Amphetamine

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This article is about mixtures of levoamphetamine and dextroamphetamine. For other uses, see Amphetamine (disambiguation).

Amphetamine
INN: Amfetamine
An image of the amphetamine compound
A 3d image of the D-amphetamine compound
Clinical data
Pronunciation/æmˈfɛtəmiːn/ ⓘ
Trade namesEvekeo, Adderall,[note 1] others
Other namesα-methylphenethylamine
AHFS/Drugs.comMonograph
MedlinePlusa616004
License data
DBH,[5][6] FMO3[5][7][8]
Legal status
Legal status
renal;
pH-dependent range: 1–75%[4]
Identifiers
  • (RS)-1-phenylpropan-2-amine
mmHg[23]
  • NC(C)Cc1ccccc1
  • InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3 checkY
  • Key:KWTSXDURSIMDCE-UHFFFAOYSA-N checkY
  (verify)

Amphetamine

alpha-methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s.[26] It exists as two enantiomers:[note 3] levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.[sources 1]

The first amphetamine pharmaceutical was

neurotransmitter systems.[sources 2]

At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as improved reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.[sources 3]

Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines,[note 5] which includes prominent substances such as bupropion, cathinone, MDMA, and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a positional isomer of amphetamine that differs only in the placement of the methyl group.[sources 4]

Uses

Medical

Amphetamine is used to treat

off-label for its past medical indications, particularly for depression and chronic pain.[1][37][51]
Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[52][53] but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth.[54][55][56] 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.[54][55][56]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[45][57][58] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[45][57] 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 6] 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.[45][58] 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.[57] 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.[45]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's

mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.[59] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[28][59][60] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[61] 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.[62][63] The Cochrane reviews[note 7] 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.[65][66] 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.[67]

Enhancing performance

Cognitive performance

In 2015, a

task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[28][72][73] 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.[28][73][74] 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.[75][76][77] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[28][73]

Physical performance

Amphetamine is used by some athletes for its psychological and

release of dopamine in the central nervous system.[80][81][82] 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.[81][83][84] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[29][80] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[30][80]

Recreational

Amphetamine, specifically the more dopaminergic

drug dependence, resulting in withdrawal symptoms when drug use stops.[87]

Contraindications

See also: Amphetamine § Drug interactions

According to the

Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine.[30][93] 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.[93] Amphetamine has also been shown to pass into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it.[30][93] Due to the potential for reversible growth impairments,[note 10] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[30]

Adverse effects

The adverse side effects of amphetamine are many and varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of adverse effects.[30][41] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[38][30] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious adverse drug effects than dosages used for therapeutic purposes.[41]

Physical

tics (a type of movement disorder), and weight loss.[sources 5] Dangerous physical side effects are rare at typical pharmaceutical doses.[41]

Amphetamine stimulates the

smooth muscle of the tract is relaxed.[41] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[1][41]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (

contraindicated in individuals with cardiovascular disease.[sources 7]

Psychological

At normal therapeutic doses, the most common psychological side effects of amphetamine include increased

Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[30][42][43] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[30][43][44] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[30]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[65][104] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[104][105]

Reinforcement disorders

Addiction

Addiction and dependence glossary[105][106][107]
  • 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 regulation – controlling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA
  • upregulation
    , activation, or promotion – increase the rate of gene transcription
  • downregulation
    , repression, or suppression – decrease 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
Note: colored text contains article links.
Nuclear membrane
Plasma membrane
Cav1.2
DARPP-32
PP2B
CREB
ΔFosB
c-Fos
HDAC1
The image above contains clickable links
This diagram depicts the signaling events in the
nuclear factor kappa B), it induces an addictive state.[111][112]

adjunct therapy with behavioral therapies for addiction.[119][121][sources 9]

Biomolecular mechanisms

Chronic use of amphetamine at excessive doses causes alterations in

substituted amphetamines, among others.[sources 10]

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.[118][117] 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.[118][132][133] These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[118][131]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[123] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[123] 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.[123] This suggests that medical use of amphetamine does not significantly affect gene regulation.[123]

Pharmacological treatments
Further information: Addiction § Research

As of December 2019, there is no effective

monotherapy for amphetamine addiction.[115]

A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in

prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.[135]

Behavioral treatments

A 2018 systematic review and

psychodynamic therapy, and other combination therapies involving these.[139]

Additionally, research on the

immunoreactivity in the striatum or other parts of the reward system.[120]

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
MSNs
Tooltip medium spiny neurons 		↑ ↑ ↑ ↑ ↑ ↑ [118]
Behavioral plasticity
Escalation of intake Yes Yes Yes [118]
Psychostimulant
cross-sensitization 		Yes Not applicable Yes Yes Attenuated Attenuated [118]
Psychostimulant
self-administration 		↑ ↑ ↓ ↓ ↓ [118]
Psychostimulant
conditioned place preference 		↑ ↑ ↓ ↑ ↓ ↑ [118]
Reinstatement of drug-seeking behavior
 ↑ ↑ ↓ ↓ [118]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation

in the nucleus accumbens 		↓ ↓ ↓ ↓ ↓ [118]
Sensitized dopamine response
in the nucleus accumbens 		No Yes No Yes [118]
Altered striatal dopamine signaling ↓
DRD3
 ↑
DRD3
 ↑
DRD3
 ↑
DRD2
 ↑
DRD2
 [118]
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 [118]
Changes in striatal opioid peptides ↑dynorphin
No change: enkephalin		 ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [118]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens ↓ ↑ ↑ [118]
Dendritic spine density in
the nucleus accumbens 		↓ ↑ ↑ [118]

Dependence and withdrawal

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.[141][142] According to a Cochrane review on

increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[143] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[143] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[1]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.

