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
Nootropics Tutorials

Nootropics: A Beginner’s Guide To Cognitive Enhancers

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

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

Nootropic Trend - Google searches of keyword "nootropics"

What is a Nootropic?

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

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

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

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

Caffeine
Caffeine

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

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

Who Uses Them?

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

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

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

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

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

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

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

Where Do I Begin?

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

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

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

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

Wakefulness and Motivation

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

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

General Cognition

piracetam nootropic adhd

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

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

Mood Improvement

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

Memory

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

What To Expect

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

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

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

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

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

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

Up Next

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Tutorials

What Happens to Drugs Inside the Body?

The wise nootropic user knows two things: his goals with nootropic use, & how to use nootropics to achieve those goals. The latter is an area not well explored by many nootropics users. Knowledge of how individual agents work guides the design of stacks. Certain drugs may work synergistically (both together produce a greater effect than either alone), additively (both agents work in combination), or antagonistically (counteract each other). Thus, it is essential to understand what exactly happens after a drug is ingested.

The science of pharmacology serves to explain how the ultimate pharmacodynamic effect is produced (the end result of a drug, e.g. improved long-term memory). This is accomplished by studying two aspects of what happens to drugs within the body: mechanisms & pharmacokinetics.

Mechanisms

The most common way in which all drugs work is by modulating a receptor. The body is full of thousands of different types of receptors. These receptors are usually small proteins embedded in the surface of cells. There are 3 types of receptors:

  • Enzyme-linked receptors include enzymes & receptors that lead to the direct activation of enzymes.
  • Ion channel-linked receptors are regulated by concentrations of positively & negatively charged ions, such as Ca2+ & Cl. Na+ channels play a central role in neurotransmission.
    • Lidocaine, a Na+ channel blocker, suppresses conduction of action potentials between neurones, resulting in nullification of pain signals, hence its use as a local anaesthetic.
Receptors exhibit selectivity for ligands like locks & keys. The degree of compatibility between a ligand & a receptor is referred to as affinity.
  • G-protein-coupled receptors (GPCRs) receive signals by binding with ligands.
    • A ligand is something that binds to a receptor & produces an effect. Some examples are hormones, neurotransmitters, & drugs. When a ligand binds a receptor, it can produce any of 4 effects:
      • A receptor agonist is a ligand which produces stimulatory effects upon binding, triggering or potentiating a biochemical pathway ultimately leading to a response in the body.
        • When histamine binds H1 receptors, it triggers the immune system in such a way that symptoms of an allergic reaction are produced.
      • A receptor antagonist is a ligand which does not exert an effect upon binding, leading to the extinguishment of a somatic response as the stimulating ligand is unable to make contact with the occupied receptor. Antagonists can be competitive (meaning they reversibly bind to the receptor) or non-competitive (irreversibly bind receptors). Non-competitive receptor antagonists are more potent.
        • Aspirin is an irreversible COX-enzyme antagonist. Its inhibitory effects on platelets are permanent– following discontinuation, normal platelet function does not return for ~10 days- the lifespan of a platelet. For this reason, aspirin should be held for at least 1 week prior to major surgeries.
      • A partial agonist is a ligand which has properties of both an agonist & an antagonist ultimately producing a mild stimulatory effect.
        • Aripiprazole (Abilify) is an antipsychotic with partial agonist activity. Aripiprazole’s mild modulation at the D2 receptor produces modest reductions in some psychotic symptoms but avoids undesirable side effects due to over-antagonism of dopamine activity caused by other antipsychotics.
      • An inverse agonist is a ligand which exerts the opposite effect upon binding to a receptor, reversing a somatic process.
        • When an antihistamine drug such as diphenhydramine (Benadryl) binds H1 receptors, it does not merely occupy the receptor, preventing histamine from binding, but actually promotes the opposite biochemical pathway, actively countering the allergic reaction.

Visualised dose-response curves for various ligand-receptor interactions.
Visualised dose-response curves for various ligand-receptor interactions.

