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Nootropics NSI-189 Recovery

NSI-189: A Nootropic Antidepressant That Promotes Neurogenesis

The use of antidepressant medications in America is a rapidly growing portion of the pharmaceutical industry. The number of people who take antidepressants has increased by almost 400% from 1990 through 2008.[1] In addition, eleven percent of Americans aged 12 years and older take some form of antidepressant medication.

Antidepressants have long been a troubled group of drugs in terms of side-effects, with even the most recent class of antidepressants (SSRIs) exhibiting potential side-effects like insomnia, sexual dysfunction, or even worsened depression. These troublesome side-effects have displayed a clear need for more effective treatment options.

Prozac capsules and packaging anti depression medication

Despite the apparent need for a more effective class of antidepressants, no new major milestones have occurred regarding antidepressants since 1987, the year fluoxetine (Prozac) was approved by the FDA.[2] Since the beginning of Prozac’s use to treat depression, SSRIs have dominated the area of medical treatment for depression. This era of depression treatment has been going on for about 29 years. However, some progress is being made in the development of new antidepressants. One of the newest experimental drugs for depression, NSI-189, also displays nootropic properties. Here we will be examining some of the claims surrounding the purported benefits of NSI-189.

Origins of NSI-189

NSI-189 is an experimental drug currently being developed and studied by Neuralstem Inc., a biotechnology company that commercially produces neural stem cells for therapy.[3] The research and development of NSI-189 began in the 1990s, during the years of Bill Clinton’s presidency.

The Clinton administration contracted Neuralstem to research the possibilities of creating a “super soldier,” one that was able to stay awake and alert for extended periods of time.[4] The researchers at Neuralstem recognized that a drug targeting the hippocampus could possibly alleviate the effects of sleep deprivation and exhaustion, and set out to find a drug that could induce neurogenesis. Neuralstem, finding their prospects to be promising, continued research in this vein even after the government program was canceled.

This preliminary research would eventually result in the drug NSI-189. Clinical research on NSI-189 has been in the works since 2011, and a phase 1b trial was completed in July of 2014.[5] Clinical phase 1 trials typically focus on finding the correct dosage range of the drug, which has been placed around 40 to 80 mg per day in the treatment of Major Depressive Disorder (MDD) and cognitive decline.

NSI-189 structure

Chemically speaking, NSI-189 is classified as a small-molecule benzylpiperazine-aminopyridine drug, making it structurally unique among other antidepressants. However, the drug has also seen increased interest in terms of its ability to stimulate nerve growth in the hippocampus.

According to the official Neuralstem, Inc. press release concerning the phase 1b trial, “[NSI-189] is a proprietary new chemical entity that stimulates new neuron growth in the hippocampus, a region of the brain believed to be implicated in MDD, as well as other diseases and conditions such as traumatic brain injury (TBI), Alzheimer’s disease, and post-traumatic stress disorder (PTSD).”[6]

The phase 1b trial of NSI-189 was “a randomized, double-blind, placebo-controlled, multiple-dose escalating trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamic effect of NSI-189 in the treatment of MDD.” Now that the trial has been completed, the results have been released, and they appear quite promising.

The study, which was conducted on 24 patients over the course of 28 days, found that NSI-189 administration reduced the symptoms of depression and cognitive decline significantly more than placebo. The drug was tolerated well by the subjects, and it “may also exhibit pro-cognitive properties associated with increases in prefrontal alpha coherence.” [7] [8]

Mechanism of Action

Selective serotonin reuptake inhibitors (SSRIs) attempt to treat depression by increasing levels of serotonin in the brain. This model of depression, known as the “monoamine hypothesis,” states that depression is caused by a shortage or imbalance of certain neurotransmitters in the depressed patient, mainly serotonin. However, this model has been quite drastically debunked in recent years.[9] Many researchers and psychiatrists now recognize that depression is far more complex than a simple chemical imbalance. New theories have emerged that recognize factors such as emotional trauma, environmental factors, glutamatergic dysfunction, and inflammation as potential causes of depression.

In short, depression is a complex web of interweaving causes and effects, both psychological and physiological. While scientists know from research that SSRIs and other antidepressants certainly have an effect in alleviating depression, the actual pharmacology behind the medications is far more unclear. Why do some respond to medication negatively? Why do some not respond at all? Because these questions are so intimately tied with genetic and biochemical factors, they are very difficult to address in a comprehensive manner.

These observations lead to two important points: First, depression is such a complex disorder that we don’t yet know the best way to treat it with medication. Second, SSRIs may be somewhat effective in alleviating depression, but we don’t completely understand why they work the way they do. Because the root causes of depression are still somewhat uncharted territory, exploration of new treatments that work differently than SSRIs is very important. By pioneering these treatments and observing their effects, the puzzle pieces that make up the full picture of depression can be pieced together into a comprehensive model.

NSI-189 vs Placebo Hippocampus
Topographs of average amplitude at 10-12 Hz showing increased high-frequency alpha in patients receiving NSI-189 at Day 28. Differences scores comparing conditions show most significant differences between total subjects receiving NSI-189 (left) vs. Placebo (right) in the left posterior temporal and parietal regions.

Some researchers, like those at Neuralstem, have noticed a correlation between reduced hippocampal volume and increased incidence of Major Depressive Disorder.[10] According to this theory, NSI-189 could potentially be a remedy to those suffering from depression by contributing to the growth of the patient’s hippocampus. Because the hippocampus is also so closely associated with memory, NSI-189 also has the potential to impact cognition.

