Adderall: America's Favorite Amphetamine

Adderall is a clever brand and a deceptive brand. In America, amphetamine has traditionally been associated with tweakers, speed freaks, bikers, truckers and all-night sex orgies. Adderall changed all that.
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By James L. Kent

Sheri* is a junior in college. In the mornings she attends class, and in the afternoons she works at a coffeeshop. Sheri has attention-deficit disorder (ADD), and without her medication she has a hard time getting out of the bed in the morning and accomplishing even the most mundane of her daily tasks. Her medication is Adderall, preferably the 30-milligram Adderall XR (extended-release) capsules, but Sheri doesn't have health insurance and can't afford to shell out a couple hundred bucks for the doctor's visit and the $200 to $300 a month for the prescription itself. But Sheri is lucky, because she knows Dan*, who sells Adderall XR to college students for $5 to $15 a pop, depending on how many pills they're buying. And Dan does good business, because Adderall is America's favorite amphetamine, especially among college students trying to maintain long hours of focus preparing their finals.

Street-level Adderall dealers (or "traders") can distribute to college students at cheaper-than-retail prices. For uninsured students like Sheri, the retail price of a monthly Adderall prescription works out to $6 to $8 a pill. If she buys 10 at a time from Dan, however, she gets them for $3 to $5 a pill. That's because Dan buys prescriptions for Adderall from students still on their parents' health-insurance plan or from members of the military, who get Adderall prescriptions like monthly paychecks. With a military or insurance discount, you can buy Adderall XR for under $1 a pill and then sell it for triple to five times the original price. Dan knows he can get $15 to $20 a pill for 30 mg XRs from the right people, so a bottle of cheap XRs is like his savings account, his investment portfolio and his spending money all rolled into one. And if he doesn't have the time or money to eat, he can just take an XR and he won't be hungry again for another six hours.

Adderall is a clever brand and a deceptive brand. In America, amphetamine has traditionally been associated with tweakers, speed freaks, bikers, truckers and all-night sex orgies. Adderall changed all that. Stimulants like Ritalin have long been shown to help people with ADD and ADHD (attention-deficit hyperactivity disorder) concentrate for longer periods. So in 1996, Shire Pharmaceuticals introduced Adderall, a patented blend of amphetamine salts, to compete in the market for ADD/ADHD medications. The product was so successful that in 2001, Shire introduced the Adderall XR capsule in order to supply a low but steady dose to users all day long. Adderall XR is marketed as a productivity drug to help people with ADD, ADHD or narcolepsy remain alert and focused, but because it's essentially pure pharmaceutical amphetamine, it quickly became the prescription stimulant of choice for college students, wage laborers, the military, and pretty much everybody else.

Amphetamine was first synthesized in Germany in 1887 and has been used pharmaceutically in the U.S. since 1927. In World War II, amphetamine and dextroamphetamine, under the names benzedrine and dexedrine, were distributed to American soldiers and pilots as "go pills" to combat fatigue and maintain alertness and morale.

Amphetamine causes the release of dopamine and norepinephrine, stress chemicals that make people feel alert, powerful, and impulsive, and the high can come on like a rush of invincibility. And even though parents would consider almost anything to help their children cope better in school, the idea of giving speed to ADD/ADHD children to keep them from fidgeting doesn't feel right to most people -- in fact, it sounds like insanity. But Shire Pharmaceuticals solved that marketing problem by rebranding amphetamine as Adderall, a "patented blend" of amphetamine salts targeted to treat ADD, ADHD, and narcolepsy. (Note that "ADD" right in the name of the brand.) Parents who would balk at giving their children trucker-style speed are happy to give them Adderall -- not because it's a different drug but because it's a brand name you can trust.

The molecule for amphetamine is in the public domain, so it's impossible for a pharmaceutical company to patent it. That means there's no profit to be made by producing amphetamine for pharmaceutical use. But Shire found a way around this problem. Adderall is a custom blend of four different types of amphetamine salts -- basically two mirror versions of the amphetamine molecule packaged in four separate ways. This is an old patent-medicine trick: When you're synthesizing a molecule in chemistry, you must attach it to a salt (such as an aspartate or sulphate) so you can easily crystallize or dissolve it. However, you can't patent amphetamine aspartate or amphetamine sulfate -- but if you make a custom mix of these salts, you can call it a patent drug, even though both salts carry the exact same amphetamine molecule when they dissolve in the bloodstream.

