So your body is fit, but there’s still that piece of your mind that isn’t quite right. Bad mental hygiene creates many problems; settle things. It may be that you need to get your head on straight. It’s easy to improve your mental health, and you’ve already taken the first step by looking into mental health. Remember, it all starts from within.

Develop a hobby or passion for your mind to express your emotions and joys for the mind to feel progress. For example, the body needs exercise and a means to channel its energy. This is one of the five life coping skills. Love your body, as exercise is a coping skill.

Feed your mind. Improve your social relations, and allow for more warmth and love between the people closest to you. Do not brag or be narcissistic (as much as possible accede to preferences of other people over your own preferences, ie: give them choices, not being pushy).

Recover old friendships, or make new true friendships to feed that part of your mind. Having good support systems from family and friends is a coping skill.

Challenge yourself once in a while. Seek a meaningful job to obtain a sense of real self-worth and confidence. A career that motivates you emotionally to get excited in the morning is a coping skill. However, if the job you have is not necessarily of your top career preferences, or even is flat out something you don’t like, you can still deal with it. In every job there can be respect found in it by doing your best and treating those you work around with warmth. Learn to love yourself. Satisfaction in a career must come from yourself and not others.

Surround yourself with beauty. Redecorate your house or garden. Do some spring cleaning. Put on some happy music. Do whatever helps you feel relaxed and at peace. Practice whatever form of spiritualism that appeals to you. This is a life coping skill and will help you recognize beauty.

Remember that, as long as you fill your mind with your personal ‘mental foods,’ you will experience less boredom and inner conflict. Boredom and marital conflict are often symptoms of mental starvation (or misunderstanding).

Be sure to identify any issues you have such as anxiety, panic attacks or other disorders. Identify these and acknowledge that you have them. Only from there can you move on and seek treatment to improve your mental health.

Make sure you’re consuming the right vitamins and minerals everyday. Follow a diet rich in omega3, vitamin E & C, and specially Antioxidants like raspberries and blackberries for example. Antioxidants help clean up the brain.

Tips:

• Keep your room neat, and you will soon feel happier. Remember, when the area around you is organized, so are your thoughts.
• Try to think before you speak in order to say only positive or harmless words.
• Anger is a secondary emotion. If you are angry about something, there is an underlying primary reason for the anger. That is the emotion that needs to be handled with the five coping skills.
• Stay away from a states of “vegetation” or defensiveness. Use the coping skills. If you are in any state other than practicing the coping skills, you are not in good mental health.
• Practice the five coping skills. They are a career (not necessarily your present job), positive support systems, exercise and health, a hobby, and spirituality.
• Use a journal to process emotions that are not pleasant such as sadness, emptiness, feelings of abandonment. This is good exercise before going to sleep.
• Don’t let any of the coping skills become addictive or controlling. For example, hobbies are good but if you play golf all the time at the expense of important time, it is no longer a coping skill.

Let’s all face it; life is not always the most exciting thing on the street. Some of us choose to occupy the blank spaces by daydreaming, but eventually this habit can get out of hand. It will also eventually lead to pain and depression, as you’re going to, at some point, realize that most of you daydreams might not come true. Here’s how to nip it in the bud.

Steps

1. Be fantastical. It is much less painful to realize that you’re not going to go on tour with your favorite musician than to realize that you might not get to go out with your crush.
2. Set guidelines for your daydreams. Choose boundaries that, when crossed, signal you to stop daydreaming. Some of them might include intimacy, spending large amounts of money, or extreme violence.
3. Occupy yourself. If you’re someone who begins to daydream when they’re not particularly engaged, such as sitting idly, grab a pillow or a stuffed animal that you can fiddle with.
4. Find a hobby. It’s almost always healthier to be very knowledgeable about something than to spend hours fantasizing.
5. Limit yourself. You’re not as likely to daydream about someone you know little about as you are to daydream about someone you know tonnes about, to limit how much you learn about people. (Until you’ve met them, of course.)
6. Get a daydream hotline. Pick someone that you know very well and feel very comfortable with. Then, ask them if they’d be available to answer their phone and chat with you if you’ve become particularly engrossed in a daydream.
7. Sleep. If you’re daydreaming because of idle time, take a nap instead. Make sure to set an alarm, though.

Some people genuinely want to improve and maintain a healthy lifestyle by using herbal remedies, nutraceuticals, and naturopathic medicines. Unfortunately, the vast selection of products offered by most vitamin stores and pharmacies can be overwhelming enough to scare these people away. Where do they even begin? Luckily, herbologist and Founder of Natural Plantation, Elsie Belcheff, has developed a simple three-step solution to introduce newcomers to the world of natural remedies and get them started on their lifelong path to healthy living.

Protect Your Body: The first important step along this path is for people to boost their immune systems. The immune system is a powerful protection mechanism designed to fight off all kinds of viruses, toxins, parasites, and bacteria that aim to invade people’s bodies each day. The immune system requires a daily dose of vitamins, minerals, anti-oxidants, and fatty acids to keep it healthy and strong. It is a good idea for beginners to take one supplement, such as 100% Pure Purslane Powder, that combines the benefits of all these elements together rather than trying to sort through the myriad of individual products out there. The key is to keep it simple, at first, so it’s easier to stay on track.

Protect Your Food: Along with boosting one’s natural immunity from the inside, people should also protect themselves from the outside by better controlling the foods they ingest. Unfortunately, today’s produce is often contaminated from dirt, animal waste, air pollutants, chemical pesticides, and bacteria-all of which can be harmful to our health over time. The best way to combat this is to wash all fresh produce (including fruits, vegetables, and raw meats) with a product like Purslane Fruit & Vegetable Wash before preparing them for dinner. The less harmful additives we introduce into our systems in the first place, the easier it is for our immune systems to remain strong and healthy in the long run.

