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


    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   [ + ]

    Dihexa Nootropics

    Dihexa: The Story and Science of a Neurogenic Wonder-Drug

    If you have spent any respectable amount of time studying the more extreme margins of nootropics lore, then you have likely stumbled upon accounts of Dihexa, the neigh-legendary Alzheimer’s drug that is purportedly “10,000,000 times stronger than BDNF for new synapse formation”.[1]

    In the past Dihexa has been notoriously difficult to find, and even now it is far from accessible to budding body hackers, but with increasingly regular group buys and even a straightforward FAQ popping up, it would seem that Dihexa has made a stable arrival on the fringe of the Nootropics community, and is here to stay.

    But despite the increase in access, Dihexa’s mechanism of action is still shrouded in a veil of mystery unperturbed by a mere Google search. Fortunately, the history and pharmacokinetics of Dihexa are as fascinating and tantalizing as the fabled experience reports and research studies purporting its potency.

    History of Dihexa

    As with many great drugs, the idea for Dihexa was conceived by the inspiration of serendipity and circumstance. In the early ‘90s, the laboratory of Joseph W. Harding was mainly focused on the cerebral control of vascular function, which is heavily influenced by the neuropeptide angiotensin. The lab’s work originally involved angiotensin blockers, specifically ACE inhibitors[2], as a novel means of cancer prevention through the lowering of prostaglandin[3] levels.

    But in their tests was an anomaly: a specific sequence of angiotensin, specifically angiotensin IV (Val-Tyr-Ile-His-Pro-Phe), did not exert hypertensive effects unlike its precursor, angiotensin II. Harding’s interest in the compound was further piqued when a colleague’s paper on angiostatin, which is essentially the opposing hormone of angiotensin, had the angiotensin IV peptide sequence incorporated into its structure. Upon testing it for binding sites, Ang-IV was found significantly in the hippocampus, suggesting it had a potential connection to memory formation. With the acquisition of funding from the pharmaceutical giant Eli Lily & Co. (the same company responsible for Cialis, Prozac, and Cymbalta), Harding was able to synthesize an unlimited number of Angiotensin IV analogues for his work. Big Pharma had just given the hunt for Dihexa the huge boost it needed.

    3D structure of Dihexa
    The 3D structure of Dihexa, with labelled amino acid groups and modifications to encourage lipophilicity and stability.

    Work with the Ang-IV analogues was nothing short of miraculous: in every model of cognitive decline, that the analogues of Ang-IV that Harding had developed were able to completely reverse impairment when intraperitoneally injected. (This even included such the reversal of damage from kainic acid brain injections that destroyed up to 60% of cerebral neurons![4]) Yet despite these remarkable findings, none of the tested analogues could pass the blood-brain barrier, and their half-lives in the brain lasted a handful of minutes, at most: none of these candidates could pass muster as a pharmaceutical drug. Unfortunately, before a more functional analogue could be found, Eli Lily was forced to cut off funding: the company had been plunged into a financial crisis when it failed to warn patients about the possible birth defects that can be caused by Prozac, launching a legion of lawsuits against the pharmaceutical giant. The strain and frustration of the period were so great that the company’s vice president actually resigned, and a happy byproduct of the resignation was the return of Harding’s intellectual property. The significant reduction of funds, however, had stopped progress with the Ang-IV analogues in its tracks.

    In the early 2000s, the work began anew. Harding and his colleagues began to zero in on the precise peptides necessary for the procognitive properties of a particularly promising analogue, Nle-Angiotensin-IV and arrived at the tripeptide sequence Nle-Tyr-Ile. This sequence was then modified to increase its stability and lipophilicity. This progress attracted the attention of ADDF and WSU, which have been funding the project since. Eventually, one particular modified analogue, MM-201, later known as Dihexa, distinguished itself from the rest of the pack, even going as far as to boost the performance of impaired mice beyond that of non-impaired controls.

    Dihexa compared with Ang-IV
    Rodent hippocampal neurons were treated for 5 days in vitro with A) water B) Dihexa C) Nle1-Ang-IV. The images show the representative dendritic arbors from each sample, with glowing dots marking synapses. D) and E) show the number of dendritic spines per 50µm of dendrite following 5 days of stimulation and 30 minutes of stimulation with solutions, respectively. [5]
    How does something this incredible happen on a chemical level? What miracles is Dihexa performing in our minds? The details are as complicated and interesting as anyone could hope for, and portray Dihexa as a very powerful drug that may also be very dangerous.

    Dimerization: a novel mechanism of action

    The major term to understand in comprehending Dihexa’s MOA is dimerization, coming from di-, or “two”, and -mer, or “part” (as in merman). Recent science has revealed that many growth factors actually come in two parts that remain apart in the cell, until conditions demand that they activate, at which point they will dimerize into a two-part complex that can then cause a signal cascade resulting in growth, survival, and regeneration of the factor’s target cells. Dihexa works with hepatocyte growth factor (HGF), which has been found in elevated levels in the cortex during the early stages of neurodegenerative disease, suggesting it is being released by the brain in an attempt to facilitate a recovery from damage.

