Some of the most widely used (and abused) smart drugs are prescription only (in the US). This article will go into the background, mechanism of action, and how to safely use these prescription smart drugs for cognitive enhancement.
There are 2 main prescription drugs that people use for cognitive performance: amphetamine salts (Adderall) and modafinil (Provigil). Both drugs have their benefits, as well as side effects and different people prefer one of the other for various reasons.
I will give my personal experiences and preferences at the end of this article. For now let’s start with amphetamine and how they became so widely used/abused.
Amphetamine salts were first synthesized in 1887 by Romanian chemist Lazăr Edeleanu, but it wasn’t until 1927 that its physiological properties would be discovered. A biochemist named Gordon Alles started looking into its properties as potential as a decongestant, based on its similar structure to ephedrine.
From there, it was released in an inhaler form named Benzedrine as a decongestant. This inhaler eventually made its way to college campuses and quickly became the “go-to” study tool if one wanted to study all night due to its extreme focus and alertness properties.
A few years later, the drug was widely used for various different ailments such as weight loss, narcolepsy, low libido, and even Parkinson’s disease. It was even used by the Allied forces and Axis powers during World War II, for its unrivaled ability to keep the troops marching, as well as for its euphoric effect.
The main medicinal application for amphetamine is for the treatment of ADHD. Amphetamine comes in a 50/50 racemic mixture of R and S isomers.
From a chemistry standpoint, amphetamine contains the phenylethylamine backbone, with an added methyl group on the carbon alpha to the amine is critical for binding and extending the half-life dramatically. Different derivatives of amphetamine, such as methamphetamine and methylpheidate (Ritalin) have carbon groups added to the amine (NH2) to help sterically prevent the enzyme monoamine oxidase (MAO) from breaking down the molecule very quickly.
For example, phenylethylamine has a half-life of only a few minutes, as it doesn’t contain any carbon/methyl groups on the alpha carbon or on the amine group. Whereas methylphenidate has the amine group in a 6-membered ring known as a piperidinyl group. Amphetamine was sold over-the-counter until 1956, when it became prescription-only.
Ampehtamine works by interacting with your body’s reward pathway and varying the way your body uses monoamines such as dopamine, serotonin, and norepinephrine for neural signaling in the brain.  Amphetamine is a substrate for the dopamine transporter (DAT), which competitively inhibits the reuptake of the neurotransmitter dopamine. It also facilitates the transport of dopamine out of the vesicles and into the cytoplasm.
Essentially, your body is flooding your brain with dopamine (the “reward” molecule) and then blocking the pathway by which your body renders dopamine inactive. This is what gives the euphoric effect of most drugs, including amphetamine and amphetamine derivatives. Both isomers bind to and are agonists of trace amine-associated receptor-1 (TAAR1), with the R isomer having a slightly higher binding affinity. 
The way amphetamine works to treat ADHD is that people who have ADHD have lower levels of dopamine in their brain, which makes them constantly search for stimulation. Amphetamine stimulates the release of dopamine, allowing them to focus and concentrate without searching for outside stimuli.
There have been a few studies involving subjects with and without ADHD using amphetamine for cognition. In subjects without ADHA, there was a noted improvement in attention, largely by increasing reaction time and improving the “hit” rate of target stimuli. However, subjects also increased the number of “false alarms,” meaning eliciting a response when there are no stimuli or there should not have been a response.
It was also noted that although performance on simple tasks was enhanced, more demanding tasks that require selective attention may be impaired by amphetamine.  In studies with participants with ADHD, the effects of amphetamine are wildly varied.
Despite the extensive studies, there is no clear evidence that amphetamine completely corrected any cognitive defects associated with ADHD. Most results are dose-dependent and even in well-controlled studies amphetamine only really helped with simplistic tasks and not with ones involving an executive function component such as working memory and planning. 
Worth noting, there are several amphetamine-derivative research chemicals that have similar or greater effects, including stronger euphoria and stimulatory effects. 4-fluoroamphetamine has the same structure as amphetamine, with the addition of a fluorine atom in the para position on the benzene ring. This addition has been shown to have a more potent release of 5-hydroxytryptamine (5-HT) compared to amphetamine. 
