Amphetamine
An image of the amphetamine compound
A 3d image of the D-amphetamine compound
Clinical data
Other namesα-methylphenethylamine
AHFS/Drugs.comamphetamine
License data
Dependence
liability
Physical: none
Psychological: moderate
Addiction
liability
Moderate
Routes of
administration
Medical: oral, nasal inhalation
Recreational: oral, nasal inhalation, insufflation, rectal, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRectal 95–100%; Oral 75–100%[2]
Protein binding15–40%[3]
MetabolismCYP2D6,[4] DBH,[12][13][14] FMO3,[15][16] XM-ligase,[17] and ACGNAT[18]
Metabolites4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, phenylacetone[4][5][6]
Onset of actionIR dosing: Immediate
XR dosing: 1.5–2 hours[7][8]
Elimination half-lifeD-amph:9–11 hours[4][9]
L-amph:11–14 hours[4][9]
pH-dependent: 8–31 hours[10]
Duration of actionIR dosing: 3–7 hours[7][11]
XR dosing: 12 hours[7][8][11]
ExcretionRenal; pH-dependent range: 1–75%[4]
Identifiers
  • (RS)-1-phenylpropan-2-amine
    (RS)-1-phenyl-2-aminopropane
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.005.543 Edit this at Wikidata
Chemical and physical data
FormulaC9H13N
Molar mass135.20622 g/mol[19] g·mol−1
3D model (JSmol)
Density0.9±0.1 g/cm3
Melting point11.3 °C (52.3 °F) (predicted)[20]
Boiling point203 °C (397 °F) at 760 mm Hg[21]
  • NC(CC1=CC=CC=C1)C
  • InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3 checkY
  • Key:KWTSXDURSIMDCE-UHFFFAOYSA-N checkY
  (verify)

Amphetamine[note 1] ( /æmˈfɛtəmn/ ; contracted from alphamethylphenethylamine) is a potent central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Amphetamine was discovered in 1887 and exists as two enantiomers:[note 2] levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, 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, depression, and obesity. Amphetamine is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription medication in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with substance abuse.[sources 1]

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions. Currently, pharmaceutical amphetamine is typically prescribed as Adderall,[note 3] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases biogenic amine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine. At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased wakefulness, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[sources 2]

Much larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk with large recreational doses, but rarely arises from medical use. 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 4] which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine[note 5] and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a constitutional isomer that differs only in the placement of the methyl group.[sources 4]

Uses

Medical

Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder), and is sometimes prescribed off-label for its past medical indications, such as depression, obesity, and nasal congestion.[9][25] Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage,[46][47] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[48][49][50] Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.[48][49][50]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[51][52][53] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.[51][53] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[51]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[54] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[54] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[26][54][55] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[56] 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.[57][58] The Cochrane Collaboration's review[note 6] on the treatment of adult ADHD with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[60] A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[61]

Enhancing performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces unambiguous improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults;[62][63] the cognition-enhancing effects of amphetamine are known to occur through its indirect activation of both dopamine receptor D1 and adrenoceptor A2 in the prefrontal cortex.[62] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[26][64] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[26][65][66] 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.[26][65][67] Based upon studies of self-reported illicit stimulant use, students primarily use stimulants such as amphetamine for performance enhancement rather than using them as recreational drugs.[68] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[26][65]

Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness;[27][39] however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies.[69][70] In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time.[27][71][72] Amphetamine improves stamina, endurance, and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[71][72][73] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[27][71][72] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[28][37][71]

Contraindications

See also: Amphetamine § Interactions

According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 7] amphetamine is contraindicated in people with a history of drug abuse, heart disease, severe agitation, or severe anxiety.[74][75] It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or hypertension.[74][75] People who have experienced allergic reactions to other stimulants in the past or who are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine.[74][75] 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.[74][75] 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.[75] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[74][75] Due to the potential for reversible growth impairments,[note 8] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[74]

