Metformin Side Effects: Gut Trouble, B12 Loss and What to Do

The most common side effects of metformin are digestive: diarrhea, nausea, gas and indigestion.12 Every medication has a cost, and the big thing metformin does over the years is deplete your body of vitamin B12 and, to a smaller degree, folate, so while your prescriber manages the dose, I want you to test those nutrients, put back what's missing and work on what's driving your blood sugar in the first place.1011

If you've just started this drug, you may be spending more of your morning near a bathroom than you'd planned, and you may be wondering whether this is how it's going to be from now on. You haven't done anything wrong. Over the years I have sat with thousands of people handed the same sentence: your numbers are creeping up, here is a prescription, and you will likely be on it for life.9 Type 2 diabetes is not a life sentence, and for many people it is not permanent at all.9

The last part of this guide, the diet and lifestyle path that can lower your need for the drug, is where your effort pays off most.

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What is metformin and how does it work in your body?

Metformin is usually the first prescription people receive after diabetes symptoms or bloodwork lead to a diagnosis of type 2 diabetes. Its story starts with a plant: the drug traces back to Galega officinalis, the herb known as French lilac or goat's rue, and the molecule in your pill was made synthetically and developed as a medicine in the 1950s.211 Most adults start at 500 mg twice a day or 850 mg once a day with meals, and the dose can climb to 2,550 mg a day. Those amounts are for metformin hydrochloride, the salt form printed on the label.1 Extended-release tablets usually start at 500 mg once a day with the evening meal and go up to 2,000 mg a day.12

Once you swallow it, metformin goes to work in two main places. In your liver, it holds back the glucose your body would otherwise release into your blood, and in your gut, it changes how sugar is absorbed and handled, which helps explain why digestion is where so many people notice it.12

Part of what happens in your liver takes place inside your mitochondria, the tiny engines of your cells. In isolated rat liver cells and mitochondria, metformin slowed complex I, the first stop on the path those engines use to turn food into energy, and that slowdown held back glucose production.13 In Heal Your Cells, Dr. Will Cole and I describe how this prescription has been shown to impair complex I, leading to reduced ATP, the energy currency your cells run on, and suppressed cellular energy metabolism.10 Much of that lab work uses isolated mitochondria at concentrations far higher than what reaches your blood on a normal dose, so the human exercise trials later on this page tell you more about what that slowdown looks like in a living body.14

Type 2 diabetes was never a sugar problem. It's a signaling problem, most often driven by insulin, and the sugar is the smoke, not the fire.9 Insulin resistance can drive this cascade silently for ten years before your fasting glucose moves, which is why I check fasting insulin first.9 Medication can help, especially when numbers keep rising, but it doesn't replace the muscle, sleep and eating habits that address why insulin is high.15 Metformin can bring your number down while the root cause, the insulin, the fat packed into your liver and pancreas and the muscle you've lost, stays right where it was, and that root cause is what the last part of this page goes after.

What are the most common side effects of metformin?

Your digestion usually takes the first hit. About 25% of people who take metformin develop digestive side effects, and about 5% end up stopping it because of them.4 The prescribing labels show how much of that comes from the drug itself, because they compare each form against placebo:

The immediate-release column comes from a single U.S. trial of 141 people on the drug, at up to 2,550 mg a day, and 145 on placebo, and its rates run well above that 25% figure. The extended-release column comes from placebo-controlled trials of 781 people on the drug and 195 on placebo, and that label gives its smaller rows only as a range, without a placebo figure. The label itself warns that rates from separate trials can't be compared directly, so read each column on its own.112 Diarrhea led 6% of people to stop the immediate-release tablets and 0.6% to stop the extended-release form in those trials, and smaller numbers of people reported a change in taste, a rash, sweating or flushing, along with constipation, bloating and dizziness on the extended-release form.112

Women and older adults tend to struggle more. In an observational study in Scotland that compared 251 people with type 2 diabetes who couldn't tolerate metformin with 1,915 who could, the intolerant group was on average 10 years older and more often female.4

Why does metformin upset your gut?