Protect Your Hands: We live in a time when we’re all aware of just how easy it is to contract a cold or The Flu with the touch of a hand. This makes it all the more important for people to keep their hands clean. Unfortunately, washing with soap and water is not always enough, which is why Canadian government health regulators recommend using an alcohol-based hand sanitizer-particularly when people are out in public. Because some alcohol-based hand sanitizers may cause dryness and cracks in people’s skin, it is a good idea to use a product like Purslane Hand Sanitizer that contains natural Purslane oil in it. This acts as a hand sanitizer and lotion all in one, leaving hands softer and smoother than some other hand sanitizers do.

Tips: These three simple steps are all it takes to put people on track toward a natural, healthy lifestyle. Why not start today?

Must Reads

• The Advanced Guide to Opioids As Antidepressants
• Agomelatine Review: The Truth about Agomelatine Use in Affective Disorders
• My Experience With NSI-189
• My Experience: The Best Nootropics For Anxiety
• 10 Vagus Nerve Symptoms and How To Treat Them
• Brain-Boosting Habits I’m Embracing in 2017

What is Agomelatine?

Do you think agomelatine is a solid antidepressant? How do you think it compares to other more typical antidepressants like Prozac?

Agomelatine’s unique pharmacology and favorable side effect profile make it a boon for depressed patients, especially those who have not responded to conventional antidepressants.

Here’s a quick and dirty fact sheet that will get you oriented if you don’t know anything about agomelatine.

• Though agomelatine was approved in Europe for the treatment of depression in 2009, it’s unavailable in the United States
• Agomelatine blocks some serotonin receptor subtypes (5-HT2B and 5-HT2C) and activates melatonin receptors (MT1/MT2)
• Agomelatine alleviates depression in part by normalizing circadian rhythym
• Agomelatine has many advantages over contentional antidepressants (e.g., SSRIs)
• Agomelatine has some nootropic and neuroprotective effects.

Agomelatine is a melatoninergic antidepressant developed by Servier and marketed under the trade names Valdoxan, Melitor, and Thymanax.

Unlike most conventional antidepressants, agomelatine’s mechanism does not hinge on boosting monoamines (e.g., serotonin). Rather, its antidepressant effect is attributed to restoring abnormal circadian rhythm in depressed individuals and promoting dopamine/norepinephrine release.

Agomelatine may have advantages over conventional antidepressants like SSRIs in terms of both efficacy and tolerability. Agomelatine has also shown therapeutic potential as a treatment for other affective disorders and even dementia. Let’s see what the most updated reviews have to say about agomelatine.

Agomelatine Dosage

Agomelatine is available as 25 mg tablets. Physicians typically prescribe one tablet to be taken at bedtime. In some instances, physicians may prescribe 50 mg (2x tablets). Agomelatine is not recommended at doses above 50 mg/night.

The Molecular Properties of Agomelatine

Agomelatine interacts with two distinct receptor systems:

• Serotonin (5-HT) System. Agomelatine is an antagonist at 5-HT2B and 5-HT2C receptors ¹.
• Melatonin System. Agomelatine is a partial agonist of the melatonin receptors MT1 and MT2²

Physiological Consequences of Agomelatine Use:

Agomelatine’s action on the serotonin and melatonin system has the following physiological effects:

• It disinhibits/increases noradrenaline and dopamine release in the frontal cortex, without affecting serotonin levels. This effect is mediated via inhibition of 5-HT2C receptor activity¹.
• It normalizes circadian rhythm (biological clock) by modulating melatonin receptors³.

Agomelatine, Sleep, And Depression

Circadian rhythm dysregulation is strongly linked to mood disorders⁴. There’s also a link between depression and abnormal sleep architecture.
Depression is associated with:

• decreased slow wave sleep (SWS)
• increased REM sleep density
• increased REM sleep duration
• shortened REM sleep latency

Slow wave sleep is the restorative, indispensable part of sleep. REM sleep coincides with dreaming and, as the name implies, is characterized by rapid eye movements.

There’s evidence that these sleep architecture alterations precede the development of depression. Riemann argues that “REM sleep alterations have been recently considered not only as biological “scars” but as true endophenotypes of depression.”¹⁸

This may explain why sleep deprivation has an antidepressant effect⁵. The picture is muddied by the fact that insomnia is a common bedfellow to depression. A classic signs of depression is early morning awakenings (e.g., waking up at 4 am and being unable to fall asleep). Since sleep deprivation itself has an antidepressant effect, researchers have proposed that early morning awakenings in depressed patients reflect a compensatory response to help reduce depression.

Some researchers have gone so far as to say that depression is primarily a sleep disorder.

Most antidepressants, independent of class, profoundly suppress rapid eye movement (REM) sleep. For example, tricyclic antidepressants and SSRIs robustly reduce REM sleep. This implies that REM sleep is dispensable (you can live without it). REM suppression is not necessarily an unwanted side effect; it contributes to the antidepressant effect of drugs like SSRIs and tricyclic antidepressants.

Further reading: REM sleep dysregulation in depression: state of the art

Agomelatine inhibits 5-HT2C serotonin receptors, increasing noradrenaline and dopamine. But the primary antidepressant effect of agomelatine is by normalizing circadian rhythm. Agomelatine binds and activates melatonin receptors² which is a key player in the biological clock.

Agomelatine Reviews

I scoured the internet for agomelatine reviews and experience reports. Here are some notable reviews:

Posted by odspot on Reddit:

I just stopped it two nights ago. I found it pretty good for getting to sleep, which was a blessing, and waking up earlier. It was pretty mentally stimulating (and potentiated other stimulants)… too much so at 25/50mg, so I cut back to 12.5mg. However, the dealbreaker was that it would render me completely exhausted/fatigued the next day. I was pretty jacked up and alert, but could barely get around. I read on psychonauts that the side-effect supposedly passes once sleep normalizes after 2-3 weeks, but I just couldn’t take it (especially because changing the dose supposedly resets the adjustment period). That said, I do have a lot of baseline fatigue, so take that all with a grain of salt.

