Categories
Biohacking Coluracetam Nootropics PRL-8-53 Tutorials

Photographic Memory: Nootropics and Mnemonic Devices 101

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

What is Photographic Memory?

According to the Merriam-Webster dictionary[1]

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

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

Case 1: The Mind of a Mnemonist

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

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

Solomon Shereshevsky Photographic Memory Nootropics
Solomon Shereshevsky

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

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

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

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

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

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

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

Case 2: The Girl with Eidetic Memory

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

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

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

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

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

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

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

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

Kim Peek Super Memory
Kim Peek

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

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

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

Stephen Wiltshire Eidetic Memory
Stephen Wiltshire

How to Develop Photographic Memory

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

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

Memory: What is It, How to Improve it

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

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

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

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

References   [ + ]

Categories
Biohacking Tutorials

The Ultimate Guide To Hair Loss: A Scientific Approach

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

What is Androgenic Alopecia?

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

Thinning Hair Treatments

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

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

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

Minoxidil

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

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

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

Finasteride

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

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

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

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

Topical Finasteride

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

Clinical Studies

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

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




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

Black Castor Oil + Peppermint Oil

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

Prostaglandin D2
Prostaglandin D2

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

Yin & Yang: Prostaglandin D2/E2

Prostaglandin E2
Prostaglandin E2

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

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

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

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

Dermaroller and Dermapen™

dermaroller
Dermaroller

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

Which Dermaroller Should I Use?

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

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

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

Tretinoin

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

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

Putting It All Together

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

Regimen A

Morning

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

Afternoon

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

Regimen B

Morning

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

Afternoon

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

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

Other Useful Tips for Thinning Hair

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

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

References   [ + ]

Categories
Biohacking

Improve Sleep Quality With This Sleep Optimization Checklist

Sleep quality naturally declines during aging. For example, sleep duration and sleep consolidation both deteriorate as we age. (Less consolidated sleep is more fragmented, with shorter mean sleep bout duration). Moreover, impaired sleep quality is a sensitive prodromal sign of future cognitive decline and Alzheimer’s disease (AD).

Improving sleep quality often translates to improved mood, enhanced cognitive function, and general well-being. We’ve cataloged ten of the most relevant ways to improve sleep quality. The first few tips apply more to healthy subjects; the latter suggestions are aimed at individuals struggling with clinically significant insomnia.

  1. Circadian rhythm is coupled to light cues from the environment. Individuals who sleep in an environment that is not dark enough will have a blunted circadian rhythm (e.g., impaired expression of the proteins that regulate sleep/wake oscillations). To maximize sleep quality, use black electrical tape to cover all light sources (e.g., blinking electronics).
  2. f.lux-iphone-comparisonThis tip is an extension of the previous one. Download the f.lux app, which calibrates the wavelength of the light emitted by your laptop screen (or monitor) according to the time of day.Screens normally emit high-energy/low wavelength blue light which interferes with the biological block. With flux activated, at night your laptop will emit warm, red/orange light (like a sunset), which is less likely to cause the “circadian rhythm phase delay” that impairs sleep onset.
  3. Turn the thermostat down at night to slightly chilly temperatures. Internal body temperature drops to a trough at around 4 AM. Low temperatures at night are considered an environmental cue that entrains the biological clock and helps facilitate sleep initiation.
  4. Vigorous exercise before bed has been consistently noted to improve sleep quality.
  5. Practice good sleep hygiene by going to bed and waking up at the same time. Humans are creatures of habit, and following a regular schedule can help synchronize your body clock. Limit stimulating activities in the evening. For years, I played computer games until 2 am right before going to bed. Suffice it to say, I had vivid dreams and sleep quality was not ideal.
  6. Nutraceuticals that show promise in alleviating (mild) insomnia
    • Magnesium (bioavailable such as glycinate, aspartate or taurate are recommended)
    • Melatonin (low doses, e.g. <1 mg are paradoxically more effective than higher doses)
    • Glycine (an inhibitory neurotransmitter and co-agonist at NMDA receptors)
    • L-Theanine
    • Herbal tea with lemon balm, passionflower, and chamomile
  7. If you have clinically significant insomnia, do not be deterred from using prescription drugs to manage your symptoms. Long-term sleep loss is extremely taxing on the body and mental health. Often primary insomnia will not respond to tips #1-6. It is tempting to dismiss patients with clinically significant insomnia with soft-core interventions like “get more exercise” but that just won’t cut it for this patient population.

