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. 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. 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).
Methylene blue supports mitochondrial respiration by functioning as an additional electron carrier. 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. In this way, leuco-MB acts to prevent direct oxidative damage caused by free radicals.
MB has been observed to preferentially localise in neurones that are more active. 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. 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.
As previously mentioned, metabolism of MB involves reduction to leukomethylene blue (MBH2). MB is primarily eliminated in the urine (75%).
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 is associated with a very favourable safety profile. It is generally well-tolerated at doses lower than 2 mg/kg. 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. 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.
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:
0.16 to 0.64 mg/kg × 54.43 kg = 8.71 mg to 34.84 mg per dose
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.
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.
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.
There are very few supplements that have a list of potential benefits as impressive as berberine. Despite the fact that berberine is not all that well known compared to many other supplements, it is extremely well researched. While not all of these benefits are guaranteed to occur for every single user, berberine has been found to
Improve gastrointestinal health
Reduce glucose production in the liver
Improve markers of insulin resistance
Lower oxidative stress
Help in losing body fat
Slow down aging
Suppress chemical-induced carcinogenesis, clastogenesis, tumor promotion and tumor invasion
Exert antiarrhythmic effects
Exert anti-microbial activity against a wide range of microorganisms.
Exert minor antidepressant effects, as well as work in a synergistic fashion with existing antidepressants
While this list of touted benefits is certainly impressive, berberine also carries with it a number medication interactions, which must be noted with caution (more on this later).
What is Berberine?
Berberine is an isoquinoline alkaloid and ammonium salt of a bright yellow color that is found in and extracted from a variety of plants from the genus berberis, as well as Coptis chinensis, Phellodendron amurense, and Hydrastis canadensis (Goldenseal) and many others. These plants have a history of being used in both traditional Chinese Medicine and Indian Ayurveda as an anti-microbial agent. Berberine appears to be effective in fighting bacteria, fungi, and protozoa.  However, these traditional uses of berberine barely scratch the surface of its full capability.
When berberine is ingested orally, it has a relatively low bioavailability of 5% or less.  Berberine increases the action of P-Glycoprotein, a substance which actually makes berberine more difficult for the intestines to absorb. Because of this, taking a P-Glycoprotein inhibitor (such as Milk Thistle) can possibly make smaller doses of berberine more effective. Another option is to take Berberine with Coconut oil that contains a fatty acid known as Sodium Caprate which significantly increases the absorption and the efficacy of Berberine.
One of berberine’s main mechanisms of action is its ability to activate an enzyme called Adenosine Monophosphate Kinase (AMPK). AMPK is crucial for maintaining energy homeostasis in cells. It is responsible for regulating glucose and other nutrients by sensing their concentrations within cells.  The activation of AMPK caused by berberine has multiple different effects. First, the AMPK activation causes an increased uptake of glucose into adipocytes (fat cells). This is one of the major methods through which berberine reduces glucose levels in the blood. In fact, berberine’s antidiabetic effect is so effective that it is regarded as one of the few supplements to be as strong as a pharmaceutical drug. When taken correctly, berberine can be as effective (or even more effective as the popular type II diabetes drug metformin.
Berberine also appears to have various positive effects on the heart and the cardiovascular system as a whole. Activated AMPK located in liver cells causes an inhibition of cholesterol and triglyceride synthesis. This change is also linked to a lowering of low-density lipoproteins (“bad” cholesterol) and raising of high-density lipoproteins (“good” cholesterol). Additionally, berberine can lower the levels of LDL by stimulating the synthesis of LDL receptors, which are responsible for removing LDL from the blood. The activation of AMPK induced by berberine also appears to inhibit the synthesis of lipids and lower triglyceride levels, which is useful for individuals who are attempting to lose weight.