Posted by Cosmicrush on Reddit:

Yes it’s awesome. I sublingual 3-5mg and I get mixed state between dazed and this paranoid empathy type state. It only shows when I socialized for the simulation and empathy. If I’m alone I go hypnogogic and get vivid hallucinations if I suddenly open my eyes after holding them shut for while.

It seems to be iffy on sleep quality. I sleep faster but the effects are short and I wake up after a couple hours.

It seems good for creative thinking. It will make you socially introverted somewhat. This might not be true. Or maybe this is only true at higher dosages.

It causes paresthesia on tongue if you sublingual. The effects aren’t felt that much but it changes your state of mind. I notice the closer I am to sleep I get happy and euphoric but then I’ll snap out of it and feel kind of anxious but not bad anxiety. It’s hard to notice the feeling at first though.

The medication it feels like is Mirtazapine. But much more lightweight and less sedating. Mirtazapine can be annoying with side effects sometimes.

Posted by nachos420 on Reddit:

if you take it ~10-30mg sublingually you can feel the 5ht2c antagonism decently strong. I can’t use it though, even at the recommended 25mg oral dose, because, like melatonin, it makes me much more likely to feel depressed the next day for no reason when normally I’m never depressed. It’s odd especially because melatonin will make colors brighter the next day and such yet somehow my mind still reacts to it(at any dose) with short lived 1-2 day depression. I think the depression is a secondary side-effect from it tiring/slowing my mind/body into the next day even at low mcg doses.

Posted by an_thr:

I was prescribed 25mg per day, then 50mg per day after that stopped working. Have recently come off it entirely due to exacerbated anhedonia/amotivation at 50mg. It is expensive and you are required to have regular liver function tests, so it no longer seems worth it.

I had tried perhaps six SSRIs/SNRIs before Valdoxan and it worked better than most with few side effects. Beyond mood, the best effect for me was on sleep. Normally I wake up and feel like I have been hit by a train, but on agomelatine I would get out of bed immediately upon waking and feel fine. My sleep time was reduced from ~10 hours to ~6 hours, and I was able to fall asleep every night.

I wouldn’t bother with it for mild depression in the absence of sleep problems.

I suspect any nootropic effects are due to improved sleep architecture and alleviation of depression.

Is Agomelatine An Effective Antidepressant?

A large number of studies have investigated the efficacy of agomelatine for depression.

David Taylor¹⁹ and colleagues published a meta-analysis of agomelatine efficacy for depression. He included 20 studies and nearly 7500 participants. There are a few takeaways from the meta-analysis:

• Agomelatine was significantly more effective than placebo
• Agomelatine efficacy was comparable to other antidepressants

One study reported that 25-50mg/day agomelatine resulted in a potent antidepressant effect as assessed by the Montgomery and Kasper diagnostic manual. Patient response was similar (if not higher) to other antidepressants⁶.

In addition, to its antidepressant properties, agomelatine (25mg/day) restored sleep architecture in depressed individuals by improving sleep quality⁶.

Agomelatine-induced sleep enhancement does not lead to daytime sedation (a common side effect of hypnotic antidepressants like Remeron)⁶. Finally, agomelatine may benefit more severe forms of depression, in which most if not all antidepressants fail; these forms are atypical⁷, melancholic ⁷, and anxious depression⁸. However, this observation may be a moot point since all antidepressant response is much higher in severely depressed patients, irrespective of the particular antidepressant.

Adverse Effects

In sharp contrast to most other clinically available antidepressant agomelatine (25-50mg/day) is not associated with⁹:

• Sexual Dysfunction
• Cardiovascular Toxicity
• Weight Gain
• Nausea
• Discontinuation Syndrome
• Gastrointestinal Disorders
• Serotonin Syndrome
• Insomnia
• Excessive daytime sleepiness

Agomelatine For Other Affective Disorders

Anxiety Spectrum-Disorders

In animal models, agomelatine has anxiolytic effects.¹⁰ Agomelatine potentiates GABAergic neurons (via melatonin receptor agonist) and by antagonizing 5-HT2C receptors.

Due to its anxiolytic properties agomelatine has been investigated for use in both social anxiety disorder and generalized anxiety disorder, were 25-50mg/day of agomelatine has been superior to placebo at alleviating symptoms.

Obsessive-Compulsive Disorder

In a small study 50mg/day agomelatine was effective at reducing symptoms associated with OCD¹¹ and also showed profound superiority when compared to SSRIs which are the standard course of treatment for OCD.

Seasonal Affective-Disorder

In one study with 37 seasonal affective disorder (SAD) patients¹², 25mg/day of agomelatine for 14 weeks was proven to be efficacious and safe for the treatment seasonal depression.

Bipolar-Disorder

In a small study¹³ involving 26 patients suffering from bipolar disorder, agomelatine (25mg/day) was effective and well-tolerated adjunct with mood stabilizers for bipolar depression.

Agomelatine For Other Conditions

Agomelatine could be of benefit in preventing the progression on two neurodegenerative disorders that are frequently co-morbid with depression and therefore, agomelatine could also be use in these disorders for its mood-enhancing properties.

Alzheimer’s Disease

Due to its melatonin mimetic effects, agomelatine could potentially be used in Alzheimer’s disease¹⁴.

That’s because melatonin has a protective effect against beta-amyloid protein. Melatonin inhibits aggregation of amyloid beta into neurotoxic aggregates. Interestingly, agomelatine has been associated with enhancement of spatial visual memory¹⁵.

