In our last article on berberine vs. metformin, we discussed how both berberine and metformin work, and how they stack up in terms of their potential benefits for longevity. But let’s say you have already considered using berberine as a natural alternative to metformin, what should you expect? Is berberine a good substitute to metformin? Is it safe? Are there any side effects? With any medication or supplement, there are always potential side effects to be aware of. And while both berberine and metformin are considered very safe, there are indeed a few side effects and downsides that need to be considered.
In this article, we continue our collaboration with Dr. Anil Bajnath, MD, the founder of the Institute for Human Optimization and an expert in the field of longevity and anti-aging medicine. We’ll dive into some of the common cautions, potential side effects, and disadvantages of berberine and metformin, along with possible strategies to mitigate them. If you find that you need more background on metformin or berberine, you may want to also read our first article, as it provides an overview on both.
Low blood sugar levels
As we mentioned in our last article, both metformin and berberine have shown to be very effective in helping manage high blood sugar levels. But what happens when healthy people with normal blood sugar take either of these compounds to support longevity? Can your blood sugar levels go too low?
Luckily, this is where certain tests can be very handy. Hemoglobin A1c (or in short, A1c) is a measurement of your average blood sugar over the past three months. It’s formed when sugar in your blood reacts with proteins in your red blood cells. When you get your A1c measured, it’s reported as a percentage.
The goal of diabetes treatment is to bring the A1c as close to the normal range as possible. Doing this can greatly reduce the risk of serious health problems and death. Because of this, many people assume that everyone should be trying to lower their A1c as much as possible. However, while going from an elevated A1c to a normal one is definitely good for your health, this doesn’t mean that going from a normal level to a lower one is better.
As we often say in precision and functional medicine, there’s no one size fits all. Everyone is different. We can clearly see it in this case. So, let’s have a look into some of the ranges of the hemoglobin A1c test:
- Lower than 4.8 – Can actually be working against longevity!
- 5.2 – Ideal score for longevity
- Over 5.7 – Prediabetic
- Over 6.5 – Diabetes.
In fact, an A1c score that’s too low is correlated with a significantly increased risk of death. To give you an idea of some of the risks, a very low A1c could indicate that you’ve had some periods of neuroglycopenia (inadequate blood sugar to the brain). While parts of the brain can run on ketones, there are also some parts that require glucose in order to function. Too many episodes of neuroglycopenia can have serious implications on your brain.
Are berberine or metformin the right options for me?
A good practical approach that may help with these potential side effects is testing. As we often say in precision medicine, you’re an “N of 1” study, not the average of a large group. Always make sure that you test to see what any drug or supplement is doing in your body. So, if you consider taking berberine or metformin, testing your A1c is a good idea to see if you’re staying in the target range. If you are going too low this can harm your longevity rather than help it.
A few things to consider that may help mitigate these risks:
- When I’m working with patients on longevity the goal is an A1c of about 5.2
- If A1c is lower than 4.8, this could be working against longevity. In these cases, you should not take metformin or berberine.
- Be mindful to other activities that may also keep your blood sugar low, such as fasting, following a keto diet, and exercising. If you start taking either berberine or metformin in addition to these, there’s the potential for the combined effect to cause hypoglycemia. With both metformin and berberine effective at controlling blood sugar, they could also both push it a little too low, potentially doing more harm than good.
GI side effects
One of the most known common side effects of metformin are digestive issues such as diarrhea, nausea, and vomiting. In fact, these types of side effects cause many people to stop taking metformin. But what about berberine? Turns out, berberine can cause digestive issues as well.
Fortunately, there are things we can do that can help minimize these GI side effects:
- Take berberine or metformin with food. For many people, this has been shown to help a lot with nausea and diarrhea.
- Start with a lower dose and ramp up slowly.
- Consider extended-release forms of metformin and berberine, which may also be helpful.
In general, the GI side effects of both metformin and berberine are usually not too severe, and we have ways to manage them. However, if you do start to have vomiting or diarrhea from taking one of these compounds, you should take this seriously. Unfortunately, I’ve seen people end up in the ICU from severe dehydration, because they continued to take metformin even though it was causing serious problems. The GI side effects are relatively mild for most people, but if they’re severe for you, stop the metformin (or berberine) right away and speak to your healthcare provider.
Reduced exercise benefits
Many people who take berberine or metformin for their anti-aging benefits, are also engaged in other activities to optimize their performance and longevity, like resistance training, high intensity interval training (HIIT) among others.
But, while individually both metformin and exercise are known to benefit longevity, could it be that together they may “cancel” each other out?