Metformin upsets your gut mostly because so much of it stays there. Only 50% to 60% of a dose is absorbed, about 30% passes out unchanged in the stool, and the concentration in your upper small intestine peaks at 30 to 300 times the level in your blood.2 Picture a crowd packed into a hallway while the room next door sits half empty, and you have a fair idea of what your gut lining is dealing with. Researchers think several things happen at once:2

• More lactate in the gut wall. Metformin pushes the cells lining your intestine to take up more glucose and burn it without oxygen, which raises lactate and may add to your discomfort.
• More bile in your bowel. Less bile gets reabsorbed near the end of your small intestine, and the extra bile salts may pull water into your bowel and loosen your stool.
• A serotonin effect. Serotonin released from the gut is tied to nausea, vomiting and diarrhea, and metformin shares some structural features with drugs that act on one of its receptors.
• A different mix of microbes. Your gut bacteria change on this drug, which may affect how your bowels behave.

That shift in your microbes is part of how the drug lowers blood sugar, too. In a placebo-controlled trial of 40 adults newly diagnosed with type 2 diabetes, 4 months of metformin strongly changed the gut microbiome, and when researchers moved those altered microbes into germ-free mice, the mice handled glucose better.16 The same gut changes that make some people miserable may be doing part of the drug's work, which is one more reason your gut health matters while you're on it.

Some people get hit harder because of a transporter called OCT1, which helps move metformin across cell walls, and researchers suspect that when it works poorly, more of the drug stays in your intestine.4 In that Scottish study, people with two reduced-function copies of the OCT1 gene had 2.41 times the odds of being intolerant, people taking another drug known to block OCT1 had 1.63 times the odds, and people with both had 4.13 times the odds.4 Those drugs include acid-blocking proton pump inhibitors and the blood pressure drug verapamil, so if your gut reaction seems out of proportion, your full medication list is a good place to look.4 If your gut reacts harder than your neighbor's, that can come down to how your body handles the drug, and none of it is your fault.

Extended-release vs. immediate-release metformin

Extended-release metformin releases the drug more slowly, spreading absorption along your gut so that less of it concentrates in one place, and it was developed to be easier to tolerate.2 Whether it's gentler depends on which kind of study you look at.

When people who are already having trouble switch, many of them feel better. In a chart review of 205 people who moved from immediate-release to extended-release at four clinics, reports of any digestive side effect fell from 26.34% to 11.71%, and diarrhea fell from 18.05% to 8.29%; that review looked back at records and had no comparison group for the switch.17 Randomized trials found the two forms much closer. A 2021 review that pooled 4 trials and 1,573 people found digestive side effects in 29.3% of people on extended-release and 26.6% on immediate-release, and diarrhea in 10.4% and 12.0%, differences small enough to be chance.18

If immediate-release is hard on you, the people who switched in that chart review are the encouraging part, because their reports of gut trouble fell by more than half after the change. Whichever form you take, food and a slow climb in dose are the first things to try, and you'll find those steps below.

How metformin lowers vitamin B12 and folate, and what to test

Your body absorbs vitamin B12 at the far end of your small intestine, in a step that depends on intrinsic factor and calcium, and metformin gets in the way of that step.120 In a small comparative study of 21 people with type 2 diabetes on a sulfonylurea, 14 of whom switched to metformin, B12 fell after the switch and oral calcium reversed the drop in the active form of B12.20 In 2022 the U.K. medicines agency reclassified B12 deficiency as a common side effect of metformin, affecting up to 1 in 10 people on it, and the U.S. label reports that about 7% of people in 29-week trials saw previously normal B12 fall below normal.211

The longer you take it and the higher the dose, the bigger the drop. In the HOME trial, 390 people with type 2 diabetes who were already on insulin took 850 mg of metformin hydrochloride or placebo three times a day for 52 months, and neither the people nor the researchers knew who got what. B12 ran 19% lower on metformin, and for roughly every 14 people treated, one extra person developed true deficiency over 4.3 years.5

