How does the drug, modafinil (Provigil), exert its eugeroic (wakefulness-promoting) effects? I've read that it works by increasing dopamine and histamine concentrations in the CNS and by serving as a partial agonist at the dopamine D2 receptor. Perhaps by interfering with the function of orexin?
The exact mechanism is not known:
Modafinil has wake-promoting actions similar to sympathomimetic agents like amphetamine and methylphenidate, although the pharmacologic profile is not identical to that of sympathomimetic amines. [… ] Modafinil-induced wakefulness can be attenuated by the α1-adrenergic receptor antagonist prazosin; however, Modafinil is inactive in other in vitro assay systems known to be responsive to α-adrenergic agonists, such as the rat vas deferens preparation. [… ] Modafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro, Modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals .
A 2010 study has concluded that:
Recent evidence suggests that modafinil may block the dopamine transporter (DAT) and that the dopamine D1 receptor (D1R) may contribute to modafinil effects .
Another one confirms modafinil's dopaminergic activity:
These findings indicate that modafinil has a long duration of action, with alerting properties arising predominantly from dopaminergic activity .
It seems to be dependent on catecholaminergic signaling:
It binds competitively to the cell-membrane dopamine (DA) transporter and is dependent on catecholaminergic (dopaminergic and adrenergic) signaling for its wake-promoting effects. [… ] Modafinil is an exceptionally weak, but apparently very selective, DA transporter inhibitor. [… ] The conformational constraints on the interaction of modafinil with the DA transporter - and probably, as a consequence, its effects on trace amine receptor signaling in the catecholaminergic cell - are unique among catecholaminergic agents .
- Drugs.com. Modafinil. Clinical Pharmacology. Available from http://www.drugs.com/pro/modafinil.html (accessed 29.07.2014)
- Young JW, Geyer MA. Action of modafinil--increased motivation via the dopamine transporter inhibition and D1 receptors? Biol. Psychiatry. 2010 Apr 15;67(8):784-7. doi: 10.1016/j.biopsych.2009.12.015. PubMed PMID: 20132929.
- Turner C, Belyavin A, Nicholson A. Duration of activity and mode of action of modafinil: Studies on sleep and wakefulness in humans. J. Psychopharmacol. (Oxford). 2013 Dec 3;28(7):643-654. doi: 10.1177/0269881113508173. PubMed PMID: 24306135.
- Wisor J. Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Front Neurol. 2013 Oct 7;4:139. doi: 10.3389/fneur.2013.00139. PubMed PMID: 24109471.
Eugeroics are a class of stimulants that produce long-lasting mental arousal. These stimulants tend to increase alertness without the peripheral (body) effects or addiction/tolerance/abuse potential of the traditional stimulants. [How to reference and link to summary or text] They have minimal effect on sleep structure, and do not cause rebound hypersomnolence or "come down" effects.
There are currently only two marketed drugs in this class, Modafinil and its earlier analogue Adrafinil. Another drug under production, code-named CX717, is being produced by the pharmacutical company Cortex.
The term itself means "Good Arousal" and has been recommended for use as a treatment for narcolepsy and to augment antidepressants. The US Air Force has spearheaded research in this field for their pilots on long missions.
A related group of drugs called Ampakines share many similar traits, although these seem to be more targeted towards specific conditions, such as memory enhancement.
When comparing Provigil (Modafinil) to drugs like Ritalin, the effect is longer lasting and avoids the cyclical effect common with Ritalin. Typically when used for the treatment of Narcolepsy, Ritalin can take up to 20 minutes for the effects to begin to work, last for 2.5 - 3 hours and the drop off quite quickly. These effects become quite difficult for a person subject to a disorder, wishing to lead a normal life. As one would expect there is a constant need to find the right timing to take the prescribed doses. Additionally, should a patient find themselves out at night, feeling sleepy, they have to choose whether or not to take another pill, even when they are only 45 minutes from their home for the risks outweigh the consequences. On the one hand, the chances are quite good that they may fall asleep during the drive home, hurting themselves or worse, someone else. The flip side is, without something else available to reduce the effects of the Ritalin once they get home they are subject to a long nights watching infomercials, not being able to get any rest until it is just about time to wake up and get ready for work. It becomes quite the vicious cycle. Now their decision was limited to calling in to work, explaining that they will be a bit late (3 hours) or take another pill and hope they could last at work without falling asleep on the copy machine or on someones lunch tray, (of which there are many anecdotal stories available) Prior to the availability of medicine like (Modafinil) this routine was typical of a patient with Narcolepsy. Now the Ritalin is used for back-up cases since the effects are relatively short term, at least in comparison to Modafinil.