In one study, reperfusion (oxidative stress) was induced in rats who had been pre-treated with berberine. The rats treated with berberine displayed significantly less heart damage than those who had not been treated. One study conducted on 24 overweight or obese subjects concluded that berberine was able to reduce blood pressure significantly more than placebo.  These effects of berberine—the inhibition of LDL cholesterol and triglyceride synthesis, increase in HDL cholesterol, decrease in lipid production, protection from oxidative stress, and the decrease in blood pressure—all work together to contribute to berberine’s overall positive effect on heart health and weight loss. But that’s not all…
Anti-aging & Anti-cancer
There is some early research evidence that seems to suggest berberine’s efficacy as telomerase inhibitor. Telomerase is a protein that is intricately linked with cell proliferation and the life cycle of cells. Telomeres (the region that telomerase acts upon) are a portion of DNA sequences located at the ends of chromosomes that keep them from deteriorating.
Essentially, the inhibition of telomerase by berberine has potential applications in the area of life extension & longevity as well as a chemopreventive supplement or in conjunction with existing cancer treatments to increase their efficacy.
Besides telomerase inhibition, berberine has also been found to suppress the growth of a wide variety of tumor cells, including breast cancer, leukemia, melanoma, epidermoid carcinoma, hepatoma, pancreatic cancer, oral carcinoma, tongue carcinoma, glioblastoma, neuroblastoma, prostate and gastric carcinoma.
Berberine also exhibits minor to moderate antidepressant effects. One study conducted on mice discovered that berberine administration reduced the immobility time of mice in a swim test, which is indicative of antidepressant effects. The same study also concluded that berberine caused significant increases in the levels of dopamine, serotonin, and norepinephrine in the whole brain. It was also discovered that berberine works synergistically with certain antidepressant medications, such as fluoxetine, imipramine, tranylcypromine, and venlafaxine.
New studies suggest berberine may have a potential for inhibition and prevention of Alzheimer’s disease through inhibition of β-amyloids pathways and cholinesterase and through antioxidant capacities. Berberine derivatives are currently being developed as potent acetylcholinesterase (AChE) inhibitors.
As a PCOS treatment
In a 2012 human study, 89 Chinese women of reproductive age who met the diagnostic criteria for polycystic ovarian syndrome (PCOS) and insulin resistance, were recruited and prescribed the anti-androgen compound cyproterone acetate (2.0 mg/day) in a combined oral contraceptive pill with 35 mcg ethinyl estradiol, taken in a cyclic fashion. They also received advice from a nutritionist to limit dietary fat and carbohydrates without restricting calories.
They were then assigned to one out of three treatment groups:
Metformin, 500 mg 2 times/day for the first week, then 3 times/day for the remainder of the study (n=30)
Placebo tablet 2 times/day (n=28)
Results of the study were:
After 3 months, all the treatment groups showed a significant reduction in body weight and BMI.
Waist circumference and waist-to-hip ratio were reduced in all 3 groups. However, the berberine group showed a significantly greater reduction in these measures.
All 3 treatment groups showed a significant reduction in fasting insulin. However, in the placebo group, fasting plasma glucose and fasting glucose/insulin ratio remained unchanged.
Fasting plasma glucose decreased and fasting glucose/insulin ratio increased in the berberine and metformin groups. There was no significant difference between them.
The berberine and metformin groups showed comparable changes in total testosterone and free androgen index, which were significantly greater than placebo. However, sex hormone–binding globulin increased significantly in the berberine group when compared with both metformin and placebo.
All 3 groups had reductions in total cholesterol and triglycerides. The berberine group had a significantly greater decrease in triglycerides, total cholesterol, and LDL (“bad” cholesterol”), and a significantly greater increase in HDL (“good” cholesterol) when compared to metformin.
Adverse effects were minimal and fewer compared to metformin. Nine subjects who received metformin complained of transient abdominal discomfort including nausea, vomiting, mild diarrhea, and flatulence, while 3 who received berberine complained of a bitter taste in the mouth.
As a result of this study, the researchers conclude that berberine may prove a viable alternative to metformin in optimizing the health outcomes of women with PCOS.
