I put down the spoon and instantly felt regret. I tossed the demolished pint of ice cream into the trash. Judging by my CGM device (see my Nutrisense review), I knew my blood sugar would peak, and then crash down. Blood sugar fluctuations can lead to side effects like fat gain, low energy, brain fog, and cravings.
Performing at your peak, feeling your best, and living a long time require stable blood sugar.
That’s where metformin and its better replacements come in. You can have both healthy blood sugar and enjoy occasional treats.
Metformin has drawbacks. Luckily there are many safe, effective, and natural over-the-counter Metformin replacements. Click To TweetToday I’ll cover the important drawbacks of off-label Glucophage use for biohacking anti-aging & longevity, and the most effective metformin alternatives you can use instead.
Lesser-Known Dangers of Metformin
Longevity researcher David Sinclair takes metformin to slow aging. There may be other longevity benefits, but he likes it primarily for the blood sugar-stabilizing effects.
Some experts advocate off-label metformin. Others warn against it.
Metformin has withstood the test of time (so far). It’s heavily studied and widely used to treat diabetes.
Off-label use for anti-aging and life extension has only recently gained popularity. Thus little research supports metformin use amongst otherwise healthy biohackers.
Before you look for a prescription, you should know the side effects and risks.
Metformin Danger #1: Vitamin B12 Deficiency
One of the many necessary vitamins and minerals. I can see why you’d shrug your shoulders at an association with vitamin B12 deficiency.
Vitamin B12 is essential to the development of your brain and nerves. Metformin increases your chances of B12 deficiency which can lead to serious permanent nerve damage, deteriorating brain function, and memory loss.
Metformin Danger #2: Wasted Exercise Sessions
Exercise is among the top strategies to live a long time.
Several studies suggest that metformin blunts the beneficial adaptations to aerobic exercise. It also makes exercise feel harder. Looking beyond aerobics, metformin may negatively affect building muscle mass.
I don’t know about you, but my workouts are hard enough as is. Blunting the beneficial effects of exercise alone would be a deal-breaker for me.
Metformin Danger #3: Extreme Muscle Soreness
Dr. Peter Attia loves cycling. As a doctor, he has all the tools and processes in place to run successful biohacking self-quantification experiments.
You know that burning feeling from really pushing yourself through a workout?
That’s lactate accumulating.
Peter experimented with metformin but ultimately stopped because it increased his lactate levels during exercise. He wrote a piece about it back in 2017.
Metformin Danger #4: Dangerously Low Blood Sugar
As a drug used to lower blood sugar, you might find it surprising to see this also listed as a side effect.
Known as hypoglycemia, certain things combined with Metformin can cause blood sugar to dip dangerously low. Healthline lists common combinations to avoid combining with Metformin:
Another strike against combining exercise and Metformin.
Metformin Danger #5: “Best Guess” Dosing
Unlike its use in treating diabetes, we don’t know much about proper longevity doses.
I heard one doctor mention that we don’t even know how long its effects last in your body.
For example, one process it affects is called AMPK. 36 hours after dosing metformin, AMPK activity remains altered. I find this concerning since the plasma half-life of the drug is just 6.2 hours.
Metformin Danger #6: Altered Cortisol Levels
Several studies have shown that Metformin alters natural cortisol (stress hormone) levels.
The body keeps this hormone in a narrow window:
- Too much cortisol and at the wrong times, it increases fat gain while degenerating and destroying the body
- Too little cortisol disrupts normal circadian rhythms, induces fatigue, causes muscle weakness, and acutely can suppress the immune system
This small study found Metformin significantly alters cortisol.
“…strongly significant increase in hepatic cortisol generation on the metformin phase in the remaining seven subjects…”
Metformin Increases Cortisol Regeneration by 11βHSD1 in Obese Men With and Without Type 2 Diabetes Mellitus
Another larger study found the same thing; Metformin increases the stress hormone cortisol and androstenedione:
No significant change was found in basal steroid levels after metformin treatment; only basal cortisol and androstenedione levels displayed a tendency towards higher values.
The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome
Most modern humans walk around with chronically elevated cortisol. Interfering with the body’s natural stress hormone modulating enzymes doesn’t seem wise.
Metformin Danger #7: Reduced Testosterone Bioavailability
In addition to cortisol, Metformin appears to modulate free testosterone.