Side effects

The side effects of amphetamine are varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of side effects.[28][37][39] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[36][37] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.[39]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[37] Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to extremities), and tachycardia (increased heart rate).[37][39][76] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[37] Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss.[37] Other potential side effects include acne, blurred vision, dry mouth, excessive grinding of the teeth, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, and tics (a type of movement disorder).[sources 5] Dangerous physical side effects are rare at typical pharmaceutical doses.[39]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[39] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[39] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control.[39] The effects of amphetamine on the gastrointestinal tract are unpredictable.[39] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[39] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[39] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[39]

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]

Psychological

Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[37][39] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 7] these effects depend on the user's personality and current mental state.[39] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[28][37][40] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[28][37][41] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[37]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[60][83] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[83][84]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[75][85] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[39][75] 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.[75] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[28][39] 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 9][86]

Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction.[87][88] Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since repeated overdoses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.[89][90][91] 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.[89][92] 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.[93] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[92][93][94] exercise therapy improves clinical treatment outcomes and may be used as a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.[93][94][95] Template:Amphetamine overdose

Addiction

Addiction and dependence glossary[84][90][96]
  • addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
  • addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
  • drug withdrawal – symptoms that occur upon cessation of repeated drug use
  • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
  • psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome)
  • reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
  • rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
  • sensitization – an amplified response to a stimulus resulting from repeated exposure to it
  • substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
  • tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
Signaling cascade in the nucleus accumbens that results in amphetamine addiction
The image above contains clickable links
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[97][98] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[97][87] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[97][91][99] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[100] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[91][99] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[91][99]

Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical medical use at therapeutic doses.[39][42][43] Drug tolerance develops rapidly in amphetamine abuse (i.e., a recreational amphetamine overdose), so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[101][102]

Biomolecular mechanisms

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.[103][104][105] The most important transcription factors[note 10] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB).[104] ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 11] for most of the behavioral and neural adaptations that arise from addiction.[89][90][104] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[89][90] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 8]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression).[90][104][109] 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).[104] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[92][104][110] Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.[92][104] Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[92][111] These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[92][110][111]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[105] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[105] The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.[105] This suggests that medical use of amphetamine does not significantly affect gene regulation.[105]

Pharmacological treatments

As of May 2014, there is no effective pharmacotherapy for amphetamine addiction.[112][113][114] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 12] in the nucleus accumbens;[88] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[88][115] One review suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[88] Supplemental magnesium[note 13] and fluoxetine treatment have been shown to reduce amphetamine self-administration (doses given to oneself) in humans, but neither is an effective monotherapy for amphetamine addiction.[88][116][needs update]

Behavioral treatments

Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction.[95] Additionally, research on the neurobiological effects of physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct therapy (i.e., a supplemental treatment) for amphetamine addiction.[92][93][94] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[93][94] In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D2 (DRD2) density in the striatum.[92] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[92]

For the silicon wafer box, see FOUP.

DL-amphetamine
Identifiers
Aliases1-phenyl-2-aminopropaneα-methylbenzeneethaneamineα-methylphenethylamineβ-aminopropylbenzeneβ-phenylisopropylamine(±)-amphetamine1-phenylpropan-2-aminalpha-methylbenzeneethaneamineamfetaminebeta-aminopropylbenzenebeta-phenylisopropylaminbeta-phenylisopropylaminedesoxynorephedrinealpha-methylphenethylamineAmphetaminealpha-methylphenethylaminebeta-Aminopropylbenzene1-Phenylpropan-2-aminbeta-Phenylisopropylaminerac-amphetaminerac-(2R)-1-phenylpropan-2-aminealpha-Methylbenzeneethaneaminealpha-methylphenylethylamineamphetaminegoeyloueespeedupperswhiz
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.[117][118][119]

The FOS gene family consists of four members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (e.g., c-Jun, JunD), thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.[117] FosB and its truncated splice variants, ΔFosB and further truncated Δ2ΔFosB, are all involved in osteosclerosis, although Δ2ΔFosB lacks a known transactivation domain, in turn preventing it from affecting transcription through the AP-1 complex.[120]