Another very strong derivative of amphetamine is the research chemical prolinatine. This compound has the amine in a 5-membered ring structure known as a pyrrolyl group, which dramatically increases the half-life and potency of the molecule. Prolintane is also one oxygen atom away from the street drug ‘Flakka’ which is known for causing extreme overheating of the body, as well as psychosis.
Vyvanse is another prescription derivative of amphetamine that contains the amino acid lysine attached to the amine group. This group must be removed before the effects of amphetamine are present.
My Take on Amphetamine
I had a prescription for amphetamine (Adderall) throughout college and grad school and I can definitely attest to how well it works for someone who does not have ADHD. I could only handle 10-15mg at a time of the drug, but it lasted about 6 hours and allowed me to study for long periods of time. I will say it has a very strong ability to decrease appetite and if you don’t remember to eat, you won’t eat for hours and hours.
As far as side effects go, it definitely made me anxious and paranoid due to my extremely heightened stimulation. As a study tool though, it’s almost unparalleled. I would only use it 3-4 times a month because I really didn’t like the feeling it gave me.
The other prescription smart drug that is very popular amongst everyone from truck drivers to CEOs in Silicon Valley is modafinil. Modafinil, trade names are Provigil (a 50/50 racemic mixture of R and S) and Nuvigil (containing only the active R isomer), is a wakefulness-promoting drug that was originally synthesized in the late 1970s in France by neurophysiologist Michel Jouvey but wasn’t used until 1986 as an experimental treatment for narcolepsy.
It wasn’t approved in the US until 1998 for narcolepsy.  Modafinil was first created as an alternative to amphetamine compounds, and usually is well-tolerated.
Chemically, it is known as a sulfinyl benzylhydryl compound, containing two benzene rings attached to the same carbon atom, as well as a double-bonded sulfur-oxygen group, which is connected to a terminal amide (NH2-C=O). It does not contain the phenylethylamine backbone, which explains why users do not get the negative side effects associated with amphetamines.
Modafinil works by increasing both dopamine and norepinephrine (just like amphetamine), most likely by blocking the reuptake of both neurotransmitters. Although its mechanism of action is still unknown, it is hypothesized that modafinil affects many different monoamines such as hypocretin, histamine, epinephrine (adrenaline), GABA, and glutamate.
One study was able to show that modafinil’s wakefulness-promoting effect was mediated by activation of noradrenergic alpha1 receptors, as its effect was blocked by using an noradrenergic alpha1 inhibitor.  One study found that using low doses of yohimbine, an alpha2 antagonist, potentiated the wakefulness and alertness feeling associated with modafinil. 
Although modafinil alters dopamine reuptake, it only weakly interacts with the D2 and DAT compared to amphetamine which is much stronger. This may be the reason its addiction potential is lower than amphetamine, due to having a substantially less euphoric effect. It is also thought that modafinil’s wakefulness effect is due to its interactions with orexin and the orexinergic system in your body which is responsible for arousal. 
Despite that the exact mechanism remains unclear, what is known is that modafinil can increase levels of dopamine, norepinephrine, serotonin and glutamate, while decreasing GABA levels in the brain.
There are a few studies directly comparing modafinil to amphetamine for ADHD. One study involving 22 subjects diagnosed with ADHD that were given either 200mg/d of modafinil, 20mg/d of amphetamine, or a placebo showed that both compounds had equal efficacy in treatment for ADHD in adults. 
As far as evidence for increased cognition, there are mixed reviews. Some studies report that modafinil can enhance working memory performance in a dose-dependent manner in as little as 8mg/kg in stressed conditions and 16mg/kg in non-stressed conditions. Another study in mice showed that daily dosing modafinil is associated with a more rapid and higher level of learning, suggesting that the full benefits come from taking the drug daily vs only when needed. 
A 2003 study in 60 healthy adults taking either 100mg, 200mg or a placebo showed an improvement in visual recognition memory and spatial planning, which suggests improved working memory and planned responses. There were no significant differences in the 100mg group vs 200mg group.  Perhaps the best benefit of modafinil is that it does not cause the extreme jitteriness and paranoia associated with most amphetamine-based medications.
