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Nootropics Tianeptine

Tianeptine Abuse, Safety and Withdrawal Syndrome

Tianeptine is a tricyclic antidepressant whose mechanism of action has been puzzling scientists for years. In fact, unlike most antidepressants, Tianeptine does not target monoamines (serotonin, norepinephrine, dopamine). It is, therefore, a very effective solution for individuals suffering from depression and anxiety, especially those who are afraid of the side effects of currently available antidepressants.

A few years ago, a new mechanism of action has been unveiled that is now thought to mediate the beneficial effects of Tianeptine on depression and cognition: mu-opioid receptor agonism. So what does this mean for Tianeptine users? Is it time to starting worrying about potential opiate-like addiction and withdrawal symptoms? Let’s find out.

1985-2009: Discovery & 5-HT theory

Tianeptine was discovered by French researchers Antoine Deslandes and Michael Spedding in the 1980s. We do not know exactly when that happened, but the first study that mentions “Tianeptine” was published in 1986.[1]

The animal studies carried in the late-90s to early 2000s showed that Tianeptine may be part of a new class of drugs named serotonin reuptake enhancers (SRE). In short, these drugs enhance serotonin uptake, instead of inhibiting it, thus reducing the overall amount of serotonin (5-HT) in the synapse. Serotonin reuptake enhancers, therefore, have the opposite mechanism of action of SSRIs drugs like Prozac and Zoloft.

Monoamines

It is important to point out that, until a couple of years ago, depression was thought to be the result of a depletion of monoamine neurotransmitters[2] [3], and, in particular, serotonin. This is known as the monoamine theory of depression.

However, when experimenting with pharmaceutical agents that are known to cause monoamine depletion, researchers have failed to generate (or worsen) depression in healthy subjects.[4] In addition, the MOA of drugs like Opipramol, — and Tianeptine itself —, is unrelated to monoamines, and they still have been found an antidepressant effect. Nowadays the monoamine theory is no longer the ruling paradigm in depression research, and depression is thought to be a consequence of several different neurotransmitters and brain changes.

So the theory that Tianeptine is an SRE may have been influenced by the technical limitations of the time, as well as the popular theory that antidepressant work by “fixing” a monoamine imbalance. But that was going to change with two new discoveries.

2010-2014: New findings

A study published in 2010[5], first mentioned the fact that Tianeptine’s antidepressant effects may have nothing to do with serotonin and other monoamines. The researchers thought, instead, that the antidepressant effects may be due to glutamateric modulation[6]. Tianeptine, in fact, has shown to be neuroprotective and to promote neurogenesis, as well as reduce the release of glutamate, a neurotransmitter that is thought to be implicated in schizophrenia, anxiety, depression, psychosis and bipolar disorder.[7]

However, the real surprise came four years later, when a study[8] showed that Tianeptine activates mu-opioid receptors[9], the same receptors targeted by frequently abused opioid drugs such as morphine, heroin and oxycodone.

Abuse of Tianeptine

Tianeptine is a relatively safe drug. However, like many pharmaceutical drugs, it can be used for purely recreational purposes.

Many heroin users in Russia, in fact, were abusing Coaxil (one of Tianeptine brand names), long before scientific research proved that it works as an opioid agonist. An article, published in the newspaper “Moscow Komsomolec” in 2008, first raised the alarm about Tianeptine abuse in Russia. This was the about the same time that Krokodil — a cheap homemade heroin substitute[10] that it is famously known to destroy body tissues[11] and cause death in a manner of weeks — hit Russia and neighboring countries, when the former USSR country started a major crackdown on heroin production and trafficking.

The drug market has changed completely in past few years in Moscow. “The time of synthetics has come!”-say drug users.

Everything was clear before: heroin, cannabis, “clubbing” pills. Today the main drugs are so-called pharmaceutical drugs: drugs that cannot be sold without a prescription, but nevertheless they are sold in big quantities through dishonest pharmacists. The most widely-spread and most dangerous one is antidepressant Coaxil. Its affordable and life-threatening if injected intravenously. […]

-If you watch the process of making coaxil substance by drug users you will see quite clearly why. They crush the pills and dissolve them in water, very often it is tap water. Then they get a disperse substance and it’s particles cause damage to a vessel and build a thrombus (clot) inside it. The thrombus starts growing rapidly. The thrombus itself is a very good environment for various microorganisms and that provokes purulent complications. If a drug user by chance injects coaxil into an artery –then that develops thrombus not only in a big vessel, but even in small ones, called arterioles. In these cases gangrene starts very quickly. As a rule complications come in the first six months of using the drug, sometimes even sooner. Very often “neophytes of coaxil” slip up at first injection. The most careful and accurate can last maximum for a year.

As a consequence, Tianeptine is now a controlled substance in Russia and France.

Tianeptine is not the only drug of the tricyclic family of antidepressants that has been banned. Amineptine – a drug closely related to Tianeptine – was banned years ago due to liver damage and frequent abuse and addiction among patients who were prescribed it as a depression treatment. I would like to point out that, unlike Tianeptine, Amineptine is also a dopamine reuptake inhibitor, so it may have a higher recreational value compared to Tianeptine.

Safety of Tianeptine

Tianeptine is safe at the recommended dose (12.5 mg three times a day) and users may benefit from the neurogenic, neuroprotective and antidepressant properties of the drug without having to worry about addiction and withdrawal symptoms.

That said, Tianeptine is not the kind of nootropic that you take every day and “forget about it.” It is still a very potent compound, with multiple molecular targets, and I can easily imagine how some people — particularly those with a history of drug abuse — may be tempted to binge on it, in an attempt to emulate the effects of prescription painkillers.

It is, therefore, a good idea to cycle it with other antidepressant nootropics, like Coluracetam or NSI-189. Tianeptine has instant mood elevating properties, and some users report tolerance to the positive effects after repeated administration, so it may be a good idea to use Tianeptine as needed instead of taking it daily for extended periods of time.

Withdrawal Symptoms

Tianeptine withdrawal is characterized by high level of anxiety and excitability[12] akin to withdrawal from opioids. The severity of the symptoms is directly influenced by the dosage used and the length of time that the drug has been taken.

A Reddit user reported full-blown withdrawal syndrome akin to opiate withdrawal when using Tianeptine at an incredible dose of 250 mg to 1 gram (!) of Tianeptine sodium a day. You can find more details about his experience here. However, as said before, it’s no wonder that the user had those symptoms when talking about that sort of amount of drug in their bodies. In my experience, Kratom is an overall better opioid replacement as far as safety and risk of addiction.

If you are going to use Tianeptine long-term, we suggest Tianeptine Sulfate or Free Acid. The slightly longer duration of effect of these compounds means a lower risk of addiction and withdrawals (though it has not been scientifically tested).

Conclusion

In the end, I feel that Tianeptine is an incredible drug, one that can be truly life-changing for those who suffer from depression and anxiety. I discourage anyone from trying Tianeptine if they are just looking for a “legal high”.

It would be a shame if the drug were banned because a few subjects exploiting the legal status of this amazing substance in search of a poor man’s high.

That’s all for now — for any question or doubts leave us a comment; and if you have enjoyed the article consider following our Facebook and Twitter age.

References   [ + ]

Categories
DMAE Nootropics Picamilon Vinpocetine

The 5 Most Overrated Nootropics

The world of nootropics is one that focuses mainly on the cognitive enhancement of individuals who are seeking to maximize their potential. However, this also means that nootropics are a commercial enterprise, with vendors and salespeople seeking to maximize their profits. Due to the commercial nature of nootropics, and the fact that many are not FDA regulated, many suppliers make exaggerated or overemphasized claims about the benefits of their products.

Quite simply, there are many well-known “nootropic” substances that either don’t work as well as advertised or don’t work at all. The placebo effect may also plays a massive role in this, as many nootropics have not been thoroughly tested in double-blind experiments to ensure they work more effectively than a placebo. For this reason, anecdotal experience reports with nootropics are important, but many people tend to give them too much weight. In order to combat misinformation (and save you some money), we will be listing a few overrated and under effective nootropics and supplements on the market today.
 

DMAE

Dimethylaminoethanol, frequently known as DMAE and Deanol, is a chemical involved in a series of reactions needed by the body to synthesize Acetylcholine, a neurotransmitter that regulates memory and mood.

DMAE Deaner advertisement nootropic
DMAE advertisement from the late 50s
The p-acetamidobenzoate salt of DMAE was originally sold by Riker Laboratories as Deaner, for the management of kids with learning disabilities. It is not known whether that form of DMAE was more effective than the bitartrate salt that is more commonly sold as a nootropic supplement.

Riker retired Deaner from the shelves in 1984 because, — according to the FDA — the clinical studies didn’t prove that the drug was effective. As of today DMAE is still sold as a nootropic supplement, but it’s more frequently used as an active ingredient in anti-aging skin creams, due to its polyunsaturated fatty acid content.

DMAE has always been a popular and widely used supplement in the nootropic community since the end 90s to early-2010s, however, it is no longer a popular nootropic supplement today for several reasons:

  • DMAE is not an effective Acetylcholine percursor[1] [2]
  • There is actually reason to believe that DMAE may act as an anticholinergic[3]
  • DMAE causes birth defects[4]
  • Some nootropic users report depression and physical anxiety as a side effect of DMAE[5]
  • DMAE reduced lifespan in a study on quails[6]

Try instead: Centrophenoxine, CDP-Choline, Alpha GPC
 

Ginkgo Biloba

Ginkgo biloba is a species of tree that has the reputation of being used in traditional Chinese medicine. Ginkgo extract is used as a mild vasodilator, and can be commonly found at almost any supermarket sold in capsule form. Its wide availability makes it a very popular supplement, especially for those who are just getting introduced to nootropics or supplementation. Ginkgo has often been touted for its alleged abilities to enhance cognition, mood, and memory.

In the 1990s, Ginkgo was heavily marketed by the supplement industry as a natural compound that enhances memory and energy. The majority of clinical studies have found ginkgo supplementation to be relatively ineffective in people who don’t already suffer from some form of cognitive deficit. While studies have confirmed that ginkgo can help counteract cognitive decline, these studies were only conducted on older individuals (65+) who were already in the process of cognitive decline.[7] So while ginkgo might be a good option for older individuals, there is no evidence to suggest it will have an effect on the cognitive health of younger individuals.

https://www.youtube.com/watch?v=YOsehMqrb1E

However, recent studies have brought into question ginkgo’s ability to slow or prevent things like mild dementia and Alzheimer’s in the elderly. One clinical trial conducted with 3,000 elderly individuals found that ginkgo is no more effective at preventing these diseases than placebo.[8]

Another one of ginkgo’s most commonly claimed benefits is that of improving mood and sense of wellbeing. However, multiple studies have confirmed that ginkgo only has the ability to slightly improve mood among individuals who are effected with a pre-existing cognitive condition, and not among healthy individuals.[9] [10] [11]

So, while Ginkgo Biloba may be worth a try in older individuals who are already experiencing cognitive decline, most evidence suggests that younger individuals have little to no reason for supplementing ginkgo to achieve cognitive enhancement.