 

Pharmacokinetics

Pharmacokinetics (PK) refers to what happens to the drug after it has been ingested in the body. It is divided into 5 major areas, denominated by the acronym ADME-Tox:

  1. Absorption is the first phase of pharmacokinetic interest. Here we consider aspects of the drug’s transit into the bloodstream.
    • The route of administration (oral, sublingual, inhalation, intravenous, etc.)
    • Foods, as well as most drugs that are taken by mouth, are absorbed in the small intestine
    • How long a drug takes to be absorbed
    • The maximum amount that is absorbed (peak concentration, CMAX) & the time it takes to achieve CMAX (TMAX)
    • The onset, which is the time it takes for drug’s effects to begin
  2. Distribution is where we examine where the drug goes in the body.
    • The bioavailability (F), which refers to the concentration of the drug at the site of action (for nootropics, this would be the brain)
    • The volume of distribution (VD) which represents the degree of absorption into fat tissue. This is important because the amount of available drug is that which is present in the blood
    • Protein binding refers to the amount of drug in the blood that is bound to proteins such as albumin where it is inactive. These proteins act as carriers of the drug, preventing it from degradation. When drugs compete for binding proteins, or chronic malnutrition leads to decreased production of plasma proteins, there is a potential for increased levels of drug in the blood
  3. Metabolism has to do with biochemical pathways of breakdown or altering the structure of the drug molecule.
    • The liver is the major site of drug metabolism
    • Cytochrome P450 is a key group of enzymes in the liver that is responsible for the degradation of many drugs. Individual enzymes include 2C9, 2D6, 3A4, & so on. When 2 drugs happen to compete for the same enzyme, there is potential for a drug interaction. Understanding CYP450 is understanding the majority of drug interactions (will be covered later!)
    • Other drugs are able to undergo alternate pathways of hepatic (via the liver) metabolism (e.g. oxidation) or non-hepatic metabolism (e.g. proteolysis)
    • Prodrugs are parent compound which are inactive when ingested but become activated when undergoing metabolism. Usually, this is through the cleavage of a portion of the molecule. Active compounds, too, may have active metabolites. Keep these in mind as the metabolites can continue to contribute to the pharmacodynamic effect of the drug.
  4. Elimination is how the parent compound of the drug & its metabolites are removed from the body. There are two major pathways of elimination: hepatic (faecal) & renal (via the kidneys; urination).
    • Dysfunction of either system could lead to accumulation of drugs that are excreted by that pathway, possibly worsening side effects
    • Some drugs can be excreted via alternate pathways if the major pathway of removal is compromised
The ideal dosage of a drug achieves levels above the MEC but does not exceed the MTC.
The ideal dosage of a drug achieves levels above the MEC but does not exceed the MTC.
  • Toxicology is the propensity of a drug to cause harm & via which mechanisms.
    • «The dose makes the poison»: every agent has the ability to cause harm given the correct amount.
    • The minimum toxic concentration (MTC) is the level at which a drug’s toxicity becomes clinically significant. This is often compared with the minimum effective concentration (MEC), where a drug’s desired effects start to work. The difference between MTC & MEC is the therapeutic range. The narrower the therapeutic range, the higher the risk of toxicity.
    • Some mechanisms by which antidotes can work include binding the toxic molecule, preventing it from triggering receptors or promoting recovery processes (e.g. antioxidants)

Pharmacokinetic
Pharmacokinetic pathways & major organs.

 

Summary

  • Mechanisms are how drugs produce their effect. Most drugs work by affecting a receptor.
  • Pharmacokinetics is the study of the changes that happen to the drug after it is introduced into the body. It is broken down into 5 major areas: absorption, distribution, metabolism, elimination, & toxicology.
  • Pharmacodynamics is the outcome effect of a drug, such as reduced depressive symptoms.
  • An understanding of mechanisms & pharmacokinetics of drugs can be useful in designing stacks which exploits the characteristics of each agent for an optimised pharmacodynamic effect.
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How to Understand Clinical Research, Part II: Quality of Evidence

The ability to critically understand & judge the data from a study is crucial in making decisions on whether a new drug is safe & effective. As we will see with studies regarding nootropics, the answer is not always clear. Understanding concepts of validity, bias, & limitation can help in the evaluation of any study.

