Is Metformin Good Or Bad For The Brain?

TLDR: Metformin has been characterized by some as a benign medication that increases lifespan and normalizes blood sugar in aging adults. But that's only part of the story. While Metformin has life-extending properties in model organisms, it negatively affects brain energy metabolism by impairing mitochondrial function. The brain is energetically expensive and is extremely sensitive to ATP status. Metformin was also recently shown to increase the expression of amyloid beta and diabetics treated with Metformin had worse cognitive performance compared with peers prescribed other treatments for diabetes. Paradoxically, other studies also report the opposite.

In the longevity research community Metformin is often cited as a potentially life-extending drug. And for good reason. In animal models (e.g., Drosophila, C. elegans, rodents) Metformin decelerates aging.

(A and B) Metformin (A) and phenformin (B) extend lifespan in a dose-dependent manner.

In humans, Metformin is prescribed for diabetes. Metformin is an "insulin sensitizer" that reduces insulin resistance and fasting insulin levels. It also directly decreases sugar production in the liver and has an overall net-beneficial effect on glucose metabolism. Metformin is uniquely effective in improving glycemic control with a low risk of inducing hypoglycemia.

If your diet is a typical western diet and you don't watch what you eat, chances are that you're consuming too much sugar. Bread, breakfast cereals, grains, crackers, and pasta are metabolized to sugar despite not tasting particularly sweet.

Carbohydrate overconsumption leads to chronically elevated blood sugar (hyperglycemia), which is harmful to the brain via multiple mechanisms. This is the takeaway from the book Grain Brain. Mild cognitive impairment goes hand-in-hand with poorly controlled diabetes.

Calorie restriction is also a frequently discussed topic among longevity researchers. Caloric deficit improves lifespan in part by normalizing glucose regulation. Perhaps Metformin captures some of the benefits of calorie restriction by improving glucose regulation?

So is Metformin helpful or harmful for the brain? More research is needed, but it seems to have effects in both directions.

Conflicting Observations

The promising effects of metformin against cognitive decline are challenged by conflicting results.

Cause For Concern: Metformin Disrupts ATP Synthesis In The Brain

The brain requires an uninterrupted supply of sugar. Under atypical conditions (diabetes, ketogenic diet) the brain can be fueled by ketone bodies.

A healthy brain is metabolically streamlined. Diseases that affect energy metabolism in the brain impair cognitive ability. Hence, mitochondrial disorders and hypothyroidism can lead to intellectual disability.

Mitochondria constitute the primary target of Metformin. Metformin is positively charged under physiologic conditions, which drives the accumulation of Metformin into the mitochondrial matrix.

Metformin inhibits the mitochondrial respiratory-chain, specifically at the level of complex 1. Metformin induces a decrease in:

  • NADH oxidation
  • proton pumping across the inner mitochondrial membrane
  • oxygen consumption rate

The net effect? Lowering of the proton gradient (Δϕ) and a reduction in proton-driven synthesis of ATP from ADP and inorganic phosphate.

The cost of Metformin's seemingly magical ability to restore normal glucose homeostasis is not without a price; it comes with impaired ATP synthesis. Metformin is blood brain barrier-permeable and thus likely impairs the activity of mitochondria in the central nervous system.

More On The Negative Side

Moreira12 writes:

Chen et al. (13) reported that metformin, at doses that lead to activation of the AMPK, significantly increased the generation of both intracellular and extracellular Aβ species in mouse primary cortical cultures and N2a neuroblastoma cells stably expressing human amyloid precursor protein (APP). The authors also demonstrated that the effect of metformin on Aβ generation was mediated by transcriptional up-regulation of β-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity (13).

Metformin increased amyloid beta (a cellular hallmark of Alzheimer's disease). This effect was mediated by upregulation of β-secretase. Note that β-secretase inhibitors are being pursued as potential Anti-dementia drugs. This finding bodes ill for Metformin.

Expectedly, Moore and colleagues13 reported that patients with type 2 diabetes had worse overall cognitive performance. But in this study Metformin-treated diabetics performed worse than their peers treated with other interventions. The authors suggested that the adverse effects of Metformin may be related to a decrease in serum vitamin B12 levels, which can be corrected by calcium supplementation.

A previous case-control study14 that enrolled 14,000 patients showed that long-term Metformin use may be associated with a modestly increased risk of Alzheimer's in older adults. This study suffered serious limitations, however. The authors were not able to adjust for potential confounds like APOE ε4 status, educational attainment, and lifestyle habits.

Basic science has also yielded conflicting results about the harm verses benefit of Metformin.

