Categories
Nootropics Phenylpiracetam Racetams

Phenylpiracetam — Stimulant Nootropic: Effects, Dosage & Experiences

Those who spend any amount of time looking into nootropics will be very familiar with the racetam class of nootropics, a group of drugs that are structural derivatives of piracetam. These drugs display variance in the details of their effects, but they all exhibit neuroprotectant and cognitive-enhancing properties.
One of these piracetam derivatives, phenylpiracetam, is appealing to many nootropic users due to its many purported benefits.

Background and Benefits

phenylpiracetam nootropicPhenylpiracetam is frequently cited to display the following effects:[1][2]

  • Memory enhancement
  • Anti-amnesia
  • Antidepressant
  • Anticonvulsant
  • Antipsychotic
  • Anxiolytic

If phenylpiracetam does indeed have these listed properties, its appeal extends beyond just the sphere of nootropics. Any drug with that kind of resume is certainly impressive. Here we will examine this unique substance and its purported effects.

Phenylpiracetam, also known by its Russian pharmaceutical names Phenotropil and Carphedon, was developed in Russia in the 1980s as a piracetam derivative, with the hopes that it would display and expand upon the nootropic properties that make piracetam such a popular drug. Specifically, phenylpiracetam is a phenylated analog of piracetam, meaning that it is essentially a piracetam molecule with a phenyl group attached. Interestingly, some have theorized that phenylpiracetam’s purported stimulant effects may be due to the molecule’s similarity to phenethylamine (and, by extension, amphetamine).

These potential stimulant properties, along with phenylpiracetam’s ability to improve physical stamina, has led to the drug being banned from use in Olympic competitions.[3]

phenylpiracetam-nootropic-stimulant

Dosage, Mechanism, and Effects

Phenylpiracetam is typically sold by online vendors in its pure powder form or as pharmaceutical tablets. Most of these sources sell a racemic mixture of the molecule, but some of the studies done on the effects of phenylpiracetam were conducted using only the R-isomer.

Phenylpiracetam Phenotropil Nootropic
Original Russian Phenylpiracetam (Phenotropil)

A single dose of phenylpiracetam typically ranges from 100200 mg. Most prescription guidelines state that phenylpiracetam can be taken 2-3 times per day, as the drug will exert effects on the body for about 4-6 hours before receding. It should be noted that most anecdotal reports from users indicate that phenylpiracetam builds up a tolerance rather quickly, so it might not be wise to use it for days in a row. That being said, the drug appears to be relatively safe to use regardless of tolerance buildup.

Phenylpiracetam’s mechanism of action still remains largely uncertain. While various studies have been conducted on its effects, few have dealt with the specifics of its pharmacology. However, one study performed on rats found that phenylpiracetam decreased the density of nACh and NMDA receptors in the hippocampus when they had previously been given scopolamine, an anticholinergic drug.

Phenylpiracetam was also found to increase the density of the D1, D2, and D3 dopamine receptors[4]. Dopamine receptors are important for motivation, arousal, pleasure, and memory.

It also appears that phenylpiracetam’s enantiomers have unique effects and properties. Most notably, studies indicate that the R-enantiomer is mostly responsible for its stimulating and cognition-enhancing effects while the S-enantiomer may be more responsible for stopping cognitive decline.[5]

One of the drug’s biggest potential uses is for treating cognitive decline brought on by diseases like Alzheimer’s. Various studies have been conducted in Russia studying the effect of phenylpiracetam on cognitive decline caused by organic causes. These studies found that phenylpiracetam improved the cognition of those with Alzheimer’s disease, and showed minor effectiveness in improving the cognition of patients afflicted with epilepsy. The drug did not, however, appear to improve cognition for those whose cognitive decline was brought on by traumatic brain injury.[6] In a study conducted on 400 patients with ischemic stroke, phenylpiracetam was able to improve cognition when taken at a dose of 400 mg per day for one year.[7]

There is currently no research conducted on phenylpiracetam’s effect on cognition in young, healthy subjects, although anecdotal reports throughout the internet suggest that it does improve cognition among those with no cognitive disorders. One study conducted on rats found that the R-enantiomer of phenylpiracetam was able to enhance cognition, but this result has not been replicated in any study using the racemic mixture.[8]

Zhiliuk, Mamchur & Pavlov[9] found that Phenylpiracetam improves the processes of learning and storing conditional skills when studying cognitive processes and functional state of mitochondria in the neocortex of alloxan-diabetic rats.[10]

Gustov, Smirnov, Korshunova IuA and Andrianova argue that Phenylpiracetam is beneficial to people who develop cognitive deficits and/or depression after encephalopathy and brain injuries.[11] It increased quality of life in patients with encephalopathy after acute lesions (30 people), brain traumas (33 people) and glioma surgery (36 people). The average Mini Mental State Examination (MMSE) scores (a 30-point questionnaire) from baseline improved in all groups. Anxiety improved and depression declined substantially, resulting in less discomfort and better ability to execute everyday activities.[12]

phenylpiracetam memorySome preliminary studies have found phenylpiracetam to have antidepressant properties. However, this area of effect has not seen as much research as the area of cognitive enhancement. A study performed on rats found that when phenylpiracetam was administered to rats, it significantly reduced depression symptoms caused by a forced-swim test.[13] A study conducted on human patients with cognitive decline concluded that phenylpiracetam is able to alleviate symptoms of depression.[14]

Perhaps one of the most unique and attractive benefits of phenylpiracetam is its ability to act as a psychostimulant. However, this effect is not very well researched, although one experiment conducted on rats found that phenylpiracetam increases locomotor activity for upwards of 2 hours.[15]

Anecdotal Reports

As with any nootropic drug that has not seen as much clinical research as one might hope, it is useful to look at anecdotal reports from users to give a fuller picture of the drug’s effects. Obviously, individual user reports are especially prone to the placebo effect and should be weighed and judged by the reader with caution.