The drop shows up even in people who only have prediabetes. In the follow-up to the Diabetes Prevention Program, a randomized trial, 1,715 adults with prediabetes had their B12 tested at 5 years, and low or borderline levels showed up in 19.1% of those on 850 mg of metformin twice a day against 9.5% on placebo. At 13 years, after the metformin group had stayed on the drug for 9 more years and everyone had been offered group lifestyle sessions, it was 20.3% against 15.6%.3 Dose showed up clearly in a Hong Kong case-control study of 155 people with low B12 and 310 without: each extra gram a day brought 2.88 times the odds of deficiency, and 3 or more years on the drug brought 2.39 times the odds.22

B12 and folate are essential methyl donors, the raw material your cells use for a chemical step called methylation, so when metformin lowers them it disrupts those pathways as well.10 Metformin's effect on B12 is why I connect this drug with fatigue, neuropathy and depression.1011 In an observational study of 550 people with type 2 diabetes on metformin, those with deficient B12 had 2.4 times the chance of depression.23 In the Diabetes Prevention Program follow-up, neuropathy was more common among metformin users with low B12, in a small number of cases.3 In a later analysis of the HOME trial, metformin raised methylmalonic acid, the marker that shows your tissues are short of B12, and that pushed nerve scores the wrong way while metformin's lower HbA1c, your average blood sugar over about three months, pushed them the right way, so the net effect on neuropathy wasn't significant.19

Metformin lowers folate too, by a smaller margin.1011 In the first 16 weeks of the HOME trial, folate ran 7% lower on metformin than on placebo, and over 52 months it ran 5% lower, a difference that stopped being significant once researchers adjusted for body mass and smoking.245 Homocysteine is the amino acid that builds up when B12 and folate run short, and a review of randomized trials in 12 publications found it rose by 2.02 µmol/L on metformin when people weren't taking B vitamins or folic acid and fell by 0.74 µmol/L when they were.25 That second number is the encouraging one, because it shows that what you put alongside this drug changes what it does to you. If you've been on metformin for years and nobody has ever checked your B12, this is the section to take with you to your next appointment.

What to test

My rule is test, don't guess.9 Ask for these four together, especially if you've been on metformin for years, take a higher dose or have noticed numbness, tingling or unusual tiredness:2122

• Serum vitamin B12. The label calls for a B12 check every 2 to 3 years and a blood count every year.1 In the studies above, low meant 203 pg/mL or less and borderline meant 298 pg/mL or less in the U.S. follow-up, and deficiency meant under 150 pmol/L in the HOME trial.35
• Serum folate. This is the folate number the HOME trial followed, and it ran 5% lower on metformin than on placebo.5
• Methylmalonic acid (MMA). It rises when your tissues are short of B12, so it shows you the shortage where it counts.19
• Homocysteine. In the HOME trial it averaged 23.7 µmol/L in people who ended up B12 deficient, 18.1 in those with low B12 and 14.9 in those with normal B12.5

How to put B12 back

This is the part of the drug's cost you can do something about, and the label notes that the drop appears to reverse quickly with B12 supplementation.1 In a 12-month placebo-controlled trial of 90 people who had been on metformin for at least 4 years and had neuropathy with B12 under 400 pmol/L, a daily 1,000 mcg methylcobalamin tablet raised B12 from 232.0 to 776.7 pmol/L, nerve conduction improved, and pain scores fell from 18.4 to 17.1 on a 38-point scale, while pain on placebo rose from 19.3 to 20.9.26 Reflex tests of the automatic nervous system and one physical exam score didn't improve significantly, and nobody reported an adverse event from the B12.26

A common vitamin B12 dosage is about 1,000 mcg of methyl-B12 a day, guided by your level, and it's worth testing before high doses.7 When folate runs low, I recommend methylfolate along with folate-rich foods such as leafy greens, liver and beans.27

Food still counts, even though absorption is the thing metformin gets in the way of. Beef liver is one of the richest foods in B vitamins and iron,28 and I recommend about 3 ounces once a week unless your bloodwork shows vitamin A running high.29 Add sardines, wild salmon and pasture-raised eggs, and you'll find more choices in our list of B12 foods. Keep your red meat fresh, unprocessed and grass-fed, because the WHO's cancer agency, IARC, classifies processed meat of every kind, processed beef included, as a Group 1 carcinogen, largely on colorectal cancer data, and rates red meat itself Group 2A, probably carcinogenic.30 As I've said on my show, the studies that link red meat to poor health mostly reflect grain-fed and processed meat, not the fresh, grass-fed red meat I recommend.31

What are the long-term side effects of metformin?

