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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   [ + ]

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Nootropics Tutorials

Nootropics: A Beginner’s Guide To Cognitive Enhancers

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

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

Nootropic Trend - Google searches of keyword "nootropics"

What is a Nootropic?

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

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

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

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

Caffeine
Caffeine

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

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

Who Uses Them?

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

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

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

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

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

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

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

Where Do I Begin?

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

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

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

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

Wakefulness and Motivation

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

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

General Cognition

piracetam nootropic adhd

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

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

Mood Improvement

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

Memory

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

What To Expect

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

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

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

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

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

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

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Fasoracetam Nootropics Racetams Reviews

Fasoracetam: How This Nootropic May Help You Focus Better

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

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

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

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

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

Mechanism of Action

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

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

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

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

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

Acetylcholine

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

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

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

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

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

Glutamate

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

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

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

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

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

GABA

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

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

Dosage and half-life

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

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

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

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

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

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

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Bacopa Nootropics

Bacopa Monnieri: The Most Impressive Natural Nootropic

Bacopa monnieri, commonly referred to as Bacopa, it’s a plant that has been used for thousands of years in Ayurvedic medicine. In India, it is also referred to as Brahmi. In the last two decades, many Ayurvedic plants, like Ashwagandha, Brahmi, and Gotu Kola, have been shown to be effective not only in Ayurveda classic books but also in scientific studies; the extract, in particular, has been shown to be as effective as some prescription medications.

Background and Benefits

Perhaps more than other top nootropics, Bacopa highlights the importance of the individual and the makeup of his biology on any given day. Although it reliably promotes enhanced memory and vivid dreaming, other effects are less consistent, often due to the large variety in potency between the different products on the market. Luckily, in the last few years, a standardized and pharmaceutical grade extract has been developed, named Bacognize®.

Bacopa Ayurvedic Medicine BenefitsIt is known to produce clarity or a slight fog, making you relaxed or slightly moody, with the potentiality of leading to mild physical symptoms (like muscle aches and intestinal bloating). In spite of all this critical talk, Bacopa is one of the most underestimated supplements, and this article will paint it as one with profound healing and nootropic abilities. Confused? Don’t worry; we got you covered!

Some of the benefits of Bacopa (according to both scientific research and anecdotal experiences) are:

  • It is neuroprotective[1] and significantly improves acquisition and retention of memories.[2]
  • It also increases acetylcholine synthesis and promotes neurogenesis by enhancing the activity of BDNF and NGF[3]
  • It has anxiolytic[4], antidepressant[5] and anti-stress effects.[6]
  • It is an antioxidant and increases lifespan in animal studies.[7]
  • It is anti-inflammatory[8] and cardioprotective.[9]
  • Bacopa may also help people with epilepsy[10], as well as children with ADHD.[11]

The sedative effect of Bacopa is almost always in the foreground, though anecdotal reports show that this effect happens most strongly at the beginning and tends to disappear after a month (or two) of consistent use. In fact, studies have shown that Bacopa’s peak nootropic effect is seen after two months[12], and keeps on getting stronger as time passes, while the anxiolytic effects are usually felt right from the first dose.

Anecdotal Reports

Before we get into the specifics of Bacopa, let’s have a look at some of the anecdotal experiences in the nootropics community to get a better understanding of how it works in healthy individuals outside the lab.

From Reddit user Nedzilla55

[…] My first nootropic experience, and it was a good one. I noticed acute effects of lowered anxiety, and over the course of a few months noticed increased memory. This amazing herb is subtle enough that I feel normal, but noticeable enough that I felt less stress and anxiety. I didn’t even realize how great it was until I got off of it, and started experiencing my usual increased anxiety. It wasn’t like an acute “Wow, I feel so calm” feeling, more like a background calm. Like turning down the volume of anxiety a couple of notches. Looking back at it, the 6-7 months I used it I was in a much better place mentally. […]

From Reddit user YoungRedPiller —

So I’ve been taking Bacopa Monnieri for about a month at this point. […] I’ll try to explain my experience with it so far.
I’ve heard that the memory effects take at least 8 weeks to show effect but I’ve been feeling some quite significant changes in my ability to recall events that have happened in the past month. It’s also improved the quality of these memories. This is a very nice effect that is very appreciated because I feel if i stick it out for another month my memory will improve noticeably.
One other effect that it’s had that I didn’t really expect it to have was that it made me completely apathetic. To everything. Studying, reading, music, doing anything at all. I’m completely careless to everything and my motivation to do things is very little. But when I start doing things, I don’t want to stop. It’s had a profound effect on my attention. I don’t know if the attention is because of the apathy or something but attention is another aspect that I like about Bacopa. Also due to the apathy, my anxiety is also very minimal in any situation. I completely have a fuck it attitude. Very appreciated as I used to be quite hyperactive.
It’s made me very calm, serene and genuinely carefree. […]

From Reddit user Tester12311

The first month: Contrary to anecdotal reports, I could definitely feel the bacopa kicking in. It acted almost as a mild downer and a definite anxiolytic. I felt calm, chilled out, and careless. […] Many initial reports include drowsiness and upset stomach. Though Bacopa did make me drowsy at first, I can only think of very specific instances with stomach upset which could easily have been as a result of what I ate that day. Besides these mild effects, there was not much else for Bacopa within the first month.
The second month and now: Throughout this entire period of taking Bacopa, I would constantly test my memory to see if it was improving. […] To be completely honest, it is very difficult to measure how much I can and cannot remember. But I can say that when people ask me if I remember something they said the week previous, I am more likely to respond positively. I am also more lucid with conversation topics as I can tie together the flow of a conversation from one topic to another. One can assume that my immediate working memory has greatly improved. […] Bacopa’s anxiolytics effects have also had a nice influence on my life. I am less nervous about social interactions especially with women or job interviews. It has gotten to the point where I really just do not care what people I don’t know think of me. […]
One of the most gratifying and prominent effects that I feel from Bacopa is the attention boost. I have a have a very strong grip on whatever I am doing. It has made reading and studying easier. I can sit and become enamored by a book. I hated reading before Bacopa. I love it now. […]