    sleep aids how they work

    Unfortunately, when it comes to sleep aids, there is an inverse relationship between long-term safety and efficacy. The most effective sleep aids are more likely to adversely affect brain health. This cost/benefits analysis and the trade-offs of different medications should be weighed by your clinician. When shopping for sleep aids, start with the safest, most suitable agents for long-term use:

    • Ramelteon (Rozarem)
    • Suvorexant (Belsomra)
    • Trazodone (Desyrel)
    • Mirtazapine (Remeron)
    • Hydroxyzine (this antihistamine has a long half-life but has negligible anticholinergic activity)
    • Other antihistamines and sedatives

    Higher-risk options:

    • Phenibut
    • Z-drugs (e.g., Ambien)
    • Benzodiazepines (e.g., Xanax)
    • Ibutamoren (aka MK-677)
  8. Resolve/treat contributory diseases. The most important disorders that can exacerbate sleep disorders are:
    • Sleep apnea
    • Hyperthyroidism/hypothyroidism
    • Disorders of hyperarousal (Anxiety disorders, PTSD, depression)
    • ADHD
    • Restless leg syndrome
    • Delayed sleep phase syndrome/other circadian rhythm disorder
  9. scumbag brain on waking up earylSometimes, chronic insomnia develops from a self-reinforcing psychological process. Let’s say a major life event disrupts your sleep and mood for a short period of time. Many people will recover the lost sleep quality, but some people will begin to obsess about their inability to get a proper night’s rest. This results in a positive feedback loop where as you become more worried about fixing your broken sleep, your sleep quality deteriorates further.Panic disorders often arise from a similar process, where the object of your anxiety is the anxiety itself. For example, you might be concerned that heightened anxiety will cause a heart attack (because your heart is palpitating), which adds more fuel to the fire, culminating in a full-blown panic. Harvard has devised some behavioral interventions that can be helpful for this kind of self-perpetuating neurotic sleep disorder. They suggest taking a sabbatical from work (if you can afford it), and instead of trying to go to bed, trying to stay up as long as possible. Chronically restricting the total amount of time in bed may be one of the most robust behavioral interventions for treating sleep-onset insomnia.
  10. A promising sleep enhancement strategy worth mentioning is the pharmacologic augmentation of slow-wave-sleep (SWS) using selective 5-HT2A antagonists.
Categories
Biohacking Caffeine Modafinil Nootropics Tutorials

Hacking Sleep How-To: Sleep Less, Do More (or How I Survived 48h Hackathons)

I started out in an Engineering program at a Canadian University a couple years ago. Shortly thereafter I decided I wanted to be a programmer. Totally reasonable life choices, that came with some slightly less reasonable time demands.

You see when you’re in an engineering program pulling all-nighters to get work done start becoming fairly normal. And then if you want to become a programmer you now need to digest thousands of lines of documentation and code, which definitely doesn’t help you get all the schoolwork done in a nice timely manner. And then we compound that with the recent phenomenon of hackathons. Hackathons are 24-48hr long programming meetups where you, alone or in a team, write code hoping to create something interesting, like a mobile app, or program. As it currently stands, getting employed at a top tier tech firm is nigh nearly impossible for an undergraduate student without hackathon experience.

So this led me to try and find some way to make it easier for myself to stay awake, and get work done.
University students are often familiar with ADHD medication of some sort or the other. These include Ritalin, Adderall, Vyvanse, Biphentin and many others. But they’re only so effective and have some undesirable side effects.
But hey, I’m not trying to tell you to not take drugs here, drugs are bad, you know this from the millions of dollars spent by many governments vilifying them under one undiscriminating umbrella term. No, I’m going to teach you how to intelligently use drugs to get the results you desire.

