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Metformin: An Alternative to SSRIs [71 studies]

Metformin has significant potential for depression and anhedonia treatment. It works even on the level of the gut microbiome - not just the nervous system. It's a safe alternative to SSRIs since it doesn't lead to developing post-SSRI sexual dysfunction (PSSD). Here, I present you a compilation of the studies and Metformin's lesser-known mechanisms of action.



Metformin is an antidiabetic drug typically used for treatment of diabetes type 2 where it's often used as adjunct therapy to virtually every other antihyperglycemic medicine available today [1]. Its main mechanism of action is activation of AMP-activated protein kinase (AMPK) [2].

It works mainly by improving insulin-mediated suppression of hepatic glucose production, and by enhancing insulin-stimulated glucose disposal in skeletal muscle [3].

That said, the focus of this article is to bring the lesser known effects to the light, including, but not limited to, its downstream effects.

What is AMPK? and what's so important about its activation?

AMP-activated protein kinase (AMPK) is an enzyme in the human body that regulates cellular energy homeostasis particularly when cellular energy is low (i.e. low glucose). Simply put, it's a metabolic "master switch" that puts the body in a resilient state [4].

It's the enzyme that gets activated when you exercise and during intermittent fasting. The numerous health benefits seen from these activities are, in a large part, downstream effects of AMPK activation [5].

Since energy modulation is so important for the human body, AMPK basically controls all bodily functions either directly or indirectly (i.e. downstream) [4].

Okay, so how can Metformin help me?

Life Extension & Anti-Aging

Recently, scientists brought Metformin to the media's attention by showing how it extends lifespan in laboratory animals [6,7,8,9,10,11]. The evidence is extensive in the animal model but no studies were done on human beings as of yet [12,13]. Hopefully, future studies would shed light on this but I'm optimistic that Metformin would, at least, help reduce the overall burden of illnesses and suffering.

Antidepressant Effect

Metformin's antidepressant effect is evident in the scientific literature [14,15,17,18]. It also has pro-cognitive effect in diabetic patients [16]. It does so by:

- Upregulation of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) [19,20]. This is a neurotrophic effect so it helps dendritic outgrowth, creating new neurons (neurogenesis) and synapses (synaptogenesis).

- Upregulation of the dopaminergic system by activating tyrosine hydroxylase enzyme (TH) [20]. TH is the rate-limiting enzyme for the synthesis of dopamine. This means it increases dopamine synthesis capacity beyond baseline. Dual upregulation of BDNF and GDNF is needed for this, which is rare to find in any other substance [22].

- AMPK activation leads to mTOR inhibition. This means it has a potent anti-inflammatory effect on the central nervous system (CNS) [21]. Low-grade neuroinflammation is a hallmark of depression and other diseases affecting the CNS [23,24].

- Inhibition of intestinal (but not central) serotonin and histamine uptake [22]. This is very important since it means it can activate serotonin and histamine neurons to the vagus nerve via the enteric nervous system [25]. Activation of the vagus nerve leads to antidepressant effect.

The vagus nerve also mediates the brain-gut axis

In fact, an invasive procedure called vagus nerve stimulation (VNS) is used for treatment-resistant depression [26,27,28].

- Downregulation of NF-kB gene expression [29,30,31,32]. Excessive NF-kB activation is associated with pathologic conditions which can impair the activity of genes involved in cell senescence, apoptosis, immunity, and inflammation.

Neuroprotective & Neurotrophic Effects

Scientists have tested Metformin extensively for neuroprotective and neurotrophic effects with conflicting results. Certain studies conclude that Metformin is not neuroprotective and leads to downregulation of neurotrophic factors in direct contradiction to other studies showing clear neurotrophic effects.

However, this conflict may be due to vitamin B12 deficiency [37]. See, Metformin was found to significantly lower vitamin B12 concentration [33,34]. This due to calcium-dependent ileal membrane antagonism which leads to vitamin B12 malabsorption [35]. Further studies found that supplementing vitamin B12 and calcium alleviated this effect [36,38].

I needed to clear this up before presenting you the neurotrophic evidence as many studies failed to take this effect into consideration, especially long-term ones [37]. Vitamin B12 deficiency, in itself, causes cognitive impairment and neurodegeneration [39,40,41].

