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{{hatnote|This article is about the free base and salts of methamphetamine. "Meth" redirects here. For other uses, see [[Meth (disambiguation)]]}}
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Revision as of 12:49, 13 April 2015

Methamphetamine
An image of the methamphetamine compound
Ball-and-stick model of the methamphetamine molecule
Clinical data
Trade namesDesoxyn
SynonymsN-methylamphetamine, desoxyephedrine
AHFS/Drugs.comMonograph
[[Regulation of therapeutic goods |Template:Engvar data]]
Pregnancy
category
  • US: C (Risk not ruled out)
Dependence
liability		Physical: none
Psychological: high
Addiction
liability		Very high
Routes of
administration		Medical: oral
Recreational: oral, intravenous, insufflation, inhalation, suppository
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: Varies widely[6]
Rectal: 99%
IV: 100%
Protein bindingVaries widely[6]
MetabolismCYP2D6,[1] DBH,[2] FMO3,[3] XM-ligase,[4] and ACGNAT[5]
Elimination half-life9–12 hours[7]
ExcretionRenal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC10H15N
Molar mass149.2337 g/mol
3D model (JSmol)
Melting point3 °C (37.4 °F) [8]
Boiling point212 °C (413.6 °F) [9] at 760 MM HG
  (verify)

Methamphetamine[note 1] ( /ˌmɛθæmˈfɛtəmiːn/; contracted from N-methyl-alpha-methylphenethylamine) is a potent central nervous system (CNS) stimulant of the phenethylamine and amphetamine classes that is used as a recreational drug and, rarely, to treat attention deficit hyperactivity disorder (ADHD) and obesity. Methamphetamine exists as two enantiomers, dextrorotary and levorotary.[note 2] Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine; however, both are neurotoxic, addictive and produce the same toxicity symptoms at high doses. 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. 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.

Methamphetamine may be sold illegally, either as pure dextromethamphetamine or in an equal parts mixture of the right and left-handed molecules (i.e., 50% levomethamphetamine and 50% dextromethamphetamine). Both dextromethamphetamine and racemic methamphetamine are schedule II controlled substances in the United States. Similarly, 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. In contrast, levomethamphetamine is an over-the-counter drug in the United States.[note 3]

In low doses, methamphetamine can cause an elevated mood and increase alertness, concentration, and energy in fatigued individuals. At higher doses, it can induce psychosis, rhabdomyolysis and cerebral hemorrhage. Methamphetamine is known to have a high potential for abuse and addiction. Heavy recreational use of methamphetamine may result in psychosis or lead to post-acute-withdrawal syndrome, a withdrawal syndrome that can persist for months beyond the typical withdrawal period.[i] Unlike amphetamine, methamphetamine is neurotoxic to humans, damaging both dopamine and serotonin neurons in the CNS.[i] Contrary to the long-term use of amphetamine,[iii] there is evidence that methamphetamine causes brain damage from long-term use in humans;[ii] 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.[ii]

Uses

Medical

In the United States, methamphetamine hydrochloride, under the trade name Desoxyn, has been approved by the FDA for treating ADHD and exogenous obesity (obesity originating from factors outside the patient's control) in both adults and children;[14][15] however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use.[14] Methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia.[16][17] In the United States, methamphetamine's levorotary form is available in some over-the-counter nasal decongestant products, such as Vicks VapoInhaler.[note 3]

As methamphetamine is associated with a high potential for misuse, the drug is regulated under the Controlled Substances Act and is listed under schedule II in the United States.[14] Methamphetamine hydrochloride dispensed in the United States is required to include the following boxed warning:[14]

“ Methamphetamine has a high potential for abuse. It should thus be tried only in weight reduction programs for patients in whom alternative therapy has been ineffective. Administration of methamphetamine for prolonged periods of time in obesity may lead to drug dependence and must be avoided. Particular attention should be paid to the possibility of subjects obtaining methamphetamine for non-therapeutic use or distribution to others, and the drug should be prescribed or dispensed sparingly. Misuse of methamphetamine may cause sudden death and serious cardiovascular adverse effects. ”

Recreational

See also: Party and play and the Recreational routes of methamphetamine administration