Learning and Memory

Bacopa Extract PowderBacopa is perhaps most notable for its ability to enhance memory and cognitive performance in mice.[13] In humans, this translates most clearly to improved consolidation of memories into long-term memory.[14] In these respects, bacopa has received a comparable amount of attention (in academic journals) as more mainstream and publicized herbal cognitive enhancers, such as ginkgo.

Later sections will expound on neurotransmitters, serotonin and acetylcholine in particular, which have, respectively anti-stress and pro-cognitive effects. Like other herbal nootropics, its mechanism also relies on adaptogenic properties or lowering stress (this is touched on below, from the perspective of “cytokines,” the body’s natural inflammatory agents).

While not as pronounced as the effect on long-term memory, Bacopa may also be useful for short-term memory, concentration, focus, motivation, and the likes. Clinical studies have found it effective against ADHD[15]. Another study has drawn the same conclusions[16]. This is especially encouraging for those who want to stay away from Adderall, Ritalin, and other pharmaceutical choices, and into other choices which may be more sustainable and less taxing on the psyche.

Inflammation

Inflammation, like oxidation, is too often presented in the press, and almost never in a light which sheds true insight on its value; gradually the public loses interest in the hype and falls into more conservative waters. Despite any skepticism, bacopa has real and impressive anti-inflammatory properties[17]. These anti-inflammatory properties are closely related to its anti-dementia effects, which are as potent as curcumin, and like curcumin may open the avenues in Alzheimer’s research for more potent semi-synthetic derivatives.

Cytokines are compounds which the body releases in response to stress or infection, and although they help to control certain illness, they can quickly lead to runaway inflammation. Many herbal nootropics work in part by regulating this runaway, negative feedback “loop.” Although it is perhaps not as strong as curcumin, there are a few studies and books summarizing bacopa’s effects on inflammation.

Epilepsy

It has been shown in multiple studies to be as effective as common antiepileptic meds. This is likely related to its effect as a modulator of GABA[18], although a direct modulation of glutamate cannot be ruled out as a contributing factor.[19]

Oxidative Stress

The anti-stress effect may be directly related to the antioxidant capacity, as suggested by evidence[20]. Although antioxidants are beaten to death in the media, it is important in the absence of rigorous ORAC testing (free radical savaging capacity) to recognize when a particular food or supplement shows promising activity[21]. Ginkgo, bacopa, turmeric and ginger all show potential here. You can look up the antioxidant and anti-inflammatory ratings for turmeric and ginger to get a rough idea of their potency.

Serotonin and BDNF

Besides its broad antioxidant properties, perhaps the most studied mechanisms of Bacopa have been centered on serotonin[22][23]. It has been shown to upregulate the serotonin transporter (SERT) and to increase brain-derived neurotrophic factor (BDNF) in an animal model of depression[24]. The magnitude of the BDNF effect is supported by studies investigating bacopa’s ability to substantially improve the growth and survival of dendrites and axons: the fragile, spindly structures allowing for communication between neurons.

Dopamine and glutamate

Although bacopa is known to restore dopamine function[25], and as mentioned above, glutamate function as well, it is still not clear the extent to which these factors play into its nootropic qualities. The acetylcholine, serotonin, antioxidant and (as we will touch on later) the cardiovascular properties all likely outshine dopamine and glutamate in this respect.

Physical Health

Bacopa Monnieri has been implicated in increasing specifically cerebral blood flow independent of overall blood pressure[26] it can also decrease blood pressure (both systolic and diastolic) independent of heart rate[27] by releasing nitric oxide — a molecule that helps cells communicate with each other — from the endothelium.

Bacopa is also cardioprotective, and in research has been showed to protect from several cardiotoxic substances, such as isoprotenerol.[28] and may likely have a protective effect for everyday cardiotoxic activities like smoking. drinking, and taking stimulants.

Although it has primarily been studied on opiate (morphine) related kidney damage (where it was found to be effective[29]), it may serve in the otherwise healthy as a general tonifying agent in the kidneys.

Contraindications

Due to its cholinergic activity, those with a known mood disorder should approach bacopa extremely cautiously. High acetylcholine levels have even been used in lab mice to simulate bipolar and borderline features[30].

Bacopa has a potent stimulatory effect on the thyroids. Persons with known thyroid conditions are accordingly advised to consult a healthcare professional before considering bacopa.
As said before, it is known to accumulate heavy metals. Nowadays, most nootropic suppliers have certificates of analysis, and this is not raised as a concern.

Closing Remarks

Buy Bacognize capsulesAlthough bacopa’s initial sedative effect may be partially balanced out by natural energizers, such as ginseng, cocoa or royal jelly, we are recommending you consult a healthcare professional before beginning such an aggressive regimen. It is instead more strongly recommended to simply lower the dose, particularly when using the 50% extract which some people may find too intense.