Try instead: Bacopa or Noopept
 

Picamilon

Picamilon is a pharmaceutical drug developed in the Soviet Union that is now used in Russia for the treatment of anxiety, among other disorders. Picamilon was recently in the news when the FDA decided that the drug did not fit into the category of dietary ingredients and subsequently banned picamilon from being included in any supplement formulas manufactured in the United States.[12] That being said, it is still fairly available online to those in the US who wish to purchase it.

Picamilon, Niacin and Gaba comparisonThe picamilon molecule is a synthetic combination of niacin and GABA. On its own, supplemented GABA cannot pass through the blood-brain barrier, meaning it will have no psychoactive anxiolytic effect. However, niacin is able to readily pass through the blood-brain barrier.[13] In theory, the picamilon molecule could cross over the blood-brain barrier, at which point it would be metabolized into GABA and niacin, thus producing an anxiolytic effect. Like phenibut, this anxiolytic effect has the potentially to improve the cognition of those whose minds are constantly preoccupied with anxious thoughts.

Picamilon Russian Nootropic
Russian Picamilon
This theory sounds promising and reasonable on paper, but there is, unfortunately, little to no evidence that it is accurate. While one Russian study concluded that picamilon did indeed cross over the blood-brain barrier, the details of its action once it crosses over have not been thoroughly analyzed.[14] Essentially all clinical experiments concerning picamilon are reported in Russian, making them inaccessible to the vast majority of the scientific community. This makes any evidence supporting picamilon dubious at best. At this point, there are no double-blind studies that test how picamilon works as an anxiolytic.

While it can’t necessarily be ruled out that picamilon has any positive effects on cognition and anxiety, there is not much evidence to believe it would. At this point, there is simply not enough research done on the substance to conclude that it is worth investing in.

Try instead: L-Theanine, Tianeptine, Phenibut
 

Vinpocetine

Vinpocetine is a classic nootropic compound often claimed to have memory-enhancing effects as well as the ability to improve brain metabolism. Vinpocetine is a semisynthetic analog of vincamine, an alkaloid derived from the periwinkle plant. It is still sold in some Eastern European countries as Cavinton for treating blood flow disorders in the brain, as well as cognitive decline caused by old age.

Vinpocetine and Vincamine comparison

Like many other drugs on this list, Vinpocetine appears to have positive effects on cognition only among people who are already experiencing age-related cognitive decline or brain injury.

  • One study found that vinpocetine was able to improve symptoms related to cognitive decline in elderly or injured patients who were suffering from cerebrovascular insufficiency.[15]
  • However, there are currently no studies that suggest vinpocetine has similar effects on healthy subjects.

That said, there is evidence that vinpocetine may be able to improve reaction time among healthy subjects.

  • A study conducted on 12 female subjects between the ages of 18 and 29 found that vinpocetine caused their reaction time to reduce by a few hundred milliseconds, depending on the dosage used. So, while vinpocetine may help improve reaction time, there is no current evidence that it will enhance memory and cognition.
  • Vinpocetine may likely help in sports where reaction time is a deciding factor, but there is no evidence (clinical or anecdotal) that it helps with learning and studying.
  • Vinpocetine is known to causes headaches, so it is a good idea to start low and experiment with ease, before stacking it with other nootropics.

Try instead: Piracetam, PRL-8-53
 

Adrafinil

Adrafinil is a prodrug to the ever-popular wakefulness-promoting drug modafinil. Essentially, this means that adrafinil is metabolized into modafinil once it is ingested. Adrafinil was once used as a prescription medication in France for enhancing wakefulness and attention but was discontinued in favor of using modafinil, which is far more potent.

How Adrafinil gets converted to Modafinil in the liver

Due to the fact that modafinil is a “prescription only” drug in many countries, many nootropic users have turned to Adrafinil for its purported cognition-boosting and memory-enhancing effects. While there is some evidence to suggest that modafinil can provide a modest boost in cognition and working memory,[16] Adrafinil does not seem to exhibit these effects as strongly. In addition to this, Modafinil’s cognition-boosting effects appear to be most effective in individuals who are sleep deprived or impaired in some ways, and not those who are already high achievers.

Because Adrafinil is a prodrug to modafinil, one would expect the two to have the same effects when taken in the correct dosages. However, even when enough adrafinil is taken to be metabolized into a full dose of modafinil, the effects do not appear to be as strong. While it is unknown exactly why this is the case, it likely has to do with the rate at which adrafinil is metabolized, as well as the fact that metabolic enzymes mutations are commonly found in the general population.

Adrafinil also appears to exhibit more side-effects than modafinil, including skin irritation, anxiety and elevated liver enzymes.[17] The latter is likely due to the fact that adrafinil is metabolized in the liver, and thus puts extra stress on it, causing it to produce more enzymes.

While adrafinil may have some potential to enhance cognition and memory, its effects are not nearly as potent as modafinil, even when taken at the proper dose. If at all possible, it would make far more sense to take modafinil or armodafinil, which is the active enantiomer of the drug.

Try instead: Modafinil or Armodafinil
 

Conclusion

While nootropics and cognitive enhancers will have different effects on different individuals, there are certain substances and supplements that simply do not have evidence backing up their ability to enhance cognition. Because the nootropics industry is one driven by profits just like any other, users need to be skeptical of the claims made by vendors. Many nootropics on the market are overrated and under effective, but thankfully there are many alternatives that are backed by research. Nootropics are often not cheap, so purchases need to be made wisely.

References   [ + ]

1. Is 2-dimethylaminoethanol (deanol) indeed a precursor of brain acetylcholine? A gas chromatographic evaluation. (1977)
2. Dimethylaminoethanol (deanol) metabolism in rat brain and its effect on acetylcholine synthesis. (1979)
3. Deanol and methylphenidate in minimal brain dysfunction. (1975)
4. Perturbations in choline metabolism cause neural tube defects in mouse embryos in vitro (2002)
5. DMAE sucks! – LONGECITY Forum
6. Effects of dimethylaminoethanol upon life-span and behavior of aged Japanese quail. (1977)
7. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomised placebo-controlled trial.
8. Ginkgo biloba for Prevention of Dementia
9. Specific memory effects of Ginkgo biloba extract EGb 761 in middle-aged healthy volunteers.
10. Phase II study of Ginkgo biloba in irradiated brain tumor patients: effect on cognitive function, quality of life, and mood.
11. Ginkgo biloba extract EGb 761® in dementia with neuropsychiatric features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg.
12. FDA sends five warning letters over supplements containing picamilon
13. Effect of Huntington’s and Alzheimer’s diseases on the transport of nicotinic acid or nicotinamide across the human blood-brain barrier. (1991)
14. [Pikamilon pharmacokinetics in animals]
15. [Efficacy of cavinton in the treatment of patients with chronic blood flow insufficiency. Russian multicenter clinical-epidemiological program “CALIPSO”].
16. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature.
17. Modafinil: past, present and future.
Categories
Life Extension Nootropics Reviews

Cerebramin and the Cytamins – My Experience

Even though the first nootropic, Piracetam, was discovered by a Romanian chemist, we can truly say that Russia is the true motherland of nootropics. From the “oldies”, such as Phenibut and Picamilon, to the newest additions, Russia has always been the bleeding edge of nootropic research. Today we are going to talk about Cerebramin and other compounds of the cytamins family.

Cytamins are nucleoproteins complex isolated from the organs of healthy cattle. These compounds are part of a new family of compounds developed in Russia, and called peptide bioregulators, that are being researched as anti-aging treatments.

Peptide bioregulators

From 1971 to 1996, researchers at the St Petersburg Bioregulation and Gerontology Institute studied and documented the role of peptides in aging. [1] [2] What they discovered is the body releases tissue-specific compounds, of peptide structure, that mediate interactions between cells. As such, they were named peptide bioregulators.

The researchers then isolated and purified those peptides from the organs of healthy cattle and pigs and found out that they had a normalizing effect on the abnormal cells of senescent and/or sick animals. These promising peptides have been developed into a new class of pharmaceuticals, the cytomedins, (e.g. Cortexin, Thymalin and Epithalamin, which has been further developed into Epitalon) as well as para-pharmaceuticals, the cytamins, such as Cerebramin, Vasalamin and Retinalamin.

Cytamins?!

So what’s the difference between the cytamins and the cytomedins?
Cytamins are “interpolymer complexes of tissue-specific proteins with nucleic acids.”[3] Essentially, they are a mixture of compounds such as nucleoproteins, vitamins, peptides and amino acids. The patented technology of cytamins manufacture includes alkaline hydrolysis from tissue cells, consecutive precipitation of nucleoprotein complexes, their purification from ballast substances, and manufacture of the ready form as enterosoluble tablets or capsules.[4]

In the manufacturing of Cytamins only calves and pigs less than 12 months old are employed, and strictly from Russian farms where “no human-endangering infectious diseases including transmissive bovine spongiform encephalopathy has been registered”.[5] Also, Russia is known for “its epizootological and epidemiological safety in respect to prion diseases.”[6] Not only that, but electrophoresis and Congo red staining (the recommended method of testing for Mad Cow disease) are employed to check for the presence of prion proteins.

There are over 17 cytamins on the market, and they are manufactured at “Longvy Farm” in Russia. More information about the cytamins can be found at the official website.