Internal validity

Internal validity is analogous to the inner workings of a clock
Internal validity is analogous to the inner workings of a clock– a study with strong internal validity will produce results that truly reflect what the investigators sought to explore, like how a clock with well-adjusted inner workings will accurately display the time.

Internal validity is the strength of the study’s purported causal or associative relationship.

Higher level studies, such as randomised controlled trials & meta-analyses, seek to demonstrate a causal relationship (e.g. drug A causes improved cognitive function). Lower level studies, such as cohort studies & case-control studies provide evidence that demonstrates an association between a cause & effect (not as strong of an assumption: drug A is associated with improved cognitive function). The tighter the study’s internal validity, the more reliance we can have that drug A does indeed cause or is associated with improved cognitive function, rather than any other conclusion (i.e. has no effect on, worsens cognitive function).

Bias

Bias comprises confounding factors which may compromise a study’s internal validity.

For example, consider a study with 2 treatment groups testing the effect of a new drug on cognitive function. The group that receives the drug is generally more educated, while the group that receives placebo is generally less educated.

How much faith would you have if the investigators concluded that the drug significantly improved cognitive function?

This is an example of sample selection bias. We will introduce more forms of bias later that could impair internal validity & thus the ability to truly believe that a study’s results are relevant to the study question.

External validity

External validity is the generalisability of a study’s findings to populations beyond the study sample.

External validity should only be assessed after a study is found to be internally valid. If a study is not found to be internally valid, then its findings could not be said to truly answer the study question; & thus there would be no reason to evaluate whether its results should be generalised to others.While internal validity is susceptible to bias, external validity is counterbalanced by limitation. These are characteristics of the study sample which add to & restrict the population to whom the results may be generalised.

Always consider the type of people who were enrolled in the study
Always consider the type of people who were enrolled in the study & whether what worked (or didn’t work) for them would work for you.

Consider the previous example of a study, but with both groups comprising generally older subjects otherwise comparable at baseline. Absent other confounding variables, the study could be said to be internally valid: if the investigators reported a significant improvement in cognitive function, then this result would be probably accurate. However, whether we could assume that this drug would work for younger individuals would be up for question as it has not been tested in this population. This limitation of generalisability applies to other demographic information such as race, sex, & even geographic location, & may include comorbidity (the presence of other health conditions), diet, & other factors depending on how the data is to be used. Including more diverse individuals within a study may decrease limitations & increase external validity, but possibly at the expense of internal validity (without randomisation). Conversely, creating a more uniform sample could increase internal validity but introduce more limitations.

Other forms of bias

Other forms of bias that could impair internal validity include:

  • Sample selection bias is when the treatment groups are not equal at baseline due to demographic differences.
  • Intervention selection bias is present if different forms of the experimental variable are used. This is a risk when the study protocol is ambiguous; for this reason study protocols are usually very detailed so as to prevent deviation. Consider the previous study with 2 treatment groups. Assume the groups are balanced at baseline. However, among the individuals in the group receiving the study drug, two different manufacturers of the drug are used. This could potentially produce variation in the results, providing an imperfect picture of how well the drug actually works. To limit this type of bias, it would be more prudent to select one manufacturer or have two treatment groups (one for each manufacturer).
  • Measurement bias is when there exist variations in how outcomes are measured. If the study drug group took an easier cognitive test than the placebo group, then the results would show that they performed better, when in fact the comparison was not equal.
  • Outcome bias occurs if the selected endpoints do not correspond to the desired outcome of interest. For instance, if the researchers claiming to measure cognitive performance instead administered a personality test.
  • Attrition bias is when more subjects from one group leave the study than in the other. Although the two groups may have been equal at baseline, attrition may result in unequal groups later on in the study which can result in confounding due to imbalanced characteristics (e.g. if all the young subjects left from one group) or simply due to number (sample size too small to detect a difference).