Dopamine-Related Motor Disorders

Due to its melatonin mimicking effects, agomelatine could also be beneficial in motor disorders such as Parkinson’s disease.

Melatonin inhibits dopamine release from the striatum¹⁶. Parkinson’s disease is caused by the neurodegeneration of dopaminergic neurons.

In Parkinson’s disease, one might think
that melatonin would exacerbate symptoms since melatonin inhibits dopamine release.
However, melatonin (and melatonin-mimetics) have a neuroprotective effect that may benefit Parkinson’s patients¹⁷.

The Verdict on Agomelatine

Taking into account the information provided above it is safe to assume that agomelatine is a unique and an effective tool against the battle with depression. It shows superiority to most clinically available antidepressants in terms of tolerability, in sleep improvement and for the treatment of drug-resistant forms of depression. Moreover, its use is not limited only to depression but other affective disorders were it is associated with significantly reduced symptomatology were it also shows some superiority to other antidepressants used.

Overall, agomelatine is completely justified for use in the clinic for affective disorders and possible not only!

References

[^1] Millan, M.J., Gobert, A., Lejeune, F., Dekeyne, A., NewmanTancredi, A., Pasteau, V., Rivet J.M., Cussac, D. The novel melatonin agonist agomelatine (S20098) is an antagonist at 5- hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J. Pharmacol. Exp. Ther., 2003, 306(3), 954-64.

1. Masson-Pevet, M., Recio, J., Guerrero, H.Y., Mocaer, E, Delagrange, P., Guardiola-Lemaitre, B., Pevet, P. Effects of two melatonin analogues, S-20098 and S-20928, on melatonin receptors in the pars tuberalis of the rat. J. Pineal. Res., 1998, 25(3), 172-6. ↩
2. Olie, J., Kasper, P.S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder. Int.. J. Neuropsychopharmacol., 2000, 10(5), 661-73. ↩
3. Srinivasan, V., Pandi-Perumal, S.R., Trakht, I., Spence, D.W., Hardeland, R., Poeggeler, B. Cardinali. D.P. Pathophysiology of depression: Role of sleep and the melatonergic system. Psychiatry Res., 2009, 165(3), 201-14. ↩
4. Svestka, J. Sleep deprivation therapy. Neuro Endocrinol. Lett., 2008, 29(Suppl1), 65-92. ↩
5. Montgomery, S., Kasper, A.S. Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. Int. Clin. Psychopharmacol., 2007, 22(5), 283-91. ↩
6. Avedisova, A; Marachev, M (2013). “2639 – The effectiveness of agomelatine (valdoxan) in the treatment of atypical depression”. European Psychiatry. 28  ↩
7. Heun, R; Coral, RM; Ahokas, A; Nicolini, H; Teixeira, JM; Dehelean, P (2013). “1643 – Efficacy of agomelatine in more anxious elderly depressed patients. A randomized, double-blind study vs placebo”. European Psychiatry. 28 ↩
8. Fornaro M, Prestia D, Colicchio S, Perugi G. A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation.Curr Neuropharmacol. 2010 Sep;8(3):287-304. ↩
9. De Berardis, D; Conti, CM; Marini, S; Ferri, F; Iasevoli, F; Valchera, A; Fornaro, M; Cavuto, M; Srinivasan, V; Perna, G; Carano, A; Piersanti, M; Martinotti, G; Di Giannantonio, M (2013). “Is there a role for agomelatine in the treatment of anxiety disorders? a review of published data”. International Journal of Immunopathology and Pharmacology. 26 (2): 299–304.  ↩
10. Fornaro, M (February 2011). “Switching from serotonin reuptake inhibitors to agomelatine in patients with refractory obsessive-compulsive disorder: a 3 month follow-up case series”. Annals of General Psychiatry. 10 (1): 5. ↩
11. Pjrek, E; Winkler, D; Konstantinidis, A; Willeit, M; Praschak-Rieder, N; Kasper, S (March 2007). “Agomelatine in the treatment of seasonal affective disorder”. Psychopharmacology. 190 (4): 575–579.  ↩
12. Fornaro, M; McCarthy, MJ; De Berardis, D; De Pasquale, C; Tabaton, M; Martino, M; Colicchio, S; Cattaneo, CI; D’Angelo, E; Fornaro, P (2013). “Adjunctive agomelatine therapy in the treatment of acute bipolar II depression: a preliminary open label study”. Neuropsychiatric Disease and Treatment. ↩
13. Pappolla, M.A., Sos, M., Omar, R.A., Bick, R.J., Hickson-Bick, D.L., Reiter, R.J., Efthimiopoulos, S., Robakis, N.K. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J. Neurosci., 1997, 17(5), 1683-90. ↩
14. Conboy, L., Tanrikut, C., Zoladz, P.R., Campbell, A.M., Park, C.R., Gabriel, C., Mocaer, E., Sandi, C. Diamond, D.M. The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats. Int. J. Neuropsychopharmacol., 2009, 12(3), 329-41. ↩
15. Tenn, C.C., Niles, L.P. The antidopaminergic action of S-20098 is mediated by benzodiazepine/GABA(A) receptors in the striatum. Brain Res., 1997, 756(1-2), 293-6. ↩
16. Zisapel, N.; Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting. Cell Mol. Neurobiol., 2001, 21(6), 605-16. ↩
17. https://www.ncbi.nlm.nih.gov/pubmed/23391633 ↩
18. Taylor D, Sparshatt A, Varma S, Olofinjana O. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ 2014; 348: g1888 ↩

Must Reads

• Sulforaphane: A Powerful Medicine of Nature
• Brain-Boosting Habits I’m Embracing in 2017
• YAABH: Yet Another Article On Brain Health
• 7 Habits That Made My Brain as Sharp as a Teenager’s
• Pterostilbene Benefits
• The Brain Food Pyramid [Infographic]

There’s something really fantastic about plant-derived nootropics. I’m a big fan of bacopa, lion’s mane and the like.