By the way, you can buy Bacognize capsules and powder at Nootropics Depot. Or, if you’re on a tight budget, check out Powder City’s bulk 50% extract and 20% extract capsules. I personally recommend the capsules as the powder has an unpleasant taste. The dosage depends on the type of extract you have, typically a 50% extract like Bacognize is taken 300 mg once or twice a daily, while a 20% extract is taken at 500-650 mg two to three times a day. It is typically taken with food.

The good news is that much of bacopa’s nootropic effect is cumulative. Although it does take up to four to six months to see full effects, modest effects can still be observed from switching to the lower dose after a mere two months. This is especially true when it is paired off in the long-term with other highly effective and synergistic supplements. You could even take it just one summer, completely remove it from your stack after that point, and still theoretically retain some of its nootropic qualities.

Bacopa Monnieri
6.5
Focus
7.5
Mood
8.5
Memory
5
Stimulation
9
Relaxation
9
Safety
Reviewer 8

References   [ + ]

1. Neuroprotective role of Bacopa monniera extract against aluminium-induced oxidative stress in the hippocampus of rat brain (2006)
2, 14. Chronic Effects of Brahmi (Bacopa monnieri) on Human Memory (2002)
3. Bacopa monnieri and L-deprenyl differentially enhance the activities of antioxidant enzymes and the expression of tyrosine hydroxylase and nerve growth factor via ERK 1/2 and NF-κB pathways in the spleen of female wistar rats. (2013)
4. Anxiolytic activity of a standardized extract of Bacopa monniera: An experimental study. (1998)
5. Antidepressant-like effects of methanolic extract of Bacopa monniera in mice (2015)
6. Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain. (2002)
7. Bacopa monnieri promotes longevity in Caenorhabditis elegans under stress conditions (2015)
8. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. (2016)
9, 28. Cardioprotective Effect of Bacopa monneira Against Isoproterenol-Induced Myocardial Necrosis in Rats (1997)
10, 19. Decreased glutamate receptor binding and NMDA R1 gene expression in hippocampus of pilocarpine-induced epileptic rats: neuroprotective role of Bacopa monnieri extract. (2008)
11, 15. An open-label study to elucidate the effects of standardized Bacopa monnieri extract in the management of symptoms of attention-deficit hyperactivity disorder in children. (2014)
12. Effects of a Standardized Bacopa monnieri Extract on Cognitive Performance, Anxiety, and Depression in the Elderly: A Randomized, Double-Blind, Placebo-Controlled Trial (2008)
13. Effect of bacosides, alcoholic extract of Bacopa monniera Linn. (brahmi), on experimental amnesia in mice (2004)
16. A Randomized Controlled Trial Investigating the Effects of a Special Extract of Bacopa monnieri (CDRI 08) on Hyperactivity and Inattention in Male Children and Adolescents: BACHI Study Protocol. (2015)
17. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. (2016)
18. Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A. (2012)
20. Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain. (2002)
21. Bacopa monnieri as an Antioxidant Therapy to Reduce Oxidative Stress in the Aging Brain. (2015)
22, 23. Bacopa monniera leaf extract up-regulates tryptophan hydroxylase (TPH2) and serotonin transporter (SERT) expression: implications in memory formation. (2011)
24. Chronic Administration of Bacopa Monniera Increases BDNF Protein and mRNA Expressions: A Study in Chronic Unpredictable Stress Induced Animal Model of Depression (2014)
25. Neuroprotective potential of Bacopa monnieri and Bacoside A against dopamine receptor dysfunction in the cerebral cortex of neonatal hypoglycaemic rats. (2013)
26. Bacopa monnieri increases cerebral blood flow in rat independent of blood pressure. (2013)
27. Bacopa monnieri and its constituents is hypotensive in anaesthetized rats and vasodilator in various artery types. (2011)
29. Beneficial effects of Bacopa monnieri extract on opioid induced toxicity (2016)
30. Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features. (2015)
Categories
Methylene Blue Nootropics Reviews

Methylene Blue as a Nootropic? (Review)

Since its initial synthesis in 1886, the phenothiazine derivative methylene blue (MB) has been established as a highly versatile chemical agent with a diverse span of uses, ranging from treating malaria to dying textiles[1]. Within the past few years, preclinical research has suggested a possible neuroprotective benefit from MB administration. MB is believed to promote neuronal cell health by supporting mitochondrial function. Animal studies have yielded promising results in neurocognitive tests[2][3]. Here is what you need to know if you’re interested in using methylene blue.

How does Methylene Blue work?

Mitochondria are organelles within cells that play the key role of energy production. Cellular energy is stored in the form of adenosine triphosphate (ATP), one of the most important molecules in the cell. As the name suggests, ATP contains three linked phosphate groups. Removal of each group releases a large amount of energy, which is expended in supporting cellular function. Subsequent removal of ATP produces ADP (adenosine diphosphate) & AMP (adenosine monophosphate). ATP is produced within mitochondria as a final product of respiration, a series of biochemical reactions that extract energy from glucose. These biochemical reactions require oxygen & electron carriers (e.g. NADH).

Poteet E, Winters A, Yan L, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue & its derivatives. PLoS One. 2012;7(10):e48279-.
Methylene blue acts as an artificial electron carrier, promoting mitochondrial respiration. The net outcome is more energy available as ATP for cellular processes.[4]
Methylene blue supports mitochondrial respiration by functioning as an additional electron carrier[5]. MB receives electrons from NADH through mitochondrial complex I, itself being reduced to leuco-MB (MBH2). Leuco-MB then donates the electrons to cytochrome C, upon which it is recycled back to MB. These reactions serve to create a high proton (H+) concentration in the space between the inner & outer mitochondrial membranes. This leads to the passage of H+ down the concentration gradient, through mitochondrial complex V. In doing so, ADP & a phosphate (Pi) are joined to form ATP. Leuco-MB can also act as a free radical scavenger, neutralising superoxides by accepting electrons & itself becoming oxidized back to MB[6]. In this way, leuco-MB acts to prevent direct oxidative damage caused by free radicals.

Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
Methylene blue preferentially accumulates in more active neurones (A), & potentiates mitochondrial & synaptic activity (B). These processes result in increased & improved neurotransmission (C), which is thought to be the mechanism behind the neurocognitive benefits associated with MB.[7]
MB has been observed to preferentially localise in neurones that are more active[3]. Stimulated mitochondria in these neurones modulate genomic expression of proteins that further potentiate mitochondrial respiration via nuclear respiratory transcription factor (NRF-1), resulting in increased expression of cytochrome oxidase (COX), nitric oxide synthase (NOS-1), NMDA receptors, & AMPA receptors. Strengthened synaptic connections as a result of these processes result in improved memory.

The pharmacologic mechanism behind the neuroprotective activity of methylene blue is unique in that it does not involve a receptor-ligand interaction, as do most drugs. In addition, MB also exhibits an atypical dose-response curve– one that has been described as hormetic[8]. Hormesis is a phenomenon where lower doses produce optimum responses while higher doses or exposures may actually produce the opposite effect. Hormesis is an intriguing pattern that may explain the dose-responses associated with exercise & oxidative stress, where the right amount of exercise-induced oxidative stress induces a cascade of favourable physiologic adaptations that can mitigate more severe stressors[9].

Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
An example hormetic dose-response curve. Note the inverse response caused with higher doses.[10]
As previously mentioned, metabolism of MB involves reduction to leukomethylene blue (MBH2). MB is primarily eliminated in the urine (75%)[11].

What is it like?

I have tested BlueBrainBoost’s formulation with the following results. I have noticed increased energy and decreased fatigue, with an onset of up to 1 hour and duration of 2-4 hours. The only adverse effects were discolouration of the mouth and urine. I used a dosage of 10 mg (20 drops) in the morning sublingually before brushing my teeth. During this time, I was also taking 30 mg/day coluracetam, 500 mg/day ashwagandha, & 600 mg/day NAC. I suspect that coadministration of CoQ10 and creatine may have a synergistic effect based on the pharmacologic site and mechanism of action.

Is it safe?

methylene blue nootropicMethylene blue is associated with a very favourable safety profile. It is generally well-tolerated at doses lower than 2 mg/kg.[12] The most noticeable side effect of MB is blue discolouration of the oral cavity and blue or blue-green discoloration of the urine. These effects are reversible and not harmful. [13] Staining of the teeth can be removed with repeated tooth-brushing, and discolouration of the urine ceases after the drug is fully removed from the system. Other reported adverse effects include a mild headache and dizziness[14].

MB does exhibit some serotonergic activity. This is due to its inhibition of enzymatic degradation of serotonin by MAO-A. Intravenous doses higher than 5 mg/kg have led to the development of serotonin syndrome. This risk is increased in individuals already taking other serotonergic agents (e.g. tianeptine, St. John’s Wort, common antidepressants, dextromethorphan, tramadol). For these reasons, individuals at risk should avoid coadministration of MB with serotonergic agents by at least 2 weeks (or more depending upon the agent), start at low doses, & increase carefully to an effective dose.

Neurotoxicity has been associated with some preparations of MB as a result of chemical impurities. The presence of heavy metals used in the synthesis of MB can have adverse effects on neurones. Thus, only pharmaceutical grade formulations are recommended for human consumption – not lab grade, & not aquarium grade. These formulations may not meet USP standards and may contain up to 11% contaminants.

How should I take it?

Because MB’s role as a neuroprotective agent in humans is still being studied, there is as yet no recommended dosage. The animal doses used in preclinical trials roughly converts to a human equivalent dose of 0.16–0.64 mg/kg administered sublingually. Sublingual administration may produce higher bioavailability than oral administration, but causes more staining of the mouth. I calculated my dose like so:

  1. 0.16 to 0.64 mg/kg × 54.43 kg = 8.71 mg to 34.84 mg per dose
  2. 10 mg/1 mL = 8.71 mg/x mL → 0.87 mL × 20 gtt/1 mL = 17 gtt to 3.5 mL per dose SL (gtt = drops)

It should be noted that due to the hormetic dose-response curve, the response to MB may decrease with higher doses. MB is typically formulated as a 10 mg/mL solution, where 1 drop = 0.05 mL = 0.5 mg. The bottle should be shaken well before administration.

Summary

Overall, I would recommend methylene blue to individuals looking for an inexpensive extra boost in energy. I have not tested MB long enough to notice changes in cognition or memory, but the pre-clinical studies & pharmacologic literature seem to support this benefit.

  • Methylene blue supports mitochondrial respiration & strengthens synaptic connections, which may lead to decreased fatigue and enhanced cognition & recall. MB exhibits a hormetic dose-response curve.
  • The safety profile has been well-characterised, and MB has generally been shown to be well-tolerated. I believe the most important warnings are those concerning serotonin syndrome and chemical impurities.
  • The best-estimated dosage is only an approximation from animal studies. MB is not yet recommended for human consumption for the purpose of improving cognition and memory.
  • Only pharmaceutical grade formulations of MB should be used.
Methylene Blue
7.5
Focus
8
Mood
7.5
Memory
8
Stimulation
5.5
Relaxation
6.5
Safety
Reviewer 8.3
Summary
Methylene Blue improves mood, memory and energy levels, as well as mitochondrial function (and may also delay aging). I think it is a powerful tool to have in your arsenal, and the BBB solution is cheap and convenient, therefore I highly recommend it to anyone.