When cognitive tests are administered to a group of subjects, two possible biases could confound the results:

  • Statistical regression to the mean is a type of bias wherein on the second administration of the same test to the same subjects, the worst performers from the first administration tend to perform better & the best performers tend to perform worse on the second exam. They regress to the mean.
  • The testing effect is when subjects who take the same test become familiar with the style & better at taking the test. Although they might perform better on subsequent applications of the same cognitive test, it may not be because the study drug resulted in cognitive improvement.
  • Other forms of biases which are less commonly implicated but could still undermine a study’s findings include maturation bias & history bias.

Summary

  • Validity, bias, & limitations are key aspects of study designs to consider when researching & evaluating clinical data. The strength of evidence is best with high internal & external validity, & low risk of bias.
  • Internal validity is the strength of a study design to determine a causal or associative relationship. Studies with highly controlled experimental methodology (which we will discuss in depth later) exhibit tight internal validity minimizing the effect of biases.
  • External validity is the extent to which findings from internally valid studies may be generalized to populations beyond the study sample. Being aware of limitations to external validity guides the extrapolation of study data.

If you are interested in reading more about validity & bias, & how to apply them when reading an article, I highly recommend the Cochrane Foundation’s tool for bias risk assessment. It has since been widely used in meta-analyses when deciding whether to include articles.

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How to Understand Clinical Research, Part III: Types of Studies

In clinical research, there exist different types of studies which serve particular purposes. These studies are distinguished based on their experimental design (how the study is conducted) & the kind of data they produce– from the way a study is designed, we can draw certain expectations about the grade of evidence it produces.

Experimental designs can be described in several ways. A basic division of study designs can be made on how test subjects are enrolled, which significantly determines the study’s strength in describing a relationship between a cause (an experimental variable such as a drug to be tested) & an effect (an outcome such as cognitive performance). This particular way of classifying studies results in two main families of studies: observational studies & assignment studies.

Observational Studies

Observational studies are conducted in order to determine associations between certain prior exposures (e.g. a drug) & outcomes of interest (e.g. death).

Here, participants are selected based on exposure or outcome, depending on the type of observational study. These are more prevalent in research on nootropics as randomised controlled trials (RCTs) are generally conducted with larger samples requiring more funding. Small observational studies build up a body of evidence which provide the grounds for an RCT, a process called «hypothesis-generating» (as opposed to hypothesis-testing). Cohort studies & case-control studies are two major types of observational studies, both of which involve following a group of patients over a period of time.

Subjects in cohort studies are selected based on their having received a particular exposure, then they are followed prospectively (forward in time) until a certain outcome of interest (e.g. death) occurs. RCTs are also prospective.

Depiction of observational studies. Prospective cohort studies work from the perspective of the left viewer, while retrospective case-control studies work from the perspective of the right viewer.

In a case-control study, subjects are selected based on their exhibiting a certain outcome & tracing their history back (retrospectively) to find out whether they have had a certain exposure (e.g. used a particular drug). Retrospective case-control studies are especially useful when studying rare diseases.

Assignment Studies

Assignment studies enroll subjects to either test or control groups.

Assignment studies are subdivided based on (1) whether the allocation of subjects into test groups is randomised & (2) whether a control group is present.

Randomised controlled trials (RCTs) are generally considered to be the gold standard of clinical evidence for their strong internal validity, & are used to demonstrate causal relationships between experimental variables & outcomes. Randomly assigning patients to either treatment or control groups theoretically establishes equal groups, as any differences in age, race, comorbidity, or other features are equally distributed (eliminates sample selection bias). Prospective follow-up & the presence of a control group allows for comparison of the experimental variable (e.g. a new drug) against a standard treatment (to demonstrate a better treatment effect) or placebo (to demonstrate a treatment effect).

