Amphetamine

Amphetamine[note 2]
(contracted from alpha-
methylphenethylamine) is a strong central nervous system (CNS) Amphetamine
stimulant that is used in the treatment of attention deficit INN: Amfetamine
hyperactivity disorder (ADHD), narcolepsy, and obesity.
Amphetamine was discovered in 1887 and 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 Benzedrine, a brand

which was used to treat a variety of conditions. Currently,
pharmaceutical amphetamine is prescribed as racemic
amphetamine, Adderall,[note 4] dextroamphetamine, or the inactive
prodrug lisdexamfetamine. Amphetamine increases monoamine
and excitatory neurotransmission in the brain, with its most
pronounced effects targeting the norepinephrine and dopamine
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 N06BA01 (WHO (https://w
compound of amphetamine, while N-methylphenethylamine is a ww.whocc.no/atc_ddd_inde
positional isomer of amphetamine that differs only in the placement x/?code=N06BA01))
of the methyl group.[sources 4] N06BA02 (WHO (https://w
ww.whocc.no/atc_ddd_inde
x/?code=N06BA02))
Contents N06BA12 (WHO (https://w
ww.whocc.no/atc_ddd_inde
Uses x/?code=N06BA12))

Medical Legal status

Legal status AU: S8 (Controlled drug)
Enhancing performance
BR: Class A3 (Psychoactive
Contraindications Adverse effects
drugs)
Physical Psychological CA: Schedule I
Reinforcement disorders
DE: Anlage III (Special
prescription form required)
Overdose
NZ: Class B
Toxicity Psychosis
UK: Class B
Drug interactions US: Schedule II
UN: Psychotropic
Pharmacology Pharmacodynamics Pharmacokinetics Pharmacomicrobiomics
Schedule II
Related endogenous compounds
Pharmacokinetic data
Chemistry Bioavailability Oral: 75–100%[3]
Substituted derivatives Synthesis Protein binding 20%[4]
Detection in body fluids Metabolism CYP2D6,[5] DBH,[13][14]
FMO3[13][15][16]
History, society, and culture Legal status Pharmaceutical products Metabolites 4-hydroxyamphetamine,
4-hydroxynorephedrine,
Notes Reference notes References External links
4-hydroxyphenylacetone,
benzoic acid, hippuric acid,
norephedrine,
phenylacetone[5][6]
Onset of action IR dosing: 30–60 minutes[7]
XR dosing: 1.5–2 hours[8][9]
Elimination D-amph: 9–11 hours[5][10]
half-life
L-amph: 11–14 hours[5][10]
pH-dependent:
7–34 hours[11]
Duration of IR dosing: 3–6 hours[1][8][12]
action
XR dosing:
Uses 8–12 hours[1][8][12]
Excretion Primarily renal;
pH-dependent
Medical range: 1–75%[5]
Identifiers
Amphetamine is used to treat attention deficit hyperactivity IUPAC name
disorder (ADHD), narcolepsy (a sleep disorder), and obesity, and is (RS)-1-phenylpropan-2-amine
sometimes prescribed off-label for its past medical indications,
particularly for depression and chronic pain.[1][33][47] Long-term CAS Number 300-62-9 (https://commonc
amphetamine exposure at sufficiently high doses in some animal hemistry.cas.org/detail?cas
species is known to produce abnormal dopamine system _rn=300-62-9)
development or nerve damage,[48][49] but in humans with ADHD, PubChem CID 3007 (https://pubchem.ncbi.
pharmaceutical amphetamines at therapeutic dosages appear to
nlm.nih.gov/compound/300
improve brain development and nerve growth.[50][51][52] Reviews of
7)
magnetic resonance imaging (MRI) studies suggest that long-term
treatment with amphetamine decreases abnormalities in brain IUPHAR/BPS 4804 (http://www.guidetoph
structure and function found in subjects with ADHD, and improves armacology.org/GRAC/Liga
function in several parts of the brain, such as the right caudate ndDisplayForward?ligandId
nucleus of the basal ganglia.[50][51][52] =4804)

Reviews of clinical stimulant research have established the safety DrugBank DB00182 (https://www.drug
and effectiveness of long-term continuous amphetamine use for the bank.ca/drugs/DB00182)
treatment of ADHD.[41][53][54] Randomized controlled trials of ChemSpider 13852819 (https://www.che
continuous stimulant therapy for the treatment of ADHD spanning
mspider.com/Chemical-Stru
2 years have demonstrated treatment effectiveness and safety.[41]
cture.13852819.html)
[53]
Two reviews have indicated that long-term continuous
UNII CK833KGX7E (https://preci
stimulant therapy for ADHD is effective for reducing the core
symptoms of ADHD (i.e., hyperactivity, inattention, and sion.fda.gov/uniisearch/srs/
impulsivity), enhancing quality of life and academic achievement, unii/CK833KGX7E)
and producing improvements in a large number of functional KEGG D07445 (https://www.kegg.j
outcomes[note 6] across 9 categories of outcomes related to p/entry/D07445)
academics, antisocial behavior, driving, non-medicinal drug use,
obesity, occupation, self- esteem, service use (i.e., academic, ChEBI CHEBI:2679 (https://www.e
occupational, health, financial, and legal services), and social bi.ac.uk/chebi/searchId.do?
function.[41][54] One review highlighted a nine-month randomized chebiId=CHEBI:2679)
controlled trial of amphetamine treatment for ADHD in children ChEMBL ChEMBL405 (https://www.e
that found an average increase of 4.5 IQ points, continued
bi.ac.uk/chembldb/index.ph
increases in attention, and
p/compound/inspect/ChEM
continued decreases in disruptive behaviors and hyperactivity. [53]
Another review indicated that, based upon the longest follow-up BL405)
studies conducted to date, lifetime stimulant therapy that begins NIAID ChemDB 018564 (https://chemdb.niai
during childhood is continuously effective for controlling ADHD d.nih.gov/CompoundDetails
symptoms and reduces the risk of developing a substance use
.aspx?AIDSNO=018564)
disorder as an adult.[41] CompTox DTXSID4022600 (https://co
Dashboard (EPA)
Current models of ADHD suggest that it is associated with mptox.epa.gov/dashboard/c
functional impairments in some of the brain's neurotransmitter hemical/details/DTXSID402
systems;[55] these functional impairments involve impaired 2600)
dopamine neurotransmission in the mesocorticolimbic projection ECHA InfoCard 100.005.543 (https://echa.e
and norepinephrine neurotransmission in the noradrenergic
uropa.eu/substance-inform
projections from the locus coeruleus to the prefrontal cortex.[55]
ation/-/substanceinfo/100.0
Psychostimulants like methylphenidate and amphetamine are
effective in treating ADHD because they increase neurotransmitter 05.543)

activity in these systems.[24][55][56] Approximately 80% of those Chemical and physical data
who use these stimulants see improvements in ADHD Formula C9H13N
symptoms.[57] Molar mass 135.210 g·mol−1
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.[58][59] The Cochrane reviews[note 7] on the treatment
of ADHD in children, adolescents, and adults with pharmaceutical 3D model Interactive image (https://ch
amphetamines stated that short-term studies have demonstrated (JSmol)
emapps.stolaf.edu/jmol/jmo
that these drugs decrease the severity of symptoms, but they have l.php?model=NC%28C%29
higher discontinuation rates than non-stimulant medications due to
Cc1ccccc1)
their adverse side effects.[61][62] A Cochrane review on the
treatment of ADHD in children with tic disorders such as Tourette
Chirality Racemic mixture[17]
syndrome
indicated that stimulants in general do not make tics worse, but Density .936 g/cm3 at 25 °C[18]
high doses of dextroamphetamine could exacerbate tics in some Melting point 146 °C (295 °F) [19]
individuals.[63] Boiling point 203 °C (397 °F) at
760 mmHg[20]
Enhancing performance SMILES
NC(C)Cc1ccccc1
InChI
Cognitive performance
InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-
6,8H,7,10H2,1H3
In 2015, a systematic review and a meta-analysis of high quality
clinical trials found that, when used at low (therapeutic) doses, Key:KWTSXDURSIMDCE-UHFFFAOYSA-N
amphetamine produces modest yet unambiguous improvements in (verify)
cognition, including working memory, long-term episodic memory,
inhibitory control, and some aspects of attention, in normal healthy
adults;[64][65] these cognition-enhancing effects of amphetamine are known to be partially mediated through the
indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex.[24][64] A
systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn
leading to improved recall of information.[66] Therapeutic doses of amphetamine also enhance cortical network
efficiency, an effect which mediates improvements in working memory in all individuals.[24][67] Amphetamine
and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal
(wakefulness), in turn promoting goal-directed behavior. [24][68][69] 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.
[24][69][70]
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.[71][72][73] However, high amphetamine doses that are above the therapeutic range can interfere with
working memory and other aspects of cognitive control.[24][69]

Physical performance

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as
increased endurance and alertness;[25][37] however, non-medical amphetamine use is prohibited at sporting
events that are regulated by collegiate, national, and international anti-doping agencies. [74][75] In healthy people
at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic
performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction
time.[25][76][77] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and
release of dopamine in the central nervous system. [76][77][78] 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.[77][79][80] At
therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; [25][76] however, at
much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle
breakdown and elevated body temperature.[26][76]