Aside from the the dual BDNF/GDNF upregulation I mentioned before, this is how Metformin can help:

- AMPK activation stimulates remyelination of neurons [42]. This means better and more efficient transmission of electrical impulses along the neurons.

- Neuroprotective effect against MPTP neurotoxicity [43]. MPTP is a prodrug to a neurotoxin that destroys dopaminergic neurons in the substantia nigra of the brain and is often used as a model for Parkinson's Disease (PD).

- Neuroprotective effect during hypoxic and ischemic conditions [44,45,46,53]. This means if neural oxygenation is limited, it helps preserve the neurons and keep them from dying.

- Neuroprotective effect against glutamate-induced excitotoxicity [47]. Metformin protects neurons from quinolinic acid (QUIN)-induced excitotoxicity [48].

- Antioxidant effect during elevated oxidative stress condition and free radicals [49,50,52]. It does so, in part, through mild inhibitory effect on the respiratory chain complex I of the mitochondria and this saves neurons from dying [51].

- Various immune-modulatory effects against

Metformin resulted in a 51% reduction of disease flares in SLE

autoimmunity. It does so through acting on AMPK/mTOR/STAT3 and on the normalization of T cell mitochondrial metabolism as well as many other pathways involving the B cells, monocytes, and neutrophils [54].

This lead to human trials in Multiple Sclerosis (MS) patients [55], and Systemic Lupus Erythematosus (SLE) patients [56] with promising results.

Effect on the Gut Microbiome

Metformin levels in the gut are 100- to 300-fold higher than those in serum, making the gut one of its main targets. Furthermore, Metformin significantly increases abundance of A. muciniphila, Bacteroides, Butyricimonas, and Parabacteroides, and this correlates with a reduced expression of inflammatory cytokines (IL-1β and IL-6) in the adipose tissue [54]. It also induces abundance of butyrate-producing bacteria [59].

A. muciniphila restores intestinal immunity and homeostasis in experimental models of inflammatory bowel disease [58]. Furthermore, it increases the number of goblet cells producing mucin. The increase in the mucus layer by goblet cells might function as a barrier for lipopolysaccharide (LPS) [60,61,62].

I've discussed in an earlier article how SSRIs can increase LPS in serum through triggering leaky gut leading to neuroinflammation. Metformin does the opposite as A. muciniphila has been shown to strengthen the intestinal barrier by increasing the expression of the tight junction proteins [64,65,66].

Metformin is shown to change the microbiome of the upper small intestine by increasing the abundance of Lactobacillus [57]. This leads to upregulation of SGLT1 expression which means better glucose sensing and regulation.

These changes can improve insulin sensitivity, glucose metabolism and reduce autoimmunity and inflammation throughout the body. This can indirectly improve depression, anhedonia and anxiety.

A more direct effect is increasing intestinal serotonin, as I mentioned earlier, by increasing A. muciniphila abundance [67]. Not to mention the mood-improving and anxiolytic effects of the Lactobacillus genus via the vagus nerve [68,69] and butyrate's ability to inhibit the microglia and improve mood [70,71].


Personal Anecdote

I had taken antidepressants in the past to control a rather treatment-resistant depression in vain. Although I got PSSD from them which made me too numb, I managed to recover but the depressive episodes returned unfortunately.

I manage my depression and anhedonia nowadays with Metformin XR (1500 mg) and Baclofen, respectively. It took 2 months for metformin to work and during these months I had suffered from nausea as a side effect of Metformin but thankfully it passed.

Metformin can be very tolerable for some people while very intolerable for others side-effect wise. If your depression is severe, it's totally worth a shot, though.

Important Notes

- Supplementing B-complex with high vitamin B12 and B6 concentration is a MUST while taking Metformin.

- Avoid drinking too much alcohol since metformin increases lactic acid and this can cause a buildup and might lead to lactic acidosis.

- Avoid dosing too much Metformin. Too much of a good thing is a bad thing applies here. Too much Metformin can cause sex hormone receptor destabilization and might lower testosterone. Although the evidence is inconclusive, it's better to be safe.


To conclude, metformin is found to have antidepressant, neuroprotective and neurotrophic effects and could be worth a trial for severe depression, anhedonia and anxiety either as a stand-alone drug or combined with other PSSD-safe antidepressants. It also improves gut health overall and permeability in particular while facilitating brain-gut interaction through stimulating the vagus nerve.

Thanks for reading! Please share the article if you found it helpful!


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