Benefits and Effectiveness
Hydrafinil, also known as Fluorenol is an unregulated synthetic drug by Cephalon Pharmaceuticals used as an eugeroic (attentiveness advancing agent). After its synthesis, fluorenol was one of the few agents to be considered as a theoretical successor to the advanced and FDA-approved drug, Provigil (Modafinil). Studies on animals demonstrated that fluorenol displayed approximately 39% more noteworthy eugeroic viability than modafinil over a short-term span.
Cephalon scrapped advancement of fluorenol as a potential eugeroic. Instead they guided their research and development in the creation of armodafinil. Armodafinil, which is sold under the brand name "Nuvigil" would get to be known as the official pharmaceutical successor to Provigil, leaving numerous to ponder why not fluorenol?
Discussions hypothesize that fluorenol's was previously used as a bug spray in the late 1930s, and that it demonstrated lethality to aquatic life, and a lapsing Cephalon patent may have been the cause to suspend its development. Starting 2015, fluorenol has recaptured prevalence among nootropic fans and is presently being sold as an unregulated compound online under the brand name "Hydrafinil."
Quick Mechanism of Action
- Dopamine reuptake inhibitor: An increase in dopamine production is known to improve cognition. Hydrafinil plays a role as a dopamine reuptake inhibitor, increasing dopamine concentrations.
- 5-HT6 antagonist: Antagonism of 5-HT6 receptor can result to increase in norepinephrine and dopamine concentrations in the prefrontal cortex, as well as increasing the production of choline and glutamate in different parts of the brain. Makers of Hydrafinil theorize that it functions as a 5-HT6 receptor antagonist.
- Increase Glutamate levels: As mentioned earlier, antagonism of 5-HT6 receptors increases the production of glutamate in the brain. This could lead to enhanced memory and learning process. There is a great possibility that Hydrafinil's function as a 5-HT6 receptor antagonist could result in the improvement of cognitive performance.
- Increase Norepinephrine levels: Manufacturers of Hydrafinil claim that it increases norepinephrine levels specifically in the prefrontal cortex by antagonizing 5-HT6 receptor. Increase in concentrations of norepinephrine could result to improvement of cognition. However, there's no enough evidence to prove this theory.
- Increase Histamine levels: Hydrafinil is known to enhance histamine levels in the hypothalamus. Histamine plays an important role in normalizing our circadian rhythm and regulating sleep-wake cycles.
Advantages of Hydrafinil
- Inexpensive: Hydrafinil is sold for about $25 for two grams by vendors online, some sell it at a much lower price. It would only cost you around $1.25 per dose if you buy it at this price and administered 100 mg.
- Mood Enhancer: Numerous individuals believe that hydrafinil may enhance their state of mind to a more prominent degree than modafinil. Numerous people have had achieve utilizing modafinil for depression and/or as an anti-depressant. Since hydrafinil might be more serotonergic than different eugeroics, its ability to enhance state of mind might be much better than related substances.
- Less stimulating: Not everybody needs the same level of stimulation that armodafinil provides. Users state that hydrafinil is likely less empowering than different eugeroics. This implies it might be more less likely to cause tension, jitters, and/or other adverse reactions. Furthermore, despite the fact that modafinil isn't viewed as addictive, hydrafinil might be less addictive as a result of decreased psycho-stimulation.
- Subtler impact: The general impact of hydrafinil is thought to be more subtle and "cleaner" than different eugeroics.
- Unregulated: The way that hydrafinil is unregulated might be seen as an advantage in that it is accessible to anybody that needs it. Subsequently, hydrafinil can be bought by anybody and can be utilized under their own discretion.
- Increase attentiveness: Hydrafinil's capacity to increase attentiveness might be predominant than different eugeroics like modafinil. In spite of the fact that it might be less stimulating, it might really maintain alertness for a more extended time.
In any case, it is always good to start at the smallest dose then gradually increase it once you have become familiar with its effects. The usual dose of Hydrafinil is 50 mg, taken 1 to 3 times a day as needed.
What are the disadvantages of Hydrafinil?
- Ineffective: It may be totally ineffective as an eugeroic for some users. There is no clinical information to propose its viability in people or in animal models. At first glance, one may conclude that since it is like modafinil, that it may be naturally "effective" which just may not be the case.
- Less stimulating: A few clients may dislike the way that hydrafinil is less stimulating than other substances like armodafinil and modafinil. In case you are searching for higher-octane eugeroics stimulation, hydrafinil might not be good choice.
- Unregulated: There is no set dose and you may not be getting a quality controlled product.
Where to Buy Fluorenol / Hydrafinil?