Another study on 102 anovulatory Chinese women was published in 2015 found that administration of berberine alone may improve the menstrual pattern and ovulation rate in anovulatory Chinese women with polycystic ovary syndrome, as well as decrease sex hormone binding globulin, insulin resistance, total cholesterol, triglycerides and low-density lipoprotein cholesterol in normal weight polycystic ovary syndrome women.
Side Effects & Interactions
Berberine is absorbed slowly by the intestine, meaning that high doses can cause diarrhea and cramping. For this reason, berberine is typically taken in various smaller doses throughout the day.
In terms of interactions, the most noteworthy is the potential interaction with macrolide antibiotics like azithromycin (Zithromax) and clarithromycin (Biaxin). The interaction between the two has the possibility of causing cardiotoxicity. Berberine also inhibits enzymes CYP2D6 and CYP3A4 which has the potential to affect how many other drugs are metabolized by the body. For this reason, it is very important to discuss berberine supplementation with a healthcare professional to ensure no dangerous interactions will take place.
Goldenseal vs Berberine Hcl
The two most common ways to supplement Berberine are to take either Berberine hydrochloride (hcl) or Goldenseal root powder. This is extremely important and I’ll explain why.
Goldenseal, – which contains a number of other compounds besides berberine – has been shown to cause DNA damage in prokaryotic and eukaryotic organisms as well as promote liver cancer in rats.
Therefore, I strongly advise against using goldenseal root and to take Berberine Hcl instead, the same way it was used in the PCOS studies. If you’re taking goldenseal supplements, stop taking them as soon as possible!
Berberine is certainly unique among supplements in the fact that it is equally as effective as some prescription medications. It also boasts a myriad of benefits that impact a variety of systems throughout the body. This article has only scratched the surface of the researched benefits of berberine. A collation of the large body of evidence concerning berberine can be found here for anyone who wants to learn more about this fascinating supplement. While there are some potential side effects and medication interactions, berberine is still well worth checking out. Berberine stands as a hidden gem among supplements – one that has the potential to greatly improve one’s quality of life.
Berberine Hcl can be bought relatively cheap at PowderCity and other supplement and vitamins shop.
Stimulants are one of the most infamous classes of drugs, whether recreational or for medical purposes. They can be unpredictable, leading to difficult side effects like anxiety, hypertension, and in extreme cases, even neurotoxicity. Members of the nootropics community have been reluctant to place the label “nootropic” on any kind of stimulant, due to these potential side effects and the risk that comes with taking them for long periods of time. However, there exists somewhat of an anomaly in the world of stimulants: the drug known as bromantane.
This unique drug is purported to possess both stimulant and anxiolytic properties. This seemingly paradoxical nature is due to bromantane’s status as an actoprotector, an obscure class of drugs that will be described below. As for bromantane’s origin: like many of the greatest cognition-enhancers, it is a product of the laboratories and pharmaceutical companies of Russia (formerly the Soviet Union).
Discovery of Bromantane
The discovery of adamantane in petroleum in 1933 launched a new field of chemistry dedicated to studying the synthesis and properties of polyhedral organic compounds.Bromantane (also known by the trade name Ladasten (Ладастен) or its structural name of adamantylbromphenylamine) arose incidentally from the research of antiviral drugs meant to treat influenza. Amantadine, a derivative of the adamantane molecule, was being researched in the 1960s for its antiviral properties. Due to the vigorous amount of research surrounding the amantadine molecule, it was soon discovered that amantadine and its derivatives possessed psychostimulant through a dopaminergic effect; thus, it has been sometimes used as a treatment for early-stage Parkinson’s disease.
The new discovery of the dopaminergic properties of adamantine led to increased research on the development of new stimulants. In the 1980s, researchers at the Russian Academy of Medical Sciences in Moscow engineered the adamantine derivative bromantane as a new stimulant drug.
While displaying stimulant properties, bromantane is also commonly categorized as an actoprotector, that is, a drug that “enhance[s] body stability against physical loads without increasing oxygen consumption or heat production. Or, in short, actoprotectors are synthetic adaptogens with a significant capacity to improve physical performance.”