A brief primer on the brain

Hackathons are great learning experiences, you get to try new frameworks and tools with minimal risk. You see, to build something in programming, you need to understand the tools and solutions that exist in that space. To engineer a better bridge, you need to understand how bridges work and are built. So we need to understand the human brain a little bit.

Most of you should know that a human brain is a biological electrochemical system consisting of cells called neurons. Neurons connect to each other and basically store you. Who you are, your memories, your ability to add numbers, everything is stored as connections in a dense mesh of cells in your cranium. Neurons communicate via signals triggered by electrical charges that cause chemical messengers to be released into a tiny gap in between them and accepted by another neuron on the other side.
So to hack it, we will either have to use electromagnetic phenomenon or chemicals.

Although transcranial direct current stimulation has been noted to positively influence wakefulness [1] wearing a magnet and electrical equipment on my head doesn’t seem too attractive so instead let us enter the wonderful world of neuropsychopharmacology.

synapseRight so about those chemical messengers.
Well, they’re called neurotransmitters. There’s oh so many of them. Their release is usually mediated by voltage differentials in the neuron itself (keep this in mind, it’ll come up later).
The place where two neurons connect is called a synapse, and there’s a tiny gap between them.
After crossing the tiny gap, which is also called the synaptic cleft, these little guys fall into receptor sites. Think of it as a jigsaw puzzle, a specific shape of receptor goes with a specific shape of neurotransmitter. But there are man-made chemicals as well that can fit into the receptor and cause interesting effects since they have somewhat similar shapes to the neurotransmitters. Not all these neurotransmitters lock into receptors, some are sucked back into the neurons via recovery vents. This is called reuptake.

The neurons also have some receptors along their bodies, which allow them to judge and react to the environment. For example slowing down if the environment tells them the person is tired or trying to go to sleep. Though these aren’t actively used to send messages along.

Well now we know a bit about the brain but what about sleep?
Sleep has a myriad of purposes, so I do not recommend long periods of severe sleep deprivation.
These include muscle recovery and repair.
Formation of long-term memories.
The brain also does housekeeping and maintenance, flushing out by-products of cellular function and rearranging neuron formations.[2]
At the end of the day, sleep is necessary, but that doesn’t mean we can’t engineer around having to sleep every night. But not sleeping at all for an extended period can have dire consequences, even death.

Wakefulness and receptors

Well, there are 3 main receptor types that I’ve identified that have something to do with wakefulness. Since many chemicals can affect the same receptor and the receptors often have subtypes these 3 receptor types provide a nice framework to reason about hacking sleep and chemical targets. I came to this hypothesis by looking at the mechanisms of actions of a plethora of drugs which are known to affect wakefulness.

These are the adrenergic, dopaminergic and adenosine receptors.
But I should mention that sleep is complex, so is the human brain, and other neurotransmitters like serotonin and glutamate also play a part. For a purely curious mind I recommend reading “Neuropharmacology of sleep” on NCBI.

Dopamine receptors

Dopamine

Ah yes dopamine, many of you have probably heard of it. It is responsible for reward-motivated behavior. If you study hard and get those grades for yourself and it makes you feel good, well it’s the dopamine. Too much dopamine and you’ll be lazy and not want to do anything, too little and you’ll get bored, yawn, maybe fall asleep(anyone else have 8 am engineering lectures?). It plays a very real role in sleep.[3][4]

You will usually have too little dopamine trying to pull all-nighters. We’ll be looking at drugs that increase dopamine concentrations in the brain and supplements that are easily metabolized to it to prevent depletion. You also want to block its reuptake to maximize signaling strength. Dopamine reuptake inhibitors, precursors or anything that increases dopamine transporter activity causing it to release more is your friend.