This “hippocampal” model of depression is still in its infancy, and NSI-189 is one of the first drugs being researched that uses this specific form of treatment. Although it is known that NSI-189 increases hippocampal volume, the exact mechanism underlying this effect is still unsure. The results of the phase 1b trial even suggested that NSI-189s effect on hippocampal volume was not as drastic as that which was seen in animal studies.[11] Whether or not the increase of hippocampal volume persists after ceasing the medication remains to be determined. As the research and experimentation with NSI-189 continue, new research will shed light on this model for depression, and the medical community will be better able to understand the correlation between depression and hippocampal volume.

Purported Benefits

As mentioned above, the potential benefits of NSI-189 are:

    1. Improvement in behavioral responses associated with depression.[12]
    2. Reversal of hippocampal atrophy.[13]
    3. May enhance memory and cognition through increase neurogenesis, particularly in depressed subjects.
    4. Positive effects may persist after treatment ceases.[14]

    Subjective Experiences

    Because NSI-189 is still in its infancy as a clinical treatment for MDD and cognitive disorders, anecdotal information is important for those determining if they want to try NSI-189. This community poll conducted by /u/MisterYouAreSoDumb on /r/nootropics is useful for seeing various users’ experiences with NSI-189

    A Reddit user, Code_of_Error, relayed his experience with NSI-189 in a post on reddit[15]:

    I have been on NSI-189 Phosphate for three weeks now. I take 40mg orally once per day. I used to take it sublingually, but I learned that doing so may be counterproductive due to the possibility that too much is absorbed. Apparently, 40mg-80mg ORALLY was the sweet spot in clinical trials, so sublingual administration has too many unknowns to be worth it. Albeit, the freebase form is a different story.
    Anyway, I started exploring this substance in hopes of counteracting my chronic brain fog, slight depersonalization, anhedonia, general feelings of haziness, and slow cognition.
    Most notably, I have noticed an intensification of emotions, as well as pleasure. The first few days, I felt the inclination to tear up at every positive emotion. It felt ridiculous, but that has mostly leveled out. Although I am only three weeks in, I notice I am more inclined to look forward to plans. I am quicker to laugh and socialize.
    Prior to NSI-189, every emotion I experienced felt like nothing more than background noise. Now a days, all of my emotions feel more genuine, as if they’re at the forefront of my brain. When I experience anxiety, I no longer feel so dissociated from it. When I feel joy, it tends to last longer. Although these new perspectives are scary, I welcome the change. My default state of mind tends to be slightly perkier as well.
    I will admit that I am more guided by my emotions than I have been in years, and I am totally enabling it. I don’t recommend falling in love while on this substance. However, this substance is bringing me closer to my long-lost inner feelings. The effects aren’t perfect, and I still often feel that irritating haze (i.e., brain fog/dulled-out sensation/whatever ambiguous symptoms) to a degree, but I hope that my mental issues continue to improve as I stay on this. I’ve certainly made strides.
    Interestingly, I have noticed that I better able to “feel” the effects of nootropics while on this as well. Caffeine has a much more profound effect on me (comparable to when I first started using it), and the effects of tianeptine are as potent as ever. Again, I feel as if this speaks MORE to NSI-189’s ability to make you feel and less to its ability to reduce tolerance.
    Lastly, I would venture to say I am bit sharper mentally, and less likely to experience “cluttering” when I go to speak.
    Side effect wise, I only experience a mild fluttering (almost like a twitch) directly behind the inner half of my right eyebrow. Other than that, no headaches. I may have a mild reduction in sex drive, but nothing too troubling.
    Overall, I am looking forward to staying on this drug for a while. My mental symptoms are nowhere near gone, but I see enough benefits to keep going. Like many people who try an under-researched compound intended for depression, I feel as if I have little to lose.

    This is the experience of flare1028us, another reddit user:[16]

    Personally, I’ve found NSI-189 to be very useful. I’m taking 50mg freebase once daily in the morning. The acute effects for me are a gentle wave of calmness, improved long-term memory, and notably improved vision.
    The improved vision, as another redditor put it, is like my vision being “zoomed out” by 5%, like having a slightly larger field of view. Improved memory is the strong point of this substance. I find myself having vivid recollection of memories going back to my single digit ages. This has also allowed me to remember times when I encountered some of the same struggles I have to this day, and how I handled them – I feel better equipped to tackle them with better memory of what did and didn’t work in the past.
    As far as side effects, child-like emotions are coming on fairly strong. This is both good and bad. The good is that the sense of wonderment that we experience as children has come forth again, the bad being somewhat immature initial emotional responses. For example, jealousy – on a very childish level. It’s not debilitating, but it’s something to be mindful of.
    Speaking of being mindful, it has gotten a whole lot easier to practice mindfulness meditation and commit experiences I’ve gained through it to long(er) term memory.
    Interactions: Cannabis now gives me a mild headache, but if the high is balanced well (sometimes I’ll add some sublingual CBD), it is a very useful state of mind – for me it’s like being high with a better ability to remember the observations I make about my decisions and behavior that I may not come to so quickly in other states of mind. I tried taking piracetam once on NSI, and I’m never doing it again. Total dysphoria for most of the day from 3.5g piracetam in the morning. This stuff is supposed to reset piracetam tolerance, but I won’t be testing that until I’m off NSI-189 for a while.
    Tianeptine (sodium and sulfate) feels like it meshes really well with NSI-189, along with neurogenic peptides – took 200ug NA-Semax Amidate (sub-q) with NSI and went to yoga class (pretty intense class too). That was a level of control I would love to be able to gain every time I exercise in general.
    Hope this helps, I’m still waking up – I’ll answer questions if you have them

    Conclusion

    If NSI-189 proves to be an effective treatment for Major Depressive Disorder, it could have a potentially large impact on the direction of depression medication in the upcoming years. The long-standing dominance of SSRI drugs in the treatment of depression has left many wondering just how much longer it will be before the next major breakthrough occurs in depression treatment.