Reddit user The_Antagonist said –

At the peak of it’s effects (about an hour in) I feel intense focus, not especially jittery, unless stacked with something else, just pure attention, and a complete abolishment of any lethargy I would have been feeling previously. It’s not really a euphoric compound, but I’ve noticed it seems to make me significantly happier when I’m accomplishing something on it. It might be the racetam effects rearing their head, but solving mathematical problems, or gaining a more complete understanding of a concept just feels plain good. This attribute [in particular], for me at least, makes it a hell of a study drug.[16]

Reddit user Notlambda

I’m not a social butterfly. I’m retarded when it comes to explaining a concept or defending an argument.
On phenylpiracetam (or daily doses of piracetam), I’m a social genius. What it feels like is that I’m not the one saying the words that I’m saying. It’s like I feed a “command” into a register in my brain that is then picked up by whatever part of my cortex deals with speech, and then I find myself just saying the perfect words to explain everything concisely.
It’s like I’m watching somebody else be awesome, but that somebody else is me. It’s really nice because I can free the rest of my mind to think about concepts while the “other” me is doing all the talking.
It’s also very subtle. I’m explaining this like it’s a dissociative experience or something like that. It’s not.[17]

From user le_unknown

I’ve had great results with phenylpiracetam. Without a doubt, it has been the nootropic that works best for me. Gives me alertness (but no jitteriness, I just feel awake and normal – kills all drowsiness), focus, and a tiny mood elevation. I’m surprised I don’t see more people talking about it…[18]

Conclusion

Phenylpiracetam’s seemingly wide array of effects and benefits makes it well worth looking into. Most notably, phenylpiracetam seems to provide many of the benefits of piracetam, while seemingly being more potent or effective in certain areas. Phenylpiracetam seems to noticeably provide cognitive capacity improvement, mood elevation, and stimulation. Experiences will vary widely among individual users, so we would highly recommend you try phenylpiracetam for yourself to see how it works for you.

You can buy Phenylpiracetam in powder form as well as in capsules at NootropicsDepot.

Phenylpiracetam
8
Focus
8
Mood
7
Memory
9
Stimulation
6
Relaxation
8.5
Safety
Reviewer 9

References   [ + ]

Categories
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
    Reviews Stacks

    Axon Labs’ NEXUS Nootropic Stack, My Experience (Review)

    Formulating nootropic stacks can sometimes be a difficult or time-consuming process. While the research that goes into drug combinations and synergy can be rewarding and even enjoyable, sometimes it’s difficult to find the right information on specific nootropics. Even when the right ratios are figured out, making multiple capsules of a certain stack can be even more time-consuming than the research.

    Although pre-made nootropic stacks can be more expensive than buying bulk powder, they are sometimes well worth the price. Nootropic blends can be specially formulated by individuals with a deep understanding of neuroscience, giving the best cognitive benefits possible. Axon Labs’ NEXUS Nootropic Stack is an encapsulated blend of aniracetam, CDP-choline, phosphatidylserine, and Pycnogenol. The serving size is two capsules, and each serving contains 1.250 mg of this nootropic blend. Although the amounts of each component are not specifically listed, we can make a plausible assumption based on standard dosages for these compounds.

    nexus-facts_large.jpg

    The key component to this blend is aniracetam, a well-respected nootropic that is gaining popularity for its unique ability to improve cognition and reduce anxiety at the same time. A more detailed look at aniracetam’s mechanism can be found here on our site. Essentially, aniracetam modulates the action of glutamate (an excitatory neurotransmitter) by reducing glutamate receptor desensitization. [1] This, in theory, would improve memory and strengthen the connections between neurons. Aniracetam is also unique among racetams in the fact that it has the ability to reduce feelings of anxiety and depression. It most likely accomplishes this by means of serotonergic, dopaminergic, and cholinergic mediation. [2]

    CDP-choline (also known as citicoline) is a source of choline that also serves as a prodrug to uridine, another nootropic supplement. Choline is essential for the production of the neurotransmitter acetylcholine in the body, which is the neurotransmitter thought to be closely involved with the regulation of cognitive processes. Aniracetam is partially cholinergic in its mechanism of action, as it potentiates the action of nicotinic acetylcholine receptors.[3] When aniracetam is paired with a choline source, the increase in acetylcholine will theoretically potentiate the cholinergic effects of aniracetam.

    Phosphatidylserine is a naturally-occurring fatty acid derivative that helps comprise cell membranes. In 2003, the Food and Drug Administration (FDA) authorized sellers of phosphatidylserine to label their products with the claim that “consumption of phosphatidylserine may reduce the risk of dementia and cognitive dysfunction in the elderly.” [4] Various studies have indeed confirmed that supplementation of phosphatidylserine can improve cognition[5], memory[6], and processing speed[7], among other factors. Phosphatidylserine also has the potential to increase levels of acetylcholine in the brain, an effect that would work synergistically with aniracetam’s cholinergic mechanisms. [8]

    Pycnogenol is a patented extract of pine bark, containing a number of antioxidant flavonoids known as procyanidins. Pycnogenol’s most notable effects include its ability to increase blood flow[9], while also improving attention and cognition.[10] Pycnogenol’s main mechanism seems to be its ability to increase concentrations of nitric oxide (NO). It does this by preventing NO from oxidizing while also inducing the Nitric Oxide Synthase (NOS) enzyme, which catalyzes the production of NO.[11]

    My Experience

    Note: When dealing with anecdotal experiences, it is difficult to completely rule out the placebo effect as the cause of certain perceived changes in cognition and mood. This is simply my own experience, and it is likely that every individual’s experience with these nootropics will vary. These are simply the effects I perceived.
    Previous to this experience, I had taken aniracetam on a few occasions with modest success, taking it with a choline source.