Most simple psychoactive molecules have mirror counterparts called stereoisomers, and drugs often contain a blend of both isomers, which is called a racemic mix. What is commonly called amphetamine, benzedrine, or speed is actually the "left-handed" isomer of the amphetamine molecule, known as levoamphetamine or l-amphetamine. The "right-handed" stereoisomer of amphetamine is dextroamphetamine, also called d-amphetamine or dexedrine.

Isomers of the same molecule, although very similar, often have different effects. For instance, the right-handed isomer of methamphetamine, dextromethamphetamine, is the most potent human stimulant known: This is the "meth" that tweakers crave. But the left-handed isomer of methamphetamine, levomethamphetamine, is a vasoconstrictor with little to no psychoactive effect and is used in nasal decongestants and inhalers.

In contrast, both isomers of amphetamine are psychostimulants, so Shire combines both the l- and d- isomers in Adderall, each packaged in two different types of salt carriers. By creating a custom racemic mix of l- and d- isomers, and by using a custom blend of salt carriers for each molecule, Adderall meets the definition of an amphetamine formulation that can be patented for prescription use. In a word: genius.

Formulating the perfect blend of speed for children sounds like a task more suited to a crime syndicate than a pharmaceutical company, but Shire put some serious thought into packaging amphetamine into pills for kids with short attention spans. The l- isomer of amphetamine, levoamphetamine, packs a euphoric rush of norepinephrine for a quick and speedy high, with a small release of dopamine for a short period of increased alertness and focus. Levoamphetamine (a.k.a. benzedrine) is a favorite of tweakers who want the most bang for their buck. The d- isomer of amphetamine, dextroamphetamine, produces less of an initial rush but increases the supply of dopamine and norepinephrine in the brain's synaptic clefts for many hours. Dextroamphetamine (a.k.a. dexedrine) is considered by many to be the first "smart drug," used experimentally to increase focus, memory, and intelligence.

Both isomers of amphetamine increase arousal and stimulate the desire to be active. Shire designed Adderall to maximize alertness and focus while not overdoing the initial euphoric rush, so the amphetamine mix in Adderall is only 25 percent l-amphetamine to 75 percent d-amphetamine. Mixing both isomers has been shown to increase the release of dopamine and norepinephrine into the synaptic cleft faster and longer than either of the two isomers individually, so Adderall was designed to be a quick pick-me-up, followed by hours of increased alertness and focus. And by all accounts, Shire did a great job: Even though the generic version of Adderall tries to match the specific mix used by Shire, regular users will tell you that the generic pills are junk compared to the real thing. This is the power of the Adderall brand.

Amphetamine potency can be measured by two things. The first is how efficiently the amphetamine molecule releases dopamine and norepinephrine into the synaptic cleft. The second is how long it takes for that amphetamine molecule to metabolize, because the longer it lingers at the synapse, the more it increases the brain's dopamine and norepinephrine supply.

Amphetamine's action of causing dopamine to be released into the brain's synapses from the axon terminals is fairly well understood, but less well known is how each isomer of amphetamine accomplishes this task. Dextroamphetamine, the major component of Adderall, is thought to be most efficient at releasing dopamine along the brain's D1 and D4 pathways, which help focus cognitive attention. Levoamphetamine, the minor component of Adderall, is thought to be better at releasing norepinephrine and dopamine along the D2 reward pathways, causing rushes of euphoria and sexual arousal, as well as enhanced reflexes and motor coordination.

Although l- and d- isomers of amphetamine differ slightly in their function and effect, both stimulate the brain's pleasure and reward centers in exactly the same way, and both are highly addictive. In fact, all addictive behaviors -- drug use, sex, gambling, and so on -- are wired into to this central dopamine reward pathway, and none stimulate it better than amphetamine. Indeed, amphetamines are the most rewarding of all reward-based addictions, which is why the most potent and longest-acting form of amphetamine, dextromethamphetamine (meth), is so widely coveted by addicts. Methamphetamine is the end of the line for chasing the norepinephrine and dopamine rush.

The mechanisms that stimulate reward and addiction are the same ones that make Adderall such a good drug for increasing focus, attention, and memory. An increased dopamine supply means more sustained focus for longer periods; an increased norepinephrine supply means stronger memory formation and better information retention. This makes Adderall the drug of choice for college students who spend long hours studying or cramming for final exams. The trade in Adderall is so commonplace that it's like an underground currency: Name-brand Adderall sells for more than generics, XR capsules sell for more than the tablets, and each little pill has a milligram dosage marked on it, which means you always know the size of the dose you're getting. The package is simple, neat, and perfect.