Methamphetamine is often used recreationally for its effects as a potent euphoriant and stimulant as well as aphrodisiac qualities.[20] According to a National Geographic TV documentary on methamphetamine, "an entire subculture known as party and play is based around methamphetamine use".[20] Members of this San Francisco sub-culture, which consists almost entirely of gay male methamphetamine users, will typically meet up through internet dating sites and have sex.[20] Due to its strong stimulant and aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters will sometimes occur continuously for several days.[20] The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia.[20]

Desoxyn tablet
Desoxyn tablets – pharmaceutical methamphetamine hydrochloride
Crystal meth
Crystal meth – illicit methamphetamine hydrochloride

Contraindications

Methamphetamine is contraindicated in individuals with a history of substance use disorder, heart disease, or severe agitation or anxiety, or in individuals currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension.[14] The USFDA states that individuals who have experienced hypersensitivity reactions to other stimulants in the past or are currently taking monoamine oxidase inhibitors should not take methamphetamine.[14] The USFDA also advises individuals with bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome to monitor their symptoms while taking methamphetamine.[14] Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of growing children and adolescents during treatment.[14]

Side effects

Physical

The physical effects of methamphetamine can include loss of appetite, hyperactivity, dilated pupils, flushed skin, excessive sweating, increased movement, dry mouth and teeth grinding (leading to "meth mouth"), headache, irregular heartbeat (usually as accelerated heartbeat or slowed heartbeat), rapid breathing, high blood pressure, low blood pressure, high body temperature, diarrhea, constipation, blurred vision, dizziness, twitching, numbness, tremors, dry skin, acne, and pale appearance.[14][21] Methamphetamine that is present in a mother's bloodstream can pass through the placenta to a fetus and is or be secreted into breast milk.[22] Infants born to methamphetamine-abusing mothers were found to have a significantly smaller gestational age-adjusted head circumference and birth weight measurements.[22] Methamphetamine exposure was also associated with neonatal withdrawal symptoms of agitation, vomiting and fast breathing.[22] This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.[23]

Meth mouth

Main article: Meth mouth

Methamphetamine users and addicts may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as meth mouth.[24] The condition is generally most severe in users who inject the drug, rather than those who smoke, ingest, or inhale it.[24] According to the American Dental Association, meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in xerostomia (dry mouth), extended periods of poor oral hygiene, frequent consumption of high-calorie, carbonated beverages and bruxism (teeth grinding and clenching)".[24][25] Many researchers suggest that methamphetamine-induced tooth decay is due to users' lifestyles, as dry mouth is also a side effect of other stimulants, which are not known to cause serious tooth decay. They suggest that the side effect has been exaggerated and stylized to deter potential users and stereotype current users.[26]

Psychological

The psychological effects of methamphetamine can include euphoria, dysphoria, changes in libido, alertness, apprehension, concentration, decreased sense of fatigue, insomnia or wakefulness, self-confidence, sociability, irritability, restlessness, grandiosity and repetitive and obsessive behaviors.[14][21][27] Methamphetamine use also has a high association with anxiety, depression, methamphetamine psychosis, suicide, and violent behaviors.[28] Methamphetamine also has a very high addiction risk.[14]

Dependence, addiction, and withdrawal

See also: ΔFosB
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
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,[29][30] 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.[29][31][32] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[29][33][34] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[35] 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.[33][34] 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.[33][34]

Tolerance is expected to develop with regular methamphetamine use and, when abused, this tolerance develops rapidly.[36][37]

The evidence on effective treatments for amphetamine and methamphetamine dependence and abuse is limited.[38] In light of this, fluoxetine[note 4] and imipramine[note 5] appear to have some limited benefits in treating abuse and addiction, "no treatment has been demonstrated to be effective for the treatment of [methamphetamine] dependence and abuse".[38]

In highly dependent amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue [methamphetamine] use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose".[39] Withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.[39] Methamphetamine withdrawal symptoms can include anxiety, drug craving, dysphoric mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and vivid or lucid dreams.[39] Withdrawal symptoms are associated with the degree of dependence (i.e., the extent of abuse).[39] The mental depression associated with methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.[23]

