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Understanding The Differences Between ‘Eugeroics’: Flmodafinil, Hydrafinil, and Adrafinil

Understanding The Differences Between ‘Eugeroics’: Flmodafinil, Hydrafinil, and Adrafinil

The world is getting more competitive by the second. Everyone wants to be smarter and faster to be able to cope with the pace. If you’ve watched the movie ‘Limitless’, you’ll probably want a pill similar to the drug that makes Bradley Cooper invincible! 

While the pill in the movie doesn’t really exist, there’s something that comes pretty close to it - nootropics.

Nootropics are smart drugs that come in numerous variants, each offering a plethora of benefits like improved cognitive function, better memory, higher energy levels, enhancing concentration, and so on. Some of the main categories of nootropics include:

  1. Anxiolytics, meaning they prevent anxiety
  2. Eugeroics where they help a person to stay awake for longer periods. Examples include Hydrafinil, Flmodafinil, and Adrafinil
  3. Mood Lifters
  4. Attentiveness Boosters
  5. Antioxidants
  6. Stimulants (Energy Boosters)

Understanding ‘Eugeroics’: The Wakefulness Enhancers

Eugeroics help a person stay awake for longer periods - preventing the side effects of sleep deprivation. They work differently from other known stimulants. Stimulants cause focus and alertness, while eugeroics essentially cause ‘wakefulness’ and a feeling of being ‘well-rested’.

Let’s take a look at some of the popular eugeroics… 

1. Adrafinil

Adrafinil, which was developed in France, is a biologically inactive compound and a prodrug, which means that it needs to interact with the body’s metabolic processes to start providing benefits.  [1]

Prodrugs may take a longer time to become active, but their effects last longer too. Hence, prodrug analgesics are usually preferred, as they relieve pain for extended periods. Some prodrugs used in pain relievers are aspirin (converted into salicylic acid), prednisone (converted into prednisolone) and codeine (converted into morphine). 

Adrafinil is metabolized in the liver and transforms into its active metabolite, modafinil.

Medical Benefits of Adrafinil

1. Wakefulness Without Side Effects  

Adrafinil induces a balanced state of focus and wakefulness. It does not have the common side effects like anxiety, hyperactivity or other stereotypical behavioral patterns experienced on taking stimulants. [2] 

Various animal studies have proved the efficacy of adrafinil in inducing alertness, without escalating the motor activity and causing other side effects that are atypical among general stimulants. [3], [4] 

A US Army test demonstrated that aviators on modafinil for 40 hours, performed demanding tasks well and were more alert. [5]

2. Enhancement of Cognitive Ability

Adrafinil, through its active metabolite modafinil, helps to enhance cognitive abilities and facilitates clarity of mind.[6]  It is beneficial for people with neuropsychiatric disorders as well.[7] 

Adrafinil is also helpful in reversing age-related mental degeneration. In a study conducted among aged canines (they were segregated into two categories, namely older vs. younger dogs), the older dogs that were on adrafinil were able to perform better in terms of learning new tasks faster as compared to the younger dogs who were not on adrafinil. [8] 

3. Memory Booster Drug

Adrafinil is an excellent ‘study drug’. It is a cerebral stimulant that leads to increasing the level of functioning of hypocretin neurons (neurons responsible for wakefulness) in the brain, thereby initiating a spike in neurotransmitters, namely dopamine, histamine, and norepinephrine. [9] 

This leads to more alertness and better focus, thereby boosting the mental abilities.

4. Acts as an Antidepressant

A two-month study that involved 70 patients suffering from depression showed that adrafinil treated depressive symptoms, as effectively as other known antidepressants. [10] 

5. Helps in Narcolepsy

Adrafinil is often prescribed for patients with narcolepsy (a neurological disorder that causes chronic sleepiness due to reduced levels of hypocretin neurons in the brain). Adrafinil helps in keeping such patients awake for longer periods. [11], [12]

6. Augments Nocturnal Behaviour

Adrafinil helps augment nocturnal behavior (being active at night) by delaying the feelings of sleepiness and boosting energy levels. The use of adrafinil on monkeys revealed an improvement in their behavioral patterns at night by doubling their nocturnal activity. 

The primates generally acted as they would perform during the day, thereby promoting the fact that adrafinil delays sleepiness. [13]

7. Neuroprotector

Adrafinil’s active form acts as a powerful neuroprotectant, by slowing the degeneration of cells associated with Parkinson's disease and keeps the brain healthy. [14] It also helps neutralize the neuroinflammation caused by the use of methamphetamines.[15] 

This neuroprotection factor associated with the active form of adrafinil plays a vital role in the management of multiple sclerosis as well. [16]

How does Adrafinil Work? 

A. Concentrates only on two sections of the brain… 

Adrafinil, post its metabolism in the liver, acts on two main sections of the brain, namely:

  • The hypothalamus - (an area of the brain that controls hormones, sleep cycles, blood pressure, heart rate, body fluid balancing, digestive juices and more) and
  • The amygdala -  (a section of the brain located on either side of the brain responsible for emotions, survival instinct factors, and memory).

This differentiates it from other psychostimulants that promote wakefulness by widespread activation of all the neurons in the brain as opposed to selective neuronal activation done by adrafinil.

This factor explains the ability of adrafinil to stimulate wakefulness without any side effects associated with other such stimulants.[17]

B. Adrafinil processes its job via a two-fold action… 

First, it helps to augment the production of the neurotransmitter called hypocretin (the main chemical produced by the hypothalamus section of the brain that helps to sustain alertness and prevent sleep from occurring at the wrong times). Hypocretin helps in promoting alertness. Higher doses will also help reduce fatigue.