Lower B12 is the best-known long-term effect, which you've seen above, and anemia is the second one to watch. When researchers went back through two large randomized trials, people on metformin had 1.93 times the odds of moderate anemia (hemoglobin under 11 g/dL) compared with a sulfonylurea in one trial of 3,967 people, and 3.40 times the odds compared with diet in another of 1,473.32 In a Scottish database of 3,485 people, each gram of metformin a day went with a 2% higher risk of anemia per year.32 In the first of those trials, hemoglobin fell within 6 months with no further drop after 3 years, and the researchers judged that timing unlikely to come from B12 shortage alone, which is why that yearly blood count is worth keeping even when your B12 looks fine.32

Your muscles are the third, and this is where the cost to your cells shows up in people. Muscle is your largest glucose sink: every pound pulls sugar out of the blood, and every contraction clears glucose without insulin.9 That makes exercise one of the best things you can do for your blood sugar, and it's why three trials on metformin and exercise matter so much.

Metformin can take some of the reward out of your workouts. In a 12-week randomized trial of 53 older adults at risk for type 2 diabetes, aerobic training raised whole-body insulin sensitivity and mitochondrial respiration on placebo, while on 2,000 mg of metformin a day neither one rose.6 In a 14-week randomized trial of 94 healthy adults 65 and older doing strength training, those on placebo gained 1.95% in lean mass and 3.90% in thigh muscle, against 0.41% and 0.45% on 1,700 mg of metformin a day, and strength gains ran lower by an amount small enough to be chance.33 A 2026 randomized trial of 91 adults at risk for metabolic syndrome found the same pattern with 16 weeks of high-intensity training, where insulin sensitivity improved on placebo and not on metformin.34

None of those people had diabetes, so these trials can't tell you exactly what happens when you take metformin to treat it. They do help explain why it makes so little sense to me when healthy people are told to take metformin as a longevity drug.11 If you take it because you need it, keep training. In that aerobic trial, HbA1c, fasting insulin and fat mass fell in both groups, the response varied widely from person to person, and the exercise paid off either way.6

What to do when side effects hit

Most of what helps is simple, and you can start today:

1. Take it with food. The label calls for metformin with meals, and doses above 2,000 mg may sit better split across three of them.1
2. Let the dose climb slowly. The label's schedule adds 500 mg a week or 850 mg every 2 weeks, and researchers who study intolerance point to a low start and slow increases as the first step.18
3. Replace what you lose. Diarrhea costs you fluid and your kidneys clear this drug, so drink extra water while your gut settles.1
4. Feed your gut. Build meals around protein and fiber, and bring in probiotics from fermented foods or a supplement, which I put alongside this drug for absorption.35 Researchers are also studying gut microbiome modulators as a way to ease intolerance.8
5. Put back what runs low. Test, then correct your B12 and folate as described above, and keep doing it for as long as you're on the drug.

If what you're feeling goes beyond stomach trouble, go straight to the safety section.

Can diet and lifestyle lower your need for metformin?