    The dimerization of hepatocyte growth factor involves the membrane-bound enzyme c-MET, a tyrosine kinase that is involved in the expression of certain genes by managing the proteins that bind onto DNA strands, preventing or enabling other enzymes to “read” the genes and produce the corresponding proteins from that code (this is the basis for changes in “gene expression”).

    This is where the monumental potential of this drug becomes apparent: the current understanding that the dimerized form of growth factors is the activated form, Dihexa both increases HGF activity and lowers dimerization. This suggests that the allosteric modulation of HGF is actually producing an active monomer complex, theoretically doubling the capacity of the available factors to promote signaling cascades and exert changes on cell development. Here is the change in effect worked out as an equation:

    Normal HGF/c-MET function: (HGF + HGF) + (c-MET) = Activation

    HGF/c-MET function with Dihexa: (HGF + Dihexa) + (c-MET) = Activation

    For analogy, imagine that the normal dimerized growth factor activity is like typing: you have to use both hands to do it properly. By allosterically binding to HGF, Dihexa is basically coming along and making it so you only need one hand to do a two-handed job, freeing the other hand to do another two-handed job.

    c-MET pathway
    An overview of the c-MET pathway. Note the dimerized c-MET complex protruding from the cell membrane.[6]
    Before Dihexa, there were no drugs looking at managing the dimerization of growth factors to restore cognition. In fact, most contemporary dimerization work focuses on its prevention. This is where some very real concerns arise concerning the use of Dihexa in healthy subjects: the contemporary work to which I am referring is anti-cancer research. As much help as these performance-enhancing growth factors are for enhancing neuroplasticity and long-term potentiation, they give just as much of a leg up to any latent tumors developing in the body. The HGF/c-MET complex is actually an explicit target for antagonism in anti-cancer research, as this illustrative video reviewing the function of the factor shows.

    Due to this implied cancer risk, one could liken the use of Dihexa to the use of nuclear power: rare but incredible power married to rare but incredible risks. But what power, indeed, we have yet to test the limits of. As suggested by its pro-tumor capacities, the HGF/c-MET pathway extends far beyond neurogenesis alone: c-MET receptors are expressed on the endothelial cells of many major organs, including the liver, kidneys, skeletal muscle, bone marrow, pancreas, and prostate. Dihexa could perhaps be used to accelerate wound healing, promote improvement of circulation, and perhaps even enhance anabolic development and prevent muscular atrophy from wasting disease. It could also facilitate recovery from diabetic neuropathy and circular dysfunction, liver cirrhosis/scarification, other types of organ damage, anemia, and perhaps even metabolic and mitochondrial disorders.

    So why is such a remarkable drug so understudied and underdeveloped? The answer can be found in several endpoints, but the biggest one is the dollar: without the support of deep pockets like Eli Lily, there is no realistic scenario in which Dihexa becomes FDA approved, a process that can easily cost hundreds of millions, if not billions, of dollars. NIH, one of the major bodies giving research grants for Alzheimer’s treatments, only cares about working with amyloid beta to manage the disease.

    The second reason is the sheer novelty of the drug means that it is not even on the radar for most organizations. In scientific research, being remarkable and unique is as much a blessing as a curse, because researchers prefer to build off of established knowledge bases, specifically the ones for which they have established a knowledge base. With the exception of some anti-cancer treatments, Dihexa is one of the only Alzheimer’s research chemicals that modulates HGF, an MOA most doctors know nothing about.

    The pharmacology of Dihexa in animals is well-documented: in vitro, the synaptogenesis of Dihexa begins at T+30:00, maximizes at +48:00:00[7]. The overall half-life of the drug is currently charted at approximately a week: longer than just about any other neurogenic compound. While the major observed effect is synaptogenesis, in models of impairment the drug also revived production of tyrosine hydroxylase (the enzyme essential for the production of catecholamines such as dopamine and noradrenaline) in the substantia nigra (one of the largest concentrations of dopaminergic neurons in the brain).

    Dihexa experiences

    Discussion of history, MOA, pharmacokinetics, and obscurity aside, one question still remains: “What does it do when a healthy human takes it?” As with many neurogenic substances, the answer to such a question is predicted heavily on the existing neurochemical environment (including other drugs in the system), route of administration, and genetic predisposition. In the absence of neurological insult (science speak for “brain damage), which gives a firm basis for improvement, these conditions have a heavy bearing on whether such a substance will influence development at all. Formal testing of Dihexa in human trials has yet to even begin, due to the lack of funding for such research, and anecdotal reports are varied. Adventurous guinea pigs on different forums have listed dosages everywhere from 8 to 45 mg per day and report a variety of benefits, from increased mental stamina to heightened articulation. Users have reported increases in creative thinking, social intuition, and problem-solving skills. There has also been a fair deal of non-responders who haven’t felt anything at all.

