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Adderall

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Adderall
an image of the amphetamine skeletal formula
a 3d image of the dextroamphetamine compound found in Adderall
Combination of
amphetamine aspartate monohydrate 25% – stimulant
(12.5% levo; 12.5% dextro)
amphetamine sulfate 25% – stimulant
(12.5% levo; 12.5% dextro)
dextroamphetamine saccharate 25% – stimulant
(0% levo; 25% dextro)
dextroamphetamine sulfate 25% – stimulant
(0% levo; 25% dextro)
Clinical data
Trade names Adderall, Adderall XR, Mydayis
AHFS/Drugs.com Monograph
MedlinePlus a601234
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Dependence
liability
Physical: none[1]
Psychological: moderate[2]
Addiction
liability
Moderate
Routes of
administration
Oral, insufflation, rectal, sublingual
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
KEGG
ChEBI
ChEMBL
  (verify)

Adderall,[note 1] Adderall XR, and Mydayis are combination drugs containing four salts of the two enantiomers of amphetamine, a central nervous system (CNS) stimulant of the phenethylamine class. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. By salt content, the active ingredients of Adderall, Adderall XR, and Mydayis are 25% levoamphetamine salts (the levorotatory or 'left-handed' enantiomer) and 75% dextroamphetamine salts (the dextrorotatory or 'right-handed' enantiomer).[note 2][sources 1]

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 decreased 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 (e.g., delusions and paranoia). 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 higher doses.[13] Recreational doses of Adderall are generally much larger than prescribed therapeutic doses, and carry a far greater risk of serious adverse effects.[sources 2]

The two amphetamine enantiomers that compose Adderall (i.e., levoamphetamine and dextroamphetamine) 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 trace amine associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (VMAT2) 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 (i.e., it remains in the body longer) 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 N-methylphenethylamine, the latter of which is a positional isomer of amphetamine.[sources 3]

Uses[edit]

Adderall 20 mg tablets
A group of 20 mg Adderall tablets, some broken in half, with a lengthwise-folded US dollar bill along the bottom (3.07 inches; 7.8 cm) for size comparison
Adderall XR 10 mg capsules
A group of 10 mg Adderall XR capsules

Medical[edit]

Adderall is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder).[7][11] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[31][32] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[33][34][35] Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.[33][34][35]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[36][37][38] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[36][38] Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes[note 3] across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.[37][38] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[36] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.[38]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[23] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.[23] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[14][23][39] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[40] Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.[41][42] The Cochrane Collaboration's reviews[note 4] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[44][45] A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[46]

Available forms[edit]

Adderall is available as immediate-release tablets or two different extended-release formulations.[11][47] The extended-release capsules are generally used in the morning.[48] 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.[47] The longer extended-release formulation, approved for 16 hours, is available under the brand Mydayis. In the United States, the immediate and extended release (XR) formulations of Adderall are both available as generic drugs, while Mydayis is available only as a brand-name drug.[citation needed]

Enhancing performance[edit]

Cognitive

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;[49][50] these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex.[14][49] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[51] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[14][52] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[14][53][54] Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.[14][54][55] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs.[56][57][58] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[14][54]

Physical

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[15][27] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[59][60] In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction time.[15][61][62] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[61][62][63] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch" that allows the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[62][64][65] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[15][61] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[16][17][61]

Adderall has been banned in the National Football League (NFL), Major League Baseball (MLB), National Basketball Association (NBA), and the National Collegiate Athletics Association (NCAA).[66] 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.[66]

Recreational[edit]

Adderall has a high potential for misuse as a recreational drug.[67][68][69] Adderall tablets can be crushed and snorted, or dissolved in water and injected.[70] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[70]

Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world.[69] Among these students, some of the risk factors for misusing ADHD stimulants recreationally include: possessing deviant personality characteristics (i.e., exhibiting delinquent or deviant behavior), 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.[69]

Contraindications[edit]

According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 5] amphetamine is contraindicated in people with a history of drug abuse,[note 6] cardiovascular disease, severe agitation, or severe anxiety.[72][73][74] It is also contraindicated in people currently experiencing advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension.[72][73][74] People who have experienced allergic reactions to other stimulants in the past or who are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine,[72][73][74] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[75][76] These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine.[73][74] Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus.[74] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[73][74] Due to the potential for reversible growth impairments,[note 7] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[73]

Side effects[edit]