Some research suggests it does so via several mechanisms:
- Increasing sex hormone-binding globulin (SHBG)
- Blunting the testosterone increasing effects of improved glucose control
- Directly reducing free testosterone
Though these are not the highest quality studies, otherwise healthy users often report similar effects observed in their bloodwork after beginning a Metformin protocol.
Metformin Danger #8: Shifts Gut Microbiome
As healthy biohackers demand Metformin, research accumulates.
Since 2018, scientists have observed that this drug impacts the composition of the gut microbiome.
Some of the 12+ known changes include:
- Decreased Intestinibacter spp.
- Decreased Clostridium spp.
- Increased Escherichia/Shigella spp.
- Increased Bilophila wadsworthia
- Increased Akkermansia muciniphila
One study listed the composition-altering effects of metformin alongside antibiotics,
“After statistically correcting for polypharmacy, PPIs, metformin, antibiotics and laxatives still showed significant associations with microbial features.”
Interaction between drugs and the gut microbiome
We don’t yet know enough about the ideal relative abundance of different microbes, and all the checks and balances, to determine the true extent and health implications of Metformin’s impact on the microbiome.
Metformin Danger #9: Birth Defects
A March 2022 study sent a shockwave through the Metformin-for-off-label-longevity use community.
This large cohort study discovered that metformin use (in men) during the sperm formation process can lead to birth defects in offspring.
Since the study is behind a paywall, you can learn more here.
Whenever a drug impacts fertility and causes birth defects, it signals the presence of a whole host of other worrisome physiological changes.
Time will tell what new dangers of metformin we don’t yet recognize.
Tools to Help You Understand & Optimize Blood Glucose
In the era of technology, we no longer have to fly blind.
You can customize your approach based on your own unique biochemistry. No wondering whether you’re making smart purchases.
Two gadgets and technologies in particular will help you get the greatest bang for your buck:
- SelfDecode
- Nutrisense
From extensive testing, I’ve found these to be the most useful for folks.
SelfDecode to understand your susceptibility to Metformin side effects and blood sugar dysregulation
People react differently to foods. Partially caused by lifestyle, but also due to their genetics.
Certain genes predispose you to a higher risk of both:
To predict how you’ll respond to both Metformin or other glucose disposal agents (GDAs), I use powerful software called SelfDecode (see my review for details).
They have a massive database of supplements, drugs, conditions, and lifestyle habits. I ran my DNA through the tool, and it showed that I do best with berberine. Continuous blood glucose measurements using my Nutrisense CGM confirm berberine (or its cousin as you’ll learn below) is my ideal blood sugar-stabilizing supplement.
Work with your genes instead of fighting them.
Use the exclusive coupon code URBAN for 10% off.
Nutrisense CGM to test supplements
How do you know if your blood glucose products actually work?
Instead of crossing your fingers, you can test.
A traditional glucose blood test gives you a single data point. Different products take different amounts of time to exert their effects.
Instead, you can use a continuous glucose monitor (see my beginner’s guide to CGMs here) to gather data around the clock.
You can measure exactly how high certain foods spike your blood sugar. You can compare foods. Most importantly, you can actually see the numerical glucose difference caused by habits and supplements.
Plus, Nutrisense is offering my audience a free 1-1 consultation with one of their registered dietitians. Read my review here, or check it out yourself.
Use the exclusive coupon code URBAN for $25 off.
Great Natural OTC Metformin Alternatives
No known side effect by itself completely negates Metformin’s potential. When you add everything together, enough unknowns pop up to warrant trying some more natural alternatives first to see if you can stabilize blood sugar through other means.
Finally, through modern science, we can relax and enjoy the occasional indulgence.
First and most obviously, you can stabilize your blood sugar by making healthy low-glycemic food choices (make sure to avoid foods with hidden sugar).
Once you do that you have two categories of blood sugar stabilizers:
I like lifestyle changes because they are cheap (or free), available to everyone, and widely accessible. However, when you’re low on time or don’t have the ability, choosing the right products can help.
Looking for even more supplements not listed here?
1. Blood Sugar Breakthrough
This is the all-in-one product for those serious about optimizing metabolic health.
If you don’t want a closet full of supplements, BiOptimizer’s Blood Sugar Breakthrough delivers a potent blend of all the top ingredients.
Blood Sugar Breakthrough’s ingredients include:
- Glucovantage® Dihydroberberine (DHB)
- Glycostat® Bitter Melon Extract
- Cinnulin PF® Cinnamon Bark 20:1
- Innoslim® (Panax notoginseng, astragalus membranaceus)
And nine other research-backed ingredients proven to balance blood glucose, enhance insulin sensitivity, and activate AMPK.