Adenosine receptors

Adenosine

Fewer people have probably heard of this one, but almost all of you have exploited this poor guy in the past. Ever drink coffee? Green tea? Energy drinks? This is the main target for all of those.

You see as you get sleepier, this pesky little molecule called adenosine builds up in your brain as a breakdown product of ATP (your cells generate energy via the ATP->ADP reaction). It binds to its namesake receptor, which in turn triggers some very calming effects like slowed heart rate, reduction in dopaminergic signalling, muscle relaxation etc. All effects we don’t want. So we drink coffee, which blocks these receptors, preventing adenosine in our brain from getting in and triggering its effects. So what you need are adenosine antagonists.

Adrenergic receptors

Epinephrine

These guys are responsible for triggering your adrenal system. The whole fight or flight response.
If you overstimulate them well you’ll be panicky, anxious, paranoid your heart will explode from the excessive beating. But a small amount can do wonders for alertness and wakefulness.
One should note that drugs that target the dopamine and adrenergic receptors can sometimes be found under the category of monoaminergics on online retail sites.

Drugs

Alright, time for the fun stuff. I didn’t just almost put you to sleep droning on about receptors and what-not for nothing. Time to teach you how to hack around the biological need for regular sleep. I can’t talk about all the drugs since new ones come out pretty often, but you can identify drugs that’ll work based on the receptors and underlying systems they target. For the best results, we want drugs that have different mechanisms of actions on these systems stacked together.

Amphetamines

AdderallRemember those drugs kids at school take we talked about earlier? Adderall etc.
They’re amphetamines or amphetamine derivatives, all of them, and share similar mechanisms of actions. They work mainly on the dopamine and adrenaline systems.

By increasing DAT (dopamine transporter) activity, they cause your neurons to dump more dopamine into the presynaptic cleft.
It works in the same way on the adrenergic system and also triggers similar effects on a myriad of other neurotransmitters like acetylcholine, glutamate, and serotonin.
But there are other drugs that can be acquired cheaper and without legal restrictions which have the same mode of action. They can often be found in supplements for weight lifting as stimulants or pre-workouts.

For example one drug that is rather easy to get at bodybuilding and supplement stores is Ephedrine. It’s similar to amphetamine in structure and affects the dopaminergic and adrenergic systems just like the most popular ADHD medication. It doesn’t work quite as well, though.

But these amphetamine derivatives also have a dark side.

First off if you take too much your neurons will fry themselves. Remember how I mentioned neurotransmitter based transmission is triggered by electric currents in the cells? When a super excited neuron dumps a ton of dopamine, the tiny electric charge causing it is enough to damage it, permanently. But then it cascades, and the next neuron in queue attempts to pass on the signal, frying itself in the process and so on and on. Don’t worry, there’s millions of them, or actually do worry a little bit. Neurons are easily excited, and like a very very old man with a myriad of health problems, too much excitement can and does kill it.[5]

Secondly, regular use of ADHD medication can and does cause a dependency. So you’ve effectively given yourself ADHD and can’t really function without it.[6]

Third, amphetamine use severely drains your neurotransmitters. You need to replenish them. Keep reading and I’ll tell you how.
They also cause stress and fatigue in the underlying systems, namely the adrenergic and dopaminergic systems and to a lesser extent the serotonergic system.
So if you feel burnt out afterwards, try taking half the dose or less the next time. a 10% constant boost is better than a 20% boost followed by a 80% degradation.

The brotherhood of Modafinil

Modafinil

Now let’s consider a slightly more exotic drug. Modafinil. This guy been around for a long time and the militaries around the world love it. I just found out my home nations (India) air force includes it in contingency plans. Brilliant! Soldiers that don’t need to sleep. Now if only they could find planes that didn’t fall out of the sky on a regular basis.[7]

Modafinil works via the dopaminergic and adrenergic systems.[8]
It works as a dopamine reuptake inhibitor, which means stronger signals due to more dopamine in the presynaptic cleft, and it increases norepinephrine levels in the synaptic cleft in a similar way to amphetamines.