The ΔFosB splice variant has been identified as playing a central, crucial[89][104] role in the development and maintenance of addiction.[89][92][90] ΔFosB overexpression (i.e., an abnormally and excessively high level of ΔFosB expression which produces a pronounced gene-related phenotype) triggers the development of addiction-related neuroplasticity throughout the reward system and produces a behavioral phenotype that is characteristic of an addiction.[89][90][121] ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only accumbal ΔFosB overexpression is associated with pathological responses to drugs.[122]

DeltaFosB

DeltaFosB – more commonly written as ΔFosB – is a truncated splice variant of the FOSB gene.[123] ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions.[104][92][110] In the brain's reward system, it is linked to changes in a number of other gene products, such as CREB and sirtuins.[124][125][126] In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.[127]

In the nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.[89][91][128] In other words, once "turned on" (sufficiently overexpressed) ΔFosB triggers a series of transcription events that ultimately produce an addictive state (i.e., compulsive reward-seeking involving a particular stimulus); this state is sustained for months after cessation of drug use due to the abnormal and exceptionally long half-life of ΔFosB isoforms.[89][91][128] ΔFosB expression in D1-type nucleus accumbens medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion.[89][90] Based upon the accumulated evidence, a medical review from late 2014 argued that accumbal ΔFosB expression can be used as an addiction biomarker and that the degree of accumbal ΔFosB induction by a drug is a metric for how addictive it is relative to others.[89]

Chronic administration of anandamide, or N-arachidonylethanolamide (AEA), an endogenous cannabinoid, and additives such as sucralose, a noncaloric sweetener used in many food products of daily intake, are found to induce an overexpression of ΔFosB in the infralimbic cortex (Cx), nucleus accumbens (NAc) core, shell, and central nucleus of amygdala (Amy), that induce long-term changes in the reward system.[129]

Role in addiction

Addiction and dependence glossary[90][84][96]
  • addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
  • addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
  • drug withdrawal – symptoms that occur upon cessation of repeated drug use
  • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
  • psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome)
  • reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
  • rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
  • sensitization – an amplified response to a stimulus resulting from repeated exposure to it
  • substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
  • tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
The image above contains clickable links
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[97][98] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[97][87] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[97][91][99] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[100] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[91][99] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[91][99]

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[104][103][105] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[104] ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction.[89][104][90] ΔFosB overexpression has been implicated in addictions to alcohol (ethanol), cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[89][104][103][107][108] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression.[104][90][109] Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[121][104] Repression of c-Fos by ΔFosB, which consequently further induces expression of ΔFosB, forms a positive feedback loop that serves to indefinitely perpetuate the addictive state.

ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[104][110] Natural rewards, similar to drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.[104][92][110] Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well;[104][92][110] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[110] Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional reward cross-sensitization effects[note 14] that are mediated through ΔFosB.[92][111] This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.[92]

ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.[130] Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors[note 15] – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged use.[121][109][131][132] These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing addictive behavior in lab animals[note 16] that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;[109][132][133][134] however, as of August 2015, few clinical trials involving humans with addiction and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen.[note 17]

Plasticity in cocaine addiction

See also: Epigenetics of cocaine addiction

ΔFosB accumulation from excessive drug use
ΔFosB accumulation graph
Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-Fos, FosB, ΔFosB, Fra1, and Fra2).
Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37 kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months.[128][99]

ΔFosB levels have been found to increase upon the use of cocaine.[136] Each subsequent dose of cocaine continues to increase ΔFosB levels with no apparent ceiling of tolerance.[citation needed] Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug.

Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to cocaine.[137] They self-administer cocaine at lower doses than control,[138] but have a greater likelihood of relapse when the drug is withheld.[128][138] ΔFosB increases the expression of AMPA receptor subunit GluR2[137] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.[128]

Neural and behavioral effects of validated ΔFosB transcriptional targets[89][124]
Target
gene
Target
expression
Neural effects Behavioral effects
c-Fos Molecular switch enabling the chronic
induction of ΔFosB[note 18]
dynorphin
[note 19]
 • Downregulation of κ-opioid feedback loop  • Diminished self-extinguishing response to drug
NF-κB  • Expansion of Nacc dendritic processes
 • NF-κB inflammatory response in the NAcc
 • NF-κB inflammatory response in the CPTooltip caudate putamen
 • Increased drug reward
 • Locomotor sensitization
GluR2  • Decreased sensitivity to glutamate  • Increased drug reward
Cdk5  • GluR1 synaptic protein phosphorylation
 • Expansion of NAcc dendritic processes
 • Decreased drug reward
(net effect)