Sure, they’re less exciting than some obscure injectable Russian peptide. But they also have much less downside risk.

All you need to do to realize the benefits of sulphoraphane is eat more cruciferous vegetables. What’s not to love?

Sulforaphane is found in broccoli, brussels sprouts and other cruciferous vegetables and has robust neuroprotective and anti-oxidative effects.

Some Studies That Piqued My Interest

• Sulphoraphane rescues damaged mitochondria after carbon monoxide poisoning.³⁰
• Sulphoraphane is an inducer of phase II antioxidant and detoxification enzymes with anticancer properties ³¹
• Sulphoraphane accumulates in cells – up to several hundred-fold over its extracellular concentration – by conjugation with intracellular GSH³².
• Sulphoraphane has a protective effect against diabetic vascular complications (e.g., neuropathy)³³. One mechanism may be inhibition of the formation of advanced glycation end products (AGEs) and suppression of AGE-induced inflammatory reactions.

Sulforaphane Sources: Food vs Supplementation

The best results are probably obtained from ingesting sulphoraphane-rich foods rather than the isolated compound.

Many nootropic foods contain a blend of hundreds of compounds which enhances bioavailability and packs more of a punch than an isolated compound.

Case in point: PEITC is a compound also found in cruciferous vegetables and is thought to also have synergistic anti-inflammatory effects with sulforaphane²⁵.

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Top Dietary Sources of Sulphoraphane

Food (raw)	Serving	Total Glucosinolates (mg)
Brussels sprouts	½ cup (44 g)	104
Garden cress	½ cup (25 g)	98
Mustard greens	½ cup, chopped (28 g)	79
Turnip	½ cup, cubes (65 g)	60
Cabbage, savoy	½ cup, chopped (45 g)	35
Kale	1 cup, chopped (67 g)	67
Watercress	1 cup, chopped (34 g)	32
Kohlrabi	½ cup, chopped (67 g)	31
Cabbage, red	½ cup, chopped (45 g)	29
Broccoli	½ cup, chopped (44 g)	27
Horseradish	1 tablespoon (15 g)	24
Cauliflower	½ cup, chopped (50 g)	22
Bok choy (pak choi)	½ cup, chopped (35 g)	19

General Characteristics of Sulforaphane

Sulforaphane is a naturally-occurring compound belonging to the isothiocyanate group of organosulfur compounds.

It is present in relatively large quantities within cruciferous vegetables, such as broccoli. Brussels sprouts deliver 2x as much Glucosinolate (the precursor to sulphoraphane) than any other source.

Sulforaphane positively modulates cellular events and has a net-beneficial effect on bodily function. This article explores the effects of sulforaphane from food and supplementation has on the body.

Graphic lifted from Sulforaphane protects against rotenone-induced neurotoxicity in vivo: Involvement of the mTOR, Nrf2, and autophagy pathways.

Sources and Catabolism of Sulforaphane

In cruciferous vegetables, sulforaphane is found in the form of a prodrug known as glucoraphanin, where it is bound to a sugar moiety.

When you chew a cruciferous vegetable, glucoraphanin is converted by Myrosinase into sulforaphane by cleaving the sugar group. Myrosinase is an enzyme present in the broccoli family of plants¹.

In broccoli, sulforaphane is found in the following quantities:

• Brocolli: 44-171mg/100g dry weight
• Brocolli sprouts: 1153mg/100g dry weight

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How to Take Sulforaphane Supplements

What’s the ideal dosage of sulforaphane? Unfortunately, it’s not well established, though we can hazard an educated guess.

Studies in animal models have shown supplementation of 0.1-0.5mg/kg sulforaphane to be biologically active. Based on these findings estimated human doses are as follows:

• 7-43mg for 150lb person
• 9-45mg for 200lb person
• 11-57 mg for 250lb person

You can obtain these doses of sulforaphane directly from cruciferous vegetables.

The effects of higher doses, while expected to be of further benefit, are not known.

Another factor to take into account when considering taking sulforaphane supplements is the formulation.

Consumers are advised to use either an a-cyclodextrin inclusion or an SF-rich commercial supplement. That’s because sulforaphane is more stable and bioavailable in these formulations.

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How Does the Body Handle Sulforaphane?

Once consumed, sulforaphane is well absorbed into the bloodstream via the small intestines. About 3/4 of the ingested dose is delivered into the bloodstream.

Sulforaphane appears in the bloodstream 1 hour post-ingestion. Peak plasma levels are reached after 4 hours. The elimination half-life of sulforaphane is 2.2 hours and it becomes undetectable in blood 12 after consumption.

Once in the bloodstream sulforaphane rapidly enters cells.

In the intracellular space, Sulforaphane interacts with glutathione, a cellular antioxidant, to form a glutathione-sulforaphane conjugate.

This process is catalyzed by the enzyme glutathione-s-transferase. Finally, once the glutathione-sulforaphane conjugate is formed, it exits the cell via the efflux protein MRP (Multidrug Resistance Protein), and to a lesser extent, P-glycoprotein.

What are the Cellular Effects of Sulforaphane?

While the mechanism of action of Sulforaphane is not completely understood, Hydrogen Sulfide (H2S) likely plays a role.

Like nitric oxide, H2S is actually a gasotransmitter.

H2S’ main purpose in the body is to transmit chemical signals which bring about specific physiological or biochemical changes in a tissue or a cell.

The ability of sulforaphane to generate H2S lies in its isothiocyanate group (-N=C=S) which behaves as a sulfur donating molecule for its production. Interestingly, in prostatic cancer cell lines and in mouse liver cells, sulforaphane acts a potent generator of H2S.

