Adderall


Adderall is the brand name of a fixed-dose combination medication used for 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 a euphoriant. Such uses are illegal in many countries. It is a central nervous system stimulant of the phenethylamine class. It contains the amphetamines dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate. It is taken by mouth.
In therapeutic doses, Adderall causes emotional and cognitive effects such as euphoria, change in sex drive, 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, provoke panic attacks, or induce psychosis. The side effects vary widely among individuals but most commonly include insomnia, dry mouth, loss of appetite and weight loss. The routine use of Adderall at higher-than-prescribed doses poses a significant risk of addiction or dependence due to the pronounced reinforcing effects that are present at high doses. Recreational doses of Adderall are generally much larger than prescribed therapeutic doses and also carry a far greater risk of serious adverse effects.
The two amphetamine enantiomers that compose Adderall, such as Adderall tablets/capsules, 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 CNS stimulant than levoamphetamine, but levoamphetamine has slightly stronger cardiovascular and peripheral effects and a longer elimination half-life than dextroamphetamine. The active ingredient in Adderall, 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 2023, Adderall was the fifteenth most commonly prescribed medication in the United States, with more than 32million prescriptions.

Uses

Medical

Adderall is indicated for the treatment of attention deficit hyperactivity disorder and narcolepsy.

Attention Deficit Hyperactivity Disorder

Narcolepsy

Available forms

Adderall is available as immediate-release tablets and extended-release capsules. Mydayis is available as an extended-release formulation. Adderall XR is approved to treat attention deficit hyperactivity disorder for up to 12 hours in individuals 6 years and older and uses a double-bead formulation. The capsule can be swallowed like a tablet, or it can be opened and the beads sprinkled over applesauce for comparable absorption. Upon ingestion, half of the beads provide immediate administration of medication, while the other half are enveloped in a coating that must dissolve, delaying absorption of its contents. It is designed to provide a therapeutic effect and plasma concentrations identical to taking two doses of Adderall IR four hours apart. Mydayis uses a longer-lasting triple-bead formulation and is approved to treat attention deficit hyperactivity disorder for up to 16 hours in individuals aged 13 years of age and older. In the United States, the immediate and extended-release formulations of Adderall are available as generic medications. Generic formulations of Mydayis became available in the US in October 2023.

Enhancing performance

Adderall is banned by the National Football League, Major League Baseball, the National Basketball Association, the National Collegiate Athletic Association, and the National Hockey League. In leagues such as the National Football League, 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 a high potential for misuse as a recreational drug. Adderall tablets can either be swallowed, 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: Inadequate accommodation of disability, basing one's self-worth on external validation, low self-efficacy, earning poor grades, and having 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

The pharmaceutical company Rexar reformulated their 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 lacking FDA approval, it still made it onto the market and was marketed and sold by Rexar for many years.
In 1994, Richwood Pharmaceuticals acquired Rexar and began promoting Obetrol as a treatment for ADHD, now marketed under the 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, introduced the 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 the 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.