Summary of addiction-related plasticity

Form of neuroplasticity
or behavioral plasticity
Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
(aerobic)
Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNsTooltip medium spiny neurons
[92]
Behavioral plasticity
Escalation of intake Yes Yes Yes [92]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [92]
Psychostimulant
self-administration
[92]
Psychostimulant
conditioned place preference
[92]
Reinstatement of drug-seeking behavior [92]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation
in the nucleus accumbens
[92]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [92]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [92]
Altered striatal opioid signaling No change or
μ-opioid receptors
μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [92]
Changes in striatal opioid peptides dynorphin
No change: enkephalin
dynorphin enkephalin dynorphin dynorphin [92]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [92]
Dendritic spine density in
the nucleus accumbens
[92]

Other functions in the brain

Viral overexpression of ΔFosB in the output neurons of the nigrostriatal dopamine pathway (i.e., the medium spiny neurons in the dorsal striatum) induces levodopa-induced dyskinesias in animal models of Parkinson's disease.[139][140] Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias;[140] postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression.[140] Levetiracetam, an antiepileptic drug, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa;[140] the signal transduction involved in this effect is unknown.[140]

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.[141][142][143]

Antipsychotic drugs have been shown to increase ΔFosB as well, more specifically in the prefrontal cortex. This increase has been found to be part of pathways for the negative side effects that such drugs produce.[144]

See also

Notes

  1. ^ Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name), α-methylbenzeneethanamine, α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, desoxynorephedrine, and speed.[19][22][23]
  2. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[24]
    Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.[19]
  3. ^ "Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"[36]) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.
  4. ^ 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 the class.
  5. ^ Again, due to confusion that may arise from use of the plural form, this article will only use "phenethylamine" and "phenethylamines" to refer to the compound itself and reserve the term "substituted phenethylamines" for the class.
  6. ^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[59]
  7. ^ The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.
  8. ^ 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.[51][53][76] The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.[76]
  9. ^ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
  10. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[106]
  11. ^ 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.
  12. ^ 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.[115]
  13. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[88] other forms of magnesium were not mentioned.
  14. ^ In simplest terms, this means that when either amphetamine or sex is perceived as "more alluring or desirable" through reward sensitization, this effect occurs with the other as well.
  15. ^ Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs that inhibit four specific histone-modifying enzymes: HDAC1, HDAC2, HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has been conducted with four drugs: butyrate salts (mainly sodium butyrate), trichostatin A, valproic acid, and SAHA;[131][132] butyric acid is a naturally occurring short-chain fatty acid in humans, while the latter two compounds are FDA-approved drugs with medical indications unrelated to addiction.
  16. ^ Specifically, prolonged administration of a class I HDAC inhibitor appears to reduce an animal's motivation to acquire and use an addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational anhedonia) and reduce the amount of the drug that is self-administered when it is readily available.[109][132][133]
  17. ^ Among the few clinical trials that employed a class I HDAC inhibitor, one utilized valproate for methamphetamine addiction.[135]
  18. ^ In other words, c-Fos repression allows ΔFosB to accumulate within nucleus accumbens medium spiny neurons more rapidly because it is selectively induced in this state.[90]
  19. ^ ΔFosB has been implicated in causing both increases and decreases in dynorphin expression in different studies;[89][124] this table entry reflects only a decrease.
Image legend
  1. ^
      (Text color) Transcription factors
  2. ^
      (Text color) Transcription factors