    A novel drug like NSI-189 could be the answer, and the studies concerning NSI-189 also give us a useful glimpse into the correlations between depression, hippocampal volume, and cognition. As we move further into the 21st century, the scientific community will undoubtedly continue to map more accurately the territory that is the human mind.

    References   [ + ]

    Categories
    Coluracetam Nootropics Racetams Reviews

    Coluracetam Review: A Nootropic With Antidepressant Properties

    The drug piracetam is often regarded as the first truly nootropic drug, due to its ability to promote healthy brain function and cognition without potentially debilitating side effects. The family of nootropics that are structurally related to piracetam, known as racetams, have also been held in high esteem by the nootropics community. Coluracetam is one of the many members of this nootropic drug class, but it has some unique properties that set it apart from the rest.

    Introduction

    ColuracetamColuracetam is a fairly new addition to the racetam category of nootropics, being developed and initially researched in the mid-1990s.[1] Coluracetam, known also by its research names of MKC-231 and BCI-540, was initially developed and researched by the Mitsubishi Tanabe Pharma Corporation in Japan as a potential treatment for Alzheimer’s disease. Coluracetam has also seen some limited research concerning its potential use for treating Major Depressive Disorder and Generalized Anxiety Disorder.[2]

    Mechanism of Action

    When ingested, coluracetam becomes present in nerve tissue within 30 minutes of administration. The concentration in the body begins to decrease about 3 hours after ingestion.[3]
    The most definitive mechanism through which coluracetam works is high-affinity choline uptake (HACU). HACU is a crucial step in the process of the body’s converting of choline into acetylcholine, a vital neurotransmitter for cognition processes. [4] In essence, this means that an increase in HACU (caused by coluracetam) will also increase the activity level of acetylcholine in the nervous system. This is the basis for coluracetam’s ability to enhance cognition

    My Experience with Coluracetam

    My trial run for NootropicsDepot’s coluracetam lasted for one week, due to the fact that coluracetam’s effects seem to all take place rather quickly. In other words, the effects do not appear to be cumulative like some other nootropics. Typically, I took 30 mg orally in the morning, along with another 30 mg in the afternoon. If necessary, I took another dose later on in the day. Dosage recommendations for coluracetam range anywhere from 3 mg up to 100 mg or more, but this dose seemed to work just fine. Having experimented with coluracetam briefly a few months ago, I had a general feel for what dose might work.

    Coluracetam powder nootropicDuring the time of this trial, I was not taking any prescription medications. In the morning, I was taking Vitamin B12, Vitamin D, potassium gluconate, fish oil, and turmeric. The effects I experienced from taking coluracetam have been very positive. However, bear in mind that this is only a subjective experience. The placebo effects cannot be ruled out (although I am convinced it was the coluracetam I felt), and experiences will vary between individuals. That being said, I will now go into what I felt are the major benefits of coluracetam:

    1. Motivation enhancement
      Right off the bat, coluracetam seems to provide a decent increase in motivation to engage in productive work. I felt a stronger desire to work on school work that I don’t find very interesting. It made it much easier to push through to get things done, leaving a very satisfactory feeling when things were accomplished.
    2. Stimulation
      This effect goes somewhat hand-in-hand with motivation enhancement. Coluracetam has the effect of making me feel more awake and alert. It seems to help me feel more ready and able to get work done. It didn’t make me feel “jittery” either – I felt quite relaxed the whole time.
    3. Reduction in fatigue
      Coluracetam appears to help alleviate both physical and mental fatigue. There were a few instances when taking it where I went from being exhausted and drained to energized and ready to go.
    4. Enhanced cognition
      This effect is very important for any nootropic compound. After all, it is the main thing that nootropics are purported to influence. Within half an hour of taking coluracetam, I felt much more able to formulate thoughts and translate them into writing. I also felt more able to connect ideas in my mind and get a better idea of the “bigger picture.” I also felt more naturally able to hold conversations with others, feeling much more engaged and fluent.
    5. Music enhancement
      While this is mostly unrelated to the topic of cognitive enhancement, listening to music while on coluracetam was very pleasant. The music itself felt more full, interwoven, and immersive than usual. Individual pieces of melody and minor details became more distinguishable than usual.
    6. Mood Boost
      After taking coluracetam, I can understand why it is being researched as a treatment for depression. It helped me remain more positive and upbeat throughout the day. I also seemed to make things more enjoyable in general.

    Drawbacks

    Coluracetam seems to be a very promising nootropic in terms of its multiple benefits and few side-effects. I did not experience any apparent increase in tolerance during the week I was taking it, even with multiple doses in one day. Experiments in which rats were given coluracetam for 14 days at a time seems to reinforce this.[5] The only possible side-effect I experience was mild to moderate headaches, which occurred throughout the week. This should be taken with a grain of salt because I am normally fairly prone to headaches in the first place. I’ve also heard that taking choline can alleviate headaches that come with racetam supplementation, so that could be a potential remedy.

    Conclusion

    All things considered, I was very pleased with the effects of coluracetam. I will certainly be implementing it into my nootropic stacks, as it is one of the most noticeable and useful nootropics I have personally taken. It seemed to have a real impact on my motivation, energy, and cognition. Everyone is bound to react differently to coluracetam, but I strongly encourage nootropics users to give it a try.

    You can buy Coluracetam powder and capsules at NootropicsDepot.

    Coluracetam
    7.5
    Focus
    8.5
    Mood
    8
    Memory
    7.5
    Stimulation
    7
    Relaxation
    8
    Safety
    Reviewer 8.4
    Summary
    I highly recommend coluracetam for anyone who needs to spend extended periods of time working on demanding mental tasks. The cognitive boost and mental stimulation was extremely useful.