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain.[40][41] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).[41] ΔFosB is the most significant, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction;[41] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phencyclidine, and substituted amphetamines.[40][41][42] ΔJunD is the transcription factor which directly opposes ΔFosB.[41] Increases in nucleus accumbens ΔJunD expression can reduce or, with a large increase, even block most of the neural alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[41] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[41][43] Since natural rewards, like drugs of abuse, induce ΔFosB, chronic acquisition of these rewards can result in a similar pathological addictive state.[41][43] Consequently, ΔFosB is the key transcription factor involved in methamphetamine addiction, especially methamphetamine-induced sex addictions.[41][43][44] ΔFosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders.[45]


Neurotoxicity

Unlike amphetamine, methamphetamine is directly neurotoxic to dopamine neurons.[46] Moreover, methamphetamine abuse is associated with an increased risk of Parkinson's disease due to excessive pre-synaptic dopamine autoxidation, a mechanism of neurotoxicity.[47][48][49][50] Similar to the neurotoxic effects on the dopamine system, methamphetamine can also result in neurotoxicity to serotonin neurons.[51] It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.[52] As a result of methamphetamine-induced neurotoxicity to dopamine neurons, chronic use may also lead to Post-acute-withdrawals which persist beyond the withdrawal period for months, and even up to a year.[47]

Sexually transmitted infection

Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both HIV-positive and unknown casual partners, an association more pronounced in HIV-positive participants.[53] These findings suggest that methamphetamine use and engagement in unprotected anal intercourse are co-occurring risk behaviors, behaviors that potentially heighten the risk of HIV transmission among gay and bisexual men.[53] Methamphetamine use allows users of both sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions as well as priapism in men.[14][54] Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.[14][54]

Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle.[55] The level of needle sharing among methamphetamine users is similar to that among other drug injection users.[55]

Overdose

A methamphetamine overdose may result in a wide range of symptoms.[7][14] A moderate overdose of methamphetamine may induce symptoms such as: abnormal heart rhythm, confusion, difficult and/or painful urination, high or low blood pressure, high body temperature, over-active and/or over-responsive reflexes, muscle aches, severe agitation, rapid breathing, tremor, urinary hesitancy, and an inability to pass urine.[7][21] An extremely large overdose may produce symptoms such as adrenergic storm, methamphetamine psychosis, substantially reduced or nil urine output, cardiogenic shock, brain bleed, circulatory collapse, dangerously high body temperature, pulmonary hypertension, kidney failure, rhabdomyolysis, serotonin syndrome, and a form of stereotypy ("tweaking").[Refnote 1] A methamphetamine overdose will likely also result in mild brain damage due to dopaminergic and serotonergic neurotoxicity.[46][51] Death from methamphetamine poisoning is typically preceded by convulsions and coma.[14]

Emergency treatment

The USFDA states[note 6] that acute methamphetamine intoxication is largely managed by treating the symptoms and includes may initially include administration of activated charcoal and sedation.[7] There is not enough evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to determine their usefulness.[14] Forced acid diuresis (e.g., with vitamin C) will increase methamphetamine excretion but is not recommended as it may increase the risk of aggravating acidosis, or cause seizures or rhabdomyolysis.[7] Hypertension presents a risk for intracranial hemorrhage and, if severe, is typically treated with intravenous phentolamine or nitroprusside.[7] Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.[7] Chlorpromazine may be useful in decreasing the stimulant and CNS effects of a methamphetamine overdose.[14] The use of a nonselective beta blocker may be required to control increased heart rate.[7]

Psychosis

Template:Main section

Abuse of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g. paranoia, hallucinations, delirium, delusions).[7][59] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely.[59][60] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[59] Methamphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[61]

Interactions

Methamphetamine is metabolized by the liver enzyme CYP2D6, so CYP2D6 inhibitors (e.g., selective serotonin reuptake inhibitors (SSRIs)) will prolong the elimination half-life of methamphetamine.[62] Methamphetamine also interacts with monoamine oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[14] Methamphetamine may decrease the effects of sedatives and depressants and increase the effects of antidepressants and other stimulants as well.[14] Methamphetamine may counteract the effects of antihypertensives and antipsychotics due to its effects on the cardiovascular system and cognition respectively.[14] The pH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.[14] Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.[14] Due to the effect pH has on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.[14]

Pharmacology

An image of methamphetamine pharmacodynamics
This illustration depicts the normal operation of the dopaminergic terminal to the left, and the dopaminergic terminal in presence of methamphetamine to the right. Methamphetamine reverses the action of the dopamine transporter (DAT) by activating TAAR1 (not shown). TAAR1 activation also causes some of the dopamine transporters to move into the presynaptic neuron and cease transport (not shown). At VMAT2 (labeled VMAT), methamphetamine causes dopamine efflux (release).