Mohamed AD, Lewis CR. Modafinil increases the latency of response in the Hayling Sentence Completion Test in healthy volunteers: a randomised controlled trial. PLoS One. 2014 Nov 12;9(11):e110639.
Standard CONSORT diagram depicting enrolment, allocation, follow-up, & analysis of subjects from an RCT comparing modafinil vs. placebo.

Synthetic Studies

Systematic reviews & meta-analyses critically evaluate the literature by consolidating the results of several studies focused on the same topic.

Synthetic studies are more recent study designs that have been developed out of a need to draw from the existing evidence on a topic. Prior to the rise of systematic reviews & meta-analyses, studies were selectively cited which led to bias (e.g. selecting only the studies which supported the use of a drug & either intentionally or unwittingly omitting the others which found significant side effects). Nowadays, both are considered the highest forms of clinical evidence, producing strong inferences of treatment effects. Synthetic studies are part of the trend of comparative efficacy analyses (CEAs): gathering data on several major drugs used for the same purpose & determining which are superior. Collecting findings from multiple RCTs & observational studies can produce a more complete picture of a drug’s safety & efficacy- in other words, considering the ‘big picture’. However, before drawing conclusions, one must be cognisant of differences between the studies that have been gathered (e.g. study protocol, different doses used, different sample characteristics).

Systematic reviews present findings from a pre-defined, reproducible search of the literature- that is, the authors exhaustively describe the methods they used to search databases & how they selected which studies to include in their systematic review, usually with a pre-defined criteria set. The importance of reproducibility is to reduce bias from selective inclusion of studies– this is a weakness of narrative reviews, in which the author performs a search & simply chooses which studies to include.

Meta-analyses are systematic reviews where the gathered data is then combined, producing an estimate of the true treatment effect from the pooled data. This is commonly expressed in what’s called a Forest plot, which shows the individual trials included in the systematic review as well as a diamond representing the estimate of the true efficacy or safety measure of the drug (how to read & interpret different tables & graphs will be covered later!).

An example Forest plot, with included trials listed on the left & their findings on the right. The findings are also plotted, with the diamond representing the composite of the studies’ results.

Summary

As we have seen, the design of a clinical trial can provide a quick way to judge its findings.

  • Observational studies produce evidence of associations by following patients over a period of time. Patients are selected based on a specific previous exposure in the case of prospective cohort studies or for a certain outcome in the case of retrospective case-control studies.
  • Assignment studies produce evidence of causal relationships by assigning patients to multiple groups including a comparator arm. The most prominent example of an assignment study is the randomised control trial, which has become the standard for clinical data.
  • Synthetic evaluations of the literature, such as systematic reviews & meta-analyses, draw on existing studies to better approximate treatment effects of drugs of interest.
  • Other experimental designs which are less commonly relevant to the area of nootropics include cross-sectional observational studies & non-randomised controlled trials.
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How to Understand Clinical Research, Part I: Accessing and Reading Research

researchA major part of the intrigue surrounding nootropics has to do with the fact that many of these compounds have not been largely studied. In effect, we are gambling with our neurochemistry in order to gain some benefit in our mental functions. But we are not without resources which can improve our chances of using nootropics safely & effectively. While the body of evidence behind nootropic agents is not large, it is growing, & will likely continue to grow with increasing rapidity as public interest in nootropics increases. Drawing upon this background of research can help us understand how nootropic agents work, in whom they work, & what the risks are. To this end, I will be launching a multi-part tutorial on how to understand & interpret clinical trials, designed for both novices & more advanced users. Topics we’ll cover include:

  • Validity & bias
  • Types of studies & hierarchy of evidence
  • Reading results (graphs & tables)
  • Methodology
  • Basic biostatistics

How to access clinical research

Pubmed search
A Pubmed search with limitations for clinical trials, free full text, & publication within the last 5 years.