    My dosing regimen of Nexus consisted of taking 2 capsules in the morning after I woke up. I took another dose in the afternoon or evening if I was working on tasks that benefit from boosts in cognition (i.e. writing, analysis). During this time period, I was also taking fish oil, bacopa monnieri, and centrophenoxine, which I have been taking regularly for at least a month. I was thus familiar with their effects and would be able to perceive any changes brought on by adding this stack. I took Nexus regularly for about one month.
    One of the most marked improvements I noticed was a modest reduction in anxiety that set in about an hour after taking Nexus. I am typically a fairly anxious person, both in general and in social situations. I felt more able to focus on important tasks, rather than focusing on anxious thoughts I was having. I also felt a noticeable clear-headedness and ability to think straight.

    There was also a subtle improvement in being able to pick up on new concepts more easily. During college courses, I felt very engaged in the materials being presented, even in the classes, I do not normally find very interesting. I also found it easier to contribute to the discussion.
    Taking another dose before working on writing essays and papers seemed to help a great deal with my cognition. Aniracetam has anecdotally been touted to improve holistic and collective thinking, and that seemed to be the case in my experience. It was much easier to weave different concepts and themes together in a way that presented a coherent bigger picture.

    Again, when it comes to nootropics, it can be difficult to differentiate legitimate effects from placebo. However, many of the effects I experienced were extreme enough that I am fairly convinced that they were effects of this stack.

    Conclusion

    Everyone is likely to react differently to a nootropic like aniracetam. There are some people I know who experience little to no effect from taking it. For others, the effects seem to be almost life-changing. However, I do feel like the additional ingredients in Nexus’s blend contribute a good deal to its effects. It seemed to have greater effects than just aniracetam alone.

    This being said I can definitely recommend trying Nexus out. It is a good stack for those who are fairly new to nootropics and aren’t sure how to formulate their own stacks, but for the expert nootropic user, it is definitely overpriced. That said, I would definitely like to use it again in the future.

    Axon Labs' NEXUS
    7.5
    Focus
    7
    Mood
    6
    Memory
    6
    Stimulation
    7
    Relaxation
    9
    Safety
    Reviewer 7.1
    Summary
    I would recommend this stack to anyone who is into experimenting with nootropics. It gave me a clear cognitive boost while simultaneously reducing anxiety.

    References   [ + ]

    Categories
    Nootropics Tutorials

    Nootropics: A Beginner’s Guide To Cognitive Enhancers

    The realm of nootropic substances (aka cognitive enhancers or smart drugs), at the time around its conception, was reserved for the very select few who had access to these novel cognition-enhancing drugs. In recent years, nootropics have gained more widespread recognition, and are more accessible to average individuals than ever before, thanks to the rising number of online vendors and communities who make these substances accessible for all.

    The term “nootropic” has been consistently more and more searched on google ever since 2011 (the year when the film Limitless was released) , and people’s interest in the subject will certainly continue to rise. Although nootropics still maintain a type of “fringe” status in the world of drugs, their infiltration into the mainstream is undeniable.

    Nootropic Trend - Google searches of keyword "nootropics"

    What is a Nootropic?

    nootropic brainCorneliu E. Giurgea, the Romanian chemist who first synthesized piracetam, developed the concept of nootropic substance in 1972.[1] It is a combination of the Greek words “νους” (nous) meaning “mind”, and “τρoπoς” (tropos) meaning “bend” or “change”. This is what nootropics do. Essentially, they positively alter the way in which your mind works.

    Nootropic drugs are a specific subtype of psychoactive substances. According to Giurgea, in order for a drug or supplement to be considered a nootropic, it must adhere to the following criteria:[2]

    1. Enhances learning and memory
    2. Enhances resistance of learned behaviors to conditions that will disrupt them
    3. Protects the brain against physical of chemical injuries (such as concussions or neurotoxic drugs)
    4. Increases the efficacy of cortical/subcortical control mechanisms of the brain (such as improving reaction time)
    5. Typically lacks negative side-effects (i.e. sedation), and possesses low toxicity

    Though these criteria lay out the foundation for what a nootropic is, most modern definitions are much more general. As a more common definition, nootropics are chemical substances or herbal supplements that enhance cognition and mental function.

    Caffeine
    Caffeine

    If we think in terms of this general definition, there is about a 90% chance you use a pseudo-nootropic substance regularly. Caffeine, the most popular drug in the world, is commonly classified as a nootropic, due to the fact that it is stimulatory and enhances attentiveness linked to cognition, learning, and memory. [3] [4]

    Certain substances that don’t explicitly enhance cognition are still sometimes grouped in with nootropics. This would include substances that improve mood, reduce anxiety, or promote an overall feeling of wellbeing. Some examples of these substances are phenibut, sulbutiamine, and ashwagandha. Even if these supplements don’t have mechanisms that directly improve cognition, their mood-improving capabilities will tend to lead to an enhanced ability to focus and think clearly.

    Who Uses Them?

    Giurgea coined the term “nootropic” after he synthesized piracetam, which is, under Giurgea’s definition, the first substance to display purely nootropic properties. Piracetam has cognitive enhancing and neuroprotective capabilities while also possessing relatively few side effects. [5] Because of this, piracetam is commonly used to improve cognition in individuals who are experiencing the cognitive decline that comes with old age, dementia, or Alzheimer’s.

    With the development of piracetam, other nootropic substances were investigated and researched for their applications in those who experience cognitive decline. Many drugs derived from piracetam (referred to as racetams) have been developed in hopes that they would yield even more benefits than piracetam. For instance, phenylpiracetam displays stimulant properties in addition to cognitive enhancement. [6] Likewise, aniracetam works as an anxiolytic. [7]

    Modafinil is wakefulness-enhancing nootropic used by college students as a safer alternative to Ritalin and Adderall

    Up until the past decade, these kinds of cognitive-enhancing drugs were only used extensively in clinical applications, such as treating cognitive illnesses. However, the past few years have seen tremendous growth in the use of nootropics among younger healthy individuals in hopes that they could improve their performance in work or academic studies. For example – modafinil (Provigil), a wakefulness-promoting nootropic substance, has seen increased usage among college students as an alternative to Adderall, due to the fact that it aids the brain in focusing on tasks for extended periods of time without fatigue. [8]

    Many nootropic substances, such as the racetams and tianeptine (an antidepressant nootropic), are prescription drugs in Europe but are unscheduled in the United States. This has led to many of them being sold online by nootropic vendors, making them readily available for those who wish to purchase them.