Amphetamines, in general, act as monoamine releasing agents and reuptake inhibitors. They inhibit VMAT-2, preventing packaging of monoamines into vesicles. As these monoamine neurotransmitters remain in the cytoplasm at an ever-climbing level, the gradient for their transporters becomes progressively less favorable, which, in combination with dopamine transporter phosphorylation caused by amphetamines, causes the transporters to work in reverse, resulting in monoamine release. There is also some evidence that amphetamines act as monoamine oxidase inhibitors, amplifying this effect by preventing degradation of these neurotransmitters.

Pharmacodynamics

Like amphetamine, methamphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor (GPCR) that regulates brain catecholamine systems.[63][64] Activation of TAAR1, via adenylyl cyclase, increases cyclic adenosine monophosphate (cAMP) production and either completely inhibits or reverses the transport direction of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT).[63][65] When methamphetamine binds to TAAR1, it triggers transporter phosphorylation via protein kinase A (PKA) and protein kinase C (PKC) signaling, ultimately resulting in the internalization or reverse function of monoamine transporters.[63][66] Other transporters that methamphetamine is known to inhibit are vesicular monoamine transporter 1 (VMAT1), vesicular monoamine transporter 2 (VMAT2), SLC22A3, and SLC22A5.[67] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes and SLC22A5 is a high-affinity carnitine transporter.[64][68] When methamphetamine interacts with VMAT2, it induces a release of monoamines from the synaptic vesicles (vesicles that stores monoamines) into the cytosol (intracellular fluid) of the presynaptic neuron.[69]

Methamphetamine is also an agonist of the alpha-2 adrenergic receptors and sigma receptors, and inhibits vesicular monoamine transporter 1 (VMAT1), monoamine oxidase B (MAO-B), and monoamine oxidase A (MAO-A).[64][70][71] Methamphetamine is known to inhibit the CYP2D6 liver enzyme as well.[62] Dextromethamphetamine is a stronger psychostimulant, but levomethamphetamine has a longer half-life and is CNS-active with weaker effects (approximately one-tenth) on striatal dopamine and shorter perceived effects among addicts.[72][73][74] At high doses, both enantiomers of methamphetamine can induce stereotypy and methamphetamine psychosis,[73] but levomethamphetamine is less desired by recreational drug users because of its weaker pharmacodynamic profile.[74]

Although all the mechanisms are not fully understood, methamphetamine is a known neurotoxin in both lab animals and humans.[46][51][75][76] Beyond neurotoxicity, magnetic resonance imaging studies on human methamphetamine addicts and abusers indicate adverse neuroplastic changes, such as significant abnormalities in various brain structures.[51] In particular, methamphetamine appears to cause white matter hyperintensity and hypertrophy, marked shrinkage of hippocampi, and a reduction in gray matter in the cingulate cortex, limbic cortex, and paralimbic cortex.[51] Moreover, there are adverse changes in various metabolic markers of metabolic integrity or synthesis in methamphetamine abusers, such as reductions in N-acetylaspartate and creatine as well as elevated choline and myoinositol levels.[51]

Comparison to amphetamine pharmacodynamics

Both amphetamine and methamphetamine are potent CNS stimulants with a few biomolecular targets and affected transporters in common; however, there are important pharmacodynamic differences between the two compounds.[Refnote 2] Both compounds are potent trace amine-associated receptor 1 (TAAR1) agonists (causing non-competitive inhibition of DAT, NET, and SERT) and inhibitors of VMAT2, SLC22A3, and SLC22A5.[Refnote 3] However, methamphetamine appears to bind at a different site at VMAT2 than amphetamine.[80] Methamphetamine also inhibits VMAT1, has agonist activity at all alpha-2 adrenergic receptor and sigma receptor subtypes, and is directly toxic to dopamine neurons in humans, whereas there is no evidence of acute amphetamine toxicity in humans.[46][51][64][70] Sigma receptor activity is known to potentiate the stimulant and neurotoxic effects of methamphetamine.[70][71]