But a little study boost can easily spiral into addiction. Prolonged use of Adderall and other stimulants can create dependence and even serious side effects when abused. The short-term effects of Adderall abuse include insomnia and loss of appetite, which can cause stress and malnutrition. A few days of amphetamine abuse coupled with sleep deprivation will cause paranoia and psychosis, and these symptoms will get worse until the person stops the amphetamine use and returns to a normal eating and sleeping schedule. Withdrawing from an amphetamine addiction doesn't cause vomiting or sickness as with heroin, but it does cause extreme agitation, irritability and (ironically) an inability to focus. Long-term amphetamine addicts also report anhedonia, or the inability to feel a sense of enjoyment or pleasure without the aid of some chemical stimulant, which can linger for long periods after quitting. Even though Adderall is considered safe for prescription use in pill form, it's still a Schedule II amphetamine (which means it's in a less restricted category than pot, by the way), and the addiction potential is high.

But does Adderall actually help students get better grades or higher test scores? For students diagnosed with ADD or ADHD, who are at a cognitive disadvantage to begin with, Adderall therapy has been shown to boost overall academic performance with long-term positive results. And 9 percent of children between the ages of five and 17 are diagnosed with ADD/ADHD, which means that 9 percent of minors are perfect targets for boosting academic performance with an Adderall prescription.

But for students not diagnosed with ADD/ADHD who pop Adderall without a prescription to pull a few all-nighters, the results are not so clear. Adderall use may help some of these students, but it can be detrimental to others, though no formal studies have been conducted to show how pervasive nonprescription Adderall use is among students and what effect, if any, it has on overall academic performance. That's because there are several big problems inherent in conducting such a study, including requiring students to report their own illegal activity and collecting urine samples from them to match test scores against the presence of amphetamine metabolites in their urine.

Unlike sports doping, which involves some pretty straightforward issues of fairness and testing, academic doping seems to be a much stickier problem. Parents paying thousands of dollars a year for college probably don't want their children screened for performance-enhancing drugs before they can graduate -- it would open up a huge can of worms if every test score could be challenged with a request for a urine sample. And on the flip side, do you want your child to be selected for the placebo control group in a class of students being given Adderall over the course of a year to see if it helps improve their test scores overall? And if Adderall does improve academic performance for non-ADD/ADHD students, should every student be allowed to get a prescription to level the playing field? You can see why few in academia care to consider the issue of students doping other than to say they oppose it, while admitting that the practice is widespread.

In contrast to academia, the military has long recognized the use of amphetamines for performance enhancement. In 2010, the Department of Defense spent $39 million for over 32,000 prescriptions for active-duty soldiers to stimulants like Adderall, Ritalin, and dexedrine. That's a 10-fold increase in the number of military prescriptions for stimulants from 2005. And the military isn't alone, because the number of civilian prescriptions is also skyrocketing. In 2010, more than 18 million Adderall prescriptions were written, which means either that a crippling epidemic of ADD/ADHD is sweeping America, or else there's a growing recreational demand for the brand of amphetamine that everyone trusts.

Indeed, the demand for Adderall became so dramatic in 2012 that the federal government had to act to combat shortages of the drug. The DEA allows only a certain amount of amphetamine to be commercially manufactured each year, and Congress annually votes to increase that quota to meet the rising demand. In 1990, that number was 417 kg of amphetamine; in 2000, it was 9,007 kg; in 2012, 25,300 kg. The number is doubling every few years, and apparently this supply is still not enough. In May 2012, two members of Congress, Chuck Grassley (R-IA) and Sheldon Whitehouse (D-RI), wrote to the U.S. Government Accountability Office on Shire Pharmaceutical's behalf to urge the DEA to consider easing its restrictions on amphetamine production. Other pharmaceutical companies that make generic versions of Adderall -- including Teva, Barr, Impax Labs, Sandoz, and CorePharma -- will also benefit if the DEA raises its annual quota on industrial amphetamine production. From which one can see that, when it comes to manufacturing and distributing large amounts of patented-blend amphetamines, it pays to have friends in high places.

The piece first appeared on High Times.

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