralose, and aspartame) as compared to mice fed normal sugars (glucose and sucrose).

Worryingly, all of the mice that were fed the artificial sweeteners quickly developed glucose intolerance, a harbinger of diabetes, obesity, and metabolic disease. The researchers also noted that the artificial sweeteners altered the mice’s gut bacteria.

To test to see if the change in the gut bacteria caused the artificial sweetener-induced metabolic disruption, the researchers transplanted the gut bacteria from the mice fed artificial sweeteners to mice that had no gut bacteria. Sure enough, the recipient mice became glucose intolerant as well, proving the change in gut bacteria was mediating the negative health effects of the artificial sweeteners.

Artificial Sweeteners in Humans

But mice are mice and humans are humans. If the story stopped there, maybe we could shrug off the results and play ignorant, enjoying our Splenda in our morning coffee guilt free. Damn scientific rigor…

The researchers next examined whether there was an association between artificial sweetener intake and poor health in humans. Sure enough, a higher intake of artificial sweeteners was associated with a greater weigh-to-hip ratio (a marker for obesity), higher fasting blood sugar, and higher HbA1c (a marker for diabetes).

But that’s not all… To prove the causative effect of the artificial sweeteners in humans, the researchers gave 7 healthy people who did not normally consume artificial sweeteners, foods containing artificial sweeteners for 1 week.

In just 1 week, 4 of the 7 people developed glucose intolerance. What’s more, when the microbiomes from these people were transferred into mice without microbiomes, those mice also became glucose intolerant. This demonstrates that artificial sweeteners can screw up the gut microbiome in humans to cause glucose intolerance and metabolic imbalances that pave the way for obesity and chronic disease.

Both animal and human data show that artificial sweeteners can screw up the gut microbiome to cause glucose intolerance and metabolic imbalances that pave the way for obesity and chronic disease.

3. How Do Artificial Sweeteners Affect Brain Function?

Finally, artificial sweeteners can directly negatively impact neurochemistry and brain function. Let’s use aspartame, the sweetener in Diet Coke, as an example. Mechanistically, aspartame can block the uptake of precursors for important neurotransmitters, like dopamine and serotonin, into the brain ( 3).

In rats, aspartame has been shown to alter activity in critical brain regions like the amygdala, the fear and anxiety center, and the cerebral cortex ( 4). The mechanisms and animal data align with associations that have been observed in humans. Specifically, aspartame consumption has been linked to learning problems, seizure, migraines, irritability, headaches, depression, and insomnia ( 5)!

Don't use aspartame. Aspartame consumption has been linked to learning problems, seizure, migraines, irritability, headaches, depression, and insomnia.

What Are the Best Low-Carb Sweeteners?

But let’s get practical. Not everyone is going to forgo sweet flavors, and that’s totally fine. So long as your decisions are informed and purposeful towards achieving your highest quality of life, I’m proud of you. And if sweetness if going to be part of that equation, here are some options to consider.

First, erythritol and stevia don’t appear to have the same negative impacts on glucose and/or insulin, the microbiome, or neurochemistry as many other sweeteners.

Opt for sweeteners made with stevia and erythritol. They don't affect blood sugar, insulin and they don't appear to have overtly negative impacts on the microbiome, neurochemistry and brain function.

Neither are insulinogenic (beyond a tiny little burst of insulin you release when your tongue tastes anything sweet), neither appears to screw up the microbiome (erythritol is mostly absorbed in the small intestine, and the 5% that makes it to the colon doesn’t usually get fermented by gut bacteria; and stevia also doesn’t appear to have overtly negative impacts on the microbiome), and neither erythritol nor stevia dramatically messes with neurochemistry (at least not to my current awareness).

But besides these two non-caloric sweeteners, you can try to go all natural and hack it with fennel or vanilla. Fennel (which contains 4 grams of net carbs per 100 grams, raw) contains anethole, a natural compound that is 13-times (6) sweeter than sugar.

Vanilla is a base flavor in many sweets and, thus, overtime your brain has learned to associate vanilla with sweetness. As a result, when you have vanilla alone, your brain is prone to perceive sweetness in the absence of sugar. So, returning to our original question, “can you have your cake and eat it too?” I’m not sure. I wonder if Martina can develop a fennel-vanilla cake?

Fun fact: Why does fennel taste sweet? Fennel (which contains 4 grams of net carbs per 100 grams) contains anethole, a natural compound that is 13-times sweeter than sugar!

