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 really problematic big pharma product.
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.
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 randomised controlled trials totalling 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 bitherapy caused an increase in mortality. That’s concerning.
Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of…
PLoS Med. 2012;9(4):e1001204. doi: 10.1371/journal.pmed.1001204. Epub 2012 Apr 10. Meta-Analysis
French lilac has been used for centuries in folk medicine of which Metformin’s properties are derived. French lilac was a remedy for frequent irritation which is now known to be symptom of diabetes.
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.
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
[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
This +700 word, $16 book is kind of like a summarization of the all the +200 interviews that Tim Ferriss has done on…
Mechanism of Action
A Metabolism Hack
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 sensitive of those receptors to have a normal life. That’s sort of what Metformin does by stimulating the GLUT4 receptors.
Metformin Regulates Glucose Transporter 4 (GLUT4) Translocation through AMP-activated Protein…
Reagents Anti-phospho-JNK (Thr 183/Tyr 185), anti-JNK, anti-phospho-c-Jun (Ser 63), and anti-c-Jun antibodies were…
An Insulin Hack
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
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
A mTOR Hack
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.
Metformin a life extension drug? - Articles - Articles - portal - LongeCity
by Sven Bulterijs For hundreds of years it has been known that a plant extract from the French lilac (Galega…
Does this mean that Rapamycin is a metformin alternative? Possible, although it’s prohibitively expensive.
Vs Type 2 Diabetes
The notable study on Metformin was The UK Prospective Diabetes Study, over 5000 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.
The UK Prospective Diabetes Study (UKPDS): clinical and therapeutic implications for type 2…
Diabetes was first recognized 3500 years ago by the Ancient Egyptians. One of the first clinical descriptions was by…
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…
10-year follow-up of intensive glucose control in type 2 diabetes. - PubMed - NCBI
N Engl J Med. 2008 Oct 9;359(15):1577-89. doi: 10.1056/NEJMoa0806470. Epub 2008 Sep 10. Multicenter Study; Randomized…
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…
[United Kingdom Prospective Diabetes Study (UKPDS): 10 years later]. - PubMed - NCBI
Rev Med Liege. 2008 Oct;63(10):624-9.
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’s 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’s a lot better options for averting diabetes than hacking your metabolism with this contentious pharmaceutical.
For 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.
An effect that caught my attention was that it maybe 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. Which 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 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
If you’ve ever had friends or family that 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.
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…
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)
Ipragliflozin — A recent Russian phase 3 randomized placebo-controlled trial totalling 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.
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 2000 milligrams to maximize muscle gains.
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.
METFORMIN® (Glucophage) IR-XR, 30-60 tabs, 500-1000 mg
Metformin is used to treat high blood sugar levels caused by type 2 diabetes in combination with diet and exercise…
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 acidosis — James 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 really don’t need to worry about it if you’re taking a reasonable 500 milligrams or 1 gram daily dose. 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)
Conflicts: In 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 had no effect on their bathroom smells.
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, Dave Asprey agreed: I’m scared of metformin and I don’t use it. Ben Greenfield disagreed saying: I am no longer opposed to the idea of using metformin… I think metformin is okay. Biohacking body builder 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 Alternative: Berberine
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.
There are four clinical studies totalling +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; that many vendors of the stuff are not selling pure Berberine. Thus I’d urge you to only order or consume it after you see COA verifying the quality.
The evidence for Berberine as an insulin hack for diabetics and as an AMPK “exercise in a bottle” hack for gym bros is not as strong as with Metformin. It seems to me that there’s a lot of better lifestyle options to turn to before using this pharmaceutical.
I think I’m going to pass on Metformin. The main upside for a healthy guy like me in my mid 30’s would be muscle gains in the gym. I don’t really care about body building, 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.
Originally Published on LimitlessMindset.com