On The Positive Side

  • Metformin prevented amyloid β generation and tau protein hyperphosphorylation (AD-like features) in a differentiated neuronal cell line [study]
  • Metformin also induced protein phosphatase 2A (PP2A) activity and reduced tau phosphorylation at PP2A-dependent epitopes.
  • Metformin apparently promotes neurogenesis and enhances spatial memory in mice.
  • Metformin reduces oxidative stress in rodent brains [study].
  • Metformin preconditioning had a protective effect against cerebral ischemia. Moreover, chronic metformin treatment facilitated post-stroke recovery by enhancing angiogenesis.
  • Metformin inhibits hepatic gluconeogenesis and opposes the action of glucagon.
  • Metformin-mediated inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signaling in response to glucagon.
  • Stimulation of AMP-activated protein kinase (AMPK) confers insulin sensitivity, mainly through the modulation of lipid metabolism.

In humans, Ng and colleagues reported that long-term Metformin may reduce the risk of cognitive decline:

Ng et al. (11) used data of 365 older persons with diabetes from the population-based Singapore Longitudinal Aging Study to investigate the effect of metformin usage on the risk of cognitive impairment and its possible modulation by apolipoprotein E (APOE) ε4 gene polymorphism. The authors found no significant interactive effects of metformin use with APOE ε4, depression, or fasting glucose level. It was also observed that among individuals with diabetes, long-term treatment (>6 years) with metformin may reduce the risk of cognitive decline.

Metformin and Cognition

Can Metformin Prevent Age-Related Declines in Cognition?

Metformin, an anti-diabetic drug, apparently improves cognition (learning, memory and understanding) in different experimental scenarios.

While some studies have found that Metformin improves cognition in older adults and animals, nearly as many studies have also found Metformin to be ineffective or even harmful to cognitive ability.

Most medications have trade-offs that must be weighed, which is the physician's dilemma. Metformin is no different.

While metformin may improve cognition, it may also increase vulnerability to environmental neurotoxins. The bottom line is more studies are needed for conclusive results.

What is Metformin?

Metformin (generic name Glucophage) is a medication approved to control blood sugar in patients with type 2 diabetes.

Although it has not been approved for other uses, Metformin is prescribed off-label for the following:

  • Diabetes prevention in high-risk populations, e.g., patients taking antipsychotics.7
  • To treat polycystic ovarian syndrome.11
  • To improve menstrual cycles regularity.3
  • To improve fertility.10

How Would Metformin Improve Cognition?

Metformin could potentially improve cognitive side effects in several brain diseases and disorders. There is evidence of its effectiveness in several conditions that impair cognition including:

  • Perinatal hypoxia-ischemia (A lack of oxygen to the brain immediately before or after birth).8
  • Cognitive decline due to old age.1
  • Cognitive dysfunction associated with diabetes.2

Perinatal Hypoxia-Ischemia

Perinatal hypoxia-ischemia damages the corpus callosum. The corpus callosum is a network of nerve cells that integrates the right and left brain hemispheres. The corpus callosum of women is more developed than men, which may enhance emotional intelligence.

Age-Related Cognitive Decline

In a rodent study, Metformin treatment prevented high-fat diet-induced declines in spatial working memory.1

These results were replicated in a clinical trial of older adults with diabetes. Metformin reduced the study participants' risk of becoming cognitively impaired.6

Diabetes-Associated Cognitive Dysfunction

Treatment with Metformin in combination with another diabetic therapy, (Val(8))GLP-1(GluPAL), improved learning and memory in animals fed a high-fat diet. It also partially reversed the neurotoxic effects of high fat diet on the hippocampus.2

How Is Metformin Taken?

Metformin comes in two 500 mg oral tablet forms: white circular tablets (generic) and off-white oval tablets (brand name). They can be taken 1 to 3 times a day. Dosage depends on the condition treated. Many patients start with a low dose and titrate upward toward effective dose to prevent or reduce side effects.9

Does Metformin Interact with Other Drugs or Conditions?

Unsurprisingly, taking Metformin with other anti-diabetic medications may cause hypoglycemia or low blood sugar. Metformin should not usually be co-administered with any of the following:9

  • Iodinated contrast materials
  • Anti-diabetic agents
    • Severe Reaction
    • Gymnema
    • Gatifloxacin
    • Moderate Reaction
    • Some quinolones
  • Cimetidine
  • Cephalexin
  • Ranolzine
  • Carbonic anhydrase inhibitors
  • Dolutegravir
  • Trimethoprim
  • Vandetanib
  • Insulin
  • Hypoglycemics

What Are Some of the Side Effects of Metformin?

Metformin is not without side effects.