Take Home Message

Most artificial sweeteners spike your blood sugar, stimulating "hormonal hunger" and compelling you to eat when your body doesn't need food.

Artificial sweeteners also tend to mess up the gut microbiome, leading to glucose intolerance and other metabolic maladies, and can even directly screw with neurochemistry in your brain!

If you need a sweet taste, erythritol and stevia are the best options. Fennel is a great vegetable because it contains a naturally sweet chemical, anethole, but is super low-carb. Vanilla is great to use because it tricks your brain into perceiving sweetness.

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Nicholas Norwitz
MD-PhD candidate at Oxford University

Nicholas Notwitz

Nicholas Norwitz is a Harvard medical student and Oxford PhD researcher who specializes in ketone metabolism. He a rising star in the scientific community, with peer-reviewed publications on topics ranging from brain health to bone health to heart health to gut health.

Informed by his own medical history, he has an infectious passion for food as medicine and a drive to find innovative ways to teach the general public about the latest nutrition science.

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Comments (19)

AB: "Mannitol has apparently major benefits for PD says Israeli research. Why?"
Someone on Twitter just asked be about the sugar alcohol, Mannitol, for Parkinson's disease. For the general population, erythritol is the best sugar alcohol least likely to have side effects because its metabolism in the body is different from those of other sugar alcohols (xylitol, sorbitol, and mannitol). However, there is some early research on Mannitol suggesting that it could be useful in Parkinson's disease. At this stage, the research is primarily pre-clincal. A phase II clinal trial is due to complete in December of thise year (2020). It will be interesting to see the results. Personally, I wouldn't make too much of the data at this time but if someone does have PD, it's up to them to determine whether the potential pros outweight the potential side effects. If I were them, I'd probably say yes (but read more first ;)).
TY AB for the question.
Nice lay article: https://scienceofparkinsons.com/2018/05/30/mannitol/
Ongoing trial: https://clinicaltrials.gov/ct2/show/NCT03823638?term=mannitol&cond=Parkinson+Disease&draw=2&rank=1

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This is really interesting Nick! I was trying to find mannitol a while ago and it seemed to be very rare, at least back then. Just to clarify for others, do not confuse mannitol with maltitol. Maltitol is a lot more common in "sugar-free" treats and should be avoided as it can spike your blood sugar levels.

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VERY good point Martina! Thanks.
Take a look on wiki at how different they look:
https://en.wikipedia.org/wiki/Mannitol
https://en.wikipedia.org/wiki/Maltitol

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I really enjoyed this video, and am looking forward to more!! In the meantime, do you have a favorite resource to help identify the GI of foods?

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Glad you enjoyed Beth! No, I don't have a go to resource myself but on a quick internet search I think this may be helpful: https://www.glycemicindex.com/foodSearch.php
It allows you to not only search foods but also specify parameters like GI less than X or food category.
If you don't like that one, this one may be good: http://www.gilisting.com

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Nick, can you make a lecture on necessary balance of SFA, MUFA if any on a keto or low-carb diet?  I am wondering if its necessary for those who are not ApoE4 to not consume their entire fat through saturated fats. Avocado oil, Macadamia nut oil,  high quality EVOO, hazelnut oil are very rarely consumed and available in South Asia, so they are 4*x the European, American price. So wanted to know if I can do a healthy keto with just cold-pressed coconut oil, ghee or other saturated fat sources.

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Noted.  I will definitely consider a diet for ApoE4 lecture in future. I can't comment on keto with just coconut oil, ghee (>50%) saturated fat but will clarify that non-dairy animal fat contains saturated fat but at levels <50%. Regardless of your saturation profile, key will be your omega-6/3 ratio. Fatty fish (salmon, mackerel, sardines) & roe/caviar. I believe my next blog to be posted will be all about omega-3s. Martina has it and it just needs to be type-set. Also, if I could politely ask you to keep questions on a given blog specific to the topic of that blog for the sake of others, we'd appreciate it. - Cheers

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1) Is https://bochasweet.com/ a better sweetener than erythritol in affects on gut microbiome?
2) Is lucuma powder an alternative to stevia/erythritol for sweetening?