Most modern drugs manage disease; they don't rebuild the body.10 You don't manage type 2 diabetes, you remove what's driving it, and when you steady the insulin and rebuild the muscle, the body remembers how to handle sugar.9 More than two thousand years ago, Chinese medicine was already describing diabetes as Xiao Ke, or wasting and thirsting, linked to rich food, alcohol and emotional strain, and its answer maps almost perfectly onto the plan below: fewer refined carbs, more fiber and protein, daily movement and better sleep.15

Lifestyle change beat metformin when the two went head to head in the Diabetes Prevention Program, which followed 3,234 adults with high blood sugar for an average of 2.8 years. An intensive lifestyle program built on losing at least 7% of body weight and moving at least 150 minutes a week cut new cases of diabetes by 58% against placebo, while 850 mg of metformin twice a day cut them by 31%.37 Diet and exercise achieved nearly twice the risk reduction of the drug, and they don't come with its side effects.35 Over 15 years the gap narrowed, to 27% and 18%, as weight crept back in the lifestyle group.38

The DiRECT trial in U.K. primary care went further and asked whether adults diagnosed within the past 6 years and not on insulin could put type 2 diabetes into remission. People knew which treatment they got, and 149 assigned to a structured program were compared with 149 on usual care. Their diabetes drugs were withdrawn at the start under the trial team's supervision, and they followed an 825 to 853 calorie formula diet for 3 to 5 months, then reintroduced food and worked on keeping the weight off.36 At 12 months, 46% were in remission against 4% on usual care, and at 24 months 36% against 3%, and by then 40% of the program group were on diabetes drugs against 84% of those on usual care.3639

The more weight people lost, the better their odds: among the 285 people with weight data, remission reached 0% of the 76 who gained weight, 7% of those who lost up to 5 kilograms, 34% at 5 to 10 kilograms, 57% at 10 to 15 and 86% at 15 kilograms or more, about 33 pounds.36

Weight loss can do what a pill can't because it clears the fat out of the organs that handle your sugar.9 In a metabolic study of DiRECT, 64 people in the program saw liver fat fall from 16.0% to 3.1% and pancreas fat fall too, and the ones whose blood sugar returned to normal were the ones whose first-phase insulin response, the quick burst of insulin your pancreas releases when you eat, came back.40

The steps I use with patients

The first thing I'd do is put you on a very specific diet high in protein and fiber and give you the nutrients you need.35 From there, my Type 2 Diabetes Protocol moves through 5 steps in order, over about 90 days:9

1. Stabilize. Calm the blood sugar swings with a diet built for insulin resistance, meal structure and food order.
2. Move. Strength-train your large muscles 2 to 3 times a week, and walk 10 to 15 minutes after every meal.
3. Nourish. Refill the nutrients you're short on and repair your gut.
4. Rebalance. Protect a 7 to 8 hour sleep window with a fixed wake time, get outdoor light within an hour of waking, and finish eating 3 hours before bed.
5. Reverse. Lose the visceral fat that's sitting in your liver and pancreas. A tighter eating window, such as intermittent fasting, can help some people here.

Our diabetic diet plan lays out what that looks like on a plate, and our guide to normal blood sugar shows you what to aim for.

Berberine, chromium, cinnamon and magnesium

These are the natural tools I reach for alongside that work, and none of them replace food and movement or a prescription; decide medications only with your doctor.9

• Berberine. Berberine is the flagship, the most-studied natural tool for glucose, at 500 mg two to three times a day before meals.9 A review of 31 studies and 2,683 people found it lowered HbA1c by 0.63 points, taken alone or added to other treatment.41
• Chromium. At 200 to 400 mcg a day, it may modestly improve glycemic control, and the evidence is favorable but mixed.9 A review of 28 studies put the HbA1c drop at 0.71 points.42
• Ceylon cinnamon. I use 1 to 2 grams with meals.9 An umbrella review of 11 meta-analyses in people with type 2 diabetes or PCOS, not limited to Ceylon cinnamon, found fasting glucose fell by 10.93 mg/dL and HbA1c by 0.10 points.43
• Magnesium glycinate. I use 300 to 400 mg in the evening.9 A dose-response review of 18 controlled trials, which its authors called too early to set guidelines, estimated that 500 mg a day of magnesium lowers HbA1c by 0.73 points.44

They support the changes above, and diet and lifestyle do the reversing.

