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Amphetamine/dextroamphetamine
salt mixture (1:1)[note 1]
an image of the amphetamine skeletal formula
a 3d image of the dextroamphetamine compound found in Adderall
Top: racemic amphetamine skeleton
Bottom: (D)-amphetamine ball-and-stick model
Combination of
amphetamine aspartate monohydrate25% – stimulant
(12.5% levo; 12.5% dextro)
amphetamine sulfate25% – stimulant
(12.5% levo; 12.5% dextro)
dextroamphetamine saccharate25% – stimulant
(0% levo; 25% dextro)
dextroamphetamine sulfate25% – stimulant
(0% levo; 25% dextro)
Clinical data
Trade namesAdderall, Adderall XR, Mydayis
Other namesMixed amphetamine salts; MAS
AHFS/Drugs.comMonograph
MedlinePlusa601234
License data
Dependence
liability
Moderate[3][4] – high[5][6][7]
Routes of
administration
By mouth, insufflation, rectal, sublingual
Drug classCNS stimulant
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: ~90%[9]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
  (verify)

Adderall and Mydayis[10] are trade names[note 2] for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine.[12] Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine,[1][2] which are marketed as Evekeo and Dexedrine/Zenzedi, respectively.[1][13][14] Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.[1]

At therapeutic doses, Adderall causes emotional and cognitive effects such as euphoria, change in sex drive, increased wakefulness, and improved cognitive control. At these doses, it induces physical effects such as a faster reaction time, fatigue resistance, and increased muscle strength. In contrast, much larger doses of Adderall can impair cognitive control, cause rapid muscle breakdown, provoke panic attacks, or induce a psychosis (e.g., paranoia, delusions, hallucinations). The side effects vary widely among individuals but most commonly include insomnia, dry mouth, loss of appetite and weight loss. The risk of developing an addiction or dependence is insignificant when Adderall is used as prescribed and at fairly low daily doses, such as those used for treating ADHD. However, the routine use of Adderall in larger and daily doses poses a significant risk of addiction or dependence due to the pronounced reinforcing effects that are present at high doses. Recreational doses of Adderall are generally much larger than prescribed therapeutic doses and also carry a far greater risk of serious adverse effects.[sources 1]

The two amphetamine enantiomers that compose Adderall, such as Adderall tablets/capsules (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 human trace amine-associated receptor 1 (hTAAR1) and vesicular monoamine transporter 2 (VMAT2) in neurons. Dextroamphetamine is a more potent Central nervous system (CNS) stimulant than levoamphetamine, but levoamphetamine has slightly stronger cardiovascular and peripheral effects and a longer elimination half-life than dextroamphetamine. The levoamphetamine component of Adderall has been reported to improve the treatment response in some individuals relative to dextroamphetamine alone. The active ingredient in Adderall, 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 2] In 2021 Adderall was the seventeenth most commonly prescribed medication in the United States, with more than 30 million prescriptions.[34][35]

Uses

[edit]
30 Adderall XR 10 mg capsules
30 capsules of 10 mg Adderall XR
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

Medical

[edit]

Adderall is commonly used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder).[36][16]

ADHD

[edit]

Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[37][38] but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth.[39][40][41] 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.[39][40][41]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[42][43][44] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[42][43] 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.[42][44] One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[43] 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.[42]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[45] 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.[45] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[17][45][46] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[47] 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.[48][49] The Cochrane reviews[note 4] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[51][52] A Cochrane 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.[53]

Narcolepsy

[edit]

Narcolepsy is a chronic sleep-wake disorder that is associated with excessive daytime sleepiness, cataplexy, and sleep paralysis.[54] Patients with narcolepsy are diagnosed as either type 1 or type 2, with only the former presenting cataplexy symptoms.[55] Type 1 narcolepsy results from the loss of approximately 70,000 orexin-releasing neurons in the lateral hypothalamus, leading to significantly reduced cerebrospinal orexin levels;[56][57] this reduction is a diagnostic biomarker for type 1 narcolepsy.[55] Lateral hypothalamic orexin neurons innervate every component of the ascending reticular activating system (ARAS), which includes noradrenergic, dopaminergic, histaminergic, and serotonergic nuclei that promote wakefulness.[57][58]

Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing monoamine neurotransmitter activity in the ARAS.[56][59][60] This includes noradrenergic neurons in the locus coeruleus, dopaminergic neurons in the ventral tegmental area, histaminergic neurons in the tuberomammillary nucleus, and serotonergic neurons in the dorsal raphe nucleus.[58][60] Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is particularly effective at promoting wakefulness because dopamine release has the greatest influence on cortical activation and cognitive arousal, relative to other monoamines.[56] In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin.[56] Noradrenergic and serotonergic nuclei in the ARAS are involved in the regulation of the REM sleep cycle and function as "REM-off" cells, with amphetamine's effect on norepinephrine and serotonin contributing to the suppression of REM sleep and a possible reduction of cataplexy at high doses.[56][55][58]

The American Academy of Sleep Medicine (AASM) 2021 clinical practice guideline conditionally recommends dextroamphetamine for the treatment of both type 1 and type 2 narcolepsy.[61] Treatment with pharmaceutical amphetamines is generally less preferred relative to other psychostimulants (e.g., modafinil) and is considered a third-line treatment option.[62][63][64] Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy.[56][62][61] Amphetamine appears to be most effective at improving symptoms associated with hypersomnolence, with three reviews finding clinically significant reductions in daytime sleepiness in patients with narcolepsy.[56][62][61] Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms.[56][62][61] However, the quality of evidence for these findings is low and is consequently reflected in the AASM's conditional recommendation for dextroamphetamine as a treatment option for narcolepsy.[61]

Available forms

[edit]

Adderall is available as immediate-release (IR) tablets and extended-release (XR) capsules.[16][65] Mydayis is only available as an extended-release formulation.[66] Adderall XR is approved to treat ADHD for up to 12 hours in individuals 6 years and older and uses a double-bead formulation. The capsule can be swallowed like a tablet, or it can be opened and the beads sprinkled over applesauce for comparable absorption.[65] Upon ingestion, half of the beads provide immediate administration of medication, while the other half are enveloped in a coating which must dissolve, delaying absorption of its contents. It is designed to provide a therapeutic effect and plasma concentrations identical to taking two doses of Adderall IR four hours apart.[65] Mydayis uses a longer-lasting triple-bead formulation and is approved to treat ADHD for up to 16 hours in individuals 13 years and older.[66] In the United States, the immediate and extended-release formulations of Adderall are both available as generic drugs.[67][68] Generic formulations of Mydayis became available in the US in October 2023.[69]

Enhancing performance

[edit]

Cognitive performance

[edit]

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;[70][71] 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.[17][70] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[72] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[17][73] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[17][74][75] 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.[17][75][76] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs.[77][78][79] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[17][75]

Physical performance

[edit]

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[18][30] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[80][81] 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.[18][82][83] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.[82][83][84] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[83][85][86] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[18][82] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[19][82]

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).[87] 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.[87]

Recreational

[edit]

Adderall has high potential for misuse as a recreational drug.[88][89][90] Adderall tablets can either be swallowed, crushed and snorted, or dissolved in water and injected.[91] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[91]

Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world.[90] 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 disability, basing one's self-worth on external validation, low self-efficacy, earning poor grades, and having an untreated mental health disorder.[90]

Contraindications

[edit]
According to the International Programme on Chemical Safety (IPCS) and the 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.[94][95][96] It is also contraindicated in individuals with advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension.[94][95][96] These agencies indicate that people who have experienced allergic reactions to other stimulants or who are taking monoamine oxidase inhibitors (MAOIs) should not take amphetamine,[94][95][96] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[97][98] 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.[95][96] 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.[96] Amphetamine has also been shown to pass into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it.[95][96] 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.[95]

Adverse effects

[edit]