95% confidence).[note 15][145]

Overdose symptoms by system
System Minor or moderate overdose[30][41][93] Severe overdose[sources 12]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic

core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity.[148] Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability.[148]

Psychosis

See also: Stimulant psychosis

An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.[42][43] A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[42][153] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[42] Psychosis rarely arises from therapeutic use.[30][43][44]

Drug interactions

See also: Amphetamine § Contraindications, and Amphetamine § Pharmacokinetics

Many types of substances are known to

minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 16][158]

In general, there is no significant interaction when consuming amphetamine with food, but the

H2 antihistamines, which increase gastrointestinal pH (i.e., make it less acidic).[30]

Pharmacology

Pharmacodynamics

For a simpler and less technical explanation of amphetamine's mechanism of action, see Adderall § Mechanism of action.
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.
CAMKIIα-dependent pathway, in turn producing dopamine efflux.[163][164]

Amphetamine exerts its behavioral effects by altering the use of

euphoric and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum.[3]

Amphetamine has been identified as a potent

presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[39][40] Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[39][40] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.[39]

In addition to the neuronal monoamine

micromolar affinity.[177][178]

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or

glutamate,[163][168] which it affects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets.[sources 15] Amphetamine also activates seven human carbonic anhydrase enzymes, several of which are expressed in the human brain.[184]

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[185] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[41][185]

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the

G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.[161][162][187]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[159][160] Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2.[159][160] Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT.[39][159][160]

Norepinephrine

Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of

epinephrine.[48][60] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[39][159][186] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.[39][159]

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[39][60] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[39][159] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[177][178]

Other neurotransmitters, peptides, hormones, and enzymes

Human carbonic anhydrase
activation potency
Enzyme KA (
nM
Tooltip nanomolar) 		Sources
hCA4 94 [184]
hCA5A 810 [184][188]
hCA5B 2560 [184]
hCA7 910 [184][188]
hCA12 640 [184]
hCA13 24100 [184]
hCA14 9150 [184]

Acute amphetamine administration in humans increases

EAAT3, a glutamate reuptake transporter, in dopamine neurons.[163][168] Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2.[159] Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.[37][182][183]

In December 2017, the first study assessing the interaction between amphetamine and human

ocular activation exacerbating glaucoma.[189]

Pharmacokinetics

The oral

plasma proteins.[12] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[18]

The half-lives of amphetamine enantiomers differ and vary with urine pH.[4] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[4] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[18] highly alkaline urine will increase the half-lives up to 34 hours.[18] 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.[4] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[4] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[4] 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.[4] Following oral administration, amphetamine appears in urine within 3 hours.[18] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[18] 

Lisdexamfetamine is a

parenteral use does not enhance the subjective effects of lisdexamfetamine.[190][192] Because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential.[190][192]

sympathomimetics are 4-hydroxyamphetamine,[193] 4-hydroxynorephedrine,[194] and norephedrine.[195] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[4][196]
The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 16]
Graphic of several routes of amphetamine metabolism
Amphetamine
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;[13] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[4] The remaining 10–20% is excreted as the active metabolites.[4] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[198]

Pharmacomicrobiomics

The

pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile.[202][203][205] The field that studies these interactions is known as pharmacomicrobiomics.[202]

Similar to most

tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019.[205] This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.[205]

Related endogenous compounds

Further information on related compounds: Trace amine

Amphetamine has a very similar structure and function to the

aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.[48][207] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[48][207] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[39][206][207] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[48][207]

Chemistry

Racemic amphetamine
The image above contains clickable links
The
skeletal structures
of L-amph and D-amph
An image of amphetamine free base
A vial of the colorless amphetamine free base
An image of phenyl-2-nitropropene and amphetamine hydrochloride
Amphetamine hydrochloride (left bowl)
Phenyl-2-nitropropene (right cups)

Amphetamine is a

1,1'-bi-2-naphthol.[212]

Substituted derivatives

For a more comprehensive list, see Substituted amphetamine.