In contrast to the adverse neuroplastic effects evident in methamphetamine addicts and abusers, long-term use of amphetamine or methylphenidate at therapeutic doses appears to produce beneficial changes in brain function and structure, such as normalization of the right caudate nucleus.[81][82]

Pharmacokinetics

Following oral administration, methamphetamine is well-absorbed into the bloodstream, with peak plasma methamphetamine concentrations achieved in approximately 3.13–6.3 hours post ingestion.[83] Methamphetamine is also well absorbed following inhalation and following intranasal administration.[7] Due to the high lipophilicity of methamphetamine, it can readily move through the blood–brain barrier faster than other stimulants, where it is more resistant to degradation by monoamine oxidase.[7][83] The amphetamine metabolite peaks at 10–24 hours.[7] It is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH.[14][83] When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.[83] Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine.[83] The half-life of methamphetamine is variable with a mean value of between 5 and 12 hours.[7][83]

CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize methamphetamine or its metabolites in humans.[2][3][4][5][62] The primary metabolites are amphetamine and 4-hydroxymethamphetamine; other minor metabolites include: 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine.[1][83][84][85] Among these metabolites, the active sympathomimetics are amphetamine, 4‑hydroxyamphetamine,[86] 4‑hydroxynorephedrine,[87] 4-hydroxymethamphetamine,[83] and norephedrine.[88]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[1][83][84] The known metabolic pathways include:[1][83][85]Template:Methamphetamine pharmacokinetics

Detection in biological fluids

Methamphetamine and amphetamine are often measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[89][90][91][92] Chiral techniques may be employed to help distinguish the source the drug to determine whether it was obtained illicitly or legally via prescription or prodrug.[93] Chiral separation is needed to assess the possible contribution of levomethamphetamine (e.g., Vicks Vapoinhaler) toward a positive test result.[93][94][95] Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.[96]

Physical and chemical properties

Methamphetamine hydrochloride
Pure shards of methamphetamine hydrochloride, also known as crystal meth

Methamphetamine is a chiral compound with two enantiomers, dextromethamphetamine and levomethamphetamine. At room temperature, the free base of methamphetamine is a clear and colorless liquid with an odor characteristic of geranium leaves.[9] It is soluble in diethyl ether and ethanol as well as miscible with chloroform.[9] In contrast, the methampetamine hydrochloride salt is odorless with a bitter taste.[9] It has a melting point between 170  (Expression error: Unexpected round operator. ) and, at room temperature, occurs as white crystals or a white crystalline powder.[9] The hydrochloride salt is also freely soluble in ethanol and water.[9]

Synthesis

Template:Details3 Racemic methamphetamine may be prepared starting from phenylacetone by either the Leuckart[97] or reductive amination methods.[98] In the Leuckart reaction, one equivalent of phenylacetone is reacted with two equivalents of N-methylformamide to produce the formyl amide of methamphetamine plus carbon dioxide and methylamine as side products.[98] In this reaction, an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-methylformamide.[98] The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product.[98] Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.[98]

Methamphetamine synthesis
Diagram of methamphetamine synthesis by reductive amination
Method of methamphetamine synthesis of methamphetamine via reductive amination
Diagram of methamphetamine synthesis by Leuckart reaction
Methods of methamphetamine synthesis via the Leuckart reaction

Degradation

Bleach exposure time and concentration are correlated with destruction of methamphetamine.[99] Methamphetamine in soils has shown to be a persistent pollutant.[100] Methamphetamine is largely degraded within 30 days in a study of bioreactors under exposure to light in wastewater.[101]

History, society, and culture

Main article: History and culture of substituted amphetamines
A methamphetamine tablet container
A Pervitin tablet container, the methamphetamine brand used by German soldiers during World War II
An advertisement for pharmaceutical methamphetamine
A 1970 advertisement for Obetrol, a pharmaceutical mixture of amphetamine and methamphetamine salts

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.[102][103] Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi.[104] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.[105]

During World War II, Pervitin (methamphetamine) developed by Berlin based Temmler pharmaceutical company was used extensively by all branches of the German armed forces (Luftwaffe pilots, in particular) for its performance enhancing stimulant effects and to induce extended wakefulness.[106][107] Pervitin became colloquially known among the German troops as "Tank-Chocolates" (Panzerschokolade), "Stuka-Tablets" (Stuka-Tabletten) and "Herman-Göring-Pills" (Hermann-Göring-Pillen).