References   [ + ]

1. Ginimuge PR, Jyothi SD. Methylene blue: revisited. J Anaesthesiol Clin Pharmacol.
2. Callaway NL, Riha PD, Bruchey AK, Munshi Z, Gonzalez-Lima F. Methylene blue improves brain oxidative metabolism & memory retention in rats. Pharmacol. Biochem. Behav. 2004; 77:175–181.
3, 7. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement & neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
4. Poteet E, Winters A, Yan L, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue & its derivatives. PLoS One. 2012;7(10):e48279-.
5. Gonzalez-Lima F, Barksdale BR, Rojas JC. Mitochondrial respiration as a target for neuroprotection & cognitive enhancement. Biochem Pharmacol. 2014 Apr 15;88(4):584-93.
6. Miclescu A, Basu S, Wiklund L. Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest. Crit. Care Med. 2006; 34:2806–2813.
8. Bruchey AK, Gonzalez-Lima F. Behavioral, physiological, and biochemical hormetic responses to the auto-oxidizable dye methylene blue. Am. J. Pharm. & Toxicol. 2008; 3:72–79.
9. Ji LL, Gomez-Cabrera MC, Vina J. Role of free radicals & antioxidant signaling in skeletal muscle health and pathology. Infect Disord Drug Targets. 2009;9(4):428–444.
10. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45.
11. Medscape® 5.1.2, (electronic version). Reuters Health Information, New York, New York.
12, 14. Ginimuge PR, Jyothi SD. Methylene blue: revisited. J Anaesthesiol Clin Pharmacol. 2010 Oct;26(4):517-20.
13. Gillett MJ, Burnett JR. Medications and green urine. Intern Med J. 2006 01;36(1):64-6.
Categories
Biohacking Nootropics Tutorials

How To Reduce Cannabis Memory Impairment (and Enhance its Effects)

Cannabis — also known as marijuana, ganja or “weed” — is, without a doubt, the most controversial herb on the planet. Whether you love it or hate it, the scientific community has long agreed that cannabinoids — the active compounds of the cannabis plant — have incredible medicinal value as they regulate several mechanisms in the body, including pain, mood, inflammation and appetite. In the first half of the article, we deal with Cannabis-specific memory impairment and strategies to deal with it. The second part of the article will focus on ways to enhance Cannabis, including commonly reputed techniques of donating blood, taking fish oil, and eating mango.

Introduction

The first point to make is that when one is spending thirty or more dollars per week on a recreational substance, and it is interfering with performance, there is a clear problem. Rather than abstain from cannabis, many users would continue to justify its use, in part by the addition of designer supplements to their regimen. These substances are supposed to cancel out the negatives. As proponents might argue, they tone down the noxious side effects of an otherwise lifesaving medicine.

These supplements, however, are unlikely to restore mental performance as effectively as abstinence, and may occasionally carry health risks of their own. They may prove especially worthless for the heaviest users of Cannabis, offering the widest scope of benefits to light users. The larger the mental deficit, the harder it is to correct. Those with non-addictive personalities often find cannabis easy to manage, and rarely progress to daily use. Others are not as lucky. Some of us do best to completely avoid recreational substances.

Marijuana
Cannabis plant under a microscope

Besides, those who consume cannabis for recreational purposes are also more likely to indulge in other unhealthy habits — like smoking tobacco or using other recreational drugs, going to sleep late and eating foods rich in salt, sugar, and fats — that supplements alone cannot fix. Therefore, recreational cannabis smokers should — as far as possible — try to improve their diet and stop the consumption of tobacco and other recreational drugs.

While these supplements may not be terribly effective against heavy cannabis use, they may help restore function after quitting or reducing consumption. They could even be used by people who have quit cannabis years ago, but who feel they have still not yet recovered all of their mental faculties to baseline. These same supplements, owing in part to their regenerative and modulatory effects on dopamine-containing cells, may eventually find a place in treating the persistent deficits seen with abuse of more toxic drugs, such as cocaine and methamphetamine, and also with Parkinson’s or Huntington’s disease.

Besides abstinence and a healthy lifestyle, another piece of advice, which will become more pertinent as laboratories widen Cannabinoid testing profiles, is to choose strains with a higher ratio of CBD to THC. A recent human study[1], compared the effects of cannabis with CBD to cannabis without CBD to see if the presence of this cannabinoid has any effect on the Cannabis-induced amotivational syndrome, as evidenced by “a lower likelihood of making a high-effort choice to earn monetary reward”. The cannabis without CBD led to an overall reduction in motivation compared to the cannabis with CBD.

Structure of THC and CBD

The cannabis can also be consumed raw, which if the reader isn’t already aware, cannabis which has not been dried delivers the drug in the form “THCA. This form of the drug is non-psychoactive, but it enjoys some of the same medicinal properties of THC, including a stronger anti-inflammatory activity.[2] Because THCA is not psychoactive, many patients (including cases of pediatric cancer and multiple sclerosis) have chosen to consume it raw, by juicing or tossing it in with their salad. This way, children are able to consume ounces per day and maximize the medicinal qualities without any cognitive side effects. However, it is extremely difficult to find cannabis that has not been dried.

CBD, which is used in epilepsy, has an analogous form in raw cannabis: CBDA. It too is antiepileptic, anti-inflammatory, and exhibits less activity on neurotransmitters than CBD (its active form which requires heat to “decarboxylate” into). Again, to get the benefits of this compound you will need to find fresh cannabis.