An important factor to keep in mind is that it’s a low-affinity binder, which means:

  • It works slowly (expect 2 hrs)
  • Its mild (you won’t necessarily feel it, but trust me, when it’s 4am and you look around and everyone but you is yawning, you’ll know it worked)
  • It won’t prevent you from falling asleep if you really want.

You can buy Modafinil and Armodafinil, an improved analog of Modafinil, at ModafinilXL.

Adrafinil

Adrafinil

This guy gets metabolized to modafinil in the liver. A strange queasiness might be felt in the liver as the enzyme activity increases. Not as effective as modafinil since a lot of it is destroyed in the metabolic process.

Hydrafinil

Hydrafinil

Some people absolutely love this stuff. The name is a marketing play and the molecule itself doesn’t have much in common with modafinil.[9] Though common criticisms are that it looks funny, clumps easily, has a very short duration of effect and it’s as effective as Modafinil.

Flmodafinil

Flmodafinil

AKA CRL-409,40 (or Bisfluoromodafinil), current heavyweight champion of the modafinil alternatives world. Basically modafinil with two fluorine atoms added to it. This increases the bio-availability of the drug by increasing its lipophilicity (it crosses the blood brain barrier easier since it’s more fat soluble)[10]

Recommended dose is 50-100 mg, up to 200mg if you plan on staying up for 48hrs.

Fladrafinil

Fladrafinil

AKA CRL-409,41 (or Bisfluoroadrafinil) I recommend you do not take this. It’s basically adrafinil with two fluorine molecules and all anecdotal reports say it doesn’t work very well. If you do try it, write to us and tell us how it went!

Modafinil and it’s derivatives is a lot safer than amphetamines and stimulants like Adderall, but still don’t take a massive dose. I can tell you from personal experience that staying awake for 3 days in a row isn’t fun.

Good ol’ cuppa joe

Caffeine

So far we’ve targeted the dopaminergic and adrenergic systems. Let’s look at adenosine real quick.
Your best bet (and cheapest) is to simply drink a cup of coffee.
Many in the nootropics community love a little bit of l-theanine with their coffee, feel free to try that if coffee makes you too jittery.

But don’t drink too much coffee. It’ll backfire.
If you drink large amounts of coffee continuously, your brain reacts by upregulating adenosine receptors on the neuron heads and by increasing the amount of adenosine in your brain, and this causes you to be constantly sleepy, tired and to need coffee to barely function. If you’re at a hackathon, hold up on the coffee till it’s near the end and you absolutely can’t function without it.

I found myself continuously getting addicted to coffee, requiring it to just stay awake and then going through a painful withdrawal/cleanse, so I switched to green tea.
There are more powerful and targeted adenosine receptor blockers though they aren’t very well known or easily found. These belong to the Xanthine family of molecules. Write to us if you have any hands on experience with them, we’d love to interview you.

Recovery

“But I feel like shit after pulling all-nighters or going to hackathons!”

Well duh, what’d you expect to feel like? A million bucks?

Here’s what happened, your brain depleted a ton of its neurotransmitters thinking your thoughts. Energy stores are also depleted. I highly recommend taking a dopamine precursor afterward or even as part of your drug stack.

N-Acetyl-L-Tyrosine, better known as NALT, is a crowd-pleaser in that category. The main part of those four letters is the T, and it stands for tyrosine. Tyrosine is an amino acid that is readily metabolized to dopamine. Dopamine is further metabolized to norepinephrine which you depleted stressing your adrenergic system. Bam! Two birds, one stone.
Mice treated to have extra dopamine also have a stronger reaction to modafinil and caffeine and ended up recovering better from sleep deprivation than untreated mice.[11]

So what about the adenosine we blocked?
Well, there isn’t much you can do about that. Take a nap, even if it’s a quick 10-30-minute nap or you just close your eyes and think about stuff during your waking stint. It’ll flush some of the adenosine out of your brain. It’ll also help you get over writers block if you feel incredibly fatigued before you can afford to sleep properly.