Actoprotectors, in theory, exhibit many advantages over traditional stimulants. For one, stimulants like Adderall typically cause a “crash” when its effects wear off. Actoprotectors like bromantane are purported to be more “smooth” and stable in their effects. However, many of these positive claims surrounding bromantane are somewhat dubious. Much of the research that has been conducted on actoprotectors like bromantane was based solely in the Soviet Union, and most of the literature have not been translated into other languages like English.
Another actoprotector, known as Bemitil (Metaprot), was commonly given to Soviet cosmonauts and soldiers in the 1990s to increase their performance and resistance to fatigue in their respective fields of work. Bromantane was also used, albeit not as commonly as bemitil, to “shorten recovery times after strong physical exertion.” Although bromantane soon fell out of use in the military, it still continued to be researched in areas such as sports medicine, as it was found to boost athletic performance. Bromantane was brought somewhat into the eyes of the public during the 1996 Summer Olympic Games, when 5 Russian athletes tested positively for using bromantane as a doping agent. Bromantane was thereafter banned from use in sporting events, relegating its use to purely medical fields.
Mechanism of Action and Side Effects
While bromantane’s mechanism of action is sadly not as well studied as other nootropic substances, it is known to exhibit characteristics of both stimulants (like amphetamine) and adaptogens (like Rhodiola Rosea). Bromantane’s two foremost modes of action are thought to be dopaminergic and serotonergic stimulation of the nervous system. Although the mechanism is not that well understood, research has indicated that the administration of bromantane triggers a release of dopamine, as well as increasing the concentration of serotonin and 5-HIAA in the frontal cortex of the brain. Bromantane also works as an anxiolytic by strengthening GABA-ergic mediation. Unlike most stimulant drugs, bromantane has not demonstrated addictive potential. Likewise, it does not appear to build a tolerance after prolonged periods of use. One study suggests that high doses of bromantane (50 mg/kg) in rats can cause an increase in the DNA-binding activity of the beta-amyloid precursor protein (β-APP) gene promoter, which is linked to the pathogenesis of Alzheimer’s disease. However, the dose used in the study is about 68 times the normal prescription dose of bromantane.
Uses of Bromantane
Bromantane is most commonly used in Russia as a treatment for neurasthenia, a somewhat vague medical condition that is marked by fatigue, irritability, anxiety, anhedonia and depressed mood.
The very favorable side-effect profile of bromantane is one contributing to factor to its increase in popularity as a potential nootropic substance. Because “true” nootropic drugs do not carry any addictive potential, bromantane is one of the few stimulating drugs that can be said to fit this definition. Unfortunately, bromantane has not yet seen any official research regarding its exact effects of cognition and cognitive health. Due to its effects as an actoprotector, bromantane would theoretically reduce any fatigue that comes alongside long periods of mental exertion, making it a possible study aid. This effect would be enhanced by bromantane’s stimulating effects, which lead to increased motivation and concentration. A typical single dose of bromantane can range from 50 to 100 mg.
Positive Effects of Bromantane
Enhances physical and mental endurance under stress
Stimulation of the nervous system
Enhances cognition and learning capability
Low to no potential for addiction
Low toxicity, especially when compared to other stimulants
Negative Effects of Bromantane
As of now, there are no established side effects in the scientific literature surrounding bromantane
As with any drug that has not been extremely well-documented in the scientific literature, it can be useful to include anecdotal reports from users to see the effects of the drug. Obviously, anecdotal reports are not to be considered hard evidence, so use good judgment. The following subjective reports have been gathered from Reddit users from /r/nootropics.
From /u/SocialT – “So the first time I tried it, it felt alright. The anxiolytic effect was good but I had taken a bunch of other noots, to the point where it was just a confusion of effects. But I took it (~50mg) yesterday and felt great. Calm, motivated, a very subtle kind of euphoric happy mood throughout the day. I was wide awake, and very sociable. I held a conversation for almost 3 hours with a coworker who I’d hardly ever talked to! Caffeine seemed to enhance the effect, though the comedown was a weird jittery-excited-slight unease mind state.”