Click the button below and scroll to the bottom of their website for 18 studies backing their formula. BiOptimizers is so confident in their formula, that they back it with an unconditional no-questions-asked 365-day money-back guarantee.
Use the exclusive BiOptimizers code URBAN for 10% off.
2. Berberine
Berberine is an extract that comes from multiple plants.
It works as an anti-inflammatory, antioxidant, anti-microbial, and liver booster.
Biohackers consider berberine the gold-standard effective metformin replacement.
Well-documented studies support berberine as an ideal medicine for its “glucose-lowering effect“.
At a dose of 500mg it lowers blood sugar. I personally take it whenever I expect to indulge.
But that’s not all.
2019 research confirms that berberine reduces fasting blood sugar and blood insulin levels too. And rat studies have found that it also helps regenerate the cells that make insulin (beta cells).
I can confirm the results. Using my Nutrisense continuous glucose monitor, I can indulge in carb-heavy meals like sushi and use berberine to minimize the spike. It works impressively.
3. Dihydroberberine
This is not a typo.
Dihydroberberine is berberine’s more potent, longer-lasting cousin.
Legendary supplement formulator Dr. Shawn Wells considers it his top anti-aging (and natural blood sugar management) ingredient.
Dihydroberberine (DHB) helps force carbs to be burned or stored in the muscle instead of becoming body fat. DHB converts into berberine in the gut, and then back into dihydroberberine inside cells. This prevents the stomach discomfort and potential minor gut irritation caused by normal berberine.
Compared to normal berberine, DHB:
- Lasts twice as long (eight hours versus hour)
- Absorbs five times better (better value)
- Requires a smaller dose
- Supports healthy gut
- Improves learning & memory
Great for getting into deep ketosis. You can learn more about this compound here.
In summary, dihydroberberine is the berberine 2.0 upgrade.
The downside? It’s harder to get.
Though it’s similar (and more effective) to traditional berberine, few supplements include DHB.
4. Bitter Melon Extract
Next, you’ll find bitter melon extract often included in high-quality fat loss supplements.
I see it in “carb blocker” formulations because it suppresses the characteristic inflammation and blood sugar spike aftermath of binging.
Bitter melon extract is mostly known (and studied) for its anti-obesity properties. That’s not all. A 2017 review found its effects extend far beyond liver protection:
“Antidiabetic, anticancer, hypotensive, anti-obesity, antimicrobial, antihyperlipidemic, antioxidant, anti-inflammatory, immuno-modulatory, anthelmintic, neuro-protective…”
This is one ingredient you’ll want to bookmark for later. Note that you’ll often see it referred to as “Momordica Charantia” in research.
When choosing a Bitter Melon product, look for the most potent formulation (Glycostat) on the label.
5. Lotus
Coming up as number three on my favorite supplements, lotus seems quite effective.
I came across lots of literature showing a significant effect on blood glucose.
Researchers call lotus a strong anti-obesity agent. Lotus works via two mechanisms:
- Reducing fat accumulation
- Increasing fat burning
I have not experimented with it yet, but lotus (or any of its other countless aliases) looks like a powerful weapon in the longevity arsenal.
6. Apple Cider Vinegar
Don’t expect huge blood sugar changes from apple cider vinegar (ACV), but it may help.
If this one is in your cabinet give it a try.
Apple cider vinegar works differently than the other compounds, but I’ve heard a fair amount of anecdotal success with it. It won’t hurt, and it has plenty of other beneficial properties.
Bragg’s is the tried and true fan favorite.
When choosing apple cider vinegar, make sure it is raw, unfiltered, unpasteurized, and “with the mother” for maximum benefit.
7. Ceylon Cinnamon
Following in apple cider vinegar’s footsteps, Ceylon cinnamon also has an effect on blood sugar.
Look for a type called Ceylon. The more common types of cinnamon, Cassia and Saigon, contain high levels of a toxic ingredient called Coumarin.
Most cinnamon is Cassia unless stated otherwise. Ceylon is less potent, so consuming the multi-gram dose is bearable.
I like to use it in my coffee after a night of bad sleep, or in my smoothies.
If you don’t mind the simple look of their label, Frontier produces a great value, high-quality, organic, non-irradiated cinnamon.