Some of the most famous cytamins are:

  • Brain (Cerebramin)
  • Liver (Hepatamin)
  • Stomach and duodenum (Ventramin)
  • Pancreas (Pancramin)
  • Lungs and respiratory system (Bronchalamin)
  • Heart (Coramin)
  • Circulatory system (Vasalamin)

Dr. A.S. Bashkireva[7] tested the use of Cerebramin and Vasalamin on driving performance, in both healthy subjects as well subjects with depression, anxiety and other mood disorders. The results were that the cytamins were “very effective in the correction of psychoemotional disorders and for attaining stable psychic adaptation”. [8]

[…] 150 professional drivers (men aged 30-59 years) were examined using a clinical questionnaire to identify, estimate and compare neurotic states according to 6 scales of anxiety, neurotic depression, asthenia, hysterical type of reacting, obsessive-phobic disorders and neurovegetative disturbances. The drivers were divided into 5 groups, 30 persons in each: I group received Cerebramin→, II — Vasalamin→, III — Cerebramin→ + Vasalamin→, IV — placebo, V — no preparations. […] The analysis of the incidence of various PES revealed a statistically significant increase in the number of drivers with stable psychic adaptation in Groups I, II, and III after cytamin correction as compared to the baseline level (3.3-, 2.4-, and 2.3-fold, correspondingly, p<0.001-0.05). A statistically relevant decrease in the number of the drivers with unstable psychic adaptation in Groups I, II, and III after a cytamin course was noted in comparison with the baseline level (2.5-, 3.0-, and 3.3-fold, respectively, p<0.001- 0.05). […] A detailed examination of the drivers’ PES according to different scales convincingly demonstrated the efficacy of combined application of Cerebramin and Vasalamin in correction of anxiety (p=0.001), neurotic depression (p=0.0001), asthenia (p=0.0001), hysterical type of reacting (p=0.0004), obsessive-phobic states (p=0.0001), and neurovegetative disorders (p=0.003). […]
The presented results showed the occupational hazards and long driving experience being the risk factors for the development of BMD. The applied parameters of PES and early manifestations of BMD are informative criteria for assessing the life quality and professional suitability of lorry-drivers. Cytamins […] are very effective in the correction of psychoemotional disorders and for attaining stable psychic adaptation. [9]

Cerebramin: My Experience

In my anecdotal, and totally unscientific experience with Cerebramin (the cattle brain extract), I can’t say to have noticed any effect. However, I am 24 years old, and this supplement is to be used in the elderly, so I cannot make any real judgment. That said, I feel that “real drugs” like the cytomedins (eg Epitalon, a pineal gland peptide, and Cortexin, a brain peptide) have a huge potential, and I’d like to try them out in the future.

You can buy Cerebramin, Cortexin and other rare Russian nootropics at RUPharma.

Cerebramin
5
Focus
6
Mood
5.5
Memory
5
Stimulation
5
Relaxation
7
Safety
Reviewer 5.5

References   [ + ]

Categories
Biohacking Coluracetam Nootropics PRL-8-53 Tutorials

Photographic Memory: Nootropics and Mnemonic Devices 101

Photographic memory, or eidetic memory, is the ability to vividly recall images after seeing them for a short period of time. A Google search shows over 16.000 results for “photographic memory nootropics”. Of all the articles I read, no one of them answer the fundamental question: Does photographic memory exist, and is it possible to achieve with a combination of mnemonic techniques, training, and nootropics?

What is Photographic Memory?

According to the Merriam-Webster dictionary[1]

Eidetic is the technical adjective used to describe what we more commonly call a photographic memory. The word ultimately derives from the Greek noun eidos, meaning “form.” The ability of certain individuals to recall images, sounds, or events with uncanny accuracy is a subject of fascination for researchers in the field of psychology. Among notable people who were reputed to have eidetic memories is the late television comic Jackie Gleason, who reportedly was able to memorize an entire half-hour script in a single read-through.[2]

There are only two case studies of eidetic memory in scientific research. Let’s take a quick look at them.

Case 1: The Mind of a Mnemonist

The first case study of a subject with an “incredible” (photographic?) memory was published in a Russian medical journal in the 1960s by psychologist Alexander Luria.

Alexander Luria was a famous Russian psychologist active in the mid-1900s. In the early days of his career, he met a young man named Solomon Shereshevsky. Shereshevky, — or simply ‘S.’, the acronym used in Luria’s writings — was a Russian reporter working for a local newspaper. Each morning the editor would meet with the staff to hand them a rather long list of assignments. Solomon was able to memorize the entire list by looking at the sheet of paper just once.

Solomon Shereshevsky Photographic Memory Nootropics
Solomon Shereshevsky

Even though he was not a brilliant student due to his shy nature, when S. was a schoolboy he could memorize every single thing he read without ever taking notes. Intrigued, Luria took S. to his lab and, over the course of several months, tested his memory using all kinds of complex mathematical formulas and rare languages. Once, he read him the first four lines of Dante’s La Divina Commedia in Italian, a language he could not understand, and he was able to recite it in a matter of seconds.

On the basis of the research’s findings, Luria diagnosed S. with a rare form of synesthesia, called ideasthesia.

Ideasthesia is a phenomenon in which letters, numbers, and other visual objects evoke a “perception”-like experience. Since humans are hardwired to memorize visual concepts more efficiently than letters or numbers, an individual with ideasthesia can memorize characters, numbers, and symbols after viewing them for a couple seconds

The theory of this phenomenon closely resembles the idea behind the Method of Loci (more on that later), a technique used by mnemonists to memorize many different chunks of information that would otherwise be difficult to memorize.

So what kind of visual perceptions did the Divine Comedy evoke?

The first line, Nel mezzo del cammin di nostra vita, he rendered into images this way: Nel, Nel’skaya, a ballerina; mezzo, she is together with (Russian vmeste) a man; del, there is a pack of Deli cigarettes near them; cammin, a fireplace (Russian kamin) is also close by; di, a hand is pointing toward a door (Russian dver); nos, a man has fallen and gotten his nose (Russian nos) pinched in a doorway (Russian tra); vita, the man steps over a child, a sign of life — vitalism; and so on, for 48 syllables.[3]

In 1968, after S.’s death, Luria published a book of his findings, The Mind of a Mnemonist. He wrote it for a non-scientific audience and I recommend it to anyone. The translated version can be easily found on the web with a quick Google search.

Case 2: The Girl with Eidetic Memory

Fast forward to the 1970s. A Harvard scientist named Charles Stromeyer III publishes a paper about a girl with an incredible ability. He gave her a sheet of paper with a pattern of 10,000 random dots, and the next day another random pattern with a different layout.

The girl was able to fuse the pattern in his mind and form a stereogram, which she saw as a three-dimensional image floating above the surface. A couple of days later, when questioned by the researcher, she could draw each pattern with astonishing accuracy.

The case study of Elizabeth – this is the name of the girl – was published in Nature. However, in a comical turn of events, the researcher later married the girl, and she was never tested again.

dot pattern photographic memory
A random dot pattern like the one given to Elizabeth

A couple of years later, in 1979, a researcher named John Merrit published the results of an eidetic memory test he had placed in magazines all over the country. After seeing Elizabeth results, he had hoped that someone might come forward and prove, once and for all, the existence of photographic memory. He figured that over 1 million people had tried the test. However, of the 30 people that were able to correctly figure it out, he went on to visit 15 of them, and nobody could repeat the experiment with the scientist looking over his/her shoulders.

So how was Elizabeth able to succeed in the test? Did she have some weird memory superpower?
Some say that the Elizabeth study was not real, but rather a silly prank between friends that got out of hand. nthomas from the Straight Dope forum explains it:[4]

When I was in a graduate seminar on the psychology of memory (about 16 years ago, at a major university) I was told by the professor, an expert in the field, that the “discovery” was, in fact, a hoax. As he told the story, “Elizabeth” was actually the girlfriend of the researcher, who had been talking to her about his interest in eidetic imagery. He had a reputation, however, for being rather gullible, and, for a joke, she, and a group of his other friends, cooked up a fake demonstration of her amazing eidetic powers. He was completely taken in, and became very excited at his amazing “discovery”. But before “Elizabeth” and her friends had the time (or maybe the heart) to let the victim in on the joke, things had got out of hand, and the discovery was already well known, and, before long, published.
The etiquette of scientific publication would make it difficult to get a story like this into the formal record, and, anyway, psychologists probably do not want it too widely known how easily they can be taken in. (Perhaps, also, people were reluctant to ruin the career of the poor, duped but not dishonest, researcher.)
[…]I got the impression from my professor that the hoax story was quite well known amongst memory researchers. Furthermore, my impression is that psychological opinion over whether eidetic imagery (as distinct from the ordinary, relatively unreliable, memory imagery, that nearly everyone experiences) really exists, is still much more divided than Cecil seems to believe. It may be the majority opinion that it is real, but a respectable minority of researchers have their doubts. The amazing abilities of “Elizabeth” do still occasionally get mentioned in the reputable psychological literature, however. Some serious scientists do seem to believe it. I myself am no longer sufficiently close to the “in group” of memory psychologists to have heard the hoax story again, or to check out how widely it is known or believed.

So there you have it: the only recorded case of a genuine photographic memory among ordinary human beings is, very likely, a hoax.

Kim Peek Super Memory
Kim Peek

That’s not to said that there aren’t folks with a really good memory. Kim Peek, the famous savant who was the inspiration behind Rain Man, could supposedly memorize each page of a 9,000+ page book, reading at a rate of 8 to 12 seconds per page (with each eye reading its own page). This has not been thoroughly tested, however.

The American actress and author Marilu Henner, on the other hand, can supposedly remember every day of his life. Again, this has not been tested in a clinical setting, and may just be a symptom of an obsessive-compulsive disorder.

Another savant, Stephen Wiltshire, has been called the “human camera” for his ability to draw objects around him several minutes (to hours) after having seen them for the first time. However, again, as precise he is, he takes liberties, so it is not clear if he truly has a “photographic” memory, but he’s the closest to it.

Stephen Wiltshire Eidetic Memory
Stephen Wiltshire

How to Develop Photographic Memory

Solomon, Kim, and Stephen are truly fascinating cases, but they are not normal guys – they have very rare abilities. So, can a normal human being develop photographic memory or the closest thing to it?

The answer is No. Photographic memory can’t be achieved, not even with nootropics. However, by taking nootropics and learning a few techniques, we can develop an exceptional memory. Let’s see how.

Memory: What is It, How to Improve it

There are several stages of memory formation: memory acquisition/encoding, working memory/short-term memory, long-term memory/consolidation, memory retrieval, and reconsolidation.

Five major pathways are essential for the formation, retrieval and reconsolidation of memory: dopamine, choline,AMPA, norepinephrine and adrenergic receptors, and neurotrophic factors (BDNF, GDNF, NGF).

