Metformin

Metformin
By Jonathan Roseland

I'm not a doctor, medical professional, or trained therapist. I'm a researcher and pragmatic biohacking practitioner exercising free speech to share evidence as I find it. I make no claims. Please practice skepticism and rational critical thinkingYou should consult a professional about any serious decisions that you might make about your health. Affiliate links in this article support Limitless Mindset - spend over $150 and you'll be eligible to join the Limitless Mindset Secret Society.

This pharmaceutical is an insulin hack and the most studied diabetes drug yet remains highly controversial as an anti-aging and longevity tool for biohackers.

Guys and gals, I have met my match as a researcher, Metformin. I pride myself on being able to discern the difference between information and misinformation, between science and marketing hype and I'm not sure if I've ascertained the truth about Metformin. I've tried to wrap my head around the vast amount of research and commentary on Metformin and honestly, I'm not sure if Metformin is a game-changing anti-aging drug or a problematic big pharma product.

Scientific Research
History
Mechanism of Action
A Metabolism Hack
An Insulin Hack
An AMPK Hack
An mTOR Hack
Vs Type 2 Diabetes
For Body Building
Experiential
A Will Power Diet Hack 

Vs Cancer
Black People Should Take Metformin

Cofactors
Usage & Dosage
Price
Side Effects
Risk Grade
Metformin Alternatives
Conclusion
Metformin Videos

This article is mostly going to focus on decoding what the human studies are saying about Metformin and how this squares up with the anecdotal experiences of Biohackers online. For more of my own personal experiences, thoughts, and comparisons please see the written and video reviews in the sidebar.

 Scientific Research

Impressively you can find +17,000 scientific papers referencing Metformin and a number of human clinical trials. The most notable meta-analysis of Metformin analyzed more than a dozen randomized controlled trials totaling over 13,000 patients was published in 2012 and concluded: 

Although metformin is considered the gold standard, its benefit/risk ratio remains uncertain.

And they had some indication that sulphonylurea therapy caused an increase in mortality. That's concerning.

 History

French lilac has been used for centuries in folk medicine of which Metformin's properties are derived. French lilac was a remedy for frequent urination which is now known to be a symptom of diabetes.

Metformin history

Metformin originates from the French lilac (Galega officinalis), a plant known to reduce the symptoms of diabetes mellitus...

From a 2012 paper out of Korea University College of Medicine. The book Rigor Mortis, about scientific rigor, mentions Metformin as an unexpected scientific success.

Some of the most successful drugs are the result of serendipity, as is the case for metformin, the most widely used drug for type 2 diabetes. Decades ago a researcher in the Philippines studying an obscure compound to treat flu and malaria reported that it also seemed to lower blood sugar. In 1957, a Parisian scientist noticed that published observation and tried the drug in animals. British researchers tried it in diabetics in the 1960s, and it worked surprisingly well. The original compound was discovered as an herbal extract, and to this day scientists don’t understand the biological mechanism. But it doesn’t matter. It works. (p. 90)

Rigor Mortis
 
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Category: Book

It's now an extremely popular drug with +80 million prescriptions written annually in the United States alone.

 Metformin makes an appearance in one of my favorite books, Tools of Titans by Tim Ferriss by Tim Ferriss:

[Dominic D’Agostino] considers it the most promising of the anti-aging drugs from a scientific standpoint, and I would estimate that a dozen of the people in this book use it. (p. 37)

Tools Of Titans: The Tactics, Routines, and Habits of Billionaires, Icons, and World-Class Performers
 
5.0
Category: Book

 Mechanisms of Action

 A Metabolism Hack

Metabolism

Biohackers may find it helpful who have indulged for years in a standard American diet rich in carbohydrates and sugars and are switching to a keto or paleo-style diet. Imagine a heroin or methamphetamine addict, they need their narcotics to feel normal because their feel-good neurotransmitter receptors have been desensitized by years of abusing drugs. They can no longer take real pleasure in a succulent meal, a conversation with a friend, or having sex with their partner because their neurobiology has grown numb to serotonin and dopamine. They need to restore the sensitivity of those receptors to have a normal life. That's sort of what Metformin does by stimulating the GLUT4 receptors.