    Not surprisingly, Russia, the country that has developed a large number of nootropics (including Phenibut, Picamilon, Phenylpiracetam, Selank, Semax, Cerebrolysin, Emoxypine and so on), it’s the place where the keyword “nootropic(s)” is most popular in 2016[9], according to Google.

    The increasing number and growth of online communities, such as the nootropics subreddit, has attracted the attention of younger individuals who seek to improve their cognitive performance and preserve their youthful cognitive capabilities. These online communities are extremely valuable sources of information on all things related to nootropics. They are open forums where anyone can ask questions about smart drugs and cognitive enhancement and engage in valuable discussion. Many newer nootropic substances have not been extensively tested in clinical settings, but anecdotal user reports can be found within these online communities.

    Where Do I Begin?

    If you are determined to make a go at nootropic supplementation, then logically the smart thing to do is implement the smartest ways to use smart drugs. You do not have to be a brain surgeon to begin effectively supplementing with nootropics, but understanding at least the bare bones of the foundations of a few related fields like neuroscience, neurology, and drug metabolism, is vital to getting the most out of them.

    Ideally, you want a good working understanding of all the major mechanisms of action, including receptor systems involved in memory, mood and cognition (dopamine, GABAacetylcholineserotonin, etc).learning memory nootropics Attempting anything other could end up as catastrophically as fiddling with the kernel of your operating system without knowing how it works. The best way to go about it is to learn what happens to drugs inside the body, how the classic nootropics work (like Piracetam and Aniracetam), and what are some of the basic nootropic stacks.

    Even though it can be a bit daunting at first, you will also want to learn how to access & read scientific researchwhat is acetylcholine (the learning and memory neurotransmitter), how it works, how the brain produces it and what is a choline precursor. Learning the major neurotransmitters, understanding the difference between excitatory and inhibitory neurotransmitters, all these are great places to start.

    When first getting into the world of cognitive enhancement, the sheer number of substances out there can be very intimidating. Here is a short list that outlines some of the most popular and proven nootropics for beginners.

    Wakefulness and Motivation

    • Caffeine and L-Theanine – Promotes wakefulness and is stimulating in general. The addition of L-theanine helps reduce the negative side effects of caffeine, such as anxiety. Additionally, L-theanine also improves cognition.
    • Modafinil, Armodafinil, and Adrafinil – These three compounds are chemically related. Armodafinil is the active isomer of modafinil and is thus generally more potent. Adrafinil is a prodrug to modafinil. In other words, it is metabolized into modafinil by the body. All three of these are used to promote wakefulness and reduce fatigue.
    • Rhodiola Rosea – A herb that acts as an adaptogen, meaning it aids the body in reacting positively to stressful stimuli. It typically reduces feelings of fatigue and is slightly stimulatory. It is also sometimes used to lessen the effects of caffeine withdrawal.

    Note: Prescription drugs such as Adderall (amphetamine) and Ritalin (methylphenidate) are especially effective at increasing feelings of motivation. However, they carry additional side effects and risks of dependency, and should be used with caution.

    General Cognition

    piracetam nootropic adhd

    • Piracetam – The original racetam, was originally developed as a sleep-aid because of it’s GABA structure, when given to rats it improved their memory and cognition.
    • Noopept – Is chemically similar to piracetam but is active at a fraction of the dose (10 mg vs 1000 mg), and also increases the production of NGF and BDNF, two neurotrophic factors that promote the survival and differentiation of neurons. It typically provides an increase in cognitive ability along with mild stimulation.
    • Aniracetam – Provides cognitive effects that are similar to Noopept, but is also anxiolytic in nature. It is especially helpful in helping the brain associate different thoughts and piecing them together to form the “bigger picture.”
    • Phenylpiracetam – Similarly aids cognition like noopept and aniracetam, but it noticeably more stimulatory. It is also known to be more neuroprotective, and aids in preventing cognitive decline. It is a good alternative to Modafinil.

    Note: Because racetams and noopept work through modulation of acetylcholine, they should be supplemented alongside a choline source, such as alpha-GPC or CDP-choline.

    Mood Improvement

    • Tianeptine – Chemically a tricyclic antidepressant, tianeptine is novel in the fact that it improves mood while also serving as a neuroprotectant and cognitive enhancer.
    • Phenibut – an anxiolytic compound that may enhance cognition in stressful situations (like exams or a public presentation) through means of reduced anxiety.

    Memory

    • Bacopa monnieri – Bacopa has been found to improve the formation, retention, and acquisition of memory. It is an adaptogen and is often taken for its anxiolytic properties
    • Huperzine A – an acetylcholinesterase inhibitor (a compound that prevents the breakdown of the neurotransmitter acetylcholine) extracted from the plant Huperzia Serrata.

    What To Expect

    Most nootropics rarely display immediate or noticeable acute effects on cognition and well-being (the only exception being stimulant nootropics like Modafinil and Phenylpiracetam) . In fact, they are typically used for long-term neuroprotection, and may not display immediate or noticeable results from use. The psychoactive effects of nootropics are more subtle than the effects of recreational drugs but are ultimately more beneficial. By definition, the daily use of nootropic substances should be far more sustainable than that of recreational drugs.

    Nootropics are meant to be safe to use indefinitely though not all drugs sometimes referred to as “nootropics” will meet these criteria. For instance, phenibut, a GABAergic anxiolytic, is sometimes discussed as having nootropic capabilities related to anxiety reduction. However, phenibut has a fairly high risk of causing dependency or withdrawal, and should not be used on a daily basis.

    coffe and modafinil pure nootropics
    Modafinil is used by college students as a safer alternative to Ritalin and Adderall

    Many people supplement multiple nootropics at once to maximize their cognitive benefits. These combinations of substances are referred to as “stacks”. For instance, one might stack caffeine and L-theanine because L-theanine is known to reduce the jitters and anxiety that come with caffeine. [10] When taking multiple nootropics, it is extremely important to research any potential negative interactions between substances. Examine.com is an invaluable resource for researching nootropics and their possible interactions.

