#21

Tell me about it. Came to same conclusion couple years ago. I did not seem to notice anything at all and decided to scrap it. I’d rather take/replace it with ginger and/or garlic extract if I wanted to go that route.

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#22

Sorry, I don’t do anything that is painful, even if it may have some benefits.
Painful workouts cause burnout, and people stop exercising because they associate it with pain.

No, I do not know of any alternative to galantamine. The synergistic positive effect of galantamine+metformin was news to me. I order galantamine from India.
I paid ~50 cents for a 4 mg tablet, which was stupid because the 8 mg tablets are essentially the same price.

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#23

I cannot believe Metformin eliminates all benefits of aerobic exercise. And, Metformin might not have any negative impact on your partner’s exercise adaptation. Everybody is different. I wouldn’t assume anything.

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#24

Let me put my 2 cents :slightly_smiling_face: , Joseph. Berberine is one of the few substances that can really kick off the AMPK cascade, both in the lab and in the body. It’s not just about blood sugar — that’s just one part of the story. AMPK activation supports fat burning, autophagy, and better mitochondrial function.

If you want to get the most out of it, try taking a solid dose (like >1000 mg) about 3-4 hours before cardio or HIIT. This lines up with its timing in the body, so it’s fully active when you’re exercising. Also, skipping your post-training meal for an hour can keep AMPK running longer…

Currently, Berberine is only pre-train for “AMPK” training, which in my eyes not interfere with natural body response to training. Studies are not so clear about cup of green tee with 60mg of EGCG - but I am also taking it sometimes as pretrain.

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#25

@SilentWatcher interesting. I guess you don’t worry about a Metformin like inhibition of adaptation to aerobic exercise? I didn’t know that such an interference effect existed with berberine until it was pointed out here (Attia thinks so) but I never wanted lower blood sugar before exercise anyway so I didn’t take berberine before exercise. I also don’t eat any carbs in the few hours before exercise to avoid a rebound hypoglycemia (except for an apple 30 minutes before).

I guess I’m good for now relying on my aerobic exercise alone for an autophagy stimulus plus any benefits related to insulin sensitivity, cardiac remodeling, vascularization, mitochondria biogenesis. I’ll keep thinking about it, though. Thanks.

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#26

Attia mentioned in an interview that he looked at the evidence on berberine ‘a long time ago.’ Here, I will cite some studies referenced on Rhonda Patrick’s site:

Like berberine, metformin activates AMPK and other cellular pathways that reduce oxidative stress and damage. Evidence suggests that metformin inhibits mitochondrial adaptations and improvements in cardiorespiratory fitness and diminishes whole-body insulin sensitivity after aerobic exercise.[46] Due to berberine’s effects on AMPK activity and the subsequent reduction in reactive species, some researchers have posited that berberine may similarly blunt the effects of exercise.[47] However, an intervention study that investigated the effects of berberine and circuit training in sedentary, overweight men found that berberine enhanced the effects of exercise.[48] Similarly, berberine potentiated the effects of aerobic exercise in diabetic rats as evidenced by higher levels of antioxidant enzymes in the animals’ pancreatic tissues.[49] Exercise to exhaustion can induce damage to the heart muscle, but berberine attenuates the harmful effects of exhaustion-induced heart damage in mice, likely via its inhibitory effects on the release of reactive oxygen species and apoptosis of cardiomyocytes.[50]

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#27

Hmm… this is an interesting idea — thank you for the food for thought. I was still in the habit of consuming moderate, slow-digesting carbs before cardio/HIIT.

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#28

Hi
So you don’t feel anything bed during prolonged endurance exercises or a high intense interval training?
I was always concern about the reduction on the glucose availability.
Thanks

#29

About avoiding carbs after exercise.

So you are not focusing on improving recovery for the next training on the same day or the day after?

After exercises our muscles are extremely avid to absorb glucose, so why would you avoid it?