The adverse side effects of Adderall are many and varied, but the amount of substance consumed is the primary factor in determining the likelihood and severity of side effects.[19][30] Adderall is currently approved for long-term therapeutic use by the USFDA.[19] Recreational use of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious adverse drug effects than dosages used for therapeutic purposes.[30]

Physical

[edit]

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).[19][30][102] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[19] Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea.[7][19][103] Other potential physical side effects include appetite loss, blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, tics (a type of movement disorder), and weight loss.[sources 3] Dangerous physical side effects are rare at typical pharmaceutical doses.[30]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[30] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[30] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[30] This effect can be useful in treating bed wetting and loss of bladder control.[30] The effects of amphetamine on the gastrointestinal tract are unpredictable.[30] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[30] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[30] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[7][30]

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 4] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.[sources 5]

Psychological

[edit]

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.[19][30] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 6] these effects depend on the user's personality and current mental state.[30] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[19][20][111] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[19][111][21] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[19]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[51][112] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[112][113]

Reinforcement disorders

[edit]

Addiction

[edit]
Addiction and dependence glossary[113][114][115]
  • addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
  • addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
  • 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 socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome)
  • 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 approach
  • 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
Transcription factor glossary
  • gene expression – the process by which information from a gene is used in the synthesis of a functional gene product such as a protein
  • transcription – the process of making messenger RNA (mRNA) from a DNA template by RNA polymerase
  • transcription factor – a protein that binds to DNA and regulates gene expression by promoting or suppressing transcription
  • transcriptional regulationcontrolling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA
  • upregulation, activation, or promotionincrease the rate of gene transcription
  • downregulation, repression, or suppressiondecrease the rate of gene transcription
  • coactivator – a protein (or a small molecule) that works with transcription factors to increase the rate of gene transcription
  • corepressor – a protein (or a small molecule) that works with transcription factors to decrease the rate of gene transcription
  • response element – a specific sequence of DNA that a transcription factor binds to
Signaling cascade in the nucleus accumbens that results in amphetamine addiction
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,[116][117] 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.[116][118][119] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[116][120][121] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[122] 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.[120][121] 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.[120][121]

Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;[22][23][62] in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult.[42] 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.[123][124] Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.[114][125][126] 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.[125][127] 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.[128][129] Exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction.[128][130][sources 7]

Biomolecular mechanisms

[edit]

Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[126][131][132] The most important transcription factors[note 8] that produce these alterations are Delta FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor-kappa B (NF-κB).[126] ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB overexpression (i.e., an abnormally high level of gene expression which produces a pronounced gene-related phenotype) in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 9] for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction.[114][125][126] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[114][125] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 8]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.[114][126][136] 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).[126] Similarly, accumbal G9a hyperexpression results in markedly increased histone 3 lysine residue 9 dimethylation (H3K9me2) and blocks the induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug use,[sources 9] which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5).[126][136][137] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[127][126][140] Since both natural rewards and addictive drugs induce the 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.[127][126] Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sexual addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[127][141][142] These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[127][140]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[132] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[132] 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.[132] This suggests that medical use of amphetamine does not significantly affect gene regulation.[132]

Pharmacological treatments
[edit]

As of December 2019, there is no effective pharmacotherapy for amphetamine addiction.[143][144][145] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[146][147] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[146][147] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 10] in the nucleus accumbens;[124] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[124][148] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[124] Supplemental magnesium[note 11] 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.[124]

A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in randomized controlled trials (RCTs) for amphetamine and methamphetamine addiction;[144] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[144] There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.[144]

Behavioral treatments
[edit]

A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).[149] Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy, 12-step programs, non-contingent reward-based therapies, psychodynamic therapy, and other combination therapies involving these.[149]

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 7] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[128][130][150] 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.[127][150] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[127] 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.[129]