Cannabis Memory Impairment

Generally, low glutamate and acetylcholine correlate with memory impairment, while low dopamine correlates with depressive anhedonia (dopamine is also involved in and may explain cannabis’ effect on higher order cognitive functions). At the same time, however, excessive glutamate is toxic to neurons, and having high levels of acetylcholine may cause depression, muscle tension, increased sweating and impairment of memory consolidation during sleep.[3]

Cannabinoids regulate many functions in our brain and body and chronic abuse of cannabis results in neuroadaptations. Let’s have a look at those neuroadaptations based on the latest scientific discoveries.

Dopamine

Dopamine release is blunted in chronic cannabis consumption[4] as a result of the body trying to adapt to the increased levels of dopamine (homeostasis).

This effect is significant in the striatum[5], a region of the brain involved in attention, memory[6], and impulsive behavior. This makes cannabis users more vulnerable to attention and memory deficits, as well as anhedonia and depression.[7]

Cannabinoid receptors

There are two type of cannabinoid receptors: type 1 (CB1) and type 2 (CB2).
CB1 receptors are expressed in the brain and the lungs, the liver and the kidneys, whereas CB2 receptors are primarily expressed in the immune system.

Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, is primarily a CB1 agonist, though it also has some activity at the CB2 receptor. CB1 mediates the recreational effects of marijuana, as well as other effects such as analgesia, increased appetite, and antiemesis. However, being a partial agonist, THC can both increase or decrease the activity of this receptor[8], and this explains why, based on an individual’s personal body chemistry, the effects of cannabis can range from relaxation and euphoria to stimulation, paranoia and anxiety.

After chronic exposure to THC and synthetic cannabinoids, CB1 receptors will downregulate[9] and internalize[10]. This process mediates tolerance to the effects of cannabis, but may also have further implications as far as brain health and memory goes, which takes us to…

5-HT2A receptor

The 5-HT2A receptor is the primary excitatory neurotransmitter of the serotonin family. It is famously known to mediate the effects of psychedelics drugs, that are in turn known as 5-HT2A agonists.

Individuals suffering from depression are known to have more postsynaptic 5-HT2A receptors compared to non-depressed patients, and downregulation of postsynaptic 5-HT2A receptor is an adaptive process provoked by chronic administration of SSRI antidepressants and may mediate some of their beneficial effects.[11]

CB1 is essential for the correct functioning of 5-HT2A receptors (5-HT2AR) and CB1 agonists like cannabis and synthetic cannabinoids upregulate these receptors.[12] This process is thought to mediate some of the negative effects associated with the use of cannabinoids, particularly anxiety-like behavior[13] and memory impairment.

To test this, scientists injected THC to a group of normal mice and another group of 5-HT2A knockout mice (mice which have been genetically modified to not express the 5-HT2A receptor). When researchers administered THC to normal mice, their memory worsened as predicted. However, when they repeated the experiment on the 5-HT2A knockout mice, this effect was significantly reduced.[14] According to the researchers, “these data suggest that specific effects of THC such as memory deficits, anxiolytic-like effects, social interaction, and DR neuronal activity are under the control of 5-HT2AR.”[15]
5-HT2A receptors, however, did not mediate the analgesic and anxiogenic effects of THC.[16]

The explanation for marijuana-induced memory deficits, according to the researchers, is as follows: 5-HT2A and CB1 receptors are closely interrelated, and CB1 agonists like THC promote the oligomerization of CB1 and 5-HT2A receptors. In simple terms, these receptors “fuse” together to form a larger complex, called heteromers (CB1R-5-HT2AR heteromers, to be precise). As reported by the research team, “CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.” However, no pharmaceutical drug or nootropic with this target exists on the market, yet.

AMPA, BDNF, mTOR and more

Cannabinoids also lower the activity of the AMPA receptor subunits GluR1 and GluR2/3[17], and may thus impair synaptic plasticity.

Acute use of cannabis in drug-naive subjects increases the levels of BDNF[18], a neurotrophin that promotes neurogenesis (though it also has a role in drug addiction[19]). Chronic users of cannabis, however, have actually lower BDNF levels.[20] It is hard to say if this is a consequence of chronic cannabis use, as maybe the patients had lower BDNF, to begin with.

THC also increases cortisol in drug-naive subjects, but not in chronic users, whom also had lower prolactin levels than the control (but, again, it is impossible to say if it is a consequence of cannabis use or not).[21]

The mTOR kinase may also be involved in marijuana’s detrimental effect on memory, particularly long-term memory.[22]
According to this research, rapamycin (an mTOR blocker) completely abolished cannabis-induced memory impairment, as did NMDA antagonists (though they reduced, — but not abolished —, the memory impairment).[23] However, an earlier study showed that mTOR is important for long-term memory and rapamycin actually hindered the consolidation of long-term memories.[24] Because of the strong immunosuppressant effect of mTOR blockers — as well as their poor safety profile — we strongly oppose their use.

These negative effects are especially magnified when the drug is discontinued and, as a result, withdrawal symptoms of psychological nature can manifest.

Reducing Memory Impairment

Huperzine A
Huperzine A

In addressing cannabis-specific mental impairments, there are many avenues to pursue. Besides the subtitles below, other supplements which did not earn a subsection or even an honorary mention may nevertheless prove useful. Many popular supplements have the potential to be very effective against cannabis-induced cognitive or emotional deficits. To name a few, galantamine, huperzine-A and centrophenoxine.