And finally, eat something, even if you’re not hungry from all the stims in your body. I’m not going to go into dieting and what proper foods are. But hopefully, you know this part.

Best of luck with your endeavors, whatever they may be.
And remember I’m not a doctor and even if I was, you take advice from a stranger on the internet at your own risk.

References   [ + ]

Categories
Biohacking Nootropics Tutorials

Microdosing Psychedelics For Cognitive Enhancement

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

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

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

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

How Does it Work?

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

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

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

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

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

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

Which Substances Can Be Used?

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

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

(Table taken from /r/microdosing)

The Potential Effects of Microdosing Psychedelics

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

Some of the purported benefits of microdosing include:

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

Some negative side effects of microdosing include:

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

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

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

Conclusion

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

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

References   [ + ]

Categories
Biohacking Cognitive Health

The Shocking Truth about tDCS and its Effects

Developed as an answer to the problem of brain injuries and certain mental illnesses, tDCS has truly made an 180° turn, heading towards a place no one could have ever predicted. For decades, it has been used as a last resort to help patients suffering from mental illnesses. It has also proven to be a highly efficient method in helping stroke patients regain control over their mental functions, including walking and talking. But its recent application as a cognitive enhancer tool has created a stir in the field of neuroscience. In the attempt to pinpoint the exact effect tDCS has on our mental powers, we have to start from the beginning: the brain.

Your Brain in the Fast Lane!

Arguably the most complex organ in the human body, the brain has baffled scientists for centuries. Aside from a few things we have learned, like its size, shape and consistency, much about it is still unknown and undiscovered. The workings of the brain are still as much of a mystery as they were a hundred years ago. What we do know is that its founding blocks, impulse-conducted cells, make up only about 10% of it, and the glia (the glue that binds the neurons together) makes up as much as 90%. It all looks a lot like a highway, with millions and millions of lanes – pathways, each going in different directions. The pathways, or synapses, are the brain’s response to outer stimuli. These pathways get created whenever a person learns something new – a language, sport, how to tie a shoelace, etc. This superpower that our brain has of creating new synapses whenever we are exposed to new stimuli is something called plasticity, and it is directly proportional to the number of synapses the brain has. The more synapses there are, the higher the plasticity of the brain. How fast you learn a second language, master a new skill, solve a math problem, etc. depends not only on the number of neurons you have but also on your brain’s plasticity.

Some simple math here: number of neurons + brain’s plasticity = degree of intelligence

Studies have shown that the higher the number of neurons and synapses you have, the higher your IQ will be.
And while the number of neurons is not something we can change (it’s written in our genetics), the plasticity of the brain is actually something we can control – through constant stimulation, or being exposed to new situations, problems, and difficulties. This often requires quite a bit of effort, and, what’s even more important: time.
But, there seems to be a shortcut to the whole story, in the form of tDCS. An electrifying shortcut indeed!

back to the future tdcs

tDCS as an outer stimulus

Studies conducted on tDCS have shown that stimulating a certain part of the brain through very low-level currents of up to 2mA, can cause an “excitability” of the brain in healthy individuals. This excitability of the brain is seen as a number of cortical changes that can last even after the stimulation is done. How long the changes last is directly linked to how long an individual has been exposed to a stimulus, the number of tDCS sessions, as well as the intensity of the stimulus.

There are two types of changes that tDCS can cause: depolarization or hyperpolarization. Namely, when the anodal tDCS is conducted, which is positive stimulation, the resting membrane potential depolarizes. This, in turn, increases the neuronal excitability and allows for more spontaneous cell firing. On the other hand, when cathodal tDCS is performed, which is negative stimulation, the resting membrane potential gets hyper-polarized, thus decreasing spontaneous cell firing, a.k.a. neuron excitability.

tDCS takes advantage of two concepts, LTP and LTD. Long-term potentiation (LTP) refers to the strengthening the connection between two neurons. LTD, or long-term depression, refers to the weakening of the same connection, thus causing the transmission between two neurons to be enhanced or hindered.