From /u/Nootrophic – “I’d like to report that this summer, I’ve took 100 mg for a month without issue and much improved effects: Stamina (++), Overall Confidence (+++), Social Confidence (++) and Motivation (+ or ++). I didn’t suffer side effects, and I stacked this dosage with insane amount of other nootropics without any issue whatsoever.”
From /u/drejp – “I literally experienced total bliss these two weeks on Bromantane, starting from day 3-4 maybe. Depression allievated, mental and physical energy increased a lot, libido restored, excersise is rewarding and general outlook on life is very positive. It seriously felt like I got my old self back to a degree. I started to experience some sides yesterday though, I still experience mood-lifting effects, but I have the worst headaches today and general brain-fog, I have hard time thinking straight and am generally confused cognitive-wise.”
From /u/somebodybettercomes – “I’ve been taking bromantane for over a month now, at least 50mg daily and most days I take around 100mg. The most I’ve had at once is around 200mg. So far I have not noticed any negative side effects from it. I’m generally in a better mood and more motivated than normal, less prone to anxiety. I believe it has improved my ability to stay focused. That said, I don’t feel like I am taking a stimulant. Even the few times I tried it close to bedtime I did not feel like it kept me from falling asleep or interfered with my ability to stay asleep.”
Bromantane is a unique drug, given that it acts as a stimulant and anxiolytic simultaneously. It also serves to enhance performance by increasing the body’s resistance to mental and physical fatigue and exhaustion. Sadly, bromantane lacks the wide spectrum of research that has been invested in other more popular cognitive enhancers and stimulants. Because of this, nootropic users may want to consider trying bromantane to see if it acts as an effective drug for enhancing their cognition.
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.
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.
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, 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.
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. 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.
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 release is blunted in chronic cannabis consumption as a result of the body trying to adapt to the increased levels of dopamine (homeostasis).
This effect is significant in the striatum, a region of the brain involved in attention, memory, and impulsive behavior. This makes cannabis users more vulnerable to attention and memory deficits, as well as anhedonia and depression.
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, 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 and internalize. 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…
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.
CB1 is essential for the correct functioning of 5-HT2A receptors (5-HT2AR) and CB1 agonists like cannabis and synthetic cannabinoids upregulate these receptors. This process is thought to mediate some of the negative effects associated with the use of cannabinoids, particularly anxiety-like behavior 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. 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.”
5-HT2A receptors, however, did not mediate the analgesic and anxiogenic effects of THC.
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, and may thus impair synaptic plasticity.
Acute use of cannabis in drug-naive subjects increases the levels of BDNF, a neurotrophin that promotes neurogenesis (though it also has a role in drug addiction). Chronic users of cannabis, however, have actually lower BDNF levels. 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).
The mTOR kinase may also be involved in marijuana’s detrimental effect on memory, particularly long-term memory.
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). However, an earlier study showed that mTOR is important for long-term memory and rapamycin actually hindered the consolidation of long-term memories. 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
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.
Green tea, a low-caffeine  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, may also be neuroprotective, though it will probably reduce the recreational effects of marijuana due to its mechanism of action.
CB1 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. CB1 antagonists are known, for instance, to improve spatial memory 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.
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 (CB1 antagonists) 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 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.” 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.
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.
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 (found in clove, nutmeg, and cinnamon oils)
Sophoricoside (from Sophora japonica)
Rutaecarpine (from Evodia rutaecarpa)
Xanthorrhizol (from Curcuma xanthorrhiza)
alpha-Viniferin (from Caragana chamlagu)
Schisandrin (from Schisandra chinensis)
Nexrutine® (a patented extract of Phellodendron amurense)
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-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).
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.
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 . 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, 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. 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.
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, a vasodilator also found in cannabis, hops and especially passionflower. Funnily enough, mango is also a COX-2 inhibitor. 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 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.