According to some studies, this indeed may be the case. Metformin has been shown to inhibit the process of mitochondrial adaptation to aerobic activity. When people exercised after taking metformin, their glucose sensitivity didn’t change as much as those who exercised without metformin. Additionally, their mitochondria didn’t get more efficient at using oxygen, which is normally what would occur after exercise. Based on this research, it looks like metformin stopped these beneficial changes from occurring. There are also studies showing that metformin blunts muscle hypertrophy in response to resistance training. This means that taking metformin may reduce the muscle mass gain you may experience from exercise.
Now, we don’t yet have specific studies on the effects of berberine on the adaptation to exercise. We do know, however, that berberine and metformin both affect similar pathways in the mitochondria so we can assume it’s likely to be similar. Do these potential disadvantages mean you should stop taking berberine or metformin all together if you want to support longevity? Not necessarily. Here are a few strategies to consider:
- Take metformin or berberine on the days that you don’t exercise. Both berberine and metformin act as fasting mimetics, and just like you are less likely to workout on a day when you fast, you may want to follow the same logic when you take these. On their own, fasting and exercise are beneficial activities for longevity, but they’re generally not done together. Especially if you plan to do high intensity workouts or high demanding physical activities.
- Cycle metformin or berberine. For example, you might go through a period when you do things like fasting and taking metformin or berberine to promote autophagy and clear out some damaged cells. During this time, work out less or reduce the intensity of your sessions. When you shift back into tissue-building mode later and exercise, stop taking these compounds. Going through cycles like these is another way to help get the beneficial effects of berberine and metformin without giving up the benefits of exercise too.
Lactic acid is a byproduct of metabolism. But when the body produces too much lactic and can’t metabolize it quick enough, it can build up in the bloodstream leading to a potentially fatal condition known as lactic acidosis. Although rare, metformin is associated with an increased risk of lactic acidosis, something that should be evaluated with a qualified health practitioner, especially for those who may have risk factors[5,6].
Back to exercise, you may be familiar with the burning sensation that sometimes occur when you workout due to the lactic acid build up in muscle tissue. This is another reason to think carefully about combining metformin with exercise. When you’re taking something like metformin that can inhibit the breakdown of lactic acid, you may not necessarily want to do something that increases production at the same time.
On that note, lactic acidosis may be more of a concern with metformin than with berberine. In fact, some animal studies have found that berberine may even protect against metformin-associated lactic acidosis. Interestingly, it looks like berberine may promote the breakdown of lactic acid in the mitochondria, helping to prevent it from building up. We don’t yet have human studies proving that berberine will have the same effect in humans, but this is one example where berberine may be safer than metformin.
While many people may not consider weight loss as a problem, for some people it can be a concern. For example, if you already have low BMI, are trying to recover from an injury, or want to gain muscle mass, you don’t want to lose any additional weight. Now, it has been known for years that weight loss is a common side effect of metformin, which is an advantage for treating type 2 diabetes, as it is typically associated with obesity. Even better, metformin-induced weight loss has been shown to affect specific fat tissue called visceral fat that is linked to multiple health risks[8,9].
But then again, the weight loss effect of metformin may not be a desirable one for everyone.
Similarly, berberine may also lead to weight loss. Animal studies have shown that mice that were given berberine, gained less weight on a diet that would normally make them obese. Other studies that compared berberine to metformin, have shown that their effects on body weight were comparable, although berberine may have a slight edge at preventing fat from accumulating in the liver.
Is berberine a good substitute to metformin? Final thoughts
Metformin has been widely studied, but we still need more research on berberine to learn about its potential adverse effects. However, the research that we do have suggests that berberine may have an edge over metformin in terms of safety. It may cause fewer side effects. For example, it seems to be less likely to cause lactic acidosis.
Still, it’s important to recognize that any compound, whether it’s a natural supplement, an over-the-counter drug, or a prescription medication can have adverse effects. This is why a personalized approach that considers the uniqueness of each person, their risk factors, lifestyle, and the way their body response to different interventions is so important. If you decide to give berberine a try, I strongly recommend working with your doctor and test to see how it may affect you. For example, start by testing your hemoglobin A1c and lipid profile before you take berberine, and again a few weeks later. It’s also important to pay attention to how berberine affects your digestion, exercise tolerance, strength, and endurance.
Overall, berberine can be a great anti-aging supplement for many people. As a natural alternative, the research has shown some very promising beneficial effects with a level of evidence not many natural ingredients have. However, I don’t believe in “one size fits all” medicine. Instead, I like to consider any new supplement or medication as an N=1 experiment. Run the relevant tests, see the results, and fine tune. So, you optimize your results, and eliminate the guesswork along with many potential side effects.