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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 though you don’t have depression.

Read this post to learn more about how agomelatine works, its health benefits, and whether you should try it.

Note: By writing this post, we are not necessarily recommending this drug. Some of our readers who were already taking the drug requested that we commission a post on it, and we are simply providing information that is available in the scientific literature. Please discuss your medications with your doctor.

Check out Biohacking insomnia if you’re looking for the sleep hacks that we recommend.

What Is Agomelatine?

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

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 receptors [R].

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

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.

How Does Agomelatine Help 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 [R].
  • Circadian rhythm. Many depressed patients have a phase shift in their circadian rhythms, so they stay up later and wake up later [R].
  • Sleep habits and sleep cycles. Depression has a high correlation with sleep disorders such as insomnia [R].
  • Inflammation in the brain and the gut. This causes sickness behavior (like chronic fatigue in humans) and also affects tryptophan and serotonin energy production [R].
  • Reduced BDNF levels [R].

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.

How Agomelatine Works

Mode of action of agomelatine. Source:

Unlike other antidepressants, agomelatine helps with several aspects of depression physiology as listed above, including:

  • Restoring normal circadian rhythm, just as melatonin would [R]
  • Reducing cortisol [R]
  • Increasing BDNF [R, R2]
  • Improving sleep quality [R]
  • Reducing inflammation in the brain due to lipopolysaccharides (a model of leaky gut) in rats [R]

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

Agomelatine has a half-life of 2.3 hours, while melatonin has a half-life of 50 minutes. Agomelatine also binds more strongly to melatonin receptors than does melatonin itself [R].

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 [R].

Advantages of Agomelatine Over Other Antidepressants

  • It is immediately effective, whereas other antidepressants may take 4 – 6 weeks (or months) to have antidepressant effects [R]
  • 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 [RR2]
  • No withdrawal symptoms after abrupt discontinuation (or other common side effects of antidepressant medication) because it does not stimulate serotonin receptors [R]

Our Personal Experience with Agomelatine

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 antihistamine, a dental appliance, a sleep position that address UARS, and blue light elimination.

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

Health Benefits of Agomelatine

1) Agomelatine Helps 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 enhanced duration of REM and slow-wave sleep after acute oral administration [R, R2].

A combination of circadian rhythm restoration and selective serotonin blockers makes agomelatine a worthy treatment for mood and sleep disorders [R].

2) Agomelatine Protects the Brain by Increasing BDNF

Hippocampal BDNF enhances synaptic plasticity, which improves the brain’s ability to learn, store, and access new information [R, R2, R3].

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 [R, R2].

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 [R, R2, R3].

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 [R, R2].

3) Agomelatine Increases Neurotransmitter Release

By blocking the serotonergic receptor 5HT-2c, agomelatine increases norepinephrine and dopamine release, which enhances daytime motivation and helps combat the physical and mental effects of mood disorders [R, R2, R3].

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

4) Agomelatine 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 within major depression, proving superior to both placebo and comparable depression medication [R].

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

In a 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 [R].

5) Agomelatine Helps 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 [R].

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

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 [R].

Agomelatine may even treat neuropathic pain in fibromyalgia cases that have previously been unresponsive to medical treatment, due to its blocking of serotonergic receptor 5HT-2C [R].

6) Agomelatine Improves Bone Health and Muscle Strength

Inflammatory cytokines are produced by cells to initiate localized inflammation and immune responses and maintain bone balance [R, R2, R3].

Uncontrolled amounts of inflammatory cytokines impair 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 [R, R2, R3, R4].

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

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

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 prevention of bone loss and muscle atrophy [R, R2, R3, R4].

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 [R, R2].

7) Agomelatine 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 [R, R2, R3].

Agomelatine’s potent antioxidant properties enhance 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 [R, R2].

8) Agomelatine 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 [R].

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

The study found that the 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.


Liver Enzyme Warning

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 recommended [R, R2].

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 [R].

Mechanism of Action

Agomelatine acts as an activator of melatonergic M1 and M2 receptors and blocker of serotonergic 5-HT-2C receptors [R].

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 [R].

Agomelatine also has no affinity for sodium, potassium, and calcium channels [R].

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 [R].

Agomelatine treatment does not decrease 5HT-1A receptors, nor does it affect extracellular levels of 5-HT [R].

This is how agomelatine avoids 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 [R].


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 [R].

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

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

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

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The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.


1 Star2 Stars3 Stars4 Stars5 Stars (73 votes, average: 4.01 out of 5)


  • Jacqui

    Does this help anxiety?

  • Jacqui

    Does this cause weight gain?

  • Shahzad

    Any one help .i am on fluvoxamine 100mg then can i use combine use with agomelatine

  • timothy

    update. My sleeping has began to settle and im falling asleep and waking up in a better sleeping pattern than before. My body is still adjusting from 25 to 50mg and im generally sensitive to medications. But I can see the improvements as everyday tasks and engaging with my interests and hobbies again gets better day by day.

