Adderall

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Adderall
an image of the amphetamine skeletal formula
Combination of
amphetamine aspartate monohydrate (25%) psychostimulant
amphetamine sulfate (25%) psychostimulant
dextroamphetamine saccharate (25%) psychostimulant
dextroamphetamine sulfate (25%) psychostimulant
Clinical data
Trade names Adderall
Adderall XR
AHFS/Drugs.com monograph
MedlinePlus a601234
Licence data US FDA:link
Pregnancy cat. C (US)
Legal status Schedule I (CA) Schedule II (US)
Dependence liability High
Routes Oral, insufflation, rectal, sublingual
Identifiers
CAS number 300-62-9 YesY 51-64-9
ATC code N06BA02 N06BA01
PubChem CID 3007
DrugBank DB00182
ChemSpider 13852819 YesY
KEGG D03740 YesY
ChEBI CHEBI:2679 YesY
ChEMBL CHEMBL405 YesY
 YesY (what is this?)  (verify)

Adderall (also known as amphetamine mixed salts or variants thereof)[note 1] is a psychostimulant pharmaceutical drug of the phenethylamine class used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The medication is a mixture of amphetamine stereoisomer salts and inactive ingredients. By salt content, the active ingredients are 75% dextroamphetamine salts[1] (the dextrorotary or "right-handed" enantiomer) and 25% levoamphetamine salts[1] (the levorotary or "left-handed" enantiomer).[note 2] Adderall is available in immediate release and extended release formulations.

While concerns have been raised over side effects and rare, serious complications, Adderall is generally well-tolerated and effective.[3] The most common side effects are cardiovascular, such as fast or irregular heartbeat, and psychological, such as anxiety.

Adderall is a common drug of abuse.[citation needed] However, abuse or dependence is very unlikely to develop in those who use it as prescribed.[citation needed]

Uses[edit]

Medical[edit]

Adderall is generally used for the treatment of ADHD and narcolepsy, the two conditions for which the United States Food and Drug Administration has approved its use.[4] However, it is sometimes prescribed off-label for other conditions such as depression. It has been used to treat obesity, but the American Society of Health-System Pharmacists does not recommend this use.[5] Nearly 14 million monthly prescriptions for the condition were written for Americans ages 20 to 39 in 2011, two and a half times the 5.6 million just four years before, according to the data company IMS Health.[6] Long-term amphetamine exposure in rats is known to produce abnormal dopamine system development or nerve damage,[7][8] but humans experience normal development and nerve growth.[9][10][11] Magnetic resonance imaging studies suggest that long-term treatment with amphetamine decrease the abnormalities of brain structure and function found in subjects with ADHD, and improve the function of the right caudate nucleus.[9][10][11]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[12][13] An evidence review by Gordon Millichap noted the findings of a randomized controlled trial of amphetamine treatment for ADHD in Swedish children following 9 months of amphetamine use.[14] During treatment, the children experienced improvements in attention, disruptive behaviors, and hyperactivity, and an average change of +4.5 in IQ.[14] He noted that the population in the study had a high incidence of comorbid disorders associated with ADHD and suggested that other long-term amphetamine trials with less comorbidity could find greater functional improvements.[14]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems,[note 3] particularly those involving dopamine and norepinephrine.[15] Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems.[15] Approximately 70% of those who use these stimulants see improvements in ADHD symptoms.[16][17] Children with ADHD who use stimulant medications generally have better relationships with peers and family members,[12][16] generally perform better in school, are less distractible and impulsive, and have longer attention spans.[12][16] The Cochrane Collaboration's review[note 4] on the treatment of adult ADHD with amphetamines stated that amphetamines improve short-term symptoms, but have higher discontinuation rates than non-stimulant medications due to their adverse effects.[19]

A Cochrane Collaboration review on the treatment of ADHD in children with comorbid tic disorders indicated that stimulants in general do not exacerbate tics, but high therapeutic doses of dextroamphetamine in such people should be avoided.[20] Other Cochrane reviews on the use of amphetamine for improving recovery following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.[21][22][23]

Dosing and administration[edit]

Adderall is available as immediate release form or extended-release form.[24] The extended release capsule is generally used in the morning.[25] The extended release formulation available under the brand Adderall XR is designed to provide therapeutic effect and plasma concentrations identical to taking two doses 4 hours apart.[26]

Performance-enhancing[edit]

Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on working memory tests in all individuals.[27][28] Amphetamine and other ADHD stimulants also improve task saliency and increase arousal.[27][29] Stimulants such as amphetamine can improve performance on difficult and boring tasks,[27][29] and are used by some students as a study and test-taking aid.[30] Based upon studies of self-reported illicit stimulant use, performance-enhancing use, rather than abuse as a recreational drug, is the primary reason that students use stimulants.[31] High amphetamine doses, above the therapeutic range, can interfere with working memory and cognitive control.[27][29]

Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness, but this is prohibited at events regulated by the World Anti-Doping Agency.[32][33][34] In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength,[34][35] acceleration,[34][35] stamina,[34][36] endurance,[34][36] and alertness,[32] while reducing reaction time.[34] Like the psychostimulants methylphenidate and bupropion, amphetamine increases stamina and endurance in humans primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[35][36] At much higher doses, amphetamine can induce side effects that impair performance, such as rhabdomyolysis and hyperthermia.[37][38][35]

Recreational[edit]

Amphetamine is considered to have a high potential for misuse.[39][40] Amphetamine salts can be crushed and snorted, or dissolved in water and injected.[41] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[41] In 2012, the US National Institute on Drug Abuse (NIDA) published the following prevalence statistics for adolescent use of prescription amphetamine and Adderall within the past year:[42]

Amphetamine Adderall
8th-graders 2.90% 1.70%
10th-graders 6.50% 4.50%
12th-graders 7.90% 7.60%

Side effects[edit]

The side effects of Adderall are many and varied, but the amount of the drug consumed is the primary factor in determining the likelihood and severity of side effects.[37][38][32] Adderall is currently approved for long-term therapeutic use by the United States Food and Drug Administration (USFDA).[38] Recreational use of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious side effects.[32]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and among individual people.[38] Cardiovascular side effects can include irregular heartbeat (usually increased heart rate), hypertension (high blood pressure) or hypotension (low blood pressure) from a vasovagal response, and Raynaud's phenomenon.[38][32][43] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. Other potential side effects include abdominal pain, acne, blurred vision, excessive grinding of the teeth, profuse sweating, dry mouth, loss of appetite, nausea, reduced seizure threshold, tics, and weight loss.[38][32][43] Dangerous physical side effects are rare in typical pharmaceutical doses.[32]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[32] In a normal person at therapeutic doses, amphetamine does not noticeably increase the stimulate breathing, but when respiration is already compromised, it may stimulate it.[32] Amphetamine also induces contraction in the urinary bladder sphincter, which can result in difficulty urinating; this effect can be useful in treating enuresis and incontinence.[32] The effects of amphetamine on the gastrointestinal tract are unpredictable.[32] Amphetamine may reduce gastrointestinal motility if intestinal activity is high, or increase motility if the smooth muscle of the tract is relaxed.[32] Amphetamine also has a slight analgesic effect and can enhance the analgesia of opiates.[32]

Recent studies by the USFDA indicate that, in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the medical use of amphetamine or other ADHD stimulants.[ref-note 1]

Psychological

Common psychological effects of therapeutic doses can include alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elevated mood or elation and euphoria followed by mild dysphoria), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[38][32] Less commonly, depending on the user's personality and current mental state, anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness can occur.[ref-note 2] Amphetamine psychosis can occur in heavy users.[37][38][50] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy as a side effect.[37][38][51] According to the USFDA, "there is no systematic evidence that stimulants cause aggressive behavior or hostility."[38]

Overdose[edit]

An amphetamine overdose is rarely fatal with appropriate care.[52] It can lead to different symptoms.[37][38] A moderate overdose may induce symptoms including irregular heartbeat, confusion, painful urination, high or low blood pressure, hyperthermia, hyperreflexia, muscle pain, severe agitation, rapid breathing, tremor, urinary hesitancy, and urinary retention.[37][38][32] An extremely large overdose may produce symptoms such as adrenergic storm, amphetamine psychosis, anuria, cardiogenic shock, cerebral hemorrhage, circulatory collapse, edema (peripheral or pulmonary), extreme fever, pulmonary hypertension, renal failure, rapid muscle breakdown, serotonin toxicity, and stereotypy.[ref-note 3] Fatal amphetamine poisoning usually involves convulsions and coma.[37][32]

Dependence, addiction, and withdrawal

Addiction is a serious risk with heavy recreational amphetamine use; it is unlikely to arise from typical medical use.[37][55][32] Tolerance develops rapidly in amphetamine abuse, so periods of extended use require increasing doses of the drug in order to achieve the same effect.[56][57]