    Nootropics can certainly be of great benefit to those who wish to improve their cognitive function and protect their minds from degradation. However, nootropics will likely be far more beneficial when they are used in combination with exercise, a proper diet, and meditation.[11] Nootropics can only do so much, and are certainly not an excuse to neglect these other primary health factors.
    In addition to this, nootropics should not be used to treat mental disorders unless under the direction of a trained health professional. It may seem tempting to use promising and novel nootropics to treat something like depression, but there is still some amount of risk involved with doing so, especially given the fact that many of the newest nootropics still require a great deal of research before they can be used clinically.

    Even if “old” nootropics like racetams are totally safe, it is still a good idea to check out interactions if you’re taking prescription medications.

    Up Next

    References   [ + ]

    Categories
    Cognitive Health Health Recovery

    9 Supplements To Counteract The Negative Effects of Alcohol

    Despite clinical proof that alcohol has detrimental effects on the human body, even more so than certain illegal substances, it still remains one of the world’s most readily available and favorite intoxicants. Alcohol has been a mainstay in nearly every society for thousands of years, and its commonality leads some people to not even recognize it as a drug. From sporting events to celebrations with family, it’s likely you will toss back a few drinks on occasion.

    However, even moderate alcohol use can carry negative side effects. Consequently, many people seek supplements that will help mitigate some of the deleterious effects on the human body caused by consumption. Whether it’s for an occasional night on the town or more frequent use, or even for recovering from years of alcoholism, there are natural herbs, supplements, and nootropics that have been proven effective for harm reduction with alcohol use.

    • Before consuming any substance along with alcohol, be careful to check for any known interactions. Some nootropics have not been extensively studied and may possess undocumented interactions.
    • GABAergic nootropics like phenibut should be avoided because they can boost the effect of alcohol by producing similar effects of intoxication. It is generally not a good idea to mix alcohol with other depressants.
    • Many ADHD medications that contain amphetamine salts or methylphenidate can delay the onset of alcohol effects leading to increased consumption and potential heart problems.

    Dihydromyricetin (DHM)

    dihydromyricetinDihydromyricetin, a flavonoid, increases metabolism of both alcohol and its primary metabolite, acetaldehyde, by increasing key enzymatic action. In addition to ridding your body of these toxins, it has demonstrated effectiveness at blocking alcohol at the neurological level by binding to GABA receptors in place of alcohol. [1] While this compound theoretically shows promise for hangover prevention, many clinical studies need to take place before it’s classified as a safe supplement for human use.

    Milk Thistle

    Milk_thistle_flowerMilk Thistle, used as a natural medicine for over 2000 years, can accelerate the regeneration of liver cells and reduce fatty liver deposits that build up with alcohol use. It has been hypothesized that milk thistle increases the rate of protein synthesis in the liver, allowing it to more readily repair itself from alcohol-induced damage. [2] Milk thistle contains silibinin, which is thought to be the main active constituent of the plant.[3] Many users take milk thistle as a daily supplement, but it can also be consumed after a night of drinking to aid the liver in detoxification.

    N-Acetylcysteine (NAC)

    NAC is a nutritional supplement that is able to increase levels of the endogenous peptide glutathione [4], an important antioxidant. If you take NAC before a session of drinking, it can potentially reduce the oxidant side effects of alcohol. [5] It can also decrease the acetaminophen toxicity induced by alcohol. [6]
    NAC also has anti-addictive properties.

    Emoxypine

    emoxypineEmoxypine (also known as Mexidol) is an antioxidant drug that is molecularly similar to pyroxidine, a form of vitamin B6. Emoxypine was first synthesized in Russia, where it is used in the medical field for its anxiolytic, nootropic, neuroprotective, and anti-inflammatory effects, among others. [7] Emoxypine possesses general antioxidant properties, but also can specifically counteract the negative effects of alcohol. It displays therapeutic effects against health issues caused by chronic alcohol use and acute intoxication. In experiments, emoxypine administration reversed the learning deficits caused by chronic alcohol use in rats. [8] Emoxypine also lowers lipofuscin amounts in the cerebrum, much like piracetam. In terms of acute alcohol use (one night of heavy drinking), emoxypine significantly reduces the physical and mental feelings of intoxication that alcohol produces, specifically improving muscle coordination and mental clarity.[9]

    Tauroursodeoxycholic Acid (TUDCA)

    TUDCATUDCA is a bile acid that is found in trace amounts within humans. However, additional supplementation may be beneficial for those who are attempting to recover from alcoholism. TUDCA is used in some countries to treat gallstones and cirrhosis of the liver, but it is not FDA approved for this purpose in the United States.[10] TUDCA has been demonstrated to increase healing rates in unhealthy livers, specifically ones that have been damaged by alcohol. [11] TUDCA should not be consumed before drinking, as it carries the possibility of potentiating liver damage. Rather, TUDCA should be supplemented after drinking, or could be used on a regular basis by former alcoholics who wish to promote healing in their liver. [12]

    Ashwagandha

    HER-ASH01-2Ashwagandha is an herbal supplement that contains various chemicals known collectively as withanolides. These chemicals have been found to be effective at decreasing social anxiety when paired with alcohol, and ineffective threshold doses of either appear to be highly effective when combined. [13] However, the social disinhibition produced by alcohol alone may make this combination unnecessary for some users. Another use of this popular supplement is to aid in quitting alcohol consumption altogether. Indeed, alcohol cessation cold turkey can lead to an increase in anxiety. Ashwagandha has been clinically proven to reduce spikes in anxiety from abstinence. [14]