Contraindications
According to the International Programme on Chemical Safety (IPCS) and the United States Food and Drug
Administration (USFDA),[note 8] amphetamine is contraindicated in people with a history of drug abuse,[note 9]
cardiovascular disease, severe agitation, or severe anxiety.[33][26][82] It is also contraindicated in individuals with
advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism
(excessive production of thyroid hormone), or moderate to severe hypertension.[33][26][82] These agencies
indicate that people who have experienced allergic reactions to other stimulants or who are taking monoamine
oxidase inhibitors (MAOIs) should not take amphetamine, [33][26][82] although safe concurrent use of
amphetamine and monoamine oxidase inhibitors has been documented. [83][84] These agencies also state that
anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania,
psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their
symptoms while taking amphetamine.[26][82] 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. [82] Amphetamine has also been shown to pass
into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it. [26][82] 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.[26]

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.[26][37] Amphetamine products such
as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term
therapeutic use.[34][26] 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. [37]

Physical

Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's
phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate).[26][37][85] Sexual
side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[26]
Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea.[1][26][86] Other
potential physical side effects include appetite loss, blurred vision, dry mouth, excessive grinding of the teeth,
nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold,
tics (a type of movement disorder), and weight loss.[sources 5] Dangerous physical side effects are rare at typical
pharmaceutical doses.[37]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths. [37] In a normal
person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it
may be evident.[37] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which
controls urination, which can result in difficulty urinating.[37] This effect can be useful in treating bed wetting and
loss of bladder control.[37] The effects of amphetamine on the gastrointestinal tract are unpredictable. [37] If
intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves
through the digestive system); [37] however, amphetamine may increase motility when the smooth muscle of the
tract is relaxed.[37] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of
opioids.[1][37]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no
association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the
medical use of amphetamine or other ADHD stimulants.[sources 6] However, amphetamine pharmaceuticals are
contraindicated in individuals with cardiovascular disease.[sources 7]
 Psychological

At normal therapeutic doses, the most common psychological side effects of amphetamine include increased
alertness, apprehension, concentration, initiative, self-confidence and sociability, mood swings (elated mood
followed by mildly depressed mood), insomnia or wakefulness, and decreased sense of fatigue.[26][37] Less
common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors,
and restlessness;[sources 8] these effects depend on the user's personality and current mental state. [37]
Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[26][38][39] Although very rare,
this psychosis can also occur at therapeutic doses during long-term therapy.[26][39][40] According to the USFDA,
"there is no systematic evidence" that stimulants produce aggressive behavior or hostility. [26]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic
doses,[61][93] meaning that individuals acquire a preference for spending time in places where they have
previously used amphetamine.[93][94]

Reinforcement disorders

Addiction

Addiction is a serious risk with heavy recreational amphetamine Addiction and dependence
use, but is glossary[94][95][96][97]
[41][42][43]
unlikely to occur from long-term medical use at therapeutic doses;
in fact, lifetime stimulant therapy for ADHD that begins during childhood
[41]
reduces
addiction the risk of developing
– a biopsychosocial substance
disorder characterized use disorders
by persistent as an
use of drugs adult.alcohol)
(including despite substantial harm and adverse conseque
Pathological overactivation of the mesolimbic pathway, a dopamine pathway
addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in la
that connects the ventral tegmental area to the nucleus accumbens, plays a
dependence – an adaptive
central role state associated
in amphetamine with a [104][105]
addiction. withdrawal Individuals
syndrome upon cessation
who of repeated exposure to a stimulus (e.g., drug intake)
frequently
self-administer high doses of amphetamine have a high risk of developing an administration at a given dose
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated
amphetamine addiction, since chronic use at high doses gradually increases
drugthe
withdrawal
level of– symptoms
accumbalthat occur, upon
ΔFosB cessation of repeated
a "molecular switch" drug
anduse "master control
[95][106][107]
protein"
physical for addiction.
dependence – dependence that involves Once nucleus accumbens ΔFosB is
sufficiently overexpressed, it begins to increase the severity of addictive
behavior (i.e., compulsive drug-seeking) with further increases in its
expression.[106][108] While there are currently no effective drugs for treating
amphetamine addiction, regularly engaging in sustained aerobic exercise
appears to reduce the risk of developing such an addiction.[109][110] Sustained
aerobic exercise on a regular basis also appears to be an effective treatment
for amphetamine addiction;[sources 9] exercise therapy improves clinical
treatment outcomes and may be used as an adjunct therapy with behavioral
therapies for addiction.[109][111]

Biomolecular mechanisms

Chronic use of amphetamine at excessive doses causes alterations in gene

expression in the mesocorticolimbic projection, which arise through
transcriptional and epigenetic mechanisms.[107][112][113] The most important
transcription factors[note 11] that produce these alterations are Delta FBJ
murine osteosarcoma viral oncogene homolog B (ΔFosB), cAMP response
element binding protein (CREB), and nuclear factor-kappa B (NF-κB).[107]
ΔFosB is the most significant biomolecular mechanism in addiction because
ΔFosB overexpression (i.e., an abnormally high level of gene expression which
produces a pronounced
persistent gene-related
physical–somatic withdrawalphenotype) in the
symptoms (e.g., D1-type
fatigue medium
and delirium spiny
tremens)
[note 12]
neurons in the nucleus accumbens is necessary and sufficient for many
psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
of the neural adaptations and regulates multiple behavioral effects (e.g.,
reward sensitization
reinforcing stimuli –and escalating
stimuli that increasedrug self-administration)
the probability involved
of repeating behaviors in with them
paired
[95][106][107]
addiction. Oncethat
rewarding stimuli – stimuli ΔFosB is sufficiently
the brain interprets asoverexpressed, it induces
intrinsically positive an or as something to approach
and desirable
addictive state that becomes increasingly more severe with further increases
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
in ΔFosB expression.[95][106] It has been implicated in addictions to alcohol,
cannabinoids,
substance use cocaine,
disordermethylphenidate,
– a condition in whichnicotine,
the use of opioids,
substancesphencyclidine,
leads to clinically and functionally significant impairment or distress
[sources 10]
propofol, and substituted amphetamines, among others.
tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme,

both oppose the function of ΔFosB and inhibit increases in its expression. [95]
[107][117]
Sufficiently overexpressing ΔJunD in the nucleus accumbens with
viral vectors can completely block many of the neural and behavioral
alterations seen in chronic drug abuse (i.e., the alterations mediated by
ΔFosB).[107] Similarly, accumbal G9a hyperexpression results in markedly
increased histone 3 lysine residue 9 dimethylation (H3K9me2) and blocks the
induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug
use,[sources 11] which occurs via H3K9me2-mediated repression of transcription
factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB
transcriptional targets (e.g., CDK5).[107][117][118] ΔFosB also plays an important
role in regulating behavioral responses to natural rewards, such as palatable
food, sex, and exercise.[108][107][121] Since both natural rewards and addictive
drugs induce the expression of ΔFosB (i.e., they cause the brain to produce
more of it), chronic acquisition of these rewards can result in a similar
pathological state of addiction.[108][107] 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.[108][122][123] These sexual
addictions are associated with a dopamine dysregulation syndrome which
occurs in some patients taking dopaminergic drugs.[108][121]
Transcription factor glossary
The effects of amphetamine on gene regulation are both dose- and route-
dependent.[113] Most of the research on gene regulation and addiction is
gene expression – the process by which information from a gene is used in the synthesis of a functional gene product such as a protein
based upon animal studies with intravenous amphetamine administration at
high doses.–[113]
verytranscription the process of making
The few messenger
studies that haveRNA used
(mRNA) from a DNA(weight-
equivalent template by RNA polymerase
adjusted) human therapeutic doses and oral administration show that
transcription factor – a protein that binds to DNA and regulates gene expression these
by promoting or suppressing transcription
[113]
changes, if they occur, are relatively minor. This suggests that medical use
transcriptional regulation – controlling the rate of gene transcription for example by helping or hindering RNA
of amphetamine does not significantly affect gene regulation. [113]

Pharmacological treatments

As of December 2019, there is no effective pharmacotherapy for amphetamine

addiction.[124][125][126] Reviews from 2015 and 2016 indicated that TAAR1-
selective agonists have significant therapeutic potential as a treatment for
psychostimulant addictions;[36][127] however, as of February 2016, the only
compounds which are known to function as TAAR1-selective agonists are
experimental drugs.[36][127] Amphetamine addiction is largely mediated
through increased activation of dopamine receptors and co-localized NMDA
receptors[note 13] in the nucleus accumbens; [105] magnesium ions inhibit
NMDA receptors by blocking the receptor calcium channel.[105][128] One
review suggested that, based upon animal testing, pathological (addiction-
 polymerase binding
inducing) psychostimulant usetosignificantly
DNA reduces the level of intracellular
[105]
magnesium throughout the brain. Supplemental magnesium[note 14]
upregulation, activation, or promotion
treatment has been shown to reduce amphetamine – increase the rate of gene transcription
self-administration (i.e.,
doses given to oneself) in humans, but it is not an effective
downregulation, repression, or suppression – decrease monotherapy for transcription
the rate of gene
[105]
amphetamine addiction.
coactivator – a protein (or a small molecule) that works with transcription factors to increase the rate of gene transcription
A systematic corepressor
review and –meta-analysis frommolecule)
a protein (or a small 2019 assessed the
that works efficacy
with of 17factors to decrease the rate of gene transcription
transcription
different pharmacotherapies used in randomized controlled trials (RCTs) for
response element – a specific sequence of DNA that a transcription factor binds to
amphetamine and methamphetamine addiction; [125] it found only low-
strength evidence that methylphenidate might reduce amphetamine or
methamphetamine self-administration.[125] There was low- to moderate-
strength evidence of no benefit for most of the other medications used in
RCTs, which included antidepressants (bupropion, mirtazapine, sertraline),
antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen,
gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa,
riluzole, atomoxetine, dextroamphetamine, and modafinil.[125]