credit: http://www.frontiersin.org/

One of the studies conducted on a group of 60 participants researched the effects of tDCS on creativity. Test participants were given a number of everyday objects, such as a baseball bat, for which they needed to come up with another use (for example, using that bat as a rolling pin). Thinking about unconventional uses of simple everyday objects requires “thinking outside the box”, which requires thinking about the size and material of the object as well as eliminating the usual things that the object is used for. This all required a high level of creativity.
The participants were presented with 60 different objects, one every nine seconds. The researchers noted down the answers, the lack of answers, as well as the time it took the participants to come up with an answer.
The study showed that the participants who received tDCS to their left prefrontal cortex didn’t know 8 answers on average. Those who received placebo or tDCS to their right prefrontal cortex missed about 15 answers out of 60. The group whose left prefrontal cortex was inhibited through tDCS was also faster in coming up with the answers – a whole one second quicker than the other two groups, which is a lot when it comes to psychological research, as the director of Penn’s Center for Cognitive Neuroscience and lead researcher Sharon Thompson-Schill concluded.

Another study on the stimulation of the left dorsolateral prefrontal cortex in patients with depression showed that 48% of participants responded well to the treatment. They received tDCS every weekday, 30 treatments in total. A majority of them noted a substantial difference in their cognitive powers, i.e. better working memory and verbal fluency.

A number of studies suggest that tDCS may improve learning, vigilance, intelligence, and working memory. However, many of these studies have been small and heterogeneous, and meta-analyses have failed to prove conclusive effects, and long-term risks have not been established. Consequently, the F.D.A. does not regulate the use of tDCS.

tDCS-distributing machine

brain_types_directcurrentA tDCS – DTC (direct-to-consumer) device consists of a main operating unit, one battery, and two electrodes: an anode and cathode with conductive sponges that can be applied to the head, held in place with a band. The principle behind it is to place the electrodes on brain regions of interest on the skull and let the low-level direct current induce intracerebral current flow which will either decrease or increase excitability of the neurons. The treatment lasts twenty to thirty minutes with the current level individually adjusted, but limited to a maximum of 2mA.

The specific placement of the electrodes is called a montage based on the “10-20 International System of Electrode Placement”. This is a mapping point for the brain with coordinates that point to specific regions of the brain. Montages vary, depending on what effects the individual would like to have. For a comprehensive list of possible montages as well as links to the studies conducted for various conditions, like mood improvement, accelerated learning, pain management, working memory improvement, etc. please check this article, which also contains brain electrode placement maps for your reference.

Should you or shouldn’t you?

Though tDCS has taken the world of neuroscience by storm, it is not the only place of its application. Scientists are not the only ones intrigued by it. Army and military forces are currently conducting many experiments in the hope that one day they’ll be able to create a “super soldier” – one with the heightened concentration, improved cognitive powers, and enhanced working memory.
So, the final question of whether to supercharge the brain or not is completely left to the reader, but with the benefits heavily outweighing the drawbacks, it seems only logical that there are many potential benefits to tDCS use.

One thing is for certain, tDCS should not be dismissed so easily! It is definitely one form of treatment that will shape our future.

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”?

References   [ + ]