  • Choline is essential for short-term memory and memory consolidation
  • Dopamine helps focus, motivation and general cognition[5]
  • Norepinephrine is a memory modulator[6] and it’s essential for memory retrieval[7]
  • AMPA improves synaptic plasticity and strengthen synapses
  • BDNF is important for long-term memory[8], learning, and synaptogenesis[9]

NGF is also important for neurons health and memory — but only in old subjects, as it actually impaired memory when given to young rats[10], so we’re not going to focus on it too much. Same for norepinephrine and adrenergic receptors, GDNF, Sigma, cAMP, PKA, CRE, CREBs and other minor neurotransmitters/neuromodulators.

References   [ + ]

Categories
Biohacking Tutorials

The Ultimate Guide To Hair Loss: A Scientific Approach

Male-pattern hair loss, also known as androgenic alopecia, or male-pattern baldness (MPB), is a very common condition, affecting 70% of males and an ever-increasing number of females at some point in their life. A British research poll conducted on males ages 18 to 30 asked the question, “what do you fear the most?” The number one answer was hair loss,[1], surpassing erectile dysfunction, sexually transmitted disease and a number of other rather worrying conditions. All over the web, we find remedies — frequently without any scientific basis — on how to “cure” ourselves of this annoying condition. This is the reason why I’ve decided to take a scientific approach to treating hair loss.

What is Androgenic Alopecia?

hair areas regions hair lossAndrogenic alopecia (AGA) is a condition in which the hair follicles progressively miniaturize due to the effects of androgenic hormones. The reason why it is more frequent in males is that the male scalp has regions that are highly sensitive to DHT (dihydrotestosterone), a potent androgenic hormone that has an adverse effect on hair. These sensitive areas are the vertex (crown) and the frontal regions. While hair recession on the temples is a normal part of the aging process of men, recession of the vertex and the midscalp is caused by androgenic alopecia.

Thinning Hair Treatments

Before we venture into the wild world of MPB treatments, it is important to point out that growing back completely miniaturized hair follicles (i.e. totally bald areas) is extremely unlikely and that treatment should be started as soon as possible.

That said, I don’t recommend taking DHT inhibitors (e.g. finasteride, dutasteride) if you are less than 23 years old, as DHT is important for developing the male body. If that’s the case, I recommend taking natural DHT inhibitors such as saw palmetto together with minoxidil until you feel safe about taking a heavy-duty DHT inhibitor. We’ll talk more about that later.

norwood hamilton hair loss scale
The Hamilton-Norwood scale, introduced by Dr. James Hamilton and revised by Dr. O’Tar Norwood, is used as a measurement scale in male pattern baldness.

Minoxidil

Since its introduction in the 1980s, Minoxidil has been used by millions of people all around the world. Everything that could be said on Minoxidil has been talked about many times over throughout the internet. However, it is worth summarizing the vast amount of info we can find on the web in a small recap.

Minoxidil is a drug that was developed as a blood pressure medication due to its vasodilating properties. The drug was effective but had a number of side effects. One of these effects was unexpected hair growth. The increase of hair growth became so obvious that dermatologists began prescribing minoxidil for androgenic alopecia without it having been approved by the FDA. The researchers thus quickly repurposed minoxidil as a hair loss treatment, and the rest is history.

Minoxidil is, as of today, the most effective drug to stimulate hair growth and it is frequently used by transgenders to stimulate beard hair growth. You can buy a 6 months supply for around 26$, which is slightly more than 4$ a month. Side effects may include black circles, body hair growth, wrinkles and faster skin aging. The last two can be prevented with retinoids (more on that later).

Finasteride

Finasteride (Proscar) is a 5-alpha reductase inhibitor (5-ARI). Basically, it inhibits 5-AR, an enzyme that converts excess testosterone into its more androgenic brother, dihydrotestosterone (DHT). As we’ve seen already, DHT — plus other factors, including elevated sebum production, stress, inflammation, and diet — is the ultimate hair killer, so we don’t want that.

Unfortunately, DHT is involved in many bodily processes and functions, such as muscle building, depression and anxiety, body hair (generally people with a lot of body hair are more susceptible to androgenic alopecia), height and so on. finasteride dht inhibitionThat said, the incidence of side effects in Proscar (finasteride) patients is very low and around the same rate as a placebo (sugar) pill. So, why there are people all over the internet screaming about how finasteride “shrunk their balls” or destroyed their life forever? As usual, I think the truth is somewhere in the middle. In my experience, yes, finasteride slightly lowers libido. However, the effect is not as bad as some people say, and it gets better with time.

Some of the complaints may come from the fact that doctors are prescribing a higher dose than needed. The dose for hair loss is 1 mg a day (and 5 mg for prostatic hyperplasia), but according to several studies, a single dose of finasteride will lower DHT for almost a week. In fact, one study demonstrated that 0.05 mg of finasteride was nearly 50% as effective as 100 times the dose of 5 mg in reducing serum DHT after a single dose. Not only that but with daily dosing it was almost 90% effective as 1 mg!

My recommendation thus is — if you choose the oral route — to take between 0.25 to 0.5 mg every other day (or every day if your DHT levels are really high).

Topical Finasteride

One question that always struck my mind about finasteride is why the scientists that were developing it never thought about going by the topical route. I’m not a scientist but it just seems more logical to me to apply a hair loss drug directly on the hair follicle rather than taking it orally, don’t you think?

Clinical Studies

Fortunately, in the last decade, we’ve seen more and more studies being done with topical finasteride. In a study conducted in India last year[2], the researcher switched patients aged 20 to 40 years old from oral finasteride to a solution of 5% minoxidil and 0.1% finasteride. Of the 45 patients that underwent treatment, 84.44% of them maintained a good hair density with the minoxidil-finasteride combination.[3] Five of them stopped the treatment for a period of 8-12 months and then resumed it. Of those five that stopped the treatment, 4 of them had a good improvement when they resumed treatment.[4]

A Swiss study[5] compared the efficacy of topical vs oral finasteride. The results were clear: 1 mg of topical finasteride once a day reduced DHT levels in the scalp more effectively than 1 mg of oral finasteride.[6] The former reduced DHT levels by 71% while the oral finasteride only reduced them by 51%. Both administrations reduced DHT blood levels, so if you get side effects with Propecia, you will likely get side effects with topical finasteride. They also tried 0.5 mg of topical finasteride twice a day, but that only reduced scalp DHT levels by 47%.




To obtain a topical finasteride solution you need to crush Proscar (or generic finasteride) tablets in your Minoxidil solution. You should try to obtain between 0.05 and 0.1% of finasteride. Start at 0.05% twice a day and work your way up.

Black Castor Oil + Peppermint Oil

Castor oil has been used as hair growth tool since early times, but only recently has it been rediscovered as a scientifically-proven hair growth oil.

Prostaglandin D2
Prostaglandin D2

Before we go any further, we need to point out the discovery in 2012 by dermatologist Luis A. Garza and his team, that men with androgenic alopecia have high levels on the scalp of the enzyme prostaglandin D2 synthase (PTGDS) and its product prostaglandin D2.

Yin & Yang: Prostaglandin D2/E2

Prostaglandin E2
Prostaglandin E2

During a normal hair cycle, the levels of PTGDS increase immediately before a regression phase. The researchers thus assume that PTGDS and PD2 have an inhibitory effect on hair growth and that prostaglandin D2 inhibitors can, therefore, be used to stimulate hair growth.

On the other hand, we have prostaglandin E2 (PGE2) that stimulates hair growth.[7] Bimatoprost, a PGE2 analog, is currently being researched as a hair loss treatment.

“That’s cool and everything,” you may say, “but what does it have to do with Castor or Peppermint oil?”

  • Castor oil contains ricinoleic acid, a fatty acid with anti-inflammatory and analgesic activity that activates the EP3 prostanoid receptor for prostaglandin E2.[8] Unfortunately, it is terribly understudied, which is quite strange since castor oil has been a popular hair treatment for years, particularly in Jamaica.
  • Peppermint oil in a 3% solution stimulated hair growth in mice[9] through an increase in IGF-1 mRNA expression. The results were similar to those obtained with Minoxidil.
  • By combining these two oils with Minoxidil and topical finasteride, we can achieve incredible hair growth. I personally have achieved hair growth in remarkably “difficult” areas such as the temples. It’s important to start as early as possible before the hair follicles miniaturize completely.
    I personally use June Milnrow Peppermint Jamaican Black Castor Oil which combines flaxseed, peppermint, and black castor oil together, but it can be a bit expensive to buy it in the US, so here’s another one manufactured in the USA.
  • There are other oils that may aid hair growth. One of these is pumpkin seed oil (PSO), which is a well-known 5-AR. A 2013 study compared the effect of pumpkin seed oil to placebo in 76 patients suffering from mild to moderate androgenic alopecia. Half of them were assigned to the treatment group (400 mg of pumpkin seed oil capsules) and the other to the placebo group. The patients were instructed to not take any hair loss treatments (both topical and oral) for the 3 months prior to the study. The Mean Hair Count in the treatment group increased by 40%, whereas in the placebo group it increased by 10%. The study did not address the topical use of PSO nor the (common) combination of pumpkin seed oil with other natural 5-alpha reductase inhibitors (like in saw palmetto complex).

Dermaroller and Dermapen™

dermaroller
Dermaroller

A dermaroller is a skin needling device. The concept behind it is that by penetrating the skin with small needles, you can stimulate collagen production without leaving scars. A dermapen is pretty much the same; the only difference is that by removing the rolling process it is more gentle on the skin, which should theoretically heal faster and have better results. It is also a hundred times more expensive, so unless you have a lot of money to throw away, I recommend going with the dermaroller.

Which Dermaroller Should I Use?

There are dermarollers of all (needle) lengths, ranging from 0.2 to 3 mm. Generally, the lengths used to stimulate hair growth are between 0.2 to 1.5 mm. So which one should you buy? The answer is: it depends.
There are two ways of doing this:

  • If you’re a minoxidil user, I recommend a 0.25 mm dermaroller to be used every other day (or every day if your skin tolerates it) before applying minoxidil. This will increase minoxidil absorption — and thus, efficacy — a lot. At this length, however, it is not able to stimulate collagen production, and its only purpose is to boost the absorption of topical products.
  • If you do not use minoxidil, or you use it but are willing to go the extra mile to regrow hair, then choose with a 1 to 1.5 mm dermaroller to be used once a week.
dermaroller-skin-penetration
Skin penetration of different dermaroller needle lengths

A 2013 study[10] compared a group of patients taking 5% minoxidil twice a day to another group taking 5% minoxidil and using a weekly dermarolling regimen (the dermaroller chosen had 1.5 mm needles). The mean change in hair count after twelve weeks was significantly better in the dermaroller group compared to the minoxidil only group (91.4 vs. 22.2 respectively).[11].