8. EGCG
EGCG is one of the primary beneficial ingredients (polyphenols) in green tea.
Preliminary findings suggest widespread benefits throughout the body:
“It is cardioprotective, neuroprotective, anti-obesity, anti-carcinogenic, anti-diabetic, anti-artherogenic, liver protective and beneficial for blood vessel health.”
Examine.com
This supplement works best when taken over the long term.
An old 2012 study showed two months of supplementation significantly reduced blood glucose.
Fascinatingly, EGCG may work as an effective carb blocker.
In another small group, 28 healthy volunteers saw a 30 percent reduction in carbohydrate absorption!
Additionally, supplementing EGCG improves LDL-cholesterol and glucose.
9. Exercise
The irony of using Metformin is that blunts one of the most effective tools available.
Strength training, high-intensity interval training (HIIT), and aerobic training all drop blood sugar. The study on HIIT showed the effect on blood glucose lasted up to three days!
10. Walking
I overlooked the power of walking for most of my life.
Now I am a big fan.
From stimulating brain growth to keeping blood sugar low, walking benefits the brain and body. Centenarians living in blue zones make these frequent micro-workouts a staple of their daily lives.
It’s easy too. Enjoy a brisk twenty-minute post-meal walk.
Or take it to the next level with a form of weighted walking called rucking.
11. Cold
Cold exposure builds resilience, fast. Biohackers wearing continuous glucose monitors (CGMs) often report drastic blood glucose effects.
Exposure to cold via a fasted morning walk, cold shower, or ice bath has a significant effect on blood sugars.
Try a cold shower before moving on to dietary supplements (which also can have side effects).
12. Inositol
Inositol, also called vitamin B8, naturally occurs in fruits, nuts, beans, and grains.
Two forms of supplemental inositol, however, have additional health benefits:
- D-chiro-inositol (DCI)
- Myo-inositol (MYO)
Inositol makes insulin more efficient which helps normalize blood sugar levels.
- One 2017 study found that supplementing 1 gram of DCI plus 400 mcg of folic acid led to better metabolic control.
- An investigation into women with PCOS supplementing MYO showed greater weight reduction than metformin.
It balances serotonin and dopamine, two neurochemicals responsible for your mood. Other notable effects on mental health with one study finding improved symptoms of depression.
13. Bergamot
Bergamot is a citrus fruit with millennia of medicinal use.
Traditionally used for its aroma and anti-septic properties, researchers are now investigating its potential to safely treat type II diabetes.
The polyphenols in it improve many facets of cardiovascular health. Such as cholesterol, triglycerides, and different markers of the blood.
Several studies have found bergamot extract (more than essential oil) effectively reduces blood glucose. The clinical extract goes by the name CitriCholess, though I couldn’t find any supplements containing that particular form.
Bergamot isn’t the most powerful option on this list, so I’d only recommend it as an adjunct to the others.
Try a Natural Metformin Alternative Today
Metformin's not the only anti-aging strategy around. Between lifestyle practices, and powerful supplements you can get all the benefits of stable blood sugar without nasty side effects. Click To TweetI’m partial to lifestyle tweaks. Once you learn them, they work effectively, anywhere, and without capsules. They aren’t as effortless but can provide even greater effects.
Regardless, occasionally I’ll use a natural blood sugar supplement to mitigate the downsides of a low-quality meal. My personal favorite is dihydroberberine.
Blood sugar regulation is but one of countless reasons to exercise. You don’t have to go all out. Something as simple, accessible, and easy as walking works.
Remember, biohacking with metformin alternatives isn’t an excuse to eat poorly, but rather damage control for the rare binge.
Thanks for the article and recommendations!
Terrific stuff and the links are helpful too.
Thanks Mike! Happy you found it helpful 🙂
Thanks! I am quitting Metformin and Lipitor!
Taking your advice.
Berberine replaces Lipitor, also, Bergamot is supposed to be good.
Hey Simone. While I love the inspiration, these articles are for information purposes only and you should consult your primary healthcare provider before making any changes.
Good point about Bergamot! I’ll have to add that to the list 🙂
When do you take Berberine? Before or after indulging in carbs/sugar? I have heard people say 30 min before and others say 30 min after.
Hey Brad! Great question. I take it before. Generally 30 minutes. From using a CGM, I have found that pre-meal works best for me. It’s possible that some people do best when they take it afterward, but that seems less likely due to the way the glucose spike works.