Thanks

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#30

I don’t avoid carbs after exercise. I avoid carbs in the 2-3 hours before exercise to avoid an insulin effect called rebound hypoglycemia. It happens to some people but not most. When I eat fast carbs in particular including fruit a few hours before I exercise, my insulin rises to tell my organs to take up the glucose. When I start exercising, my muscles also start to take up glucose in a non- insulin mechanism. The combination results in too much glucose being taken out of my blood causing my brain to shut me down (weakness, tiredness). If I don’t eat carbs until I am warming up or just a few minutes before I start exercising, then the problem is avoided (less insulin is produced). The effort and complexity I will tolerate in my solution will depend on the event. A race will demand a lot of attention. A workout less so. A short workout even less.

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#31

Hello

Check this last opinion of Attia about metformin. He changed his mind about it.

What do you guys think @John_Hemming @RapMet @约瑟夫_拉维尔 @RapAdmin @SilentWatcher @DeStrider @DrFraser

Thank you guys.

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#32

I’ve always been a fan of Metformin up to 1 g daily. I personally take 500 mg daily. My dad takes Metformin and his muscles are as strong as ever. Only statins caused us muscle weakness.

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#33

I think it is interesting that Attia hasn’t moved towards berberine vs metformin. I think it is because berberine is very weak compared to metformin, which is a very effective drug to lower blood sugar. The only knock is the PROVEN negative effect on exercise adaptation. Attia does not dispute those results in this video but only speaks to lactate rise from metformin coming from the liver instead of the muscle. I don’t see why that matters nor do I believe it. I found metformin made aerobic exercise much harder…I couldn’t sustain high heart rates for as long without metformin.

So, if you need to lower blood sugar, metformin is a great drug. If you are looking for a longevity boost but don’t want to lower your vo2max, look elsewhere.

I take metformin around my rapa dosing (1000mg 3 days out of 14 days)

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#35

I just started taking berberine, sanctioned by my nephrologist, for Stage 3 kidney disease. Metformin, on the other hand, is contraindicated for the same condition. A paper posted here before says that berberine “inhibits the production of uremic toxins,” which has a positive effect on kidney function.

https://www.sciencedirect.com/science/article/pii/S2211383522005184

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#36

Metformin inhibits mitochondrial complex I, which is essential for energy (ATP) production during aerobic exercise. This inhibition reduces ATP production and increases AMP (adenosine monophosphate) levels, thereby activating AMP-activated protein kinase (AMPK), a key regulator of cellular energy balance. Due to metformin’s pharmacokinetics, its effects on AMPK activation can persist for 6-12 hours and beyond after a single dose and beyond. This prolonged activation of AMPK can suppress mTOR (mechanistic target of rapamycin), a crucial pathway for muscle protein synthesis and recovery.

Given these effects, it seems logical to avoid metformin before and after Zone 3-5 running, HIIT, or strength training. These forms of exercise rely on ATP production from glycolysis and oxidative phosphorylation, and mTOR activation is essential for muscle repair, hypertrophy, and adaptation. Metformin’s sustained activation of AMPK can blunt these critical adaptations.

However, I have a speculative hypothesis regarding Zone 2 cardio. Unlike Zone 3-5 running or resistance training, Zone 2 cardio relies primarily on the aerobic system for energy production. In this case, the goal is not to drive mTOR-mediated hypertrophy but rather to increase mitochondrial density, improve metabolic flexibility, and enhance fat oxidation. The primary adaptation to Zone 2 cardio is driven by PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), which is stimulated by AMPK activation.