Obetrol, patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of obesity, was one of the first brands of pharmaceutical methamphetamine products.[108] Due to the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.[108] Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.[103] For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act.[109] Currently, methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck.[110] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.[111]

Present legal status

Main article: Legal status of methamphetamine

The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions.[112][113] Methamphetamine has been placed in schedule II of the United Nations Convention on Psychotropic Substances treaty.[113]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. December 2013. pp. 12–13. Retrieved 30 December 2013.
  2. ↑ 2.0 2.1 Lemke TL, Williams DA, Roche VF, Zito W (2013). Foye's Principles of Medicinal Chemistry (7th ed. ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 648. ISBN 1609133455. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
  3. ↑ 3.0 3.1 Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacol. Ther. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602. PMID 15922018.
  4. ↑ 4.0 4.1 "Substrate/Product". butyrate-CoA ligase. BRENDA. Technische Universität Braunschweig. Retrieved 7 May 2014.
  5. ↑ 5.0 5.1 "Substrate/Product". glycine N-acyltransferase. BRENDA. Technische Universität Braunschweig. Retrieved 7 May 2014.
  6. ↑ 6.0 6.1 "Toxicity". Methamphetamine. PubChem Compound. National Center for Biotechnology Information. Retrieved 31 December 2013.
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 Schep LJ, Slaughter RJ, Beasley DM (August 2010). "The clinical toxicology of metamfetamine". Clinical Toxicology (Philadelphia, Pa.). 48 (7): 675–694. doi:10.3109/15563650.2010.516752. ISSN 1556-3650. PMID 20849327.
  8. ↑ "Properties: Predicted – EP|Suite". Methmphetamine. Chemspider. Retrieved 3 January 2013.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "Chemical and Physical Properties". Methamphetamine. PubChem Compound. National Center for Biotechnology Information. Retrieved 31 December 2013.
  10. ↑ "Methamphetamine". Drug profiles. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). 16 August 2010. Retrieved 1 September 2011.
  11. ↑ "Identification". Methamphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 31 December 2013.
  12. ↑ "Meth Slang Names". MethhelpOnline. Retrieved 1 January 2014.
  13. ↑ http://www.police.govt.nz/advice/drugs-and-alcohol/methamphetamine-and-law
  14. ↑ 14.00 14.01 14.02 14.03 14.04 14.05 14.06 14.07 14.08 14.09 14.10 14.11 14.12 14.13 14.14 14.15 14.16 14.17 14.18 14.19 14.20 14.21 14.22 14.23 14.24 14.25 "Desoxyn Prescribing Information" (PDF). United States Food and Drug Administration. December 2013. Retrieved 6 January 2014.
  15. ↑ Hart, Carl; Marvin, Caroline; Silver, Rae; Smith, Edward (16 November 2011). "Is Cognitive Functioning Impaired in Methamphetamine Users? A Critical Review". Neuropsychopharmacology. 37: 586–608. doi:10.1038/npp.2011.276. PMC 3260986. PMID 22089317. Retrieved 6 March 2015.
  16. ↑ Mitler MM, Hajdukovic R, Erman MK (1993). "Treatment of narcolepsy with methamphetamine". Sleep. 16 (4): 306–317. PMC 2267865. PMID 8341891.
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  19. ↑ "Identification". Levomethamphetamine. Pubchem Compound. National Center for Biotechnology Information. Retrieved 2 January 2014.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 San Francisco Meth Zombies (TV documentary). National Geographic Channel. August 2013. ASIN B00EHAOBAO. |access-date= requires |url= (help)
  21. ↑ 21.0 21.1 21.2 21.3 Westfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic Agonists". In Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman's Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. ISBN 978-0-07-162442-8.
  22. ↑ 22.0 22.1 22.2 Chomchai C, Na Manorom N, Watanarungsan P, Yossuck P, Chomchai S (December 2010). "Methamphetamine abuse during pregnancy and its health impact on neonates born at Siriraj Hospital, Bangkok, Thailand. | PubMed". Southeast Asian J. Trop. Med. Public Health. 35 (1): 228–231. PMID 15272773.
