出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2019/08/08 20:31:40」(JST)
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| Pronunciation | /æmˈfɛtəmiːn/ (listen) |
| Trade names | Adderall, Adzenys XR-ODT, Dyanavel XR, Evekeo, others |
| Synonyms | α-methylphenethylamine |
| AHFS/Drugs.com | amphetamine |
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| Dependence liability | Moderate[1] |
| Addiction liability | Moderate |
| Routes of administration | Medical: oral, intravenous[2] Recreational: oral, insufflation, rectal, intravenous, intramuscular |
| Drug class | CNS stimulant, anorectic |
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| Bioavailability | Oral: 75–100%[8] |
| Protein binding | 15–40%[9] |
| Metabolism | CYP2D6,[3] DBH,[4][5] FMO3[4][6][7] |
| Metabolites | 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, phenylacetone[3][10] |
| Onset of action | IR dosing: 30–60 minutes[11] XR dosing: 1.5–2 hours[12][13] |
| Elimination half-life | D-amph: 9–11 hours[3][14] L-amph: 11–14 hours[3][14] pH-dependent: 7–34 hours[15] |
| Duration of action | IR dosing: 3–6 hours[1][12][16] XR dosing: 8–12 hours[1][12][16] |
| Excretion | Primarily renal; pH-dependent range: 1–75%[3] |
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| ECHA InfoCard | 100.005.543 |
| Chemical and physical data | |
| Formula | C9H13N |
| Molar mass | 135.20622 g/mol[17] g·mol−1 |
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| Chirality | Racemic mixture[18] |
| Density | .936 g/cm3 at 25 °C[19] |
| Melting point | 11.3 °C (52.3 °F) (predicted)[20] |
| Boiling point | 203 °C (397 °F) at 760 mmHg[21] |
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Amphetamine[note 1] (contracted from alpha-methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered 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. 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 3] 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 4] which includes prominent substances such as bupropion, cathinone, MDMA, and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a positional isomer of amphetamine that differs only in the placement of the methyl group.[sources 4]
Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy (a sleep disorder), and obesity, and is sometimes prescribed off-label for its past medical indications, particularly for depression and chronic pain.[1][34][49] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[50][51] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[52][53][54] 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.[52][53][54]
Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[43][55][56] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[43][55] Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes[note 5] across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.[43][56] One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[55] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.[43]
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[57] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.[57] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[25][57][58] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[59] 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.[60][61] The Cochrane reviews[note 6] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[63][64] A Cochrane review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[65]
In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;[66][67] 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.[25][66] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[68] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[25][69] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[25][70][71] 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.[25][71][72] 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.[73][74][75] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[25][71]
Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[26][39] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[76][77] 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.[26][78][79] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.[78][79][80] 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.[79][81][82] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[26][78] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[27][38][78]
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,[note 8] cardiovascular disease, severe agitation, or severe anxiety.[34][84][85] It is also contraindicated in people currently experiencing advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension.[34][84][85] 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,[34][84][85] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[86][87] 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.[84][85] 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.[85] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[84][85] Due to the potential for reversible growth impairments,[note 9] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[84]
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.[27][38][39] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[35][38] 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.[39]
At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[38] 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).[38][39][88] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[38] Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea.[1][38][89] 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.[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.[39] 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.[1][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] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.[sources 7]
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.[38][39] 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.[39] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[38][40][41] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[38][41][42] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[38]
Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[63][96] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[96][97]
| Addiction and dependence glossary[97][98][99][100] | |
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Signaling cascade in the nucleus accumbens that results in amphetamine addiction
Note: colored text contains article links.
Nuclear pore
Nuclear membrane
Plasma membrane
Cav1.2
NMDAR
AMPAR
DRD1
DRD5
DRD2
DRD3
DRD4
Gs
Gi/o
AC
cAMP
cAMP
PKA
CaM
CaMKII
DARPP-32
PP1
PP2B
CREB
ΔFosB
JunD
c-Fos
SIRT1
HDAC1
[Color legend 1] 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,[101][102] 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.[101][103] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[101][104][105] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[106] 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.[104][105] 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.[104][105]
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Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;[43][44][45] in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult.[43] 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.[107][108] Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.[98][109][110] 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.[109][111] 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.[112][113] 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 a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.[112][114][115]
Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[116][117][118] The most important transcription factors[note 10] 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).[117] ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB overexpression (i.e., an abnormally high level of gene expression which produces a pronounced gene-related phenotype) in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 11] for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction.[98][109][117] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[98][109] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 10]
ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.[98][117][122] 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).[117] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[111][117][123] 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.[111][117] Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sexual addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[111][124][125] These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[111][123]
The effects of amphetamine on gene regulation are both dose- and route-dependent.[118] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[118] 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.[118] This suggests that medical use of amphetamine does not significantly affect gene regulation.[118]
As of 2015,[update] there is no effective pharmacotherapy for amphetamine addiction.[126][127][128] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[37][129] however, as of February 2016,[update] the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[37][129] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 12] in the nucleus accumbens;[108] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[108][130] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[108] Supplemental magnesium[note 13] treatment has been shown to reduce amphetamine self-administration (i.e., doses given to oneself) in humans, but it is not an effective monotherapy for amphetamine addiction.[108]
Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addictions.[115] Additionally, research on the neurobiological effects of physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct therapy (i.e., a supplemental treatment) for amphetamine addiction.[sources 9] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[112][114][131] 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.[111][131] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[111] One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system.[113]
| Form of neuroplasticity or behavioral plasticity |
Type of reinforcer | Sources | |||||
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| Opiates | Psychostimulants | High fat or sugar food | Sexual intercourse | Physical exercise (aerobic) |
Environmental enrichment | ||
| ΔFosB expression in nucleus accumbens D1-type MSNs |
↑ | ↑ | ↑ | ↑ | ↑ | ↑ | [111] |
| Behavioral plasticity | |||||||
| Escalation of intake | Yes | Yes | Yes | [111] | |||
| Psychostimulant cross-sensitization |
Yes | Not applicable | Yes | Yes | Attenuated | Attenuated | [111] |
| Psychostimulant self-administration |
↑ | ↑ | ↓ | ↓ | ↓ | [111] | |
| Psychostimulant conditioned place preference |
↑ | ↑ | ↓ | ↑ | ↓ | ↑ | [111] |
| Reinstatement of drug-seeking behavior | ↑ | ↑ | ↓ | ↓ | [111] | ||
| Neurochemical plasticity | |||||||
| CREB phosphorylation in the nucleus accumbens |
↓ | ↓ | ↓ | ↓ | ↓ | [111] | |
| Sensitized dopamine response in the nucleus accumbens |
No | Yes | No | Yes | [111] | ||
| Altered striatal dopamine signaling | ↓DRD2, ↑DRD3 | ↑DRD1, ↓DRD2, ↑DRD3 | ↑DRD1, ↓DRD2, ↑DRD3 | ↑DRD2 | ↑DRD2 | [111] | |
| 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 | [111] |
| Changes in striatal opioid peptides | ↑dynorphin No change: enkephalin |
↑dynorphin | ↓enkephalin | ↑dynorphin | ↑dynorphin | [111] | |
| Mesocorticolimbic synaptic plasticity | |||||||
| Number of dendrites in the nucleus accumbens | ↓ | ↑ | ↑ | [111] | |||
| Dendritic spine density in the nucleus accumbens |
↓ | ↑ | ↑ | [111] | |||
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.[127][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]
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[1][85][134] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[39][85] 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.[85] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[27][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 14][135]
| System | Minor or moderate overdose[27][39][85] | Severe overdose[sources 11] |
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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 12] 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]
An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.[40][41] A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[40][143] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[40] Psychosis rarely arises from therapeutic use.[38][41][42]
Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.[3][144] Inhibitors of enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer.[6][144] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[144] therefore, concurrent use of both is dangerous.[144] 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.[144] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[144] Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 15][149]
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.[144] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[144] 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).[144]
Pharmacodynamics of amphetamine in a dopamine neuron
via AADC Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[36] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[36][150] 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.[150][151] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[36][152][153] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[36] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[36] 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.[154][155]
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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.[36][58] 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.[36][58][150] The reinforcing and motivational salience-promoting effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[25] 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 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.[36][156] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function.[36][157] 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.[36][37] Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[36][37] 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.[36] As of 2010,[update] 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.[36]
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 13] 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 13] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[9][163] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[9][164][165] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[165][166] Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines.[17][167] 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.[168][169]
The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine,[36] serotonin,[36] norepinephrine,[36] epinephrine,[150] histamine,[150] CART peptides,[9][163] endogenous opioids,[170][171][172] adrenocorticotropic hormone,[173][174] corticosteroids,[173][174] and glutamate,[154][159] which it effects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets.[sources 14]
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.[39][175]
In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[36] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[36] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[36] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[36] 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 15][36][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.[156][154][155] Through direct activation of G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.[152][153][177]
Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[150][151] 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.[150][151] Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT.[36][150][151]
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[46][58] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[36][150][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.[36][150]
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[36][58] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[36][150] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[168][169]
Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system.[170][171][172] Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine.[154] This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons.[154][159] Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2.[150] Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.[34][173][174]
The oral bioavailability of amphetamine varies with gastrointestinal pH;[144] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[8] Amphetamine is a weak base with a pKa of 9.9;[3] 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.[3][144] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[3] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[9] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[15]
The half-lives of amphetamine enantiomers differ and vary with urine pH.[3] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[3] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[15] highly alkaline urine will increase the half-lives up to 34 hours.[15] 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.[3] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[3] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[3] 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.[3] Following oral administration, amphetamine appears in urine within 3 hours.[15] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[15]
The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[178] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[178] The elimination half-life of lisdexamfetamine is generally less than 1 hour.[178]
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 15] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[3][10] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine,[179] 4-hydroxynorephedrine,[180] and norephedrine.[181] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[3][182] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:
Metabolic pathways of amphetamine in humans[sources 15]
4-Hydroxyphenylacetone
Phenylacetone
Benzoic acid
Hippuric acid
Amphetamine
Norephedrine
4-Hydroxyamphetamine
4-Hydroxynorephedrine
Para-
Hydroxylation Para-
Hydroxylation Para-
Hydroxylation CYP2D6
CYP2D6
unidentified
Beta-
Hydroxylation Beta-
Hydroxylation DBH
DBH
[note 16] Oxidative
Deamination FMO3
Oxidation
unidentified
Glycine
Conjugation XM-ligase GLYAT The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[10] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[3] The remaining 10–20% is excreted as the active metabolites.[3] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[184]
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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.[188][189] Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers Homo sapiens cells (tens of trillions),[note 17][188][190] 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.[188][189][191]
Similar to most biomolecules and other orally administered xenobiotics (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by human gastrointestinal microbiota prior to absorption into blood plasma.[191] The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019.[191] This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.[191]
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.[36][46][192] 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).[36][46][193] 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.[46][193] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[46][193] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[36][192][193] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[46][193]
Racemic amphetamine
Levoamphetamine
Dextroamphetamine The skeletal structures of L-amph and D-amph
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Amphetamine is a methyl homolog of the mammalian 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.[22] This racemic mixture can be separated into its optical isomers:[note 18] levoamphetamine and dextroamphetamine.[22] 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.[21] Frequently prepared solid salts of amphetamine include amphetamine aspartate,[27] hydrochloride,[194] phosphate,[195] saccharate,[27] and sulfate,[27] the last of which is the most common amphetamine salt.[47] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[4][22] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[196]
The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";[4][48][197] specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents.[4][48][198] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[4][48][197]
Since the first preparation was reported in 1887,[199] numerous synthetic routes to amphetamine have been developed.[200][201] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1).[47][202] 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.[202][203]
A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[200] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[204] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[205] 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.[205]
A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.[200][201] 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).[206] 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.[207][208] 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 4).[209]
A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime, or other nitrogen-containing functional groups.[201] 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).[202][210] 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).[202]
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Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[sources 16] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[214] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[215] 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 19] or illicitly obtained substituted amphetamines.[215][218][219] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[2][220][221] These compounds may produce positive results for amphetamine on drug tests.[220][221] 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.[214]
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.[218] 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.[215] 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.[215] 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.[215]
| 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;[199][223][224] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[224] Amphetamine had no medical use until late 1933, when Smith, Kline and French began selling it as an inhaler under the brand name Benzedrine as a decongestant.[28] Benzedrine sulfate was introduced 3 years later and was used to treat a wide variety of medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain, among others.[49][28] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[199][225][226] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[199] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[227] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[228] musicians,[229] mathematicians,[230] and athletes.[26]
Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[231] Among European Union (EU) member states in 2018,[update] 11.9 million 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 last year.[232] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[233] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.[233] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[231]
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.[29] Consequently, it is heavily regulated in most countries.[234][235] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[236][237] In other nations, such as Canada (schedule I drug),[238] the Netherlands (List I drug),[239] the United States (schedule II drug),[27] Australia (schedule 8),[240] Thailand (category 1 narcotic),[241] and United Kingdom (class B drug),[242] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[231][30]
Several currently prescribed amphetamine formulations contain both enantiomers, including Adderall, Adderall XR, Mydayis, Adzenys XR-ODT, Dyanavel XR, and Evekeo, the last of which contains racemic amphetamine sulfate.[1][34][89] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[35][178] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[178] 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][35][47] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively.[89][243][244] Some of the current brands and their generic equivalents are listed below.
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|
| drug | formula | molecular mass [note 20] |
amphetamine base [note 21] |
amphetamine base in equal doses |
doses with equal base content [note 22] | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| (g/mol) | (percent) | (30 mg dose) | ||||||||
| total | base | total | dextro- | levo- | dextro- | levo- | ||||
| dextroamphetamine sulfate[249][250] | (C9H13N)2•H2SO4 | |||||||||
| amphetamine sulfate[251] | (C9H13N)2•H2SO4 | |||||||||
| Adderall | ||||||||||
| 25% | dextroamphetamine sulfate[249][250] | (C9H13N)2•H2SO4 | ||||||||
| 25% | amphetamine sulfate[251] | (C9H13N)2•H2SO4 | ||||||||
| 25% | dextroamphetamine saccharate[252] | (C9H13N)2•C6H10O8 | ||||||||
| 25% | amphetamine aspartate monohydrate[253] | (C9H13N)•C4H7NO4•H2O | ||||||||
| lisdexamfetamine dimesylate[178] | C15H25N3O•(CH4O3S)2 | |||||||||
| amphetamine base suspension[note 23][89] | C9H13N | |||||||||
The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation. ... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).
The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
Onset of action: 30–60 min
Table 9.2 Dextroamphetamine formulations of stimulant medication
Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
Adderall [Peak:2–3 h] [Duration:5–7 h]
Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
Adderall XR [Peak:7–8 h] [Duration:12 h]
Vyvanse [Peak:3–4 h] [Duration:12 h]
Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine). ... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3 hours following oral administration. ... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine
Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane. ... In its broadest context, however, the term [amphetamines] can even embrace a large number of structurally and pharmacologically related substances.
One of a pair of molecular entities which are mirror images of each other and non-superposable.
Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ...
Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.
Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
Physiologic and performance effects
• Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
• Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
• Improved reaction time
• Increased muscle strength and delayed muscle fatigue
• Increased acceleration
• Increased alertness and attention to task
However the firm happened to discover the drug, SKF first packaged it as an inhaler so as to exploit the base's volatility and, after sponsoring some trials by East Coast otolaryngological specialists, began to advertise the Benzedrine Inhaler as a decongestant in late 1933.
Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...
Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.
In principle, INNs are selected only for the active part of the molecule which is usually the base, acid or alcohol. In some cases, however, the active molecules need to be expanded for various reasons, such as formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection of INN decided to adopt a new policy for naming such molecules. In future, names for different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule. ... The latter are called modified INNs (INNMs).
When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.
A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
psychotic symptoms of individuals with amphetamine psychosis may be due exclusively to heavy use of the drug or heavy use of the drug may exacerbate an underlying vulnerability to schizophrenia.
In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine ... Secondly, psychosis has been viewed as an adverse event, although rare, in children with ADHD who have been treated with amphetamine
Several other studies,[97-101] including a meta-analytic review[98] and a retrospective study,[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). ... Beyond (1R,2S)-ephedrine and (1S,2S)-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. ... For example, (S)-amphetamine (Figure 4b), a key ingredient in Adderall® and Dexedrine®, is used to treat attention deficit hyperactivity disorder (ADHD) [79]. ...
[Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.
Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
Ongoing research has provided answers to many of the parents' concerns, and has confirmed the effectiveness and safety of the long-term use of medication.
The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.
Only one paper53 examining outcomes beyond 36 months met the review criteria. ... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term.
The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ... The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall.
Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. ... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students.
Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.
In 1980, Chandler and Blair47 showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.
In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is 'off-limits' in a normal (placebo) situation.
Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing.
Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the "safety switch" or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.
statements on package inserts are not intended to limit medical practice. Rather they are intended to limit claims by pharmaceutical companies. ... the FDA asserts explicitly, and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations.
DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1 ... The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6–12 years) were: epistaxis, allergic rhinitis and upper abdominal pain. ...
DOSAGE FORMS AND STRENGTHS
Extended-release oral suspension contains 2.5 mg amphetamine base per mL.
Table 2. Decongestants Causing Rhinitis Medicamentosa
– Nasal decongestants:
– Sympathomimetic:
• Amphetamine
This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.
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.
Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
[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.
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.
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.
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.
The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
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
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
ΔFosB serves as one of the master control proteins governing this structural plasticity.
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).
These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.
Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.
The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.
ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
Pharmacologic treatment for psychostimulant addiction is generally unsatisfactory. As previously discussed, cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria, anhedonia, and an intense desire to reinitiate drug use.
To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment. ... Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy
Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.
Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction.
Physical Exercise
There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.
The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) ...
Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.
Amphetamine use disorders ... 3,788 (3,425–4,145)
Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. ... The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. ... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.
Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.
Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
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.
They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002).
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.
Coadministration of Zn(2+) and AMPH consistently reduced WT-hDAT trafficking
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
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.
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.
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.
• tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
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
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].
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.
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.
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
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 ...
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).
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).
Findings from several prior investigations have shown that plasma levels of glucocorticoids and ACTH are increased by acute administration of AMPH in both rodents and humans
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.
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.
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).
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.
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.
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)].
The composition of the microbiome varies by anatomical site (Figure 1). The primary determinant of community composition is anatomical location: interpersonal variation is substantial23,24 and is higher than the temporal variability seen at most sites in a single individual25. ... How does the microbiome affect the pharmacology of medications? Can we “micro-type” people to improve pharmacokinetics and/or reduce toxicity? Can we manipulate the microbiome to improve pharmacokinetic stability?
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.
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 caused variation in the drug response among different populations.
A single dose of amphetamine or methamphetamine can be detected in the urine for approximately 24 hours, depending upon urine pH and individual metabolic differences. People who use chronically and at high doses may continue to have positive urine specimens for 2–4 days after last use (SAMHSA, 2010b).
Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in each 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.
1.2 million or 0.9% of young adults (15–34) used amphetamines in the last year
ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.
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† References for all endogenous human TAAR1 ligands are provided at List of trace amines
‡ References for synthetic TAAR1 agonists can be found at TAAR1 or in the associated compound articles. For TAAR2 and TAAR5 agonists and inverse agonists, see TAAR for references.
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