Behavioral treatments

A 2018 systematic review and network meta-analysis of 50 trials involving 12

different psychosocial
interventions for
amphetamine,
methamphetamine, or
cocaine addiction found
that combination therapy
with both contingency
management and
community
reinforcement approach
had the highest efficacy
(i.e., abstinence rate) and
acceptability (i.e., lowest
dropout rate).[129] Other
treatment
modalities examined in
the analysis included
monotherapy
with contingency
management or
community
reinforcement approach,
cognitive behavioral
therapy, 12-step
programs, non-
contingent reward-based
therapies,
psychodynamic therapy,
and other combination
therapies involving
these.[129]
Additionally, research on
the neurobiological Signaling cascade in the nucleus accumbens that results in amphetamine addiction
effects of physical Note: colored text
exercise suggests that contains article links.
[Color legend 1]
daily aerobic exercise,
Cav1.2
especially endurance
exercise (e.g., marathon
running), prevents the NMDAR CaMKII
development of drug CaM
addiction and is
an effective PP2B PP1 CREB
adjunct therapy (i.e., a
AMPAR
supplemental
treatment)
DARPP-32
for amphetamine DRD1 ΔFosB
c-Fos
[sources 9] Gs JunD
addiction.
Exercise leads to better DRD5 AC SIRT1
treatment PKA
HDAC1
outcomes
when used as an adjunct DRD2 Gi/o Nuclear pore
cAMP
treatment, particularly
for psychostimulant DRD3 Nuclear membrane
DRD4
addictions.[109][111][130]
In particular, aerobic
exercise decreases Plasma membrane
psychostimulant self-
administration,
reduces the
reinstatement (i.e.,
relapse) of drug-seeking,
and induces
increased dopamine
receptor D2
cAMP
(DRD2) density in the
striatum.[108][130] This is This diagram depicts the signaling events in the brain's reward center that are induced by chronic
the opposite high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine,
of pathological like
stimulant use, which amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and
induces glutamate co-release by such psychostimulants,[98][99] postsynaptic receptors for these
decreased striatal DRD2 neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-
dependent pathway that ultimately result in increased CREB phosphorylation.[98][100] Phosphorylated
density.[108] One review
CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;
noted that exercise may [98][101][102] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the
also prevent the
neuron.[103] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2
development of a drug
months, slowly accumulates following repeated high-dose exposure to stimulants through this process.
addiction by altering [101][102] ΔFosB functions as "one of the master control proteins" that produces addiction- related
ΔFosB or c-Fos
structural changes in the brain, and upon sufficient accumulation, with the help of its downstream
immunoreactivity in the
targets (e.g., nuclear factor kappa B), it induces an addictive state.[101][102]
striatum or other parts of
the reward system.[110]
 Summary of addiction-related plasticity

Form of Type of reinforcer

neuroplasticity Physical
High fat or Sexual Environmental Sources
or behavioral Opiates Psychostimulants exercise
plasticity sugar food intercourse enrichment
(aerobic)
ΔFosB expression in
nucleus accumbens ↑ ↑ ↑ ↑ ↑ ↑ [108]
D1-type MSNs

Behavioral plasticity

Escalation of intake Yes Yes Yes [108]

Psychostimulant [108]
Yes Not applicable Yes Yes Attenuated Attenuated
cross-sensitization

Psychostimulant [108]
↑ ↑ ↓ ↓ ↓
self-administration

Psychostimulant
conditioned place ↑ ↑ ↓ ↑ ↓ ↑ [108]
preference
Reinstatement of
drug-seeking ↑ ↑ ↓ ↓ [108]
behavior
Neurochemical plasticity
CREB
phosphorylation [108]
↓ ↓ ↓ ↓ ↓
in the
nucleus accumbens
Sensitized dopamine
response [108]
No Yes No Yes
in the
nucleus accumbens

↑DRD1,
Altered striatal ↓DRD2, ↑DRD1, ↓DRD2, [108]
↓DRD2, ↑DRD2 ↑DRD2
dopamine signaling ↑DRD3 ↑DRD3
↑DRD3

No change ↑μ-opioid
Altered striatal or receptors ↑μ-opioid ↑μ-opioid [108]
No change No change
opioid ↑μ-opioid ↑κ-opioid receptors receptors
signaling receptors receptors

↑dynorphin
Changes in [108]
No change: ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin
striatal opioid
enkephalin
peptides
Mesocorticolimbic synaptic plasticity
Number of
dendrites in ↓ ↑ ↑ [108]
the
nucleus accumbens
Dendritic spine
density in [108]
↓ ↑ ↑
the
nucleus accumbens
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.[131][132]
According to a Cochrane review on withdrawal in individuals who compulsively use amphetamine and
methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-
limited withdrawal syndrome that occurs within 24 hours of their last dose." [133] This review noted that
withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for
3–4 weeks with a marked "crash" phase occurring during the first week. [133] Amphetamine withdrawal symptoms
can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased
movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[133] The review indicated that the
severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their
dependence.[133] 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.[1][82]
[134]
The severity of overdose symptoms increases with dosage and decreases with drug tolerance to
amphetamine.[37][82] Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day,
which is roughly 100 times the maximum daily therapeutic dose.[82] Symptoms of a moderate and extremely
large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[26][37]
In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine
use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence).[note 15][135]
 Overdose symptoms by system

System Minor or moderate overdose[26][37][82] Severe overdose[sources 12]

Cardiogenic shock (heart not pumping enough blood)

Cardiovascular Abnormal heartbeat Cerebral hemorrhage (bleeding in the brain)
High or low blood pressure Circulatory collapse (partial or complete failure of the
circulatory system)

Acute amphetamine psychosis (e.g., delusions and

Confusion paranoia)
Central nervous Abnormally fast reflexes Compulsive and repetitive movement
system
Severe agitation Serotonin syndrome (excessive serotonergic nerve activity)
Tremor (involuntary muscle twitching) Sympathomimetic toxidrome (excessive adrenergic
nerve activity)

Musculoskeletal Muscle pain Rhabdomyolysis (rapid muscle breakdown)

Pulmonary edema (fluid accumulation in the lungs)

Respiratory Pulmonary hypertension (high blood pressure in the arteries
Rapid breathing
of the lung)
Respiratory alkalosis (reduced blood CO2)

Urinary Painful urination No urine

Urinary retention (inability to urinate) production Kidney
failure

Elevated or low blood potassium

Other Elevated body temperature
Hyperpyrexia (extremely elevated core body temperature)
Mydriasis (dilated pupils)
Metabolic acidosis (excessively acidic bodily fluids)

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to
dopamine neurons, which is characterized by dopamine terminal degeneration and reduced transporter and
receptor function.[137][138] There is no evidence that amphetamine is directly neurotoxic in humans. [139][140]
However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of
hyperpyrexia, the excessive formation of reactive oxygen species, and increased autoxidation of dopamine.[sources
13]
Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of
hyperpyrexia (i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced
neurotoxicity.[138] 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.[138]

Psychosis

An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as
delusions and paranoia.[38][39] A Cochrane review on treatment for amphetamine, dextroamphetamine, and
methamphetamine psychosis states that about 5–15% of users fail to recover completely.[38][143] According to the
same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of
acute amphetamine psychosis.[38] Psychosis rarely arises from therapeutic use.[26][39][40]
Drug interactions
Many types of substances are known to interact with amphetamine, resulting in altered drug action or
metabolism of amphetamine, the interacting substance, or both.[26] Inhibitors of enzymes that metabolize
amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last
longer.[15][26] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both
MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[26] therefore,
concurrent use of both is dangerous.[26] Amphetamine modulates the activity of most psychoactive drugs. In
particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of
stimulants and antidepressants.[26] Amphetamine may also decrease the effects of antihypertensives and
antipsychotics due to its effects on blood pressure and dopamine respectively.[26] Zinc supplementation may
reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD. [note 16][148]

In general, there is no significant interaction when consuming amphetamine with food, but the pH of
gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.[26] Acidic
substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the
opposite.[26] Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such
as proton pump inhibitors and H2 antihistamines, which increase gastrointestinal pH (i.e., make it less acidic).
[26]