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1. Bharat, thanks for the question and for bringing bochasweet to my attention. I’d never never of it and, given that the companies copyright is 2020, it appears new to the scene. The website you linked to looks very professional and I see how it would appear convincing in terms of its contents. The story they tell is basically that Japanese people live a long time. They also include in their diet a particular type of pumpkin, Kabocha. This pumpkin has nutrients that are presumed to be healthy. They extracted the pentose (five-carbon sugar) from the pumpkin and sell it as a sweetener.
This sort of stringing together of “evidence” is great for advertising purposes, but is truly meaningless when it comes to the product you’re buying.
The fact that Japanese people live a long time and the fact that they eat some special pumpkin does not mean it contributes to their longevity.
Also, it’s just a pumpkin and, like all vegetables, it’s going to have micronutrients that people can flash as healthy and contributing to longevity. This is true for almost all real foods.
But the kicker is, just because the pumpkin has purported benefits, says nothing about its sugar extract.
I also did a pubmed search for terms like, bochasweet, Kabocha extract, kabocha diabetes, kabocha glucose, kabocha insulin, etc. and nothing came up. I couldn’t find good a paper saying anything positive about this special pumpkin and, more specifically, it’s pentose sugar.
I further found the absence of cited evidence (on the website I couldn’t find links to the studies they talk about, nor could I easily find them online – maybe they are just in Japanese?) interesting in light of contradictions found on the website and Amazon. For example, the website reads, “The 5 carbon kabocha pentose could be utilized by the body as a pure source of energy“ but they say it’s zero-calorie. Am I missing something or is that a direct contradiction.
I’d be happy to take a deeper look if you have data on this sugar, but I think it’s just marketing and that there is little-to-no data on this pumpkin sugar.
2. Lucuma powder is sugar plus fiber. While a tablespoon of sucrose is 45 calories of sugar, a tablespoon a lucuma is 30. Is that an answer for you?

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Thanks Nick. Regarding lucama powder, Martina herself used it for her white chocolate recipe, so I thought it is good enough in small amounts like she did in her recipe 🤔

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I think it's ok if you use it as a supplement in small amounts but it is definitely the kind of ingredient to keep an eye on. There are other similar examples of foods that are acceptable in small amounts, for example arrowroot powder (often used instead of cornstarch), cashew nuts, 85-90% dark chocolate etc. Ia always it depends on your goals and how clean you want your diet to be.

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Thanks Martina. I understand why you said cashews/arrowroot powder are preferred to be eaten in smaller amounts but could you explain further on 85% dark chocolate? Isn't eating an organic dark chocolate containing only organic stevia, cocao actually good for health? Lets say 30-40g daily?

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Sure! This doesn't apply to chocolate bars sweetened with stevia or erythritol but only to chocolate bars that are sweetened with sugar (fine in small amounts, at least for most people). If you're aiming for perfection, then it's best to use 100% chocolate and add (optional) sweetener and/or some cacao butter (that will make it mild/less bitter).

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Thank you very much for this, I loooove the video. Such an eye opener about calories, explains why it never worked for me. I was so surprised to learn that gorillas can convert cellulose to fat, did I get that right?
I have one question if that's ok. What do you think about Sucralose? I've seen mixed articles about this one. Much appreciated!

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Emily, I'm glad you liked the lecture and thank you for the compliment and question! Yes, gorillas can turn fiber into fat at high rates (short chain fatty acids, to be specific), and this fat provides them with 60% of their caloric needs.
(i) Regarding sucralose. It was included in the microbiome Nature study referenced in the blog (reference 2).
If you can access the paper, you can check out Figure 1A-B which show that it causes glucose intolerance in mice as well. The researchers chose to do the human experiments just with saccharin, but since the response in mice and humans to saccharin was the same, I’d expect the response to sucralose to be the same as well. In other word, I think sucralose would risk the integrity of your microbiome and lead to glucose intolerance.  I’m also aware of other rodent studies that show similar negative effects of sucralose on the microbiome. Additional concerns regarding sucralose are as follows:
(ii) It’s potentially insulinogenic. This might not be a direct effect, but rather primarily either a cephalic phase response mechanism (which is us that anything that tastes sweet causes some insulin release) and/or via increasing the expression of other food-responsive hormones first, like GLP-1, which it has been shown to do in some studies. Since GLP-1 it satiating, I can imagine that short term trials of sucralose could be constructed to show sort term beneficial effect, though I doubt they would translate into long-term benefits. Having said all this, I do know of a study showing sucralose does increase insulin response in women (linked below).
(iii) Sucralose may affect the pharmacokinetics of certain drugs by changing the levels of certain transporters in the gut, like P-glycoprotein, CYP3A, and CYP2D1.
(iv) if you heat sucralose above 120C, it begins to generate compounds called chloropropanols, some of which are carcinogenic. (As an aside, other sources of the cloroproanol, 3-MCPD, are margarine, vegetable oils [olives and avocados are fruits, thank goodness], preserved meats and some breads. Also, it can cross the blood brain barrier, uh oh…).
I could go on generating a list of cons, but I think you can gather what my stance is. Admittedly, I set a very high bar for nutrition. I’m sure you can find others who would tell you there is conflicting evidence over sucralose safety. But my question to such people is always, “Why risk it to get the sugar-free biscuit?”
;)
Sucralose causes poor glycemic response, Nature: https://www.nature.com/articles/nature13793
Sucralose increases insulin response to glucose : pubmed.ncbi.nlm.nih.gov/23633524/
Splenda changes transporters in gut (and alter microbiome): pubmed.ncbi.nlm.nih.gov/18800291/
Sucralose review: www.ncbi.nlm.nih.gov/pmc/articles/PMC3856475/

