---
title: 'A 40% Energy Rescue for the Aging Brain in Clinical Trial | Dr Stephen Cunnane'
source: 'https://youtube.com/watch?v=XqvXzesMbo4'
video_id: 'XqvXzesMbo4'
date: 2026-08-04
duration_sec: 669
---

# A 40% Energy Rescue for the Aging Brain in Clinical Trial | Dr Stephen Cunnane

> Source: [A 40% Energy Rescue for the Aging Brain in Clinical Trial | Dr Stephen Cunnane](https://youtube.com/watch?v=XqvXzesMbo4)

## Summary

Dr. Stephen Cunnane discusses the BENEFIC trial, a clinical study funded by the Alzheimer's Association, which investigated the effects of medium-chain triglycerides (MCTs) on brain energy metabolism in patients with mild cognitive impairment (MCI). The trial aimed to correct the brain energy deficit by providing exogenous ketones, showing that MCT supplementation can reduce the brain energy gap by 30-40% at peak ketone levels, with cognitive improvements correlated to the degree of energy correction.

### Key Points

- **Theory Behind Ketones** [00:04] — The root cause of cognitive decline may be reduced glucose uptake in the brain, which can be addressed with ketones as an alternative fuel.
- **BENEFIC Trial Design** [00:18] — The BENEFIC trial was the longest controlled trial of medium-chain triglycerides in mild cognitive impairment, funded by the Alzheimer's Association of the USA, with 19 completers in the placebo group and 20 in the active group.
- **Metabolic Outcomes** [01:11] — The study used brain PET imaging to measure glucose and ketone uptake at start and end, focusing on metabolic outcomes to establish improvement in brain energy status.
- **Cognitive Improvements** [01:54] — Cognitive improvements in memory, executive function, and language were positively related to the extent of reduction in the brain energy gap.
- **MCI Criteria** [02:23] — Participants had to be over 55, have a subjective memory complaint, and score at least one standard deviation below normal on one of five cognitive domains.
- **Intervention** [03:19] — Participants received 30g of medium-chain triglyceride per day, emulsified in 250ml of low-fat cow's milk, split into two doses (breakfast and supper).
- **Energy Gap Reduction** [05:24] — The brain energy gap was reduced by about 30-40% at peak ketone levels, but over 24 hours, the average reduction was likely less than 10% due to the short half-life of ketones.
- **Splitting Doses** [06:53] — The MCT was split into two doses to create two peaks of ketones and reduce gastric side effects, with a ramp-up period starting at 5g to improve tolerance.
- **C8 and C10 Composition** [08:05] — The MCT mixture was 55% C8 and 35% C10, with C8 being more ketogenic than C10. The choice was based on availability and regulatory approval in Canada.
- **Placebo Use** [09:38] — A placebo was essential to reduce bias in cognitive testing, as the subjective nature of tests could be influenced by the administrator or participant.

### Conclusion

The BENEFIC trial demonstrated that MCT supplementation can partially correct the brain energy deficit in MCI, with cognitive benefits linked to the degree of correction. However, the effect is transient, and more frequent dosing or more potent ketogenic agents may be needed for sustained improvement.