What Benefits Does Sulforaphane have on the Body?

Effects on the Cardiovascular System

Sulforaphane exhibits cardio-protective effects.

By producing H2S, it acts on smooth muscle present in blood vessels positively impacting blood pressure and helping to prevent cardiovascular disease.

Neurological Effects

Sulforaphane is without a doubt a neuroprotective agent.

In neurons, sulforaphane is a potent inducer of Nrf-2 and an inhibitor of Nf-kB. Inducement of Nrf-2 and inhibition of Nf-kB protects against neurotoxicity and oxidative stress.

Due to its neuroprotective properties sulforaphane supplements could be of use in neurodegenerative disorders and for the management of neuropathic pain. In addition to its neuroprotective effects, sulpforaphane possesses anti-addictive properties whereby associated with reduced cocaine cravings in mice by inhibiting neuronal HDCA (Histone Deacetylase).

Anti-Aging Effects

Aging is associated with reduced Proteosomal activity and the build up to modified proteins in cells.

Sulforaphane enhances Proteosome activity, preventing cellular build-up of modified proteins and thus combats cellular aging. This effect lies in its ability to increase HSP27 and activate the heat shock response.

Effects of Sulforaphane on Adipose tissue

Sulforaphane induces lipolysis. This is the processes where fat cells are broken down. This effect of sulofraphane is mediated by its ability to inhibit a protein known as AMPK which in turn enhances activity of the hormone sensitive lipase (HSL).

Effects on Skeletal Muscle

Sulforaphane acts on skeletal muscle by repressing a protein known as Myostatin.

Abolishment of Myostatin in the body results in muscle growth and reduction in fat mass. This effect of sulforaphane is the result of HDCA and Nrf2 inhibition in myocytes.

Effects on Metabolism

Sulforaphane normalizes blood glucose and insulin sensitivity. However, the exact mechanism of this effect is unknown.

Effects on the Immune System

Sulforaphane posses potent anti-inflammatory properties by disrupting the generation of pro-inflammatory signals, an effect mediated by its ability to inhibit the action of NF-kB¹⁷.

Interestingly, it has shown promise for rheumatoid arthritis an autoimmune inflammatory disease. In synovial cell cultures, sulforaphane suppresses inflammation by inhibiting TNF-a generation.

Effects on Cancer Cells

Sulforaphane acts as a potent anti-cancer agent.

Via HDCA inhibition, sulforaphane stimulates expression of p21 helps cells correct mutations prior to cell division.

This effect is most obvious in prostate and colorectal as it is able to reach these sites at sufficient amounts to produce anti-cancerous effects.

Effects on Kidneys

Sulforaphane slows the progression of kidney disease by suppressing inflammation and oxidative stress. Once again, this effect is mediated by Nrf2.

Does Sulforaphane Have Any Unwanted Effects?

Sulforaphane could theoretically harm the liver indirectly by increasing liver enzymes and cholesterol.

Does Sulforaphane Interact with Other Substances?

Interaction with Curcumin

Synergistic effects are observed when sulforaphane is co-administered with curcumin in regard to its anti-inflammatory actions.

Interaction with PhenylIsothiocyanate (PEITC)

PEITC is a compound also found in cruciferous vegetables. It has synergistic anti-inflammatory effects with sulforaphane.

Interaction with Neoglucobrassicin

Neoglucobrassicin, an agent also found in cruciferous vegetables, may reduce the anti-oxidative properties of Sulforaphane by preventing its interaction with Nrf2.

Interaction with Mustard

When directly consuming cruciferous vegetables, mustard increases the amount of sulforaphane entering the bloodstream by stabilizing the enzyme Myrosinase leading the production of more sulforaphane.