The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";

empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[5][50][213]

Synthesis

Further information on illicit amphetamine synthesis: History and culture of substituted amphetamines § Illegal synthesis

Since the first preparation was reported in 1887,

N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.[218][219]

A number of

benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.[221]

A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.

methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 4).[225]

A significant number of amphetamine syntheses feature a

nitro, imine, oxime, or other nitrogen-containing functional groups.[217] In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 5).[218][226] Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6).[218]

Amphetamine synthetic routes
Diagram of amphetamine synthesis by the Leuckart reaction
Method 1: Synthesis by the Leuckart reaction 
Diagram of a chiral resolution of racemic amphetamine and a stereoselective synthesis
Top: Chiral resolution of amphetamine 
Bottom: Stereoselective synthesis of amphetamine 
Diagram of amphetamine synthesis by Friedel–Crafts alkylation
Method 2: Synthesis by Friedel–Crafts alkylation 
Diagram of amphetamine via Ritter synthesis
Method 3: Ritter synthesis
Diagram of amphetamine synthesis via Hofmann and Curtius rearrangements
Method 4: Synthesis via Hofmann and Curtius rearrangements
Diagram of amphetamine synthesis by Knoevenagel condensation
Method 5: Synthesis by Knoevenagel condensation
Diagram of amphetamine synthesis from phenylacetone and ammonia
Method 6: Synthesis using phenylacetone and ammonia

Detection in body fluids

Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[sources 17] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[230] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[231] Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products that contain levomethamphetamine,[note 20] or illicitly obtained substituted amphetamines.[231][234][235] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[3][236][237] These compounds may produce positive results for amphetamine on drug tests.[236][237] Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for 2–4 days.[230]

For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay for amphetamine and methamphetamine may produce more false positives than liquid chromatography–tandem mass spectrometry.[234] Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine.[231] GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.[231] Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug.[231]

History, society, and culture

Main article: History and culture of substituted amphetamines
Global estimates of drug users in 2016
(in millions of users)[238]
Substance Best
estimate		 Low
estimate		 High
estimate
Amphetamine-
type stimulants
 34.16 13.42 55.24
Cannabis 192.15 165.76 234.06
Cocaine 18.20 13.87 22.85
Ecstasy 20.57 8.99 32.34
Opiates 19.38 13.80 26.15
Opioids 34.26 27.01 44.54

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist

low blood pressure, low libido, and chronic pain, among others.[51][31] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[215][241][242] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[215] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[243][244] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[245] musicians,[246] mathematicians,[247] and athletes.[29]

Amphetamine is still illegally synthesized today in

metric tons of illicit amphetamine were seized within EU member states;[250] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.[250] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[248]

Legal status

As a result of the

schedule II drug),[30] Australia (schedule 8),[257] Thailand (category 1 narcotic),[258] and United Kingdom (class B drug),[259] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[248][33]

Pharmaceutical products

Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, Adderall XR, Mydayis,[note 1] Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo, and Evekeo ODT. Of those, Evekeo (including Evekeo ODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose active moiety can be accurately referred to simply as "amphetamine".[1][37][97] Dextroamphetamine, marketed under the brand names Dexedrine and Zenzedi, is the only enantiopure amphetamine product currently available. A prodrug form of dextroamphetamine, lisdexamfetamine, is also available and is marketed under the brand name Vyvanse. As it is a prodrug, lisdexamfetamine is structurally different from dextroamphetamine, and is inactive until it metabolizes into dextroamphetamine.[38][191] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[3] Levoamphetamine was previously available as Cydril.[3] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[3][38][49] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively.[97][260][261] Some of the current brands and their generic equivalents are listed below.

Amphetamine pharmaceuticals
Brand
name 		United States
Adopted Name 		(D:L) ratio
 Dosage
form 		Marketing
start date 		Sources
Adderall – 3:1 (salts) tablet 1996 [3][38]
Adderall XR – 3:1 (salts) capsule 2001 [3][38]
Mydayis – 3:1 (salts) capsule 2017 [262][263]
Adzenys ER amphetamine 3:1 (base) suspension 2017 [264]
Adzenys XR-ODT amphetamine 3:1 (base) ODT 2016 [261][265]
Dyanavel XR amphetamine 3.2:1 (base) suspension 2015 [97][260]
Evekeo amphetamine sulfate 1:1 (salts) tablet 2012 [37][266]
Evekeo ODT amphetamine sulfate 1:1 (salts) ODT 2019 [267]
Dexedrine dextroamphetamine sulfate 1:0 (salts) capsule 1976 [3][38]
Zenzedi dextroamphetamine sulfate 1:0 (salts) tablet 2013 [38][268]
Vyvanse lisdexamfetamine dimesylate 1:0 (prodrug) capsule 2007 [3][191][269]
tablet
Xelstrym dextroamphetamine 1:0 (base) patch 2022 [270]
Amphetamine base in marketed amphetamine medications
drug formula molar mass
[note 21] 		amphetamine base
[note 22] 		amphetamine base
in equal doses 		doses with
equal base
content
[note 23]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[272][273] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
—
22.0 mg
—
30.0 mg
amphetamine sulfate[274] (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[272][273] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
—
25% amphetamine sulfate[274] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[275] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
—
25% amphetamine aspartate monohydrate[276] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[191]
 C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
—
8.9 mg
—
74.2 mg
amphetamine base suspension[97] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