First of all, clinical research is generally accessible by online databases through universities or hospitals. If you have access to some of these databases through your institution, such as Medline or Ebscohost, I highly recommend familiarizing yourself with them. For those without institutional database access, Pubmed offers a large open-access catalog of many journal articles. Google Scholar is another option for finding studies, but does not offer advanced search functions.

Pubmed screenshot 2
The abstract is shown, as well as full-text links on the right side.

Here are some other tips when searching for journal articles:

  • I would generally recommend limiting one’s search to full text articles, as abstracts do not often reveal the full story of a study.
  • Searching by MeSH terms (analogous to tags for topics) usually provides more relevant results than a basic keyword search. This involves searching for a MeSH term, selecting it, then running the search.
  • More recent results (preferably within the last 5 years) are preferable, as scientific research can move fast. Depending on the topic area, however, you might find yourself stretching your search to include up to 10 years.
  • Be aware of the country of origin of the article, as standards for publication may vary.
  • Authors who write many articles on the same topic may be biased &/or highly knowledgeable.
Pubmed screenshot 3
Select the desired MeSH term, add it to your search on the right side, then run your search.

Structure of a journal article

So you have located a journal article of interest. Fortunately, every journal article generally follows a similar structure. This organisation is designed to present the details of the study in an intuitive order.

  • The abstract is a short summary of study’s methods & results.
  • The background section reviews the current state of understanding in the topic area of interest. The investigators conducting the study also explain what they are trying to show.
  • In the methods portion, key details of how the study works are defined:
    • Endpoints or outcomes are what is being measured, such as performance on a cognitive test
    • Experimental variables are what is being tested, such as the study drug & the control against which it is compared (placebo or standard treatment)
    • The type of individuals the investigators wanted to analyse in their study as test subjects
    • The allocation or assignment of enrolled individuals to either treatment groups (who receive the study drug) or control groups is typically visualized in a flowchart
    • Statistical tests used to analyse the data
  • The results section is where authors list their findings only (without interpretation). These include:
    • Baseline characteristics– a description of the final sample. Most often, this is summarized in table labelled as Table 1. When reading this section, think about the age, race, geography, & health status of the sample, & whether they are similar to you.
    • Outcomes– how did people who took the drug do in comparison to those who took the control? These data will be presented in tables, charts, graphs, & text.
  • Considered to be the most important section, the discussion area is where investigators interpret the results- what they mean, whether they are significant, where there could be error, the weaknesses of their study, & areas for further research. What is stated in this section can sometimes be highly contentious.

Some tips for reading an article:

  • The background section is not usually necessary unless if the topic area is new to the reader- if you are extensively researching a drug by reading multiple articles, you will find that many of their background sections are similar. However, if you don’t understand what’s covered in the background section, bring yourself up to speed with other resources such as Wikipedia.
  • Some prefer to read the abstract first to obtain a rapid summary of the study, then the discussion second for a detailed look at how the authors felt about the findings.
  • Always compare the raw numbers from the results section against the authors’ interpretation in the discussion section. Never take what the authors state at face value. Do the numbers actually show what they claim is happening?
  • Yes, the word «data» is plural.
  • I personally prefer to print out the pdf article & write comments on the hard copy as I read.
  • It’s not uncommon to read the same article several times. These subjects are quite advanced, & many details are important.
  • Check the articles cited in the bibliography for other studies that might be related to your topic.
Table 1.
A (very short) table 1. More meticulous studies will list more baseline characteristics of test subjects.

Summary

In review, using clinical data can provide a powerful edge when making decisions about nootropics. The informed nootropic user is better able to discern which nootropics are safe & effective.

  • Clinical research is accessible within databases which are offered through institutions. The general public can access some research through resources such as Pubmed or Google Scholar.
  • All journal articles follow the same general format consisting of an abstract, background, methods, results, & discussion sections. Knowing where to find what information you need within an article can make reading articles faster.