References

1. Perocco P, et al. Glucoraphanin, the bioprecursor of the widely extolled chemopreventive agent sulforaphane found in broccoli, induces phase-I xenobiotic metabolizing enzymes and increases free radical generation in rat liver . Mutat Res. (2006) ↩
2. Nakagawa K, et al Evaporative light-scattering analysis of sulforaphane in broccoli samples: Quality of broccoli products regarding sulforaphane contents . J Agric Food Chem. (2006) ↩
3. Fahey JW, Wade KL, Wehage SL, et al. Stabilized sulforaphane for clinical use: Phytochemical delivery efficiency. Mol Nutr Food Res. (2016) ↩
4. Benavides GA, et al Hydrogen sulfide mediates the vasoactivity of garlic . Proc Natl Acad Sci U S A. (2007) ↩
5. Pei Y, et al Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells . Toxicol Appl Pharmacol. (2011) ↩
6. Benavides GA, et al Hydrogen sulfide mediates the vasoactivity of garlic . Proc Natl Acad Sci U S A. (2007) ↩
7. Negi G, Kumar A, Sharma SS Nrf2 and NF-κB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes . Curr Neurovasc Res. (201 ↩
8. Host L, et al Cocaine self-administration alters the expression of chromatin-remodelling proteins; modulation by histone deacetylase inhibition . J Psychopharmacol. (2011) ↩
9. Stadtman ER. Protein oxidation and aging . Science. (1992) ↩
10. Gan N, et al. Sulforaphane activates heat shock response and enhances proteasome activity through up-regulation of Hsp27 . J Biol Chem. (2010) ↩
11. Lee JH, et al Sulforaphane induced adipolysis via hormone sensitive lipase activation, regulated by AMPK signaling pathway . Biochem Biophys Res Commun. (2012) ↩
12. Fan H, et al Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells . Epigenetics. (2012) ↩
13. Oh CJ, et al Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling . Free Radic Biol Med. (2012) ↩
14. de Souza CG, et al Metabolic effects of sulforaphane oral treatment in streptozotocin-diabetic rats . J Med Food. (2012) ↩
15. Heiss E, et al Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms . J Biol Chem. (2001) ↩
16. Fragoulis A, et al Sulforaphane has opposing effects on TNF-alpha stimulated and unstimulated synoviocytes . Arthritis Res Ther. (2012) ↩
17. Myzak MC, et al A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase . Cancer Res. (2004) ↩
18. Kaminski BM, et al Isothiocyanate sulforaphane inhibits protooncogenic ornithine decarboxylase activity in colorectal cancer cells via induction of the TGF-β/Smad signaling pathway . Mol Nutr Food Res. (2010) ↩
19. Clarke JD, et al Metabolism and tissue distribution of sulforaphane in Nrf2 knockout and wild-type mice . Pharm Res. (2011) ↩
20. Cui W, et al Prevention of diabetic nephropathy by sulforaphane: possible role of nrf2 upregulation and activation . Oxid Med Cell Longev. (2012) ↩
21. de Souza CG, et al Metabolic effects of sulforaphane oral treatment in streptozotocin-diabetic rats . J Med Food. (2012) ↩
22. Cheung KL, Khor TO, Kong AN Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation . Pharm Res. (2009) ↩
23. Cheung KL, Khor TO, Kong AN Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation . Pharm Res. (2009) ↩
24. Haack M, et al Breakdown products of neoglucobrassicin inhibit activation of Nrf2 target genes mediated by myrosinase-derived glucoraphanin hydrolysis products . Biol Chem. (2010) ↩
25. Ghawi SK, Methven L, Niranjan K The potential to intensify sulforaphane formation in cooked broccoli (Brassica oleracea var. italica) using mustard seeds (Sinapis alba) . Food Chem. (2013) ↩
26. Li YJ, Shi ZQ et al.. Hydrogen sulfide is a novel gasotransmitter with pivotal role in regulating lateral root formation in plants. Plant Signal Behav. 2014 May 15;9(): ↩
27. Bi M, Li Q et al.. Sulphoraphane Improves Neuronal Mitochondrial Function in Brain Tissue in Acute Carbon Monoxide Poisoning Rats. Basic Clin Pharmacol Toxicol. 2016 Dec 16;(): ↩
28. Yamagishi S, Matsui T. Protective role of sulphoraphane against vascular complications in diabetes. Pharm Biol. 2016 Oct;54(10):2329-39 ↩
29. Zhang Y, Callaway EC. High cellular accumulation of sulphoraphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. Biochem J. 2002 May 15;364(Pt 1):301-7 ↩
30. Yamagishi S, Matsui T. Protective role of sulphoraphane against vascular complications in diabetes. Pharm Biol. 2016 Oct;54(10):2329-39 ↩

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This post is an experience report graciously provided by HDL. The author offers suggestions about nootropics and supplements for social and generalized anxiety.

To give a bit of history, I came a very long way from where I was to where I am now.

I suffered from generalized anxiety disorder (GAD) and social anxiety for about 20 years. I developed coping mechanisms and probably put myself into a somewhat dissociative state to be able to function occupationally and socially.

This took a toll on me and resulted in a lot of frustration. Every once in a while I would crash. Survival instincts would eventually kick in allowing to continue my daily routine.

I started researching natural supplements in 2015. Since then, I was able to improve my condition to a point where I enjoy social interactions. They give me that fuzzy warm feeling inside – something I completely forgot existed.

There’s still progress to be made and I’m not (at least not yet) cured, but my functional level and anxiety levels are nowhere where they were for about 20 years.

Quest For Nootropics
In my quest for supplements/nootropics I targeted all bodily systems I knew of that could be contributing to my condition. Here are the nootropics and supplements that work for me and how I use them. It is a big list. But buying these items from bulk sellers (PowderCity, PureBulk, others) can bring the costs down.

Some of the supplements below are for nighttime use, some for day use, some for both. I developed this stack progressively. I used to take all of the nootropics I suggest below for about 6 months. Now I only take a few every day – the rest I take when I need to – either all or some – depending on how I feel.

I hope my experience will be helpful, at least in part, to anyone that has to deal with the reality of anxiety, whether generalized or social.

Note that many conditions such as chronic sinusitis, gut issues, nutritional deficiencies, infections in general can all contribute to underlining anxiety so a doctor checkup can also help.

I’m not sure if I can post links to research, so I’ll only post some abstracts.

N-Acetyl Cysteine
This is one of the principal supplements in my stack.

I take NAC every day.

It has many benefits; it replenishes glutathione, a primary endogenous antioxidant and has a stabilizing effect on many psychiatric conditions.
Melatonin
Another principal supplement in my stack. I take this every night.

Melatonin is a hormone made by the brain to regulate sleep cycles, but it can also play a role in mood and anxiety.
It helps control the level of stimulation and activity experienced by the body, and demonstrates anxiolytic effects.
Vitamin D
A must have. I take Vitamin D every day.

Several studies report an association between low levels of vitamin D – or hypovitaminosis D – and neuropsychiatric disorders.

Magnesium
Magnesium (bisglycinate or other bioavailable forms) is a great supplement – a must have. Take at night and/or day.

Studies demonstrate involvement of the NMDA/glutamate pathway in magnesium’s anxiolytic activity.
Zinc (Picolinate)
Take at night and/or day.

Zinc plays an important role in axonal and synaptic transmission.
Vitamin C
As a smoker, Vitamin C is good to have. I take this every day.

General Supplements
B6(P5P and not pyridoxine) (day). B6 (as P-5-P) boosts brain neurotransmitters
B12 (methylcobalamin) (day) – has a neuroprotective effect
Folate
I don’t have enough experience with one yet – I just bought this for a trial along with Uridine – to research

Neurotransmitters precursors
These are the levers that control your mood behind the scene. I cycle them; sometimes I take one, sometimes all, sometimes more, and sometimes less.