    References   [ + ]

    Categories
    Fasoracetam Nootropics Racetams Reviews

    Fasoracetam: How This Nootropic May Help You Focus Better

    Originally known as NS-105, Fasoracetam is one of the newest nootropics on the market. Besides being the latest racetam to be discovered, it has some unique properties unlike any other racetam on the market. Let’s find out what makes this substance a truly unique nootropic, and why you should (or should not) try it.

    One of the primary effects of Fasoracetam is the modulation of metabotropic glutamate receptors II and III (mGluR).[1] mGlu receptors have been shown to be involved in synaptic plasticity and neuroprotection. In addition, LY354740, am mGlu2/3 agonist, has been shown to be effective in generalized anxiety disorder.[2]

    Fasoracetam is also the only racetam that significantly enhances cAMP formation[3] and that has been shown to be potentially effective in individuals with glutamatergic gene variants that are suffering from ADHD[4]. A Phase III clinical trial is near completion, but the drug is not currently listed as an ADHD treatment by the FDA.

    Fasoracetam has also shown to have antidepressant effects[5] and to counteract learned helplessness, an avoidance behavior typically associated with depression. Fasoracetam, however, does not act on serotonin and other monoamines, and researchers think the antidepressant effect may stem from its ability to upregulate GABA-B receptors.[6]

    Generally speaking, Fasoracetam has shown to be more effective with chronic use, and, in the ADHD study, most benefits were felt at week five onward.[7]
    Fasoracetam ADHD

    Mechanism of Action

    In rat studies, fasoracetam restores the function of key receptors, glutamate mGluR II and III[8].  It also upregulates GABA-B receptors through receptor antagonism[9], a fact which may be related to its ability to reverse phenibut tolerance (which is one of the few supplements reported to relieve anhedonic depression). The GABA-B receptor is very important and has been found to play a role in cognition[10], anxiety and mood.

    Alcohol, a very disinhibiting and fog-inducing compound (with pleasurable effects similar to phenibut) is thought to achieve its activity by activating GABA-B and A receptors (as well as dopamine).  However, because it downregulates these receptors, prolonged use may cause anxiety and cognitive disruptions.  Phenibut binds in a similar fashion to GABA-B.

    FasoracetamBecause of its relatively narrow range of receptor targets, fasoracetam does not feel like a classic stimulant nor does it alter one’s feeling of wakefulness.  It lacks clinical dopamine activity but remarkably still managed to address ADHD symptoms, according to the study.  It is not clear how fasoracetam has such a specific utility in treating ADHD, more research on other neurotransmitters may be turned up in coming years, but judging on present evidence, it seems that Fasoracetam could reduce ADHD symptoms by modulating glutamatergic receptors.

    That being said, the FDA does not list Fasoracetam as an ADHD medication and it should not be used as such. Only a professional can prescribe medications for ADHD and you should not self medicate.

    Although it is a newer supplement without much of a user-base, it does appear to be well-tolerated even in large doses or extended periods. Among college students, it may soon become a mainstay, alongside other trusted nootropics such as Bacopa, Modafinil, and Noopept.

    Acetylcholine

    In addition to the findings surrounding glutamate and ADHD, rat studies have also revealed fasoracetam to have profound cholinergic activity.  Many common nootropics work by controlling acetylcholine, including several drugs used in the treatment of Alzheimer’s.

    It increases the uptake of choline at sites in key brain regions involved in intelligence and mood, the hippocampus and cerebral cortex.  This, in turn, results in increased production and release of acetylcholine.[11]
    This, similarly to what has been commonly reported with piracetam, may explain a need for choline supplementation in the case of symptoms such as low mood, headache or brain-fog.

    Although I personally have only ever tried piracetam and aniracetam (and found, despite a slight cognitive boost, that they both caused a slightly lowered mood, with piracetam being more stimulating and anxiety-prone while aniracetam was calm and relaxing), I haven’t read any complaints of fasoracetam and depression (on the contrary it appears to be a robust antidepressant nootropic, similar to tianeptine). This is remarkable because excessive acetylcholine production is typically associated with low mood and depression. Even with something as mild as bacopa, reports of moodiness are easy to pin down.

    Since all three of the mentioned racetams seem to operate through a shared mechanism of acetylcholine, it’s not clear how fasoracetam achieves a similar cognitive boost without side effects on mood.  Perhaps it has been less trialed and as more users sample it, more negative reports will pour in.  This seems unlikely, however, given multiple reports of antidepressant effects, and at higher doses, near euphoria.

    Fasoracetam and coluracetam are interesting racetams with multiple mechanisms of action compared to piracetam. Although they both share a cholinergic effect, the former modulates mGlu receptors (as well as GABA-B receptors) while the latter interacts with a process named high-affinity choline uptake.  This may explain their calm, clear effects when compared with the more bland effects of piracetam.

    Glutamate

    Of the eight known metabotropic glutamate receptors, only one and five are believed to increase NMDA receptor activity and neural excitation (these two are postsynaptic).  The other six receptors all function to lower NMDA (and are presynaptic), lessen excitation and thus reduce potential neurotoxicity.

    By slightly lowering glutamate activity and at the same time boosting GABA-B levels, fasoracetam offers a collected state of mind compared to piracetam’s more scattered one.  Normal tasks would flow much easier, and performance would be improved without adverse effect.
    While OCD and more recently schizophrenia have been described as hyperglutamatergic, ADHD has always been thought of as a condition of low glutamate.[12]

    However, fasoracetam may very well regulate the metabotropic receptors in both directions and benefit everyone equally (restoring both high and low activity of the receptors to normal).