Berberine vs. metformin

Berberine has gone head to head with metformin, and it held its own. In my Insulin Resistance & Prediabetes protocol, I describe it this way: it lowered blood sugar and HbA1c comparably to a common diabetes medication in a small 3-month trial.15 The table lays that trial out:

The researchers called berberine's blood sugar lowering similar to metformin's in that pilot, and by the end of the trial triglycerides and total cholesterol were significantly lower on berberine than on metformin.45

I'm sure a research study can show that metformin supports the body in some area, and maybe even with a group of people who are severely diabetic it will increase their longevity; I've seen those research studies myself.35 Where metformin clearly does better is in the size and length of the evidence behind it: in the UKPDS trial of 753 overweight people with newly diagnosed type 2 diabetes, followed for a median of 10.7 years, those assigned to metformin had 36% fewer deaths from any cause than those on conventional, mainly diet-based care.46

Berberine has been used for centuries in Chinese and Ayurvedic medicine to support digestion, immunity and overall vitality.10 It works by activating AMPK, a pathway that enhances insulin sensitivity and regulates glucose,35 and metformin activates it too.2 It earns its place right beside the food and movement that do the reversing.

Metformin safety: lactic acidosis, kidneys, alcohol and contrast

Never stop or change a diabetes medication on your own; it can be dangerous. As your numbers improve, bring your labs and home readings to your prescriber and let them adjust your doses.9

Lactic acidosis. Metformin carries a boxed warning for this dangerous buildup of acid in the blood, and fatal cases have been reported.1 It is rare: a Cochrane review of 347 trials and cohort studies found no cases in 70,490 patient-years on metformin and none in 55,451 on other treatments.47 The onset can be subtle. Unusual tiredness or weakness, muscle pain, trouble breathing, unusual sleepiness or stomach pain, sometimes with feeling cold, lightheaded or a slow, irregular heartbeat, are the signs to act on.1 If you have them, don't take another dose, and get to an emergency room right away.1

Who's at higher risk. The label names kidney disease, age 65 or older, heart failure and other low-oxygen states, liver disease, heavy drinking, dehydration from vomiting, diarrhea or fever, surgery and contrast imaging.1 If any of these fit you, make sure your prescriber knows.

Kidneys. Your kidneys clear this drug, and your eGFR, the blood-test estimate of how well they filter, sets the rules. The label says not to use metformin below an eGFR of 30, not to start it between 30 and 45, and to reassess if you fall below 45.1 In a cohort of 75,413 people, the risk of hospitalization with acidosis rose significantly only below an eGFR of 30, to 2.07 times the risk.48 Get your eGFR checked at least yearly.1

Alcohol. Alcohol strengthens metformin's effect on lactate, so avoid heavy drinking.1

Contrast imaging and surgery. Tell the imaging team you take metformin. The label calls for stopping it at or before an iodinated contrast scan if your eGFR is 30 to 60, you have a history of liver disease, alcoholism or heart failure, or the contrast goes into an artery, then rechecking eGFR 48 hours later and restarting if it's stable. It's also paused while food and fluids are restricted around surgery.1

Low blood sugar. Metformin alone seldom drops blood sugar too low, with hypoglycemia reported in 1% to 5% of people in the U.S. trial. The risk climbs with insulin or a sulfonylurea such as glipizide, whose dose may need to come down.1 The same goes when diet, time-restricted eating or supplements start lowering your blood sugar, so check your readings and let your prescriber make the adjustment.9

Other drugs. Carbonic anhydrase inhibitors such as topiramate can raise the risk of lactic acidosis, so ask about closer monitoring. Drugs that slow metformin's clearance, such as cimetidine, can raise your exposure to it, so ask whether the combination still makes sense.1 Berberine can compound prescription drugs, so clear it with your doctor first.9

Pregnancy and liver. If you're pregnant or planning to be, keep your diabetes care with your OB and confirm every dose there, including the berberine and beef liver on this page. Cases of liver injury have been reported since approval, so keep your routine labs current.1