Tretinoin

Tretinoin (Retin-A), is a vitamin A (retinol) derivative. Retinoids are terribly understudied as hair loss treatments, but according to a clinical review,[12] they are important for hair growth, especially when paired with minoxidil[13] and used on females.[14] A study showed that tretinoin and 5% minoxidil once a day was as effective as 5% minoxidil twice a day.[15]

I think tretinoin 0.025% (or even just retinol itself), is a good addition to my hair loss regimen but it is not as important as the other compounds. They are important, however, to make once a day dosing of minoxidil/topical finasteride possible. So, in the end, I’ll probably keep using it (or resort to retinol should tretinoin get too expensive).

Putting It All Together

Now that we have discussed some of the most effective and convenient treatments for combating hair loss, we can use this information to develop a treatment regimen.

Regimen A

Morning

  1. wake up
  2. do a 0.25 dermaroller routine on the scalp alternating a day on and one off (or 1.5 mm once a week)
    go back and forth each roll
    dermaroller technique
  3. apply minoxidil-finasteride 5%/0.1% solution on dry hair
  4. apply a thin film of tretinoin or retinol on the hair line and vertex

Afternoon

  1. apply castor oil on the hair line, vertex and other balding areas

Regimen B

Morning

  1. wake up
  2. split a 1 mg tablet of finasteride and take half of it (every other day)
  3. do a 0.25 dermaroller routine alternating a day on and one off (or 1.5 mm once a week)
    go back and forth each roll
    dermaroller technique
  4. if the skin is not bleeding, apply 5% minoxidil solution, otherwise wait for it to stop bleeding

Afternoon

  1. apply 5% minoxidil
  2. apply castor oil on hairline and vertex

Do not dermaroll if skin if hasn’t healed yet and follow the instructions on the box closely.

Other Useful Tips for Thinning Hair

  • I recommend a complete head shave when starting the regimen. The reason is simple: doing so will allow the dermaroller (and thus the minoxidil/finasteride) to penetrate deep into the skin and strengthen the hair follicle significantly. After that you can grow your hair normally.
  • Avoid wearing hats or other constrictive headwear, they will speed up hair loss and cause more problems such as traction alopecia or scalp folliculitis.
  • To stimulate hair growth, use shampoos or creams containing caffeine[16] [17], copper peptides or miconazole (the -azoles have a synergistic effect with minoxidil).
  • Supplementing Biotin, Copper, Zinc, MSM and the amino acids L-Cysteine, L-Methionine, and L-Lysine will also stimulate hair growth. A good overall supplement is Country Life Maxi-Hair Plus
  • In my experience, N-Acetylcysteine (NAC), a more bioavailable form of the amino acid Cysteine in high doses (600 mg twice a day) will significantly stimulate hair and beard growth.
  • Blocking DHT with finasteride will increase estradiol (estrogen), a female hormone. To avoid that, consider buying a diindolylmethane supplement, which is a compound found in cruciferous vegetables that reduces the levels of estrogen.
  • Other supplements to help reduce or eliminate Propecia’s side effects are zinc and grape seed extract. The latter is a strong aromatase inhibitor, a substance that inhibits the conversion of testosterone to estrogen.
  • Aromatase inhibitors may reduce finasteride efficacy — particularly the pharmaceutical ones — so keep that in mind should you consider taking one.

So that’s it for now, folks! For any questions or suggestions leave us a comment and we’ll get back to you!

References   [ + ]

Categories
Modafinil Nootropics

Modafinil is the New Ritalin© — Where To Buy It

Modafinil, also known as Provigil, is a drug used to treat chronic daytime sleepiness. An entire generation of students and entrepreneurs, however, certify its use as a study aid. It is a prescription medication, but generic Modafinil can be bought on the internet without issues as long as it is for personal use. Let’s have a look at some of the basic things you need to know before you buy Modafinil online.

What is Modafinil?

ModafinilModafinil is a “eugeroic”, aka a wakefulness-promoting agent – that is, a drug used to enhance wakefulness among individuals suffering from excessive daytime sleepiness. It is clinically used in narcolepsy, to treat shift pattern sleep disorders, sleepiness induced by sleep apnea and so forth. The drug boosts wakefulness in individuals, but obviously, it does not make up for the loss of sleep one may experience. Modafinil works by relieving individuals from the symptoms related to lack of sleep or fatigue. It works on various parts of the brain that play a pivotal role in the wake and attention process.

Modafinil is also used off-label to treat fatigue and sedation in a number of conditions, including fibromyalgia, depression, Parkinson’s disease, myotonic dystrophy and opioid-induced sleepiness. A study done on 72 patients with multiple sclerosis showed that modafinil improves the symptoms of fatigue related to MS. [1] Modafinil also improved mood and relieved sleepiness and fatigue when used as an adjunct to antidepressants, in particular, SSRIs. [2] [3]

Modafinil as a Learning Tool

Modafinil Use Ranking UK UniversitiesFrom what we gathered so far, Modafinil seems to be an excellent stimulant and fatigue-relieving drug in some medical conditions. If you are reading this article, however, it is likely that you are interested in using Modalert as a cognitive-enhancing nootropic.

A 2014 online survey by the students website The Tab[4] showed that 1 in 5 students[5] (out of a sample of almost 2000 UK students)[6], has taken Modafinil to enhance their study sessions. Topping that list, the University of Oxford, one of the most prestigious schools in the world, with 26% of Oxonians who participated in the survey being Modafinil users. Another interesting find of the survey is that 9% of those who use Modafinil think it of it as cheating (but they keep on taking it).[7]

Sounds too good to be true? It isn’t.

A systematic review of 24 studies on Modafinil done last year[8] concluded that Modafinil improves learning —particularly in long and complex tasks—, as well as enhancing decision-making and planning, while also having at the same time an excellent safety profile.[9] Some of those studies also showed an improvement in flexible thinking and concepts association, as well as other cognitive benefits.

Adrafinil vs Modafinil

Adrafinil is the oldest of the afinil drug family. It is a pro-drug of modafinil: when the liver metabolizes Adrafinil, it converts it into Modafinil. The main difference between Modafinil and Adrafinil are efficacy (Adrafinil is a lot less efficient compared to Modafinil) and side effects profile. Adrafinil can cause pain, anxiety, skin irritation and increased liver enzymes with long-term use It has been abandoned in clinical practices due to less desirable pharmacological profile.

modafinil liver metabolization modafinil

Modafinil vs Armodafinil

Technically speaking, Armodafinil consist of solely the (R) enantiomer of Modafinil. There are subjective differences between how these two drugs affect your brain. Armodafinil appears to be cleaner and more effective, but it is also a lot more expensive. Some say that Armodafinil was developed by Cephalon — the company that owns the rights of -afinil drugs — simply because the Modafinil patent expired and they did not want to lose their primary source of income. But this, of course, is only a speculation.

Where to Buy Modafinil

Modafinil requires a prescription, but because of affordability and quality of the generic equivalents Modalert and Modvigil, in the past years, it has turned be the brand of choice for millions of students and entrepreneurs around the globe. We recommend ModafinilXL as a legit and reliable supplier of Modafinil and Armodafinil for the USA, and RUPharma for the EU and UK markets.

Conclusion

Modafinil is a one-of-a-kind drug. Not only that but its safety profile and its nootropic potential has been used by students all over the world to boost their grades and learning abilities with excellent results. That said, there is a minority of individuals that are non-responders: they are naturally immune to Modafinil (and other -afinils). The majority of people that try it, however, has a positive experience.

Modafinil
10
Focus
8
Mood
8.5
Memory
9
Stimulation
6.5
Relaxation
8.5
Safety
Reviewer 9.5

References   [ + ]

Categories
Health

10 Conditions That Cause Chronic Fatigue

With our hectic lifestyles and less than optimal health habits, feeling like you have no energy is a modern day epidemic. For an ever-increasing number of individuals, however, feeling tired

Sleep

Sleep is essential to our body. It allows the brain to consolidate memories and thoughts, and to work more efficently. Poor or inadequate sleep can wreak havoc on your mental health by disrupting your circadian rhythm, and this, in turn, causes fatigue and brain fog just like chronic fatigue syndrome.

Check out our Sleep Optimization Checklist for a list of useful tips on how to improve your sleep quality.

Diet

The most common cause of fatigue is a poor diet. A good diet is not necessarily about losing weight, it’s about eating healthy food and feeling better. In this highly advanced and globalized society where you can buy and eat all kinds of delicious foods from all over the world, we are getting fatter and sicker compared to previous generations. Here’s why…

a. Nutritional deficiencies

Iron deficiency (often found with vegetarians and vegans) and lack of vitamin B12 can cause anemia, a common pathology where the blood cannot supply enough oxygen to the body due to a lack of important nutrients.

High-potassium-foodLow potassium and magnesium levels are also associated with low energy and fatigue. Low potassium can be easily treated by eating bananas: one banana contains around 425 mg of potassium [1], so eating two bananas a day for a week can easily replenish the potassium stores of the body.

Magnesium is a key nutrient. Over 300 enzymes require the presence of magnesium ions, including all enzymes synthesizing ATP (the primary source of energy in cells) as well as DNA and RNA. It is, unfortunately, becoming harder and harder to find in today’s highly-processed food. Because of this, the only method to replenish the magnesium ions in the body is to use a magnesium supplement. It’s essential to get a good magnesium supplement – most of the commercial magnesium brands contain “cheap” inorganic forms for economic reasons. These are usually magnesium oxide, magnesium chloride or sulfate, which have very low bioavailability and are often used as laxatives. The most effective magnesium forms are malate, glycinate, orotate, and taurate. We recommend the malate salt which is especially effective for pain and fatigue. A less expensive option is magnesium citrate.

b. Excessive carb intake

99carbsOther than nutritional deficiency, an excessive intake of carbohydrates is a very common cause of chronic fatigue.

First of all, we need to remember that the “modern” Western diet is full of carbohydrates, particularly refined carbs such as sugar, corn syrup, fructose, as well as refined flours, grains, and starches. Not all carbs are immediately used by the body. Excessive glucose (sugar) gets stored in the body for future use as glycogen and fat. However, there is one thing that all carbs do: they make the body secrete insulin, and insulin decreases plasma levels of large amino acids that would ordinarily compete with tryptophan for transport (particularly in the blood-brain barrier), therefore increasing tryptophan availability.