Pharmacology

Pharmacodynamics

Amphetamine exerts its

behavioral effects by altering the
use of monoamines as neuronal
signals in the brain, primarily in
catecholamine neurons in the
reward and executive function
pathways of the brain.[35][56] The
concentrations of the main
neurotransmitters involved in
reward circuitry and executive
functioning, dopamine and
norepinephrine, increase
dramatically in a dose-dependent
manner by amphetamine because
of its effects on monoamine
transporters.[35][56][149] The
reinforcing and motivational
salience-promoting effects of
amphetamine are due mostly to
enhanced dopaminergic activity
in the mesolimbic pathway.[24]
The 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.[2]
Amphetamine has been identified
as a potent full agonist of trace Pharmacodynamics of amphetamine in a dopamine neuron
amine-associated receptor 1
(TAAR1), a Gs-coupled and
Gq-coupled G protein-coupled via AADC
receptor (GPCR) discovered in
2001, which is important for
regulation of brain
monoamines.[35][155] Activation
of TAAR1 increases cAMP
production via adenylyl cyclase
activation and inhibits
monoamine transporter
function.[35][156] Monoamine
autoreceptors (e.g., D2 short,
presynaptic α2, and presynaptic
5- HT1A) have the opposite effect
of TAAR1, and together these
receptors provide a regulatory
system for monoamines. [35][36]
Notably, amphetamine and trace
amines possess high binding
affinities for TAAR1, but not for
monoamine autoreceptors.[35][36]
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.[35]

In addition to the neuronal

monoamine transporters,
amphetamine also inhibits both
vesicular monoamine
transporters, VMAT1 and VMAT2,
as well as SLC1A1, SLC22A3, and
SLC22A5.[sources 14] SLC1A1 is
excitatory amino acid transporter
3 (EAAT3), a glutamate
transporter located in neurons,
SLC22A3 is an extraneuronal
monoamine transporter that is
present in astrocytes, and
SLC22A5 is a high-affinity
[sources 14]
carnitine transporter.
Amphetamine is known to
strongly induce cocaine- and
amphetamine-regulated
transcript (CART) gene expression,[4][162] a neuropeptide involved in feeding behavior, stress, and reward, which
induces observable increases in neuronal development and survival in vitro.[4][163][164] The CART receptor has yet
Amphetamine enters the presynaptic neuron across the neuronal membrane or through
DAT.[35] Once inside, it binds to TAAR1 or enters synaptic vesicles through
VMAT2.[35][149] When amphetamine enters synaptic vesicles through VMAT2, it collapses
the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol
(light tan-colored area) through VMAT2.[149][150] When amphetamine binds to TAAR1, it
reduces the firing rate of the dopamine neuron via potassium channels and activates protein
kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylates DAT.[35]
[151][152] PKA-phosphorylation
causes DAT to withdraw into the presynaptic neuron
(internalize) and cease transport.[35] PKC-phosphorylated DAT may either operate in
reverse or, like PKA-phosphorylated DAT, internalize and cease transport. [35] Amphetamine
is also known to increase intracellular calcium, an effect which is associated with DAT
phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[153]
[154]
to be identified, but there is significant evidence that CART binds to a unique G i/Go-coupled GPCR.[164][165]
Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine
metabolism and consequently higher concentrations of synaptic monoamines. [21][166] In humans, the only post-
synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with
low micromolar affinity.[167][168]

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular
communication or neurotransmission of dopamine,[35] serotonin,[35] norepinephrine,[35] epinephrine,[149]
histamine,[149] CART peptides,[4][162] endogenous opioids,[169][170][171] adrenocorticotropic hormone,[172][173]
corticosteroids,[172][173] and glutamate,[153][158] 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. [174]

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[175] Consequently,

dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more,
but levoamphetamine has slightly stronger cardiovascular and peripheral effects. [37][175]

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[35]
Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal
membrane directly.[35] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition
at the transporter.[35] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through
protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[35] Phosphorylation
by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-
mediated phosphorylation alone induces the reversal of dopamine transport through DAT (i.e.,
dopamine efflux).[note 16][35][176] Amphetamine is also known to increase intracellular calcium, an effect which is
associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase
(CAMK)- dependent pathway, in turn producing dopamine efflux. [155][153][154] Through direct activation of G
protein- coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons,
preventing a hyper-dopaminergic state.[151][152][177]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[149][150]
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.[149][150] Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into
the synaptic cleft via reverse transport at DAT.[35][149][150]

Norepinephrine

Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct
precursor of epinephrine.[44][56] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to
affect norepinephrine analogously to dopamine. [35][149][176] 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.[35][149]

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.
[35][56]
Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT
via TAAR1.[35][149] Like dopamine, amphetamine has low, micromolar affinity at the human
 Enzyme
[167][168]
5-HT1A receptor. KA (nM)

Sources
Other neurotransmitters, peptides, hormones, and enzymes
hCA4
Acute amphetamine administration in humans increases endogenous opioid 94 anhydrase
Human carbonic
release in several brain structures in the reward system.[169][170][171] activation potency
[174]

Extracellular levels of glutamate, the primary excitatory neurotransmitter in the hCA5A

brain, have been shown to increase in the striatum following exposure to
810
amphetamine.[153] This increase in extracellular glutamate presumably occurs [174][178]
via the amphetamine- induced internalization of EAAT3, a glutamate reuptake
hCA5B
transporter, in dopamine neurons.[153][158] Amphetamine also induces the
selective release of histamine from mast cells and efflux from histaminergic 2560
neurons through VMAT2.[149] Acute amphetamine administration can also [174]
increase adrenocorticotropic hormone and corticosteroid levels in blood plasma hCA7
by stimulating the hypothalamic–pituitary– adrenal axis.[33][172][173]
910
[174][178]
In December 2017, the first study assessing the interaction between
hCA12
amphetamine and human carbonic anhydrase enzymes was published;[174] of the
eleven carbonic anhydrase enzymes it examined, it found that amphetamine 640
potently [174]
activates seven, four of which are highly expressed in the human brain, with low nanomolar hCA13
through low
micromolar activating effects.[174] Based upon preclinical research, cerebral carbonic anhydrase activation has
24100
cognition-enhancing effects;[179] but, based upon the clinical use of carbonic anhydrase inhibitors, carbonic
[174]
anhydrase activation in other tissues may be associated with adverse effects, such as ocular activation
exacerbating glaucoma.[179] hCA14
9150
[174]
Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH; [26] it is well absorbed from the gut, and
bioavailability is typically over 75% for dextroamphetamine. [3] Amphetamine is a weak base with a pKa of 9.9;[5]
consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed
through the lipid-rich cell membranes of the gut epithelium.[5][26] Conversely, an acidic pH means the drug is
predominantly in a water-soluble cationic (salt) form, and less is absorbed.[5] Approximately 20% of
amphetamine circulating in the bloodstream is bound to plasma proteins.[4] Following absorption, amphetamine
readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and
brain tissue.[11]

The half-lives of amphetamine enantiomers differ and vary with urine pH. [5] At normal urine pH, the half-lives of
dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[5] Highly acidic urine
will reduce the enantiomer half-lives to 7 hours; [11] highly alkaline urine will increase the half-lives up to 34
hours.[11] 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. [5] Amphetamine is eliminated via the kidneys, with
30–40% of the drug being excreted unchanged at normal urinary pH. [5] When the urinary pH is basic,
amphetamine is in its free base form, so less is excreted.[5] 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.[5] Following oral administration, amphetamine appears in urine within 3 hours. [11] Roughly
90% of ingested amphetamine is eliminated 3 days after the last oral dose. [11]

Lisdexamfetamine is a prodrug of dextroamphetamine.[180][181] It is not as sensitive to pH as amphetamine when

being absorbed in the gastrointestinal tract. [181] Following absorption into the blood stream, lisdexamfetamine is
completely converted by red blood cells to dextroamphetamine and the amino acid L-lysine by hydrolysis via
undetermined aminopeptidase enzymes.[181][180][182] This is the rate-limiting step in the bioactivation of
lisdexamfetamine.[180] The elimination half-life of lisdexamfetamine is generally less than 1 hour.[181][180] Due to
the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with
lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release
dextroamphetamine.[180][182] Presumably due to its rate-limited activation by red blood cells, intravenous
administration of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to
intravenous administration of an equivalent dose of dextroamphetamine. [180] The pharmacokinetics of
lisdexamfetamine are similar regardless of whether it is administered orally, intranasally, or intravenously.[180]
[182]
Hence, in contrast to dextroamphetamine, parenteral use does not enhance the subjective effects of
lisdexamfetamine.[180][182] 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.[180][182]

CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase

(XM- ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its
metabolites in humans.[sources 16] Amphetamine has a variety of excreted metabolic products, including
4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid,
norephedrine, and phenylacetone.[5][6] Among these metabolites, the active sympathomimetics are
4-hydroxyamphetamine,[183] 4-hydroxynorephedrine,[184] and norephedrine.[185] The main metabolic pathways
involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and
deamination.[5][186] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in
humans include the following:

Metabolic pathways of amphetamine in humans[sources 16]

Beta-
Hydroxylation
DBH
[note 17]

4-Hydroxyamphetamine 4-Hydroxynorephedrine
Para- Para-
Hydroxylation Hydroxylation
CYP2D6 CYP2D6

Beta-
Hydroxylation
DBH

Amphetamine Oxidative
Norephedrine
Deamination
FMO3

Para- Glycine
Hydroxylation Oxidation Conjugation

unidentified unidentified XM-ligase

GLYAT
4-Hydroxyphenylacetone Phenylacetone Benzoic acid Hippuric acid
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[6] at normal urine
pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive
metabolites (bottom row).[5] The remaining 10–20% is excreted as the active metabolites.[5] Benzoic acid is
metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into
hippuric acid.[188]