Notes

  1. ^ a b Adderall and other mixed amphetamine salts products such as Mydayis are not racemic amphetamine – they are a mixture composed of equal parts racemate and dextroamphetamine.
    See
    Mixed amphetamine salts for more information about the mixture, and this section for information about the various mixtures of amphetamine enantiomers
    currently marketed.
  2. International Nonproprietary Name [INN]), β-phenylisopropylamine, thyramine, and speed.[24][12][25]
  3. INN) and D-amph or dexamfetamine (INN) respectively.[24]
  4. ^ The brand name Adderall is used throughout this article to refer to the amphetamine four-salt mixture it contains (dextroamphetamine sulfate 25%, dextroamphetamine saccharate 25%, amphetamine sulfate 25%, and amphetamine aspartate 25%). The nonproprietary name, which lists all four active constituent chemicals, is excessively lengthy.[38]
  5. ^ The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines,[5] the "amphetamines" class does not have a standardized definition in academic literature.[20] One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine.[20] The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds.[20]
    Due to confusion that may arise from use of the plural form, this article will only use the terms "amphetamine" and "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for its structural class.
  6. 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).[58]

    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.[58]
  7. ^ Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[64]
  8. ^ 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]
  9. ^ 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.[3]
  10. ^ 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.[45][57][96] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[96]
  11. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[124]
  12. ^ 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.
  13. D-serine or glycine) to open the ion channel.[138]
  14. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[115] other forms of magnesium were not mentioned.
  15. ^ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
  16. ^
    dopamine efflux.[154][155][156][157] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[156]
  17. ^ 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.[5][197] 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;[197][199] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[200][201]
  18. ^ There is substantial variation in microbiome composition and microbial concentrations by anatomical site.[202][203] 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.[202]
  19. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[27]
  20. INN and USAN of levomethamphetamine.[232][233]
  21. ^ For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator[271] and were within 0.01 g/mol of published pharmaceutical values.
  22. ^ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  23. ^ 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. G proteins & linked receptors
      (Text color) Transcription factors

Reference notes

  1. ^ [3][20][28][29][30][31][32][33][34][35][36][37]
  2. ^ [3][17][28][31][37][39][40]
  3. ^ [17][28][29][30][34][41][42][43][44][45][46][47]
  4. ^ [48][49][50]
  5. ^ [1][30][41][96][97][98]
  6. ^ [99][100][101][102]
  7. ^ [30][93][99][101]
  8. ^ [34][30][41][103]
  9. ^ a b [118][119][120][121][140]
  10. ^ [116][118][117][125][126]
  11. ^ [117][128][129][130]
  12. ^ [25][30][41][144][146]
  13. ^ [52][148][151][152]
  14. ^ a b [159][163][167][168][169][170][171]
  15. ^ [39][159][167][168][172][177]
  16. ^ a b [4][5][6][7][8][13][197][198]
  17. ^ [29][227][228][229]

References

  1. ^
    ISBN 9781108228749
    . Retrieved 5 August 2017.
  2. ISBN 9781455701506. Archived
    from the original on 10 January 2023. Retrieved 20 August 2019.
  3. ^
    PMID 23539642
    . The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation. ... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).
  4. ^ a b c d e f g h i j k l m n o p q r s "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013.
  5. ^
    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.
  6. ^
    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.
  7. ^
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    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
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  10. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 3 August 2023.
  11. ^
    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).
  12. ^ a b c d e f g h i Wishart DS, Djombou Feunang Y, Guo AC, Lo EJ, Marcu A, Grant JR, et al. "Amphetamine | DrugBank Online". DrugBank. 5.0.
  13. ^
    PMID 12191709
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  14. ^ "Pharmacology". amphetamine/dextroamphetamine. Medscape - WebMD. Retrieved 21 January 2016. Onset of action: 30–60 min
  15. ^
    ISBN 9781441913968
    .
    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]
  16. S2CID 31791162
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  17. ^ a b c d "Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet". DailyMed. Teva Pharmaceuticals USA, Inc. 8 November 2019. Retrieved 22 December 2019.
  18. ^ a b c d e f "Metabolism/Pharmacokinetics". Amphetamine. Hazardous Substances Data Bank. United States National Library of Medicine – Toxicology Data Network. Archived from the original on 2 October 2017. Retrieved 2 October 2017. Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine). ... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3 hours following oral administration. ... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine
  19. ^
    PMID 23065655
    .
  20. ^
    ISBN 9789057020810
    . Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane. ... In its broadest context, however, the term [amphetamines] can even embrace a large number of structurally and pharmacologically related substances.
  21. ^ "Density". Amphetamine. United States National Library of Medicine – National Center for Biotechnology Information. PubChem Compound Database. 5 November 2016. Retrieved 9 November 2016.
  22. ^ Amphetamine. American Chemical Society. CAS Common Chemistry. Retrieved 25 October 2022.
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    ISBN 9780967855097. Archived from the original
    on 17 March 2013. Retrieved 14 March 2014. One of a pair of molecular entities which are mirror images of each other and non-superposable.
  28. ^
    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.
  29. ^
    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
  30. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an "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.
  31. ^
    S2CID 24974454
    . However the firm happened to discover the drug, SKF first packaged it as an inhaler so as to exploit the base's volatility and, after sponsoring some trials by East Coast otolaryngological specialists, began to advertise the Benzedrine Inhaler as a decongestant in late 1933.
  32. ^ a b "Convention on psychotropic substances". United Nations Treaty Collection. United Nations. Archived from the original on 31 March 2016. Retrieved 11 November 2013.
  33. ^
    PMID 18174822
    . Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...

    Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.
  34. ^
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  36. ^ "Guidelines on the Use of International Nonproprietary Names (INNS) for Pharmaceutical Substances". World Health Organization. 1997. Archived from the original on 9 January 2015. Retrieved 1 December 2014. In principle, INNs are selected only for the active part of the molecule which is usually the base, acid or alcohol. In some cases, however, the active molecules need to be expanded for various reasons, such as formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection of INN decided to adopt a new policy for naming such molecules. In future, names for different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule. ... The latter are called modified INNs (INNMs).
  37. ^ a b c d e f g h i "Evekeo- amphetamine sulfate tablet". DailyMed. Arbor Pharmaceuticals, LLC. 14 August 2019. Retrieved 22 December 2019.
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  39. ^
    PMID 21073468
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  40. ^
    PMID 26644139
    . When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.
  41. ^
    ISBN 9780071624428
    .
  42. ^
    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.
  43. ^
    PMID 23216941
    . In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine ... Secondly, psychosis has been viewed as an adverse event, although rare, in children with ADHD who have been treated with amphetamine
  44. ^ a b c Greydanus D. "Stimulant Misuse: Strategies to Manage a Growing Problem" (PDF). American College Health Association (Review Article). ACHA Professional Development Program. p. 20. Archived from the original (PDF) on 3 November 2013. Retrieved 2 November 2013.
  45. ^
    S2CID 3449435
    . Several other studies,[97-101] including a meta-analytic review[98] and a retrospective study,[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
  46. ^
    ISBN 9780071827706
    . Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
  47. ^
    S2CID 71267668
    . When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
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    PMID 22502775
    . Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). ... Beyond (1R,2S)-ephedrine and (1S,2S)-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. ... For example, (S)-amphetamine (Figure 4b), a key ingredient in Adderall and Dexedrine, is used to treat attention deficit hyperactivity disorder (ADHD) [79]. ...
    [Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.
  51. ^
    PMID 20997404
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  52. ^
    S2CID 2873101
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  56. ^
    S2CID 25954331
    . Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
  57. ^
    ISBN 9781441913968
    . Ongoing research has provided answers to many of the parents' concerns, and has confirmed the effectiveness and safety of the long-term use of medication.
  58. ^
    PMID 25714373. The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.
    Figure 3: Treatment benefit by treatment type and outcome group
  59. ^
    ISBN 9780071481274
    .
  60. ^
    PMID 21596055
    .
  61. PMID 24082796
    . Only one paper53 examining outcomes beyond 36 months met the review criteria. ... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term.
  62. ISBN 9781441913968
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  63. ^ "Stimulants for Attention Deficit Hyperactivity Disorder". WebMD. Healthwise. 12 April 2010. Retrieved 12 November 2013.
  64. S2CID 29410060
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    PMID 30091808
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  66. PMID 26844979
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  67. PMID 29944175
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  68. ^
    PMID 25499957
    . The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
  69. S2CID 15788121
    . Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ... The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
  70. PMID 24749160
    . Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall.
  71. PMID 11337538
    .
  72. ISBN 9780071481274
    . Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
  73. ^
    PMID 24344115
    .
  74. ^ Twohey M (26 March 2006). "Pills become an addictive study aid". JS Online. Archived from the original on 15 August 2007. Retrieved 2 December 2007.
  75. PMID 16999660
    .
  76. PMID 25228824
    . misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. ... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students.
  77. S2CID 207580823
    . Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.
  78. ^ Bracken NM (January 2012). "National Study of Substance Use Trends Among NCAA College Student-Athletes" (PDF). NCAA Publications. National Collegiate Athletic Association. Archived (PDF) from the original on 9 October 2022. Retrieved 8 October 2013.
  79. PMID 18500382
    .
  80. ^
    PMID 21658550
    . In 1980, Chandler and Blair47 showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.
  81. ^
    S2CID 30392999
    . In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is 'off-limits' in a normal (placebo) situation.
  82. PMID 24198770
    . Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing.
  83. PMID 25852568
    . Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
  84. S2CID 22782401
    . This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the "safety switch" or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.
  85. ^ "Commonly Abused Prescription Drugs Chart". National Institute on Drug Abuse. Retrieved 7 May 2012.
  86. ^ "Stimulant ADHD Medications – Methylphenidate and Amphetamines". National Institute on Drug Abuse. Archived from the original on 2 May 2012. Retrieved 7 May 2012.
  87. ^ a b c d e "National Institute on Drug Abuse. 2009. Stimulant ADHD Medications – Methylphenidate and Amphetamines". National Institute on Drug Abuse. Retrieved 27 February 2013.
  88. ^
    SSRN 1339332. Archived from the original
    (PDF) on 13 July 2011.
  89. PMID 26109341