Tryptophan and its metabolite, serotonin, have a complex role in the brain, but the two things they are most known for is regulating mood and hunger. Low levels of serotonin[2] have been associated with depression (even though this is recently being disputed) while high levels (especially its precursor, tryptophan[3]) have been correlated with fibromyalgia and chronic fatigue.

It should also be noted that an insulin spike is followed by a crash, which can further exacerbate symptoms of mental fatigue and depression. And that’s not all!

A group of researchers at the University of Bordeaux found that when rats were given a choice between a sugar substitute and intravenous cocaine, 94% of them chose the sugar substitute.[4]

While the research on cardiovascular disease in the last fifty years has been focusing mainly on the dangers of fats, new research reveals that carbs are actually more dangerous to health than fats. A study showed that a high-carb diet increased blood fats level more than a high-fat diet![5]

If you crave carbohydrates as your primary source of energy, it’s time to cut them back. But the brain needs glucose to function, how can glucose be produced without carbs?

Luckily, this is not really a problem for the human body. If you think about it, the early human diet was made almost entirely of protein and fats. As a matter of fact, the body can produce glucose from proteins through a process called gluconeogenesis. [6]

low-carb-foods

While this idea of a low carb diet [7] may seem a crazy, it actually goes back to the 1920s [8]. Originally developed to reduce symptoms of epilepsy, (back when anticonvulsant drugs did not exist), the ketogenic diet has helped millions people all over the world lose weight and overcome their chronic fatigue as of today.

Without getting too technical, the ketogenic diet forces the body to burn fats rather than carbohydrates. In this process, ketone bodies are created, and they replace glucose as the body’s primary source of energy. When there is a high blood level of ketones the body goes into a ketosis state, which leads to a reduction of the frequency of epileptic seizures.

But that’s not all! Without carbs to get in the way, the body starts burning fats at a much higher rate, and this helps those in overweight in shedding excessive fats and reach the desired weight.
For more information check the keto subreddit.

Parasites

Even though parasites may make you think of Third World countries, they are still fairly common in civilized nations. Tapeworms, hookworms, pin worms, liver flukes, giardia, these are just a few of the parasites that cause disease in humans.

intestinal parasites

Symptoms of parasitic infestation include:

  • fatigue and lethargy
  • abdominal pain and swelling
  • fever
  • vomiting
  • diarrhea
  • malnutrition and anemia
  • loss of appetite and blood

The severity of these symptoms depends on the type of parasite, the number of parasites, and the site of the infestation. Most infections are asymptomatic, especially in the early stages. Parasitic infections are usually treated with benzimidazoline drugs like mebendazole (Vermox) and albendazole (Albenza) while protozoan parasites (like giardia) are treated with nitroimidazole antibiotics like metronidazole (Flagyl) and tinidazole (Tindamax).

“Colon cleanse” supplements have never been proved to work, and they should not be used as a primary treatment but only to augment the efficacy of antiparasitic drugs.

Eating good amounts of garlic, papaya, and black pepper, and taking a zinc supplement, may reduce the severity of the infestation.

Thyroid

thyroidHypothyroidism is a common condition caused by the thyroid not producing enough thyroid hormones (T4 and T3). This generally happens for two reasons: Iodine deficiency or Hashimoto’s thyroiditis.

Iodine deficiency is the most common form, and it is caused by an inadequate amount of iodine in the diet. This type of hypothyroidism is fairly widespread in second and third world countries. One of the ways in which governments have tried to prevent this is by promoting the use of iodized salt (table salt with additional potassium iodide).

Hashimoto’s thyroiditis, on the other hand, is an autoimmune disease in which the immune system sees the thyroid cells as an enemy and attacks them. It is one of the most common causes of hypothyroidism in the United States.

But fatigue is not only a symptom of hypothyroidism: it can, (even though it’s less prevalent), also be a symptom of hyperthyroidism, the opposite of hypothyroidism.

If your metabolism is too slow (or too fast), or if you can’t stand hot (or cold) temperatures, you should check TSH, T4, and T3 levels through a blood test.

It is a good idea to supplement the building blocks of thyroid cells: iodine and selenium (200 mcg each). Iodine can be supplemented with a potassium iodide supplement or Lugol’s iodine. Selenium should be supplemented in the selenomethionine form since sodium selenite is a pro-oxidant, which is not something we generally want (unless you have cancer).[9]

Medications

A fairly common side effect of some medications (especially those that act on the brain) is fatigue. If you are taking supplements, it’s also a good idea to stop taking them one at a time for a couple days and see if there is an improvement.

In general, the worst offenders are antidepressants, antipsychotics, antihistamines, and beta blockers. Please consult a medical professional before you stop taking a psychiatric medication.

That being said said, here is a list of medications commonly associated with fatigue, sedation and brain fog:

  • Antidepressants: mirtazapine (Remeron), citalopram (Celexa), paroxetine (Paxil), trazodone (Desyrel), mianserin (Norval), amitriptyline (Elavil), imipramine (Tofranil), clomipramine (Anafranil) etc.
  • Antipsychotics: all of them
  • Antihistamines: diphenhydramine (Benadryl), promethazine (Phenergan), hydroxyzine (Atarax)
  • Beta-blockers: all of them
  • Benzodiazepines: alprazolam (Xanax), diazepam (Valium), lorazepam (Ativan), clonazepam (Klonopin)

Adrenals

adrenal-hormonesThe adrenal glands are two small glands that sit on top of the kidneys. They produce a variety of hormones, including cortisol, adrenaline, and aldosterone, through a process called steroidogenesis.

The adrenals produce three types of hormones: mineralocorticoids, glucocorticoids, and androgens.
Mineralocorticoids help blood pressure regulation and electrolyte balance.
Glucocorticoids — including cortisol and corticosterone — regulate the immune system as well as metabolism.
Androgens are steroids that get converted to fully functional sex hormones in the gonads and other target organs.

There are a number of diseases that affect the adrenal glands. An overproduction of cortisol causes Cushing’s syndrome and a deficiency of cortisol causes Addison’s disease. Cortisol and adrenaline are implicated in the stress response (“fight-or-flight response“). Too much cortisol promotes stress and anxiety and not enough cortisol causes chronic fatigue.

But why do the adrenals stop working properly? Two common reasons are either stress or a over-consumption of drugs that affect the adrenal glands, like caffeine and amphetamines.

About caffeine and stimulants…

Seriously, who doesn’t love a cup of coffee in the morning? It tastes great, helps you wake up and stay focused, it’s full of antioxidants, and protects your liver — this “liquid gold” can truly be a lifesaver when used correctly. But an excessive or poorly timed use of coffee and other caffeine sources, on the other hand, can stress your adrenal glands and disrupt your sleep cycle (which by itself increases cortisol).

As a rule of thumb:

  • avoid taking caffeine after 5 pm
  • limit intake of caffeine to no more than 300 mg a day (a cup of coffee usually contains between 60 to 100 mg of caffeine)
  • do not mix caffeine p0wder or coffee with other stimulants

The same principles more or less apply to stimulants. They may seem like a good idea when you’re feeling exhausted and unmotivated, but if the fatigue is a symptom of a chronic condition they end up doing more harm than good.

Excessive use of stimulants may lead to burn-out, psychosis, and neurotoxicity.

Inflammation

disease caused by chronic inflammationInflammation is part of the process that begins as a response of the body to harmful stimuli. Inflammation is usually caused by an infection, but that is not always the case – in some cases, the harm done by years of an unhealthy lifestyle (through smoking, drug abuse, over-consumption of alcohol, or an inadequate diet), can produce a chronic inflammatory state.

Chronic inflammation – whether caused by infection or a bad lifestyle – is associated with heart disease, muscle loss, cancer, depression (and other mood disorders), shortened lifespan, and autoimmune diseases.

Methylation cycle

The methylation cycle is a biochemical pathway that regulates a number of bodily functions, including detoxification, the immune system, energy production, and mood. Explaining the methylation cycle is a bit out of the scope of this article, and I’ll address it in a future one.

What is important to know is that individuals generally fall into two categories: under-methylators and over-methylators. Typically these genetic differences in methylation are discovered by genome testing, like 23andme.

Here you can read more about the methylation cycle, how it works and how is it linked to chronic fatigue and poor mental performance.

Conclusion

In the end, there are many conditions that cause or mimic chronic fatigue. As chronic fatigue is a relatively complex and still pretty unknown syndrome, it is a good idea to test for all the conditions we just explained, before giving up to the diagnosis.

As a matter of fact, there are other conditions that may cause this syndrome – like hypogonadism (low testosterone levels), or high blood ammonia – but we left those out to cover them in detail in future articles.

Have you enjoyed the article? Do you feel like you may have one of this conditions? Leave us a comment!

References   [ + ]

Categories
Life Extension

Metformin, A Breakthrough in Life Extension Research

As we already covered before, 2016 shows a lot of promise to be a great year for life extension research. One of the most interesting studies planned for this year is the TAME trial[1] (Targeting Aging with Metformin), a study that will test the use of aforementioned compound as a longevity drug in older adults who have cancer, heart disease, or cognitive impairment (or are at risk for these diseases).

What is it, exactly?

Metformin 3d skeleton
Metformin 3D structure

Metformin, also known as Glucophage ®, is an anti-diabetic drug that works by suppressing glucose production in the liver. Unlike the majority of diabetes drugs, however, it does not cause hypoglycemia (low blood sugar), even when given to non-diabetics.

Metformin is a drug of the biguanide class. As such, it resembles the compounds guanidine and galegine, found in the Galega officinalis plant (aka goat’s rue). Goat’s rue was known to have anti-diabetic activity since ancient times, but it proved too toxic to use.

The beginning of the history of metformin, however, has almost nothing to do with type 2 diabetes, but with an even worse disease: malaria.

History of Metformin

Cinchona officinalis bark
Harvested bark of Cinchona officinalis

Malaria is a disease caused by a parasitic microorganism of the Plasmodium species. The typical treatment for malaria before the advent of synthetic drugs was quinine, an alkaloid extracted from the bark of the South American tree Cinchona officinalis.

Quinine was expensive, and some parasites became resistant to it. Furthermore, the drug was imported from Java and the supply was unpredictable. In the 1930s, researchers began to discover and synthesize alternatives to quinine. A chemist named Francis H. S. Curd started investigating pyrimidine analogs at the ICI laboratories at Blackley, Manchester, after he noticed that some drugs with mild antimalarial activity had a pyrimidine ring in their structure.