    Agmatine

    Agmatine is an amino acid and neurotransmitter derived from the amino acid, L-Arginine. It has been noted for its positive effects on neuropathic pain and drug addiction. Agmatine appears to reduce symptoms of alcohol withdrawal and dependence, such as anxiety and tremors. [15] [16] One note of caution: Agmatine is known to be a gastro-protective agent but when co-ingested with alcohol it can enhance ulcer formation. [17]

    Piracetam

    piracetam_structure_500pxWhile moderate alcohol use does not typically cause damage to the brain, cognitive functions are significantly impaired following the consumption of alcohol, and can continue to be impaired the next day or so after it is consumed. Nootropics that possess cholinergic mechanisms are potentially effective in improving cognition against alcohol-induced impairment. [18] Alcohol consumption increases neuronal lipofuscin, which contributes to age-related neurodegenerative disorders. [19] Piracetam and other racetams, in general, inhibit the accumulation of neuronal lipofuscin, counteracting neurodegeneration. [20]

    L-Theanine

    Matcha
    Matcha is a Japanese green tea with a very high content of L-Theanine

    The amino acid theanine, which is naturally found in green tea, is another important supplement that may provide liver protection from alcohol consumption. In one study, mice treated with L-theanine prior to alcohol consumption had lower ethanol concentrations in their blood after one hour compared to mice that were administered only alcohol. [21] This implies that L-Theanine could help the body recover faster from the negative effects of alcohol. (Consequently, this also implies Theanine could also decrease the duration of alcohol’s “positive” recreational effects.) Alcohol use typically impairs the antioxidant capabilities of hepatocytes (liver cells), and L-theanine has been found to restore the antioxidant capabilities of these cells. [22]

    Conclusion

    Alcohol has maintained its status as society’s drug of choice throughout history. As a result, it will continue to be used extensively and excessively by many despite its potential health risks. Those who are well armed with the knowledge of the aforementioned substances can use them to counteract and overcome the neurological and physical difficulties caused by alcohol consumption.

    At the end of the day, supplements and nootropics can only do so much to prevent the negative effects of alcohol. A cautious and responsible approach to alcohol consumption is ultimately the most important component of using alcohol safely.

    References   [ + ]

    1. Dihydromyricetin As A Novel Anti-Alcohol Intoxication Medication (2012)
    2. Biochemical effects of the flavonolignane silibinin on RNA, protein and DNA synthesis in rat livers. (1986)
    3. Silibinin protects OTA-mediated TNF-alpha release from perfused rat livers and isolated rat Kupffer cells. (2009)
    4. Alcohol and thermally oxidized pufa induced oxidative stress: role of N-acetyl cysteine (2004)
    5. Antioxidant therapy attenuates deficient bone fracture repair associated with binge alcohol exposure (2011)
    6. Clinical course of repeated supratherapeutic ingestion of acetaminophen.
    7. Comparative Analysis of the Anxiolytic Effects of 3-Hydroxypyridine and Succinic Acid Derivatives (2015)
    8, 9. Antioxidant Mexidol. The main neuropsychotropic effects and the mechanism of action. mechanism of action. (2009)
    10. The clinical profiles of primary biliary cirrhosis with a suboptimal biochemical response to ursodeoxycholic acid. (2011)
    11. Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion. (2010)
    12. Toxicity of ethanol and acetaldehyde in hepatocytes treated with ursodeoxycholic or tauroursodeoxycholic acid. (2004)
    13. Effect of Withania somnifera Dunal in ethanol-induced anxiolysis and withdrawal anxiety in rats. (2008)
    14. Evaluation of Ashwagandha in alcohol withdrawal syndrome (2012)
    15. Effects of agmatine on ethanol withdrawal syndrome in rats. (2000)
    16. Agmatine, an endogenous imidazoline receptor ligand modulates ethanol anxiolysis and withdrawal anxiety in rats. (2010)
    17. Investigation on the mechanism involved in the effects of agmatine on ethanol-induced gastric mucosal injury in rats. (2000)
    18. Can nootropic drugs be effective against the impact of ethanol teratogenicity on cognitive performance? (2001)
    19. Chronic alcohol consumption induces lipofuscin deposition in the rat hippocampus. (1986)
    20. The effects of piracetam on lipofuscin of the rat cerebellar and hippocampal neurons after long-term alcohol treatment and withdrawal: a quantitative study. (1991)
    21. Effects of theanine on alcohol metabolism and hepatic toxicity. (2005)
    22. L-Theanine prevents alcoholic liver injury through enhancing the antioxidant capability of hepatocytes. (2012)
    Categories
    L-Theanine Nootropics Stacks

    Caffeine & L-Theanine: The Beginner’s Nootropic Stack

    Caffeine: it’s everywhere. Apart from alcohol, no other substance is as widely used and accepted by society as caffeine. From traditional sources like tea and coffee to energy drinks, to supplements found in the supermarket, caffeine is affordable, convenient, and effective. It has permeated the lives of the majority of people in the world – 90% of the world’s population consume some form of caffeine on a daily basis.[1]

    Caffeine, mainly in its beverage form of coffee, is used en masse by society, so much so that it is hardly even thought of as a drug. It is so casually consumed by most people that not much thought is given to how it works, how it can be beneficial, and how it can be potentially harmful.

    It is well known that caffeine can carry with it several unpleasant side effects. Certain individuals can be more sensitive to caffeine than others, and some are more susceptible than others to these side effects. The most commonly reported side effects of caffeine include increased blood pressure [2], anxiety, jitters, and insomnia. [3] Luckily, many caffeine users have found a potential way in which these uncomfortable effects can be prevented. The answer comes in the form of one non-essential amino acid: theanine.

    L-theanine

    Theanine chemical formulaTheanine is a naturally-occurring amino acid found in various plants, mainly certain types of green tea. Only the L (“levo”, left)-enantiomer of theanine has been extensively researched for its effects in humans, and references to “theanine” typically imply only L-theanine.