 An Insulin Hack

Insulin

Insulin is a crucial hormonal regulator of our internal homeostasis. From a 2012 paper detailing its mechanism:

Metformin has many effects on insulin sensitivity in muscle and liver, including a decrease in hepatic glucose production, an increase in peripheral glucose utilization, and positive effects on insulin receptor expression and tyrosine kinase activity...

  • Metformin increases the body's sensitivity to insulin.
  • Reduces liver gluconeogenesis - the production of glucose. The liver converts a lot of the protein that we consume into glucose (sugar). Metformin prevents this which is beneficial to gym bros (like me) who are consuming a lot of protein. If you're spending your hard-earned money on fancy whey protein powder or steak dinners you want as much of that protein as possible to contribute to muscle growth.

 An AMPK Hack

AMPK

Metformin activates the AMPK energy system - the endurance energy system - which switches the body over to more of a fat-burning energy mode. Naturally, the body prefers to burn glucose, the body prefers to burn sugars, Metformin hacks this which is obviously beneficial for those who need to lose weight.

The 2012 paper explains...

AMP-activated protein kinase (AMPK) is an enzyme that plays a role in cellular energy homeostasis. AMPK is activated when cellular energy is depleted

 An mTOR Hack

mTOR

From a detailed Longecity article:

The mechanisms for lifespan extension by metformin are not completely understood yet but probably involve AMPK and its downstream target mTOR... mTOR is also the target of the famous life extension drug rapamycin that increases lifespan in mice both when administered early and during middle life... mTOR inhibits autophagy thus metformin activates autophagy by inhibiting mTOR. Autophagy clears cells from dysfunctional organelles – such as mitochondria – and other junk that can impair normal cellular functions and thereby extends lifespan.

Does this mean that Rapamycin is a metformin alternative? Possible, although it's prohibitively expensive.

 Vs Type 2 Diabetes

Diabetes

The notable study on Metformin was The UK Prospective Diabetes Study, over 5,000 people struggling with diabetes participated making it the largest diabetes study ever. It begins with an interesting tidbit of history

Diabetes was first recognized 3500 years ago by the Ancient Egyptians. One of the first clinical descriptions was by Aretaeus, who practised in Cappadocia around 120 AD. He wrote that the condition was ‘fortunately rare’, but ‘short will be the life of the man in whom the disease is fully developed’... In modern society, the first statement is far from true.

Being such a substantial study, a 10-year follow-up was conducted.

Among patients in the metformin group, as compared with overweight patients in the conventional-therapy group, significant reductions in relative risk that were observed during the interventional trial for any diabetes-related outcome...

And a 2008 French paper added:

A continued benefit after metformin therapy was evident during the ten-year post-trial follow-up among overweight patients...

It would be smart to get your personal genotyping done to determine if you carry many of the 48 risk factor genes for diabetes. If you do there are some evidence-backed preventative measures you would want to make a part of your lifestyle. Doctors will often prescribe Metformin to people who are prediabetic but there are a lot better options for averting diabetes than hacking your metabolism with this contentious pharmaceutical.

 For Body Building

Body Building

Is AMPK "exercise in a bottle"? That's the premise of a very thorough 2016 article published in EMBO Reports:

In mice models, irisin causes some of the metabolic benefits of exercise, such as reducing weight and offsetting the negative effects of a high‐fat diet.

It goes on to explain...

AMPK, or AMP‐activated protein kinase, was identified in 1999 as the metabolic master switch and the central regulator of both lipid and glucose metabolism, making it an obvious target for therapeutic intervention against metabolic conditions, especially type‐2 diabetes.

 Experiential

An effect that caught my attention was that it may be a shortcut to a more adonis-esque body. According to Dan the Bodybuilding Knowledge Bro, it has a notable effect on your physique and musculature.

Glucose aversion was reported by Dr. Edward Omron, it makes consumption of carbs and sugary food a distinctly unpleasant experience. Thus, it conditions you to avoid unhealthy food. This sounds great for those struggling with obesity or diabetes or failing to find the self-control to change their diets. He also reported...

  • Improved his long-term memory recall.
  • It made him look less old, it made his face less round and fat and more angular and defined.