Hydrafinil can be purchased online from various vendors, however we recommend you buy adrafinil instead as it has a better safety profile and the vendors selling it are reputable online and can provide a certificate of authenticity if requested. Additionally, it just happens to be the case that Hydrafinil is about the same price as Adrafinil as well, although anecdotal evidence suggests it may be slightly more potent, it is better to stick to a compound that has a relatively thorough research and testing associated with it. If you chose to buy Adrafinil in powder form click here.
Why modafinil could be the 'smart drug' that changes how we live and work
So-called "smart drugs" are increasingly being used "off-label" by students and professionals trying to get ahead.
It's called modafinil, and it's going to change your life.
The drug typically is prescribed to treat narcolepsy, but research shows it's effective for much more than that. In short, it makes people smarter.
That is, the drug will sharpen your focus, allowing you to make better decisions and retain more information, deal successfully with new ideas and dexterously handle multitasking.
Modafinil will change your life because you soon may feel like you have to take it if you want to keep up with your professional or academic peers.
"Modafinil is one of an arsenal of drugs, which includes Adderall, Ritalin and Concerta, that are increasingly used 'off-label' by college students and adults seeking greater productivity," Olga Khazan writes for The Atlantic. Read the story.
How does modafinil work? Here's a brief explanation in a study published in the journal European Neuropsychopharmacology: "Modafinil is an FDA-approved eugeroic that directly increases cortical catecholamine levels, indirectly upregulates cerebral serotonin, glutamate, orexin and histamine levels, and indirectly decreases cerebral gamma-amino-butrytic acid levels." The paper's researchers, from Harvard and Oxford universities, reviewed 24 studies about modafinil's effect on users published over 24 years.
The trend of "off-label" use of the drug is likely to accelerate, seeing as the researchers found that the side effects are about the same as drinking coffee, though there can be significant negative consequences if it's taken in large doses.
UCLA clinical psychiatrist James McGough, who was not part of the European Neuropsychopharmacology study, believes cognitive stimulants such as modafinil offer few dangers for people taking them for reasons beyond their current medically approved uses. He says, simply, "they're safe."
And that may end up being the problem. Writes Khazan:
"Will we soon be locked in a productivity arms race, pumping out late-night memos with one hand while Googling for the latest smart-drug advancement with the other? Some sports organizations, for what it's worth, already ban the use of these drugs without an ADHD diagnosis for the same reasons they ban steroids and other performance enhancers. Will employer drug tests soon screen for off-label modafinil use? Or on the contrary, will CEOs welcome the rise of extra-sharp workers who never need sleep?"
Microsoft co-founder Bill Gates and SpaceX CEO Elon Musk have publicly worried about the potential rise of artificial intelligence -- that computers will make humans obsolete. But a greater risk might be that we become machines ourselves, increasingly immune to basic human needs like downtime. There's already a term for it: "Extreme worker."
Although the exact mechanisms by which modafinil and its R-enantiomer, armodafinil, decrease sleepiness are not fully understood, evidence suggests that these agents promote wakefulness by acting directly or indirectly on many components of the sleep / wake circuit. Modafinil and armodafinil are hypothesized to inhibit GABA and promote dopamine, norepinephrine, histamine, and hypocretin / orexin.    
Modafinil and its R-enantiomer, armodafinil, increase both norepinephrine (NE) and dopamine (DA), possibly via their blockade of both the NE and DA reuptake transporters (NET and DAT, respectively). The actions of NE at alpha-adrenergic receptors and DA at dopamine D2 receptors are thought to contribute to the wake-promoting properties of modafinil. Orexin is a key component of the arousal system thus, the hypothesized action of modafinil on the orexinergic system may help increase alertness. Additionally, modafinil may indirectly increase histamine, either by reducing GABAergic inhibition of histaminergic neurons or via actions at orexinergic neurons. The increase in histamine may contribute to both the wake-promoting effects of modafinil as well as the potential of modafinil to increase alertness.   
In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not reduced by the dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, blocks the action of amphetamine but does not block locomotor activity induced by modafinil.
I don’t take any pills for energy enhancement. However, after reading this article, I think that Adrafinil would be the way to go if I ever had a need for this type of pill. Not only can you take it later in the day and not interrupt your sleep patterns because of its half-life, it comes on slow and goes away slow. There is no crash associated with this type of pill. Even though all medicines have side effects, Adrafinil seems to have non threatening ones when taken occasionally. This seems a much better route to me than drinking those energy drinks. With energy drinks all you get is a sugar high and then you crash. Like I said, I don’t energy enhancement pills, but if I ever had a situation where I needed one I would consider Adrafinil.