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 MSNsTooltip medium spiny neurons
[127]
Behavioral plasticity
Escalation of intake Yes Yes Yes [127]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [127]
Psychostimulant
self-administration
[127]
Psychostimulant
conditioned place preference
[127]
Reinstatement of drug-seeking behavior [127]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation
in the nucleus accumbens
[127]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [127]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [127]
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 [127]
Changes in striatal opioid peptides dynorphin
No change: enkephalin
dynorphin enkephalin dynorphin dynorphin [127]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [127]
Dendritic spine density in
the nucleus accumbens
[127]

Dependence and withdrawal

[edit]

Drug tolerance develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect.[151][152] According to a Cochrane 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."[153] 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.[153] 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.[153] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[153] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[7]

Overdose

[edit]

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[154][96][155] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[156][96] 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.[96] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[95][156] 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 12][157]

Overdose symptoms by system
System Minor or moderate overdose[95][156][96] Severe overdose[sources 10]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Interactions

[edit]

Pharmacology

[edit]
Pharmacodynamics of amphetamine in a dopamine neuron
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.[27] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[27][28] 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.[28][167] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via G protein-coupled inwardly rectifying potassium channels (GIRKs) and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[27][168][169] PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[27] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[27] 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.[170][171]

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.[26][46] 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).[28][172] Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets,[30][31] but their binding affinities (that is, potency) differ somewhat.[30][31] 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.[31] Consequently, dextroamphetamine produces more CNS stimulation than levoamphetamine;[31][173] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[30] It has been reported that certain children have a better clinical response to levoamphetamine.[32][33]

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.[28] 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.[28] 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;[27] 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.[27] 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).[27][28]

Pharmacokinetics

[edit]

The oral bioavailability of amphetamine varies with gastrointestinal pH;[19] it is well absorbed from the gut, and bioavailability is typically 90%.[9] Amphetamine is a weak base with a pKa of 9.9;[174] 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.[174][19] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[174] Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins.[175] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[176]

The half-lives of amphetamine enantiomers differ and vary with urine pH.[174] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[174] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[176] highly alkaline urine will increase the half-lives up to 34 hours.[176] 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.[174] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[174] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[174] 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.[174] Following oral administration, amphetamine appears in urine within 3 hours.[176] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[176]

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 11] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[174][177] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine,[178] 4-hydroxynorephedrine,[179] and norephedrine.[180] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[174][181] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 11]
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;[177] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[174] The remaining 10–20% is excreted as the active metabolites.[174] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[186]

Pharmacomicrobiomics

[edit]

The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals.[190][191] Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions),[note 15][190][192] there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile.[190][191][193] The field that studies these interactions is known as pharmacomicrobiomics.[190]

Similar to most biomolecules and other orally administered xenobiotics (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by human gastrointestinal microbiota (primarily bacteria) prior to absorption into the blood stream.[193] The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019.[193] This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.[193]
[edit]

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neuromodulator molecules produced in the human body and brain.[27][194][195] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, a structural isomer of amphetamine (i.e., it has an identical molecular formula).[27][194][196] 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.[194][196] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[194][196] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[27][195][196] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[194][196]

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 lacking FDA approval, it still made it onto the market and was marketed and sold by Rexar for many years.

In 1994, Richwood Pharmaceuticals acquired Rexar and began promoting Obetrol as a treatment for ADHD (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.[197] 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.[198][199] In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a $186 million transaction.[197]

Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet.[200] In 2006, Shire agreed to sell rights to the Adderall name for the instant-release form of the medication to Duramed Pharmaceuticals.[201] DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 during their acquisition of Barr Pharmaceuticals, including Barr's Duramed division.[202]

The first generic version of Adderall IR was introduced to market in 2002.[11] 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.[11][203]

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.[65] This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine.[27][30] Adderall is produced as both an immediate-release (IR) and extended-release (XR) formulation.[11][16][65] As of December 2013, ten different companies produced generic Adderall IR, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals manufactured generic Adderall XR.[11] 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.[11]

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 U.S.-approved forms):