  23. ↑ 23.0 23.1 Winslow BT, Voorhees KI, Pehl KA (2007). "Methamphetamine abuse". American Family Physician. 76 (8): 1169–1174. PMID 17990840.
  24. ↑ 24.0 24.1 24.2 Hussain F, Frare RW, Py Berrios KL (2012). "Drug abuse identification and pain management in dental patients: a case study and literature review". Gen. Dent. 60 (4): 334–345. PMID 22782046.
  25. ↑ "Methamphetamine Use (Meth Mouth)". American Dental Association. Archived from the original on June 2008. Retrieved December 2006. Check date values in: |accessdate= (help)
  26. ↑ Hart CL, Marvin CB, Silver R, Smith EE (February 2012). "Is cognitive functioning impaired in methamphetamine users? A critical review". Neuropsychopharmacology. 37 (3): 586–608. doi:10.1038/npp.2011.276. PMC 3260986. PMID 22089317.
  27. ↑ 27.0 27.1 O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012.
  28. ↑ Darke S, Kaye S, McKetin R, Duflou J (May 2008). "Major physical and psychological harms of methamphetamine use". Drug Alcohol Rev. 27 (3): 253–262. doi:10.1080/09595230801923702. PMID 18368606.
  29. ↑ 29.0 29.1 29.2 Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3): 257–268. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
    Figure 2: Psychostimulant-induced signaling events
  30. ↑ Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
  31. ↑ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
  32. ↑ Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Mol. Neurobiol. 51 (2): 696–717. doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695. Figure 1
  33. ↑ 33.0 33.1 33.2 Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
    Figure 4: Epigenetic basis of drug regulation of gene expression
  34. ↑ 34.0 34.1 34.2 Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clin. Psychopharmacol. Neurosci. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
  35. ↑ Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
  36. ↑ O'Connor, Patrick. "Amphetamines: Drug Use and Abuse". Merck Manual Home Health Handbook. Merck. Retrieved 26 September 2013.
  37. ↑ Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M (2013). Pérez-Mañá, Clara, ed. "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". Cochrane Database Syst. Rev. 9: CD009695. doi:10.1002/14651858.CD009695.pub2. PMID 23996457.
  38. ↑ 38.0 38.1 38.2 38.3 Srisurapanont M, Jarusuraisin N, Kittirattanapaiboon P (2001). Srisurapanont, Manit, ed. "Treatment for amphetamine dependence and abuse". Cochrane Database Syst. Rev. (4): CD003022. doi:10.1002/14651858.CD003022. PMID 11687171. Although there are a variety of amphetamines and amphetamine derivatives, the word "amphetamines" in this review stands for amphetamine, dextroamphetamine and methamphetamine only.
  39. ↑ 39.0 39.1 39.2 39.3 Shoptaw SJ, Kao U, Heinzerling K, Ling W (2009). Shoptaw SJ, ed. "Treatment for amphetamine withdrawal". Cochrane Database Syst. Rev. (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMID 19370579.
    The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... 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)
  40. ↑ 40.0 40.1 Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597.
  41. ↑ 41.0 41.1 41.2 41.3 41.4 41.5 41.6 41.7 41.8 Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
  42. ↑ Kanehisa Laboratories (2 August 2013). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 10 April 2014.
  43. ↑ 43.0 43.1 43.2 Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". J. Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ...these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
  44. ↑ Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.
  45. ↑ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 384–385. ISBN 9780071481274.
  46. ↑ 46.0 46.1 46.2 46.3 Malenka RC, Nestler EJ, Hyman SE (2009). "15". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 370. ISBN 978-0-07-148127-4. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
  47. ↑ 47.0 47.1 Cruickshank CC, Dyer KR (July 2009). "A review of the clinical pharmacology of methamphetamine". Addiction. 104 (7): 1085–1099. doi:10.1111/j.1360-0443.2009.02564.x. PMID 19426289.
  48. ↑ Thrash B, Thiruchelvan K, Ahuja M, Suppiramaniam V, Dhanasekaran M (2009). "Methamphetamine-induced neurotoxicity: the road to Parkinson's disease" (PDF). Pharmacol Rep. 61 (6): 966–977. doi:10.1016/s1734-1140(09)70158-6. PMID 20081231.