The 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.[16][17][27] Adderall is currently approved for long-term therapeutic use by the USFDA.[17] Recreational use of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious side effects.[27]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[17] Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate).[17][27][77] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[17] Abdominal side effects may include abdominal pain, appetite loss, nausea, and weight loss.[2][17][78] Other potential side effects include blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, and tics (a type of movement disorder).[sources 4] Dangerous physical side effects are rare at typical pharmaceutical doses.[27]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[27] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[27] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[27] This effect can be useful in treating bed wetting and loss of bladder control.[27] The effects of amphetamine on the gastrointestinal tract are unpredictable.[27] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[27] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[27] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[2][27]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 5] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.[sources 6]

Psychological

At normal therapeutic doses, the most common psychological side effects of amphetamine include increased alertness, apprehension, concentration, initiative, self-confidence, and sociability, mood swings (elated mood followed by mildly depressed mood), insomnia or wakefulness, and decreased sense of fatigue.[17][27] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 7] these effects depend on the user's personality and current mental state.[27] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[16][17][18] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[16][17][19] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[17]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[44][85] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[85][86]

Overdose[edit]

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[2][74][87] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[27][74] Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose.[74] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[16][27] In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence).[note 8][88]

Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction.[89][90] Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since repeated overdoses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.[91][92][93] Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression.[91][94] While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction.[95][96] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[sources 8] exercise therapy improves clinical treatment outcomes and may be used as a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.[95][97][98]

Overdose symptoms by system
System Minor or moderate overdose[16][27][74] Severe overdose[sources 9]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Addiction

Addiction and dependence glossary[86][92][101][102]
addiction – a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences
addictive behavior – a behavior that is both rewarding and reinforcing
addictive drug – a drug that is both rewarding and reinforcing
dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
drug withdrawal – symptoms that occur upon cessation of repeated drug use
physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to be approached
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
substance use disorder - a condition in which the use of substances leads to clinically and functionally significant impairment or distress
tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
(edit | history)
Signaling cascade in the nucleus accumbens that results in amphetamine addiction
v · t · e
The image above contains clickable links
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[103][104] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[103][105][106] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[103][107][108] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[109] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[107][108] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[107][108]

Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical long-term medical use at therapeutic doses.[20][21][22] Drug tolerance develops rapidly in amphetamine abuse (i.e., a recreational amphetamine overdose), so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[110][111]

Biomolecular mechanisms

Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[112][113][114] The most important transcription factors[note 9] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[113] ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 10] for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction.[91][92][113] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[91][92] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 10]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.[92][113][118] Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[113] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[94][113][119] Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.[94][113] Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[94][120][121] These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[94][119]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[114] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[114] 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.[114] This suggests that medical use of amphetamine does not significantly affect gene regulation.[114]

Pharmacological treatments

As of 2015, there is no effective pharmacotherapy for amphetamine addiction.[122][123][124] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[125][126] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[125][126] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 11] in the nucleus accumbens;[90] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[90][127] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[90] Supplemental magnesium[note 12] treatment has been shown to reduce amphetamine self-administration (i.e., doses given to oneself) in humans, but it is not an effective monotherapy for amphetamine addiction.[90]

Behavioral treatments

Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addictions.[98] Additionally, research on the neurobiological effects of physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct therapy (i.e., a supplemental treatment) for amphetamine addiction.[sources 8] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[95][97][128] In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D2 (DRD2) density in the striatum.[94][128] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[94] One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system.[96]

Summary of addiction-related plasticity
Form of neuroplasticity
or behavioral plasticity
Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
(aerobic)
Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNs
[94]
Behavioral plasticity
Escalation of intake Yes Yes Yes [94]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [94]
Psychostimulant
self-administration
[94]
Psychostimulant
conditioned place preference
[94]
Reinstatement of drug-seeking behavior [94]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens
[94]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [94]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [94]
Altered striatal opioid signaling No change or
μ-opioid receptors
μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [94]
Changes in striatal opioid peptides dynorphin
No change: enkephalin
dynorphin enkephalin dynorphin dynorphin [94]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [94]
Dendritic spine density in
the nucleus accumbens
[94]

Dependence and withdrawal

According to another Cochrane Collaboration review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[129] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week.[129] Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[129] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[129] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[2]

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminal degeneration and reduced transporter and receptor function.[130][131] There is no evidence that amphetamine is directly neurotoxic in humans.[132][133] However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia, the excessive formation of reactive oxygen species, and increased autoxidation of dopamine.[sources 11] Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity.[131] Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability.[131]

