Adderall


Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder and narcolepsy. It is also used as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as an aphrodisiac and euphoriant. It is a central nervous system stimulant of the phenethylamine class.
Adderall is generally well tolerated and effective in treating the symptoms of ADHD and narcolepsy. At therapeutic doses, Adderall causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. At these doses, it induces physical effects such as a faster reaction time, fatigue resistance, and increased muscle strength. In contrast, much larger doses of Adderall can impair cognitive control, cause rapid muscle breakdown, or induce a psychosis. The side effects of Adderall vary widely among individuals, but most commonly include insomnia, dry mouth, and loss of appetite. The risk of developing an addiction is insignificant when Adderall is used as prescribed at fairly low daily doses, such as those used for treating ADHD; however, the routine use of Adderall in larger daily doses poses a significant risk of addiction due to the pronounced reinforcing effects that are present at high doses. Recreational doses of amphetamine are generally much larger than prescribed therapeutic doses, and carry a far greater risk of serious adverse effects.
The two amphetamine enantiomers that compose Adderall alleviate the symptoms of ADHD and narcolepsy by increasing the activity of the neurotransmitters norepinephrine and dopamine in the brain, which results in part from their interactions with human trace amine-associated receptor 1 and vesicular monoamine transporter 2 in neurons. Dextroamphetamine is a more potent stimulant than levoamphetamine, but levoamphetamine has slightly stronger cardiovascular and peripheral effects and a longer elimination half-life than dextroamphetamine. The levoamphetamine component of Adderall has been reported to improve the treatment response in some individuals relative to dextroamphetamine alone. Adderall's active ingredient, amphetamine, shares many chemical and pharmacological properties with the human trace amines, particularly phenethylamine and, the latter of which is a positional isomer of amphetamine. In 2017, Adderall was the 27th most commonly prescribed medication in the United States, with more than 24 million prescriptions.

Uses

Medical

Adderall is used to treat attention deficit hyperactivity disorder and narcolepsy.

Available forms

Adderall is available as immediate-release tablets or two different extended-release formulations. The extended-release capsules are generally used in the morning. A shorter, 12-hour extended-release formulation is available under the brand Adderall XR and is designed to provide a therapeutic effect and plasma concentrations identical to taking two doses 4 hours apart. The longer extended-release formulation, approved for 16 hours, is available under the brand Mydayis. In the United States, the immediate and extended release formulations of Adderall are both available as generic drugs, while Mydayis is available only as a brand-name drug.

Enhancing performance

Adderall has been banned in the National Football League, Major League Baseball, National Basketball Association, and the National Collegiate Athletics Association. In leagues such as the NFL, there is a very rigorous process required to obtain an exemption to this rule even when the athlete has been medically prescribed the drug by their physician.

Recreational

Adderall has high potential for misuse as a recreational drug. Adderall tablets can be crushed and snorted, or dissolved in water and injected. Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.
Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world. Among these students, some of the risk factors for misusing ADHD stimulants recreationally include: possessing deviant personality characteristics, inadequate accommodation of special needs, basing one's self-worth on external validation, low self-efficacy, earning poor grades, and suffering from an untreated mental health disorder.

Contraindications

Adverse effects

The adverse side effects of Adderall are many and varied, but the amount of substance consumed is the primary factor in determining the likelihood and severity of side effects. Adderall is currently approved for long-term therapeutic use by the USFDA. Recreational use of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious adverse drug effects than dosages used for therapeutic purposes.

Overdose

Interactions

Mechanism of action

Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain. It also triggers the release of several other hormones and neurotransmitters as well as the synthesis of certain neuropeptides. Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets, but their binding affinities differ somewhat. Dextroamphetamine and levoamphetamine are both potent full agonists of trace amine-associated receptor 1 and interact with vesicular monoamine transporter 2, with dextroamphetamine being the more potent agonist of TAAR1. Consequently, dextroamphetamine produces more stimulation than levoamphetamine; however, levoamphetamine has slightly greater cardiovascular and peripheral effects. It has been reported that certain children have a better clinical response to levoamphetamine.
In the absence of amphetamine, will normally move monoamines from the intracellular fluid of a monoamine neuron into its synaptic vesicles, which store neurotransmitters for later release into the synaptic cleft. When amphetamine enters a neuron and interacts with VMAT2, the transporter reverses its direction of transport, thereby releasing stored monoamines inside synaptic vesicles back into the neuron's intracellular fluid. Meanwhile, when amphetamine activates, the receptor causes the neuron's cell membrane-bound monoamine transporters to either stop transporting monoamines altogether or transport monoamines out of the neuron; in other words, the reversed membrane transporter will push dopamine, norepinephrine, and serotonin out of the neuron's intracellular fluid and into the synaptic cleft. In summary, by interacting with both VMAT2 and TAAR1, amphetamine releases neurotransmitters from synaptic vesicles into the intracellular fluid where they subsequently exit the neuron through the membrane-bound, reversed monoamine transporters.

Pharmacokinetics

Pharmacomicrobiomics

Related endogenous compounds

History, society, and culture

History

The pharmaceutical company Rexar reformulated their popular weight loss drug Obetrol following its mandatory withdrawal from the market in 1973 under the Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act due to the results of the Drug Efficacy Study Implementation program. The new formulation simply replaced the two methamphetamine components with dextroamphetamine and amphetamine components of the same weight, preserved the Obetrol branding, and despite it utterly lacking FDA approval, it still made it onto the market and was marketed and sold by Rexar for a number of years.
In 1994 Richwood Pharmaceuticals acquired Rexar and began promoting Obetrol as a treatment for ADHD, now marketed under the new brand name of Adderall, a contraction of the phrase "A.D.D. for All" intended to convey that "it was meant to be kind of an inclusive thing" for marketing purposes. The FDA cited the company for numerous significant CGMP violations related to Obetrol discovered during routine inspections following the acquisition, then later issued a second formal warning letter to Richwood Pharmaceuticals specifically due to violations of "the new drug and misbranding provisions of the FD&C Act". Following extended discussions with Richwood Pharmaceuticals regarding the resolution of a large number of issues related to the company's numerous violations of FDA regulations, the FDA formally approved the first Obetrol labeling/sNDA revisions in 1996, including a name change to Adderall and a restoration of its status as an approved drug product. In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a $186 million transaction.
Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet. In 2006, Shire agreed to sell rights to the Adderall name for the instant-release form of the medication to Duramed Pharmaceuticals. DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 during their acquisition of Barr Pharmaceuticals, including Barr's Duramed division.
The first generic version of Adderall IR was introduced to market in 2002. Later on, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the extended-release drug beginning in April 2009.

Commercial formulation

Chemically, Adderall is a mixture of four amphetamine salts; specifically, it is composed of equal parts of amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine sulfate, and dextroamphetamine saccharate. This drug mixture has slightly stronger effects than racemic amphetamine due to the higher proportion of dextroamphetamine. Adderall is produced as both an immediate release and extended release formulation., ten different companies produced generic Adderall IR, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals manufactured generic Adderall XR., Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactured brand name Adderall XR, but not Adderall IR.

Comparison to other formulations

Adderall is one of several formulations of pharmaceutical amphetamine, including singular or mixed enantiomers and as an enantiomer prodrug. The table below compares these medications :

Legal status