Expect a bit of diarrhea and discomfort during the first week on Metformin, after one month the gastrointestinal discomfort will go away.

Apparently, it makes your poop and pee smell worse. So keep the damn window open in your bathroom!

 A Will Power Diet Hack

Diet HackIf you've ever had friends or family who tried to quit smoking cigarettes, they may have tried this drug Chantix® that makes smoking a really awful experience. Conditioning them to overcome their self-destructive addiction. Metformin, for many, has a similar effect on their urge to eat sugary, carbohydrate-rich foods. It's an appetite suppressant for many, on Longecity it was reported...

appetite suppression and incidental calorie restriction: I experienced a significant dose-dependent suppression of appetite and thus the number of consumed calories. This effect was significant enough to make me suspect that at least some of the benefits of Metformin may be explained by the effects of "accidental" calorie restriction.

 Vs Cancer

cancer

Lewis Cantley of the Cancer Center at Weill Cornell Medicine asserted...

“Metformin may have already saved more people from cancer deaths than any drug in history.”

 Why black people should take metformin...

Mitochondria and the Future of MedicineFrom Dr. Lee Know's recent book:

A thought - provoking study published in June of 2014 demonstrated that metformin consistently benefited African Americans more than their Caucasian counterparts with respect to blood sugar control . Based on our earlier discussion regarding “ tight ” mitochondria in people with equatorial origins , it’s predictable this uncoupler would have benefited these individuals to a significantly greater extent (2101-2104)

 Cofactors

Ipragliflozin - A recent Russian phase 3 randomized placebo-controlled trial totaling 165 patients noted that Ipragliflozin was safe and enhanced Metformin's positive effect in reducing HbA1c and body weight after 12 weeks.

Vitamin B-12 - Metformin is especially problematic for those who are B12 deficient. It's a really smart idea to supplement methylated B-12 with Metformin.

Niacinamide - There's an interesting presentation on a self-experimenter's 23-month trial stacking the two.

 Usage & Dosage

1000 milligrams daily is a typical dosage. With Metformin you want to start with a smaller dosage and work up to a larger dose (or whatever your physician has prescribed)

For example, start with 500 milligrams, taken with your largest meal of the day, and incrementally increase the dose. Add another 500 milligrams with your other meals. Increase the dose gradually by 500 milligrams weekly.

  • 1 - 2 grams total daily is a typical dosage for treating or preventing diabetes.
  • Bodybuilders may want to take up to 2000 milligrams to maximize muscle gains.

 Price

It's an off-patent and very affordable drug, costing $5 - $25 monthly for regular users, depending upon the source. A month's supply from RUPharma.com is just about $8.

 Side Effects

Increasing Metformin dosage too fast often results in some unpleasant side effects; diarrhea, nausea, heartburn, stomach cramps, etc. This can be avoided by starting with a low dose and working your way up slowly.

Lactic acidosisJames McCormack makes the case at the BCCFP Family Medicine Conference that Lactic acidosis is really not a concern unless you're taking Metformin in ridiculous dosages. You don't need to worry about it if you're taking a reasonable 500 milligrams or 1 gram daily dose. It can be reversed by taking Vitamin B1.

 Mcmanis, a very thorough biohacker on Longecity reported that when starting with Metformin...

[The] initial gastrointestinal discomfort which quickly subsides: I found
this initially to be significant side-effect with the regular
fast-release version of Metformin, even at small doses (e.g., 500mg). This was significantly less of an issue with the slow release version. This side-effect seems to go away once the bioflora in your gut rebalances.

Metformin might lower testosterone, from Tim Ferriss's interview with Dominic D'agostino:

Dom did a test where he took 1 g of metformin daily for 12 weeks, and had blood work done throughout. His diet and exercise didn’t change. In his “post” test, his triglycerides were the lowest they had ever been, his HDL was around 98 (bumping up from 80), and his C-reactive protein wasn’t even measurable. The only side effect he saw was that his testosterone was lower, and that came back into normal range once he stopped taking metformin. (p. 37)

ConflictsIn combination with beta-blockers (Acebutolol, Atenolol, Bisoprolol, etc) it may lower blood sugar. Quinolones (antibiotics) may increase blood sugar. Cimetidine, a heartburn drug has been implicated in one of the rare cases of Lactic Acidosis.