The bottom line

Metformin side effects: frequently asked questions

References

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2. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426-35. doi:10.1007/s00125-015-3844-9. PMID:26780750
3. Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016;101(4):1754-61. doi:10.1210/jc.2015-3754. PMID:26900641
4. Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CN, Pearson ER. Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. Diabetes. 2015;64(5):1786-93. doi:10.2337/db14-1388. PMID:25510240
5. de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010;340:c2181. doi:10.1136/bmj.c2181. PMID:20488910
6. Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019;18(1):e12880. doi:10.1111/acel.12880. PMID:30548390
7. Axe J. Brain Fog: Causes, Symptoms and How to Clear It Naturally. DrAxe.com; 2026 ("Dose — guided by your level; methyl-B12 around 1,000 mcg daily is common"; test before high doses).
8. Bonnet F, Scheen A. Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes Metab. 2017;19(4):473-481. doi:10.1111/dom.12854. PMID:27987248
9. Axe J. The Type 2 Diabetes Protocol. DrAxe.com protocol; 2026 (letter, p. 3: thousands handed a prescription, "keep taking it exactly as prescribed"; section 02, signaling problem and sugar as smoke; section 03, fasting insulin first; section 17, Test, don't guess; the 5 steps Stabilize, Move, Nourish, Rebalance, Reverse; p. 14, Step 5 Reverse; p. 17, supplement protocol; p. 22, Troubleshooting & FAQ, "I take metformin or insulin. Do I stop?").
10. Axe J, Cole W. Heal Your Cells. Avery; 2026. ISBN 9798217181353 (pp. 23-24, "Every medication has a cost": complex I, ATP, B12 and folate as methyl donors; p. 24, fatigue, neuropathy and depression; p. 25 depletion table; berberine's use in Chinese and Ayurvedic medicine).
11. Axe J. Best Natural Alternatives for Common Prescription Drugs. The Dr. Josh Axe Show. 2025 (at 34:59 to 37:25, metformin).
12. Metformin hydrochloride extended-release tablets [prescribing information]. DailyMed, U.S. National Library of Medicine; label effective 2025-06-30 (section 6.1, Table 1).
13. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348 Pt 3(Pt 3):607-14. PMID:10839993
14. Fontaine E. Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences. Front Endocrinol (Lausanne). 2018;9:753. doi:10.3389/fendo.2018.00753. PMID:30619086
15. Axe J. Insulin Resistance & Prediabetes protocol. DrAxe.com protocol; 2026 (p. 10, East and West, Xiao Ke; p. 20, top blood-sugar supports; FAQ & the medication question).
16. Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23(7):850-858. doi:10.1038/nm.4345. PMID:28530702
17. Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin. 2004;20(4):565-72. doi:10.1185/030079904125003278. PMID:15119994
18. Tan J, Wang Y, Liu S, Shi Q, Zhou X, Zhou Y, et al. Long-Acting Metformin Vs. Metformin Immediate Release in Patients With Type 2 Diabetes: A Systematic Review. Front Pharmacol. 2021;12:669814. doi:10.3389/fphar.2021.669814. PMID:34079464
19. Out M, Kooy A, Lehert P, Schalkwijk CA, Stehouwer CDA. Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3year trial. J Diabetes Complications. 2018;32(2):171-178. doi:10.1016/j.jdiacomp.2017.11.001. PMID:29174300
20. Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000;23(9):1227-31. doi:10.2337/diacare.23.9.1227. PMID:10977010
21. Medicines and Healthcare products Regulatory Agency. Metformin and reduced vitamin B12 levels: new advice for monitoring patients at risk. Drug Safety Update. 2022 Jun.
22. Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch Intern Med. 2006;166(18):1975-9. doi:10.1001/archinte.166.18.1975. PMID:17030830
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Dr. Josh Axe, DC, DNM, CNS

Doctor of Natural Medicine · Founder, DrAxe.com

Dr. Axe is a certified doctor of natural medicine, clinical nutritionist, and multiple New York Times bestselling author. He has spent 20+ years in clinical practice helping people heal at the root cause and founded one of the most-visited natural-health platforms in the world.

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