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  90. ^ a b c d e f g h i j k l Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. Cite error: The named reference "Cellular basis" was defined multiple times with different content (see the help page).
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  95. ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 386. ISBN 9780071481274. Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.((cite book)): CS1 maint: multiple names: authors list (link)
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  97. ^ a b c d e f Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
    Figure 2: Psychostimulant-induced signaling events
  98. ^ a b Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
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  122. ^ Ohnishi YN, Ohnishi YH, Vialou V, Mouzon E, LaPlant Q, Nishi A, Nestler EJ (January 2015). "Functional role of the N-terminal domain of ΔFosB in response to stress and drugs of abuse". Neuroscience. 284: 165–70. doi:10.1016/j.neuroscience.2014.10.002. PMC 4268105. PMID 25313003.
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  124. ^ a b c Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure—cited earlier (Renthal et al. in press). The mechanism responsible for ΔFosB repression of c-fos expression is complex and is covered below. ...
    Examples of validated targets for ΔFosB in nucleus accumbens ... GluR2 ... dynorphin ... Cdk5 ... NFκB ... c-Fos

    Table 3
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     • Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation". Nat. Neurosci. 16 (4): 434–440. doi:10.1038/nn.3354. PMC 3609040. PMID 23475113. While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity3,5,11,12. ... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug1,3,4,13,14. In contrast, experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several days prior to psychostimulant exposure, show inhibited expression3 or decreased acquisition of behavioral adaptations to drug5,11,12. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of psychostimulant-regulated target genes. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression.

     • Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (July 2015). "The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol. 20 (4): 676–689. doi:10.1111/adb.12161. PMID 25041570. S2CID 28667144. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.

     • Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats". PLOS ONE. 10 (4): e0124796. Bibcode:2015PLoSO..1024796C. doi:10.1371/journal.pone.0124796. PMC 4399837. PMID 25880762. treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately ... These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.
  134. ^ Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic remodeling in alcoholism". Neurosci. Lett. 601: 11–9. doi:10.1016/j.neulet.2015.01.051. PMC 4506731. PMID 25623036. Increased HDAC2 expression decreases the expression of genes important for the maintenance of dendritic spine density such as BDNF, Arc, and NPY, leading to increased anxiety and alcohol-seeking behavior. Decreasing HDAC2 reverses both the molecular and behavioral consequences of alcohol addiction, thus implicating this enzyme as a potential treatment target (Fig. 3). HDAC2 is also crucial for the induction and maintenance of structural synaptic plasticity in other neurological domains such as memory formation [115]. Taken together, these findings underscore the potential usefulness of HDAC inhibition in treating alcohol use disorders ... Given the ability of HDAC inhibitors to potently modulate the synaptic plasticity of learning and memory [118], these drugs hold potential as treatment for substance abuse-related disorders. ... Our lab and others have published extensively on the ability of HDAC inhibitors to reverse the gene expression deficits caused by multiple models of alcoholism and alcohol abuse, the results of which were discussed above [25,112,113]. This data supports further examination of histone modifying agents as potential therapeutic drugs in the treatment of alcohol addiction ... Future studies should continue to elucidate the specific epigenetic mechanisms underlying compulsive alcohol use and alcoholism, as this is likely to provide new molecular targets for clinical intervention.
  135. ^ Kheirabadi GR, Ghavami M, Maracy MR, Salehi M, Sharbafchi MR (2016). "Effect of add-on valproate on craving in methamphetamine depended patients: A randomized trial". Advanced Biomedical Research. 5: 149. doi:10.4103/2277-9175.187404. PMC 5025910. PMID 27656618.
  136. ^ Hope BT (May 1998). "Cocaine and the AP-1 transcription factor complex". Annals of the New York Academy of Sciences. 844 (1): 1–6. Bibcode:1998NYASA.844....1H. doi:10.1111/j.1749-6632.1998.tb08216.x. PMID 9668659. S2CID 11683570.
  137. ^ a b Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (September 1999). "Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine". Nature. 401 (6750): 272–6. Bibcode:1999Natur.401..272K. doi:10.1038/45790. PMID 10499584. S2CID 4390717.
  138. ^ a b Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (March 2003). "Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine". The Journal of Neuroscience. 23 (6): 2488–93. doi:10.1523/JNEUROSCI.23-06-02488.2003. PMC 6742034. PMID 12657709.
  139. ^ Cao X, Yasuda T, Uthayathas S, Watts RL, Mouradian MM, Mochizuki H, Papa SM (May 2010). "Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements". The Journal of Neuroscience. 30 (21): 7335–43. doi:10.1523/JNEUROSCI.0252-10.2010. PMC 2888489. PMID 20505100.
  140. ^ a b c d e Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, Papa SM, Cao X (2015). "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease. 2015: 253878. doi:10.1155/2015/253878. PMC 4322303. PMID 25692070. Furthermore, the transgenic overexpression of ΔFosB reproduces AIMs in hemiparkinsonian rats without chronic exposure to L-DOPA [13]. ... FosB/ΔFosB immunoreactive neurons increased in the dorsolateral part of the striatum on the lesion side with the used antibody that recognizes all members of the FosB family. All doses of levetiracetam decreased the number of FosB/ΔFosB positive cells (from 88.7 ± 1.7/section in the control group to 65.7 ± 0.87, 42.3 ± 1.88, and 25.7 ± 1.2/section in the 15, 30, and 60 mg groups, resp.; Figure 2). These results indicate dose-dependent effects of levetiracetam on FosB/ΔFosB expression. ... In addition, transcription factors expressed with chronic events such as ΔFosB (a truncated splice variant of FosB) are overexpressed in the striatum of rodents and primates with dyskinesias [9, 10]. ... Furthermore, ΔFosB overexpression has been observed in postmortem striatal studies of Parkinsonian patients chronically treated with L-DOPA [26]. ... Of note, the most prominent effect of levetiracetam was the reduction of ΔFosB expression, which cannot be explained by any of its known actions on vesicular protein or ion channels. Therefore, the exact mechanism(s) underlying the antiepileptic effects of levetiracetam remains uncertain.
  141. ^ "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Retrieved 6 September 2014.
  142. ^ Furuyashiki T, Deguchi Y (August 2012). "[Roles of altered striatal function in major depression]". Brain and Nerve = Shinkei Kenkyū No Shinpo (in Japanese). 64 (8): 919–26. PMID 22868883.
  143. ^ Nestler EJ (April 2015). "∆FosB: a transcriptional regulator of stress and antidepressant responses". European Journal of Pharmacology. 753: 66–72. doi:10.1016/j.ejphar.2014.10.034. PMC 4380559. PMID 25446562. In more recent years, prolonged induction of ∆FosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ∆FosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ∆FosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ∆FosB within the NAc. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development.
  144. ^ Dietz DM, Kennedy PJ, Sun H, Maze I, Gancarz AM, Vialou V, Koo JW, Mouzon E, Ghose S, Tamminga CA, Nestler EJ (February 2014). "ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes". Neuropsychopharmacology. 39 (3): 538–44. doi:10.1038/npp.2013.255. PMC 3895248. PMID 24067299.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


Dependence and withdrawal

According to another Cochrane Collaboration review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[1] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.[1] 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.[1] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[1] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[2][3][4]

Toxicity and psychosis

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by reduced transporter and receptor function.[5] There is no evidence that amphetamine is directly neurotoxic in humans.[6][7] However, large doses of amphetamine may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[8][9][10]

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as paranoia and delusions.[11] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[11][12] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[11] Psychosis very rarely arises from therapeutic use.[13][14]

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.[15][16] Inhibitors of the enzymes that metabolize amphetamine (e.g., CYP2D6 and flavin-containing monooxygenase 3) will prolong its elimination half-life, meaning that its effects will last longer.[17][16] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[16] therefore, concurrent use of both is dangerous.[16] 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.[16] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[16] 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.[16] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[16] 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).[16]

Pharmacology

Pharmacodynamics

Pharmacodynamics of amphetamine in a dopamine neuron
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[18] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[18][19] 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.[19][20] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via G protein-coupled inwardly rectifying potassium channels (GIRKs) and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[18][21][22] PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[18] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[18] 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.[23][24]

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.[18][25] 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 due to its effects on monoamine transporters.[18][25][19] The reinforcing and task saliency effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[26]

Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[18][27] Activation of TAAR1 increases cAMPTooltip cyclic adenosine monophosphate production via adenylyl cyclase activation and inhibits monoamine transporter function.[18][28] 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.[18] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.[18] 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.[18] As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[18]

In addition to the neuronal monoamine transporters, amphetamine also inhibits vesicular monoamine transporter 2 (VMAT2), SLC1A1, SLC22A3, and SLC22A5.[sources 9] 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 carnitine transporter.[sources 9] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[33][34] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[34][35][36] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[36][37] Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.[38][39] 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 micromolar affinity.[40][41]

The full profile of amphetamine's short-term drug effects is mostly derived through increased cellular communication or neurotransmission of dopamine,[18] serotonin,[18] norepinephrine,[18] epinephrine,[19] histamine,[19] CART peptides,[33][34] acetylcholine,[42][43] endogenous opioids,[44][45] and glutamate,[46][47] which it effects through interactions with CART, 5-HT1A, EAAT3, TAAR1, and VMAT2.[sources 10]

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[48] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[49][48]

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[18] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[18] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[18] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[18] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).[18][50] Amphetamine is also known to increase intracellular calcium, a known effect of TAAR1 activation, which is associated with DAT phosphorylation through a Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux.[27][23][24] Through direct activation of G protein-coupled inwardly-rectifying potassium channels and an indirect increase in dopamine autoreceptor signaling, TAAR1 reduces the firing rate of postsynaptic dopamine receptors, preventing a hyper-dopaminergic state.[21][22][51]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[19] Following amphetamine uptake at VMAT2, the synaptic vesicle releases dopamine molecules into the cytosol in exchange.[19] Subsequently, the cytosolic dopamine molecules exit the presynaptic neuron via reverse transport at DAT.[18][19]

Norepinephrine

Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[52][25] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[18][19][50] 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.[18][19]

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[18][25] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[18][19] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[40][41]

Other neurotransmitters and peptides

Amphetamine has no direct effect on acetylcholine neurotransmission, but several studies have noted that acetylcholine release increases after its use.[42][43] In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream effect.[42] In humans, a similar phenomenon occurs via the ghrelin-mediated cholinergic–dopaminergic reward link in the ventral tegmental area.[43] Acute amphetamine administration in humans also increases endogenous opioid release in several brain structures in the reward system.[44][45]

Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase upon exposure to amphetamine.[46][47] This cotransmission effect was found in the mesolimbic pathway, an area of the brain implicated in reward, where amphetamine is known to affect dopamine neurotransmission.[46][47] Amphetamine also induces effluxion of histamine from synaptic vesicles in CNS mast cells and histaminergic neurons through VMAT2.[19]

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;[16] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[53] Amphetamine is a weak base with a pKa of 9–10;[15] 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.[15][16] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[15] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[54]

The half-life of amphetamine enantiomers differ and vary with urine pH.[15] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[15] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[55][56] 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.[15] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[15] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[15] 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.[15] Amphetamine is usually eliminated within two days of the last oral dose.[55] Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.[57]

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[58] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[58] The elimination half-life of lisdexamfetamine is generally less than one hour.[58]

CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase 3, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize amphetamine or its metabolites in humans.[sources 11] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[15][55][65] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[66] 4‑hydroxynorephedrine,[67] and norephedrine.[68] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[15][55] The known pathways and detectable metabolites in humans include the following:[15][17][65]

Metabolic pathways of amphetamine in humans[sources 12]
Graphic of several routes of amphetamine metabolism
Amphetamine
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
The image above contains clickable links
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[65] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[15] The remaining 10–20% is excreted as the active metabolites.[15] Benzoic acid is metabolized by butyrate-CoA ligase into an intermediate product, benzoyl-CoA,[63] which is then metabolized by glycine N-acyltransferase into hippuric acid.[64]

Related endogenous compounds

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain.[18][52] 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).[18][52][74] 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.[52][74] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[52][74] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;[18][74] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[52][74]

Physical and chemical properties

An image of amphetamine free base
A vial of the colorless amphetamine free base
An image of phenyl-2-nitropropene and amphetamine hydrochloride
Amphetamine hydrochloride (left bowl)
Phenyl-2-nitropropene (right cups)

Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula Template:Chemical formula. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomeric mirror images.[75] This racemic mixture can be separated into its optical isomers:[note 2] levoamphetamine and dextroamphetamine.[75] Physically, 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.[77] Frequently prepared solid salts of amphetamine include amphetamine aspartate,[78] hydrochloride,[79] phosphate,[80] saccharate,[78] and sulfate,[78] the last of which is the most common amphetamine salt.[81] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[75] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[82]

Derivatives

Amphetamine derivatives, often referred to as "amphetamines" or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone".[83][84] The class includes stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[83][84] This class of chemicals is sometimes referred to collectively as the "amphetamine family."[85]

Synthesis

Template:Details3 Since the first preparation was reported in 1887,[86] numerous synthetic routes to amphetamine have been developed.[87][88] Many of these syntheses are based on classic organic reactions. One such example is the Friedel–Crafts alkylation of chlorobenzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 1).[89] Another example employs the Ritter reaction (method 2). 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.[90][91] 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 Hofmann or Curtius rearrangement (method 3).[92]

A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime or other nitrogen-containing functional groups.[87] 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 4).[93][94] 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 5).[94]

The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 6).[81][94] 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.[94][95]

A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[88] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[96] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[97] 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.[97]

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

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 13] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[102] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[103] 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 (e.g., the American version of Vicks VapoInhaler,[104] which contains levomethamphetamine) or illicitly obtained substituted amphetamines.[103][105][106] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[107][108][109] These compounds may produce positive results for amphetamine on drug tests.[108][109] Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for two to four days.[102]

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.[105] 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.[103] 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.[103] 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.[103]

History, society, and culture

Global estimates of drug users in 2016
(in millions of users)[110]
Substance Best
estimate
Low
estimate
High
estimate
Amphetamine-
type stimulants
34.16 13.42 55.24
Cannabis 192.15 165.76 234.06
Cocaine 18.20 13.87 22.85
Ecstasy 20.57 8.99 32.34
Opiates 19.38 13.80 26.15
Opioids 34.26 27.01 44.54

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[86][111][112] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[112] Amphetamine had no pharmacological use until 1934, when Smith, Kline and French began selling it as an inhaler under the trade name Benzedrine as a decongestant.[113] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[86][114][115] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[86] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[116] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[117] musicians,[118] mathematicians,[119] and athletes.[98]

Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[120] Among European Union (EU) member states, 1.2 million young adults used illicit amphetamine or methamphetamine in 2013.[121] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[121] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.[121] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[120]

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.[122] Consequently, it is heavily regulated in most countries.[123][124] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[125][126] In other nations, such as Canada (schedule I drug),[127] the Netherlands (List I drug),[128] (Dutch) the United States (schedule II drug),[78] Thailand (category 1 narcotic),[129] and United Kingdom (class B drug),[130] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[120][131]

Pharmaceutical products

The only currently prescribed amphetamine formulation that contains both enantiomers is Adderall.[note 3][75][107] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[132][133] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[133] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[75][107] Levoamphetamine was previously available as Cydril.[107] All current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[107][132][81] Some of the current brands and their generic equivalents are listed below.

Amphetamine pharmaceuticals
Brand
name
United States
Adopted Name
(D:L) ratio
of salts
Dosage
form
Source
Adderall 3:1 tablet [107][132]
Adderall XR 3:1 capsule [107][132]
Dexedrine dextroamphetamine sulfate 1:0 capsule [107][132]
ProCentra dextroamphetamine sulfate 1:0 liquid [132]
Vyvanse lisdexamfetamine dimesylate 1:0 capsule [107][133]
Zenzedi dextroamphetamine sulfate 1:0 tablet [132]
 
An image of the lisdexamphetamine compound
The skeletal structure of lisdexamfetamine

Notes

  1. ^ 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.[69][70] 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;[70][61] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[72][73]
  2. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[76]
  3. ^ Cite error: The named reference Adderall was invoked but never defined (see the help page).
Image legend


Reference notes

References

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