Pharmacomicrobiomics
The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or
within the individual's body) varies considerably between individuals.[192][193] Since the total number of
microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of
trillions),[note 18][192][194] there is considerable potential for interactions between drugs and an individual's
microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial
enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical
efficacy and toxicity profile.[192][193][195] The field that studies these interactions is known as
pharmacomicrobiomics.[192]

Similar to most biomolecules and other orally administered xenobiotics (i.e., drugs), amphetamine is predicted to
undergo promiscuous metabolism by human gastrointestinal microbiota (primarily bacteria) prior to absorption
into the blood stream.[195] The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain
of E. coli commonly found in the human gut, was identified in 2019. [195] This enzyme was found to metabolize
amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.
[195]

Related endogenous compounds

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally
occurring neuromodulator molecules produced in the human body and brain. [35][44][196] Among this group, the
most closely related compounds are phenethylamine, the parent compound of amphetamine, and
N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula). [35][44][197] In
humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase
(AADC) enzyme, which converts L-DOPA into dopamine as well. [44][197] In turn, N-methylphenethylamine is
metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes
norepinephrine into epinephrine.[44][197] Like amphetamine, both phenethylamine and N-
[35][196][197]
methylphenethylamine regulate monoamine neurotransmission via TAAR1; unlike amphetamine,
both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than
amphetamine.[44][197]

Chemistry
Amphetamine is a methyl homolog of the mammalian Racemic amphetamine
neurotransmitter phenethylamine with the chemical formula
C9H13N. The carbon atom adjacent to the primary amine is a
stereogenic center, and amphetamine is composed of a racemic 1:1
mixture of two enantiomers.[4] This racemic mixture can be Levoamphetamine Dextroamphetamine
separated into its optical isomers: [note 19] levoamphetamine and The skeletal structures of L-amph and D-amph
dextroamphetamine.[4] At room temperature, the pure free base of
amphetamine is a mobile, colorless, and volatile liquid with a
characteristically strong amine odor, and acrid, burning taste.[20] Frequently prepared solid salts of
amphetamine include amphetamine adipate, [198] aspartate,[26] hydrochloride,[199] phosphate,[200] saccharate,
[26]
sulfate,[26] and tannate.[201] Dextroamphetamine sulfate is the most common enantiopure salt. [45]
Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive
derivatives.[13][4] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis
of 1,1'-bi-2-naphthol.[202]

Substituted derivatives

The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that
contain amphetamine as a "backbone";[13][46][203] specifically, this chemical class includes derivative compounds
that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with
substituents.[13][46][204] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic
empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[13][46][203]

Synthesis

Since the first preparation was reported in 1887, [205] numerous synthetic routes to amphetamine have been
developed.[206][207] The most common route of both legal and illicit amphetamine synthesis employs a non-
metal reduction known as the Leuckart reaction (method 1).[45][208] In the first step, a reaction between
phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing
agent, yields 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.[208][209]

A number of chiral resolutions have been developed to separate the

two enantiomers of amphetamine.[206] For example, racemic
amphetamine can be treated with d-tartaric acid to form a
diastereoisomeric salt which is fractionally crystallized to yield
dextroamphetamine.[210] Chiral resolution remains the most
economical method for obtaining optically pure amphetamine on a
large scale.[211] In addition, several enantioselective syntheses of
amphetamine have been developed. In one example, optically pure
(R)-1-phenyl-ethanamine is condensed with phenylacetone to yield
a chiral Schiff base. In the key step, this intermediate is reduced by
catalytic hydrogenation with a transfer of chirality to the carbon
atom alpha to the amino group. Cleavage of the benzylic amine
bond by hydrogenation yields optically pure
dextroamphetamine.[211] A vial of the colorless amphetamine free base

A large number of alternative synthetic routes to amphetamine

have been developed based on classic organic reactions. [206][207]
One example is the Friedel–Crafts alkylation of benzene by allyl
chloride to yield beta chloropropylbenzene which is then reacted
with ammonia to produce racemic amphetamine (method 2). [212]
Another example employs the Ritter reaction (method 3). In this
route, allylbenzene is reacted acetonitrile in sulfuric acid to yield
an organosulfate which in turn is treated with sodium hydroxide to
give amphetamine via an acetamide intermediate.[213][214] A third
route starts with ethyl 3-oxobutanoate which through a double
alkylation with 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 Amphetamine hydrochloride (left
[215] bowl) Phenyl-2-nitropropene (right
Hofmann or Curtius rearrangement (method 4).
cups)
A significant number of amphetamine syntheses feature a reduction
of a nitro, imine, oxime, or other nitrogen-containing functional groups.[207] 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).[208][216] 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).[208]

Amphetamine synthetic routes

 Method 1: Synthesis by the Leuckart reaction
Method 3: Ritter synthesis

Method 4: Synthesis via Hofmann and Curtius rearrangements

Top: Chiral resolution of amphetamine

Bottom: Stereoselective synthesis of amphetamine

Method 5: Synthesis by Knoevenagel condensation

Method 2: Synthesis by Friedel–Crafts alkylation

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. [220] Chromatographic methods
specific for amphetamine are employed to prevent false positive results. [221] 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. [221][224][225] Several prescription drugs produce
amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex,
lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[2][226][227] These
compounds may produce positive results for amphetamine on drug tests.[226][227] 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.[220]

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.[224] 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.[221] 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. [221] 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.[221]

History, society, and culture

 Substance
Amphetamine-type stimulants were originally derived from the
Best estimate
Global estimates of drug users in 2016
plant Ephedra, which contains the amphetamine-like stimulant
ephedrine and had been used for its effects in China dating (in Low
millions of users)[228]
estimate
back an estimated 5,000 years.[229][230] Ephedrine was High estimate
isolated from Ephedra vulgaris in Japan in 1885 and was
Amphetamine- type
studied for its medicinal properties through the 1920s. [229] The stimulants
scarce amounts of ephedrine in the Ephedra plant led to
investigations of synthetic analogues of ephedrine.[229] 34.16

13.42
Amphetamine was first synthesized in 1887 in Germany by
Romanian chemist Lazăr Edeleanu who named it 55.24
[205][231][232]
phenylisopropylamine; its stimulant effects Cannabis
remained unknown until 1927, when it was independently 192.15
resynthesized by Gordon Alles and reported to have
165.76
sympathomimetic properties.[232] Amphetamine had no
medical use until late 1933, when Smith, Kline and French began selling it as an inhaler under234.06 the brand name
[27]
Benzedrine as a decongestant. Benzedrine sulfate was introduced 3 years later and was used to treat a wide
Cocaine
variety of medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain,
18.20
among others.[47][27] During World War II, amphetamine and methamphetamine were used extensively by both
13.87
the Allied and Axis forces for their stimulant and performance-enhancing effects. [205][233][234] As the addictive
properties of the drug became known, governments began to place strict controls on the 22.85 sale of amphetamine.
[205]
For example, during the early 1970s in the United States, amphetamine became Ecstasy a schedule II controlled
substance under the Controlled Substances Act.[235][236] In spite of strict government controls,
20.57 amphetamine has
[237]
been used legally or illicitly by people from a variety of backgrounds, including authors,
8.99 musicians,[238]
mathematicians,[239] and athletes.[25] 32.34

Amphetamine is still illegally synthesized today in clandestine labs and sold on the blackOpiates
market, primarily in
[240]
European countries. Among European Union (EU) member states in 2018, 11.9 million
19.38 adults of ages 15–64
have used amphetamine or methamphetamine at least once in their lives and 1.7 million have used either in the
13.80
[241]
last year. During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member
26.15
states;[242] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same
Opioids
period.[242] Outside Europe, the illicit market for amphetamine is much smaller than the market for
methamphetamine and MDMA.[240] 34.26
27.01
44.54
Legal status

As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule
II controlled substance, as defined in the treaty, in all 183 state parties. [28] Consequently, it is heavily regulated in
most countries.[243][244] Some countries, such as South Korea and Japan, have banned substituted
amphetamines even for medical use. [245][246] In other nations, such as Canada (schedule I drug),[247] the
Netherlands (List I drug),[248] the United States (schedule II drug),[26] Australia (schedule 8),[249] Thailand
(category 1 narcotic),[250] and United Kingdom (class B drug),[251] amphetamine is in a restrictive national drug
schedule that allows for its use as a medical treatment. [240][29]

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][33][86] 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.[34][181] The free base of racemic amphetamine was previously available as Benzedrine,
Psychedrine, and Sympatedrine.[2] Levoamphetamine was previously available as Cydril. [2] Many current
amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[2][34][45]
However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were
introduced in 2015 and 2016, respectively.[86][252][253] Some of the current brands and their generic equivalents
are listed below.