    The compound itself was first isolated from tea leaves in 1950 and has since gained widespread popularity as a dietary supplement. In the United States, it has been approved for over-the-counter use. Response to L-theanine in Europe has not been as favorable. The European Food Safety Authority (EFSA) has objected to claims of L-theanine being beneficial to cognition and stress, and it is not sold under any kind of health claims.

    Perhaps the most alluring aspect of L-theanine comes with its ability to promote relaxation without being sedating. This property has led to its widespread use alongside caffeine. Potentially, the relaxing effects of L-theanine “take the edge off” of caffeine use by mitigating the jitters that come with caffeine, all while working alongside caffeine to improve cognition and alertness.[4] It has also been found to reduce blood pressure, which is especially helpful for those who experience high blood pressure from caffeine use. [5]

    After ingestion, L-theanine crosses the blood-brain barrier (BBB) with relative ease.[6] Its effects set it within an hour from ingestion, and effects last for about 5 to 6 hours after administration. [7]

    Theanine does not have a significant impact on increasing the levels of monoamines (i.e. serotonin) or catecholamines (i.e. norepinephrine) in the bloodstream. [8]

    Because theanine is structurally similar to the neurotransmitters glutamate and glutamine, it competes with them at their transporters, which can reduce synaptic levels of glutamate, a dangerous neurotransmitter that causes neurotoxicity in high levels. [9]

    Additionally, administration of L-theanine has been found to increase GABA levels in the cerebrum by nearly 20%.[10] GABA is an inhibitory neurotransmitter, and this is largely thought to be a major contributor to Theanine’s anxiolytic and relaxing effects. However, research has not yet provided a conclusive answer to L-theanine’s exact mechanism of action.

    Caffeine

    While L-theanine is a respectable anxiolytic and cognitive enhancer in its own right, most users find it most effective when paired with caffeine, as mentioned above. To understand the power of stacking caffeine with L-theanine, it’s also important to know the way in which caffeine operates.

    Caffeine

    Caffeine’s stimulant properties come mainly from its action as an adenosine receptor antagonist. When adenosine receptors are activated by adenosine, it causes drowsiness in the individual. Adenosine accumulates naturally in neuronal synapses, and lower levels of adenosine translate to feelings of alertness and wakefulness. Because caffeine binds to adenosine receptors competitively, it inhibits adenosine from binding to the adenosine receptors, which in turn makes the body feels more awake.[11] Of course, when caffeine is eliminated from the system, adenosine is once again free to bind to its natural receptors, returning the body to feelings of drowsiness.

    Even though caffeine’s main effects are due to its adenosinergic mechanism, caffeine consumption also has an impact on other neurotransmitters. Caffeine (particularly in high doses) reduces the conversion of tryptophan to serotonin and this may exacerbate depression, especially if caffeine use is suddenly stopped.[12] Therefore, 5-HTP, a serotonin precursor, can be used to counteract Caffeine withdrawal symptoms.

    Stacking Caffeine & L-Theanine

    Theanine and Caffeine have powerful synergistic effectsThe simultaneous use of caffeine and L-theanine appears to be the most common combination or “stack” of substances utilized by users of nootropics. Because both caffeine and L-theanine are cheap, well-studied, and generally accessible, it is a good starting point for those who are just getting into nootropics and cognitive enhancement. If you already use caffeine in any form, it wouldn’t hurt to see how L-theanine works for you.

    Common combinations of caffeine and L-theanine are a 1:1, 1:2, 2:1, or 2:3 ratio of caffeine to theanine. The effectiveness of each ratio varies widely among individuals, so some trial and error might be necessary to find the right amounts. If you do not use caffeine regularly, it would be wise to start with a 1:2 ratio – that is, 100 mg of caffeine with 200 mg of theanine – and adjust from there. There is no “correct” way to stack the two, and it is mainly a matter of preference and personal brain chemistry.

    Multiple studies using about 100 mg of L-theanine alongside 50 mg of caffeine demonstrated that the combination of the two had a fairly significant impact on cognition, even more so than either substance by itself. [13] [14] L-theanine use in combination with caffeine also helps users remain focused on single tasks without being distracted by outer stimuli. [15]

    Conclusion

    Many nootropics are most effective when combined with other complementary substances. Researching different nootropics and their effects and benefits can be both fun and rewarding. However, sometimes the amount of information available makes it difficult to find a starting point. A combination of caffeine and L-theanine is the perfect starting point for anyone who is interested in nootropic supplementation and increasing their cognition. Because both compounds are well-studied both separately and in combination, it is a safe starting point for introducing people into the world of cognitive enhancement.

    For those of you who don’t like messing up with powders (or just like the convenience of pills), try premixed Caffeine and Theanine caps

    References   [ + ]

    Categories
    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
    Biohacking Nootropics Tutorials

    Microdosing Psychedelics For Cognitive Enhancement

    Most drugs used for nootropic purposes are far different from drugs that are used recreationally. However, a handful of substances with “no accepted medical use” in countries like the United States hold great promise as cognitive enhancers and therapeutic agents. Case in point: psychedelics

    It has been common knowledge since the 1960s that psychedelic drugs, such as LSD, psilocybin and mescaline, are potent enhancers of creativity and divergent thinking. However, at common recreational doses, this boost in creativity is often accompanied by feelings of intoxication, rendering the user incoherent and unable to get any “serious” work done.

    That said, a new trend in psychedelic usage has emerged in the past few years that seeks to reap the creative and cognitive benefits of these drugs, while still leaving the user sober and able to function normally. This method, known as microdosing, is the practice of consuming a psychedelic substance at a dosage lower than the threshold of noticeable effects, in order to produce subtle yet effective increases in cognition and creativity. Because the dosage consumed is below the threshold of recreational effects for the substance, the user does not experience the inebriating effects of the substance. The hope is to maximize cognitive enhancement while minimizing any effects that would impair the user as they go about their day.

    Microdosing with psychedelic substances is by no mean a new concept, with Albert Hofmann (the creator of LSD) himself having used microdoses of LSD frequently and having called microdosing a regretfully “under-researched” area of psychedelics.[1] However, microdosing has not seen substantial popularity until very recently, and it appears to be an emerging trend in 2015.