    It is not clear how to explain the remarkable improvements reported in samples of both schizophrenia and ADHD. An explanation may be the selectiveness for the presynaptic mGluRs (mGluR1 and mGluR5) coupled with the fact that these receptors both elevate cAMP and lower NMDA activity. Levels of these receptors in the body are both altered in schizophrenia (so fasoracetam would produce two favorable alterations for the schizophrenic patient).

    Despite all this fine talk about schizophrenia and glutamate, most of the reports surrounding fasoracetam are concerned with ADHD symptoms, specifically motivation and focus.  It is not widely known for its use as psychiatric medicine, and it may be considered by ADHD patients who have not responded well to conventional treatments. Again, it is not approved by the FDA as an ADHD treatment, and we are not suggesting people suffering from that disease to use it without a medical prescription.

    GABA

    As stated above fasoracetam appears to have GABA-B antagonistic properties[13], and it may upregulate these receptors and thus diminish the tolerance to GABA-B agonists like Phenibut, Baclofen, and Alcohol, and may even act as an “antidote” to a Phenibut overdose.

    Before many of the newer designer supplements hit the market and much was known about fasoracetam, Noopept was one of the more recommended supplements for alcoholics to recover cognitive capacities. But in light of this newer evidence, fasoracetam may address the issue more directly. Because of its activity here, fasoracetam may eventually find use in treating age-related memory decline, dementia, and even depression. For now, the research and hype seem to surround the potential treatment of ADHD symptoms.

    Dosage and half-life

    Buy Fasoracetam CapsulesNo dependence potential was noted in the rhesus monkey over the course of four weeks.[14]  However. users cannot be completely absolved of concern, due to interspecies differences and the possibility of an only mildly addictive substance requiring an exceptionally long habituation period.

    If its use is not completely discouraged in elderly patients, significant caution and close monitoring are recommended.  Its metabolism and clearance depend heavily on the kidneys and at least one studied has reported significant accumulation in the elderly (whose renal function is typically compromised).[15]

    It is typically taken at 10mg twice daily, but it is probably best to start with 5 mg and taper up. Even though the dosage is very low, bitterness is still a problem and the use of capsules or parachuting is recommended.

    Although some work their way up to 30 mg in one dose, this may not be the most effective strategy (due to a short half-life of the compound) and this pattern of use is more likely to be helped along by a large meal.  A potent nootropic with a half-life of around 90 minutes, taking it even once a day may be enough for active levels to build up in your system, but tolerance will be close behind.

    You can buy Fasoracetam capsules and powder at Nootropics Depot. Fasoracetam is not approved by the FDA as an ADHD treatment.

    Fasoracetam
    8.5
    Focus
    7.5
    Mood
    7.5
    Memory
    7.5
    Stimulation
    7.5
    Relaxation
    8
    Safety
    Reviewer 8.8

    References   [ + ]

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    Nootropics Tianeptine

    Tianeptine: A Nootropic Antidepressant?

    Tianeptine is an antidepressant, neuroprotective, and anxiolytic drug developed by French researchers Antoine Deslandes and Michael Spedding in the 1980s. It is currently marketed under the trade names Stablon and Coaxil in some European, Asian, and South American countries.

    In the United States, Tianeptine is not FDA approved, mainly due to a lack of interest in the drug within the American pharmaceutical sphere. Although it is typically used in a clinical setting to treat depression and related illnesses, it has recently gained favor among nootropic users for its mood and cognition-boosting capabilities. It remains an unscheduled substance in the US, and can be purchased online via several nootropic vendors.

    How it Works

    Relation to Other Antidepressants

    Chemical structure of TianeptineIn strict terms of chemical structure, Tianeptine is a tricyclic antidepressant (TCA) and is structurally similar to many prescription TCAs, such as amitriptyline and doxepin. However, Tianeptine’s mechanism of action varies drastically from classical TCAs

    Most TCAs work as serotonin-norepinephrine reuptake inhibitors (SNRIs), increasing the levels of extracellular serotonin and norepinephrine. Tianeptine, however, has been found to enhance the reuptake of serotonin, which would consequently decrease serotonin levels in subjects. In addition, Tianeptine does not possess affinity for most neurotransmitter receptors, meaning it has little to no direct impact on norepinephrine and dopamine.[1]

    These findings have led some researchers to question what is known as the monoamine hypothesis of depression, which has prevailed in medical circles for around half a century. Monoamines are a group of neurotransmitters that includes dopamine, serotonin, and norepinephrine, the three of which are linked to motivation and mood. The monoamine hypothesis of depression posits that depression is caused by a shortage of monoamine neurotransmitters in the brain.

    Most classical antidepressants, (SSRIs, SNRIs, MAOIs, etc.) seek to restore balance to monoamine levels in the brain, thus alleviating symptoms of depression.[2] The fact that Tianeptine has little effect on monoamine levels, yet still alleviates symptoms of depression, has fortified the evidence that depression is much more complex than just an imbalance of monoamine neurotransmitters.

    Mechanism of Action

    So, then, how exactly does Tianeptine mitigate the symptoms of depression? Some researchers have hypothesized that depression is directly linked to lowered neuroplasticity (the ability of the brain to adapt to new stimuli) and that an increase in neuroplasticity in the human brain will contribute to reducing symptoms of depression. Studies conducted on Tianeptine’s action certainly support this idea.

    Essentially, Tianeptine modulates the action of glutamate, the main excitatory neurotransmitter in the brain. Stressful situations tend to augment glutamate’s pathways, either causing too much or too little activity. These fluctuations in glutamatergic action lead to degradation of nerve and brain tissue. [3]

    Glutamate

    By keeping glutamatergic pathways under control, Tianeptine inhibits the body’s harmful responses to stress. This leads to increased neuroplasticity, which allows the brain to handle anxiety and depression more readily. The benefits of neuroplasticity also extend into the domain of nootropics by having a positive impact on cognition and working memory.[4] Tianeptine’s positive effects on neuroplasticity suggest that it may treat one of the root cause of severe depression rather than simply treat its symptoms. This would imply that Tianeptine has lasting effects on depression and cognition, even when it is no longer administered.