Psychosis

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.[18] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[18][136] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[18] Psychosis very rarely arises from therapeutic use.[19][73]

Interactions[edit]

Pharmacology[edit]

Pharmacodynamics of amphetamine in a dopamine neuron
v · t · e
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[24] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[24][25] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[25][143] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[24][144][145] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[24] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[24] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[146][147]

Mechanism of action[edit]

Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain.[23][39] It also triggers the release of several other hormones (e.g., epinephrine) and neurotransmitters (e.g., serotonin and histamine) as well as the synthesis of certain neuropeptides (e.g., cocaine and amphetamine regulated transcript (CART) peptides).[25][148] Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets,[27][28] but their binding affinities (that is, potency) differ somewhat.[27][28] Dextroamphetamine and levoamphetamine are both potent full agonists (activating compounds) of trace amine-associated receptor 1 (TAAR1) and interact with vesicular monoamine transporter 2 (VMAT2), with dextroamphetamine being the more potent agonist of TAAR1.[28] Consequently, dextroamphetamine produces more CNS stimulation than levoamphetamine;[28][149] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[27] It has been reported that certain children have a better clinical response to levoamphetamine.[29][30]

In the absence of amphetamine, VMAT2 will normally move monoamines (e.g., dopamine, histamine, serotonin, norepinephrine, etc.) from the intracellular fluid of a monoamine neuron into its synaptic vesicles, which store neurotransmitters for later release (via exocytosis) into the synaptic cleft.[25] 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.[25] Meanwhile, when amphetamine activates TAAR1, the receptor causes the neuron's cell membrane-bound monoamine transporters (i.e., the dopamine transporter, norepinephrine transporter, or serotonin transporter) to either stop transporting monoamines altogether (via transporter internalization) or transport monoamines out of the neuron;[24] 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.[24] In summary, by interacting with both VMAT2 and TAAR1, amphetamine releases neurotransmitters from synaptic vesicles (the effect from VMAT2) into the intracellular fluid where they subsequently exit the neuron through the membrane-bound, reversed monoamine transporters (the effect from TAAR1).[24][25]

Pharmacokinetics[edit]

The oral bioavailability of amphetamine varies with gastrointestinal pH;[137] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[150] Amphetamine is a weak base with a pKa of 9.9;[10] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[10][137] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[10] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[151] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[152]

The half-life of amphetamine enantiomers differ and vary with urine pH.[10] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[10] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[152] highly alkaline urine will increase the half-lives up to 34 hours.[152] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[10] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[10] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[10] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.[10] Following oral administration, amphetamine appears in urine within 3 hours.[152] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[152]

CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans.[sources 12] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[10][153] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine,[154] 4-hydroxynorephedrine,[155] and norephedrine.[156] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[10][157] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 12]
Graphic of several routes of amphetamine metabolism
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
The image above contains clickable links
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[153] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[10] The remaining 10–20% is excreted as the active metabolites.[10] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[162]

Related endogenous compounds[edit]

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain.[24][26][166] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula).[24][26][167] In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.[26][167] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[26][167] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[24][166][167] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[26][167]

History, society, and culture[edit]

Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet.[168] In 2006, Shire agreed to sell rights to the Adderall name for the instant-release form of the medication to Duramed Pharmaceuticals.[169] DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 during their acquisition of Barr Pharmaceuticals, including Barr's Duramed division.[170]

The first generic version of Adderall IR was introduced to market in 2002.[3] 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.[3][171]

Commercial formulation[edit]

Chemically, Adderall is a mixture of four amphetamine salts; specifically, it is composed of equal parts (by mass) of amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine sulfate, and dextroamphetamine saccharate.[47] This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine.[24][27] Adderall is produced as both an immediate release (IR) and extended release (XR) formulation.[3][11][47] As of December 2013, ten different companies produced generic Adderall IR, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals manufactured generic Adderall XR.[3] As of 2013, Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactured brand name Adderall XR, but not Adderall IR.[3]

Comparison to other formulations[edit]

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 (based on US approved forms):