    How Does it Work?

    Microdosing, in the form discussed here, is performed by using psychedelic drugs that act on serotonin receptors, such as LSD, psilocybin, mescaline, 2C-B, and many others . The impact that psychedelics have on cognition has not been extensively researched due to government restrictions on research of illegal drugs. However, as the scientific community continues to push more and more against research limitations, more studies are being published that give us a glimpse into how psychedelic substances affect human cognition.

    lsd-nootropic
    Enhancement of associative learning produced by the 5-HT2A agonist LSD under different experimental conditions.

    The psychedelics most commonly used for microdosing work by acting upon serotonin (5-hydroxytryptamine, or 5-HT) receptors. Thus, in order to understand microdosing, one must first recognize that the serotonergic system regulates cognition and the way in which we learn. There are numerous unique serotonin receptors within the nervous system, collectively regulating everything from mood to gastrointestinal motility. The receptors most involved with learning, memory, and cognition, however, are the 5-HT1A, 5-HT2A, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors, with 5-HT2A being the most acted upon by psychedelics.[2]

    In the sober individual, serotonin molecules bind to these receptors, stimulating the receptors and their respective neurons, which is partially responsible for learning, cognition, and memory acquisition. The cognitive boosts that come from microdosing psychedelics are thought to be due to their action of agonists at the 5-HT2A receptor. Although this is an oversimplification, it provides the basis for understanding why microdosing does what it does.

    A 2003 study[3] conducted by John A. Harvey at Drexel University explored these effects on cognition by administering LSD to rabbits and recording their performance on cognitive tests. The doses used in this study were equivalent to about 1 µg/kg in humans, which amounts to 80-100 µg in the average human, which is a common recreational dosage for LSD. When the rabbits were given LSD, they performed significantly better on learning and cognitive tests than those that has not been given LSD.[4]

    There is also relevant research that was conducted by Willis Harman and James Fadiman before the FDA placed a moratorium on psychedelic research. In one study[5] conducted in 1966, researchers gave 200 mg of mescaline (equivalent to 100 µg of LSD) to a group of 27 professionals who worked in high-level occupations, such as engineers and mathematicians. Each subject came to the experiment with a particular problem from their occupation that they were having trouble solving. All but four subjects, after they had worked on these problems under the influence of psychedelics, were able to make significant progress on the problems they had been struggling with, many of which turned out to be innovative solutions.[6]

    Which Substances Can Be Used?

    Microdosing can potentially be carried out with any serotonergic psychedelic, but some are more popularly used and tested than others. Typically, the most popular choices are LSD and Psilocybin. As long as the threshold dose of the drug is known, it can be effectively microdosed, although results will certainly vary from person to person. The following is a tentative list that includes common microdosage amounts of various psychedelics.

    Drug Dose Threshold Duration Note
    LSD 10 – 30µg 20µg 8 – 12h
    AL-LAD 10 – 30µg >20µg 6 – 8h
    Psilocybin 2 – 5mg 0.25g 4 – 6h dry weight with uniform blending; corresponds to 0.15 – 0.4g Psilocybe Cubensis
    Mescaline 50 – 150mg 100mg 6 – 10h dry weight with uniform blending; corresponds to 4.5 – 13.5g L. williamsii or 10 – 25g T. pachanoi
    DMT 2 – 6mg ~3.5mg 5 – 20m
    4-AcO-DMT 1 – 4mg 2.5mg 4 – 6h
    2C-B 2 – 6mg ~3.5mg 4 – 6h
    2C-E 2 – 6mg ~3.5mg 4 – 9h
    2C-I 2 – 6mg ~3.5mg 5 – 8h
    2C-D 2 – 6mg ~3.5mg 3.5 – 5h

    (Table taken from /r/microdosing)

    The Potential Effects of Microdosing Psychedelics

    As with the usage of any drug, microdosing psychedelics can have both positive and negative effects. Due to the lack of clinical and experimental evidence dealing with psychedelics, most of this information is anecdotal, and must be regarded of as such. Users must proceed with caution in order to find if microdosing is of benefit to them.

    Some of the purported benefits of microdosing include:

    • Increases in energy and wakefulness
    • Enhanced creativity and cognition
    • Enhanced concentration and motivation
    • Increased ability to learn new material
    • Positive changes in mood
    • Empathy when interacting with others
    • Better stamina and performance in athletic activities

    Some negative side effects of microdosing include:

    • Headaches (due to increase in blood pressure)
    • Problems falling asleep, or poor quality of sleep
    • Stomach discomfort
    • Anxiety and irritability
    • Permanent personality changes (can be both negative or positive)

    Addiction or withdrawals may be a concern with certain psychedelics, but the most commonly used psychedelics, including LSD, have not displayed addictive properties. It is also important to note that while psychedelic drugs have the ability to enhance cognition, they can also induce effects that make it harder to think clearly and analytically.

    Some might find it harder to focus on tasks while microdosing (especially if the dose is too high), and the introspective nature of many psychedelics might cause some users to focus on their own internal problems rather than external ones. Although microdosing seeks to prevent these effects with lower (and less impairing) doses, it is not guaranteed that they will not occur. In some circumstances, users might find microdosing to be of little to no benefit to their cognition. As stated before, results will vary for each individual.

    Conclusion

    Microdosing psychedelics for cognitive enhancement is far from a traditional nootropic, and must be regarded as such. Because there is not much solid clinical evidence to attest to its efficacy, it must be used cautiously. However, most common psychedelics are considered very safe to use, especially in lower doses that are not as physically and mentally impairing. Due to the illegal status of psychedelics in most of the world, it is advised that you proceed with caution and remain aware of the drug laws where you live.

    Microdosing may hold a significant amount of promise for some nootropic users. As the use of psychedelics becomes more and more accepted by society, in general, we can expect to see an increase in scientific research on the subject, giving us a more detailed glimpse into how psychedelics affect our minds.

    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