    . Rewards in operant conditioning are positive reinforcers. ... Operant behavior gives a good definition for rewards. Anything that makes an individual come back for more is a positive reinforcer and therefore a reward. Although it provides a good definition, positive reinforcement is only one of several reward functions. ... Rewards are attractive. They are motivating and make us exert an effort. ... Rewards induce approach behavior, also called appetitive or preparatory behavior, sexual behavior, and consummatory behavior. ... Thus any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward. ... Rewarding stimuli, objects, events, situations, and activities consist of several major components. First, rewards have basic sensory components (visual, auditory, somatosensory, gustatory, and olfactory) ... Second, rewards are salient and thus elicit attention, which are manifested as orienting responses. The salience of rewards derives from three principal factors, namely, their physical intensity and impact (physical salience), their novelty and surprise (novelty/surprise salience), and their general motivational impact shared with punishers (motivational salience). A separate form not included in this scheme, incentive salience, primarily addresses dopamine function in addiction and refers only to approach behavior (as opposed to learning) ... Third, rewards have a value component that determines the positively motivating effects of rewards and is not contained in, nor explained by, the sensory and attentional components. This component reflects behavioral preferences and thus is subjective and only partially determined by physical parameters. Only this component constitutes what we understand as a reward. It mediates the specific behavioral reinforcing, approach generating, and emotional effects of rewards that are crucial for the organism's survival and reproduction, whereas all other components are only supportive of these functions. ... Rewards can also be intrinsic to behavior. They contrast with extrinsic rewards that provide motivation for behavior and constitute the essence of operant behavior in laboratory tests. Intrinsic rewards are activities that are pleasurable on their own and are undertaken for their own sake, without being the means for getting extrinsic rewards. ... Intrinsic rewards are genuine rewards in their own right, as they induce learning, approach, and pleasure, like perfectioning, playing, and enjoying the piano. Although they can serve to condition higher order rewards, they are not conditioned, higher order rewards, as attaining their reward properties does not require pairing with an unconditioned reward. ... These emotions are also called liking (for pleasure) and wanting (for desire) in addiction research and strongly support the learning and approach generating functions of reward.
  90. ^ Canadian ADHD Practice Guidelines (PDF) (Fourth ed.). Canadian ADHD Resource Alliance. 2018. p. 67. Archived from the original (PDF) on 2 May 2023. Retrieved 2 May 2023.
  91. PMID 18596945
    .
  92. S2CID 12798818
    . statements on package inserts are not intended to limit medical practice. Rather they are intended to limit claims by pharmaceutical companies. ... the FDA asserts explicitly, and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations.
  93. ^ a b c d e f g h i j k Heedes G, Ailakis J. "Amphetamine (PIM 934)". INCHEM. International Programme on Chemical Safety. Retrieved 24 June 2014.
  94. PMID 15554766
    .
  95. PMID 24972362
    .
  96. ^
    PMID 18295156
    .
  97. ^ a b c d e f "Dyanavel XR- amphetamine suspension, extended release". DailyMed. Tris Pharma, Inc. 6 February 2019. Retrieved 22 December 2019. DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1 ... The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6 to 12 years) were: epistaxis, allergic rhinitis and upper abdominal pain. ...
    DOSAGE FORMS AND STRENGTHS
    Extended-release oral suspension contains 2.5 mg amphetamine base equivalents per mL.
  98. PMID 16784007
    . Retrieved 29 April 2015. Table 2. Decongestants Causing Rhinitis Medicamentosa
    – Nasal decongestants:
     – Sympathomimetic:
       • Amphetamine
  99. ^ a b "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults". United States Food and Drug Administration. 1 November 2011. Archived from the original on 25 August 2019. Retrieved 24 December 2019.
  100. PMID 22043968
    .
  101. ^ a b "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults". United States Food and Drug Administration. 12 December 2011. Archived from the original on 14 December 2019. Retrieved 24 December 2013.
  102. PMID 22161946
    .
  103. ^ O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012.
  104. ^
    PMID 19111278
    . This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.
  105. ^
    ISBN 9780071481274
    .
  106. ^
    PMID 24459410
    . Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
  107. PMID 26816013
    . Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
    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.
  108. ^
    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
  109. 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.
  110. ^ 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.
  111. ^
    PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
    Figure 4: Epigenetic basis of drug regulation of gene expression
  112. ^
    PMID 23430970
    . The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
  113. PMID 18640924
    . Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
  114. ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
  115. ^
    PMID 18557129.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link
    )
  116. ^
    S2CID 19157711
    . ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
  117. ^
    PMID 21989194
    . ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. ... ΔFosB serves as one of the master control proteins governing this structural plasticity.
  118. ^
    PMID 21459101
    . Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).
  119. ^
    PMID 23806439
    . These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.
  120. ^
    PMID 26182835
    . Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.
  121. ^
    PMID 25397661
    . The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
  122. S2CID 15139406. Archived from the original