I find this article very interesting in the sense that this is probably pretty important to a lot of people. I appreciate that it is your own opinion and you go through the positive and negative reasons to use either Adrafinil or Modafinil. Although I don’t see myself using either in the near future, it was interesting to learn about how each of them are unique.
Armodafinil – Another Nootropic Eugeroic Prescription DrugRating:
Armodafinil is categorized a wakefulness promoting agent very similar to Modafinil. It is prescribed for the treatment and management of sleep disorders such as narcolepsy, excessive daytime sleepiness (EDS), shift work disorder, and obstructive sleep apnea. Some have also been using Armodafinil off-label to manage the symptoms of attention deficit hyperactivity disorder (ADHD), depression, and fatigue. Just like Modafinil, Armodafinil is widely used to increase wakefulness and focus even by healthy individuals especially as study or work aids.
Although the structure of Armodafinil is similar to that of Modafinil, the former consists only of just the (−)-(R)-enantiomer of the racemic Modafinil. This produces subtle differences in effects of the drugs, primarily in the area of duration of effect where Armodafinil is observed to have a more delayed peak concentration compared to Modafinil. Having a delayed peak concentrations makes Armodafinil a better treatment option for EDS.
Armodafinil is manufactured by Cephalon Inc., the same pharmaceutical company who developed Modafinil. Cephalon was founded in 1987 with Dr. Frank Baldino, Jr., being one of the co-founders. Dr. Baldino was a former scientist with DuPont. Cephalon specializes in the research and development of drugs for neurodegenerative diseases.
The approval of Armodafinil as a prescription drug was granted by the USFDA in the middle of 2007. The drug is being sold in the United States under the brand Nuvigil. The drug is currently being studied for the treatment of schizophrenia and initial results show that Armodafinil has the ability to decrease the negative symptoms of schizophrenia. Cephalon applied for Armodafinil to be approved for the treatment of jet lag but the application was denied by the FDA.
As far as being a wakefulness promoting agent, studies have shown that the effectiveness of Armodafinil is comparable to Modafinil, but with fewer side effects. Both have similar half-lives but Armodafinil takes a longer time to achieve peak concentrations in the blood. This makes it ideal for individuals suffering from EDS who have daytime working hours. Another advantage of Armodafinil is that it does not seem to affect nighttime sleeping patterns, unlike Modafinil, which has been observed to sometimes affect the quality of sleep of some of its users.
For people suffering from obstructive sleep apnea, treatment with Armodafinil can be in conjunction with therapy with continuous positive airway pressure machine (CPAP) therapy. It must be noted however that Armodafinil cannot treat obstructive sleep apnea or any of its underlying causes.
Just like Modafinil, Armodafinil provides an energy boost for the brain that is smoother than the wakefulness provided by ampethamines. It also doesn’t have the unpleasant effects of amphetamine or caffeine stimulation like edginess, fast heartbeat, and racing thoughts. As a cognitive enhancer, Armodafinil may be helpful in warding off mental fatigue and brain fog. Some users reported of experiencing enhanced focus, of being in a better mood, and of having more motivation to accomplish tasks. It is unclear if Armodafinil has any direct effect on other cognitive processes of the brain like memory, learning skills, logical reasoning, and communication skills. Armodafinil has also been used for weight loss, and as part of pre-workout supplements to improve physical performance.
Armodafinil does have some side effects that are similar to that of Modafinil. Some of it include nausea, dizziness, upset stomach, loss of appetite, and insomnia if taken in large doses.
- It is a good wakefulness promoting agent.
- It can ward off mental fatigue and brain fog.
- It helps increase concentration and alertness.
- It has side benefits.
- It does not disrupt sleep patterns.
- It is only available by prescription.
- It has its own share of unpleasant side effects.
- It has no direct effect on other cognitive processes of the brain.
- It can also cause skin rashes and irritation like Modafinil.
The effective dose for Armodafinil is set at 150mg taken in the morning or an hour before your work shift if you plan to stay awake. It is important to follow the directions of your attending physician when taking Armodafinil and it should not be taken continuously for more than 12 weeks.
Thursday, 22 February 2007
Genetics - Transcriptionally-mediated DNA damage
There seems to be some solid evidence that transcription promotes mutation because the untranscribed strand is able to form secondary structures which expose bases to chemical mutagenesis.
Here is a recent paper about transcription-associated mutagenesis:
Kim H et al.(2010) Transcription-associated mutagenesis increases protein sequence diversity more effectively than does random mutagenesis in Escherichia coli. PLoS One 5(5):e10567. doi: 10.1371/journal.pone.0010567.