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, 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.
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”?
It’s becoming a given — whether you’re stuck in a traffic jam on your way to work, arguing with your partner over finances, coordinating the family’s busy schedule, or having difficulty turning down your racing thoughts at night, most of us encounter daily stresses. According to the National Institute of Health, 40 million adults in the US have anxiety disorders.  These can range in severity from Generalized Anxiety Disorder and Social Phobia to more extreme versions including Panic Disorder, OCD, and Post Traumatic Stress Disorder.
Traditional treatments for anxiety disorders have included a class of medications known as benzodiazepines (Xanax, Valium). However, many clinicians have growing concern over prescribing such medications due to their addictive nature and impact on cognition. New reports are emerging that demonstrate a direct correlation of benzo use to an increased risk of Alzheimer’s Disease. A recent study published in the British Medical Journal showed “the risk of Alzheimer’s disease was increased by 43-51% among those who had used benzodiazepines in the past. Risk increased with density of exposure and when long acting benzodiazepines were used”. 
With these statistics in mind, many Nootropic enthusiasts have focused attention for anxiety relief on a particular class of Nootropics, peptides.
A peptide is a chemical compound containing two or more amino acids that are coupled by a peptide bond. There are 20 naturally-occuring amino acids and they can be combined together to form new molecules. When a molecule consists of 2-50 amino acids it is called a peptide, whereas a chain of 50 or more amino acids is referred to as a protein.
Discovery of Selank
Research on peptides began in the 1970’s in Russia following the UN “Convention on Psychotrophic Substances” that essentially banned drugs traditionally used by militaries worldwide. This ban included amphetamines, a widely employed wakeful and focusing drug. The Ministry of Russian defense tasked the Research Institute of Molecular Genetics in Moscow to develop comparable chemical agents. It was at this time Nikolai Myasoedov, a researcher at the institute, focused his attention on endogenous compounds, peptides, to provide harmless stimulation.
Dozens of molecules previously unexplored came to light out of this research, including Tuftsin (aka TP-1), a tetrapeptide produced primarily in the spleen. The researchers discovered that this peptide had nootropic, anxiolytic and immunostimulating effects
The researchers found out that they could prevent premature decomposition of the molecule by attaching a ‘tail’ of amino acids to the tuftsin molecule. Selank (formerly TP-7) is born.
Clinical trials on this novel compound concluded in 2004 and Selank was proven effective for treating an array of anxiety disorders. In addition, many patients were able to conquer their fears coupled with “improved mood, mental and motor activity, and most importantly, Selank was demonstrated as not addictive”. 
According to research provided by the Institute of Molecular Genetics, drops “that must be instilled into the nose” is still considered the best way to take neuropeptides. With this in mind, a >1% solution of Selank can be prepared for sterile instillation.
My experience with Selank
I have personally tried Selank on several occasions to help quell feelings of anxiety and have found it to be quite effective. 400 mcg instilled intranasal provided me with several hours of great clarity, focus, and organized thought. My mind doesn’t feel cloudy or groggy like I’ve experienced from other anxiolytics, mood is noticeably improved, and a slight energy lift is detectable. In my opinion, Selank is a viable treatment option for those suffering from anxiety and for certain aspects of motivation especially those with an inability to see projects through to completion.
Sarcosine and D-Serine are two endogenous substances that are currently being researched for a number of conditions. Although these substances have many interesting properties and may be effective add-on treatments to disorders such as depression and schizophrenia, they are too nonspecific to work effectively as a standalone, and should never be used in place of a doctor’s recommendation. That being said, there is some promising evidence for a nootropic, antidepressant and antipsychotic effect.
D-serine vs L-serine
This article includes references from studies using both enantiomers of serine. The two may have somewhat similar effects since L-serine is converted to D-serine by serine racemase, an enzyme that requires vitamin B6 to function. It is thus important to supplement vitamin B6 when supplementing L-serine.
Studies involving both forms of serine clearly demonstrate its interesting scope of effect. That being said, L-serine may be less effective since it requires an extra step before it can be used by the body.