Second, it increases the release of glutamate, the most abundant ‘excitatory neurotransmitter’ in our body. This helps in increasing cognitive performance and improving memory.

Disadvantages of Adrafinil

Adrafinil being a prodrug, needs to be processed by the liver. During this metabolism, the liver transforms adrafinil into two compounds, namely modafinil and modafinilic acid with a metabolic rate of 50% each. 

Of the two, the latter is not of much use and circulates in the bloodstream for a few hours before being eliminated from the body resulting in wastage of half of the adrafinil dose. This requires an intake of more adrafinil to achieve the desired results. [18]

Also, adrafinil takes longer to be absorbed by the body - say around 45 minutes to an hour as against modafinil that requires just 25 to 40 minutes. Not only does adrafinil have a longer absorption time, but it also stays in the body for a longer time. While one may think this is beneficial… It actually is not.

This is because the half-life of adrafinil is very long, at 60. By half-life of 60, we mean it takes around 60 minutes for half of the adrafinil to be processed into its active metabolite modafinil and enter the bloodstream and then a couple or more hours for it to produce enough modafinil to start giving results. This results in wastage of a substantial portion of the day to attain the benefits. This, in turn, creates another cascading problem mentioned next below.

Adrafinil takes a long time to break down (as it has to get converted into modafinil and modafinilic acid before working on the body), and hence it tends to stretch into the early hours at night leading to a common side effect of a severe form of insomnia. 

Therefore it is ideal to take it early in the morning to have the optimal effect during your work hours. 

Adrafinil and the liver

To process adrafinil, the liver has to secrete more enzymes. This can be problematic when one is consuming high doses of adrafinil, or is taking the drug for an extended period of time. Hence it is best to take adrafinil for a shorter duration and in recommended doses.

Also, people on other medications that require some processing by the liver and people with liver problems are advised to use this drug with care, as it will put an additional burden on the liver.

Adrafinil and hormonal contraception

Use of  Adrafinil may interfere with the efficacy of birth control by decreasing the effectiveness of contraceptives. [19] Usage of adrafinil (active modafinil) stimulates the production of certain liver enzymes that are required to break down adrafinil, and these are the same enzymes that break down the birth control hormones. [20] 

Adrafinil and Orofacial Dyskinesia

Certain studies [21] have proved that adrafinil may lead to orofacial dyskinesia (a disorder that leads to repetitive movements in the body like sticking out the tongue, smacking lips, etc.)

2. Flmodafinil / Lauflumide

Flmodafinil is a derivative of modafinil. A first derivative means that a compound must be derived from the parent compound with some adaption to make it better. Flmodafinil is derived from modafinil and is very similar to modafinil, but it has two fluoro-groups attached to it. [21]

The addition of two fluoro-groups paves the way for enhanced bioavailability, which means that a higher percentage of the drug gets absorbed in the digestive tract, thereby permitting intake of smaller doses. This gives it an edge over adrafinil.

Medical Benefits Of Flmodafinil

1. Acts as a Dopamine Reuptake Inhibitor

A dopamine reuptake inhibitor helps in alleviating certain physical and mental disorders through the brain’s neurotransmitter chemical dopamine. Flmodafinil works with the brain's dopamine system (that part of the brain responsible for feelings of motivation, pleasure, etc.) by making full use of the chemical dopamine and thereby improving mental disorders like depression, narcolepsy, and ADHD

Further, it also helps get rid of certain addictions like cigarettes, drugs, binge eating and the like. [22]

2. Acts as an Antidepressant and Anti-aggressive Medication:

The decrease in dopamine levels on account of lesser dopamine receptors may cause depression and anxiety. [23] Flmodafinil, by acting as a dopamine reuptake inhibitor, helps to make use of dopamine to the fullest extent possible and thereby offset depressive symptoms and anxiety levels and also makes a person less aggressive. 

However, the drug is still in the clinical trial phase, and hence, there has been no conclusive evidence on its efficacy over modafinil.

Hydrafinil / Fluorenol

Hydrafinil, also known as fluorenol, is a next generation cognitive stimulant. It is less addictive compared to modafinil while at the same time being 40% more effective than modafinil. [24] 

Also, it does not last long in the body, thereby aiding a good night's sleep. It is more potent than modafinil. Fluorenol is a 5-HT6 antagonist, in that it helps to increase dopamine and norepinephrine in the brain’s hippocampus section leading to a mild boost in cognition and mood due to its serotonergic effects. 

Increased serotonin levels, coupled with increased dopamine and norepinephrine levels, help to alleviate depressive symptoms and gives a modest boost to the mood. [25] However, this drug is unregulated in the market.

[a] https://www.phcoker.com/crl40940-flmodafinil-vs-modafinil/

[a1] https://modafinil.org/modafinil-vs-flmodafinil/

[b] https://nootropicsandglitches.wordpress.com/2015/03/11/fluorenol-going-beyond-caffeine-and-modafinil/

[b1] https://mentalhealthdaily.com/2015/12/23/hydrafinil-fluorenol-a-modafinil-analogue-with-questionable-safety/

[c] https://healthtrends.com/adrafinil/

[c1] https://en.wikipedia.org/wiki/Modafinil

It is important to note that adrafinil, and its active metabolite, were added to the list of prohibited substances for athletic competitions by the World Anti-Doping Agency in 2004.

Eugeroics can be extremely useful, when consumed in moderation, to help you achieve a state of wakefulness that helps you get through the day and perform with a lot more alertness than usual. Whichever eugeroic you choose, make sure you do so only after consulting a doctor. 

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