Amphetamine base in marketed amphetamine medications
drug formula molar mass
[note 16]
amphetamine base
[note 17]
amphetamine base
in equal doses
doses with
equal base
content
[note 18]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[205][206] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
22.0 mg
30.0 mg
amphetamine sulfate[207] (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[205][206] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
25% amphetamine sulfate[207] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[208] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
25% amphetamine aspartate monohydrate[209] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[210] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
8.9 mg
74.2 mg
amphetamine base suspension[103] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

Society and culture

[edit]
[edit]
  • In Canada, amphetamines are in Schedule I of the Controlled Drugs and Substances Act, and can only be obtained by prescription.[211]
  • In Japan, the use, production, and import of any medicine containing amphetamines is prohibited.[212]
  • In South Korea, amphetamines are prohibited.[213]
  • In Taiwan, amphetamines including Adderall are Schedule 2 drugs with a minimum five years prison term for possession.[214] On the contrary, Ritalin can be legally prescribed as a form of treatment of ADHD.[215]
  • In Thailand, amphetamines are classified as Type 1 Narcotics.[216]
  • 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.[217]
  • In the United States, amphetamine is a Schedule II prescription drug, classified as a central nervous system (CNS) stimulant.[218]
  • Internationally, amphetamine is in Schedule II of the Convention on Psychotropic Substances.[219][220]

Shortages

[edit]

In February 2023, news organizations began reporting on shortages of Adderall in the United States that have lasted for over five months.[221][222] The Food and Drug Administration first reported the shortage in October 2022.[223] In May 2023, 7 months into the shortage, the Food and Drug Administration commissioner Robert Califf stated that "a number of generic drugs are in shortage at any given time because there's not enough profit". He points out that Adderall is a special case because it is a controlled substance and the amount available for prescription is controlled by the Drug Enforcement Administration. He also faults a "tremendous increase in prescribing" due to virtual prescribing and general overprescribing and overdiagnosing, adding that "if only the people that needed these drugs got them, there probably wouldn't be a [stimulant medication] shortage".[224][225] Some Americans have been outsourcing the time-consuming task of calling nearby pharmacies to check their Adderall availability.[226]


The shortage has continued into 2024. Despite efforts to increase production and improve distribution, supply chain issues and increased demand have perpetuated the scarcity of the medication.[227] Patients and healthcare providers have expressed concerns about the impact on treatment plans for ADHD and narcolepsy, as many individuals rely on this medication for managing their symptoms.[228] The FDA continues to monitor the situation and is working with manufacturers to address the shortage.[229]

Notes

[edit]
  1. ^ Salts of racemic amphetamine and dextroamphetamine are mixed in a (1:1) ratio to produce this drug. Because the racemate is composed of equal parts dextroamphetamine and levoamphetamine, this drug can also be described as a mixture of the D and (L)-enantiomers of amphetamine in a (3:1) ratio, although none of the components of the mixture are levoamphetamine salts.[1][2]
  2. ^ The trade name Adderall is used primarily throughout this article because the four-salt composition of the drug makes its nonproprietary name (dextroamphetamine sulfate 25%, dextroamphetamine saccharate 25%, amphetamine sulfate 25%, and amphetamine aspartate 25%) excessively lengthy.[11] Mydayis is a relatively new trade name that is not commonly used to refer generally to the mixture.[10]
  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).[44]

    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).[44]

    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.[44]
  4. ^ Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[50]
  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.[92]
  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.[93]
  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.[99][100][101] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[101]
  8. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[133]
  9. ^ 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.
  10. ^ 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.[148]
  11. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[124] other forms of magnesium were not mentioned.
  12. ^ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
  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.[163][164][165] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[165]
  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.[182][185] 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;[185][187] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[188][189]
  15. ^ There is substantial variation in microbiome composition and microbial concentrations by anatomical site.[190][191] Fluid from the human colon – which contains the highest concentration of microbes of any anatomical site – contains approximately one trillion (10^12) bacterial cells/ml.[190]
  16. ^ For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator[204] and were within 0.01 g/mol of published pharmaceutical values.
  17. ^ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  18. ^ 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.
Image legend
  1. ^
      (Text color) Transcription factors