There is also a few research chemicals floating around that are derivatives or prodrugs of modafinil. Adrafinil, a precursor to modafinil, is the most common one. Adrafinil contains a hydroxyl (OH) group attached to the amine of the amide group on modafinil (see structure above).
This group is quickly removed after oral ingestion and converts directly to modafinil in the body. Another derivative is fluoromodafinil aka CRL-40,941, which contains two fluorine atoms, one on each of the two benzene rings. The addition of fluorine atoms can do many things to a drug including increasing the bioavailability, potency, and half-life of the parent compound.
A carbon-fluorine bond is extremely strong and hard to remove during metabolism. Many times, it can often block part of the enzyme trying to breakdown the drug. Fluorine is also a hydrogen bond acceptor, which makes it bind to receptors much more tightly. It also adds a level of hydrophobicity, allowing for greater passage across the blood-brain barrier.
According to the patent for fluoromodafinil, it is said to be 4x stronger than modafinil and 20x stronger than adrafinil on a milligram per milligram basis. If that is true, much lower doses, 20-50mg, are needed to get the same effect.
My Take on Modafinil
I have used modafinil a few times and it is a much cleaner stimulant than amphetamine. Focus is very good, with the main benefit for me is that it does not cause the appetite suppression, paranoia, and jitters associated with amphetamine.
I have used adrafinil many times and I like it a lot. However, because it’s a prodrug to modafinil, higher doses are needed. I usually dose anywhere from 300-600mg at a time for adrafinil.
I have also tried fluoromodafinil a handful of times and will say that it is noticeably stronger than either of the parent compounds. As little as 20-30mg was perfect for studying and focus.
In general, none of these caused significant side effects and dramatically increased work production and concentration. I would definitely recommend any of these compounds to someone looking to increase focus without the side effects associated with amphetamines. I have not tried stacking this with low dose (2mg) of yohimbine, but I plan on trying it soon. I have stacked them with some of the racetams and choline donors for an additive effect, since they have different mechanisms of action.
2) Bidwell, L. Cinnamon, F. Joseph McClernon, and Scott H. Kollins. "Cognitive enhancers for the treatment of ADHD." Pharmacology Biochemistry and Behavior 99.2 (2011): 262-274.
3) Lewin, Anita H., Gregory M. Miller, and Brian Gilmour. "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class." Bioorganic & medicinal chemistry 19.23 (2011): 7044-7048.
4) Advokat, Claire. "What are the cognitive effects of stimulant medications? Emphasis on adults with attention-deficit/hyperactivity disorder (ADHD)." Neuroscience & Biobehavioral Reviews 34.8 (2010): 1256-1266.
5) Swanson, James, Ruben D. Baler, and Nora D. Volkow. "Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: a decade of progress." Neuropsychopharmacology36.1 (2011): 207-226.
6) Wee, S., et al. "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs." Journal of Pharmacology and Experimental Therapeutics313.2 (2005): 848-854.
7) Winkelmayer, Wolfgang C., et al. "The Prevalence and Cost of Unapproved Uses of Top-Selling Orphan Drugs." (2012).
8) Stone, Eric A., et al. "Role of brain α1B‐adrenoceptors in modafinil‐induced behavioral activity." Synapse 46.4 (2002): 269-270.
9) Lin JS, Roussel B, Akaoka H, Fort P, Debilly G, Jouvet M (1992). Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res 591: 319–326.
10) Darwish, Mona, et al. "Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: a randomized, open-label, crossover study." Clinical therapeutics 32.12 (2010): 2074-2087.
11) Taylor, Fletcher B., and Joan Russo. "Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults." Journal of child and adolescent psychopharmacology 10.4 (2000): 311-320.
12) Pierard C, Liscia P, Valleau M, Drouet I, Chauveau F, Huart B et al (2006). Modafinil-induced modulation of working memory and plasma corticosterone in chronically-stressed mice. Pharmacol Biochem Behav 83: 1–8.
13) Beracochea D, Celerier A, Borde N, Valleau M, Peres M, Pierard C (2002). Improvement of learning processes following chronic systemic administration of modafinil in mice. Pharmacol Biochem Behav 73: 723–728.
14) Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ (2003). Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology 165: 260–269.