Amphetamine pharmaceuticals

Brand United States Dosage Marketing US consumer

(D:L) ratio Sources
name Adopted Name form start date price data

GoodRx (https://www.goodrx. [2][34]

Adderall – 3:1 (salts) tablet 1996
com/adderall)
GoodRx (https://www.goodrx. [2][34]
Adderall XR – 3:1 (salts) capsule 2001
com/adderall-xr)
GoodRx (https://www.goodrx. [254][255]
Mydayis – 3:1 (salts) capsule 2017
com/mydayis)
GoodRx (https://www.goodrx. [256]
Adzenys ER amphetamine 3:1 (base) suspension 2017
com/adzenys-er)
GoodRx (https://www.goodrx. [253][257]
Adzenys XR-ODT amphetamine 3:1 (base) ODT 2016
com/adzenys-xr-odt)
GoodRx (https://www.goodrx. [86][252]
Dyanavel XR amphetamine 3.2:1 (base) suspension 2015
com/dyanavel-xr)
GoodRx (https://www.goodrx. [33][258]
Evekeo amphetamine sulfate 1:1 (salts) tablet 2012
com/evekeo)
GoodRx (https://www.goodrx.
com/evekeo?dosage=10mg&
Evekeo ODT amphetamine sulfate 1:1 (salts) ODT 2019 form=orally-disintegrating-tab [259]
&label_override=Evekeo&qu
antity=60)
GoodRx (https://www.goodrx. [2][34]
Dexedrine dextroamphetamine sulfate 1:0 (salts) capsule 1976
com/dexedrine-spansule)
GoodRx (https://www.goodrx. [34][260]
Zenzedi dextroamphetamine sulfate 1:0 (salts) tablet 2013
com/zenzedi)
capsule GoodRx (https://www.goodrx.
Vyvanse lisdexamfetamine dimesylate 1:0 (prodrug) 2007 [2][181][261]
tablet com/vyvanse)

GoodRx (https://www.goodrx. [262]

Xelstrym dextroamphetamine 1:0 (base) patch 2022
com/xelstrym)
 Amphetamine base in marketed amphetamine medications

amphetamine doses
molar mass amphetamine base
[note 21] [note 22] base with
in equal doses equal
drug formula base
(g/mol) (percent) (30 mg dose)
content
[note 23]
total base total dextro- levo- dextro- levo-
dextroamphetamine
(C9H13N)2•H2SO4 368.49 270.41 73.38% 73.38% — 22.0 mg — 30.0 mg
sulfate[264][265]

amphetamine sulfate[266] (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

dextroamphetamine
25% (C9H13N)2•H2SO4 368.49 270.41 73.38% 73.38% —
sulfate[264][265]
amphetamine
25% (C9H13N)2•H2SO4 368.49 270.41 73.38% 36.69% 36.69%
sulfate[266]
dextroamphetamine
25% (C9H13N)2•C6H10O8 480.55 270.41 56.27% 56.27% —
saccharate[267]
amphetamine
25% aspartate (C9H13N)•C4H7NO4•H2O 286.32 135.21 47.22% 23.61% 23.61%
monohydrate[268]

lisdexamfetamine
C15H25N3O•(CH4O3S)2 455.49 135.21 29.68% 29.68% — 8.9 mg — 74.2 mg
dimesylate[181]

amphetamine base
C9H13N 135.21 135.21 100% 76.19% 23.81% 22.9 mg 7.1 mg 22.0 mg
suspension[86]

Notes
1. 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. Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name),
α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine,
and speed.[21][4][22]
3. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of
the opposite orientation.[23]
Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or
dexamfetamine (INN) respectively.[21]
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.[34]
5. The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines,
[13]
the "amphetamines" class does not have a standardized definition in academic literature.[17] One of the
more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and
methamphetamine.[17] The most general definition of the class encompasses a broad range of
pharmacologically and structurally related compounds. [17]
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. The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from
long- term continuous stimulant therapy include academics (≈55% of academic outcomes improved), driving
(100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved),
obesity (≈65% of obesity-related outcomes improved), self-esteem (50% of self-esteem outcomes improved),
and social function (67% of social function outcomes improved). [54]

The largest effect sizes for outcome improvements from long-term stimulant therapy occur in the domains
involving academics (e.g., grade point average, achievement test scores, length of education, and education
level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide
rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and
romantic relationships).[54]

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. [54]
7. Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[60]
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. [81]
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.[2]
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.[41][53][85] The average reduction in final adult height from 3
years of continuous stimulant therapy is 2 cm. [85]
11. Transcription factors are proteins that increase or decrease the expression of specific genes.[114]
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. NMDA receptors are voltage-dependent ligand-gated ion channels that requires simultaneous binding
of glutamate and a co-agonist (D-serine or glycine) to open the ion channel.[128]
14. The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes
in addictive behavior;[105] 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. The human dopamine transporter (hDAT) contains a high-affinity, extracellular, and allosteric Zn2+ (zinc
ion) binding site which, upon zinc binding, inhibits dopamine reuptake, inhibits amphetamine-induced
hDAT internalization, and amplifies amphetamine-induced dopamine efflux.[144][145][146][147] The human
serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[146]
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.[13][187] 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;[187][189] however, other evidence from animal studies suggests that this reaction is
catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[190][191]
18. There is substantial variation in microbiome composition and microbial concentrations by anatomical
site.[192][193] 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. [192]
19. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of
the opposite orientation.[23]
20. The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and
 USAN of levomethamphetamine.[222][223]
21. For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator[263] 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. Ion channel
G proteins & linked receptors
(Text color) Transcription factors

Reference notes
1. [2][17][24][25][26][27][28][29][30][31][32][33]
2. [2][10][24][27][33][35][36]
3. [10][24][25][26][30][37][38][39][40][41][42][43]
4. [44][45][46]
5. [1][26][37][85][86][87]
6. [88][89][90][91]
7. [26][82][88][90]
8. [30][26][37][92]
9. [108][109][110][111][130]
10. [106][108][107][115][116]
11. [107][118][119][120]
12. [22][26][37][134][136]
13. [48][138][141][142]
14. [149][153][157][158][159][160][161]
15. [35][149][157][158][162][167]
16. [5][13][14][15][16][6][187][188]
17. [25][217][218][219]