Apparently, Metformin has a very distinctive scent that often makes your poop and pee smell awful and according to some biohackers, this smell persists as long as you are taking Metformin. It doesn't make your skin or breath stink, but your family, roommates, or coworkers may hate you if they have to use the bathroom after you! I polled the members of a Metformin Facebook group about this very unappealing potential side effect and the majority of users responded that it did not affect their bathroom smells.

Metformin poll

 Risk Grade: B-

  • It is heavily studied worldwide which is encouraging. However, the most authoritative meta-analysis of clinical trials couldn't conclude that it was useful and helpful.
  • It has undergone a massive clinical trial giving Metformin to over 5000 people and a 10-year follow-up study was conducted. If it produced serious negative side effects in a statistically significant proportion of its users this giant study would have noted that.
  • The major thing that scares people about Metformin is the Lactic acidosis which can actually kill you. However, unless you have liver or renal issues or you're drastically deficient in B vitamins you really don't need to worry much about this.
  • There's some concern about its effect on kidney function, from a 2017 study of 600 Taiwanese Metformin may have an adverse effect on renal function in patients with type 2 DM and moderate CKD.

It's a somewhat contentious drug amongst the biohacking gurus; Dr. Mercola called it a Mitochondrial poison, and Dave Asprey agreed: I’m scared of metformin and I don’t use it. Ben Greenfield disagreed sayingI am no longer opposed to the idea of using metformin... I think metformin is okay. Biohacking bodybuilder extraordinaire Jay Campbell has used it for 17 years and contends that Metformin is a perfectly safe medication and also the most studied in the history of the world.

 The Metformin Alternatives

At this point you may be saying to yourself, Metformin sounds awful! No thanks!

I'll direct your attention to the nutraceutical Berberine; It simulates the effects of diet, exercise, and weight loss. T-Nation.com advises a dosage of 500 milligrams three times a day, you can take it as a capsuled supplement or as an herbal tea steeped in boiling water.

Citrus Bergamot Extract, is a potent supplement for glucose management and is often paired with Berberine.

There are four clinical studies totaling +1300 diabetics evaluating Berberine's effect on Insulin.

A 2003 Chinese study evaluated its effect on exercise capacity 

After treatment with berberine, there was a significantly greater increase in... exercise capacity, improvement of the dyspnea-fatigue index...

Although, I've heard from a credible source that Berberine as a supplement is problematic; many vendors of the stuff are not selling pure Berberine. Thus I'd urge you to only order or consume it after you see a COA verifying the quality. The evidence for Berberine as an insulin hack for diabetics and an AMPK "exercise in a bottle" hack for gym bros is not as strong as Metformin. It seems to me that there are a lot of better lifestyle options to turn to before using this pharmaceutical.

Downloadable Metformin?

Given all the questions about Metformin, you may be interested in taking it as an infocuetical (IC) - a non-pharmacological, side-effect-free version of the drug that takes advantage of the phenomenon water memory - which is imprinted on water with electromagnetism and trippy lights using this device...

If you're skeptical of Infopathy that's understandable but consider that 6 diabetic obese patients in a 2012 practitioner-run trial switched from Metformin to this Glucophage IC for 16 months and lost on average 30 kilograms.

 Conclusion...

Metformin packageI think I'm going to pass on Metformin. The main upside for a healthy guy like me in my mid-30s would be muscle gains in the gym. I don't really care about bodybuilding, I don't care about having huge muscles. I go to the gym several times a week to stay lean and maintain health. The first week on Metformin is supposed to be pretty unpleasant and it makes your business in the bathroom a very pungent affair supposedly, I don't see the smell being worth the potential muscle gains. The potential side effects make it very unappealing to an otherwise healthy, happy non-diabetic biohacker like myself.

Photos

Metformin
Metformin
Insulin
AMPK mechanisms
mTOR mechanisms

Videos

Metformin: This AMPK/mTOR Longevity Hack Stinks!
Metformin: This AMPK/mTOR Longevity Hack Stinks! What to take instead to hack insulin...

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