Goat's rue
Goat’s rue

A number of compounds were synthesized and tested on malaria-infected chicks. Some of them were also tested on humans, but they proved too toxic for clinical use. Nonetheless, Curd persisted on in his research, and he figured out that using only a portion of the pyrimidine structure could potentially minimize toxicity while maximizing antimalarial effects. Paludrine, the fruit of Curd’s successful hypothesis, was synthesized in 1945. It is also interesting to note that part of Paludrine’s structure closely resembled galegine, the active component in goat’s rue mentioned above. Animal studies conducted two years after Paludrine’s discovery established that it was able to cause a small decrease in blood glucose. At the same time, in the Philippines, molecules of the same biguanide class were used by Dr. Eusebio Garcia, a local expert in infectious diseases. He noticed that flumamine, a guanidine analog, cured malaria in addition to lowering blood sugar levels.

The real breakthrough came with the work of French diabetologist Jean Sterne. While working at Aron Laboratories in Paris, he was prompted to action by Garcia’s report on flumamine. In collaboration with Denise Duval and others, he evaluated the anti-diabetic effect of flumamine in animals. It showed a powerful glucose-lowering effect which led him to coin the name Glucophage ®, meaning “glucose eater”. He published his results in 1957.[2]

Flumamine eventually became metformin and, in 1962, the first major clinical trial that tested metformin’s efficacy in type 2 diabetes was published.[3] 39 subjects were involved in the study, with almost all of them being over 30 years old. The study came to the following conclusions:

  • of the 39 patients, 14 showed satisfactory control of the disease with metformin
  • another 6 showed some improvement if the metformin was combined with low-dose insulin or another oral anti-diabetic agent
  • ‘pancreatic’ diabetics (now known as type 1 diabetes) did not respond to the treatment
  • treatment was with 1–3 grams of metformin per day, given as three divided doses, titrating up slowly and limited by the emergence of certain side effects.

Metformin was not the only biguanide anti-diabetic discovered in the 1930s. Phenformin and Buformin, used respectively in America and Europe, were actually stronger in anti-diabetic activity and had been the drugs of choice for type 2 diabetes up until the 70s, when they were banned after an ever-increasing number of deaths by lactic acidosis. Because metformin was seen as closely related to these two drugs, metformin’s public image was damaged. Although metformin hardly ever causes lactic acidosis, its damaged reputation meant it would take longer to catch on.

The next few decades saw a steady accumulation of data concerning metformin’s effectiveness and safety. One study, in particular, helped establish Glucophage ® as a safe and effective treatment for diabetes. The United Kingdom Prospective Diabetes Study, conducted from 1977 through 1997, effectively gave scientific evidence that metformin increases the lifespan of patients with obesity and type 2 diabetes.[4] Patients treated with metformin also had less incidence of heart attacks when compared to those treated with insulin or other diabetes drugs.

The Food and Drug Administration (FDA) of the United States approved metformin in 1994, which prompted its ascent as a popular diabetes drug in America. The patents covering metformin expired in 2002, which allowed it to be produced and sold inexpensively as a generic drug.[5]

New uses for an old drug

Cancer

fight cancer with metforminEven though the research on Metformin as a cancer prevention tool is still in its infancy, it appears to be very promising. Metformin and other biguanide medications have been increasingly investigated for their chemopreventive (cancer-preventive) and antineoplastic (tumor growth-inhibiting) properties. There have been various studies conducted on lab animals that investigate metformin’s ability to reverse or prevent tumor growth. One meta-analysis on the subject reported that metformin’s effects on cancer have been tested on 17 different organs in various strains of rats, mice, and hamsters. Some studies investigated its effects on naturally-occurring cancer while others investigated how it affected cancer induced in the lab by 16 different chemical classes of carcinogens. In other words, metformin’s anticancer effects were studied under a wide variety of unique and nuanced cases of tumor growth. Many different dosing regimens and routes of administration were also tested.[6] In the majority of cases (86%) the treatment with metformin and other biguanides led to inhibition of carcinogenesis. No cases of stimulation of carcinogenesis by the antidiabetic biguanides were ever detected.

While the mechanism of action for the chemopreventive activity of Metformin is not entirely clear, it is likely caused by the activation of AMPK-dependent and AMPK-independent pathways, in addition to energy metabolism aberration, cell cycle arrest, apoptosis or autophagy induction,[7] as well as mTOR signaling inhibition.[8]

Life Extension

In April of 2003, researchers at Biomarker Pharmaceuticals in California studied the effects of metformin on aging processes and longevity. The researchers found that metformin actually mimics the anti-aging effects of caloric restriction. Caloric restriction is a type of dietary method that involves consuming a significantly reduced amount of calories while still consuming proper amounts of essential vitamins and nutrients. This method has been touted by some to slow the aging process and extend lifespan. When tested on mice, metformin appears to induce a change in gene expression that is identical to that caused by a CR diet. This change in gene expression has the potential to extend animal life spans by 20 percent. Metformin is the first medication that has been discovered to mimic the effects of a CR-induced lifespan extension.[9]

Another study published in the AGING Journal showed that female mice treated with metformin from an early age lived longer and had fewer tumors. These effects were not seen in aged mice[10]

Contraindications and Side effects

Metformin is a relatively safe drug. As said before, it can be taken by non-diabetics as long as the dose does not exceed 1500-1700 mg. A good idea is to check blood glucose levels. It’s not advised to take Glucophage ® should the blood glucose levels be equal or lower than 80mg/dL.

Metformin should not be used in those with liver disease, kidney problems or lung disease, and any other condition that could increase the risk of lactic acidosis.

Long-term use of high doses of Metformin may cause Vitamin B12 deficiency[11], especially in those who do not consume animal products (vegetarians and vegans). The amount of B12 in a multivitamin is generally not enough to correct the deficiency[12]. It is therefore a good idea to supplement Vitamin B12 when taking Metformin.

Even though it doesn’t have serious interactions, be sure to check the Metformin page on Drugs.com or the patient information leaflet.

The most common adverse effect are related to the gastrointestinal system, and may include diarrhea, cramps, nausea, vomiting, and increased flatulence. To avoid these side effects Metformin should be started at the lowest dose (500 mg) and slowly increased to the desired dose.

Conclusion

Metformin has been a revolutionary drug for diabetes, and new research on biguanides shows that these drugs may enhance lifespan as well as prevent cancer. While it’s still a bit early to recommend metformin to every >50 years old, (or subjects in high-risk populations, like smokers), we’re finally getting closer to a real breakthrough in life extension research.

More research is needed in order to understand the correct dosage and efficacy of Metformin in humans.

References   [ + ]

Categories
Nootropics

The 14 Best Nootropics for Anxiety

As we collect evidence provided to us by our ever-expanding group, we’ve come up with a few good remedies. Anxiolytic drugs are known to “relieve anxiety”.[1] Many of us suffer from anxiety ranging from slight to severe impairment. It is wise to note that some drugs, such as Bacopa, have enhanced efficacy after chronic administration.[2] Others, such as Tenoten, are applied sublingually and can be used to treat acute anxiety.[3] Any of the information here is not to be used or substituted for medical advice.

Bacopa

4 out of 5 stars
Bacopa monnieri nootropics for anxiety
Bacopa monnieri

Bacopa monnieri (also known as Brahmi) is one of the most important herbs in Ayurvedic medicine. It has been used for centuries as a mental tonic originating in India.

Bacopa has been shown in studies to relieve anxiety, improve cognition, and enhance memory formation.[4] [5] In a rat study, Bacopa increased the levels of serotonin and enhanced the gene expression of serotonin transporters[6]. Studies have shown a relationship between high levels of serotonin and positive mood.[7] [8]

Bacopa also appears to have an adaptogenic effect by reducing the biochemical effects of stress.[9]

To fully appreciate the positive effects of Bacopa, it needs to be taken consistently. Studies have shown more improvement as time passes. [10]

Ashwagandha

4 out of 5 stars

Withania somnifera, commonly known as Ashwagandha, is a popular herb used in Ayurvedic medicine. In Sanskrit, Ashwagandha means “the smell of a horse”, because of its unmistakable smell. It is also believed to give vitality and the “strength of a stallion”.

Ashwagandha is believed to act as a neuroprotector, anxiolytic, anti-inflammatory, thyroid-booster, and libido enhancer.

Ashwagandha activates GABA-A receptors, the mechanism of action responsible for its anxiolytic and sleep-inducing effects.[11]

It has been shown to be as effective as fluoxetine for obsessive-compulsive disorder (OCD) in a mice study.[12]

L-Theanine

3 out of 5 stars
Matcha
Matcha is a Japanese green tea with a very high Theanine content

L-Theanine is a natural amino acid contained in green tea. Most store-bought teas contain minimal amounts of L-Theanine, however, concentrations are greater in teas such as matcha, gyokuro, and kabusecha.

L-Theanine is structurally similar the neurotransmitters glutamate and GABA.[13] L-Theanine is also a neuroprotective agent[14] which increases the amounts of serotonin, dopamine, and GABA in various areas of the brain.[15] It’s commonly used with stimulants, — like caffeine or amphetamines —, to reduce side effects, but it is also effective by itself.

Inositol

3 out of 5 stars

Inositol is a sugar involved in cellular signaling and as a component of cell membranes. There are nine different inositol molecules. The most abundant of these being myo-inositol.

Inositol was once considered a B vitamin (formerly Vitamin B8). It was later found to be producible by the human body, disproving it as an essential nutrient. It is naturally found in small quantities in milk products, fruits, and vegetables.

Research shows high dose Inositol supplementation (18 g) was as effective as fluvoxamine (150 mg) in decreasing the number of panic attacks[16] and reducing the symptoms of obsessive-compulsive disorder (OCD). [17]

Phenibut

5 out of 5 stars

Phenibut is a gamma-aminobutyric acid (GABA) derivative.

GABA is the major inhibitory neurotransmitter in the brain. The mechanism of action of conventional anxiolytics, hypnotics, and sedatives (such as benzodiazepines, barbiturates, and alcohol) increase GABA levels. This is what gives them anti-anxiety, sleep-inducing, tranquilizing, and anticonvulsive effects.

Phenibut was developed in the Soviet Union in the 1960s as a non-sedative alternative to benzodiazepines. Phenibut is part of the Russian cosmonaut medical kit as a treatment for stress.

Phenibut activates GABA-B receptors[18] and boosts dopamine levels.[19]

Picamilon

2 out of 5 stars

Picamilon is another Russian nootropic made by combining niacin (vitamin B3) and GABA. This allows Picamilon to cross the blood–brain barrier[20] and have anxiolytic and vasodilating[21] effects.