    Dihexa experienceThe author has personally experimented with a DMSO+Dihexa solution with a 16.67mg/mL concentration, applying .5mL to clean, exfoliated inner forearms every other evening for a week (3 doses, total). The experience was transformative in many of the ways purported by anecdote, including an increase in creativity, articulation, and problem-solving. What really distinguished the drug from other neurogenic substances in the author’s personal repertoire was how well it accelerated deliberation of social conflict. Remarkably large and fast leaps in logic allowed for prompt and thorough insight into the dynamics of ethical quandaries, suggesting a boost in critical thinking via the anterior cingulate cortex, the malfunction of which has been associated with such mental disabilities as ADHD[8] and ASD.[9]

    Of course, this is only an informal study, complete with exposure to a multitude of confounding factors. Despite the promise already posed by Dihexa, poor funding and a lack of interest from much of the scientific community means that the chemical has a long way to go before human trials, let alone becoming an FDA-approved pharmaceutical, and if the view of the HGF/c-MET system as a vehicle for tumor growth persists, it may always be reserved for only the most severe cases of cognitive decline and physical distress. Still, for those determined few transhumanists willing to go to any lengths to transcend their normal limitations, Dihexa holds great promise and, despite its difficult procurement, doesn’t seem to be disappearing anytime soon. It is the imposing poster child of a new frontier in medicine, where the hopes of expectations met are to meet our expectations of ourselves.

    References   [ + ]

    Noopept Nootropics

    Noopept Review: Effects, Dosage and Side Effects

    Noopept is a cognitive-enhancing peptide synthesized in Russia in 1996, as a successor to prototypical nootropic drug Piracetam. It was based off the endogenous neuropeptide cycloprolylglycine.[1] Peptides are molecules consisting of 2 or more amino acids linked together by peptide bonds. Depending on the number of amino acids, peptides are called dipeptides, tripeptides, tetrapeptides, etc.


    As said before, Noopept is a dipeptide. Peptides are not well absorbed in the GI tract and need to be injected via intramuscular or intravenous injection. Noopept, however, is a peptide that is only two amino acids long (dipeptide), and this allows it to be small enough to be absorbed orally, without being ripped apart by digestive enzymes and acids.[2]

    It is commonly thought to be a racetam, but it is not since it does not have a pyrrolidinone nucleus.
    It is said to be 1000 times stronger than Piracetam in effective dose level and nootropic activity[3], however, this statement doesn’t seem to have a scientific foundation.

    The advantage of Noopept over Piracetam is its ability to stimulate the expression of the neurotropic factors NGF and BDNF.[4]

    • NGF (Nerve Growth Factor) prevents neuronal degeneration and promotes myelin repair. Dysregulation of NGF signaling has also been linked to Alzheimer’s disease[5] and other psychiatric disorders, such as dementia, depression, schizophrenia, autism.
    • BDNF (Brain-derived neurotrophic factor), like NGF, plays a significant role in neurogenesis. It controls synaptic function and plasticity and modulates neuronal survival[6].

    The major metabolite of Noopept, cycloprolylglycine, has anxiolytic effect in animal models[7]. Scientists hypothesize this effect is a consequence of increased inhibitory transmission in the hippocampus.[8]

    Another interesting effect of Noopept is its immune boosting ability. It reduces immunosuppression induced by cyclophosphamide, stimulates immune response to various antigens, and increases phagocytic activity of macrophages.[9]

    Benefits of Noopept

    1. Improves memory recall and it is neuroprotective.
    2. Reduces brain fog and promotes mental clarity.
    3. May enhance focus and attention span.
    4. May have weak stimulant properties.
    5. Increases levels of neurotrophic factors NGF and BDNF.

    How to Take

    Noopept is sold in Russia in 10 mg tablets to be taken 2-3 times a day, but the most common dose is 20 mg twice a day.

    Even though it is orally bioavailable, anecdotal reports indicate that oral and sublingual routes of absorption have different effects. The sublingual route has a stronger nootropic effect while the oral route is slightly more anxiolytic. No human studies comparing the absorption of Noopept via different routes have been conducted, however.

    Noopept, as it is sold in Russia

    Another way that nootropic users like to take their Noopept is through nasal administration, by using either a solution or insufflating the powder by itself. For more information read our article on the intranasal administration of Noopept.

    The effect of Noopept becomes stronger with chronic treatment[10] and the official drug package insert recommends taking Noopept in a “3 months on, 1 month off” cycle.

    Side Effects

    Noopept doesn’t have serious side effects or contraindications.
    The most common reported side effects are irritability and problems with short-term memory. These side effects usually go away after a week of dosing and can be a consequence of excessively high dose.
    Most nootropics have a bell-shaped response curve, so taking a higher dose than recommended will not necessarily make the positive effects stronger and could potentially increase the negative effects.

    Reviewer 7.7

    References   [ + ]

    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]


    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.


    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.

    Reviewer 8.9
    I highly recommend Tianeptine to anyone who's looking for an antidepressant that does not impair cognition.

    References   [ + ]