  • Jordan

    I Just started this drug 3 days ago. I went to the GP and said I need help! After trying all sorts of medications and being mis diagnosed a few times I stopped everything! That was not a good move. Over the last 6 months I became such an angry person and couldnt sleep. I had nightmares every night and would hit the ground at a car backfiring. 4 days a go (day before seeing the GP I broke down! As a man that is hard to admit but I cried my eyes out and said how did I let myself get to this point. Anyway I said enough is enough. Saw the GP and said how can I be treated for Depression, Anxiety and PTSD? Without all the side effects. He told me to try Valdoxan and see how I go. The next day I felt like a new person, I still have a long way to go but I already feel a change in my mood and I feel happier. Cant wait to see how the next few weeks go. Hope to be a better husband and father.

  • Timothy

    This medication helped improve daily living and combat of anxiety & sadness to a small degree. Whilst the drug instantly makes you drowsy and sleepy it didn’t actually help improve my sleeping pattern very much, not sleeping until 5am was quite common.

  • Elizabeth

    Probably would have been better off just trying Melatonin to help sleep, then depression would lift a bit from getting a good sleep.

  • Elizabeth

    Update: day 9 and I hate Valdoxan for the nightmares, I have also put on 2kgs in that time, the anxiety has leveled out but the nightmares make it hard to go back to sleep once you wake up from nightmare, I still feel depressed but not as bad as before I went on Valdoxan. I went to sleep clinic today and specialist didn’t like me taking Valdoxan, said people should only be on it for a couple of months, not long term which then off course made me worry. I have had bit of swelling under base of rib cage which is what happend last time my liver played up. Will be seeing my doctor next week to request to be taken off it. It’s meant to help sleep, it doesnt if it gives you nightmares.

  • Petra

    After a life time of dealing with debilitating winter SADS (Australia) and trying every antidepressants medication available with unbearable side effects and allergic reactions, my Psyciatrist put me onto Valdoxan and it has been my saving grace.
    I start at 25mg and increase to 50mg after about a month for around 6 months a year, starting around April.
    It stops my depression, anxiety and I can sleep and feel like a normal human during the cold months. I always felt helpless and doomed every winter and even though it is expensive, this medication is worth every cent.

  • Elizabeth

    I have been on 25mg of Valdoxan (agomeltatine) for 4 days now, for depression/sleep/pain and have noticed a significant difference in mood, not fluctuating hardly at all which it used to about 10 times a day, I have been on effexor, zoloft, prozac, mirtazone (i think that’s how it’s spelled) and a lot more but were years ago. Im interested in seeing the effects after a month, at the moment the one and only side effect i am getting is Nightmares each time i go to sleep, first night i was able to go back to sleep after nightmare (they seem to happen in first few hours of drifting off to sleep) then last night i woke wide awake after nightmare and couldn’t get back to sleep. I have Chronic Fatigue Syndrome, arthritis and have noticed a massive difference in pain as well which i’m extremely happy to say. I only want the nightmares to go away, will keep you updated as previous anti depressants have really done some damage from the side effects and bringing pain on worse and also making me feel depression worse. Oh i also do know that the melatonin in the drug can cause nightmares for some reason but i am hoping they will pass. I haven’t been angry or upset or burst into tears or felt frustrated with my life since day 3. yes it’s early days and yes the drug is expensive but compared to the amount of side effects other drugs have, the cost is worth it at this stage. I have tried SSRI’s, MAOI’s, Trycylic’s so let’s hope this is the one for me. p.s. i had suicidal thoughts last week (didn’t act on them though) and now……it’s the furtherest thing from my mind.

  • [email protected]

    There is a Valdoxan Support Group on Facebook some 60 odd members run by I think a psychiatrist
    Not the one with 17 members
    Lots of posting

  • Deb

    Hi all, My husband has just been prescribed this. Its darn expensive at nearly $70 for I think 20 tablets!

    I am hoping this works on him as he is not sleeping, wish it was on the PBS.

    Thanks for sharing your experiences. I will update to let you know how it affects him.

  • Derek

    I was sceptical about Valdoxan, having tried other anti anxiety medications, non of which were satisfactory.
    It’s not been 2 weeks yet, and this is a great medication. 1/- I’m now sleeping 6-8 hours solid 2/- have lost about 4 kilos already 3/- muscle strength and prominence is well evident 4/- no dizziness or headaches or anything detrimental 5/- anxieties have been vanished 6/- I have 3 times the energy and feel like I’m on a natural high 7/- I have completely stopped drinking alcohol and no longer overeat , just don’t feel the need to. All of this in 2 weeks, unbelievable improvement.