Reference notes

[edit]

References

[edit]
  1. ^ a b c d Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642.
  2. ^ a b Joyce BM, Glaser PE, Gerhardt GA (April 2007). "Adderall produces increased striatal dopamine release and a prolonged time course compared to amphetamine isomers". Psychopharmacology. 191 (3): 669–677. doi:10.1007/s00213-006-0550-9. PMID 17031708. S2CID 20283057.
  3. ^ Vitiello B (April 2008). "Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function". Child and Adolescent Psychiatric Clinics of North America. 17 (2): 459–74, xi. doi:10.1016/j.chc.2007.11.010. PMC 2408826. PMID 18295156.
  4. ^ Graham J, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, Dittmann RW, et al. (January 2011). "European guidelines on managing adverse effects of medication for ADHD". European Child & Adolescent Psychiatry. 20 (1): 17–37. doi:10.1007/s00787-010-0140-6. eISSN 1435-165X. PMC 3012210. PMID 21042924.
  5. ^ Kociancic T, Reed MD, Findling RL (March 2004). "Evaluation of risks associated with short- and long-term psychostimulant therapy for treatment of ADHD in children". Expert Opinion on Drug Safety. 3 (2): 93–100. doi:10.1517/14740338.3.2.93. eISSN 1744-764X. PMID 15006715. S2CID 31114829.
  6. ^ Clemow DB, Walker DJ (September 2014). "The potential for misuse and abuse of medications in ADHD: a review". Postgraduate Medicine. 126 (5): 64–81. doi:10.3810/pgm.2014.09.2801. eISSN 1941-9260. PMID 25295651. S2CID 207580823.
  7. ^ a b c d e Stahl SM (March 2017). "Amphetamine (D,L)". Prescriber's Guide: Stahl's Essential Psychopharmacology (6th ed.). Cambridge, United Kingdom: Cambridge University Press. pp. 45–51. ISBN 9781108228749. Retrieved 5 August 2017.
  8. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  9. ^ a b Patel VB, Preedy VR, eds. (2022). Handbook of Substance Misuse and Addictions. Cham: Springer International Publishing. p. 2006. doi:10.1007/978-3-030-92392-1. ISBN 978-3-030-92391-4. Amphetamine is usually consumed via inhalation or orally, either in the form of a racemic mixture (levoamphetamine and dextroamphetamine) or dextroamphetamine alone (Childress et al. 2019). In general, all amphetamines have high bioavailability when consumed orally, and in the specific case of amphetamine, 90% of the consumed dose is absorbed in the gastrointestinal tract, with no significant differences in the rate and extent of absorption between the two enantiomers (Carvalho et al. 2012; Childress et al. 2019). The onset of action occurs approximately 30 to 45 minutes after consumption, depending on the ingested dose and on the degree of purity or on the concomitant consumption of certain foods (European Monitoring Centre for Drugs and Drug Addiction 2021a; Steingard et al. 2019). It is described that those substances that promote acidification of the gastrointestinal tract cause a decrease in amphetamine absorption, while gastrointestinal alkalinization may be related to an increase in the compound's absorption (Markowitz and Patrick 2017).
  10. ^ a b Sagonowsky E (28 August 2017). "Shire launches new ADHD drug Mydayis as it weighs a neuroscience exit". Fierce Pharma. Questex LLC. Archived from the original on 16 December 2019. Retrieved 2 May 2020.
  11. ^ a b c d e f "National Drug Code Amphetamine Search Results". National Drug Code Directory. United States Food and Drug Administration. Archived from the original on 16 December 2013. Retrieved 16 December 2013.
  12. ^ Babiskin AH, Zhang X (September 2015). "Application of Physiologically Based Absorption Modeling for Amphetamine Salts Drug Products in Generic Drug Evaluation". Journal of Pharmaceutical Sciences. 104 (9): 3170–3182. doi:10.1002/jps.24474. PMID 25973928.
  13. ^ "Pharmacology". Evekeo CII (amphetamine sulfate) HCP. Arbor Pharmaceuticals, LLC. Archived from the original on 21 September 2020. Retrieved 2 May 2020.
  14. ^ "Prescribing Information & Medication Guide" (PDF). Zenzedi (dextroamphetamine sulfate, USP). Arbor Pharmaceuticals LLC. Archived (PDF) from the original on 11 November 2020. Retrieved 2 May 2020.
  15. ^ a b Montgomery KA (June 2008). "Sexual desire disorders". Psychiatry. 5 (6): 50–55. PMC 2695750. PMID 19727285.
  16. ^ a b c d "Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet". DailyMed. Teva Pharmaceuticals USA, Inc. 8 November 2019. Archived from the original on 2 October 2019. Retrieved 22 December 2019.
  17. ^ a b c d e f g Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. pp. 318, 321. ISBN 9780071481274. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ...
    Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.
  18. ^ a b c d Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Primary Care: Clinics in Office Practice. 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID 23668655. Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