Common Side Effects

  • Nausea
  • Vomiting
  • Stomach upset
  • Diarrhea
  • Weakness
  • Metallic taste
  • Initial stomach upset
  • Infection of the nose, throat or sinuses
  • Gas
  • Head pain
  • Bloating

Severe Side Effects

Severe side effects should be reported to your physician immediately. These include:

  • Return of stomach upset
  • Lactic acidosis
  • Rash
  • Itching
  • Extreme dizziness
  • Trouble breathing
  • Low Blood Sugar Side Effects
    • Sudden sweating
    • Shaking
    • Fast heartbeat
    • Hunfer
    • Blurred vision
    • Dizziness
    • Tingling hands/feet
  • Anemia

Rare side effects

  • High Blood Sugar Side Effects
    • Thirst
    • Increased urination
    • Confusion
    • Tiredness
    • Flushing
    • Rapid breathing
    • Fruity breath
  • Chills
  • Dizziness
  • Excessive sweating
  • Nail disease
  • Flu-like symptoms
  • Abnormal heartbeat
  • Constipation
  • Muscle pain

Are There Any Precautions I Should Take While Taking Metformin?

Metformin can interfere with surgeries, X-rays, and scans. Most physicians therefore advise that metformin be stopped before these interventions.

Metformin has also been noted to contribute to dehydration. Drink plenty of fluids!

Since metformin promotes ovulation and affects menstrual cycles, it is important that reliable birth control is taken to prevent unwanted pregnancy.

Finally, Metformin can be passed through breast milk.9

Please consult your doctor about the previously mentioned issues before making any changes to your medication.

Metformin in Children and the Elderly

The effect of Metformin on children is not well-researched.

Children are more likey to experience lactic acidosis and kidney issues with Metformin.9

Why Isn't Metformin Approved for Mild Cognitive Impairment?

More research is needed, and the research that has been conducted to-date is contradictory.

While some studies have found Metformin to improve cognition in aging people and animals, the animals and people used in these studies had symptoms similar to diabetes.1

For example, a recent study found that treatment with metformin for a year did not improve cognitive impairment in patients with amnestic mild cognitive impairment.5

Metformin has been noted to alter neurochemistry in a way that may leave it more vulnerable to oxidative stress.1

More studies are needed to pin down the effects of Metformin on cognition and overall wellbeing.

References

  1. Allard, J., Perez, E., Fukui, K., Carpenter, P., Ingram, D., & de Cabo, R. (2016). Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice. Behav Brain Res, 1-9.

  2. Lennox, R., Porter, D., Flatt, P., Holscher, C., Irwin, N., & Gault, V. (2014). Comparison of the independent and combined effects of sub-chronic therapy with metformin and a stable GLP-1 receptor agonist on cognitive function, hippocampal synaptic plasticity and metabolic control in high-fat fed mice. Neuropharmacology, 22-30.

  3. Li, R., Zhao, J., & Wu, R. (2017). Predictors of menstruation restoration during metformin administration for treatment of antipsychotic drug-induced amenorrhea: A post hoc analysis. Schizophr Res, 30140-8.

  4. Luchsinger, J., Perez, T., Chang, H., Mehta, P., Steffener, J., Pradabhan, G., et al. (2016). Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis, 501-14.

  5. Moore, E., Mander, A., Ames, D., Kotowicz, M., Carne, R., Brodaty, H., et al. (2013). Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care, 2981-7.

  6. Ng, T., Feng, L., Yap, K., Lee, T., Tan, C., & Winblad, B. (2014). Long-term metformin usage and cognitive function among older adults with diabetes. Alzheimers Dis, 61-8.

  7. O'Brien, M., Perez, A., Scanlan, A., Alos, V., Whitaker, R., Foster, G., et al. (2017). PREVENT-DM Comparative Effectiveness Trial of Lifestyle Intervention and Metformin. Am J Prev Med, 30014-4.

  8. Qi, B., Hu, L., Zhu, L., Shang, L., Sheng, L., Wang, X., et al. (2016). Metformin Attenuates Cognitive Impairments in Hypoxia-Ischemia Neonatal Rats via Improving Remyelination. Cell Mol Neurobiol.

  9. Thomas, I., & Gregg, B. (2017). Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes, 10-6.

  10. Zhang, J., Si, Q., & Li, J. (2017). Therapeutic effects of metformin and clomiphene in combination with lifestyle intervention on infertility in women with obese polycystic ovary syndrome. Pak J Med Sci, 8-12.

  11. Zhang, Y., Hu, M., Meng, F., Sun, X., Xu, H., Zhang, J., et al. (2017). Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome. EBioMedicine, 30119-6.

  12. Moreira PI. Metformin in the diabetic brain: friend or foe? Ann Transl Med. 2014 Jun;2(6):54

  13. Moore EM, Mander AG et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care. 2013 Oct;36(10):2981-7

  14. Imfeld P, Bodmer M et al. Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. J Am Geriatr Soc. 2012 May;60(5):916-21

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Xavier Kent

I'm interested in nutrition, nootropics, and javascript. I'm a firm believer in getting really good at one thing.

Maryland

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