## Transcript

BENEFIC trial. So the So the theory is, right, that we and the root cause is that the glucose is not taking up, but we can kind of address it with uh ketones.
So you ran a trial, the BENEFIC trial, where you were you were giving people uh exogenous ketones, well, MCT oil. So could you
trial? You What was the design? How many people were there? And what was uh some of the key outcomes? So the BENEFIC trial was um I think it still is the the longest
control trial of of medium-chain triglyceride in mild cognitive Um it was funded by the Alzheimer's Association of the USA. Um and we had a ceiling, we had a a budget that allowed us to study
call completers, people who have completed the intervention, uh in both groups. So a placebo group and and an active group. And I think we had 19 in one and 20 in the other. Um and it was expensive because we were
doing the brain PET imaging, the glucose and the ketone uptake at the start and at the end of the study because the purpose was a metabolic outcome. The purpose was to establish to what extent have we improved the
metabolic status, to what extent have we reduced the brain energy gap in mild cognitive impairment. Cognitive outcomes were of interest and beginning and then 6 months later, but they were a secondary outcome because we
knew the study wasn't powered to uh be sure about uh whether or not we were onset of Alzheimer's disease in these patients. So the metabolic outcomes showed that the ketones were getting into the brain.
They showed that the uh that uptake of ketones was was variable. Some people had a big improvement. Some people had a smaller improvement. And the improvement on cognitive outcomes was positively related in terms of
memory, in terms of executive function, and in terms of language to the extent to which we reduced the brain energy gap. That's what the first paper of of benefit paper published in 20 19
Right. And these were people with MCI. It's kind of clinical Yeah, I didn't impairment, which means two criteria for that. Three criteria.
They had to be over 55 years old. They had to have a subjective memory complaint, which means I'm worried about my memory, yes or no. If the answer is even if your spouse thinks that you definitely should be worried about your
your memory, if you say it's no, then you're not eligible. And the third is that on of the five major domains of cognition for which we have the battery of tests that we do at the start, they have to be
one standard deviation below the normal value on score for the score on at least one of those domains to be considered objectively memory impaired. So, a mild cognitive impairment, any one
of those five domains. Okay. And what was the intervention that these people were given? They were given 30 g of medium-chain triglyceride per day.
So, when we got funded by the Alzheimer's Association, we had proposed that we were going to make this emulsion of a medium-chain make this emulsion of a medium-chain triglyceride in in cow's milk in in in
low-fat cow's milk. Um we had never done that before. And we weren't quite sure how to do it. We weren't sure how long it was going to last. We we got up to speed reasonably
well, but we ended up with a sterilized product that people got an emulsion emulsification of 30 g of medium-chain triglyceride in 250 mils of milk in each A a cup. In American terms, a cup. A 250
ml of of this drink, half at breakfast and of of this drink, half at breakfast and half at supper. reasons. Our preliminary studies suggested that most people weren't going
to take more than that, weren't going to tolerate more than 30 g a day. that and let's hope let's cross our fingers that the you know, enough people are going to finish the study that we can actually interpret the results." We
didn't know the extent to which 30 g of medium-chain triglyceride would help correct the brain energy gap cuz it had never been measured. been good to know before we'd started, but you know, sometimes
uh you don't have all the pieces of the puzzle ready to to to to ask you know, to before starting a what was for us a major clinical study. It was a still a us. With the PET imaging and the supplement
blood samples, um it was quite an involved uh study for us to do. Did you Did you look at how much Did you Did you look at how much the energy increased? The brain energy I
did What was that? So, I I I'll give you the the the it has to be qualified by the what I'll say afterwards. So, the the gap was reduced by about 30 to 40%.
So, the glucose should be going in it's down about 7 to 8% from where it should be in in a cognitively healthy older person. And we we improved that to down by down by about 4 to 5% instead of 7 to 8%
roughly speaking. The but that's that's difficult to um to generalize and that's why I'm sort of hesitating because when you take a dose of these ketones of of the MCT, the ketones go up and but they'll be
back down within 2 and 1/2 to 3 hours. So, the degree to which you correct the energy deficit depends on where you are on that curve and at the peak of the ketone levels in the blood, we're correcting about 40% of the energy gap.
But for the rest of the time we're we're correcting less than that. supplement, you get a peak maximum of maybe for 15 40% of the energy gap, but otherwise you're contributing you're correcting
you're contributing you're correcting zero zero to maybe 20%. So, over 24 if we improve the reduce the brain energy gap by more than 10% I'd be surprised. Right. So, I was going to ask why split
Right. So, I was going to ask why split the MCT into two chunks? Was it A to give two peaks or was it to give two peaks or was it to reduce gastric possible gastric problems? Both. Both. Even if there were no
gastric problems, we would have split it. We would have split it more than that, but we were strongly advised not to try to to uh re- require people to take it more than twice because it's just too much annoyance during the day
and if you want to go out and play golf this afternoon, you've got to bring your know, you're going out on a picnic. All all the reasons all the good reasons people have for forgetting it or not not wanting to bother. So, two we figured
was the most we could expect twice a day. Um and there were would have been side effects, so we you reduce the side effects, but that could all of them started out of a smaller than those than the 15 g at breakfast
and 15 g at supper. They all started about five and within 10 days or so, they were they ramped up and and the intestine and the microbiome seems to adapt under those circumstances better than going in cold turkey.
a C8 and C10. Yes. Yeah. Can you go into any more detail? We What were the percentages and how [clears throat] kind of sure are you that this is or how how strongly do you
feel that this is perhaps the best mix to uh create ketones? Be- Because basically the MCT goes into the liver, right? And then you create ketones from it. Yeah. I So
Well, it it it So, and back in 2015 when we started the study, when we got funded, uh there were no alternatives. There was nothing that was available to to replace them or if they were, they
we weren't aware of it in in Canada at the time. And we have a regulatory Canada, which uh regulates the use of of of
natural food products, they call them. So, a ketone ester or a ketone salt would have to receive Health Canada approval to be used in a clinical study. Whereas, MCT were already on the market in Canada. So, the those were the two
logistical reasons why it it it was the it was the the product of choice. The mixture that we used, I didn't know at the time that C8 and C10 actually had a different ketogenic effect. So, C8 is moderately more ketogenic than C10.
Uh but the two of them together were over 90% of the MCT. Uh 55% and and 35% I think were the ratios for or are percentages for C8 and C10.
it's sort of thing you should we should have known beforehand, but we didn't than C10. Um and but I'm glad we ended up using Um and we were able to produce a placebo, which is is
absolutely essential in this sort of study because so much of the evaluation is is not subjective, but it's it's open to influence. When when you're sitting across the desk from me doing your test uh your memory test, your trail making
uh your memory test, your trail making test um for instance, um it's it's unconsciously, it's easy for you to look for help from me or for me to offer help for help from me or for me to offer help from you to you, whether it's time or uh
something and it if and that's going to happen. you're on and I don't know and you don't know which product you're on, then it it it all comes out in the wash. Uh and and the the subjective effects of
Uh and and the the subjective effects of having a person-to-person available for for uh more ketogenic uh um exogenous ketones that are available today. Um you you can make your own placebo for the ketone
esters uh and for the for the salts um in-house as we did with the MCT, but um it wasn't available at the time anyway. So uh we were one of the first to do
So uh we were one of the first to do this.