Amphetamine base in marketed amphetamine medications
drug formula molecular mass
[note 15]
amphetamine base
[note 16]
amphetamine base
in equal doses
doses with
equal base
content
[note 17]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[173][174] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
22.0 mg
30.0 mg
amphetamine sulfate[175] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
11.0 mg
11.0 mg
30.0 mg
Adderall
62.57%
47.49%
15.08%
14.2 mg
4.5 mg
35.2 mg
25% dextroamphetamine sulfate[173][174] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
25% amphetamine sulfate[175] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[176] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
25% amphetamine aspartate monohydrate[177] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[178] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
8.9 mg
74.2 mg
amphetamine base suspension[note 18][78] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

History[edit]

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 (DESI) program (which indicated a lack of efficacy). The new formulation simply replaced the two methamphetamine components with dextroamphetamine and amphetamine components of the same weight (the other two original dextroamphetamine and amphetamine components were preserved), 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 (and later narcolepsy as well), 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.[179] The FDA cited the company for numerous significant CGMP violations related to Obetrol discovered during routine inspections following the acquisition (including issuing a formal warning letter for the violations), 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.[180][181] In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a $186 million transaction.[179]

Legal status[edit]

See also[edit]

Notes[edit]

  1. ^ "Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"[3]) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.
  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 term amphetamine properly refers to a specific chemical, the racemic free base, which is an equal parts mixture of the two enantiomers (i.e., a mixture of 50% levoamphetamine and 50% dextroamphetamine) in their pure amine forms.[4][5][6]
  3. ^ The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (~55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (~65% of obesity-related outcomes improved), self-esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved).[37]

    The largest effect sizes for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g., grade point average, achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).[37]

    Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.[37]
  4. ^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[43]
  5. ^ The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA. USFDA contraindications are not necessarily intended to limit medical practice but limit claims by pharmaceutical companies.[71]
  6. ^ According to one review, amphetamine can be prescribed to individuals with a history of abuse provided that appropriate medication controls are employed, such as requiring daily pick-ups of the medication from the prescribing physician.[7]
  7. ^ In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.[36][38][77] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[77]
  8. ^ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
  9. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[115]
  10. ^ In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
  11. ^ NMDA receptors are voltage-dependent ligand-gated ion channels that requires simultaneous binding of glutamate and a co-agonist (D-serine}} or glycine) to open the ion channel.[127]
  12. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[90] other forms of magnesium were not mentioned.
  13. ^ The human dopamine transporter contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro.[139][140][141] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[141]
  14. ^ 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[158][161] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[161][163] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[164][165]
  15. ^ For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[172] and were within 0.01g/mol of published pharmaceutical values.
  16. ^ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  17. ^ dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
  18. ^ This product (Dyanavel XR) is an oral suspension (i.e., a drug that is suspended in a liquid and taken by mouth) that contains 2.5 mg/mL of amphetamine base.[78]The amphetamine base contains dextro- to levo-amphetamine in a ratio of 3.2:1,[78] which is approximately the ratio in Adderall. The product uses an ion exchange resin to achieve extended release of the amphetamine base.[78]
Image legend

Reference notes[edit]

References[edit]

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    Physiologic and performance effects
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    Figure 3: Treatment benefit by treatment type and outcome group
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    DOSAGE FORMS AND STRENGTHS
    Extended-release oral suspension contains 2.5 mg amphetamine base per mL.
     
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    Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
     
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    Figure 2: Psychostimulant-induced signaling events
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  109. ^ Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320Freely accessible. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure 
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  122. ^ Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706. Pharmacologic treatment for psychostimulant addiction is generally unsatisfactory. As previously discussed, cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria, anhedonia, and an intense desire to reinitiate drug use. 
  123. ^ Stoops WW, Rush CR (May 2014). "Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research". Expert Rev. Clin. Pharmacol. 7 (3): 363–374. doi:10.1586/17512433.2014.909283. PMC 4017926Freely accessible. PMID 24716825. Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved. 
  124. ^ Perez-Mana C, Castells X, Torrens M, Capella D, Farre M (September 2013). "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". Cochrane Database Syst. Rev. 9: CD009695. doi:10.1002/14651858.CD009695.pub2. PMID 23996457. To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment. ... Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy 
  125. ^ a b Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMC 4724540Freely accessible. PMID 26644139. When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse. 
  126. ^ a b Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615Freely accessible. PMID 26092759. Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction. 
  127. ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 124–125. ISBN 9780071481274. 
  128. ^ a b c Carroll ME, Smethells JR (February 2016). "Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments". Front. Psychiatry. 6: 175. doi:10.3389/fpsyt.2015.00175. PMC 4745113Freely accessible. PMID 26903885. Physical Exercise
    There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.
     