1. Acute and chronic effects of cannabinoids on effort-related decision-making and reward learning: an evaluation of the cannabis ‘amotivational’ hypotheses (2016)
2. What is THCA and What are the Benefits of This Cannabinoid?
3. Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation. (2004)
4, 5. Deficits in striatal dopamine release in cannabis dependence. (2016)
6. Striatal dopamine and working memory. (2009)
7. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity (2014)
8. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin (2008)
9. Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. (1999)
10. Agonist-Induced Internalization and Trafficking of Cannabinoid CB1 Receptors in Hippocampal Neurons (2001)
11. Regulation of central 5-HT2A receptors: a review of in vivo studies. (1996)
12. CANNABINOID RECEPTOR AGONISTS UPREGULATE AND ENHANCE SEROTONIN 2A (5-HT2A) RECEPTOR ACTIVITY VIA ERK1/2 SIGNALING (2013)
13. Cannabinoid-induced upregulation of serotonin 2A receptors in the hypothalamic paraventricular nucleus and anxiety-like behaviors in rats. (2013)
14, 15, 16. Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors (2015)
17. Down-regulation of the AMPA glutamate receptor subunits GluR1 and GluR2/3 in the rat cerebellum following pre- and perinatal delta9-tetrahydrocannabinol exposure. (2004)
18, 20. Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans (2008)
19. Ventral tegmental area BDNF induces an opiate-dependent-like reward state in naive rats. (2009)
21. The effects of cannabinoids on serum cortisol and prolactin in humans. (2009)
22, 23. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. (2009)
24. mTOR signaling in the hippocampus is necessary for memory formation. (2007)
25. Citicoline Treatment Improves Measures of Impulsivity and Task Performance in Chronic Marijuana Smokers: A Pilot BOLD fMRI Study. (2015)
26. Can coffee enhance cannabis’ high? Study reveals how marijuana’s effect can change based on how much caffeine you’ve drunk
27. Potential Role of N-Acetylcysteine in the Management of Substance Use Disorders (2014)
28. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. (2012)
29. N-Acetylcysteine (NAC) in Young Marijuana Users: An Open-Label Pilot Study (2010)
30. The cannabinoid CB(1) receptor antagonist CE prolongs spatial memory duration in a rat delayed radial arm maze memory task. (2008)
31. Discovery of indole alkaloids with cannabinoid CB1 receptor antagonistic activity. (2011)
32, 33. Pregnenolone can protect the brain from cannabis intoxication. (2014)
34. Rapid Changes in CB1 Receptor Availability in Cannabis Dependent Males after Abstinence from Cannabis. (2016)
35. Eugenol suppresses cyclooxygenase-2 expression in lipopolysaccharide-stimulated mouse macrophage RAW264.7 cells. (2003)
36, 47, 48. Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells. (2002)
37, 38, 40. Cyclooxygenase inhibitory natural products: current status. (2006)
39. A new class of COX-2 inhibitor, rutaecarpine from Evodia rutaecarpa. (1999)
41. Suppressive effect of natural sesquiterpenoids on inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) activity in mouse macrophage cells. (2002)
42. Xanthorrhizol inhibits 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation and two-stage mouse skin carcinogenesis by blocking the expression of ornithine decarboxylase, cyclooxygenase-2 and inducible nitric oxide synthase through mitogen-activated protein kinases and/or the nuclear factor-kappa B. (2007)
43. Anti-inflammatory effect of the oligomeric stilbene alpha-Viniferin and its mode of the action through inhibition of cyclooxygenase-2 and inducible nitric oxide synthase. (2003)
44. Anti-inflammatory effects of schisandrin isolated from the fruit of Schisandra chinensis Baill. (2008)
45. Regulation of Cox-2 by Cyclic AMP Response Element Binding Protein in Prostate Cancer: Potential Role for Nexrutine (2007)
46. Bromelain inhibits COX-2 expression by blocking the activation of MAPK regulated NF-kappa B against skin tumor-initiation triggering mitochondrial death pathway. (2009)
49. Effects of resveratrol alone or in combination with piperine on cerebral blood flow parameters and cognitive performance in human subjects: a randomised, double-blind, placebo-controlled, cross-over investigation. (2014)
50. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects (2011)
51. Chronic exposure to THC downregulates oxytocin and oxytocin-associated neurophysin in specific brain areas (2006)
52. Nicotinic alpha 7 receptors as a new target for treatment of cannabis abuse. (2007)
53. Does eating mango boost the effect of marijuana?
54. Anti-inflammatory effects of Mangifera indica L. extract in a model of colitis (2010)
55. Transdermal drug delivery formulations with optimal amounts of vasodilators therein.