    It was recently discovered in 2014 that Tianeptine works as a µ-opioid receptor agonist, which is believed to contribute to its anxiolytic properties. This could also be linked to the possible euphoric effects of Tianeptine that some users experience at higher (recreational) doses. Although Tianeptine acts on µ-opioid receptors, it does not have the high addictive potential that is associated with many opioid drugs.[5] That said, it is still a good idea to avoid taking Tianeptine for long periods of time without interruptions and/or at higher doses than those used in clinical practice.

    Positive Effects of Tianeptine

    • Boosting mood and alleviating depression. [6]
    • Reducing anxiety and vulnerability to panic attacks. [7]
    • Improving overall brain health as a neuroprotectant.[8]
    • Enhancing cognition, memory, attention, and reaction time. [9]

    Dosage Information

    tianeptine stablon nootropicPrescription Tianeptine (Stablon) comes packaged in 12.5 mg tablets, which is considered a single dose. Tianeptine sold by nootropics vendors come in powder form, so doses should be measured out with a milligram scale to ensure accuracy.

    Because Tianeptine has a relatively short duration of action (about 3-4 hours), three of these doses are taken throughout the day, waiting 3-4 hours between each dose. Tianeptine is administered orally, and there is no evidence that would warrant any other route of administration.

    Recently some nootropic vendors have started selling tianeptine sulfate, which, according to them, is longer lasting compared to the regular sodium salt. There doesn’t seem to be any scientific evidence for this statement, however.

    Side Effects, Tolerance, and Toxicity

    Tianeptine has a similar side effect profile to more traditional antidepressants but does not cause the sexual dysfunction associated with SSRIs. It also does not exhibit anticholinergic effects that are common with TCAs. The most common side effects include nausea, constipation, abdominal pain, headache, and dizziness. However, all of these possible effects only occur in less than 1% of users.

    Because Tianeptine is not monoaminergic in its mechanism of action, it is not considered a risk to take it alongside monoaminergic antidepressants. However, it should not be taken with MAOIs to avoid the risk of hypertension and seizures.

    Tianeptine is considered safe to take indefinitely, although tolerance can develop over an extended period of use. If you find it necessary to take higher and higher doses to achieve any positive effects, it would be wise to taper off of the substance and take a tolerance break if you still want to use Tianeptine.

    Although discontinuation symptoms of Tianeptine are not nearly as severe as with SSRIs and TCAs, it is still not recommended to suddenly stop usage. In addition, Tianeptine can be cycled with other antidepressant nootropics (like selegiline, NSI-189, or moclobemide) to stop tolerance from developing.

    The LD50 of Tianeptine is estimated to be 980 mg/kg, so there is a very low chance of consuming a lethal or harmful dose on accident.

    Summary

    Tianeptine stands out among other antidepressants because of its novel modes of action. Rather than temporarily modifying a monoamine imbalance, it aids the brain in healing itself by increasing neuroplasticity.

    It is unfortunate that its use has mostly been ignored by the American medical community, but its unscheduled status has opened up opportunities for nootropic usage. Because of its effects on mood, cognition, stress, and neuroplasticity, Tianeptine should definitely be considered by serious users of nootropics.

    Tianeptine
    6
    Focus
    10
    Mood
    6
    Memory
    7.5
    Stimulation
    8.5
    Relaxation
    6.5
    Safety
    Reviewer 8.9
    Summary
    I highly recommend Tianeptine to anyone who's looking for an antidepressant that does not impair cognition.

    References   [ + ]

    Categories
    Health

    Is Berberine the New Resveratrol?

    There are very few supplements that have a list of potential benefits as impressive as berberine. Despite the fact that berberine is not all that well known compared to many other supplements, it is extremely well researched. While not all of these benefits are guaranteed to occur for every single user, berberine has been found to

    1. Reduce inflammation
    2. Improve gastrointestinal health
    3. Reduce glucose production in the liver
    4. Improve markers of insulin resistance
    5. Lower cholesterol
    6. Lower oxidative stress
    7. Help in losing body fat
    8. Slow down aging
    9. Suppress chemical-induced carcinogenesis, clastogenesis, tumor promotion and tumor invasion
    10. Exert antiarrhythmic effects
    11. Exert anti-microbial activity against a wide range of microorganisms.
    12. Exert minor antidepressant effects, as well as work in a synergistic fashion with existing antidepressants

    While this list of touted benefits is certainly impressive, berberine also carries with it a number medication interactions, which must be noted with caution (more on this later).

    What is Berberine?

    goldenseal
    Goldenseal

    Berberine is an isoquinoline alkaloid and ammonium salt of a bright yellow color that is found in and extracted from a variety of plants from the genus berberis, as well as Coptis chinensisPhellodendron amurense, and Hydrastis canadensis (Goldenseal) and many others. These plants have a history of being used in both traditional Chinese Medicine and Indian Ayurveda as an anti-microbial agent. Berberine appears to be effective in fighting bacteria, fungi, and protozoa. [1] However, these traditional uses of berberine barely scratch the surface of its full capability.