It is used in Russia as a treatment for anxiety, depression[22], alcoholism[23], and brain damage.[24]

Aniracetam

3 out of 5 stars

Aniracetam (known as Ampamet in Europe) is a compound of Racetam family. It is a fat-soluble derivative of Piracetam.

Aniracetam modulates AMPA receptors. AMPA is one of the main three excitatory neurotransmitters (the other two being NMDA and kainate receptors). Compounds that act on AMPA receptors are called AMPAkines.

AMPAkines are substances which exhibit neuroprotective and cognition enhancing effects[25]. Some of these have been investigated as treatment for Alzheimer’s disease and other neurodegenerative conditions[26]. Aniracetam is also a potential anxiolytic[27] and antidepressant.[28] Anecdotal evidence states that Aniracetam is effective in some individuals, while others are non-responders.

Coluracetam

4 out of 5 stars

Coluracetam is a relatively new Japanese nootropic drug with little clinical backing. Unlike Piracetam, Coluracetam directly affects High Affinity Choline Uptake.[29] It was shelved after failing to demonstrate efficacy for Alzheimer’s.

Phase IIa clinical trials have demonstrated efficacy for comorbid MDD with GAD (Generalized Anxiety Disorder).

Anecdotal reports state Coluracetam is responsible for a sensation of “HD Vision” as well as lowered anxiety.

Fasoracetam

3 out of 5 stars
Fasoracetam, a novel nootropic
Fasoracetam, a potent and novel nootropic which shows promise to relieve anxiety, as well as reduce ADHD symptoms.

Fasoracetam, also referred to as NS-105, is a novel cognitive enhancer. Fasoracetam is a high-affinity choline reuptake inhibitor, similar to Coluracetam.[30] Many refer to this particular mechanism of action as “HD vision”.

Fasoracetam can act as a sustainable anxiolytic since long-term administration upregulates GABA-B receptors.[31] Anecdotal reports have noted both acute and chronic anxiolytic effects.

Treatment of ADHD, by NS-105, is mediated through modulation of mGluR glutamate receptors.[32] In other words, those suffering from ADHD and/or anxiety may benefit from Fasoracetam’s purported effects.

Tianeptine

5 out of 5 stars

Tianeptine is a tricyclic antidepressant (TCA) developed in France circa 1960. Tianeptine embodies a unique mechanism of action, unlike other TCAs.

Tianeptine was originally believed to be a Serotonin Reuptake Enhancer. Recent research suggests its antidepressant effect is due to the activation of μ-opioid and δ-opioid receptors[33] as well as modulation of AMPA and NMDA receptors.[34]

Tianeptine efficacy is comparable to fluoxetine, amitriptyline, and imipramine (with significantly fewer side effects).[35]

Tenoten

2.5 out of 5 stars

Tenoten is a simultaneous nootropic and anxiolytic with novel properties. Unlike GABA agonists, Tenoten treats anxiety “based on antibodies to the brain-specific protein S-100B”.[36]

“Testing at the Russian Institute of Molecular Biology and Biophysics indicate Tenoten was as clinically effective as amitryptiline (Elavil), sertraline (Zoloft), and phenazepam (a benzodiazepine) for the reduction of anxiety but without sedation. It further recommended Tenoten for patients with moderate cognitive impairment”.[37]

“[Tenoten] demonstrated considerable improvement of the control over brain frontal compartment effector functions”.[38]

In a small trial group of 50 children, Tenoten showed efficacy for the treatment of ADHD symptoms.[39]

Selank

3.5 out of 5 stars

Selank, is an analog of the endogenous peptide tuftsin. Since tuftsin has innate immunomodulatory capabilities, Selank is also able to regulate T cell cytokines.[40] In this way, Selank can be seen as having immunomodulatory properties.

Unlike common anxiolytics, Selank does not cause sedation or cognitive impairment. It is non-habit forming and does not cause withdrawal symptoms.

Selank modulates monoamine transmitters[41] and catalyzes the metabolism of serotonin.[42] Selank causes rapid elevation of BDNF, solidifying its place as a cognitive enhancer.[43]

Although Selank’s mechanism of action is largely misunderstood, evidence suggests it lowers levels of tau(1/2) leu-enkephalin.[44]

Afobazole

3 out of 5 stars

Afobazole (also known by its scientific name Fabomotizole) is a Russian anxiolytic drug which does not possess sedative properties unlike most anxiolytics. Afobazole, similar to Fasoracetam, upregulates GABA receptors.[45] Afobazole restores GABA to healthy levels following ischemia.[46] This is widely regarded to be Afobazoles main anxiolytic mechanism of action.

Fabomotizole also induces BDNF and NGF release, agonizes MT3 receptors, and reversibly inhibits MAO-A [47] [48] [49] [50] [51]. Since Afobazole directly effects BDNF and NGF, it is also classified as a nootropic. Caution should be taken when combining Afobazole with other MAO inhibiting substances. Afobazole may also have an antidepressant effect.

Kava

4 out of 5 stars

Kava is a GABAergic drug which affects the GABA-A receptor in several ways. Kava exhibits reverse tolerance. It is a less-harmful alternative to common GABA-A benzodiazepine receptor agonists. The alkaloids chiefly responsible for Kava’s mechanism of action are called kavalactones.[52] It is becoming apparent that although Kava is confirmed to modulate GABA-A receptors, it may do so in a different method than direct agonism.[53] It appears Kava potentiates GABA-A through poorly understood means.[54] GABA-A receptor density increased following administration of Kava, suggesting both upregulating and sensitizing properties.[55]

A common concern for Kava usage lies in its purported hepatotoxicity. Hepatotoxicity of Kava is a direct result of the extract or plant matter obtained, suggesting quality is paramount to avoiding liver damage. “Risk factors included overdose, prolonged treatment, and comedication with synthetic drugs and dietary supplements”.[56] Indigenous tribes have been using Kava for centuries, with minimal consequences. One can assume toxicity is directly affected by the quality of the plant used.

Most, but not all, of clinical studies, have demonstrated Kava’s efficacy as an anxiolytic. Standardized extract demonstrated the highest efficacy versus placebo. 1 week of chronic administration may be necessary to feel its effects. Evidence suggests Kava may aid in the treatment of insomnia and sleeplessness.[57]

References   [ + ]

1. Definition of anxiolytic by Merriam-Webster
2, 10. Enhanced dendritic arborization of hippocampal CA3 neurons by Bacopa monniera extract treatment in adult rats.
3. The use of tenoten and tenoten (pediatric formulation) as a drug for premedication in adults and children during outpatients dentist visit.
4. Randomized controlled trial of standardized Bacopa monniera extract in age-associated memory impairment.
5. Bacopa monniera, a reputed nootropic plant: an overview.
6. Bacopa monniera leaf extract up-regulates tryptophan hydroxylase (TPH2) and serotonin transporter (SERT) expression: implications in memory formation.
7. Associations between whole-blood serotonin and subjective mood in healthy male volunteers.
8. Serotonergic function in the central nervous system is associated with daily ratings of positive mood.
9. Adaptogenic effect of Bacopa monniera (Brahmi).
11. Pharmacological effects of Withania somnifera root extract on GABAA receptor complex.
12. Influence of Withania somnifera on obsessive compulsive disorder in mice.
13, 14. Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction
15. The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent.
16. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder.
17. Inositol treatment of obsessive-compulsive disorder.
18. On neurotransmitter mechanisms of reinforcement and internal inhibition.
19. Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug.
20. Pikamilon pharmacokinetics in animals.
21. The new cerebrovascular preparation pikamilon.
22. The results of clinical study of the drug Picamilon (analysis of data of neurologic and psychiatric clinics) – AP Huaichenko, RP Kruglikova-Lvova
23. Picamilon Application in Therapy of Patients with Alcoholism, – Novikov VE, Kovaleva LA
24. Picamilon Application in the Complex of Regenerative Therapy of Patients after Insultus
25. AMPA receptor potentiators for the treatment of CNS disorders.
26. Benzofurazan compounds which enhance AMPA receptor activity
27. Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism.
28. Antidepressant-like effects of aniracetam in aged rats and its mode of action.
29. MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal acetylcholine induced by ethylcholine aziridinium ion in mice
30. Involvement of cholinergic and GABAergic systems in the reversal of memory disruption by NS-105, a cognition enhancer.
31. Effect of a novel cognition enhancer NS-105 on learned helplessness in rats: possible involvement of GABA(B) receptor up-regulation after repeated treatment.
32. A novel cognition enhancer NS-105 modulates adenylate cyclase activity through metabotropic glutamate receptors in primary neuronal culture.
33. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist.
34. The neurobiological properties of Tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation
35. Tianeptine: a review of its use in depressive disorders.
36, 37, 38. Tenoten in the therapy of patients with moderate cognitive impairment.
39. Clinical efficacy of tenoten for children in treatment of attention deficit and hyperactivity disorder
40. Immunomodulatory effects of selank in patients with anxiety-asthenic disorders
41. Effects of heptapeptide selank on the content of monoamines and their metabolites in the brain of BALB/C and C57Bl/6 mice: a comparative study
42. Comparison of the effects of selank and tuftsin on the metabolism of serotonin in the brain of rats pretreated with PCPA
43. Intranasal administration of the peptide Selank regulates BDNF expression in the rat hippocampus in vivo.
44. Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia
45, 46. Effects of afobazole on the content of neurotransmitter amino acids in the striatum in global transient ischemia.
47. Clinical study of the selective anxiolytic agent afobazol
48. Gabaergic mechanism of cerebrovascular and neuroprotective effects of afobazole and picamilon
49. Effects of afobazole on the BDNF content in brain structures of inbred mice with different phenotypes of emotional stress reaction
50. Selective anxiolytic afobazole increases the content of BDNF and NGF in cultured hippocampal HT-22 line neurons
51. Interaction of afobazole with sigma1-receptors
52, 57. Kava kava | University of Maryland Medical Center
53, 54, 55. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain.
56. Kava hepatotoxicity–a clinical review.
Categories
Noopept Nootropics

Noopept Review: Effects, Dosage and Side Effects

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

Overview

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

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

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

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

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

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

Benefits of Noopept

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

How to Take

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

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

Noopept
Noopept, as it is sold in Russia

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

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

Side Effects

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

Noopept
7
Focus
5
Mood
7.5
Memory
6.5
Stimulation
6.5
Relaxation
10
Safety
Reviewer 7.7

References   [ + ]