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Nick, thank you so much for taking the time to reply in such a great detail! This is the best explanation I've seen so far and confirms my skeptical thoughts on Sucralose. Still I had no idea it could release carcinogenic compounds when heated! Even more reasons to avoid it, especially when there are better options.
More sweetener questions 😊 ... Any thoughts are on Choc Zero syrups? I think they are made from soluble corn fiber and don't seem to spike my blood sugar. It's thick and tastes so good, but maybe too good to be true?
Finally Allulose... I've been using this one for a while now and like it. Any thoughts on Allulose?

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No worries Emily. I'm glad you found my response helpful. In terms of Choc Zero, the ingredients are, "Soluble Corn Fiber (Non-GMO Resistant Dextrin), Cocoa Powder, Natural Chocolate Fudge Flavor, Coconut Oil, Monk Fruit Extract" Starting with the sweetener, Monk fruit extract is considered among the better sweeteners. I'm not aware of negative effects, including on the microbiome, of including a reasonable amount of monk fruit extract in the diet. The coconut oil component is certainly refined, which isn't great. But if you're only using 1 Tbsp of the Choc Zero that's only about 1/10 Tbsp of coconut oil, so also probably fine. I have no clue what natural fudge flavor is, but it's definitely not natural. Probably won't kill you. Cocoa powder is fine. Then there is the soluble corn fiber/non-GMO resistant dextrin. This is what is known as a "resistant starch." I wrote a video for Thomas DeLauer all about them that you can find here: www.youtube.com/watchFilter (I plug it in part because he is PRing a book we wrote on Medi-Keto diet, due to come out March 9). I could drop the video notes/studies here, but it's longish so I will only do so if you reply you want me to. If you feel you need a sweet taste, Choc Zero is probably on okay option.
Regarding allulose, see Patrica P's question below

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Thanks Nick for another awesome blog!!! That’s an awesome Nature study. I didn’t know that about the microbiome! Yikes!!!
I also noticed you didn’t mention allulose. Do you have an opinion on it?

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Thank you Patricia. I’m glad you enjoyed the blog. I could have called that allulose would be the topic of a question. In short, I think it’s a fine option for those who want to use low-cal sweeteners. Still, here are some thinks you’re should know about it:
(I) it’s natural, not artificial (stevia is the same).
(II) It’s not quite zero calorie, but it’s caloric content is only 1/20-1/10 that of normal sugar.
(III) It weakly inhibits certain enzymes important for breaking down starch and disaccharide sugars and also weakly inhibits glucose absorption. This may account for its ability to slightly attenuate post-prandial spiked in blood sugar (it’s even been considered in the context of diabetes: https://www.sciencedirect.com/science/article/abs/pii/S016372581500162X?via%3Dihub ).
(IV) Having said that I don’t know if the ability of allulose to inhibit glucose uptake is necessarily beneficial long-term given the putative/unknown impact in the microbiome. (If you are keto, this effect isn’t as relevant as you’re not eating starches or many disaccharides: maltose in cereals, lactose in milk/yogurt, sucrose as processed sugar). Also, the retention of carbs in the lumen of the GI system is associated with GI upset that has been reported. Personally, I’m very conservative and cautious when it comes to my microbiome. But that’s me.
Hope that helps and thanks for the Q!

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