A Cochrane Collaboration review on amphetamine and methamphetamine dependence and abuse indicates that the current evidence on effective treatments is extremely limited.[58] The review indicated that fluoxetine[note 5] and imipramine[note 6] have some limited benefits in treating abuse and addiction, but concluded, "no treatment has been demonstrated to be effective for the treatment of amphetamine dependence and abuse."[58] A corroborating review indicated that amphetamine dependence is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic pathway.[59] This review also noted that magnesium ions, which inhibit NMDA receptor calcium channels, and serotonin have inhibitory effects on NMDA receptors.[59] It also suggested that, based upon animal testing, pathological amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[59] Supplemental magnesium,[note 7] like fluoxetine treatment, has been shown to reduce self-administration in both humans and lab animals.[58][59]

According to another Cochrane Collaboration review on withdrawal in highly dependent amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[60] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.[60] Amphetamine withdrawal symptoms can include anxiety, drug craving, dysphoric mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and vivid or lucid dreams.[60] The review suggested that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[60] The USFDA does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[61][62][63]

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain.[64][65][66] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).[65] ΔFosB is the most significant, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction;[65] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, and substituted amphetamines.[64][65][67] ΔJunD is the transcription factor which directly opposes ΔFosB.[65] Increases in nucleus accumbens ΔJunD expression can reduce or, with a large increase, even block most of the neural alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[65] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[64][65] Since natural rewards, like drugs of abuse, induce ΔFosB, chronic acquisition of these rewards can result in a similar pathological addictive state.[64][65] Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction, especially amphetamine-induced sex addictions.[64][65][68] ΔFosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders.[69]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[66] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[66] The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.[66]

Psychosis

Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia, hallucinations, delusions).[50] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely.[50][70] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[50] Psychosis very rarely arises from therapeutic use.[51][71]

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function.[72] There is no evidence that amphetamine is directly neurotoxic in humans.[73][74] High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[7][75][76]

Contraindications, interactions, and precautions[edit]

  • MAOIs (monoamine oxidase inhibitors, e.g., phenelzine, selegiline, iproniazid, etc.): There is a high risk of a hypertensive crisis if amphetamine is administered within two weeks after last use of an MAOI type drug. Preliminary trials of low-dose amphetamine and MAOIs being administered together are in progress. However, this is to be done only under strict supervision of the prescribing parties.
  • SSRIs (selective serotonin reuptake inhibitors, e.g., fluvoxamine, citalopram, paroxetine, etc.): While a common combination, and although rare, the risk for serotonin syndrome exists. (Use only when directed)
  • NRIs (norepinephrine reuptake inhibitors, e.g., atomoxetine, etc.): NRI medications and amphetamine both enhance noradrenergic activity. Possible augmentation/potentiation of effects. (Use only when directed)
  • SNRIs (selective serotonin-norepinephrine reuptake inhibitors): See SSRIs and NRIs.
  • Bupropion : Both bupropion and amphetamine have noradrenergic and dopaminergic activity. Bupropion is a potent CYP2D6 inhibitor. Bupropion has pro-convulsant properties that may be enhanced or cumulatively potentiated by amphetamine.[77] (Use only when directed)
  • Monoaminergic tricyclic antidepressant: See NRIs, SNRIs, and SSRIs. Possible potentiation of serotonin-, dopamine-, and/or norepinephrine-related drug effects. The combination of monoaminergic tricyclics and amphetamine compounds has been associated with increased sympathomimetic effects. The exceptions to this class (i.e. non-monoaminergic tricyclic antidepressants) include the glutamatergic tricyclic tianeptine and sigmaergic tricyclic opipramol.
  • CYP2D6 (liver enzyme) inhibitors, e.g., Bupropion and most SSRIs such as fluoxetine, citalopram, paroxetine, etc. Some anti-psychotics such as thioridazine, haloperidol, and levomepromazine, as well as cocaine, the opioid agonist methadone, and others. It is important to determine if any medication or drug taken is a CYP2D6 inhibitor. Taking a CYP2D6-inhibiting drug along with amphetamine will lead to an elevated level of amphetamine in the system, resulting in the drug's remaining in the body for a longer period, which can lead to undesirable and possibly serious side effects.
  • Individuals with pre-existing cardiac conditions or mental illnesses.
  • Individuals with a history of drug abuse

Mechanism of action[edit]

Pharmacodynamics of amphetamine enantiomers in a dopamine neuron

A pharmacodynamic model of amphetamine and TAAR1
via AADC
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine binds to TAAR1, it reduces dopamine receptor firing rate and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation. PKC-phosphorylated DAT operates in reverse, while PKA-phosphorylated DAT withdraws into the presynaptic neuron and ceases transport. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow-orange area).