  • Pen

    I have been taking this for 18 months now (in Australia). This was prescribed after having unmanageable side ffects with six SSRI prescriptions.
    I have had no negative side effects. I started on 25mg for 6 months then went up to 50mg. My sleep has improved in that I can now get to sleep but I still cannot stay asleep so am averaging about 4 hours broken sleep a night.
    There has been no adverse reactions when taking ant-anxiety medications and I (and my family) have noticed an increase in positive mood. Concentration has improved somewhat. All improvements have changed me from not beginning no able to leave my home or get out of bed some days, to getting regular everyday things done, like groceries, cooking cleaning etc. I have even now been able to start socializing in safe circles again.

    It’s by no means a wonder drug, but it has changed my life for the better without hash side effects.

  • Diane

    Very interested.After Years of trying to find an effective treatment. Huge weight gain, and many side effects, still not well, and so frustrated.

  • Jennyrabbit

    Glad I found this! Have just been Rx agomelatine (my GP had never heard about it btw) following 25yrs on mainly Lustral. I tried everywhere, including my local pharmacist, to find out if it actually had a different mode of action to melatonin, which I use quite often (but not together!). The information here is all I’ve found, so thank you.

  • Julz

    Any updates?

  • Maria

    Any known interactions with common anti-anxiety drugs or anti-depressants?

  • Lou

    Any update on this please Nicole?

  • Jedd

    I’ve just started using this drug for depression and the relief was literally the next day. My thinking and ability to function has already improved and I have major depression

  • Nicole B

    Julia, this is for sure not a short term drug, you really have to take it for a few weeks to see the benefits. It doesn’t make you sleepy like Valium, it’s more like your head just feels heavy… if you push past this feeling you get a bit of a headache I’ve found.. it has done nothing for me in terms of reducing pain like pain killers, so far.

  • Nicole B

    I am about to start taking Valdoxan, as it is available in Australia. I found this page super useful, but as there is not very much user experience out there on the internet, I thought it was important to share my symptoms and experiences. I have always suffered anxiety, and gone through several elongated periods of depression starting from the age of 12 years old. I have always been prone to fatigue, even when my depression and anxiety seem less intense and life “feels good” if I don’t have 10 hours sleep I find I struggle through the day and wonder how other people seem to cope just fine on 6 hours, meanwhile I will be having a nap in my lunchbreak or after work. The naps always cause me to not feel ready for normal sleep later on- although I seem to get to sleep fine after about 15 minutes. I recently suffered an injury to my lower lumbar spine causing two bulged discs and sciatica. After 3 months of inactivity, and pain everyday, my anxiety was overwhelming to the point my doctor prescribed Escitalopram. The Escitalopram was okay and stopped all anxiety but I had problems with concentrating on things I wanted to do, having to remind myself constantly out loud of the next thing job- a task like cooking dinner seemed impossible due to the steps involved because I would forget what to do next after I had read the recipie. I also suffered from sexual dysfunction and loss of other urges, especially when going to the bathroom. In addition I was also taking Valium to go to sleep. Hopefully this replaces both Valium and Escitalopram… I will be able to report back with the sustained affects of my personal experience within a few weeks. I will also be able to let everyone know how it goes with pain management as well, specifically for inflammation in the discs in my back.

  • Brian

    Methyl donors make me nutty even in small doses. I can confirm that while melatonin was very obviously a methyl donor to me, agomelatin was not! L-theanine is a methyl donor. Tianeptine is not. I have never found any meds to be methyl donors although maoi’s aggravate me in a similar way.

  • Justin

    Where did you guys get the agomelatine? It’s not available in the us

    1. Nattha Wannissorn, PhD


  • Nancy Smith

    I am very interested in this. I just joined Selfdecode about a week ago and I now know I have huge issues with 5HT2C in addition to depession and fatigue.I ave never found an effective antidepressant and as you can imagine have reacted very adversly to SSRI’s.However I am now trying yibird at 5mg for about three weeks without any success(but so far no serotonin syndrome).I would like to get more nfo on this produt.Is it available in the US? I have also been trying to join the VIP membership but an’t get it to take me info even after I was on SelfDecode. Thanks for any hep! Nancy Smith

  • julia jason

    you mentioned at self hacked HQ you use agomelatine occasionally to help fall asleep, does it actually make you sleepy like a sleeping pill? or does it reduce pain, like tranquillisers do ? could you use it occasionally to relive anxiety or depression, or does it work better on a long term basis ? thanks

    1. Nattha Wannissorn, PhD

      Yes, it makes you sleepy. We don’t know if it reduces pain because none of us suffer from extreme pain of sorts. We don’t use it for anxiety/depression per se but it has an anti-anxiety/antidepressant effect. And no we haven’t tried it long term because we need the time to work on SelfHacked.

  • Elahn Ientile

    This looks interesting, is agomelatine a methyl donor?

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