Mood and Depression
D-serine produces both acute and chronic antidepressant effects in animal models. Chronic use was also reported to lower markers of anxiety. Studies have also shown that it may prevent cognitive impairment in subjects exposed to stressful situations (like a job interview) but not in normal day-to-day situations. D-serine, therefore, does not strictly meet the definition of a nootropic. It is, however, ubiquitous in the body, and with many interesting effects in promoting cerebral health, certainly a worthy supplement.
Sarcosine was the star of a landmark 2013 study, which underpinned a role of the Glycine transporter 1 (GlyT1) in depression. The antidepressant effect of sarcosine and other GlyT1 inhibitors may be related to the increased levels of glycine, an inhibitory neurotransmitter that seems to have an anti-stress effect. Thestudy found sarcosine monotherapy to be superior to the SSRI citalopram (Celexa) in remitting depression, with rapid onset of action and few side-effects. The role of glycine in mental disorder may be much larger than originally thought.
As expected, users have reported varying levels of effectiveness from sarcosine as an antidepressant, with some drawing a comparison between ketamine or citalopram, while others have not noticed a significant effect. The research has suggested a strong general effect, which may still nevertheless depend on the individual.
Schizophrenia and Psychosis
The glutamate system is the largest excitatory system in the brain and it commands functions across every region, so one would expect sarcosine to be useful in depression, memory loss, or interestingly, psychotic disorders. The glycine transporter’s influence over NMDA receptors (which are essential for memory and learning) may also explain why sarcosine makes a useful adjunctive therapy to antipsychotics. It’s all to do with the involvement of NMDA and glutamate in schizophrenia:
… the hypofunction hypothesis of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of schizophrenia suggests that increasing NMDA receptor function via pharmacological manipulation could provide a new therapeutic strategy for schizophrenia. The glycine modulatory site on NMDA receptor complex is the one of the most attractive therapeutic targets for schizophrenia. […] Some clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methylglycine) shows antipsychotic activity in patients with schizophrenia. Currently, a number of pharmaceutical companies have been developing novel and selective GlyT-1 inhibitors for the treatment of schizophrenia..
Because of the diverse actions of the glycine transporter and its involvement in other neurotransmitter systems, sarcosine has also been found to modulate striatal dopamine release. This may help further explain its antipsychotic properties.
While it may not be terribly effective on its own, used in conjunction with pharmaceuticals, sarcosine can deliver a real knockout blow, conveniently complimenting pharmaceuticals in treating both negative and positive symptoms. This is particularly remarkable because most pharmaceuticals were developed to address only positive symptoms; there has been a race to find more effective treatments for the negative symptoms, which have often come in the form of over-the-counter supplements, exercise programs, and specific diets.
Sarcosine and N-acetylcysteine were both found to restore glutamate activity in mGluR5 knockout mice Low activity of this receptor may be related to schizophrenia. Interestingly, positive allosteric modulators of mGluR5 may have nootropic properties. 
Sarcosine is known to have potential in Parkinson’s and other dopamine dysfunction disorders, such as ADHD. Sarcosine and its metabolite glycine modulate dopamine in the striatum, which includes the hippocampus.
Another study has confirmed as helpful the addition of sarcosine to antipsychotic therapy, concluding it increases survival of neurons and glial cells in the dorsolateral prefrontal cortex (a key structure damaged by aging and drug abuse, it is involved in executive functions, such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning). Sarcosine may soon become a popular supplement in the psychiatric industry.
Even though they are far from being popular nootropic supplements, D-Serine and Sarcosine are two fascinating compounds.
If you are being medicated for schizophrenia or depression, you should definitely consider supplementing one of these two compounds to augment your psychiatric medication. Sarcosine, in particular, is very inexpensive and has a lot of evidence backing up its use. 
Nootropic users who have tried Sarcosine report improvements in focus, motivation and visual acuity, and there is some evidence that it may help those living with ADHD.