    (PDF) on 19 September 2018.
  123. ^
    PMID 23085425
    .
  124. ISBN 9780071481274
    .
  125. ^ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
  126. PMID 19202072
    .
  127. ^
    PMID 23643695
    .
  128. ^
    PMID 23020045
    .
  129. PMID 23475113
    .
  130. S2CID 11513288
    .
  131. ^
    PMID 22641964
    . It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
  132. PMID 23426671
    .
  133. S2CID 25317397
    .
  134. ISBN 9780071827706
    . Pharmacologic treatment for psychostimulant addiction is generally unsatisfactory. As previously discussed, cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria, anhedonia, and an intense desire to reinitiate drug use.
  135. ^
    S2CID 198136436
    .
  136. PMID 24716825
    . Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.
  137. ^
    PMID 26092759
    . Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction.
  138. ^
    ISBN 9780071481274
    .
  139. ^
    PMID 30586362
    .
  140. ^
    PMID 26903885
    . Physical Exercise
    There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.
  141. PMID 23996457
    .
  142. ^ "Amphetamines: Drug Use and Abuse". Merck Manual Home Edition. Merck. February 2003. Archived from the original on 17 February 2007. Retrieved 28 February 2007.
  143. ^
    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) ...
  144. ^
    S2CID 40931380
    . Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.
  145. PMID 25530442
    . Amphetamine use disorders ... 3,788 (3,425–4,145)
  146. ISBN 9780071668330
    .
  147. S2CID 7582744
    .
  148. ^
    PMID 27626044
    . Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40 °C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. ... The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. ... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.
  149. ^ "Amphetamine". United States National Library of Medicine – Toxicology Data Network. Hazardous Substances Data Bank. Archived from the original on 2 October 2017. Retrieved 2 October 2017. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.
  150. ISBN 9780071481274
    . Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
  151. S2CID 21892355
    .
  152. PMID 18596830
    .
  153. ISBN 9780195030570
    .
  154. S2CID 58557130
    . Although the monoamine transport cycle has been resolved in considerable detail, kinetic knowledge on the molecular actions of synthetic allosteric modulators is still scarce. Fortunately, the DAT catalytic cycle is allosterically modulated by an endogenous ligand (namely, Zn2+; Norregaard et al., 1998). It is worth consulting Zn2+ as an instructive example, because its action on the DAT catalytic cycle has been deciphered to a large extent ... Zn+ binding stabilizes the outward-facing conformation of DAT ... This potentiates both the forward-transport mode (i.e., DA uptake; Li et al., 2015) and the substrate-exchange mode (i.e., amphetamine-induced DA release; Meinild et al., 2004; Li et al., 2015). Importantly, the potentiating effect on substrate uptake is only evident when internal Na+ concentrations are low ... If internal Na+ concentrations rise during the experiment, the substrate-exchange mode dominates and the net effect of Zn2+ on uptake is inhibitory. Conversely, Zn2+ accelerates amphetamine-induced substrate release via DAT. ... t is important to emphasize that Zn2+ has been shown to reduce dopamine uptake under conditions that favor intracellular Na+ accumulation
    —Fig. 3. Functional selectivity by conformational selection.
  155. 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.
  156. ^
    S2CID 10521850
    . 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). ... 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. ... Thus, when Zn2+ is co-released with glutamate, it may greatly augment the efflux of dopamine.
  157. S2CID 10317113
    . Coadministration of Zn(2+) and AMPH consistently reduced WT-hDAT trafficking
  158. PMID 23021477
    . 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
  159. ^
    PMID 21272013
    . VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). ... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.
  160. ^
    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.
  161. ^
    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.
  162. ^ a b "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)
  163. ^
    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
  164. ^
    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].
  165. ^ a b Maguire JJ, Davenport AP (2 December 2014). "TA1 receptor". IUPHAR database. International Union of Basic and Clinical Pharmacology. Archived from the original on 29 June 2015. Retrieved 8 December 2014.
  166. PMID 11459929
    .
  167. ^ a b "SLC18 family of vesicular amine transporters". IUPHAR database. International Union of Basic and Clinical Pharmacology. Retrieved 13 November 2015.
  168. ^ a b c d "SLC1A1 solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 [ Homo sapiens (human) ]". NCBI Gene. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 11 November 2014. Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. ... internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission.
  169. PMID 20402963
    .
  170. S2CID 31465243
    .
  171. PMID 13677912
    .
  172. ^
    S2CID 14212763
    . The physiological importance of CART was further substantiated in numerous human studies demonstrating a role of CART in both feeding and psychostimulant addiction. ... Colocalization studies also support a role for CART in the actions of psychostimulants. ... CART and DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB.
  173. S2CID 25134612
    . Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. ... The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART
  174. ^
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    . Several studies on CART (cocaine- and amphetamine-regulated transcript)-peptide-induced cell signalling have demonstrated that CART peptides activate at least three signalling mechanisms. First, CART 55–102 inhibited voltage-gated L-type Ca2+ channels ...