A 2013 study compared the cognitive performance of rats who consumed either cannabis or cannabis plus a nootropic drug (Piracetam, Donepezil, Vinpocetine or Ginkgo biloba). The most effective nootropic was Piracetam, though it decreased dopamine and increased noradrenaline — possibly worsening the demotivational effect of cannabis — while Donepezil improved memory while further increasing dopamine (likely due to its sigma agonism). Vinpocetine was also effective, though it may significantly reduce the recreational effects of cannabis due of its mechanism of action.

In another, more recent human study, CDP-Choline reduced impulsivity, improved cognitive performance, and normalized the activity of some regions of the brain (like the ACC) in chronic marijuana smokers.[25]

Green tea, a low-caffeine [26] neurotrophin inducer and serotonin modulator. The L-theanine enhances effects while curbing cravings and reducing cannabis anxiogenic effects.

NAC, a glutamate regulator with a proven efficacy in treating cannabis dependence[27][28][29], may also be neuroprotective, though it will probably reduce the recreational effects of marijuana due to its mechanism of action.

CB1 antagonists

Cannabis memory impairmentCB1 antagonists occur alongside THC in cannabis — though in much smaller quantities — in the form of CBD and THCV. In high doses, they counteract the recreational effects of marijuana, though small quantities of CBD actually enhance the positive effects while reducing the adverse effects. CBantagonists are known, for instance, to improve spatial memory[30] in healthy volunteers and this may in part explain the nootropic qualities of CBD.

Rimonabant was initially studied for obesity, dementia, and cannabis dependence, but withdrawn due to psychiatric effects. Falcarinol is found in carrots, although in such low amounts it would require the reader to consume a kilo per day. Voacanga africana, an uncommon supplement, is the only other potent CB1 antagonist known in the plant kingdom.[31]

Since they act by opposing cannabis at its primary site of action, they have potential in easing withdrawal and addiction, but also in restoring cognitive function more quickly. It’s important to keep in mind these compounds (CBantagonists) are very selective and potent, often with downstream effects, as seen in Rimonabant.

The easiest way — and also beneficial in regards to analgesia and inflammation — is to buy an electronic cigarette and some CBD e-liquid and vape it whenever you one feels the need to reduce the effects of THC.

Another substance that indirectly abolishes cannabis intoxication is pregnenolone. According to a 2014 study[32] pregnenolone “acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.”[33] It may be a good option to sober up quickly before an interview or an exam.

Lastly, CB1 antagonists upregulate receptors (including downstream dopamine) and may make for speedier tolerance breaks. Luckily, a recent study showed that downregulation of CB1 receptors starts to reverse as fast as 2 days into cannabis withdrawal.[34]

COX-2 inhibitors

COX inhibitors
COX selectivity of commonly used NSAIDs

The COX-2 pathway appears to be more relevant for glutamate than dopamine. Glutamate is the chief excitatory neurotransmitter, responsible for learning, memory, and many higher order processes. As depicted in the above diagram, COX-2 occurs as roughly the ‘midway’ step in the ladder. Nevertheless, multiple studies have confirmed it is a critical step, mediating much of cannabis’ cognitive side effects.

Cyclooxygenase 1 and 2 are enzymes that participate in the synthesis of prostaglandins from arachidonic acid. Prostaglandins are hormone-like molecules in the body that have a wide range of functions, some of which lead to inflammation and fever.

Rutaecarpine
Evodia rutaecarpa

The reason for using selective COX-2 inhibitors instead of the cheaper unselective NSAIDs, like ibuprofen and aspirin, is that COX-2 is specific to inflamed tissues, whereas inhibition of COX-1 stops the production of prostaglandins all over the body, like the gastrointestinal tract, where they have a (positive) role in protecting the gastric mucosa.

The most potent natural COX-2 inhibitors are (ordered by COX-2 affinity, when the information was available):

  • Eugenol[35][36][37] (found in clove, nutmeg, and cinnamon oils)
  • Sophoricoside[38] (from Sophora japonica)
  • Rutaecarpine[39][40] (from Evodia rutaecarpa)
  • Xanthorrhizol[41][42] (from Curcuma xanthorrhiza)
  • alpha-Viniferin[43] (from Caragana chamlagu)
  • Schisandrin[44] (from Schisandra chinensis)
  • Nexrutine®[45] (a patented extract of Phellodendron amurense)
  • Bromelain[46] (from pineapple)
  • Tribulus terrestris[47]
  • Rehmannia glutinosa[48]

Note: C. xanthorrhiza is a different herb from turmeric (aka C. lunga, which is less effective as a COX-2 inhibitor). There is also some conflicting evidence about bromelain being a direct COX-2 inhibitor. Some of these compounds are not bioavailable in isolation (like rutaecarpine), so an extract should be used rather than the isolated compounds.

Other, like eugenol, should never be used as an isolated compound, but only in minute quantities using an essential oil, as they have a bi-phasic action (with low doses being protective, and high doses toxic — particularly to the gastrointestinal mucosa). Eugenol is also a MAO inhibitor and may cause serotonin syndrome when taken alongside SSRIs, SNRI, and TCA antidepressants.

alpha-Viniferinalpha-Viniferin (in the form of C. chamlagu extract) is one of the most interesting compounds, as it also an acetylcholinesterase inhibitor (it increases the levels of acetylcholine), so it has two nootropic mechanisms and may be the perfect candidate to reduce memory impairment caused by THC. However, stilbenoids like resveratrol and pterostilbene have famously poor bioavailability, so either a liposomal solution or the addition of piperine may be necessary to fully benefit from it (though piperine failed to increase plasma concentrations of resveratrol[49]).