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 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
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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
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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.,
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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
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94. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor
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95. Nestler EJ (December 2013). "Cellular basis of memory for addiction"
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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."
96. "Glossary of Terms" (http://neuroscience.mssm.edu/nestler/glossary.html). Mount Sinai School of Medicine.
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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."
98. Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression" (https://www
.ncbi.nlm.nih.gov/pmc/articles/PMC2834246). Dialogues in Clinical Neuroscience. 11 (3): 257–268.
PMC 2834246 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834246). PMID 19877494 (https://pubmed.ncbi
.nlm.nih.gov/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 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834246/fi
gure/DialoguesClinNeurosci-11-257-g002/)
99. Broussard JI (January 2012). "Co-transmission of dopamine and glutamate" (https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC3250102). The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659
(https:// doi.org/10.1085%2Fjgp.201110659). PMC 3250102
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250102). PMID 22200950
(https://pubmed.ncbi.nlm.nih.gov/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."
0. Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)"
(http://www.genome.jp/ke gg-bin/show_pathway?hsa05031+2354). 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."
01. Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction"
(https://ww w.ncbi.nlm.nih.gov/pmc/articles/PMC3272277). Nature Reviews Neuroscience. 12 (11): 623–637.
doi:10.1038/nrn3111 (https://doi.org/10.1038%2Fnrn3111). PMC 3272277 (https://www.ncbi.nlm.nih.gov/pmc/ar
ticles/PMC3272277). PMID 21989194 (https://pubmed.ncbi.nlm.nih.gov/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
(https://www.ncbi.nlm.nih.gov/pmc/articles/PM C3272277/figure/F4/)
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10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136 (https://doi.org/10.9758%2Fcpn.2012.10.3.136). PMC 3569166
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 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"
03. Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB" (https://www.ncbi.nlm.nih
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0924). "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"
04. Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)"
(http://www.genome.jp/ke gg-bin/show_pathway?hsa05031). KEGG Pathway. Retrieved 31 October 2014.
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American Journal of Drug and Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840
(https://doi
.org/10.3109%2F00952990.2014.933840). PMID 25083822 (https://pubmed.ncbi.nlm.nih.gov/25083822).
S2CID 19157711 (https://api.semanticscholar.org/CorpusID:19157711). "ΔFosB is an essential transcription
factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure."
07. Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction"
(https://ww w.ncbi.nlm.nih.gov/pmc/articles/PMC3272277). Nature Reviews Neuroscience. 12 (11): 623–637.
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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 exposure 14,22–24. 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 consumption 14,26–30. 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."
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459101). "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)."
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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."
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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."
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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."
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DeltaFosB expression
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There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug
addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic
interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding
effects of drug abuse The value of this form of treatment for drug addiction in laboratory animals and
humans is that
exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended
period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for
drug addiction supports this hypothesis.Animal and human research on physical exercise as a treatment
for
stimulant addiction indicates that this is one of the most promising treatments on the horizon."
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more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999)...The
severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who
have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present
within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases
that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about
a week (Gossop 1982;McGregor 2005) "
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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."
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enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and
enhanced ROS production The hyperthermia and the hypertension produced by high doses
amphetamines are a primary
cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional
neurodegeneration and neuroinflammation in laboratory animals.......In animal models that evaluate
the
neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components
necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in
cortex, striatum, thalamus and hippocampus."
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at the Monoamine Transporters: A Unified Model of Allosteric Modulation and Amphetamine-Induced
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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."
45. Krause J (April 2008). "SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity
disorder". Expert Review of Neurotherapeutics. 8 (4): 611–625. doi:10.1586/14737175.8.4.611
(https://doi.org/10.1586%2 F14737175.8.4.611). PMID 18416663 (https://pubmed.ncbi.nlm.nih.gov/18416663).
S2CID 24589993 (https://a pi.semanticscholar.org/CorpusID: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."
46. Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH (June 2002). "The role of zinc ions in
reverse transport mediated by monoamine transporters" (https://doi.org/10.1074%2Fjbc.M112265200).
Journal of Biological Chemistry. 277 (24): 21505–21513. doi:10.1074/jbc.M112265200
(https://doi.org/10.1074%2Fjbc. M112265200). PMID 11940571 (https://pubmed.ncbi.nlm.nih.gov/11940571).
S2CID 10521850 (https://api.sem anticscholar.org/CorpusID: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."
47. Kahlig KM, Lute BJ, Wei Y, Loland CJ, Gether U, Javitch JA, Galli A (August 2006). "Regulation of dopamine
transporter trafficking by intracellular amphetamine". Molecular Pharmacology. 70 (2): 542–548.
doi:10.1124/mol.106.023952 (https://doi.org/10.1124%2Fmol.106.023952). PMID 16684900 (https://pubmed.nc
bi.nlm.nih.gov/16684900). S2CID 10317113 (https://api.semanticscholar.org/CorpusID:10317113).
"Coadministration of Zn(2+) and AMPH consistently reduced WT-hDAT trafficking"
48. Scassellati C, Bonvicini C, Faraone SV, Gennarelli M (October 2012). "Biomarkers and attention-
deficit/hyperactivity disorder: a systematic review and meta-analyses". Journal of the American Academy of
Child & Adolescent Psychiatry. 51 (10): 1003–1019.e20. doi:10.1016/j.jaac.2012.08.015 (https://doi.org/10.101
6%2Fj.jaac.2012.08.015). PMID 23021477 (https://pubmed.ncbi.nlm.nih.gov/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"
49. Eiden LE, Weihe E (January 2011). "VMAT2: a dynamic regulator of brain monoaminergic neuronal function
interacting with drugs of abuse" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183197). Annals of the
New York Academy of Sciences. 1216 (1): 86–98. doi:10.1111/j.1749-6632.2010.05906.x
(https://doi.org/10.1111%2 Fj.1749-6632.2010.05906.x). PMC 4183197
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183197).
PMID 21272013 (https://pubmed.ncbi.nlm.nih.gov/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."
50. Sulzer D, Cragg SJ, Rice ME (August 2016). "Striatal dopamine neurotransmission: regulation of release and
uptake" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850498). Basal Ganglia. 6 (3): 123–148.
doi:10.1016/j.baga.2016.02.001 (https://doi.org/10.1016%2Fj.baga.2016.02.001). PMC 4850498 (https://www.n
cbi.nlm.nih.gov/pmc/articles/PMC4850498). PMID 27141430 (https://pubmed.ncbi.nlm.nih.gov/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."
51. Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (July 2011). "Electrophysiological effects
of trace amines on mesencephalic dopaminergic neurons"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC313 1148). Frontiers in Systems Neuroscience. 5: 56.
doi:10.3389/fnsys.2011.00056 (https://doi.org/10.3389%2Ffns ys.2011.00056). PMC 3131148
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131148). PMID 21772817 (htt
ps://pubmed.ncbi.nlm.nih.gov/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."
52. "TAAR1" (http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=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)"
53. Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). "Amphetamine modulates
excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons"
(h ttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159050) . Neuron. 83 (2): 404–416.
doi:10.1016/j.neuron.2014.05.043 (https://doi.org/10.1016%2Fj.neuron.2014.05.043). PMC 4159050
(https://w ww.ncbi.nlm.nih.gov/pmc/articles/PMC4159050). PMID 25033183
(https://pubmed.ncbi.nlm.nih.gov/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"
54. Vaughan RA, Foster JD (September 2013). "Mechanisms of dopamine transporter regulation in normal and
disease states" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831354). Trends in Pharmacological
Sciences. 34 (9): 489–496. doi:10.1016/j.tips.2013.07.005 (https://doi.org/10.1016%2Fj.tips.2013.07.005) .
PMC 3831354 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831354). PMID 23968642 (https://pubmed.ncbi
.nlm.nih.gov/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]."
55. Maguire JJ, Davenport AP (2 December 2014). "TA1 receptor" (http://www.iuphar-db.org/DATABASE/ObjectDis
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56. Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini
JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C (July 2001).
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98 (16): 8966–8971. Bibcode:2001PNAS...98.8966B (https://ui.adsabs.harvard.edu/abs/2001PNAS.
98.8966B).
doi:10.1073/pnas.151105198 (https://doi.org/10.1073%2Fpnas.151105198). PMC 55357 (https://www.ncbi.nlm.
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57. "SLC18 family of vesicular amine transporters" (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForw
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58. "SLC1A1 solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member
1 [ Homo sapiens (human) ]" (https://www.ncbi.nlm.nih.gov/gene/6505). 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."
59. Zhu HJ, Appel DI, Gründemann D, Markowitz JS (July 2010). "Interaction of organic cation transporter
3 (SLC22A3) and amphetamine" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775896). Journal of
 Neurochemistry. 114 (1): 142–149. doi:10.1111/j.1471-4159.2010.06738.x (https://doi.org/10.1111%2Fj.1471-41
59.2010.06738.x). PMC 3775896 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775896). PMID 20402963 (
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60. Rytting E, Audus KL (January 2005). "Novel organic cation transporter 2-mediated carnitine uptake in
placental choriocarcinoma (BeWo) cells". Journal of Pharmacology and Experimental Therapeutics. 312 (1):
192–198. doi:10.1124/jpet.104.072363 (https://doi.org/10.1124%2Fjpet.104.072363) . PMID 15316089
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61. Inazu M, Takeda H, Matsumiya T (August 2003). "[The role of glial monoamine transporters in the central
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62. Vicentic A, Jones DC (February 2007). "The CART (cocaine- and amphetamine-regulated transcript) system
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doi:10.1124/jpet.105.091512 (https://doi.org/10.1124%2Fjpet.105.091512). PMID 16840648 (https://pubmed.nc
bi.nlm.nih.gov/16840648). S2CID 14212763 (https://api.semanticscholar.org/CorpusID: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."
63. Zhang M, Han L, Xu Y (June 2012). "Roles of cocaine- and amphetamine-regulated transcript in the
central nervous system". Clinical and Experimental Pharmacology and Physiology. 39 (6): 586–592.
doi:10.1111/j.1440-1681.2011.05642.x (https://doi.org/10.1111%2Fj.1440-1681.2011.05642.x). PMID 22077697
(https://pubmed.ncbi.nlm.nih.gov/22077697). S2CID 25134612 (https://api.semanticscholar.org/CorpusID:2513
4612). "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"
64. Rogge G, Jones D, Hubert GW, Lin Y, Kuhar MJ (October 2008). "CART peptides: regulators of body weight,
reward and other functions" (https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC4418456). Nature Reviews
Neuroscience. 9 (10): 747–758. doi:10.1038/nrn2493 (https://doi.org/10.1038%2Fnrn2493). PMC 4418456
(htt ps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418456). PMID 18802445
(https://pubmed.ncbi.nlm.nih.gov/1880 2445). "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 "
65. Lin Y, Hall RA, Kuhar MJ (October 2011). "CART peptide stimulation of G protein-mediated signaling in
differentiated PC12 cells: identification of PACAP 6–38 as a CART receptor antagonist"
(https://www.ncbi.nlm.n ih.gov/pmc/articles/PMC3170513). Neuropeptides. 45 (5): 351–358.
doi:10.1016/j.npep.2011.07.006 (https://doi
.org/10.1016%2Fj.npep.2011.07.006). PMC 3170513
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855138).
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67. "Targets". Amphetamine (http://www.t3db.ca/toxins/T3D2706). T3DB. University of Alberta. Retrieved
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A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS (March 1998). "Standard binding and functional
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69. Finnema SJ, Scheinin M, Shahid M, Lehto J, Borroni E, Bang-Andersen B, Sallinen J, Wong E, Farde L,
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neurotransmitter release in brain" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600473) .
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 00213-015-3938-6). PMC 4600473 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600473). PMID 25921033
(https://pubmed.ncbi.nlm.nih.gov/25921033). "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)."
70. Loseth GE, Ellingsen DM, Leknes S (December 2014). "State-dependent μ-opioid modulation of social
motivation" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264475). Frontiers in Behavioral Neuroscience. 8:
430. doi:10.3389/fnbeh.2014.00430 (https://doi.org/10.3389%2Ffnbeh.2014.00430). PMC 4264475 (https://ww
w.ncbi.nlm.nih.gov/pmc/articles/PMC4264475). PMID 25565999 (https://pubmed.ncbi.nlm.nih.gov/25565999).
"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)."
71. Colasanti A, Searle GE, Long CJ, Hill SP, Reiley RR, Quelch D, Erritzoe D, Tziortzi AC, Reed LJ, Lingford-
Hughes AR, Waldman AD, Schruers KR, Matthews PM, Gunn RN, Nutt DJ, Rabiner EA (September 2012).
"Endogenous opioid release in the human brain reward system induced by acute amphetamine
administration". Biological Psychiatry. 72 (5): 371–377. doi:10.1016/j.biopsych.2012.01.027
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72. Gunne LM (2013). "Effects of Amphetamines in Humans" (https://books.google.com/books?id=gb_uCAAAQBA
J&pg=PA247). Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence. Berlin,
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73. Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L, Brasic J, Wand GS (April 2005).
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amphetamine" (https:// doi.org/10.1038%2Fsj.npp.1300667). Neuropsychopharmacology. 30 (4): 821–832.
doi:10.1038/sj.npp.1300667 (https://doi.org/10.1038%2Fsj.npp.1300667). PMID 15702139 (https://pubmed.ncb
i.nlm.nih.gov/15702139). S2CID 12302237 (https://api.semanticscholar.org/CorpusID:12302237). "Findings
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by acute administration of AMPH in both rodents and humans"
74. Angeli A, Vaiano F, Mari F, Bertol E, Supuran CT (December 2017). "Psychoactive substances belonging to
the amphetamine class potently activate brain carbonic anhydrase isoforms VA, VB, VII, and XII"
(https://www.ncbi. nlm.nih.gov/pmc/articles/PMC6009978). Journal of Enzyme Inhibition and Medicinal
Chemistry. 32 (1): 1253– 1259. doi:10.1080/14756366.2017.1375485
(https://doi.org/10.1080%2F14756366.2017.1375485).
PMC 6009978 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009978). PMID 28936885 (https://pubmed.ncbi
.nlm.nih.gov/28936885). "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]"
75. Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective
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R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG,
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hyperdopaminergic and hypoglutamatergic activity"
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ology&ligandId=4804). IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical
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79. Bozdag M, Altamimi AA, Vullo D, Supuran CT, Carta F (2019). "State of the Art on Carbonic Anhydrase
Modulators for Biomedical Purposes". Current Medicinal Chemistry. 26 (15): 2558–2573.
doi:10.2174/0929867325666180622120625 (https://doi.org/10.2174%2F0929867325666180622120625) .
PMID 29932025 (https://pubmed.ncbi.nlm.nih.gov/29932025). S2CID 49345601 (https://api.semanticscholar.or
g/CorpusID:49345601). "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."
80. Ermer JC, Pennick M, Frick G (May 2016). "Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine
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82. Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME (2017). "Pharmacokinetics and
Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects" (https://www.nc
bi.nlm.nih.gov/pmc/articles/PMC5594082). Front Pharmacol. 8: 617. doi:10.3389/fphar.2017.00617 (https://doi.
org/10.3389%2Ffphar.2017.00617). PMC 5594082 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594082).
PMID 28936175 (https://pubmed.ncbi.nlm.nih.gov/28936175). "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)."
83. "Compound Summary" (https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3651) . p-
Hydroxyamphetamine. PubChem Compound Database. United States National Library of Medicine –
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84. "Compound Summary" (https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11099) . p-
Hydroxynorephedrine. PubChem Compound Database. United States National Library of Medicine –
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 85. "Compound Summary" (https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=26934) .
Phenylpropanolamine. PubChem Compound Database. United States National Library of Medicine –
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86. "Pharmacology and Biochemistry" (https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#section
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87. Sjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using
hydroxyamphetamine as substrate" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1703637). British Journal of
Pharmacology and Chemotherapy. 20: 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x (https://doi.org/10.11
11%2Fj.1476-5381.1963.tb01467.x). PMC 1703637 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1703637).
PMID 13977820 (https://pubmed.ncbi.nlm.nih.gov/13977820). "Hydroxyamphetamine was administered orally
to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by
the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme
and the effect of its inhibitors in man The lack of effect of administration of neomycin to one patient
indicates that
the hydroxylation occurs in body tissues.....a major portion of the β-hydroxylation of hydroxyamphetamine
occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the
hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts
dopamine to noradrenaline."
88. Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation:
importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual
variation". Expert Opinion on Drug Metabolism & Toxicology. 9 (9): 1139–1153.
doi:10.1517/17425255.2013.796929 (https://doi.o rg/10.1517%2F17425255.2013.796929). PMID 23650932
(https://pubmed.ncbi.nlm.nih.gov/23650932). "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."
89. Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase.
Relationship to hypertension and sympathetic activity". Circulation Research. 32 (5): 594–599.
doi:10.1161/01.RES.32.5.594 (https://doi.org/10.1161%2F01.RES.32.5.594). PMID 4713201 (https://pubmed.n
cbi.nlm.nih.gov/4713201). "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)."
90. Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following
intraventricular administration of p-hydroxyamphetamine". Neuropharmacology. 13 (12): 1187–1190.
doi:10.1016/0028-3908(74)90069-0 (https://doi.org/10.1016%2F0028-3908%2874%2990069-0) .
PMID 4457764 (https://pubmed.ncbi.nlm.nih.gov/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."
91. Matsuda LA, Hanson GR, Gibb JW (December 1989). "Neurochemical effects of amphetamine metabolites
on central dopaminergic and serotonergic systems". Journal of Pharmacology and Experimental
Therapeutics. 251 (3): 901–908. PMID 2600821 (https://pubmed.ncbi.nlm.nih.gov/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."
 92. ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK (July 2014). "Pharmacomicrobiomics: the
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.ncbi.nlm.nih.gov/pmc/articles/PMC4086029). Omics. 18 (7): 402–414. doi:10.1089/omi.2014.0018 (https://doi.
org/10.1089%2Fomi.2014.0018). PMC 4086029 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086029).
PMID 24785449 (https://pubmed.ncbi.nlm.nih.gov/24785449). "The hundred trillion microbes and viruses
residing in every human body, which outnumber human cells and contribute at least 100 times more genes
than those encoded on the human genome (Ley et al., 2006), offer an immense accessory pool for inter-
individual genetic variation that has been underestimated and largely unexplored (Savage, 1977; Medini et
al., 2008; Minot et al., 2011; Wylie et al., 2012). Meanwhile, a wealth of literature has long been available
about
the biotransformation of xenobiotics, notably by gut bacteria (reviewed in Sousa et al., 2008; Rizkallah et al.,
2010; Johnson et al., 2012; Haiser and Turnbaugh, 2013). This valuable information is predominantly about
drug metabolism by unknown human-associated microbes; however, only a few cases of inter-individual
microbiome variations have been documented [e.g., digoxin (Mathan et al., 1989) and acetaminophen
(Clayton et al., 2009)]."
93. Cho I, Blaser MJ (March 2012). "The human microbiome: at the interface of health and disease"
(https://www.n cbi.nlm.nih.gov/pmc/articles/PMC3418802). Nature Reviews Genetics. 13 (4): 260–270.
doi:10.1038/nrg3182 ( https://doi.org/10.1038%2Fnrg3182). PMC 3418802
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418802). PMID 22411464
(https://pubmed.ncbi.nlm.nih.gov/22411464). "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 individual 25
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?"
94. Hutter T, Gimbert C, Bouchard F, Lapointe FJ (2015). "Being human is a gut feeling"
(https://www.ncbi.nlm.nih. gov/pmc/articles/PMC4359430). Microbiome. 3: 9. doi:10.1186/s40168-015-0076-7
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PMID 25774294 (https://pubmed.ncbi.nlm.nih.gov/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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amphetamine metabolism by tyramine oxidase from human gut microbiota using molecular dynamics
simulations". Journal of Cellular Biochemistry. 120 (7): 11206–11215. doi:10.1002/jcb.28396 (https://doi.org/10.
1002%2Fjcb.28396). PMID 30701587 (https://pubmed.ncbi.nlm.nih.gov/30701587). S2CID 73413138 (https://a
pi.semanticscholar.org/CorpusID:73413138). "Particularly in the case of the human gut, which harbors a large
diversity of bacterial species, the differences in microbial composition can significantly alter the metabolic
activity in the gut lumen.4 The differential metabolic activity due to the differences in gut microbial species
has been recently linked with various metabolic disorders and diseases. 5–12 In addition to the impact of gut
microbial diversity or dysbiosis in various human diseases, there is an increasing amount of evidence which
shows that the gut microbes can affect the bioavailability and efficacy of various orally administrated drug
molecules through promiscuous enzymatic metabolism. 13,14. . .The present study on the atomistic details of
amphetamine binding and binding affinity to the tyramine oxidase along with the comparison with two natural
substrates of this enzyme namely tyramine and phenylalanine provides strong evidence for the promiscuity-
based metabolism of amphetamine by the tyramine oxidase enzyme of E. coli. The obtained results will be
crucial in designing a surrogate molecule for amphetamine that can help either in improving the efficacy and
bioavailability of the amphetamine drug via competitive inhibition or in redesigning the drug for better
pharmacological effects. This study will also have useful clinical implications in reducing the gut microbiota
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External links
"Amphetamine" (https://druginfo.nlm.nih.gov/drugportal/name/amphetamine). Drug Information Portal. United
States National Library of Medicine.
CID 5826 (https://pubchem.ncbi.nlm.nih.gov/compound/5826) from PubChem –
Dextroamphetamine CID 32893 (https://pubchem.ncbi.nlm.nih.gov/compound/32893) from PubChem
– Levoamphetamine
Comparative Toxicogenomics Database entry: Amphetamine (http://ctdbase.org/query.go?type=ixn&chemqt=e
quals&chem=name%3AAmphetamine&actionDegreeTypes=increases&actionDegreeTypes=decreases&action
DegreeTypes=affects&actionTypes=ANY&geneqt=equals&gene=&pathwayqt=equals&pathway=&taxonqt=equ
als&taxon=TAXON%3A9606&goqt=equals&go=&sort=chemNmSort&perPage=500&action=Search)
Comparative Toxicogenomics Database entry: CARTPT (http://ctdbase.org/detail.go?type=gene&acc=9607&qi
d=2119242)

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