  49. ↑ Sulzer D, Zecca L (February 2000). "Intraneuronal dopamine-quinone synthesis: a review". Neurotox. Res. 1 (3): 181–195. doi:10.1007/BF03033289. PMID 12835101.
  50. ↑ Miyazaki I, Asanuma M (June 2008). "Dopaminergic neuron-specific oxidative stress caused by dopamine itself". Acta Med. Okayama. 62 (3): 141–150. PMID 18596830.
  51. ↑ 51.0 51.1 51.2 51.3 51.4 51.5 51.6 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).
  52. ↑ Yuan J, Hatzidimitriou G, Suthar P, Mueller M, McCann U, Ricaurte G (March 2006). "Relationship between temperature, dopaminergic neurotoxicity, and plasma drug concentrations in methamphetamine-treated squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics. 316 (3): 1210–1218. doi:10.1124/jpet.105.096503. PMID 16293712.
  53. ↑ 53.0 53.1 Halkitis PN, Pandey Mukherjee P, Palamar JJ (2008). "Longitudinal Modeling of Methamphetamine Use and Sexual Risk Behaviors in Gay and Bisexual Men". AIDS and Behavior. 13 (4): 783–791. doi:10.1007/s10461-008-9432-y. PMID 18661225.
  54. ↑ 54.0 54.1 Patrick Moore (June 2005). "We Are Not OK". VillageVoice. Retrieved January 2011. Check date values in: |accessdate= (help)
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  56. ↑ Albertson TE (2011). "Amphetamines". In Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AHB. Poisoning & Drug Overdose (6th ed.). New York: McGraw-Hill Medical. pp. 77–79. ISBN 978-0-07-166833-0.
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  59. ↑ 59.0 59.1 59.2 Shoptaw SJ, Kao U, Ling W (2009). Shoptaw SJ, Ali R, ed. "Treatment for amphetamine psychosis". Cochrane Database Syst. Rev. (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMID 19160215. A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
    About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
    Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
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  99. ↑ Nakayama, MT. "Chemical Interaction of Bleach and Methamphetamine: A Study of Degradation and Transformation Effects". gradworks. UNIVERSITY OF CALIFORNIA, DAVIS. Retrieved 17 October 2014.
  100. ↑ Pal R, Megharaj M, Kirkbride KP, Heinrich T, Naidu R (October 2011). "Biotic and abiotic degradation of illicit drugs, their precursor, and by-products in soil". Chemosphere. 85 (6): 1002–9. doi:10.1016/j.chemosphere.2011.06.102. PMID 21777940.
  101. ↑ Bagnall J, Malia L, Lubben A, Kasprzyk-Hordern B (October 2013). "Stereoselective biodegradation of amphetamine and methamphetamine in river microcosms". Water Res. 47 (15): 5708–18. doi:10.1016/j.watres.2013.06.057. PMID 23886544.
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  104. ↑ Grobler, Sias R.; Chikte, Usuf; Westraat, Jaco (2011). "The pH Levels of Different Methamphetamine Drug Samples on the Street Market in Cape Town". ISRN Dentistry. 2011: 1–4. doi:10.5402/2011/974768. PMC 3189445. PMID 21991491.
  105. ↑ "Historical overview of methamphetamine". Vermont Department of Health. Retrieved January 2012. Check date values in: |accessdate= (help)
  106. ↑ "The Nazi Death Machine: Hitler's Drugged Soldiers". Der Spiegel, 6 May 2005.
  107. ↑ Defalque RJ, Wright AJ (April 2011). "Methamphetamine for Hitler's Germany: 1937 to 1945". Bull. Anesth. Hist. 29 (2): 21–24, 32. PMID 22849208.
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  109. ↑ "Controlled Substances Act". United States Food and Drug Administration. 11 June 2009. Retrieved 4 November 2013.
  110. ↑ "Desoxyn". Lundbeck: Desoxyn. Retrieved December 2012. Check date values in: |accessdate= (help)
  111. ↑ "Recordati: Desoxyn". Recordati SP. Retrieved May 2013. Check date values in: |accessdate= (help)
  112. ↑ United Nations Office on Drugs and Crime (2007). Preventing Amphetamine-type Stimulant Use Among Young People: A Policy and Programming Guide (PDF). New York: United Nations. ISBN 978-92-1-148223-2. Retrieved 11 November 2013.
  113. ↑ 113.0 113.1 "List of psychotropic substances under international control" (PDF). International Narcotics Control Board. United Nations. August 2003. Archived from the original (PDF) on 5 December 2005. Retrieved 19 November 2005.

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