    Physiologic and performance effects
     • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
     • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
     • Improved reaction time
     • Increased muscle strength and delayed muscle fatigue
     • Increased acceleration
     • Increased alertness and attention to task
  19. ^ a b c d e f g h i j k l m n o p "Adderall XR- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate capsule, extended release". DailyMed. Shire US Inc. 17 July 2019. Retrieved 22 December 2019.
  20. ^ a b Shoptaw SJ, Kao U, Ling W (January 2009). Shoptaw SJ, Ali R (eds.). "Treatment for amphetamine psychosis". Cochrane Database of Systematic Reviews. 2009 (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMC 7004251. PMID 19160215. A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
    About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
    Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
    psychotic symptoms of individuals with amphetamine psychosis may be due exclusively to heavy use of the drug or heavy use of the drug may exacerbate an underlying vulnerability to schizophrenia.
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    Figure 3: Treatment benefit by treatment type and outcome group
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    All patients with low CSF Hcrt-1 levels are considered as NT1 patients, even if they report no cataplexy (in about 10–20% of cases), and all patients with normal CSF Hcrt-1 levels (or without cataplexy when the lumbar puncture is not performed) as NT2 patients (Baumann et al., 2014). ...
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    Amphetamines are exceptionally wake-promoting, and at high doses also reduce cataplexy in narcoleptic patients, an effect best explained by its action on adrenergic and serotoninergic synapses. ...
    The D-isomer is more specific for DA transmission and is a better stimulant compound. Some effects on cataplexy (especially for the L-isomer), secondary to adrenergic effects, occur at higher doses. ...
    Numerous studies have shown that increased dopamine release is the main property explaining wake-promotion, although norepinephrine effects also contribute.
  57. ^ a b Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. pp. 456–457. ISBN 9780071827706. More recently, the lateral hypothalamus was also found to play a central role in arousal. Neurons in this region contain cell bodies that produce the orexin (also called hypocretin) peptides (Chapter 6). These neurons project widely throughout the brain and are involved in sleep, arousal, feeding, reward,aspects of emotion, and learning. In fact, orexin is thought to promote feeding primarily by promoting arousal. Mutations in orexin receptors are responsible for narcolepsy in a canine model, knockout of the orexin gene produces narcolepsy in mice, and humans with narcolepsy have low or absent levels of orexin peptides in cerebrospinal fluid (Chapter 13). Lateral hypothalamus neurons have reciprocal connections with neurons that produce monoamine neurotransmitters (Chapter 6).
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    Key cell populations of the ascending arousal pathway include cholinergic, noradrenergic, serotoninergic, dopaminergic, and histaminergic neurons located in the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT), locus coeruleus, dorsal and median raphe nucleus, and tuberomammillary nucleus (TMN), respectively. ...
    The mechanism of action of sympathomimetic alerting drugs (eg, dextro- and methamphetamine, methylphenidate) is direct or indirect stimulation of dopaminergic and noradrenergic nuclei, which in turn heightens the efficacy of the ventral periaqueductal grey area and locus coeruleus, both components of the secondary branch of the ascending arousal system. ...
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    Table 9.2 Dextroamphetamine formulations of stimulant medication
    Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
    Adderall [Peak:2–3 h] [Duration:5–7 h]
    Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
    Adderall XR [Peak:7–8 h] [Duration:12 h]
    Vyvanse [Peak:3–4 h] [Duration:12 h]
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    DOSAGE FORMS AND STRENGTHS
    Extended-release oral suspension contains 2.5 mg amphetamine base equivalents 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.
  116. ^ a b c Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
    Figure 2: Psychostimulant-induced signaling events
  117. ^ Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
  118. ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
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    Figure 4: Epigenetic basis of drug regulation of gene expression