    When berberine is ingested orally, it has a relatively low bioavailability of 5% or less. [2] Berberine increases the action of P-Glycoprotein, a substance which actually makes berberine more difficult for the intestines to absorb. Because of this, taking a P-Glycoprotein inhibitor (such as Milk Thistle) can possibly make smaller doses of berberine more effective.[3] Another option is to take Berberine with Coconut oil that contains a fatty acid known as Sodium Caprate which significantly increases the absorption and the efficacy of Berberine.[4][5]

    AMPK Modulation

    One of berberine’s main mechanisms of action is its ability to activate an enzyme called Adenosine Monophosphate Kinase (AMPK). AMPK is crucial for maintaining energy homeostasis in cells. It is responsible for regulating glucose and other nutrients by sensing their concentrations within cells. [6] The activation of AMPK caused by berberine has multiple different effects. First, the AMPK activation causes an increased uptake of glucose into adipocytes (fat cells). This is one of the major methods through which berberine reduces glucose levels in the blood.[7] In fact, berberine’s antidiabetic effect is so effective that it is regarded as one of the few supplements to be as strong as a pharmaceutical drug. When taken correctly, berberine can be as effective (or even more effective[8] as the popular type II diabetes drug metformin.[9]

    Molecular structure of BerberineBerberine also appears to have various positive effects on the heart and the cardiovascular system as a whole. Activated AMPK located in liver cells causes an inhibition of cholesterol and triglyceride synthesis.[10] This change is also linked to a lowering of low-density lipoproteins (“bad” cholesterol) and raising of high-density lipoproteins (“good” cholesterol). Additionally, berberine can lower the levels of LDL by stimulating the synthesis of LDL receptors, which are responsible for removing LDL from the blood.[11] The activation of AMPK induced by berberine also appears to inhibit the synthesis of lipids and lower triglyceride levels, which is useful for individuals who are attempting to lose weight.[12]

    In one study, reperfusion (oxidative stress) was induced in rats who had been pre-treated with berberine. The rats treated with berberine displayed significantly less heart damage than those who had not been treated.[13] One study conducted on 24 overweight or obese subjects concluded that berberine was able to reduce blood pressure significantly more than placebo. [14] These effects of berberine—the inhibition of LDL cholesterol and triglyceride synthesis, increase in HDL cholesterol, decrease in lipid production, protection from oxidative stress, and the decrease in blood pressure—all work together to contribute to berberine’s overall positive effect on heart health and weight loss. But that’s not all…

    Anti-aging & Anti-cancer

    There is some early research evidence that seems to suggest berberine’s efficacy as telomerase inhibitor.[15] Telomerase is a protein that is intricately linked with cell proliferation and the life cycle of cells. Telomeres (the region that telomerase acts upon) are a portion of DNA sequences located at the ends of chromosomes that keep them from deteriorating.

    Essentially, the inhibition of telomerase by berberine has potential applications in the area of life extension & longevity as well as a chemopreventive supplement or in conjunction with existing cancer treatments to increase their efficacy.[16]

    fight cancerBesides telomerase inhibition, berberine has also been found to suppress the growth of a wide variety of tumor cells[17][18], including breast cancer,[19] leukemia[20], melanoma,[21] epidermoid carcinoma, hepatoma[22], pancreatic cancer[23], oral carcinoma, tongue carcinoma[24], glioblastoma, neuroblastoma[25], prostate[26][27][28] and gastric carcinoma.

    Mental Health

    Berberine also exhibits minor to moderate antidepressant effects. One study conducted on mice discovered that berberine administration reduced the immobility time of mice in a swim test, which is indicative of antidepressant effects. The same study also concluded that berberine caused significant increases in the levels of dopamine, serotonin, and norepinephrine in the whole brain. It was also discovered that berberine works synergistically with certain antidepressant medications, such as fluoxetine, imipramine, tranylcypromine, and venlafaxine.[29]

    New studies suggest berberine may have a potential for inhibition and prevention of Alzheimer’s disease through inhibition of β-amyloids pathways and cholinesterase[30] and through antioxidant capacities. Berberine derivatives are currently being developed as potent acetylcholinesterase (AChE) inhibitors.[31]

    As a PCOS treatment

    In a 2012 human study[32], 89 Chinese women of reproductive age who met the diagnostic criteria for polycystic ovarian syndrome (PCOS) and insulin resistance, were recruited and prescribed the anti-androgen compound cyproterone acetate (2.0 mg/day) in a combined oral contraceptive pill with 35 mcg ethinyl estradiol, taken in a cyclic fashion. They also received advice from a nutritionist to limit dietary fat and carbohydrates without restricting calories.

    They were then assigned to one out of three treatment groups:

    1. Berberine hydrochloride, 500 mg 3 times/day (n=31)
    2. Metformin, 500 mg 2 times/day for the first week, then 3 times/day for the remainder of the study (n=30)
    3. Placebo tablet 2 times/day (n=28)

    Results of the study were:[33]

    • After 3 months, all the treatment groups showed a significant reduction in body weight and BMI.
    • Waist circumference and waist-to-hip ratio were reduced in all 3 groups. However, the berberine group showed a significantly greater reduction in these measures.
    • All 3 treatment groups showed a significant reduction in fasting insulin. However, in the placebo group, fasting plasma glucose and fasting glucose/insulin ratio remained unchanged.
    • Fasting plasma glucose decreased and fasting glucose/insulin ratio increased in the berberine and metformin groups. There was no significant difference between them.
    • The berberine and metformin groups showed comparable changes in total testosterone and free androgen index, which were significantly greater than placebo. However, sex hormone–binding globulin increased significantly in the berberine group when compared with both metformin and placebo.
    • All 3 groups had reductions in total cholesterol and triglycerides. The berberine group had a significantly greater decrease in triglycerides, total cholesterol, and LDL (“bad” cholesterol”), and a significantly greater increase in HDL (“good” cholesterol) when compared to metformin.
    • Adverse effects were minimal and fewer compared to metformin. Nine subjects who received metformin complained of transient abdominal discomfort including nausea, vomiting, mild diarrhea, and flatulence, while 3 who received berberine complained of a bitter taste in the mouth.