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  131. ^ a b c d Bowyer JF, Hanig JP (November 2014). "Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity". Temperature (Austin). 1 (3): 172–182. doi:10.4161/23328940.2014.982049. PMC 5008711Freely accessible. PMID 27626044. Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. ... The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. ... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus. 
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  133. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 370. ISBN 9780071481274. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons. 
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  138. ^ a b Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacol. Ther. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602Freely accessible. PMID 15922018. 
    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
  139. ^ Krause J (April 2008). "SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder". Expert Rev. Neurother. 8 (4): 611–625. doi:10.1586/14737175.8.4.611. PMID 18416663. Zinc binds at ... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm. 
  140. ^ Sulzer D (February 2011). "How addictive drugs disrupt presynaptic dopamine neurotransmission". Neuron. 69 (4): 628–649. doi:10.1016/j.neuron.2011.02.010. PMC 3065181Freely accessible. PMID 21338876. They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002). 
  141. ^ a b Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH (June 2002). "The role of zinc ions in reverse transport mediated by monoamine transporters". J. Biol. Chem. 277 (24): 21505–21513. doi:10.1074/jbc.M112265200. PMID 11940571. The human dopamine transporter (hDAT) contains an endogenous high affinity Zn2+ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396). ... Although Zn2+ inhibited uptake, Zn2+ facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET). ... Surprisingly, this amphetamine-elicited efflux was markedly enhanced, rather than inhibited, by the addition of 10 μM Zn2+ to the superfusion buffer (Fig. 2 A, open squares). We stress that Zn2+ per se did not affect basal efflux (Fig. 2 A). ... In many brain regions, Zn2+ is stored in synaptic vesicles and co-released together with glutamate; under basal conditions, the extracellular levels of Zn2+ are low (∼10 nM; see Refs. 39, 40). Upon neuronal stimulation, however, Zn2+ is co-released with the neurotransmitters and, consequently, the free Zn2+ concentration may transiently reach values that range from 10–20 μM (10) up to 300 μM (11). The concentrations of Zn2+ shown in this study, required for the stimulation of dopamine release (as well as inhibition of uptake), covered this physiologically relevant range, with maximum stimulation occurring at 3–30 μM. It is therefore conceivable that the action of Zn2+ on hDAT does not merely reflect a biochemical peculiarity but that it is physiologically relevant. ... Thus, when Zn2+ is co-released with glutamate, it may greatly augment the efflux of dopamine. 
  142. ^ Scassellati C, Bonvicini C, Faraone SV, Gennarelli M (October 2012). "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses". J. Am. Acad. Child Adolesc. Psychiatry. 51 (10): 1003–1019.e20. doi:10.1016/j.jaac.2012.08.015. PMID 23021477. Although we did not find a sufficient number of studies suitable for a meta-analysis of PEA and ADHD, three studies20,57,58 confirmed that urinary levels of PEA were significantly lower in patients with ADHD compared with controls. ... Administration of D-amphetamine and methylphenidate resulted in a markedly increased urinary excretion of PEA,20,60 suggesting that ADHD treatments normalize PEA levels. ... Similarly, urinary biogenic trace amine PEA levels could be a biomarker for the diagnosis of ADHD,20,57,58 for treatment efficacy,20,60 and associated with symptoms of inattentivenesss.59 ... With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110 
  143. ^ Sulzer D, Cragg SJ, Rice ME (August 2016). "Striatal dopamine neurotransmission: regulation of release and uptake". Basal Ganglia. 6 (3): 123–148. doi:10.1016/j.baga.2016.02.001. PMC 4850498Freely accessible. PMID 27141430. Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient. 
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  145. ^ "TAAR1". GenAtlas. University of Paris. 28 January 2012. Retrieved 29 May 2014.  • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA) 
  146. ^ Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). "Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons". Neuron. 83 (2): 404–416. doi:10.1016/j.neuron.2014.05.043. PMC 4159050Freely accessible. PMID 25033183. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH 
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  152. ^ a b c d e "Metabolism/Pharmacokinetics". Amphetamine. United States National Library of Medicine – Toxicology Data Network. Hazardous Substances Data Bank. Archived from the original on 2 October 2017. Retrieved 2 October 2017. Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine). ... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3 hours following oral administration. ... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine 
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    The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
     
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