Excess serotonin can worsen social anxiety based on the latest research, so I try to keep serotonin in check.

L-Tryptophan
Taken at night and/or day. L-tryptophan is precursor to both serotonin and melatonin (indirectly). As mentioned above, too much serotonin can be a factor in social anxiety.

I usually use L-tryptophan with L-phenylalanine or by itself when I feel too irritable.

L-Phenylalanine
To be taken during the day.

The precursor for tyrosine; the monoamine neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline).

I usually check my dose with this one because it can produce agitation. L-phenylalanine can help lower anxiety levels, especially social anxiety.

Both L-tryptophan & L-phenylalanine above need to be balanced. My sweet spot is 500mg l-tryptophan & 250mg L-Phenylalanine.

I had fewer benefits with 5-HTP and l-tyrosine which are one step above in the biological conversion path.

Myo-Inositol
To be taken at night and/or day.

Myoinositol is found in high concentrations in the brain where it influences neuroplasticity and signal transduction.

Alpha-GPC and CDP-Choline
To be taken during the day only.

Alpha-GPC and CDP-Choline are both precursor to acetylcholine and may regulate dopamine.

CDP-choline (citicoline) is a nootropic compound that converts to both choline and cytidine after ingestion. The latter converts further converted to uridine in the body. CDP-choline confers cognitive-promoting properties as a prodrug for these two compounds. CDP-choline may also regulate dopamine receptor density.

Alpha-GPC seems to increase acetylcholine, which is important for learning and memory. Alpha-GPC has been noted to increase dopamine transporter (DAT) density and potassium-stimulated dopamine release, along with raising DOPAC levels in the cerebellum as well as the frontal cortex.

I do better with Alpha-GPC. CDP-Choline is somewhat depressogenic for me.

I use cholinergics with Noopept, which I’ll touch base on later in the post.

Anti-Inflammatories
Cytokines regulate functions in the central nervous system (CNS) that ultimately modulate behavior.

Dysregulation of cytokine signaling can lead to depression, anxiety, and cognitive dysfunction.

MSM (Methylsulfonylmethane)
Taken at night and/or day.

MSM is a natural and effective anti-inflammatory because of how sulfur impacts the immune system and facilitates normal cellular activity.

Curcumin 95%/Peperine
Taken at night and/or day.

Curcumin is a potent anti-inflammatory. Piperine enhances its effects.

Trimethylglycine (betaine)
Taken at night and/or day.

I’m not confident about trimethylglycine. It could be an issue for overmethylators. The reason I’ve included it is that it has the potential to lower homocysteine. I take this from time to time when I’m feeling low.

Betaine acutely reduces the increase in homocysteine after methionine loading

Others (Energy or Circulation)
L-Arginine
Take at night and/or day.

L-arginine promotes NO production.

ALCAR (night and/or day)
Take at night and/or day.

Shows promise for alleviating social anxiety and phobias.

Adaptogens
I use them at night only – some users find them helpful during the day. Adaptogens are natural substances considered to help the body adapt to stress and to exert a normalizing effect upon bodily processes

Principal supplements in my stack:

L-Theanine
Ashwagandha
Lion’s Mane
Bacopa Monierri
Valerian root (night only – on and off – needs to be cycled. I get depressive if I take this too many days in a row )
Adaptogens have too many benefits to be listed here.

Nootropics
To be taken during the day only.

Noopept
Noopept literally changed the way I viewed the word. Noopept was a potent anxiolytic in my case, though I’ve heard different subjective experiences. It also greatly reduced my anxiety levels and increased my focus and confidence.

Noopept’s effect build up with use, along with benefits which seem to remain after discontinuation. Noopept should be used with a choline source (Alpha-GPC or CDP Choline).

Noopept stimulates the expression of NGF and BDNF in hippocampus. It’s always great when regeneration happens 🙂
Mexidol
I experienced great results with Mexidol. Note that it should be cycled. Mexidol has an anxiolytic effect and seems to regulate dopamine.

The level of dopamine and of its metabolite dihydroxyphenylacetic acid is found to be considerably elevated in the frontal cortex, suggesting a pronounced cortical component in the mechanism of action of mexidol.
Mildronate
Mildronate is great for resetting glucose metabolism. Mildronate boosted my energy levels.

Semax
Great results.

Rapidly elevates the levels and expression of brain-derived neurotrophic factor (BDNF) and its signaling receptor T rkB in the hippocampus, and rapidly activates serotonergic and dopaminergic brain systems.
Semax also boosts immune system.
Selank
Great results (see note below).

Selank drug has shown to provide a sustained nootropic and anxiolytic effect which is useful for the treatment of generalized anxiety disorder (GAD). Selank has an advantage over traditional anxiety treatments, such as benzodiazepines, as it has no sedating or negative cognitive side effects and no associated addiction or withdrawal problems
P21 peptide
I’m new to P21 and not yet sure about my results with it. I mix P21 with the two nootropics above.

Derived from Cerebrolysin
Potential others: Cerebrolysin, other racetams
Gut
N-Acetyl-Glucosamine (NAG)
I take NAG every day for its effects on the immune system and intestinal mucosa
NAG can correct an overactive immune system so that autoimmune reactions occur less frequently.
The mechanism is that NAG controls immune T-cell over activity and stabilizes mast cells.
NAG also helps to correctly regulate your gut flora by maintaining the mucosal barrier
Probiotics
I take probiotics every day.

My experience with probiotics is very positive. They have a mood-leveling effect.
You can prepare them at home from capsules, tabs or liquids. Look for recipes online. Most recipes involve warming milk to 110 F and leaving a probiotic in the milk overnight. Using this method, you can produce a gallon of probiotics in 1 day.
Of interest: strain L. reuteri ATCC PTA 6475 found in BioGaia Gastrus. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin.