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Stimulant

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Ritalin sustained-release (SR) 20 mg tablets

Stimulants (also referred to as psychostimulants) are psychoactive drugs that induce temporary improvements in either mental or physical functions or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others. Due to their rendering a characteristic "up" feeling, stimulants are also occasionally referred to as "uppers". Depressants or "downers", which decrease mental and/or physical function, are in stark contrast to stimulants and are considered to be their functional opposites. Stimulants are widely used throughout the world as prescription medicines and without prescription both as legal substances and illicit substances of recreational use or abuse.

Effects

Stimulants produce a variety of different kinds of effects by enhancing the activity of the central and peripheral nervous systems. Common effects, which vary depending on the substance and dosage in question, may include enhanced alertness, awareness, wakefulness, endurance, productivity, and motivation, increased arousal, locomotion, heart rate, and blood pressure, and the perception of a diminished requirement for food and sleep. Many stimulants are also capable of improving mood and relieving anxiety, and some can even induce feelings of euphoria. However different effects are often dose related, such as amphetamine causing anxiety, dysthymia, hyperactivity and potentially heart failure at high doses, but relieving anxiety, producing euthymia or euphoria, reducing hyperactivity and being generally free of serious side effects at moderate doses used in clinical medicine. Stimulants exert their effects through a number of different pharmacological mechanisms, the most prominent of which include facilitation of norepinephrine (noradrenaline) and/or dopamine activity (e.g., via monoamine transporter inhibition or reversal),[1] adenosine receptor antagonism, and nicotinic acetylcholine receptor agonism.

Medical uses

Stimulants are used both individually and clinically for therapeutic purposes in the treatment of a number of indications, including the following:

ADHD drugs

Main article: Attention deficit hyperactivity disorder management § Stimulants

Stimulants are the most effective, most commonly prescribed medications for ADHD.[7] The most common stimulant medications are substituted phenethylamines: amphetamine, methylphenidate (Ritalin, Metadate, Concerta), dexmethylphenidate (Focalin), dextroamphetamine (Dexedrine, Zenzedi), mixed amphetamine salts (Adderall),[8] dextromethamphetamine (Desoxyn)[9] and lisdexamfetamine (Vyvanse).[10] Controlled-release formulations may allow once or twice daily administration of medication. Once daily morning administration is especially helpful for children preferring not to take their medication in the middle of the school day. Several controlled-release methods are used.

Ampakines

Main article: Ampakine

Ampakines are a class of compounds observed to enhance attention span and alertness, and facilitate learning and memory in clinical trials. They take their name from the glutamatergic AMPA receptor with which they strongly interact.

These stimulants tend to increase alertness without the peripheral (body) effects or addiction/tolerance/abuse potential of "traditional" stimulants (such as amphetamine),[medical citation needed] as they lack direct dopaminergic action. Their effect on sleep structure is not fully established and may reduce quality of sleep. The ampakine CX717, when administered at doses necessary to reduce the effects of sleep deprivation, reduced subsequent stage 4 and slow-wave recovery sleep.[11] Ampakines such as ampalex and CX717 have been developed but are awaiting further research before being commercially released. They have been investigated by DARPA for potential use in increasing military effectiveness.[12]

Eugeroics

Main article: Eugeroics

A wakefulness-promoting agent (eugeroic) is a type of psychoactive drug that improves wakefulness and alertness, and reduces tiredness, drowsiness, and the need for sleep. They are used mainly in the treatment of sleeping disorders, excessive daytime sleepiness, and narcolepsy, though they are also used merely to counteract fatigue and lethargy and to enhance motivation and productivity. Wakefulness-promoting agents appear to function primarily by increasing catecholaminergic (adrenergic, dopaminergic) and histaminergic activity in the brain. Unlike many other stimulants, eugeroics are relatively non-addictive and non-dependence-forming.[medical citation needed]

The prototype drug in this class is modafinil, and other drugs include adrafinil, hydrafinil, 2C-NPH and armodafinil. The primary difference between these drugs and amphetamine-like stimulants is that wakefulness-promoting agents trigger activation of neurons in the hypothalamus-based wakefulness circuits, as opposed to producing diffuse neuronal activation.[13]

The functional opposites of wakefulness-promoting agents would be hypnotics/sedatives like antihistamines, opioids, and benzodiazepines.

Chemistry

For details on stimulant classes, see Substituted phenethylamine and Substituted amphetamine.

Classifying stimulants is difficult, because of the large number of classes the drugs occupy, and the fact that they may belong to multiple classes; for example, ecstasy is a substituted methylenedioxyphenethylamine as well as a substituted amphetamine (and consequently, a substituted phenethylamine as well).

When referring to stimulants, the parent drug (e.g., amphetamine) will always be expressed in the singular; while the word "substituted" before the parent drug (substituted amphetamines).

Major stimulant classes include phenethylamines and their daughter class substituted amphetamines.

Amphetamines (class)

Main article: Substituted amphetamines
A chart comparing the chemical structures of different amphetamine derivatives

Substituted amphetamines are a group of phenylethylamine stimulants such as amphetamine and methamphetamine. With the exception of cathinones, many drugs in this class work primarily by activating trace amine-associated receptor 1 (TAAR1);[14] in turn, this causes reuptake inhibition and effluxion, or release, of dopamine, norepinephrine, and serotonin.[14] An additional mechanism of some substituted amphetamines is the release of neurotransmitters from synaptic vesicles into the cytosol, or intracellular fluid of the presynaptic neuron.[15]

Amphetamines-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treat major depression, where subjects do not respond well to traditional SSRI medications,[citation needed] but evidence supporting this use is poor/mixed.[16] Notably, two recent large phase III studies of lisdexamfetamine (a prodrug to amphetamine) as an adjunct to an SSRI or SNRI in the treatment of major depressive disorder showed no further benefit relative to placebo in effectiveness.[17] Numerous studies have demonstrated the effectiveness of drugs such as Adderall (a mixture of salts of amphetamine and dextroamphetamine) in controlling symptoms associated with ADD/ADHD. Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse.[18]

Dopamine precursors

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Dopamine is one of the principal neurotransmitters involved with stimulant activity in the brain, (others being norepinephrine and serotonin). Increase in its precursors may result in increased dopamine biosynthesis, especially in malnourished individuals. However levels of the enzyme tyrosine hydroxylase ultimately limit the biosynthesis regardless of increased tyrosine.

L-Tyrosine is the precursor that is 'closest' to being dopamine among those supplements legally available without prescription in most jurisdictions. It is converted by tyrosine hydroxylase into L-Dopa. Some of this L-Dopa is converted into dopamine and norepinephrine. Because tyrosine competes with other amino acids for entry into the brain supplement makers recommend tyrosine be taken on an empty stomach. However tyrosine hydroxylase is the rate limiting factor and even large dosages recommended by most supplement companies may not produce any noticeable effect. L-Phenylalanine is 'one step back' from L-Tyrosine—it must be converted into tyrosine before the tyrosine can be converted into L-Dopa, which in turn becomes dopamine. Dopamine is also the direct precursor of norepinephrine.

Biosynthetic pathways for catecholamines and trace amines in the human brain[19][20][21]
The image above contains clickable links
This is the biosynthesis of catecholamines, including dopamine, as well as phenethylaminergic trace amines from the amino acid phenylalanine. Trace amines are endogenous agonists of TAAR1, the same receptor activated by amphetamine;[14] consequently, all of these trace amines are stimulants. Abbreviations:
DBH: Dopamine β-hydroxylase;
AADC:Aromatic L-amino acid decarboxylase;
AAAH: (Biopterin-dependent) aromatic amino acid hydroxylase;
COMT: Catechol O-methyltransferase;
PNMT: Phenylethanolamine N-methyltransferase

Notable stimulants

Amphetamine (drug)

Main article: Amphetamine

Amphetamine is a potent central nervous system (CNS) stimulant of the phenethylamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.[22] Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine.[note 1][23] Amphetamine refers to equal parts of the enantiomers, i.e., 50% levoamphetamine and 50% dextroamphetamine.[24][25] Historically, it has been used to treat nasal congestion, depression, and obesity.[23][26] Amphetamine is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant.[27][28][29][30] Although it is a prescription medication in many countries, unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use.[31][32] As a consequence, amphetamine is illegally synthesized by clandestine chemists, trafficked, and sold.[33] Based upon drug and drug precursor seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of methamphetamine.[33]

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions.[23][26] Because the dextro isomer has greater stimulant properties, Benzedrine was gradually discontinued in favor of formulations containing all or mostly dextroamphetamine. Presently, it is typically prescribed as Adderall, dextroamphetamine (e.g., Dexedrine), or the inactive prodrug lisdexamfetamine (e.g., Vyvanse).[23][34] Amphetamine, through activation of a trace amine receptor, increases biogenic amine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine.[14] At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved cognitive control.[28][29][35] Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[27]

In contrast, much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown.[22][28][36] Substance dependence (i.e., addiction) is a serious risk of amphetamine abuse, but only rarely arises from proper medical use.[22][37] Very high doses can result in a psychosis (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use.[38][39] As recreational doses are generally much larger than prescribed therapeutic doses, recreational use carries a far greater risk of serious side effects.[22][36]

Amphetamine is the parent compound of its own structural class, the (substituted) amphetamines, which includes prominent substances such as bupropion, cathinone, ecstasy, and methamphetamine.[40][41] It is chemically related to methamphetamine; however, unlike methamphetamine, its salts lack sufficient volatility to be smoked.[40] During long-term treatment in humans, amphetamine has been shown to normalize, or improve, brain function, in particular in the right caudate nucleus;[42][43] in contrast, methamphetamine induces permanent reductions in brain structure and function.[44][45] Amphetamine is also chemically related to the naturally occurring trace amines, to be specific phenethylamine and N-methylphenethylamine, both of which produced within the human body.[41]

Caffeine

Main article: Caffeine
Roasted coffee beans, a common source of caffeine.

Caffeine is a stimulant compound belonging to the xanthine class of chemicals naturally found in coffee, tea, and (to a lesser degree) cocoa or chocolate. It is included in many soft drinks, as well as a larger amount in energy drinks. Caffeine is the world's most widely used psychoactive drug and by far the most common stimulant. In North America, 90% of adults consume caffeine daily.[46] A few jurisdictions restrict its sale and use. Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient, or reducing one of its side-effects (especially drowsiness). Tablets containing standardized doses of caffeine are also widely available.

Ephedrine

Main article: Ephedrine

Ephedrine is a sympathomimetic amine similar in molecular structure to the well-known drugs phenylpropanolamine and methamphetamine, as well as to the important neurotransmitter epinephrine (adrenaline). Ephedrine is commonly used as a stimulant, appetite suppressant, concentration aid, and decongestant, and to treat hypotension associated with anaesthesia.

In chemical terms, it is an alkaloid with a phenethylamine skeleton found in various plants in the genus Ephedra (family Ephedraceae). It works mainly by increasing the activity of norepinephrine (noradrenaline) on adrenergic receptors.[47] It is most usually marketed as the hydrochloride or sulfate salt.

The herb má huáng (Ephedra sinica), used in traditional Chinese medicine (TCM), contains ephedrine and pseudoephedrine as its principal active constituents. The same may be true of other herbal products containing extracts from other Ephedra species.

MDMA

Illicit tablets containing MDMA
Main article: MDMA
See also: Its parent class and MDA

3,4-Methylenedioxymethamphetamine (MDMA or ecstasy), typically comes as tablets, capsules, and in powder/crystal form. Briefly used by some psychotherapists as an adjunct to therapy, the drug became popular recreationally and the DEA listed MDMA as a Schedule I controlled substance, prohibiting most medical studies and applications. MDMA is known for its entactogenic properties. The stimulant effects of MDMA include hypertension, anorexia (appetite loss), euphoria, social disinhibition, insomnia (enhanced wakefulness/inability to sleep), improved energy, increased arousal, and increased perspiration, among others.

MDMA differs from most stimulants in that its primary pharmacological effect is on the neurotransmitter serotonin rather than dopamine, epinephrine, or norepinephrine. Because of this, it is considered to be primarily an entactogen or an empathogen.

MDPV

Main article: MDPV

Methylenedioxypyrovalerone (MDPV) is a psychoactive drug with stimulant properties that acts as a norepinephrine-dopamine reuptake inhibitor (NDRI).[48] It was first developed in the 1960s by a team at Boehringer Ingelheim.[49] MDPV remained an obscure stimulant until around 2004, when it was reported to be sold as a designer drug. Products labeled as bath salts containing MDPV were previously sold as recreational drugs in gas stations and convenience stores in the United States, similar to the marketing for Spice and K2 as incense.[50][51]

Incidents of psychological and physical harm have been attributed to MDPV use.[52][53]

Prolintane

Main article: Prolintane

Prolintane is a stimulant that has been around since the 1950s. It is stronger than caffeine and has a very good safety profile. Prolintane use isn't very common, though some people[who?] use it as a safer and more effective alternative to caffeine.

Mephedrone

Main article: Mephedrone

Mephedrone is a synthetic stimulant drug of the amphetamine and cathinone classes. Slang names include drone[54] and MCAT.[55] It is reported to be manufactured in China and is chemically similar to the cathinone compounds found in the khat plant of eastern Africa. It comes in the form of tablets or a powder, which users can swallow, snort, or inject, producing similar effects to MDMA, amphetamines, and cocaine.

Mephedrone was first synthesized in 1929, but did not become widely known until it was rediscovered in 2003. By 2007, mephedrone was reported to be available for sale on the Internet; by 2008 law enforcement agencies had become aware of the compound; and, by 2010, it had been reported in most of Europe, becoming particularly prevalent in the United Kingdom. Mephedrone was first made illegal in Israel in 2008, followed by Sweden later that year. In 2010, it was made illegal in many European countries, and, in December 2010, the EU ruled it illegal. In Australia, New Zealand, and the USA, it is considered an analog of other illegal drugs and can be controlled by laws similar to the Federal Analog Act. In September 2011, the USA temporarily classified mephedrone as illegal, in effect from October 2011.

Methamphetamine

Main article: Methamphetamine

Methamphetamine (contracted from N-methyl-alpha-methylphenethylamine) is a neurotoxin and potent psychostimulant of the phenethylamine and amphetamine classes that is used to treat attention deficit hyperactivity disorder (ADHD) and obesity.[44][56][45] Methamphetamine exists as two enantiomers, dextrorotary and levorotary.[57][58] Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine;[36][57][58] however, both are addictive and produce the same toxicity symptoms at high doses.[58] Although rarely prescribed due to the potential risks, methamphetamine hydrochloride is approved by the United States Food and Drug Administration (USFDA) under the trade name Desoxyn.[56] Recreationally, methamphetamine is used to increase sexual desire, lift the mood, and increase energy, allowing some users to engage in sexual activity continuously for several days straight.[56][59]

Methamphetamine may be sold illicitly, either as pure dextromethamphetamine or in an equal parts mixture of the right- and left-handed molecules (i.e., 50% levomethamphetamine and 50% dextromethamphetamine).[59] Both dextromethamphetamine and racemic methamphetamine are schedule II controlled substances in the United States.[56] Also, the production, distribution, sale, and possession of methamphetamine is restricted or illegal in many other countries due to its placement in schedule II of the United Nations Convention on Psychotropic Substances treaty.[60][61] In contrast, levomethamphetamine is an over-the-counter drug in the United States.[note 2]

In low doses, methamphetamine can cause an elevated mood and increase alertness, concentration, and energy in fatigued individuals.[36][56] At higher doses, it can induce psychosis, rhabdomyolysis, and cerebral hemorrhage.[36][56] Methamphetamine is known to have a high potential for abuse and addiction.[36][56] Recreational use of methamphetamine may result in psychosis or lead to post-withdrawal syndrome, a withdrawal syndrome that can persist for months beyond the typical withdrawal period.[64] Unlike amphetamine and cocaine, methamphetamine is neurotoxic to humans, damaging both dopamine and serotonin neurons in the central nervous system (CNS).[44][45] Entirely opposite to the long-term use of amphetamine, there is evidence that methamphetamine causes brain damage from long-term use in humans;[44][45] this damage includes adverse changes in brain structure and function, such as reductions in gray matter volume in several brain regions and adverse changes in markers of metabolic integrity.[42][43][45]

Nicotine

Main article: Nicotine

Nicotine is the active chemical constituent in tobacco, which is available in many forms, including cigarettes, cigars, chewing tobacco, and smoking cessation aids such as nicotine patches, nicotine gum, and electronic cigarettes. Nicotine is used widely throughout the world for its stimulating and relaxing effects.

Phenylpropanolamine

Main article: Phenylpropanolamine

Phenylpropanolamine (PPA; Accutrim; β-hydroxyamphetamine), also known as the stereoisomers norephedrine and norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine chemical classes that is used as a stimulant, decongestant, and anorectic agent.[65] It is commonly used in prescription and over-the-counter cough and cold preparations. In veterinary medicine, it is used to control urinary incontinence in dogs under trade names Propalin and Proin.

In the United States, PPA is no longer sold without a prescription due to a proposed increased risk of stroke in younger women. In a few countries in Europe, however, it is still available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001.[66] In India, human use of PPA and its formulations were banned on 10 February 2011.[67]

Propylhexedrine

Main article: Propylhexedrine

Propylhexedrine (Hexahydromethamphetamine, Obesin) is a stimulant medication, sold over-the-counter in the United States as the cold medication Benzedrex.[68] The drug has also been used as an appetite suppressant in Europe. Propylhexedrine is not an amphetamine, though it is structurally similar; it is instead a cycloalkylamine, and thus has stimulant effects that are less potent than similarly structured amphetamines, such as methamphetamine.

The abuse potential of propylhexedrine is fairly limited, due its limited routes of administration: in the United States, Benzedrex is only available as an inhalant, mixed with lavender oil and menthol. These ingredients cause unpleasant tastes, and abusers of the drug have reported unpleasant "menthol burps." Injection of the drug has been found to cause transient diplopia and brain stem dysfunction.[69][70][71]

Dimethylamylamine

Main article: Dimethylamylamine

Dimethylamylamine is a stimulant drug, once sold in over-the-counter workout supplements and study aids in the United States as in the supplement Jack 3D, but it was later discontinued. Dimethylamylamine is not an amphetamine, though it is structurally similar, and thus has stimulant effects that are less potent than similarly structured amphetamines, such as amphetamine.

Pseudoephedrine

Main article: Pseudoephedrine

Pseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant,[72] or as a wakefulness-promoting agent.[73]

The salts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many over-the-counter preparations, either as a single ingredient or (more commonly) in combination with antihistamines, guaifenesin, dextromethorphan, and/or paracetamol (acetaminophen) or another NSAID (such as aspirin or ibuprofen).

Catha edulis (Khat)

Main article: Khat
Photograph of the khat plant
Catha edulis

Khat is a flowering plant native to the Horn of Africa and the Arabian Peninsula.[74][75]

Khat contains a monoamine alkaloid called cathinone, a "keto-amphetamine", that is said to cause excitement, loss of appetite, and euphoria. In 1980, the World Health Organization (WHO) classified it as a drug of abuse that can produce mild to moderate psychological dependence (less than tobacco or alcohol),[76] although the WHO does not consider khat to be seriously addictive.[75] It is a controlled substance in some countries, such as the United States, Canada, and Germany, while its production, sale, and consumption are legal in other nations, including Djibouti, Ethiopia, Somalia, and Yemen.[77]

Cocaine

Main article: Cocaine

Cocaine is an SNDRI. Cocaine is made from the leaves of the coca shrub, which grows in the mountain regions of South American countries such as Bolivia, Colombia, and Peru. In Europe, North America, and some parts of Asia, the most common form of cocaine is a white crystalline powder. Cocaine is a stimulant but is not normally prescribed therapeutically for its stimulant properties, although it sees clinical use as a local anesthetic, in particular in ophthalmology. Most cocaine use is recreational and its abuse potential is high(albeit higher than amphetamine), and so its sale and possession are strictly controlled in most jurisdictions. Other tropane derivative drugs related to cocaine are also known such as troparil and lometopane but have not been widely sold or used recreationally.[78]

Abuse

Main article: Recreational drug use § Stimulants
See also: Bath salts (drug)

Abuse of central nervous system (CNS) stimulants is common. Addiction to some CNS stimulants can quickly lead to medical, psychiatric, and psychosocial deterioration. Drug tolerance, dependence, and sensitization as well as a withdrawal syndrome can occur.[79]

Stimulants enhance the activity of the central and peripheral nervous systems. Common effects may include increased alertness, awareness, wakefulness, endurance, productivity, and motivation, arousal, locomotion, heart rate, and blood pressure, and a diminished desire for food and sleep.

Use of stimulants may cause the body to reduce significantly its production of natural body chemicals that fulfill similar functions. Until the body reestablishes its normal state, once the effect of the ingested stimulant has worn off the user may feel depressed, lethargic, confused, and miserable. This is referred to as a "crash", and may provoke reuse of the stimulant.

Testing

The presence of stimulants in the body may be tested by a variety of procedures. Serum and urine are the common sources of testing material although saliva is sometimes used. Commonly used tests include chromatography, immunologic assay, and mass spectrometry.[80] Patients taking ADHD-prescribed, Adderall-type amphetamine compounds are commonly surprised upon being tested as "positive" for "meth", or methamphetamine (Desoxyn—its licit, FDA-licensed, medicinal form) in forensically unsophisticated urinalysis, as methamphetamine is the active ingredient of the drug Desoxyn, and is chemically similar to the active ingredients of other ADHD medications.

See also

Notes

  1. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.
    Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.
  2. ^ The active ingredient in Vicks VapoInhaler is listed as Levmetamfetamine, the INN of Levomethamphetamine.[62][63]

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  27. ^ a b Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Prim. Care. 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID 23668655. Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training...
    Physiologic and performance effects
     • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
     • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
     • Improved reaction time
     • Increased muscle strength and delayed muscle fatigue
     • Increased acceleration
     • Increased alertness and attention to task
  28. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 318. ISBN 978-0-07-148127-4. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in individuals with ADHD and in normal subjects...it is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control, as will be discussed below. It is important to recognize, however, that 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.{{cite book}}: CS1 maint: multiple names: authors list (link)
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    Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.    {{cite journal}}: CS1 maint: multiple names: authors list (link)
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    Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2)...It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone...
    Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines. It is not often realized, however, that this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut...
    Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life,...
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  43. ^ a b Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J (September 2013). "Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies". J. Clin. Psychiatry. 74 (9): 902–917. doi:10.4088/JCP.12r08287. PMC 3801446. PMID 24107764.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  44. ^ a b c d Malenka RC, Nestler EJ, Hyman SE (2009). "15". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 370. ISBN 9780071481274. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.{{cite book}}: CS1 maint: multiple names: authors list (link)
  45. ^ a b c d e Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...
    Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ...
    There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ...
    Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic, and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007).
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