Agomelatine was developed under the assumption that one of the main causes of depression is abnormal circadian rhythm. Unlike other antidepressants, agomelatine is a melatonin analog that helps with many root causes of depression. It also has fewer side effects and withdrawal symptoms.

Because depression shares several root causes as other chronic health problems, such as chronic fatigue, brain fog, IBS, anxiety, and chronic inflammation, agomelatine may help you even if you don’t have depression. Read this post to learn more about how agomelatine works, its health benefits, and whether you should try it.

What Is Agomelatine?

Agomelatine (Valdoxan) is an atypical antidepressant drug developed on the basis that abnormal circadian rhythm causes depression [1].

While most other (typical) antidepressant drugs are selective serotonin reuptake inhibitors (SSRIs) that seek to increase serotonin in the brain, agomelatine activates melatonin (MT1 and MT2) receptors and blocks the 5-HT2C serotonin receptor [2].

Presently, agomelatine is approved in the European Union for the treatment of major depression [3].

In the United States, it is presently under a phase 3 trial for regulatory approval by the FDA, so it is considered a dietary supplement and doctors in the US do not prescribe agomelatine.

Mechanism of Action

Agomelatine activates melatonergic M1 and M2 receptors and inhibits serotonergic 5-HT2C receptors [2].

Although agomelatine is molecularly very similar to melatonin, it is more potent than melatonin because of the longer half-life [4].

Agomelatine has a half-life of 2.3 hours, while melatonin has a half-life of 50 minutes. Agomelatine also binds to melatonin receptors better than melatonin itself [4].

By blocking 5-HT2C receptors on dopaminergic and noradrenergic neurons, agomelatine elevates dopamine and norepinephrine levels in the brain (prefrontal cortex, but not limbic system), proving beneficial to both nootropic cognitive enhancement and treatment of depression [5].

Agomelatine has no affinity (Ki > 10 μM) for most receptors including adenosine, adrenoceptors, dopamine, GABA, muscarinic, nicotinic, histamine, excitatory amino acid, benzodiazepine, and sigma receptors. It also has no affinity for sodium, potassium, and calcium channels [22].

Agomelatine does not interact with conventional targets of antidepressant drugs like MAOA/B, nor the transporters responsible for reuptake of 5-HT, NA, or DA [2].

Agomelatine treatment does not decrease 5-HT1A receptors, nor does it affect extracellular levels of 5-HT [2].

This is how agomelatine avoids the common adverse effects of conventional antidepressants.

Long-term administration of agomelatine enhances the number of spontaneously active neurons and the bursting activity of dopaminergic neurons in the ventral tegmental area [2].

How It Helps with Depression and Other Chronic Diseases

Depression is a disorder of the limbic system (part of the brain that controls emotions and memory) that is categorized by abnormalities in:

  • The stress responses or HPA Axis dysfunction. Many depressed patients have elevated CRH and cortisol, but are cortisol resistant because they have reduced cortisol receptors in the brain [6].
  • Circadian rhythm. Many depressed patients have a phase shift in their circadian rhythms, so they stay up later and wake up later [7].
  • Sleep habits and sleep cycles. Depression has a high correlation with sleep disorders such as insomnia [8].
  • Inflammation in the brain and the gut. This causes sickness behavior (like chronic fatigue in humans) and also affects tryptophan and serotonin energy production [9].
  • Reduced BDNF levels [10].

We think agomelatine is relevant for many SelfHacked readers and clients because, even though you are not diagnosed with depression, you likely suffer from one or a few such abnormalities.

Advantages Over Other Antidepressants

  • Agomelatine is immediately effective, whereas other antidepressants may take 4-6 weeks (or months) to have antidepressant effects [11].
  • It has milder side effects than other drugs. SSRIs and other antidepressants can have severe stomach side effects (nausea and vomiting), sexual dysfunction, bleeding disorders, and many potentially life-threatening interactions with other drugs [114].
  • No withdrawal symptoms after abrupt discontinuation (or other common side effects of antidepressant medication) because it does not act on other neurotransmitter receptors in the brain, including most serotonin receptors [2].

Potential Uses of Agomelatine

1) May Help Treat Mood Disorders by Restoring Normal Circadian Rhythm

By stimulating melatonin receptors, agomelatine can resynchronize circadian rhythm with the external environment. In animal studies, agomelatine restored dysfunctional sleep/wake cycles, represented by an enhanced duration of REM and slow-wave sleep after acute oral administration [2, 2].

A combination of circadian rhythm restoration and selective serotonin receptor inhibition (5-HT2C), makes agomelatine a worthy treatment for mood and sleep disorders [12].

2) Protects the Brain by Increasing BDNF

Hippocampal BDNF enhances synaptic plasticity, which improves the brain’s ability to learn, store, and access new information [13, 14, 15].

Agomelatine increases BDNF levels in the hippocampus, thereby enhancing the survival of existing neurons and synapses, as well as the growth and production of newly generated ones [16, 17].

Elevated BDNF helps prevent stress-induced impairment of visual memory and spatial learning. For this reason, agomelatine treatment may influence long-term behavioral response to stress, which can help mitigate symptoms of mood disorders and physiologically enhance the brain’s ability to cope with stressful situations [16, 17, 18].

Agomelatine also increases CREB (cAMP response element-binding protein), which helps prevent the degenerative effect of environmental stressors on the hippocampus. This neuroprotective property may contribute to agomelatine efficacy for treating mood disorders related to stress-induced deterioration of memory and mood [19, 5].

3) Increases Neurotransmitter Release

By blocking the serotonergic receptor 5-HT2C, agomelatine increases norepinephrine and dopamine release in the frontal cortex, which enhances daytime motivation and helps combat the physical and mental effects of mood disorders [5, 14].

Some aspects of agomelatine antidepressant characteristics may also be attributed to these pro-cognitive or nootropic effects.

4) Reduces Anxiety Symptoms

Agomelatine may be used as an adjunctive treatment for depression-related anxiety symptoms. In clinical studies, agomelatine demonstrated the ability to improve anxiety symptoms of major depression, proving superior to both placebo and comparable depression medication [20].

Agomelatine may also treat generalized anxiety disorders (those not linked to depression).

In a study (double-blind randomized controlled study) involving over 400 patients over the course of 12 weeks, agomelatine was shown to be as effective as escitalopram in mitigating anxiety symptoms and had less adverse effects as a result of its novel mechanism of action [21].

5) May Help with Neuropathic Pain

Due to the neurological causes of neuropathy, antidepressants (not painkillers) are among the go-to treatments for otherwise treatment-resistant neuropathic pain. Melatonin, serotonin, and norepinephrine play a major role in neuropathic pain disorders [22].

Melatonin reduces pain by simultaneously stimulating melatonin receptors and blocking specific serotonin receptors in rodents [23].

Agomelatine also reduced symptoms of pain hypersensitivity and abnormal pain sensation (from touch and temperature) in diabetic rats. Agomelatine ultimately restored pain sensitivity and response in the diabetic rats to the levels of non-diabetic control rats [24].

Agomelatine may even treat neuropathic pain in fibromyalgia cases that have previously been unresponsive to medical treatment, due to its blocking of serotonergic receptor 5-HT2C [25].

6) May Improve Bone Health and Muscle Strength

Inflammatory cytokines are produced by cells to initiate localized inflammation and immune responses and maintain bone balance [26, 27, 27].

Uncontrolled amounts of inflammatory cytokines impair the generation of important bone cells called osteoblasts and osteoclasts, which are involved in bone restoration and maintenance.

High amounts of IL-1β, IL-6, and TNF-α may even weaken bones and ultimately lead to osteoporosis, arthritis, bone erosion, cartilage degradation, and even gum disease [27, 28, 29, 30].

Agomelatine reduces the levels of proinflammatory cytokines TNF-α, IL-1β, and IL-6 [31].

By suppressing these potentially harmful cytokines, agomelatine helps keep bones healthy and prevents loss of bone density [27].

Agomelatine consistently raises both IGF-1 and growth hormone levels by stimulating melatonin receptors, which regulate hormone secretion during sleep. This is beneficial not only to healthy bone development but also for the prevention of bone loss and muscle atrophy [32, 2, 2].

By increasing IGF-1 and growth hormone secretion, while simultaneously reducing catabolic proinflammatory cytokines, agomelatine may even enhance muscle strength. Rodents treated with agomelatine showed an increase in muscle strength and density after five weeks of treatment [33, 34].

7) Protects Mitochondria from Oxidative Stress

Agomelatine offers similar antioxidant and mitochondrial benefits due to its chemical similarity to melatonin. It also has a longer half-life, better oral bioavailability, and higher affinity for melatonergic receptors than melatonin itself [35, 36, 37].

Agomelatine’s potent antioxidant properties enhance the natural elimination of 3-nitropropionic acid (3-NPA), a dangerous mitochondrial toxin that causes neuromuscular disorders.

3-NPA toxicity usually occurs as a result of prolonged ingestion of slightly moldy crops (like sugarcane or peanuts). 3-NPA causes health problems such as weight loss, motor impairment, and learning-memory deficits [38, 39].

8) Reduces Inflammation from Leaky Gut

Lipopolysaccharides (LPS) is a bacterial toxin that can leak into the bloodstream when there is leaky gut. It can cause inflammation and metabolic problems like insulin resistance, obesity, diabetes, and heart diseases [40].

In rats, chronic treatment with agomelatine reduces the inflammatory cytokines IL-1beta and IL-6 induced by LPS. The same study also finds deactivation of NF-kB, the protein that turns on inflammatory responses in the immune system [31].

The study found that inflammatory cytokines decreased both in the brain and throughout the body. Interestingly, Nattha also (unexpectedly) discovered that agomelatine helped with eczema during the day following agomelatine use.

Side Effects and Dangers of Agomelatine

The possible side effects of agomelatine include [41]:

  • Anxiety
  • Back pain
  • Constipation
  • Diarrhea
  • Dizziness
  • Drowsiness
  • Excessive sweating
  • Fatigue
  • Insomnia
  • Migraines and headaches
  • Nausea

Importantly, agomelatine can increase liver enzyme levels and damage the liver.

Dangers of Use

Liver Damage

Before starting agomelatine, it is important to screen liver enzyme levels. Additional enzyme screening should be performed after 3, 6, 12, and 24 weeks. If the dosage is increased, the screening period should restart. A final screening after the treatment is also recommended [42].

The use of agomelatine should be stopped immediately if liver enzyme screening indicates a 3X increase of blood transaminases. Beware of symptoms that may indicate potential liver damage, such as dark urine, light-colored stool, yellowing skin or eyes, stomach pain, or new/worsening fatigue [43].


The data on agomelatine overdose is limited but symptoms of an overdose may include [41]:

  • Agitation
  • Anxiety
  • Dizziness
  • Drowsiness
  • Fatigue
  • Malaise
  • Tension

In a case report, an individual overdosed on 2,450 mg but was able to recover [41].

Risk of Suicide

As with all antidepressants, there is a potential risk of suicide [41].

Agomelatine Dosage And Experiences

Pharmaceutical agomelatine is prescribed (as Valdoxan) in 25 mg tablets, typically taken once daily at bedtime. Dosage may be adjusted to 50 mg (2 x 25 mg tablets) taken at bedtime if agomelatine treatment has no effect after two weeks [43].

Antidepressant treatment using agomelatine typically lasts at least six months [43].

Agomelatine should not be used by elderly people (75+ years) [43].

Our Personal Experience

We use agomelatine at SelfHacked HQ when we want to catch up on sleep or get a night of long sleep.

Nattha’s experience: Personally, I find that agomelatine puts me to sleep but it doesn’t increase deep sleep if I have other problems that are preventing me from getting deep sleep. Sometimes, I don’t sleep well because I have high histamine and I may have a sleep-breathing disorder called upper airway resistance syndrome (UARS). Therefore, I’ve found agomelatine works for me best together with antihistamines, a dental appliance, a sleep position that address UARS, and blue light elimination.

I do experience a better and calmer mood, in general, the morning after agomelatine use.

About the Author

Nattha Wannissorn - PHD (MOLECULAR GENETICS) - Writer at Selfhacked

Nattha Wannissorn, PhD

PhD (Molecular Genetics)

Nattha received her Ph.D. in Molecular Genetics from the University of Toronto and her undergraduate degree in Molecular and Computational Biology from the University of Pennsylvania.

Aside from having spent 15 years in biomedical research and health sciences, Nattha is also a registered holistic nutritionist, a certified personal trainer, has a precision nutrition level 1 certification, and is a certified functional diagnostic nutrition practitioner. As a holistic practitioner with a strong science background, Nattha is an advocate of science literacy in health topics and self-experimentation.

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