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    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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  153. ^ a b c d Shoptaw SJ, Kao U, Heinzerling K, Ling W (April 2009). Shoptaw SJ (ed.). "Treatment for amphetamine withdrawal". Cochrane Database of Systematic Reviews. 2009 (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMC 7138250. PMID 19370579. The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) ...
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  163. ^ 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. S2CID 24589993. 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.
  164. ^ 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 3065181. 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).
  165. ^ 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.
  166. ^ 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
  167. ^ 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 4850498. 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.
  168. ^ Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (July 2011). "Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons". Front. Syst. Neurosci. 5: 56. doi:10.3389/fnsys.2011.00056. PMC 3131148. PMID 21772817. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
  169. ^ "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)
  170. ^ 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 4159050. 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
  171. ^ Vaughan RA, Foster JD (September 2013). "Mechanisms of dopamine transporter regulation in normal and disease states". Trends Pharmacol. Sci. 34 (9): 489–496. doi:10.1016/j.tips.2013.07.005. PMC 3831354. PMID 23968642. AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
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  182. ^ a b Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7th ed.). Philadelphia, US: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN 9781609133450. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
  183. ^ Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). Journal of Biological Chemistry. 249 (2): 454–458. doi:10.1016/S0021-9258(19)43051-2. PMID 4809526. Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
  184. ^ Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication". Journal of Pharmacology and Experimental Therapeutics. 288 (3): 1251–1260. PMID 10027866.
  185. ^ a b c Sjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate". British Journal of Pharmacology and Chemotherapy. 20 (2): 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC 1703637. PMID 13977820. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
  186. ^ a b Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation". Expert Opinion on Drug Metabolism & Toxicology. 9 (9): 1139–1153. doi:10.1517/17425255.2013.796929. PMID 23650932. S2CID 23738007. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
  187. ^ Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity". Circulation Research. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID 4713201. S2CID 28641000. The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
  188. ^ Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine". Neuropharmacology. 13 (12): 1187–1190. doi:10.1016/0028-3908(74)90069-0. PMID 4457764. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
    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.
  189. ^ Matsuda LA, Hanson GR, Gibb JW (December 1989). "Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems". Journal of Pharmacology and Experimental Therapeutics. 251 (3): 901–908. PMID 2600821. The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
  190. ^ a b c d e f ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK (July 2014). "Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics". Omics. 18 (7): 402–414. doi:10.1089/omi.2014.0018. PMC 4086029. PMID 24785449. The hundred trillion microbes and viruses residing in every human body, which outnumber human cells and contribute at least 100 times more genes than those encoded on the human genome (Ley et al., 2006), offer an immense accessory pool for inter-individual genetic variation that has been underestimated and largely unexplored (Savage, 1977; Medini et al., 2008; Minot et al., 2011; Wylie et al., 2012). ... Meanwhile, a wealth of literature has long been available about the biotransformation of xenobiotics, notably by gut bacteria (reviewed in Sousa et al., 2008; Rizkallah et al., 2010; Johnson et al., 2012; Haiser and Turnbaugh, 2013). This valuable information is predominantly about drug metabolism by unknown human-associated microbes; however, only a few cases of inter-individual microbiome variations have been documented [e.g., digoxin (Mathan et al., 1989) and acetaminophen (Clayton et al., 2009)].
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