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    . More recently, Colasanti and colleagues reported that a pharmacologically induced elevation in endogenous opioid release reduced [11C]carfentanil binding in several regions of the human brain, including the basal ganglia, frontal cortex, and thalamus (Colasanti et al. 2012). Oral administration of d-amphetamine, 0.5 mg/kg, 3 h before [11C]carfentanil injection, reduced BPND values by 2–10%. The results were confirmed in another group of subjects (Mick et al. 2014). However, Guterstam and colleagues observed no change in [11C]carfentanil binding when d-amphetamine, 0.3 mg/kg, was administered intravenously directly before injection of [11C]carfentanil (Guterstam et al. 2013). It has been hypothesized that this discrepancy may be related to delayed increases in extracellular opioid peptide concentrations following amphetamine-evoked monoamine release (Colasanti et al. 2012; Mick et al. 2014).
  180. ^
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    . Similar MOR activation patterns were reported during positive mood induced by an amusing video clip (Koepp et al., 2009) and following amphetamine administration in humans (Colasanti et al., 2012).
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    . Findings from several prior investigations have shown that plasma levels of glucocorticoids and ACTH are increased by acute administration of AMPH in both rodents and humans
  184. ^
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    . Here, we report the first such study, showing that amphetamine, methamphetamine, phentermine, mephentermine, and chlorphenteramine, potently activate several CA isoforms, some of which are highly abundant in the brain, where they play important functions connected to cognition and memory, among others26,27. ... We investigated psychotropic amines based on the phenethylamine scaffold, such as amphetamine 5, methamphetamine 6, phentermine 7, mephentermine 8, and the structurally diverse chlorphenteramine 9, for their activating effects on 11 CA isoforms of human origin ... The widespread hCA I and II, the secreted hCA VI, as well as the cytosolic hCA XIII and membrane-bound hCA IX and XIV were poorly activated by these amines, whereas the extracellular hCA IV, the mitochondrial enzymes hCA VA/VB, the cytosolic hCA VII, and the transmembrane isoform hCA XII were potently activated. Some of these enzymes (hCA VII, VA, VB, XII) are abundant in the brain, raising the possibility that some of the cognitive effects of such psychoactive substances might be related to the activation of these enzymes. ... CAAs started to be considered only recently for possible pharmacologic applications in memory/cognition therapy27. This work may bring new lights on the intricate relationship between CA activation by this type of compounds and the multitude of pharmacologic actions that they can elicit.
    —Table 1: CA activation of isoforms hCA I, II, IV, VII, and XIII [5: amphetamine]
    —Table 2: CA activation of isoforms hCA VA, VB, VI, IX, XII, and XIV [5: amphetamine]
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    . CARBONIC ANHYDRASE INHIBITORS (CAIs). The design and development of CAIs represent the most prolific area within the CA research field. Since the introduction of CAIs in the clinical use in the 40', they still are the first choice for the treatment of edema [9], altitude sickness [9], glaucoma [7] and epilepsy [31]. ... CARBONIC ANHYDRASE ACTIVATORS (CAAs) ... The emerging class of CAAs has recently gained attraction as the enhancement of the kinetic properties in hCAs expressed in the CNS were proved in animal models to be beneficial for the treatment of both cognitive and memory impairments. Thus, CAAs have enormous potentiality in medicinal chemistry to be developed for the treatment of symptoms associated to aging, trauma or deterioration of the CNS tissues.
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    . Inactive lisdexamfetamine is completely (>98%) converted to its active metabolite D-amphetamine in the circulation (Pennick, 2010; Sharman and Pennick, 2014). When lisdexamfetamine is misused intranasally or intravenously, the pharmacokinetics are similar to oral use (Jasinski and Krishnan, 2009b; Ermer et al., 2011), and the subjective effects are not enhanced by parenteral administration in contrast to D-amphetamine (Lile et al., 2011) thus reducing the risk of parenteral misuse of lisdexamfetamine compared with D-amphetamine. Intravenous lisdexamfetamine use also produced significantly lower increases in "drug liking" and "stimulant effects" compared with D-amphetamine in intravenous substance users (Jasinski and Krishnan, 2009a).
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    . 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.
  198. ^
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    . 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.
  199. 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).
  200. 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.
  201. 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.
  202. ^
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    . 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)].
  203. ^
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    . The composition of the microbiome varies by anatomical site (Figure 1). The primary determinant of community composition is anatomical location: interpersonal variation is substantial23,24 and is higher than the temporal variability seen at most sites in a single individual25. ... How does the microbiome affect the pharmacology of medications? Can we "micro-type" people to improve pharmacokinetics and/or reduce toxicity? Can we manipulate the microbiome to improve pharmacokinetic stability?
  204. PMID 25774294
    . Some metagenomic studies have suggested that less than 10% of the cells that comprise our bodies are Homo sapiens cells. The remaining 90% are bacterial cells. The description of this so-called human microbiome is of great interest and importance for several reasons. For one, it helps us redefine what a biological individual is. We suggest that a human individual is now best described as a super-individual in which a large number of different species (including Homo sapiens) coexist.
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External links

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