Adderall's active ingredients dextroamphetamine and levoamphetamine have identical pharmacodynamics, but their binding affinities to their biomolecular targets vary.[32][78] Dextroamphetamine is a more potent agonist of the trace amine-associated receptor 1 (TAAR1) than levoamphetamine.[78] Consequently, dextroamphetamine produces roughly two times more CNS stimulation than levoamphetamine;[78][79] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[32] Levoamphetamine provides Adderall with a quicker onset and longer-lasting effects than dextroamphetamine alone.[80] It has been reported that certain children have a better clinical response to levoamphetamine.[81]

History[edit]

Adderall is available as an instant-release (IR) and an extended-release (XR) drug.[2] As of December 2013, ten different companies have produced generic Adderall IR at one point, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals currently manufacture generic Adderall XR.[2] Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactures brand name Adderall XR, but not Adderall IR.[2]

Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet.[82] In 2006, Shire agreed to sell rights to the Adderall name for this instant-release medication to Duramed Pharmaceuticals[83] DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 when Teva completed its acquisition of Barr Pharmaceuticals, including Barr's Duramed division.[84]

The first generic version of Adderall IR was introduced to market in 2002.[2] Later on, in 2009, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the drug beginning 1 April 2009.[2][85]

Patent disputes[edit]

Manufacturer's claims of instant release have been disputed. A US patent granted for Adderall was a pharmaceutical composition patent listing a rapid immediate-release oral dosage form.[86] No claim of increased or smooth drug delivery was made. A study by James and colleague as published in the November 2001 issue of the Journal of the American Academy of Child and Adolescent Psychiatry, placebo-controlled crossover study conducted among 35 children ages 5–12 indicated that patients behaved similarly to those having taken other immediate-release amphetamines. The authors found that sustained-release dextro-amphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action; however, D-amphetamine was less effective in the first few hours.[87]

Commercial formulations[edit]

Historical[edit]

Rexar, a pharmaceutical company, reformulated another drug, branded as Obetrol, to exclude methamphetamine and continued to sell this new formulation under the same brand name. This new unapproved formulation was later rebranded and sold as Adderall by Richwood after it acquired Rexar resulting in FDA warning in 1994. Richwood submitted this formulation as NDA 11-522 and Adderall gained FDA approval for the treatment of attention-deficit/hyperactivity disorder therapy on 13 February 1996.[88]

Current[edit]

In the United States, Adderall is used primarily for the treatment of ADHD and narcolepsy.[5]

It is a mixture of amphetamine salts consisting of equal amounts by mass of:[26]

This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine.[32][89]

Adderall is available in immediate release and extended release formulations. The immediate release formulation is indicated for use in ADHD and narcolepsy.[24] The extended release formulation is only approved for the treatment of ADHD.[90]

Legal status[edit]

  • In Canada, amphetamines are in Schedule I of the Controlled Drugs and Substances Act, and can only be obtained by prescription.[91]
  • In Japan, the use, production, and import of any medicine containing amphetamine are prohibited.[92][93]
  • In South Korea, amphetamines are prohibited.[94]
  • In Thailand, Amphetamines are classified as Type 1 Narcotics.[95]
  • In the United Kingdom, amphetamines are regarded as Class B drugs. The maximum penalty for unauthorized possession is five years in prison and an unlimited fine. The maximum penalty for illegal supply is 14 years in prison and an unlimited fine.[96]
  • In the United States, amphetamine is a Schedule II prescription drug, classified as a CNS (central nervous system) stimulant.[97]
  • Internationally (United Nations), amphetamine is in Schedule II of the Convention on Psychotropic Substances[98][99]

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Notes[edit]

  1. ^ The US nonproprietary name of Adderall is dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate.[1][2]
  2. ^ Enantiomers are molecules that are "mirror images" of one another; they are structurally identical but of the opposite orientation, like left and right hands. The compound "amphetamine" (racemic amphetamine) refers to equal parts of the enantiomers, i.e. 50% levoamphetamine and 50% dextroamphetamine.
  3. ^ This involves impaired dopamine neurotransmission in the mesocortical and mesolimbic pathways and norepinephrine neurotransmission in the prefrontal cortex and locus coeruleus.[15]
  4. ^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[18]
  5. ^ During short-term treatment, fluoxetine may decrease drug craving.[58]
  6. ^ During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.[58]
  7. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[59] other forms of magnesium were not mentioned.

Reference notes[edit]

  1. ^ [44][45][46][47]
  2. ^ [48][38][32][49]
  3. ^ [37][38][32][49][52][53][54]