Common poorly selective (or indirect) COX inhibitors include fish oil, resveratrol, and three root supplements: ginger, turmeric, and ginseng. To combat fatigue and demotivation, about 10 g of ginger, 2 g of turmeric, and/or 1600 mg ginseng extract can be taken daily, and the user will likely notice an array of other healthful benefits.

Misc

Ampakines are substances that activate the AMPA receptor. This receptor is involved in synaptic plasticity and drugs that target this receptor are currently being researched as treatments for Alzheimer’s disease and dementia. Cannabis and synthetic cannabinoids cause deficits in AMPA transmission, and ampakines may counteract this effect. Some of the most famous and commonly used ampakines are Aniracetam, Sunifiram, and IDRA-21.

Fasoracetam and Coluracetam, two recently discovered racetams, are also anecdotally known to reduce the detrimental effect of cannabis and enhance the “high”.

Minor compounds in cannabis besides THC may be responsible for the depressive and memory-impairing effects, especially when using low-quality hash or weed: citral, pinene, limonene and myrcene perhaps the most well-known. At the CNS myrcene acts as both a depressant and a vasodilator, and it is thought by some to explain the stone or couch-lock of indica strains [50]. According to another study, “… citral, limonene and myrcene presented sedative as well as motor relaxant effects.” The vasodilatory effects lead nicely into our next section, which explains that opening the blood vessel (a method of enhancing desirable effects) enhances drug delivery to the brain.

Forskolin promotes cAMP activity, dopamine transmission, and memory. It also increases oxytocin, which is downregulated in chronic cannabis users[51], and may help reduce emotional blunting.

Memantine, amantadine and other specific alpha-7 nicotinic receptor antagonists may offer a novel approach to treating dependence and cognitive dysfunction[52]. However, memantine is known to significantly potentiate cannabis (as well as synthetic cannabinoids and other psychotropic drugs like caffeine and amphetamine) and reduce the tolerance to its effects. This effect is particularly pronounced at doses higher than 5 mg and can make the experience particularly intense and unpleasant. It also has a long half-life, so it is important that you start low and work your way up to avoid a dangerous 24h-long dissociative trip.

Flavonoids and natural phytochemicals that reduce stress or improve memory in mice studies may also find use. As said before, adopting a healthier diet is only going to improve performance.

Enhancing Desirable Effects

There are many folk remedies for someone seeking to enhance their high. Exercising in a fasted state, giving blood, taking a tolerance break, mixing with alcohol or LSD, and switching to a high-efficiency vaporizer are among the most effective methods of conserving one’s stash and enhancing one’s high.

Vasodilators

As far as supplements go, mango, fish oil and dark chocolate are repeatedly mentioned, although their effectiveness is dubious and difficult to replicate in self-experiments.

Mango is supposed to work through myrcene[53], a vasodilator also found in cannabis, hops and especially passionflower. Funnily enough, mango is also a COX-2 inhibitor.[54] The reader is invited, so long as he is a medical patient, to try cannabis with mango or passionflower and gauge himself whether there has been an appreciable enhancement.

Fish oil capsules
Fish oil

Fish oil and dark chocolate are both said to work by enhancing the endocannabinoid system and also (like mango) by dilating blood vessels, which is supposed to let more blood and more drug into the brain. The dark chocolate is probably a better vasodilator than mango. An English team has even filed a patent for including vasodilators in topical formulas, with the same idea that wider blood vessels enhance drug delivery[55].

Ginkgo and ginger may also be used, as both are potent vasodilators. But like the other supplemental vasodilators, they are not as effective as fasting or giving blood. Giving blood is often reported to be the most effective technique.

Dopamine and Glutamate Modulators

The weak antidepressant nootropic property seen with low dose cannabis can be augmented by many things mentioned in this article: exercise, good diet, and ginseng. Though not limited to dopamine or glutamate, here is a brief overview of supplements that would enhance the desirable effects,

Ginkgo biloba
Ginkgo biloba

Ginkgo biloba, a vasodilator, GABA-A antagonist and weak dopaminergic herb, though it may increase the anxiogenic effect of cannabis.

Forskolin, Uridine, and Fish Oil will enhance dopamine release, thus increasing the rewarding effects. Uridine has the additional effect of increasing expression of dopamine receptors, especially when paired with fish oil and CDP-Choline

Noopept and Tianeptine are anecdotally known to enhance the high, but the latter can cause memory impairment at higher doses, as well as presenting addictive properties of its own. Noopept, on the other hand, may increase marijuana’s demotivational effects in some individuals.

Agmatine appears to enhance effects, at least ones related to painkilling, perhaps by direct modulation of the CB1 receptor. Glycine has also been reported to enhance the analgesic activity.

ALCAR and Piracetam are more active on acetylcholine, but both work to restore memory. ALCAR, in particular, offers a host of other benefits (such as helping energy production) and is strongly recommended for the reader to try if he has not.

Conclusion

More research needs to be carried out on the treatment options (both natural and synthetic) for cannabis withdrawal and for cannabis-specific mental impairments. Alongside this, we will gain an understanding of which compounds have a synergy with cannabis to enhance its effects (or allow for the same effect at a lower dose).

In the coming decades before the research culminates, we will need to take a closer look at cannabis itself and gain a clearer picture of how it works on the mind. Until then, moderation, a healthy diet and meditation may be the best choices to compliment the use of a potent psychoactive drug.

What Is The Best Nootropic Supplement For “Stoners”?

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