Here’s where metformin might help:

  1. AMPK Synergy: Since Zone 2 cardio naturally depletes ATP (converting it to AMP), it already activates AMPK. Metformin’s ability to inhibit mitochondrial complex I further amplifies this signal, leading to a stronger AMPK cascade.
  2. PGC-1α and Mitochondrial Biogenesis: Activation of AMPK enhances PGC-1α activity, promoting mitochondrial biogenesis, which is the primary goal of Zone 2 cardio. In this context, metformin might act as a synergistic amplifier of this effect.
  3. Reduced Need for mTOR in Recovery: Unlike strength training or HIIT, Zone 2 cardio causes minimal muscle damage and does not require significant mTOR-driven muscle protein synthesis for recovery. Instead, the key goal is mitochondrial adaptation, which is facilitated by AMPK and PGC-1α. Since mTOR activation is less critical for Zone 2 recovery, metformin’s impact on mTOR suppression is less relevant.

Possible Downsides of Metformin During Zone 2 Cardio

  1. Reduced Exercise Capacity: By inhibiting mitochondrial complex I, metformin may reduce ATP production and increase reliance on anaerobic metabolism, leading to early fatigue. While this could increase perceived effort, it may also enhance metabolic stress that drives beneficial adaptations like increased mitochondrial biogenesis.
  2. Blunted VO2 Max Gains: Some studies have shown that metformin blunts improvements in VO2 max during aerobic training, particularly for higher-intensity cardio. However, for low-intensity Zone 2 cardio, the effect may be less pronounced since VO2 max is not the primary adaptation goal.

Conclusion The idea of taking metformin before Zone 2 cardio may have merit. Since mTOR is not essential for Zone 2 recovery, the inhibition caused by metformin is less of a concern. In contrast, the combined activation of AMPK and PGC-1α may actually enhance mitochondrial biogenesis and fat oxidation.

It is clear, that my reasoning is purely theoretical and supported only by indirect evidence.

Any argumented critiques is highly welcome!

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#37

The current issue of Consumer Reports has an article on supplements. Berberine was one of the few that they recommended.

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#38

That may play into it; I expect the bigger factor is just that we have massively more safety and efficacy data on met than on berberine.

I’m inclined to believe it — he’s saying he changed his mind on that basis, and he’s unlikely to have done so without having the facts nailed down — but like you, I don’t see why that matters. Regardless of the source of the lactate, it clearly impairs exercise adaptation.

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#39

That’s misleading. First, when we say that metformin blunts exercise adaptations, we’re talking about the aerobic and muscular fitness adaptations; her citation 48 doesn’t even measure these, but only looks at cardiovascular risk factors (which, at least by reputation, you would expect berberine to improve). Second, this is a study from Iranian researchers in an Iranian scientific journal. Iran is a notorious location for scientific fraud, among other infamy.

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#40

I don’t think lactate impairs exercise adaptation. Lactate is a fuel and a signaling molecule that leads to positive adaptation.

Lactate in the blood is a sign of higher than “zone 2” level of exercise intensity which combined with power output or heart rate may be a marker of cardiovascular fitness. But not of a molecule that causes problems.

Attia was referring rather casually to “a study” that showed blah blah blah. I don’t believe in any single study (especially one that I cannot read) without some confirming evidence (a second study by a different lab). The problem with higher lactate from metformin in my experience was that higher lactate made the exercise harder (essentially impossible) to do at my normal level of intensity doing a high intensity workout. Did that affect my adaptation? I don’t know.

That said, I don’t know why metformin interferes with exercise intensity in the studies that showed that effect. But it does interfere. Still, if a person has persistently high blood sugar, lowering it is the priority. I wouldn’t rely on berberine as a substitute after my testing with a CGM.

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#41

I was always baffled by so called effects of metformin on exercise.

I do heavy resistance 5-6x/week and as whole food plant based I am 87kg lean and looking like a bodybuilder ( doesnt look cool to me at this point … seems too much ).

I take Metformin 1g/per day cuz I always have high morning glucose. I measure glucose 1 h, 2h, 4h after a meal and im never above 6.3 … I go to bed and after 15 hours of fasting I measure my glucose next day … 6.5.

My liver is bugging with glucose excess output.

Metformin fixes it and I have same energy in the gym + I am gaining lots of muscle … im 44y old.

I dont see negatives of Metformin on my exercise … on the macro level.

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