During transcription, the nontranscribed DNA strand becomes single-stranded DNA (ssDNA), which can form secondary structures. Unpaired bases in the ssDNA are less protected from mutagens and hence experience more mutations than do paired bases. These mutations are called transcription-associated mutations. Transcription-associated mutagenesis is increased under stress and depends on the DNA sequence. Therefore, selection might significantly influence protein-coding sequences in terms of the transcription-associated mutability per transcription event under stress to improve the survival of Escherichia coli.
The authors cite a number of papers in their introduction which document the phenomenon that you could follow up. Just in case the focus on a bacterial system puts you off, the Kim et al. paper has in turn been cited in:
Wright et al. (2011) The roles of transcription and genotoxins underlying p53 mutagenesis in vivo. CARCINOGENESIS 32:1559-1567
Transcription drives supercoiling which forms and stabilizes single-stranded (ss) DNA secondary structures with loops exposing G and C bases that are intrinsically mutable and vulnerable to non-enzymatic hydrolytic reactions. Since many studies in prokaryotes have shown direct correlations between the frequencies of transcription and mutation, we conducted in silico analyses using the computer program, mfg, which simulates transcription and predicts the location of known mutable bases in loops of high-stability secondary structures. Mfg analyses of the p53 tumor suppressor gene predicted the location of mutable bases and mutation frequencies correlated with the extent to which these mutable bases were exposed in secondary structures. In vitro analyses have now confirmed that the 12 most mutable bases in p53 are in fact located in predicted ssDNA loops of these structures. Data show that genotoxins have two independent effects on mutagenesis and the incidence of cancer: Firstly, they activate p53 transcription, which increases the number of exposed mutable bases and also increases mutation frequency. Secondly, genotoxins increase the frequency of G-to-T transversions resulting in a decrease in G-to-A and C mutations. This precise compensatory shift in the 'fate' of G mutations has no impact on mutation frequency. Moreover, it is consistent with our proposed mechanism of mutagenesis in which the frequency of G exposure in ssDNA via transcription is rate limiting for mutation frequency in vivo.
Homework - At what substrate concentration will an enzyme work at 40% of its maximum rate if its Km = 0.095M?
To be honest I know very few about enzymes and absolutely nothing about Michaelis–Menten.
However, when I "took the Michaelis-Menten equation, replaced v with 0.4Vmax, canceled the Vmaxes (one on each side), and solved for [S]", my result is positive:
Human biology - Is reproduction intrinsically part of life?
Every species has the ability to reproduce. Of course, individuals within a species can be born with a mutation that keeps them from reproducing, or lose the ability to reproduce at some point in life. However, to say that once these individuals fail to meet that criteria they are no longer forms of life would be a fairly absurd semantics argument. It might be useful to note in an evolutionary sense that those individuals can no longer pass on their genes, which is could select against whatever it was the resulted in that individual being sterile.
You could probably reword the characteristics of life to stress species instead of individuals, but then theres a problem with microbes which have very poorly, or non-existent species. But in general, this is not something a biologist is going to lose sleep over.
How modafinil enhances your brain and mood
Unlike some smart drugs, there’s a good deal of evidence to back up the effects of Modafinil.
- It has been shown to increase your resistance to fatigue and improve your mood. 
- In healthy adults, modafinil improves “fatigue levels, motivation, reaction time and vigilance.” 
- A study published by the University of Cambridge found Modafinil to be effective at reducing “impulse response”, i.e., bad decisions. 
- Modafinil even improves brain function in sleep deprived doctors. 
- There is some evidence Modafinil only helps people with lower IQ,  but after years of experimenting (and upgrading my IQ), it doesn’t feel that way.
Which smart drug is right for you?
Is Modafinil better than Adderall as far as benefits are concerned? Not necessarily. Keep in mind that different chemicals can have varying effects on people. The potency and side effects of psychostimulants will be unique to the individual based on the chemical makeup of their brain. Physiologically, we’re all a little bit different. What works well for one person may have negative side effects on another. The strength of prescription ADHD medications is why most users prefer natural brain fog remedies.
Adderall, when compared to Modafinil (Provigil), stimulates a user much more strongly. The neurotransmitters which are increased by Adderall are vital to the performance of a person’s central nervous system. Once the drug enters your brain, it mimics the effects of neurotransmitters epinephrine (adrenaline), dopamine, and norepinephrine at unnaturally high levels. That makes it ideal for combating both fatigue and narcolepsy. The drug also enhances blood flow to the brain, creating an intense feeling of energy and focus. Adderall is more potent than Modafinil but brings the risk of more adverse side effects.