    As a result of this study, the researchers conclude that berberine may prove a viable alternative to metformin in optimizing the health outcomes of women with PCOS.
    Another study[34] on 102 anovulatory Chinese women was published in 2015 found that administration of berberine alone may improve the menstrual pattern and ovulation rate in anovulatory Chinese women with polycystic ovary syndrome, as well as decrease sex hormone binding globulin, insulin resistance, total cholesterol, triglycerides and low-density lipoprotein cholesterol in normal weight polycystic ovary syndrome women.

    Side Effects & Interactions

    Berberine is absorbed slowly by the intestine, meaning that high doses can cause diarrhea and cramping. For this reason, berberine is typically taken in various smaller doses throughout the day.

    In terms of interactions, the most noteworthy is the potential interaction with macrolide antibiotics like azithromycin (Zithromax) and clarithromycin (Biaxin). The interaction between the two has the possibility of causing cardiotoxicity. Berberine also inhibits enzymes CYP2D6 and CYP3A4 which has the potential to affect how many other drugs are metabolized by the body.[35] For this reason, it is very important to discuss berberine supplementation with a healthcare professional to ensure no dangerous interactions will take place.

    Goldenseal vs Berberine Hcl

    berberine supplement
    Berberine hydrochloride powder

    The two most common ways to supplement Berberine are to take either Berberine hydrochloride (hcl) or Goldenseal root powder. This is extremely important and I’ll explain why.

    Goldenseal, – which contains a number of other compounds besides berberine – has been shown to cause DNA damage in prokaryotic and eukaryotic organisms[36] as well as promote liver cancer in rats.[37]

    Therefore, I strongly advise against using goldenseal root and to take Berberine Hcl instead, the same way it was used in the PCOS studies. If you’re taking goldenseal supplements, stop taking them as soon as possible!

    Conclusion

    Berberine is certainly unique among supplements in the fact that it is equally as effective as some prescription medications. It also boasts a myriad of benefits that impact a variety of systems throughout the body. This article has only scratched the surface of the researched benefits of berberine. A collation of the large body of evidence concerning berberine can be found here for anyone who wants to learn more about this fascinating supplement. While there are some potential side effects and medication interactions, berberine is still well worth checking out. Berberine stands as a hidden gem among supplements – one that has the potential to greatly improve one’s quality of life.

    Berberine Hcl can be bought relatively cheap at PowderCity and other supplement and vitamins shop.

    References   [ + ]

    1. Berberine at Examine.com
    2. Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats.
    3. Effect of berberine on the pharmacokinetics of substrates of CYP3A and P-gp.
    4. Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis (2012)
    5. Enhancement of Sodium Caprate on Intestine Absorption and Antidiabetic Action of Berberine (2010)
    6. Effect of AMPK activation on muscle glucose metabolism in conscious rats.
    7. Berberine inhibits PTP1B activity and mimics insulin action.
    8. Berberine Compared to Metformin in Women with PCOS | Natural Medicine Journal
    9, 35. Berberine at Examine.com
    10. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine.
    11. Berberine inhibits dyslipidemia in C57BL/6 mice with lipopolysaccharide induced inflammation.
    12. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine
    13. Berberine attenuates ischemia-reperfusion injury via regulation of adenosine-5′-monophosphate kinase activity in both non-ischemic and ischemic areas of the rat heart.
    14. Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion.
    15. Human telomeric G-quadruplex: the current status of telomeric G-quadruplexes as therapeutic targets in human cancer.
    16. Human telomeric G-quadruplex: the current status of telomeric G-quadruplexes as therapeutic targets in human cancer.
    17. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs (2009)
    18. Berberine and Coptidis Rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations (2009)
    19. The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell cycle arrest (2009)
    20. Down-regulation of cyclin B1 and up-regulation of Wee1 by berberine promotes entry of leukemia cells into the G2/M-phase of the cell cycle (2006)
    21. Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line (2008)
    22. Coptis chinensis inhibits hepatocellular carcinoma cell growth through nonsteroidal anti-inflammatory drug-activated gene activation (2009)
    23. Berberine Inhibits Cell Growth and Mediates Caspase-Independent Cell Death in Human Pancreatic Cancer Cells (2010)
    24. Berberine induced apoptosis via promoting the expression of caspase-8, -9 and -3, apoptosis-inducing factor and endonuclease G in SCC-4 human tongue squamous carcinoma cancer cells (2009)
    25. Berberine inhibits human neuroblastoma cell growth through induction of p53-dependent apoptosis (2008)
    26. Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells (2006)
    27. Butanol fraction containing berberine or related compound from nexrutine inhibits NFκB signaling and induces apoptosis in prostate cancer cells (2009)
    28. Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells (2009)
    29. On the mechanism of antidepressant-like action of berberine chloride.
    30. Conformation-activity studies on the interaction of berberine with acetylcholinesterase: Physical chemistry approach (2009)
    31. Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors (2009)
    32, 33. Effect of berberine on insulin resistance in women with polycystic ovary syndrome: study protocol for a randomized multicenter controlled trial
    34. A Single Arm Pilot Study of Effects of Berberine on the Menstrual Pattern, Ovulation Rate, Hormonal and Metabolic Profiles in Anovulatory Chinese Women with Polycystic Ovary Syndrome
    36. Genotoxicity of the isoquinoline alkaloid berberine in prokaryotic and eukaryotic organisms
    37. Toxicology and carcinogenesis studies of goldenseal root powder (Hydrastis Canadensis) in F344/N rats and B6C3F1 mice